Drug Evaluation

Drugs 32: 383-424 (1986)

0012-6667/86/1100-0383/$21.00/0
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Inosine Pranobex
A Preliminary Review of its Pharmacodynamic and
Pharmacokinetic Properties, and Therapeutic Efficacy

Deborah M. Campoli-Richards, Eugene M. Sorkin and

Rennie C. Heel
ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: M. Altes, Department of Neurology,

Temple University Hospital, Philadelphia, Pennsylvania, USA; I.G. Be/cesi, Department
of Neoplastic Diseases, Mount Sinai Medical Center, New York, New York, USA; T.-
W. Chang, Infectious Diseases Service, Tufts University School of Medicine, Boston,
Massachusetts, USA; E. De Clercq, Rega Institut, Katholieke Universiteit, Leuven, Bel-
gium; G.J. Galasso, Department of Health and Human Services, National Institutes of
Health, Bethesda, Maryland, USA; R.B. Herberman, Pittsburgh Cancer Institute, Pitts-
burgh, Pennsylvania, USA; A. Pompidou, Laboratoire Central d' Anatomie Pathologique
Cytologie-Cytogenetique, H6pital Saint-Vincent-de-Paul, Paris, France; P.G. Reizenstein,
Division of Hematology, Karolinska Hospital, Stockholm, Sweden; E. Sandstrom, De-
partment of Dermatology, Sodersjukhuset, Stockholm, Sweden; I.-L. Touraine, Profes-
seur Agrege, H6pitaux de Lyon, Lyon, France.

Summary ......................... ........................................................................................................... 384

I. Pharmacodynamic Studies ................................................................................................... 386
1.1 The Immune System in Humans .................................................................................. 386
1.2 Immunomodulating Activity ........................................................................................ 387
1.2.1 In Vitro Effects on Immune Function ................................................................ 388
1.2.2 In Vivo Effects on Immune Function: Experimental Animals ......................... 395
1.2.3 Effect on Immune Function of Patients with Herpesvirus Infection ............... 395
1.2.4 Effect on Immune Function of Patients with Subacute Sclerosing
Panencephalitis (SSPE) ................................................................................................... 395
1.2.5 Effect on Immune Function of Patients with the Acquired
Immunodeficiency Syndrome (AIDS), AIDS-Related Complex or Persistent
Generalised Lymphadenopathy ..................................................................................... 396
1.2.6 Effect on Immune Function of Patients with Cancer ....................................... 397
1.2.7 Effect on Immune Function of Patients with Type B Viral Hepatitis ............ 398
1.2.8 Effect on Immune Function of Patients with Autoimmune Diseases ............. 399
1.2.9 Effect on Immune Function of Other Patients .................................................. 399
1.3 Antiviral Activity ........................................................................................................... 399
1.3.1 In Vitro Antiviral Activity ................................................................................... 399
1.3.2 In Vivo Antiviral Activity .................................................................................... 401
1.4 Antitumour Activity ...................................................................................................... 401
1.4.1 In Vitro Antitumour Activity ....... ....................................................................... 401
1.4.2 In Vivo Antitumour Activity ......... ...................................................................... 401
1.5 Mechanism of Action .................................................................................................... 402
Inosine Pranobex: A Preliminary Review 384

2. Pharmacokinetic Studies ...................................................................................................... 402

3. Therapeutic Trials ................................................................................................................ 403
3.1 Herpesvirus Infections ................................................................................................... 403
3.1.1 Mucocutaneous Herpes Simplex Infections ........................................................ 403
3.1.2 Herpetic Keratitis or Uveitis ............................................................................... 404
3.1.3 Varicella Zoster Virus Infections ......................................................................... 405
3.2 Subacute Sclerosing Panencephalitis ............................................................................ 407
3.2.1 Case Reports and Open Studies .......................................................................... 407
3.2.2 Studies with Historical Controls .......................................................................... 407
3.3 Acquired Immunodeficiency Syndrome and Persistent Generalised
Lympbadenopathy ................................................................................................................ 411
3.4 'Genital Warts ................................................................................................................. 412
3.5 Influenza and Rhinovirus Infections ........................................................................... 414
3.6 Viral Hepatitis ................................................................................................................ 416
3.7 Autoimmune Diseases ................................................................................................... 416
3.8 Other Diseases and Infections ...................................................................................... 416
4. Side Effects ............................................................................................................................ 417
5. Dosage and Administration ................................................................................................. 417
6. Place of Inosine Pranobex in Therapy ............................................................................... 417

Summtll'Y Synopsis: Inosine pranobex 1 is a synthetic compound formed from the p-acetamido
benzoate salt of N-N dimethylamino-2-propanol and inosine in a 3 : 1 molar ratio. It has
been reported to exert antiviral and antitumour activities in vivo which are secondary to
an immunomodulating effect, and early results suggest beneficial clinical effects in several
diseases and infections including mucocutaneous Herpes simplex infections, subacute scle-
rosing panencephalitis, genital warts, influenza. zoster, and type B viral hepatitis, as well
as in homosexual men with persistent generalised lymphadenopathy. However, many of
the studies have been preliminary in nature and deficient in design or in the reporting of
their results. One must therefore conclude that while inosine pranobex may prove to be a
valuable and innovative therapy for a number of diseases and infections for which no
satisfactory therapy exist, further long term well controlled studies in larger numbers of
patients are required before definitive conclusions about the efficacy of inosine pranobex
in these disorders will be possible.

Pharmacodynamic Studies: The in vivo antiviral and antitumour effects of inosine

pranobex are secondary to the immunomodulating activity of the drug. Although reports
of poor in vitro antiviral activity of inosine pranobex are often in conflict with the re-
ported in vivo antiviral activity of the drug, synergistic antitumour activity has been
reported both in vitro and in vivo when the drug was used in combination with fluo-
rouracil.
In vitro exposure of cells to inosine pranobex induces T-Iymphocyte differentiation
and potentiation of induced lymphoproliferative responses. The drug has been shown to
modulate T-lymphocyte and natural killer cell cytotoxicity, suppressor and helper cell
functions, as well as to increase the number of IgG and complement surface markers.
Interleukin-l and -2 production, and neutrophil, monocyte and macrophage chemotaxis
and phagocytosis are also potentiated by inosine pranobex.

1 'Delimmun' (Delalande); 'Immunovira!' (lnstituto Luso-Farmaco); 'Imunovir' (Burgess; Newport);

'Isoprinosin' (Andreu); 'Isoprinosina' (DelaIande); 'Isoprinosine' (Delalande, Fisons, Leclerc, Roussel,
P.T. Indexim, Marsman, Merrell, Newport); 'Modimmunal' (Ravizza); 'Prinosine' (Chong Kun Dang);
'Viruxan' (Gramon, Sigma Tau); 'Viruxprine' (Faes).
Inosine Pranobex: A Preliminary Review 385

Some of the immunomodulating effects listed above have also been demonstrated in
cells from patients administered the drug. In a double-blind comparison in patients with
Herpes zoster, inosine pranobex produced a significantly greater restoration of E-rosette
activity than placebo, and in 3 of 5 double-blind comparisons in patients with initial or
recurrent Herpes simplex genital is or labialis the drug significantly improved one or two
of several immunological responses tested (phytohaemagglutinin response, Iymphotoxin
production, lymphocyte transformation response, skin test reactivity). Although open
studies in patients with subacute sclerosing panencephalitis showed some immunological
indices to vary during long term treatment with inosine pranobex, it is difficult to as-
certain whether these were effects of the drug or manifestations of the disease process.
Open studies in patients with Hodgkin's or non-Hodgkin's lymphoma and several studies
in irradiated or post-surgery cancer patients (in which full details were not given) have
reported that inosine pranobex may induce positive immunomodulating effects. How-
ever, further study is needed in this area. As compared with placebo, inosine pranobex
has significantly increased the graft versus host response (an indicator of T-Iymphocyte
competence) in irradiated or chemotherapy-treated patients with cancer of the stomach,
colon and/or rectum.
In male patients with persistent generalised lymphadenopathy, who received inosine
pranobex 3 or 4g daily for 28 days, several studies reported an improvement in natural
killer cell number and function and some of them also reported a concomitant increase
in total T-Iymphocytes and helper T-Iymphocytes; however, significant immunomodu-
lation in patients with clinically apparent acquired immunodeficiency syndrome (AIDS)
has not been reported. Two controlled studies have shown that long term treatment with
inosine pranobex is associated with an increased rate of clearance of hepatitis B antigen
from the serum of patients with acute hepatitis, and open studies in asymptomatic car-
riers and patients with chronic aggressive infection suggest a similar effect. In patients
with autoimmune disease (alopecia totalis, universalis or areata, rheumatoid arthritis or
aphthous stomatitis), small open studies intimate some positive inosine pranobex
immunomodulating effects, but further study is needed.
The mechanism of action of inosine pranobex remains unknown. However, the drug
may act to restore depressed T-Iymphocyte function to normal by increasing Iymphokine
(interleukin-I and -2) elaboration, or alternatively by increasing cell ribosomal RNA and
protein synthesis while simultaneously inhibiting the use of cell ribosomal RNA for viral
replication.

Pharmacokinetics: Following a single oral dose of inosine pranobex, peak plasma

concentrations of inosine occur after I hour. However, 2 hours after administration,
plasma concentrations decrease to undetectable amounts. Inosine pranobex has a very
short plasma half-life of 50 minutes following an oral dose. The major excretion product
of the inosine moiety is uric acid, while the p-acetamido-benzoic acid and N-N dimethyl-
amino-2-propranol components are excreted in the urine as glucuronidated and oxidised
products, respectively, as well as being excreted unchanged.

Therapeutic Trials: In therapeutic trials the usual daily oral dosage of inosine pra-
nobex was 25 to 100 mg/kg or 3 to 6g divided into 4 to 6 doses.
Double-blind placebo-controlled trials reported encouraging results in the clinical re-
sponse and a decrease in the number of disease recurrences with the use of inosine pra-
nobex in Herpes simplex labialis and Herpes simplex genitalis. However, conflicting re-
sults have also been reported in Herpes simplex genitalis. Similarly, while the drug appeared
to be beneficial in the treatment of herpetic keratitis, zoster and varicella, further well-
designed studies are needed.
Long term studies in subacute sclerosing panencephalitis, which compared inosine
pranobex-treated patients to historical controls, determined that the drug both increased
survival and decreased neurological deficiencies. The problems inherent in historically
controlled studies, in particular the inability to know and therefore to match treatment
Inosine Pranobex: A Preliminary Review 386

and control groups for all relevant variables which might influence the study outcome,
indicate the need for caution in interpreting these results.
While inosine pranobex effected symptomatological benefits (vs placebo) in patients
with experimentally induced influenza infection, several studies have reported that nei-
ther the incidence of illness nor seroconversion was significantly altered. Similarly, 2
double-blind placebo-controlled comparisons in experimentally induced rhinovirus in-
fection reported conflicting results as to the benefits of inosine pranobex therapy.
Preliminary evidence suggests that inosine pranobex may improve some of the clinical
symptoms associated with persistent generalised lymphadenopathy in immunodepressed
males. However, these results must be interpreted with caution. The combined use of
oral inosine pranobex plus conventional non-surgical treatment of genital warts resulted
in greatly increased cure rates versus the rates for conventional treatment alone. Confir-
mation of these highly encouraging results in well-designed comparative studies will be
awaited with interest.
A double-blind placebo-controlled study reported a statistically significant beneficial
effect of inosine pranobex on liver function tests and some of the symptomatology in
patients with acute type B viral hepatitis.
Double-blind placebo-controlled studies have also reported statistically significant
therapeutic benefits with the use of inosine pranobex in tropical, but not ordinary, mea-
sles. Similarly, the infection frequency and duration (respiratory and/or urinary tract) in
elderly institutionalised, seriously ill or surgical patients was significantly reduced after
long term (3 months) therapy with the drug. Furthermore, open studies and case reports
suggest possible therapeutic benefits with the use of inosine pranobex in other infectious
diseases, and in alopecia, rheumatoid arthritis and other autoimmune disorders. Patients
with amyotrophic lateral sclerosis given inosine pranobex for 3 to 6 months, and patients
with progressive rubella panencephalitis, have not been reported to derive significant
therapeutic benefit from the drug.

Side Effects: Inosine pranobex has not produced serious side effects. The only side
effects associated with inosine pranobex therapy to date have been transient increases in
serum and urinary uric acid concentrations and occasional transient nausea associated
with the large number of tablets ingested.

Dosage and Administration: The recommended adult oral dosage of inosine pranobex
is Ig 4 times daily. In children the usual dosage is 50 mg/kg per day given in divided
doses throughout the waking hours.

1. PharmtICodYlIamic Studies 1.1 The Immune System in Humans

Inosine pranobex (inosiplex, methisoprinol) is a The immune system is a complex interaction of

synthetic compound formed from the p-acetami- checks and balances that allows regulation by op-
dobenzoate salt ofN-N dimethylamino-2-propanol posing stimulatory and inhibitory influences. The
and inosine in a 3 : I molar ratio (fig. 1). It exerts following discussion is based on reviews by Play-
antiviral and antitumour activities in vivo which fair (1979) and Turk and Hosokawa (1985).
are secondary to an immunomodulating effect on The mechanisms mediating resistance to dis-
both natural (nonspecific) and adaptive (specific) ease, or the immune response, can be divided into
host defences. natural (nonspecific) and adaptive responses. Each
Inosine Pranobex: A Preliminary Review 387

Fig. 1. Structural formula of inosine pranobex.

of these mechanisms may further be divided into bound to a cell or micro-organism may also result,
its cellular and humoral components (fig. 2). Hu- with the cooperation of complement or killer cells
moral processes occur in extracellular body fluids (K cells), in the killing of the cell or micro-organ-
and involve the interactions between antigens and ism in antibody-dependent cell-mediated cyto-
antibodies, while cellular processes involve inter- toxicity reactions. Cytotoxicity is also effected by
actions between antigens and lymphocytes, of which natural killer cells (NK cells) and T-Iymphocytes.
2 major populations are recognised: B-Iympho- Regulatory molecules such as interleukins (pro-
cytes, which secrete antibodies, the humoral ele- duced by lymphocytes and monocytes), interferon
ments of adaptive immunity; and T -lymphocytes, (possibly lymphocyte derived), prostaglandins
which are further divided into subpopulations (synthesised by macrophages) and thymic hor-
which 'help' B-Iymphocytes, kill virus-infected cells, mones have been shown to enhance, suppress or
activate macrophages, etc. Help by T -cells is re- both enhance and suppress various immunological
quired for the secretion of most antibodies by B- processes.
cells; 'suppressor' T -cells have the opposite effects.
The humoral and cell-mediated processes are 1.2 Immunomodulating Activity
thought of as adaptive (or 'specific') mechanisms
because lymphocytes and antibodies can recognise, Several excellent reviews have compiled a large
remember and respond to unique pattern config- amount of data on the immunomodulating activity
urations on the surfaces of the antigens. In addi- of inosine pranobex (Fudenberg & Whitten 1984;
tion, the lymphocytes and antibodies will only re- Ginsberg & Hadden 1984; Hadden & Wybran 1981;
spond to this specific antigen configuration. Wybran & Appelboom 1984). The following dis-
Phagocytosis and complement activation, how- cussion of in vitro immunomodulating activity is
ever, are 'nonspecific' in nature since they do not based on these reviews.
possess the ability to recognise specific antigenic The immunomodulating effect of inosine pra-
configurations. Rather, these nonspecific processes nobex in vivo has been assessed in many diseases,
often act together with antibodies and lymphocytes including Herpes infections, subacute sclerosing
in reactions against antigenic substances. Further- panencephalitis (SSPE), cancer, the acquired im-
more, although the adaptive mechanism can func- munodeficiency syndrome (AIDS) and persistent
tion on its own, the majority of its effects are ex- generalised lymphadenopathy, type B viral hepa-
erted by means of interactions of antibody with titis and autoimmune diseases. The usual oral daily
complement and the phagocytic cells of natural im- dosage was 3 to 4g or 50 mg/kg in divided doses.
munity, and of T -cells with macrophages (dashed Unfortunately, although several placebo-controlled
lines of fig. 2). Rather than phagocytosis, antibody investigations have been well designed and exe-
Inosine Pranobex: A Preliminary Review 388

Natural ('nonspecific') Adaptive

Viruses+----1.' '/---.... Block

Humoral
Some
bacteria Neutralisation (toxin)

(activation)
+---------- -

I I
__ -.JI
_ __ I

Tissue
damage

(presentation) Cellular
Some ---
bacteriarr--------r~-...::.:;=:.:..:.:.::.:.=-___r...I
(activation)

(activation)

IN\Cen!
Phagocytosis Cytotoxicity - - -- -t-- - - - '
Tissues Myeloid cells Lymphocytes
SpeCifiC antigens
(all bacteria, viruses,
tumour cells, etc.)

Fig. 2. The immune system divided into natural or nonspecific and adaptive elements, and composed of both cellular (shaded)
and humoral (free in serum or body fluids) elements (after Playfair 1979; Turk & Hosokawa 1985). IL 1 = interleukin 1; IL 2 =
=
interleukin 2; K cell =
killer cell; NK cell natural killer cell,

cuted, many of the studies were small, uncon- agents such as mitogens, antigens, phagocytic stim-
trolled and/or poorly reported. uli or lymphokines. The effect of inosine pranobex
on NK cells has varied (increase, decrease or no
1.2.1 In Vitro Effects on Immune Function change) between different studies utilising different
Inosine pranobex potentiates or augments im- methodologies. In cells from patients with im-
munological events initiated by other triggering paired polymorphonuclear leucocyte function due
Inosine Pranobex: A Preliminary Review 389

to Hodgkin's disease, acute type B viral hepatitis tohaemagglutinin-stimulated B-Iymphocytes pre-

(neutrophils) or parasitic infection (eosinophils), treated with inosine pranobex (Pasino et al. 1982).
inosine pranobex has restored chemotaxis and B-Iymphocyte differentiation may be promoted by
phagocytosis in vitro. inosine pranobex, but the effect of the drug on B-
cells may result from its effect on macrophage or
Effect on Lymphocyte Function T-helper cells (see below).
Mitogen- or antigen-stimulated T -lymphocyte Inosine pranobex and NPT 15392, another syn-
differentiation and proliferation are accelerated by thetic immunomodulator, were strongly synergistic
concurrent exposure to inosine pranobex (tables I at stimulating differentiation of cells of the T-
and II). All of the mitogenic agents listed in table lymphocyte lineage (Touraine et al. 1982). The
II are principally active on T-Iymphocyte prolif- synergistic effect was found in 3 assays (E-rosette
eration, but Morin et al. (1980) observed augmen- formation, concanavalin A-induced lymphocyte
tation of T-lymphocyte-dependent B-Iymphocyte proliferation and concanavalin A-induced activa-
proliferative responses using the pokeweed mito- tion of suppressor T-Iymphocytes) and was appar-
gen. In addition, there was a non-significant trend ent in 2 different culture media (Sanhadji et al.
to decreased proliferative responsiveness of phy- 1984).

Table I. In vitro effects of inosine pranobex on lymphocyte differentiation (after Ginsberg & Hadden 1984)

Test Results References

Human
Induction of human T-Iymphocyte (HTLA) marker in Augmentation of T-cell (HTLA) marker Touraine et al. (1980)
bone marrow cells acquisition

Peripheral blood lymphocytes; (PBl)-active rosette test Increase in active rosettes Consolini et al. (1985);
Wybran (1978)

Autologous rosette test (PBl) Increase in active rosettes (immunodepressed Consolini et al. (1985)
cancer patients)
Increase in autologous rosettes Wybran (1980)

Assay of resynthesis of SRBC binding sites in Increase in rate of resynthesis of SRBC- Nekam et at. (1981)
trypsinised lymphocytes binding sites

Influence on the expression of IgG Fc receptors by Increase in receptors De Simone et al. (1982a)
peripheral blood T-Iymphocytes

Peripheral blood nuclear cells Increase in percentage and number of T-4 Pompidou et al. (1985b)
lymphocytes

Mouse
Komuro-Boyse assay; induction of marker in Nu/Nu Augmentation of T-cell marker acquisition Hadden & Giner-Sorolla
spleen cells (1981)

Twomey assay; induction of Thy 1 marker in spleen Augmentation of T-cell marker acquisition Ikehara et al. (1981)
cells

Soyse assay; induction of Thy 1 marker in spleen cells Augmentation of T-cell marker acquisition Renoux et al. (1979a)

Induction of complement receptor (CR) marker in Augmentation of S-cell marker acquisition Hadden & Giner-Sorolla
spleen cells (1981)

Abbreviations: SRSC = sheep red blood cell; Thy 1 = mouse T-cell surface antigen.
Inosine Pranobex: A Preliminary Review 390

Table II. In vitro proliferative responses of lymphocytes to inosine pranobex (after Ginsberg & Hadden 1984)

Mitogen or antigen Increase in lymphocyte response References

(Type of patient) (pretreatment = 1.0)

Human
Phytohaemagglutinin 1.7 Simon et al. (1977)
1.6 Hadden et al. (1976)
1.3 Nakamura et al. (1983)
(rheumatoid arthritis ) 1.2 Nakamura et al. (1983)
(serum lupus erythematosus) 1.4 Nakamura et al. (1983)
(AIDS-related complex) 1.8 Pompidou et al. (1985b)

Concanavalin A 3.4 Morin et al. (1980)

(serum lupus erythematosus) 2.5 Sanhadji et al. (1985)
1.3 Nakamura et al. (1983)

Pokeweed mitogen 1.6 Hadden et al. (1977)

(serum lupus erythematosus) 1.6 Morin et al. (1980)
1.2 Nakamura et al. (1983)

Mixed leucocyte culture 2.4 Wybran (1978)

Tetanus toxoid 2.7 Morin et al. (1980)

Mouse
Phytohaemagglutinin 1.6 Hadden et al. (1977)
1.7 Simon et al. (1977)
1.9 Renoux et al. (1979b)
1.4 Ohnishi et al. (1983)
3.8 Ikehara et al. (1981)

Concanavalin A 1.8 Simon et al. (1977)

1.7 Renoux et al. (1977)
1.4 Ohnishi et al. (1983)
2.3 Ikehara et al. (1981)

Lipopolysaccharide 2.2 Ikehara et al. (1981)

1.0 Ohnishi et al. (1983)

Mixed leucocyte culture 1.3 Ohnishi et al. (1983)

Influenza virus 3.9 Simon & Glasky (1978)

Herpes simplex virus 1.5 Simon & Glasky (1978)

The inosine pranobex-induced increase in the paired cell-mediated responsiveness, including

concanavalin A-stimulated blastogenic response was patients with AIDS, AIDS-related complex or per-
more apparent in cell cultures showing an initially sistent generalised lymphadenopathy (Campo et al.
low blastogenic response (artificially induced by in 1982; Tsang et al. 1983a, 1984b), and in ageing hu-
vivo treatment of mice with cyclophosphamide - mans (Tsang et al. 1985a). Additionally, the drug
i.e. immunodepressive conditions) [Portoles et al. induced an early chromatin activation in peri-
1983]. Similarly, in vitro inosine pranobex mark- pheral blood mononuclear cells from patients with
edly enhanced phytohaemagglutinin-stimulated and the AIDS-related complex (Pompidou et al. 1985b).
concanavalin A-stimulated T -lymphocyte cell pro- The pokeweed mitogen-stimulated T -cell-depend-
liferation in cells from patients with severely im- ent B-cell proliferative responses in cells from
Inosine Pranobex: A Preliminary Review 391

patients with AIDS or AIDS-related complex have virtually similar to that of control subjects, but the
also been reported to be enhanced (Tsang et al. number of circulating helper T -lymphocytes was
I 984b, 1985b) by inosine pranobex. reduced and both the phytohaemagglutinin-stim-
In addition to proliferative and differentiation ulated T-lymphocyte proliferative response and the
responses, in vitro inosine pranobex potentiation pokeweed mitogen-stimulated T-lymphocyte de-
of lymphocyte function has been reported in other pendent B-lymphocyte proliferative response were
assays (table III). However, although the mitogen- severely impaired), co-incubation of lymphocytes
stimulated activity of suppressor T-lymphocytes has in vitro with inosine pranobex potentiated the im-
been shown to be both induced and suppressed by paired functions, although lymphocyte functions
inosine pranobex in different assays (Renoux et al. were not restored to the normal range in any ofthe
1979c; Rey et al. 1983; Touraine et al. 1980, 1982), AIDS patients with severe immunodeficiencies. The
the biological significance of these effects remains results of Rey et al. (1983) also indicated that in-
to be established. Furthermore, while the poke- osine pranobex acts by increasing the number of
weed mitogen-induced production of IgG- contain- non-suppressor T -lymphocytes.
ing peripheral blood lymphocytes was augmented
(Ballet et al. 1980; Hersey et al. 1984; Morin et al. Effect on Monocyte and Macrophage
1980), which may indicate inhibition of suppressor Function (table III)
cell activity or stimulation of helper activity, the By direct interaction in vitro, inosine pranobex
characteristically high immunoglobulin synthesis has been shown to stimulate various indices of
by patients with serum lupus erythematosus was metabolic activity of macrophages and monocytes
decreased by in vitro incubation with inosine pra- (Hadden et al. 1979; Joseph et al. 1982; Ohnishi et
nobex (Nakamura et al. 1983). A concentration-re- al. 1983; Wybran 1978, 1980; Zerial & Werner
lated effect has been suggested by one of the above 1981 ).
researchers (J-L Touraine, personal communica- Concanavalin A-induced monocyte chemotaxis
tion), based on his observations that the enhance- is depressed in cells from cancer patients; in vitro
ment of suppressor T -lymphocyte activity is ob- exposure to inosine pranobex or to 24-hour super-
served at relatively large concentrations in vitro and natants obtained from mononuclear cells pre-
in vivo (Touraine et al. 1980, 1982), while the aug- treated with the drug restored chemotaxis to nor-
mentation of helper T -lymphocyte activity is pre- mal or near normal levels (Tsang et al. 1983a),
dominant at lower concentrations. which suggests the release by mononuclear cells of
Inosine pranobex potentiated the production of factors which may have immune response stimu-
interleukin-2 in cultures of blood mononuclear lating abilities. Incubation with inosine pranobex
lymphocytes from healthy subjects (Hersey et al. in vitro stimulated the production of interleukin-l
1984; Nakamura et al. 1983; Tsang et al. 1983b) (lymphocyte activating factor) in human mono-
and patients with rheumatoid arthritis, serum lu- cytes (Hersey et al. 1984) and human alveolar mac-
pus erythematosus (Nakamura et al. 1983) or AIDS rophages, and increased the levels of lysosomal en-
(Tsang et al. 1984a, 1985b), whose interleukin-2 zymes in the latter (Joseph et al. 1982). In cultures
production had been depressed. In the AIDS of human lymphocytes stimulated with soluble
patients, the number of Tac antigen (interleukin-2 antigens, the drug could not replace the helper
receptor)-bearing lymphocytes and the ability of Leu function of monocytes on specific lymphocyte pro-
3( +) cells to absorb interleukin-l was also restored liferative responses (Ballet et al. 1982). However,
to normal or nearly normal levels (Tsang et al. inosine pranobex did not affect monocytes and
1984a, 1985b). Tsang et al. (1984b, 1985c) further probably acted on T-lymphocytes to produce its
reported that in male homosexuals with the AIDS- stimulatory effect in an in vitro blast transforma-
related complex and in patients with AIDS (in tion assay using the mitogen, phytohaemagglutinin
whom the number of suppressor T-Iymphocytes was (Jacobsen & Greenspan 1982, 1983).
Inosine Pranobex: A Preliminary Review 392

Table III. In vitro effects of inosine pranobex on lymphocytes and immune cells (after Ginsberg & Hadden 1984)

Test Results References

Effects on lymphocytes
Mouse spleen cells; Jerne (SRBC) plaque assay Increase in T-dependent B-cell function Glasky & Ginsberg (1975)
(higher PFC/spleen cell)
Direct and indirect IgM PFC (SRBC) assay on Increase in IgM PFC In normal and Ohnishl et a!. (1982)
mouse spleen cells chemically immunosuppressed mice
IgM PFC response restored after Ohnishi et a!. (1982)
influenza virus-induced
immunosuppression
Pokeweed-mitogen induction of IgG-containing Augmentation of percent IgG-containing Morin et al. (1980)
peripheral blood lymphocytes cells Ballet et a!. (1980)
Hersey at a!. (1984)

Peripheral blood lymphocytes - incubated with Augmentation of ConA-lnduced Touraine et a!. (1980)
ConA, then .assayed in MLC suppressor cells

Rosette-purified T-Iymphocytes incubated with Augmentation of ConA-induced Touraine et a!. (1980)

ConA, then assayed in MLC suppressor cells

Peripheral blood lymphocytes - incubated directly Direct suppressor cell induction Touraine et a!. (1982)
with inosine pranobex, then assayed in MLC
Peripheral blood lymphocytes - incubated with Blunted induced suppressor activity Rey et a!. (1983)
ConA, then induced with ConA and
phytohaemagglutinin
Spleen lymphocytes incubated with ConA, then Augmentation of suppressor cell Renoux et a!. (1979c)
assayed in MLC induction
LAI test Increase of factor Wybran (1980)

Peripheral blood lymphocytes - incubated with Accelerated immune interferon De Simone et al. (1985a)
eonA production
Peripheral blood lymphocytes from Positive modifications of T-cell Bene & Faure (1985)
immunosuppressed patients - immunoflourescent membrane antigens from 17 of 22 pts
assay
Theophylline-resistant human peripheral blood Increase in % of cells with antigen Leu De Simone et a!. (1985b)
lymphocytes 3a. Helper-suppressor cell ratio
increased

Effect on Natural Killer (NK) Cell Function melanoma cells, apparently due to inhibitory mon-
In various studies, inosine pranobex has been ocyte influences; after removal of adherent cells NK
shown to increase, decrease or have no effect on cell activity was stimulated. Exposure in vitro of
spontaneous NK cell cytotoxicity (table III). How- inosine pranobex to peripheral blood mononuclear
ever, in general the effect has been to increase NK cells of cancer patients, 68% of whom were shown
cell activity (Balestrino et al. 1983; Hersey & Ed- to have depressed NK cell activity, and of aged
wards 1984; Welch & Duong 1982). Hersey and adults, who also had significantly (p < 0.(05) de-
Edwards (1984) reported that the addition of ino- pressed NK cell activity, restored NK cell activity
sine pranobex to cultures of blood mononuclear to normal or near normal levels (Tsang et al. 1983a,
cells inhibited NK cell activity against myeloid and 1985a).
Inosine Pranobex: A Preliminary Review 393

Table III. Contd

Test Results References

Effect. on other cell.

Guinea-pig peritoneal cells phagocytosis and Increased Iymphokine mediated Hadden et al. (1979)
bactericidal capacity macrophage phagocytosis and killing of
Listeria monocytogenes

Mouse peritoneal cells Increased macrophage phagocytosis of Zerial & Werner (1981)
SRBC Ohnishi et al. (1983)

Macrophage interleukin-1 synthesis Increased induction of B-cell Hadden & Giner-Sorolla (1981)
differentiation by soluble factor
(interleukin-1 )

Peripheral blood monocyte phagocytosis assay Increased phagocytosis of yeast cells Wybran (1978, 1980)

NK cell activity No change or decreased NK Goutner (1980)

cytotoxicity Rey et al. (1983)

Increased NK cytotoxicity Balestrino et al. (1983)

Hersey & Edwards (1984)
Tsang et al. (1983a, 1985a)

Chemotaxis of PMN cells Decreased PMN neutrophil chemotaxis Corberand et al. (1980)

Increased PMN neutrophil chemotaxis Patrone & Dallegri (1980)

Decreased PMN chemotaxis of normal Roch-Arveiller et al. (1982)

cells but restored impaired
responsiveness of inflammatory cells

Phagocytosis and killing of PMN neutrophils of pts Improved phagocytosis and killing Lazzarin et al. (1982)
with HBsAg-positive hepatitis

Phagocytosis of PMN neutrophils of pts with Improved (restored) phagocytosis Ambrogi et al. (1982)
Hodgkin's disease Azzara et al. (1982a)

Surface characteristics and killer function of Increase in IgG Fc and C3 receptors. De Simone et al. (1982b)
eosinophils of parasitised human subjects CytotOXiCity and chemotaxis increased

Abbreviations: SRBC = sheep red blood cell; PFC = plaque-forming cell; NK = natural killer; ConA = concanavalin A; MLC = mixed
lymphocyte culture; PMN = polymorphonuclear; LAI = leucocyte adherence inhibition.

Effect on Polymorphonuclear Leucocyte complement (C3) receptors of eosinophils from

Function patients with parasitic infections and enhanced the
In vitro. inosine pranobex appeared to improve cytotoxicity and chemotaxis of the cells (De Si-
or restore to normal levels the impaired chemo- mone et al. 1982b).
taxis and phagocytosis of neutrophils from patients
with Hodgkin's disease (Ambrogi et al. 1982; Az- Other Immunological Effects
zanl et al. 1982a) or acute type B viral hepatitis In human serum in vitro. inosine pranobex ac-
(Lazzarin et al. 1982) [table III]. Exposure to the tivated the alternative complement system in a
drug also increased immunoglobulin (IgG Fc) and dose-dependent manner and inhibited platelet ag-
Inosine Pranobex: A Preliminary Review 394

Table IV. In vivo effects of inosine pranobex on immune cell function in experimental animals (after Ginsberg & Hadden 1984)

Immune function Re~ults (species) [change from pretreatment values] References

Lymphoblast transformation (LBT) t ConA-induced LBT (m) [2-3x] Simon & Glasky (1978)
t ConA-induced LBT (m) [2-3x] Vecchi et a\. (1978)
t ConA-induced LBT (h) [normal 1.5X; tumour bearing Tsang & Fudenberg (1981a)
2X]
t PHA-induced LBT (h) [l.3X] Tsang & Fudenberg (1981b)
t Influenza virus-induced LBT (m) [3x] Simon & Glasky (1978)
t LPS-induced LBT (m) [1.3-1.9X] Florentin et a\. (1981)
t Tetanus toxoid and PHA-induced LBT (gp) [healthy Castelli et a\. (1984)
1.8 to 2x; burned 1.2 to l.4x]
t PHA-induced LBT (aged h) Tsang et a\. (1983c)
- ConA-induced LBT (immunodepressed m) Portoles et a\. (1983)

T-cell differentiation t In specific T-cell marker (Nu/Nu m) Renoux et a\. (1979b)

- T-ceil mitogenosis (normal r) Binderup (1985)
t T-cell mitogenosis (immunodepressed r) Binderup (1985)

Leucocyte adherence inhibition t In Ehrlich's ascites tumour (m) Fehous et a\. (1980)

Cytotoxic T-cell function I T-cell cytotoxicity (2.2X) (m) Florentin et a\. (1981)
- T-cell cytotoxicity (m) Ohnishi et al. (1983)
t T-cell responsiveness (arthritic r) Binderup (1985)

Antibody-dependent cellular I ADCC (1.5X) (m)' Florentin et a\. (1981)

cytotoxicity (ADCC) -ADCC(m) Ohnishi et a\. (1983)

Natural killer cell (NK) activity t Spleen and peritoneal cells (m) Florentin et a\. (1981)
- No stimulation of cytolysis (m) Ohnishi et a\. (1983)
t (aged h) Tsang et a\. (1983c)
t (osteosarcoma-bearing h) Tsang & Fudenberg (1981b)

Delayed type hypersensitivity (DTH) t DTH-picryl chloride (m) Ohnishi et a\. (1983)

Anti-inflammatory activity I Heat-killed E. coli and human serum albumin-induced Gordon & Majde (1982)
inflammation (m)

Anti-SRBC immunoplaque formation Jerne plaque assay: t IgM and IgG PFC (m) [2-3X] Renoux et al. (1977)
t PFC/spleen (aged m) [5-6X] Fernandes et al. (1983)
t IgG/lgM (aged m) [2-3x] Fernandes et a\. (1983)

Suppressor T-cell function Restoration of suppressor T-cell function Touraine et a\. (1982);
(Swan m) Sanhadji et a\. (1985)
I Suppressor T-cell activity (aged h) Tsang et a\. (1983c)
- Suppressor T-cell activity (arthritic r) Binderup (1985)

Macrophage phagocytOSis t Phagocytic action on SRBC Ohnishi et a\. (1983)

Monocyte chemotaxis Restored (tumour-bearing h) Tsang & Fudenberg (1981a)

t (aged h) Tsang et a\. (1983c)

Interferon potentiation t Survival (EMC-virus-infected m) (inosine pranobex Chany & Cerutti (1977)
+ IF)
t Survival (tumour-bearing m) (inosine pranobex Cerutti et a\. (1979)
+ IF)
t Survival (Forest-Spring encephalitis infected m) Fomina et a\. (1980)
(inosine pranobex + IF)
Interferon production t Yield with interferon inducer Fomina et a\. (1980)
Inosine Pranobex: A Preliminary Review 395

Table IV. Contd

Immune function Results (species) [change from pretreatment values) References

Antibodies to influenza virus r Antineuraminidase and antihaemagglutinin antibodies Ohnishi et al. (1983)
following mild infection (immunisation) (m)

Acquired immunity to schistosomes r Protection after primary infection (r) (1.3X) Joseph et al. (1982)

Protection by lymphocyte r Survival of lethal challenge of influenza (recipient m) Ohnishi et al. (1982)
in recipients of IV injection of spleen cells from
influenza-infected and inosine pranobex-treated (donor
m)

r
Key: = increase; --+ = no change; l = decrease.
Abbreviations: m = mice; h = hamsters; gp = guinea-pigs; r = rats; ConA = concanavalin A; PHA = phytohaemagglutinin; LPS =
lipopolysaccaride; SRBC = sheep red blood cell; PFC = plaque-forming cells; EMC = encephalomyocarditis virus; IF = interferon;
IV = intravenous.

gregation induced by ADP and collagen (Ferri et to interpret; if the values had been normal an im-
al. 1982). provement would have been unexpected. The lack
of effect of inosine pranobex on immunoglobulin
1.2.2 In Vivo Effects on Immune Function: concentrations was confirmed in these studies. Also,
Experimental Animals most of the other results with inosine pranobex were
While there were variations in responsiveness not statistically different from those in patients ad-
depending on the experimental in vivo animal ministered placebo. However, two of the studies
model used, most of several tested mediators of (Bradshawet a1. 1980; Coreyet a1. 1979) found that
immune function were stimulated by inosine pra- the drug potentiated mitogen- or antigen-induced
nobex in at least 1 animal model, and in some in- T-lymphocyte proliferation. Bradshaw et a1. (1980)
stances in several models (table IV). The only ex- further reported an 87% increase in the lympho-
ceptions reported were antibody-dependent cellular toxin assay among inosine pranobex-treated
cytotoxicity which was either unchanged or de- patients (vs a 30% decrease in the placebo group)
creased in mice (Florentin et a1. 1981; Ohnishi and Salo and Lassus (1983) reported increased de-
et al. 1983), and the inflammatory response to layed cutaneous hypersensitivity to Candida alhi-
heat-killed E. coli and human serum albumin, cans.
which was decreased in mice (Gordon & Majde 36 patients were included in a double-blind pla-
1982). cebo-controlled assessment of the effect of inosine
pranobex in Herpes zoster infections (Lesourd et
1.2.3 Effect on Immune Function of Patients a1. 1982). There was no difference between the
with Herpesvirus Infection treatment and placebo groups in skin reactivity to
Several double-blind p1acebo-controlled studies, antigens or the total number of lymphocytes, but
including one of crossover design (Kalimo et a1. there was a significantly (p < 0.01) greater resto-
1983), have assessed the effect of inosine pranobex ration of E-rosette activity among the inosine pra-
on immunological parameters in otherwise healthy nobex-treated patients. Similarly, E-rosette activity
patients with initial or recurrent Herpes simplex and delayed cutaneous hypersensitivity reaction to
labialis or genitalis infection (table V). Unfortu- 2,4-dinitrochlorobenzene appeared to return to
nately, as these studies did not clearly state whether normal faster in 7 patients with Herpes zoster in-
immunological parameters were significantly de- fections treated with inosine pranobex 2g daily
pressed prior to treatment, the results are difficult (divided doses) for 10 to 14 days than in 10
Inosine Pranobex: A Preliminary Review 396

control patients with zoster infection (Tanphaich- spectrum of immunological changes in individuals
itra 1982). at risk for AIDS that ranges from mild abnormal-
1.2.4 Effect on Immune Function of Patients ities to profound immunodeficiency (Daul et al.
with Subacute Sclerosing Panencephalitis 1986) and the natural immunological course of
(SSPE) these patients has not been clearly defined.
In 8 SSPE patients with a stable clinical con- As compared with 20 placebo-treated patients,
dition, both the percentage of 'avid' IgG Fc a statistically significant increase in mean NK cell
receptors and the phytohaemagglutinin-induced function which remained elevated for up to 11
lymphocyte proliferation significantly (p < 0.05) months after cessation of therapy (p = 0.003 on
increased after 14 weeks of therapy with inosine day 14; p = 0.050 on day 90; p = 0.024 on day
pranobex. However, in 6 patients whose clinical 180; and p = 0.006 on day 360 vs placebo) was
status was deteriorating rapidly, both of these im- reported in 21 male homosexuals with persistent
munological parameters, as well as the total generalised lymphadenopathy who were admini-
lymphocyte count, decreased significantly during stered inosine pranobex 3g daily (in divided doses)
therapy with the drug (Vainiene et al. 1983). Sim- for 28 days. Increases were also reported in total
ilarly, longitudinal studies performed in 6 SSPE T -lymphocytes (p = 0.036 on day 90) and T-helper
patients during 7 to 34 months of inosine pranobex lymphocytes (p = 0.06 on day 90), but these in-
therapy revealed a time-dependent decrement of dices remained elevated for a shorter period of time
the percentage of E-rosette forming cells (T- (Bekesi et al. 1984; Wallace 1984; Wallace & Be-
lymphocytes) and ofEA-rosette forming cells (TG- kesi 1986).
lymphocytes, suppressor T-Iymphocytes) in the Early observations from the 2 other double-blind
cerebrospinal fluid (Marrosu et al. 1983). However, placebo-controlled multicentre studies, which are
in both of these studies it was difficult to ascertain as yet unpublished, appear to confirm these results
whether the immunological changes were related to with a 28-day course of inosine pranobex 3 gfday.
the drug or to the disease. The first of these unpublished studies (Starrett et
al.) included 40 evaluable immunologically de-
1.2.5 Effect on Immune Function of Patients pressed males with persistent generalised lymph-
with the Acquired Immunodeficiency adenopathy. At the end ofthe treatment course the
Syndrome (AIDS), AIDS-Related Complex or 21 patients in the active treatment group had a sig-
Persistent Generalised Lymphadenopathy nificantly (p < 0.05) greater increase in NK cell
Male homosexual patients with AIDS, the AIDS- activity than the placebo patients, as well as a
related complex or persistent generalised lymph- greater (but non-significant) increase in the num-
adenopathy frequently have inverted helper/su- ber of T-Iymphocytes and helper T-Iymphocytes.
pressor T-Iymphocyte ratios attributable to a The second unpublished study (Conant et al.) eval-
marked reduction in the helper T -lymphocyte uated 76 immunologically depressed males with
population and a lesser decrease in the T -suppres- persistent generalised lymphadenopathy. There was
sor population. In addition, these patients often no drug effect on the numbers of T-Iymphocytes
have reduced numbers and depressed function of in the 38 patients treated with inosine pranobex.
NK cells, with an accompanying depression of T- A t-test analysis revealed no statistically significant
lymphocyte-dependent B-Iymphocyte function. drug effect on helper T -lymphocytes and a signifi-
Three double-blind placebo-controlled studies cant (p < 0.05) effect on the percentage increase in
have reported statistically significant immunosti- NK cell activity only on day 14.
mulant effects with the use of inosine pranobex in In an open study, administration of inosine pra-
immunodepressed male patients with persistent nobex 4g daily (divided doses) for 28 days to 4
generalised lymphadenopathy. However, these re- patients with AIDS-related complex or persistent
sults should be interpreted with care as there is a generalised lymphadenopathy was associated with
 Inosine Pranobex: A Preliminary Review 397

!!l Qj
e:
Ol
0
e: significantly (p < 0.05) improved lymphocyte pro-
~ I/)
en I- ~
liferation induced by concanavalin A (but not by
0. ::> Ol

;;'" al~ en
e: .-
i==" 0
z
;t:
"0 pokeweed mitogen or phytohaemagglutinin). The
OJ s~ "E
Ol i3 .~ helper/suppressor T-lymphocyte ratio was not sig-
.<:
Ol "OOl
Cl.
'"
0
;;::
I/)
.~
Ol I/)
","
'5 '"
"0
/\
0>
'2
0>
nificantly altered. In 5 patients with AIDS, none
~!
Ol",
e: co 'iii
of these parameters were significantly altered by
Ol
.<:
'0
"0'<:
'"
0 9: ~
OJ
0 inosine pranobex treatment (Grieco et al. 1984).
.S ~
f! ::i; Additionally, 7 LAV/HTLV III virus-infected
~
0>
-I/)
.. e: ~ patients (3 AIDS-related complex, 2 AIDS and 2
E Q..Q II
~ +0; /\ patients with Kaposi's Sarcoma) were treated with
<~
'"
0.
OJ
o>e:
-Ol
.0
ii
$
inosine pranobex 50 mg/kg daily for 5 days every
0 (!le:
'c, 0>0
_ 0
0
Z
0
z e: 15 days for the first 2 months, and then for 5 days
.Q :i<
0
e:
I/)

Ol
every 2 months for 1 year; a prolonged restoration
::>
E .. ''"
e: " I/)
of immune responses was noted in the patients with
.5
01/)
Q) +=i as
I/)
'"
e:
(;
the AIDS-related complex (a 50% increase in T4-
e:
0 ~~! "0

~ lymphocytes and a normalisation of quantities of

[ a!3! ~
E~ e 0 00 T8-lymphocytes) and the patients with Kaposi's
x
Ol ~:ow z zz ~
Ol
.c
0
I/)
Sarcoma (a 30% increase in T4-lymphocytes; quan-
e:
a:- '"
e:
~ e:
Ol
:i<
0
tities of T8-lymphocytes were not abnormal and
Ol
e:
0> /\ 0. were unaffected by treatment), but no beneficial ef-
'iii ~ Q;" 0 ~
Ol Z 1;)
0
.S >. '" feet was obtained in the patients with AIDS.
g ~
11
~ .<: 0
co I-

~
0 0.
'0 E
"'.2
e:
a:- en 1.2.6 Effect on Immune Function of Patients
ti -a; ~
Ol
;:
I/)

'3
"0 ..
Ol _
0 Ol
0
en iii with Cancer
Ol I/) ;:,= < Ii) $
Ol Ol "0 0
.50..
J: Q;" 00
zz z
0 0
z
e: Several open and both non-blinded and double-
;; [[ Cl. :i<
I/)
0> blind placebo-controlled comparative studies have
e:
.~ ~
''""
s-Ol "0 '"
·2
assessed the immunomodulating activity of ino-
!~
Ol Q
:2Cl. t 0>0> sine pranobex in immunologically depressed can-
'" 0
1/).2<
>-
:0(1)
~ 0>
~
0
0. .>t: .>t:
0;(;; 0>
co
'"
~E cer patients.
.!E .5 (ij >- cu EE
_=:0 (; 'g~
"01/)
~~
0'" 0
1-"0"0
(5
Z
0>
"<t ,....,....
0 0 .,.
0> .,. ~~
Treatment with inosine pranobex 100 mg/kg
'0=2 11 ~ daily (in divided doses) for 2 weeks was associated
....
Ol Ol
'gO>
"EO <ii
e me;)
~
'" E
"0 .-
'g 11
with significant (p < 0.05) increases in the abnor-
01/)
0=
~~
~'"
~
e:
Ol
~
.!!!
~
'2
~
~~

~-
_e:
.. ..
e:
Ol
Ol
..
.~
~
'2
-
e:
~
"'~
0··
.• 0
e:.c
:5 ~
mal lymphocyte proliferative responses induced by
phytohaemagglutinin and concanavalin A in 12
0- OJ .. ::> 50 patients with Hodgkin's disease, as compared with
0. Ol Ol~
-'"
..
.cx E ::> 0
0> O>~ -§,o..
Ol Ol
~o.. '0 (;
.s o
Ol
Ol
. 0::- ~
..
-E O>E untreated controls (Pasino et al. 1984). In 9 patients
0.._
"01/)
e:
.2
0-
ci
e: .!!!
OJ
.!!i en:,: .~ i .!!i
•

~e: ~.~ .-
I/)

-'" ::> OJ
'2
.... E
'" ..
Ol-
0
with Hodgkin's disease, non-Hodgkin's lymphoma
..
e: I/)
=Ol
,
.co.
Olf!
-0
:0 Ol :Oi
~(!l
.co Ol "'-
.<:e:
or myelomas, inosine pranobex 3g daily for 7 days
Ol Ol
nJ:
~:t::.. '"
..J (!l "'Ol
..J .. (!l o Ol
>.:V
.<:;:
increased the previously depressed leucocyte mi-
6c
"OOl
s
CO"
~
co M
0.'5
11~
gration response to normal levels (p < 0.001) [Az-
enOl ~ co
o~ ~e: a;-
,.... N
M
co en <OJ
it~
~E
1/)0
-'::> en co
en ~ zanl et al. 1984]. Furthermore, treatment of pri-
s~ "'en ~ I/)
I/) .. ~ en ::> (,)~ mary malignant melanoma patients with inosine
OlO I/) Qioe ~ OJ
I/)
I/)
",-
01/)
OJ
a:~ ~ ~ ~
Qi OJ Qi '"
..J io pranobex 50 mg/kg daily for 5 days every 15 days
::~
e:
~
'" '"
~~;::- Qi 0 011 'S c:
during the first 2 months, and then for 5 days every
~'" C!l
.5 ~ II
t.E "0"0,.... = 0
I- ~
*
[[
~~Q)
[!)[!)~ 0 '" OJ
::.::
OJ
en :So
«z 2 months for a year resulted in a prolonged res-
Inosine Pranobex: A Preliminary Review 398

toration of immune responses (Pompidou et al. of E-rosettes and of the phytohaemagglutinin-in-

1986). duced lymphocyte proliferation than in 10 un-
In irradiated cancer patients, 2 double-blind treated control patients (Catania et al. 1981).
comparisons with placebo in which 13 and 53
patients, respectively, were treated with inosine 1.2.7 Effect on Immune Function of Patients
pranobex reported statistically superior restoration with Type B Viral Hepatitis
of immune function after 3 months of therapy In patients with acute type B viral hepatitis, an
(Fenton 1981; Fridman et al. 1980; unpublished unblinded controlled study (Frappampina et al.
data on file, Newport Pharmaceuticals). Immu- 1982), and a double-blind placebo-controlled study
noresponsiveness was determined based on (Scasso et al. 1983), assessed the efficacy of inosine
lymphocyte proliferation, differentiation and count, pranobex 30 to 40 mg/kg daily (divided doses) for
delayed cutaneous hypersensitivity and serum im- 15 days and 6g daily for a mean duration of 28
munoglobulin concentrations, but the results for days, respectively. The former study showed sig-
these individual tests were not provided. nificantly (p < 0.005) more rapid clearing ofHBeAg
Two non-blinded clinical trials have assessed the from the serum of treated patients after only 1 week
effect of inosine pranobex on various immune (60% of 30 treated patients vs 28% of 25 untreated
functions in irradiated or chemotherapy-treated control patients), and the latter study found a more
patients with adenocarcinoma of the stomach, co- rapid clearance of HBsAg among the inosine pra-
lon and/or rectum. The local graft versus host re- nobex-treated patients, the statistical significance
sponse, an indicator ofT-lymphocyte competence, of which was not reported. In this second study
was significantly increased in patients admini- there was no statistically significant difference be-
stered total daily inosine pranobex dosages of Ig tween the patient groups in serum concentrations
(20 patients; p < 0.05) or 4g (20 patients; p < 0.01) of IgA, IgG or IgM. Clearing of HBsAg from
for 1 week but not in 20 untreated control patients asymptomatic carriers has been attributed to treat-
(Talpaz et al. 1983). In addition, Midiri et al. (1981; ment with inosine pranobex 3g daily for 20 days
unpublished data on file, Newport Pharmaceuti- (De Luca et aI. 1980).
cals) reported that skin test reactivity and both the Small open studies in patients with chronic ag-
number and percentage of active E-rosettes were gressive type B viral hepatitis suggested that ino-
increased in 20 patients treated with inosine pra- sine pranobex 4g daily (divided doses) for 4 to 8
nobex at a total daily dose of 4g but not in 20 weeks may promote the seroconversion of HBeAg
patients administered placebo. but not HBsAg (Cianciara et al. 1982; Dabrowska-
The efficacy of inosine pranobex in post-sur- Bernstein et al. 1983), while another open study in
gical cancer patients has also been assessed in 2 6 such patients found that the same dosage for up
non-blinded controlled comparative trials. Bene- to 9 weeks had no statistically significant effect on
detti et al. (1984) compared the effect of inosine serum IgG, IgA or IgM concentrations (Migneco et
pranobex (20 patients) and total parenteral nutri- al. 1981). Dabrowska-Bernstein et al. (1983) also
tion (TPN; 10 patients) on post-surgery gastric or reported an increase in the numbers of E-rosette
oesophageal cancer patients. Both treatments ap- forming T -lymphocytes, and normalisation of the
peared to improve delayed cutaneous hypersensi- phytomitogen responsiveness and concanavalin A-
tivity and increase Ea rosette-formation, and TPN induced suppression in their patients administered
increased the total lymphocyte count. Unfortu- the drug in a divided daily dosage of 4g for 4 to 8
nately, a statistical analysis was not provided. Post- weeks.
surgical administration of inosine pranobex 4g daily Boron-Kaczmarska (1985) reported statistically
to 6 patients suffering from malignant neoplasias significant changes in serum concentrations of IgM
(rectal, breast or thyroid cancer) resulted in a more (but not IgG or IgA), percentages ofB-lymphocytes
rapid return to presurgical levels of the percentage and the level of circulating immune complexes in
Inosine Pranobex: A Preliminary Review 399

10 patients suffering from viral hepatitis B who to 100 mgJkg has been reported to exert some posi-
were administered doses of 3 to 4g daily. tive immunomodulatory effects in patients with
influenza, rhinovirus infection, active pulmonary
1.2.8 Effect on Immune Function of Patients
with Autoimmune Diseases tuberculosis, Thai haemorrhagic fever, extensive
A few small open studies have tried to find a bums and recurrent infections, and in seriously ill,
relationship between the administration of inosine post-surgical and elderly patients (table VI). How-
pranobex and the immunological competency of ever, few of these studies stated inclusion/exclu-
patients with autoimmune diseases. sion criteria, only 2 of the studies reported on group
A divided daily dosage of inosine pranobex 50 comparability in any detail (Meroni et al. 1984;
mg/kg for 3 to 7 days weekly was administered for Tanphaichitra & Panupornprapongs 1981) and the
6 to 12 months to patients with alepecia. In 9 in- statistical significance of the results was reported
osine pranobex-treated patients with alopecia to- in less than half of the studies (table VI). Thus,
talis, interactive T-Iymphocyte rosette formation while the results are encouraging, further study is
became normal (p < 0.01) after 8 weeks of therapy needed both to confirm the findings and establish
and leucocyte migration inhibition factor appeared their clinical significance, if any.
in 7 of the 8 in whom it was initially absent (Gal- In a group of surgical patients, a single 3g intra-
braith et al. 1984). Lowy et al. (1985) reported that venous dose of inosine pranobex increased the
the concentration of EAC rosettes significantly (p serum immunopotentiating activity in a mixed
= 0.01) increased during inosine pranobex admin- lymphocyte culture, but it also potentiated the in-
istration to 14 patients with alopecia universalis, hibition of activity in patients concomitantly given
semiuniversalis or areata and that autoantibodies a single dose of intravenous prednisolone 40mg
disappeared from or decreased in 7 of 8 patients (De Simone et al. 1984a).
(Lowy et al. 1985).
20 patients with rheumatoid arthritis were ad- 1.3 Antiviral Activity
ministered inosine pranobex 25 to 50 mgJkg daily
in divided doses for 2 months, followed by 5 con- Inosine pranobex has only a modest and incon-
secutive days fortnightly for the next several months sistent antiviral effect in standard tissue cultures.
(Bonvoisin et al. 1983). A further 4 rheumatoid The antiviral activity which it has demonstrated in
arthritis patients and 7 patients with aphthous sto- vivo in several animal models of infection, in ex-
matitis received a total daily dosage of 50 mgJkg perimentally induced influenza in volunteers and
for 6 weeks (Wybran & Schandene 1984). In the in 1 study of cytomegalovirus shedding by male
former study, of several immunological indices as- volunteers is generally considered to be secondary
sessed, only the lymphocyte proliferative response to its immunopotentiation.
to phorbolmyristate acetate (a mitogen which might
be preferentially active on helper T-Iymphocytes) 1.3.1 In Vitro Antiviral Activity
was significantly (p < 0.01) increased. In the latter In tissue cultures inosine pranobex has been re-
study the percentage of active T -rosettes (p < 0.01), ported to inhibit the replication of several RNA
the phytohaemagglutinin-stimulated T -lymphocyte and DNA viruses, including Herpes simplex, cy-
response (p < 0.05) and interleukin-2 production tomegalovirus, LAV/HTLV-III, adenovirus, vac-
(p < 0.01) were increased, but E-rosette formation cinia, poliovirus, influenza types A and B, rhino-
and concentrations of OKT3, OKT4 and OKT8 virus, and ECHO, rabies, encephalomyocarditis and
lymphocytes were unchanged. Eastern equine encephalitis viruses (Chang &
1.2.9 Effect on Immune Function in Weinstein 1973; Ginsberg et al. 1973, 1976; Gor-
Other Patients don et al. 1974; Hernandez-Jiluregui et al. 1980;
Treatment with inosine pranobex in a divided Marks 1974; Muldoon et al. 1972; Ohnishi et al.
daily dosage generally ranging from 2 to 8g or 25 1983; Pompidou et al. 1985a; Simon et al. 1977;
Table VI. Effect of oral inosine pranobex (IP) on various immunological parameters in several patient groups

References Study Diagnosis No. of Total divided daily Assayt> Resultsc Statistical
-
t:I
0
~.
design" pts IP dosage (duration, in analysis
days) if
Azzara et al. 0 Recurrent infections 3 4g (15) Neutrophil chemotaxis Increased to normal No
6g-
(1982b) values ~

Betts et al. (1978) db Influenza infection 33 4g (6) PHA lymphocyte proliferation IPt ~ placebo t No >

Delogu et al. (1982) n, c Seriously ill intensive 57 8g (14)

Lymphocyte cytotoxicity
Skin test reactivity
Ipt ~ placebo t
IP ~ placebo
No
No
~a
Donati et al. (1983) n, Cd
care patients
35-60% surface area 20 70-100 mg/kg (8) PMN% phagocytosis Ipt > control t Yes l
burns PMN% killing Ipt > control t Yes
~~.
Khakoo et al. (1981) db Influenza 41 4g (9) PHA lymphocyte proliferation Ipt > placebo t Yes
Meroni et al. (1984) db Elderly 10 4g (90) Lymphocyte concentration Ipt = placebo t Yes
(T3, T4, T8, T4/T8)
Cutaneous hypersensitivity Ipt> placebo t Yes
(Candida alb/cans)
Renoux et al. (1985) n Elderly women 5 3g (2) Lymphocyte concentration Yes
5 3g (5) (T3, T4, T8, T4/T8)
5 3g (10)
Tanphaichitra (1982) n, c' Thai haemorrhagic 15 2g (10-14) E-rosette formation Ipt faster than control t No
fever Cutaneous hypersensitivity (2,4- Ipt faster than control t No
dinltrochlorobenzene)
Tanphaichitra & n, c 9 Active pulmonary 53 0.5g 2 days weekly (90), E-rosette formation L ~ IP ~ control No
Panupornprapongs tuberculosis then 0.25g 2 days weekly Cutaneous hypersensitivity (2,4- L ~ IP ~ control No
(1981) (90) dinitrochlorobenzene)
Waldman & db Rhinovirus infection 39 4g PHA lymphocyte proliferation IPt> Pt Yes
Ganguly (1977)
Ronconi et al. n, c Anergic surgery 37 4g (14) Skin test reactivity IP ~ P No
(1981) patients

a o = open; db = double-blind; n = non-blinded; c = controlled.

b =
PHA phytohaemagglutinin-induced; PMN = polymorphonuclear leucocyte.
c t = improvement; > = statistically significant difference; ~ =nonsignificant trend or statistical significance not analysed.
d Controls were untreated burn patients.
e T3 unchanged; T4 significantly decreased in IP patients (p < 0.005); 5-day treatment increased (p < 0.05) and 10-day treatment decreased (p < 0.05) T8; no change
in T4/T8.
f Controls were untreated patients with Thai haemorrhagic fever.
g There were 3 treatment groups, all of which received a daily regimen of isoniazid 300mg, ethambutol 800mg and rifampicin 600mg. Additionally, 1 group (IP) received
the stated dosage of inosine pranobex and 1 group (L) received levamisole 150mg 2 days weekly for 3 months then 75mg 2 days weekly for 3 more months. I 8
Inosine Pranobex: A Preliminary Review 401

Tsang & Fudenberg 1982; Venuti et al. 1984). eitis or panleucopenia virus infection, ferrets with
However, there have also been reports of a lack of distemper virus infection or swine with influenza
effect of inosine pranobex on the replication of or transmissible gastroenteritis virus infection
some of these and other viruses, including aden- (Glasgow & Galasso 1972).
ovirus, parainfluenza virus, measles, mumps, rhi- A double-blind placebo-controlled study re-
novirus, Western equine encephalitis virus and ported a statistically significant (p < 0.005) de-
others (Chang & Weinstein 1973; Eggers et al. 1972; crease in the quantity of cytomegalovirus shed in
Ginsberg et al. 1973; Muldoon et al. 1972). the semen of 5 male homosexual volunteers ad-
ministered inosine pranobex 3g daily for 28 days,
1.3.2 In Vivo Antiviral Activity in comparison with 9 male volunteers admini-
Inosine pranobex administration has generally stered placebo (Conant et al. 1986; Drew et al.
been shown to increase the survival of mice in- 1986). The decrease was significant when meas-
fected experimentally with influenza A or B virus ured during weeks 2 and 12, but not week 4.
(Glaskyet al. 1971; Muldoon et al. 1972; Ohnishi 33 volunteers challenged with influenza A/Vic-
et al. 1983), including animals having artificially toria received inosine pranobex 4g daily or placebo
depressed immunity (Ohnishi et al. 1983). The drug beginning 24 hours after the challenge for 6 days
also increased the survival of mice infected with in a double-blind study (Betts et al. 1978). Begin-
Forest spring encephalitis virus; survival was fur- ning at 48 hours the inosine pranobex-treated
ther improved in animals administered interferon patients shed significantly less virus. However, de-
plus inosine pranobex (Fomina et al. 1980). Com- tails of the study design and results were not avail-
bined therapy with inosine pranobex (administered able.
24 hours before inoculation) plus interferon (ad-
ministered I hour after inoculation) improved the 1.4 Antitumour Activity
survival of mice infected with encephalomyocar-
ditis (Chany & Cerutti 1977), but inosine pranobex While there are only a limited number of in vi-
alone was ineffective (Chang & Weinstein 1973; tro studies, inosine pranobex has demonstrated in
Chany & Cerutti 1977; Glasgow & Galasso 1972). vivo antitumour activity in experimental animal
The drug did not significantly improve the sur- models. Of particular interest is the synergistic
vival of mice infected with type 2 Herpesvirus antitumour activity reported with fluorouracil (in
Hominis, influenza A or B virus or rabies virus vitro and in vivo) and with interferon (in vivo).
(Glasgow & Galasso 1972), had no effect on the
incubation period of Creutzfeldt-Jakob disease 1.4.1 In Vitro Antitumour Effects
(Tateishi 1981) and did not affect the number of Inosine pranobex produced no antitumour ef-
pocks caused by vaccinia virus (Ohnishi et al. 1983). fect on a tissue culture of cervical carcinoma (HeLa)
Other animal models have also shown increases cells (GonzaIez-Diddi et al. 1980; Miyoshi et al.
in survival rate when inosine pranobex was ad- 1984; Namba et al. 1984). However, when HeLa
ministered for treatment of experimental viral in- cultures were exposed to inosine pranobex 100 mgt
fections, including hamsters with Herpes simplex L in combination with fluorouracil 0.5 to 2.0 mgt
infection (Chang & Weinstein 1973; Gordon et al. L, the cytotoxic effects of the latter drug were in-
1974; Ohnishi et al. 1983) or influenza infection creased (Miyoshi et al. 1984; Namba et al. 1984).
(Chang & Weinstein 1973), and chickens with
Newcastle disease, fowl plague and avian infec- 1.4.2 In Vivo Antitumour Effects
tious bronchitis (Moya et al. 1984). The drug did The in vivo antitumour effects of inosine pra-
not significantly improve the survival of rats with nobex have been studied in several animal models.
Herpes simplex encephalitis (Marks 1975), rabbits In one study, mice challenged with small doses of
with vaccinia virus infection, cats with rhinotrach- Ehrlich ascites tumour cells had a small but con-
Inosine Pranobex: A Preliminary Review 402

sistently increased survival time when treated with synthesis and translational ability in lymphocytes
inosine pranobex compared with untreated con- (Ohnishi et al. 1982). As cellular RNA and protein
trols, the statistical significance of which was not synthesis is markedly depressed shortly after viral
reported (Fellous et al. 1980). In contrast, using the infection, one may speculate that the depression
same model Namba and colleagues (1984) [Mi- might be reversed in the presence of inosine pra-
yoshi et al. 1984] found no increase in the duration nobex, leading to an increase in cell survival. In
of survival of inosine pranobex-treated mice, but fact, while host cell RNA synthesis is stimulated
a prolonged (p < 0.01) survival time among those by inosine pranobex, viral RNA synthesis is de-
animals treated with fluorouracil plus inosine pra- creased (Ohnishi et al. 1982).
nobex. Similarly, mice inoculated with Crocker A theory which has been advanced for the effect
tumour cells and treated with inosine pranobex and of inosine pranobex on host and viral RNA syn-
interferon had an improved mean survival time (64 thesis is that one component of the drug or the
days) over animals treated with inosine pranobex drug complex links itself to the ribosomes of the
alone (45 days) or control animals (26 days) [Cer- infected cells, provoking a sterical modification
utti et al. 1979]. Spreafico (1979) reported that the which renders an advantage to cellular RNA over
protection given by a previous immunisation with viral RNA in the competition for linkage with the
irradiated LI210 leukaemic cells against subse- ribosomal combining sites. The consequence would
quent inoculation with cells of the same line was be a non-reading or incorrect reading of viral RNA,
increased if the mice were treated with inosine pra- with incorrect transcription of the viral genetic code
nobex before the tumour challenge. Inosine pra- (De Simone 1985).
nobex treatment improved the survival rate of rats A second theory for the immunostimulatory ac-
inoculated with ascites tumour cells only when a tion of inosine pranobex is that the drug stimulates
moderate inocula was used (10 2 or 5 X 102 cells); the production of lymphokines which trigger the
the survival rate of rats inoculated with small or molecular events that lead to the altered expression
large inocula was unaffected (Amato et al. 1983). of immune function. This theory is supported by
reports that mononuclear cells from peripheral
1.5 Mechanism of Action blood of healthy subjects, the aged, and patients
with rheumatoid arthritis, systemic lupus ery-
The in vivo antiviral and possible antitumour thematosus or AIDS respond to inosine pranobex
activity of inosine pranobex is believed to result in vitro by increased elaboration of lymphokines
from an enhancement of host immune responses (interleukin-l and -2) [Hersey et al. 1984; Naka-
due to the drug. The drug does not by itself stim- mura et al. 1983; Tsang et al. 1984a, 1985a,b].
ulate resting lymphocytes, but augments immu-
nological processes by lymphocytes once they have 2. Pharmacokinetic Studies
been triggered by mitogens or viral antigens.
The biochemical action of inosine pranobex is Inosine pranobex is broken down into a number
not known. Inosine pranobex penetrates lympho- of naturally occurring chemical components, mak-
cytes as a complex (Morin et al. 1982; Ohnishi et ing pharmacokinetic analysis extremely difficult.
al. 1982). Increased ribosomal RNA synthesis and The pharmacokinetics of the drug have received
protein synthesis have been observed in phytohae- limited investigation in humans because the ino-
magglutinin-stimulated lymphocytes exposed to sine component must be radiolabelled and the pos-
inosine pranobex (Ginsberg and Glasky 1977). sibility of a long half-life of RNA/DNA-incorpo-
Furthermore, the drug has been shown to enhance rated radioactivity has caused concern (Taylor et
both RNA synthesis and enzymatic activity in both al. 1984). However, the biochemical basis for this
virus-infected and non-infected rat and mouse em- concern has been questioned (E. De Clercq, per-
bryo cells (Tempera et al. 1984), and promote RNA sonal communication).
Inosine Pranobex: A Preliminary Review 403

In volunteers administered a single 1.5g oral nobex has also been assessed in double-blind com-
dose, a peak plasma inosine concentration of 0.6 parisons with placebo -in immunocompromised and
mg/L was reached after 1 hour. However, the immunocompetent patients with zoster, in im-
plasma inosine concentration was unmeasurable 2 munocompromised males with persistent general-
hours post-administration (Pfadenhauer & Glasky ised lymphadenopathy or AIDS, in elderly insti-
1974). tutionalised patients, and in patients with viral
Following oral or intravenous administration, hepatitis, measles, amyotrophic lateral sclerosis or
inosine pranobex is rapidly metabolised. The half- experimentally induced influenza or rhinovirus in-
life of the inosine moiety is 50 minutes following fection. Unblinded or open studies examined the
an oral dose, and only 3 minutes following an potential efficacy of the drug in several other dis-
intravenous dose. In humans, the major excretion eases and infections.
product is uric acid. The other moieties of inosine
pranobex are oxidised or glucuronidated and ex- 3.1 Herpesvirus Infections
creted in the urine (Ginsberg 1972; Ginsberg et al.
1978; Simon & Glasky 1978). Nielsen and Beckett Several double-blind placebo-controlled studies
( 1981) described the pharmacokinetics of the p- of inosine pranobex in mucocutaneous Herpes
acetamido-benzoic acid (PAcBA) and the N-N di- simplex infections (labialis or genitalis) suggest
methylamino-2-propanol (DIP) components of a positive therapeutic effects. Unfortunately, many
Ig dose of the inosine pranobex complex in 2 of these results are at present only published in ab-
volunteers. The urinary excretion of unchanged DIP stract form and so details were filled in with un-
reached a maximum of 19.2 mg/h from 30 to 60 published data provided by the manufacturer. Ad-
minutes after ingestion of the complex and the ditional well controlled, designed and reported
elimination half-life was 3 to 5 hours. 30% of the studies are needed to make firm conclusions on the
DIP was recovered unchanged in the urine and 65% efficacy of the drug in these and other types of her-
as DIP-N-oxide. The absorption and elimination petic infections, such as herpetic keratitis or uvei-
of PAcBA was even faster: urinary excretion tis, varicella or zoster. Inosine pranobex has also
reached a maximum of III mg/h during the first shown encouraging results in a few patients with
30 minutes and the elimination half-life was 50 herpetic encephalitis (Cocchi et al. 1983; Rancurel
minutes. 30% of PAcBA was recovered unchanged & Buge 1981).
in the urine and 55% as PAcBA-glucuronide.
3.1.1 Mucocutaneous Herpes Simplex
3. Therapeutic Trials Infections
Double-blind placebo-controlled studies as-
In therapeutic trials the usual oral daily dosage sessed the efficacy of inosine pranobex in acute pri-
of inosine pranobex has been 25 to 100 mg/kg or mary or recurrent Herpes labialis infections. The
3 to 6g given in 4 to 6 divided doses. However, drug was reported to be significantly superior to
further dose-response studies on the optimal im- placebo (table VII) in clinical response in both
munomodulatory dose and the optimal therapeutic diagnostic subgroups of patients. Furthermore, 1
dose could help to define more clearly the potential study reported that intermittent therapy over a 12-
benefits obtainable with the drug (R.B. Herber- month period reduced the number of recurrences
man, personal communication). The drug has been (Galli et al. 1982, 1984).
compared with placebo in several double-blind Both of the studies which examined patients with
trials in patients with mucocutaneous Herpes sim- primary herpes genitalis (Corey & colleagues, Cut-
plex infections (labialis and/or genitalis) and to ler & Talbot; table VIII) found the difference in
historical controls in patients with subacute scle- healing rates between inosine pranobex and pla-
rosing panencephalitis. The efficacy of inosine pra- cebo to be statistically significant. Also, Corey and
Inosine Pranobex: A Preliminary Review 404

~c:: colleagues found that the duration of viral shed-

'6 ding, itching and tender adenopathy were statisti-
.
.!!l
"iii
:c
.!!!
'01
o~...
c::
i'5'
cO"':
I
~
cally shorter with inosine pranobex. U nfortu-
nately, in this study the comparability of the patient
groups before treatment was not discussed
discussed..
.;Co ~ Among the studies which examined recurrent
E ~ genital herpes infections the overall healing rate was
·iii '0 .Q.
I
J:

j
C:""
c::""
oal
0

~i
111

:::J:::J
"Co
"00

~
v
eo I
i
not shortened with the use of inosine pranobex
(Cutler & Talbot; table VIII), but some analyses of
symptomatology showed an improvement which
was statistically significant (table VIII), and Miller
i .5 ~
.·
~...:.
010 and colleagues found a statistically significant de-
~

! :E Q.
CDOD
.;.~ crease in the number of positive viral cultures
.5 :-[ ~~ among inosine pranobex-treated patients. One of
"'E A 111"0
[ Ill>.
"0'" eo ~i the 3 studies which assessed recurrence rates found
"S:::t
a significantly (p < 0.025) greater reduction with

i I'" 1-
0011

'3l .
Q.
.·it. .:Q. .~~
Q.. -Co a;:- CD III
inosine pranobex than with placebo (Miller & col-
leagues), while the second found no statistically
"=oQI ~ =QI
.~ §c::
QI
A A A !>.
10111
significant difference (Galli et al. 1982, 1984). The
.5 eo eo eo third study found that recurrence rates versus pre-
~~
II: 0 ...
'0
• ...c:: =0 treatment recurrence rates were significantly re-
~()>-
~I~~ .!!l CD .'!i :::JQI
duced by both the drug (p < 0.01) and placebo (p
.~ i:5 '"c::o E
... '"g "''''
!c 'I"""
o -8. g. < 0.025); and that crossing over from placebo to
~ [aI
=..,- III
0'0 ! ..5 ... ~ III",
.c QI 0
~c:: E ~i: g",!B·-CD
~>."OOI -&~ v inosine pranobex for a further 6 months' therapy
·00
'6 8 ~C::"'~~ _c "':0.
Co :i.2
. a;
CIJ!6U) !...
QI 0
:>. II resulted in a further reduction in recurrence rates
~ ~ .........~ .. S"> .. c:
&UG)CDoQ ~ R as: (Lawrence & colleagues; table VIII, fig. 3). Unfor-
<! a~~
0>- :::J
011"
c::
<.5 "0 co.
aI.:
0..-
.... ~
tunately the significance of the 45% greater pre-
"O.iij :Go treatment recurrence rate among the inosine pra-
"=: c_ u v
c::
'"III -~
III.
°CD eoQ. eoQ. eoQ.eoQ. ","0
58
QI Co
~ II
nobex group was not discussed, and the inosine
'"'6QI ZCo
0111
-:;::::t
~~
M<O
N..-
..,.<0<0..,.
t')CIO'I"""Q
t\I
__ 'I""" (\I ... 01 0 pranobex-treated patients were not crossed over to
~:a ! ..
i >'"0 i:g placebo to check for the magnitude of the placebo
~31

~I .-
ll...
"0 Sci effect.
!:::. rJ '" '"v
~ Q.CDSU; N ~
c; __ 'in::
:E'III
=e.
E II
The efficacy of inosine pranobex in mucocutan-
o
o
- C)~
>'111111111
>..
VI E !:::.!:::. ~-g ~. eous Herpes simplex infections has also been as-
...L. =0~"O -
!!:. 2l.g ~.5 !f ~ !f!f c:: ~ cO j ~ sessed in several additional double-blind placebo-
~~.Q >- i
.8 !"iia;-g~ controlled trials (Bouffaut & Saurat 1980; Bunta
~ 0 - E ...
uQl E "''6
= 1980; Kalimo et al. 1983; Wickett et al. 1976).
Q.
-g III
...0... ... E
c ~.!! .! . . .
.2 CD c"",c However, these studies combined results from
'"
·iii
"iii
o
~c:: c:: ~ !... ....- . . . rJ
'OQ.-g0;
~ c:: cal! ! III patients with Herpes labialis and Herpes genitalis.
~ ~
c:
~ .§ E G c 5 CD ~ "§,
Since these 2 infections have importantly different
.c
C Q: ! ~
.~
Q. CD
II: ~Ug'"O·iii
5
"0
.!QI:E!ij>.
>- u = clinical courses and prognoses, combined results
~.5~CDrl
'0 5 make conclusions as to the efficacy in either
12 :! :~.5~]i
:::J
-",-(\,1
~ -S.~[~§ difficult.
{!j "B8l "0
l ai~8.~-,
'01::' .. ::,. i 58 5 ~ ~
-I~
:::t
> c:: Q;~~aI! 011 i ~i I v 3.1.2 Herpetic Keratitis or Uveitis
.cCDEQI_ :a:::J:a~A Encouraging results have been reported with the
.I ; il:a~~=~ ~:g III 8 III u. ~
! ~ !CQ).c:CGcn
0':'; a.. C!J ~
-01
~~ III .co:\C use of oral inosine pranobex in several case reports
Inosine Pranobex: A Preliminary Review 405

double-masked comparative study in herpetic ker-

1.2 n = 17 atitis (Haut et al. 1983). Reassessment after 10 days
of treatment with a daily dose of 4g orally per day
1.1
showed that a greater percentage of the 16 inosine
1.0
.r: pranobex-treated patients had improvement in the
E 0.9
0 physical and functional signs of infection than did
E
~ 0.8 the 15 evaluable placebo-treated patients. How-
VI 0.7 ever, the design and reporting of this study were
lSc:
flawed in several respects and thus the results are
~::I 0.6
of dubious value. Further well-designed compara-
~ 0.5
0 0.4 tive studies are needed to clarify the value of in-
n = 14
.8E 0.3
osine pranobex in herpetic keratitis.
::I
c:
c: 0.2
'"
Q)
~ 0.1 3.1.3 Varicella Zoster Virus Infections
Several comparative trials (vs placebo, un-
Pretreatment 6 months 12 months treated controls or patients treated symptomati-
cally) reported an amelioration of the signs and
symptoms of zoster or varicella in patients admin-
Fig. 3. Effect of inosine pranobex • and placebo ([]) on re-
istered inosine pranobex (table IX). However, only
currence rates in a double-blind study of genital herpes infec-
tion . 17 patients were randomly assigned to treatment with ino- 3 of the studies were double-blinded (Calonghi et
sine pranobex 3g daily (women) or 4g daily (men) during each al. 1980; Feldman et a1. 1978; Lesourd et al. 1982)
recurrence, and then 1g daily between recurrences, for 6 months. and only Lesourd et a1. (1982) reported the com-
The placebo-treated patients were crossed over to active treat-
parative number of days of illness before the onset
ment for a further 6 months (Lawrence 1986; Lawrence et al.
1985; unpublished data on file, Newport Pharmaceuticals). of therapy with inosine pranobex (7.2) and placebo
(6.5; difference not statistically significant). Three
of the studies did not report the comparability of
of herpetic uveitis or keratitis (Berkman et al. 1979; the treatment groups, but 2 noted that the groups
Di Tizio et a1. 1979; Gorgone et a1. 1980; Gualdi
'appeared' similar (Bunta & Peris 1981: age, sex,
et a1. 1980). Additionally, an open non-randomised
location of lesions and underlying disease; Feld-
comparative study reported that lesions were healed
man et al. 1978: age and type of underlying malig-
in an average time of 25 days and 13.3 days, re-
nancy), and Lesourd et a1. (1982) found no statis-
spectively, in 15 evaluable patients with herpetic
tically significant difference between the groups in
dendritic keratitis who were treated with tradi-
age or sex, or in the location, extent or intensity of
tional therapy (including atropine 1% eyedrops or
cream daily and cytosine eyedrops 2-hourly) and the lesions. In the latter study, the inosine pra-
13 patients treated with traditional therapy plus in- nobex-treated group initially required significantly
osine pranobex 5 to 10% eyedrops (Sellitti et a1. (p = 0.01) more treatment for pain than the pla-
1982). An additional comparative study, details of cebo group. However, after 7 to 8 days of treat-
which were unavailable, reported a statistically sig- ment the difference in pain between the groups was
nificant decrease in the duration of corneal injec- no longer significant. In this study, a significantly
tions: from 21.4 to 14 days (p < 0.025) among the (p < 0.01 vs placebo) greater number of inosine
5 patients administered inosine pranobex Ig 4 times pranobex-treated patients were healed after 5 or 6
daily versus the 5 control patients (Visco et a1. un- days of treatment, with no patients in either group
published data on file, Newport Pharmaceuticals). developing neuralgia. The statistical significance of
Inosine pranobex has also been evaluated in a the results of the other studies was not reponed.
Table VIII. Results of double-blind placebo (P)-controlled studies assessing the clinical efficacy of oral inosine pranobex (IP) in Herpes simplex genltalis

References Diagnosis Daily IP No. of Results

-
::s
0
'"ff
dosage
(duration,
pts.
healing (days duration of no. of positive symptom symptom no. of time to ;r::s
in days) to complete viral shedding viral cultures duration severity score recurrences recurrence 0
healing or % (days) during study (days) during study (months) g
~
healed at 7 duration duration
days)
>
~
Corey et al.
(1979);
Primary 4g (12) 191po
20 pa
18.Cd
22.3d
f. 7.0t·
11.3
IP < pb 2.
::s
~
unpublished data
~
on file, Newport g.
Pharmaceuticals ~

Cutler & Talbot

(1985);
Primary 4g (7) 531P
51P
70%
43%
l... 71%"
51%"
unpublished data
on file, Newport Recurrent 4g (7) 271P 76%"
85%f NS
Pharmaceuticals 37 P 68% 66%"

Galli et al. (1982,

1984)
Recurrent 70 mg/kg
(7}d
161P
16 P
6.53
6.81
t NS

Lawrence (1986); Recurrent e 17IP 2.9***1

unpublished data 17P 3.6**1
on file, Newport
Pharmaceuticals

1.5 ~ **
g
2.7 ~ *(per
Miller (1984); Recurrent 351P
2.3 f **
Ginsberg et al.
(1985); Glasky
41 P 2.3
iM th)h 3.2

& Miller (1985);

unpublished data
on file, Newport
Pharmaceuticals
Salo & Lassus
(1983); unpublish-
ed data on file,
Recurrent 6g (14) or
4g (14)
15 IP 6g
161P 4g
30 P
. 'j
6.6
7.7
NSI
'51
3.8
3.0
NS

Newport
Pharmaceuticals

~
0\
Inosine Pranobex: A Preliminary Review 407

'C '" Gl Ul Gl
; S
.!!! !,S 3.2 Subacute Sclerosing Panencephalitis
It) c::! Ii>.
::: .~; £ ~
;; C)~ ~.Q Research suggests that SSPE is caused by a com-
g. 311.,~
t!"O bination of immunological pathogenic mechan-
i
~
..-
o
~
.8
5
m:t::
c!~
:!:1-g
.~!
[<
~ii
0 ~
isms and a continuous slow growth of the measles
virus in the central nervous system (Dyken &
..-
.8 !'C £;!l:E.
",g .. ~
DuRant 1983). However, the exact aetiology and
§ C ·'2 2= pathogenesis of the disease remain speculative.
c. '"
~
.0
'" Cl
~·iii
!>.
°It)omQ;~
i,... 'Q.
.!
g
l!
~'ii
3J~
~.,
en
v-g
Q.GS

i"- -
..:
C
~
3.2.1 Case Reports and Open Studies
Several case reports have suggested that inosine
....: -~ GlS t::"- ;;:::
~Ul 8.~...:.·2 pranobex may provide beneficial therapeutic ef-
i~ a·iii
EO
.5
coQ)
~o
c"':>,
.9
Gl:E.It)·2I
_Cal:>.
II) fects in patients with subacute sclerosing panen-
~
(soC :;:-! f3:8:E.ij cephalitis (Fhigel et al. 1979; Goetz 1981; McGrath
~.:: c; cnaJcu
~ ai 0 ui31~ ~E.Q';i & Rosenbloom 1980; Poloni et al. 1981; Streletz &
Om 'c'o>. e"'=
I Cm
CD4="
~l!
aQ)
1:",-
0-41»
EO:f.
co-oeD
Ul",.!!!",
iil;;:::::t-
Ul.5.~=
S'-CDO
eraceo 1977; Trauner & Stockard 1983). Hutten-
locher and Mattson (1979) reported that inosine
i Gl 0
...
c!
15
C "'Q)CI)
.eiiG)
ui 0
~

":.
0 >
oa-
"",,:'gll
-2o",CI)
Cl)vr:::: z
C
pranobex 100 mg/kg daily in divided doses was ef-
fective in either improving or stabilising 9 of 15
I.. !lil
!~
>.:E
5:11.
ic-g
t: 0as
~c."Co
~-gic:i
SSPE patients and Dyken et al. (1982) used the
~ 'ij1: Gi!!: ~",It)v same dosage to treat 15 patients over a 5-year pe-
c
II "O~ !go ~:::-~Q. riod and concluded that the drug decreased or sta-
~1: i m- ~II
~
,,;
'OQ) Q)>.B 0."0-: bilised neurological disabilities of 10 of them.
en' Q) 5 ! J.,.; 5i .~ ~ ..
~i:;i!!l: !u'C ~It)£~ However, after treating 6 SSPE patients, Silverberg
"O:2C1)"Ol=c».m.;
coEi:>-Q)!"-.c
crn:t::f:!
Q)~ ... O et al. (1979) concluded that inosine pranobex 100
O ... --uQ. -o~~ ~"O.ev
O' ... cQ) '.r:;- mg/kg daily in divided doses was not effective
.8c::m
15.e!:s
fD ....
:!S
ot:!::
Bacie.
= II clinically: 1 patient improved, 1 stabilised, 2 de-
.~CI)CD'EO
'C",.-O·a;,...
"O~.!!
Gl~>
easY.
GlE~'
Gl - Ul C E +0" .. >0 ... E .• teriorated and 2 died. Likewise, Noetzel and Dod-
t::o.~! == c=tD~:! "08
8..;~;ca'i asasc.!!.-!~. son (1983) reported unabated progression of cere-
e~~~i:a jg-;;~.5·E~
_"0"' ..
2-c-E
O ......
.&;0. ci'-a.-"C'"
'(i"08Q)i c j!!a.
bral pathology in the computerised tomographic
~"":~!oi8 EasCl)U).g!~1I scans of a patient with SSPE despite continuous
as)(1ii~~- >-:»ci:t:cn ...
~!u.;as!~ ~-g=~a,>!;..:. treatment with inosine pranobex (70 mgJkg
mgJlcg daily)
"'0 CD ... :;:: "CCDE-,;;ca:tg
ii!E6~ ca~c~-&~ci and periods of considerable clinical improvement
E ... O.cCDJ! cas·_cagm-
1iia.~~~cn CD'§BcCl)~~v or stabilisation.
!~_~O~ :Scnc!aJualS
ti·iii;>o:'" ui~!!!~~:!::EGl
a.gs-gacD-c8 -:!:e-rnE,g!g
Cl)°-as_c-G)c.!!o_CI) -G) 3.2.2 Studies with Historical Controls
! CI) o§ f! 1:: ! ~ 'C os;: S fL >- Q;
0. -;
5oEt;~'C ~ 8.5S~ Q; ~JIJ~~ The debate over the use of historical controls
0,'6 a':
_o~Eoas,--
~ i ~ ~ 0. ~ ~ CD ~
as::J'- C):Qic
! - has several pros and cons (table X). While the eth-
CG) C\I'C'-OC)CI).QO=CD>as
CD '- 0
ECD.=
6 c c >- ~ >- as '- 0 0
CCDCI)o£:'C££_oc.:E ics of withholding a potentially effective therapy
1ii ~ a -g ~ ~ ",.g.g
! ! ! i · - " ' - C ~ Ul:!:: E 0 cn.·iii·iii
a C :;~ '" §, were obviously involved in the decisions to use
: 1:: g
en ~ ~ ~ ~ SOli:::"~ ~
o 8.'C16,--; ~'tJ°ii G)oEo!! ~ cli
c '- historical controls in the studies below, the diffi-
~!!~;:!tslt)S~[Oo~~ culty in obtaining large enough samples to conduct
:a
CI) 8,CI) ia; 8.0 CI) 0 ,-S ~~~
randomised comparative trials also influenced the
;~~:EQ.:II;~bl.g~;~~
~Eo.8 ~ ~!g ... ·a;o.c:ll., Gl.g 1\ investigators. The largest of the 3 studies (Jones et
E .. .. - ~ ~ 'C E '" 5 Gl E ~
o >oGl OllJlD": Cl>-Gl o.c c c V al. 1982) recruited only 98 SSPE patients from 28
ucnn.u. :>ot')CI)E"''''._:::>~
",.cO'CGl_ Cl.c :.c separate medical centres in the US and Canada be-
Table IX. Results of controlled comparative trials of inosine pranobex (IP) in patients with infection due to Varicella zoster virus 5"'
0
References Study design Patient Total daily No. of Results '"
S·
(1)
population dosage pts '"1:1
{duration, in crusting or healing pain (time, in duration of new lesions neuralgia moderate to j;l
::s
days) {time, in days· or % days· or % symptoms {time, in (% pts) severe skin 0
pts at a given time) pts at a given days· or dissemination ~
~
time) % pts) (% pts) ~
'"1:1
Bunta & Peris
(1981)
m, n, r Normal and
immuno-
IP 4g (10)
symptomatic
69
57
62%~
6% day 10
10%
19%
a8'
compromised meds b S·
I»
w/zoster ~

Calonghi et al. db Normal IP 70-100 14 4.7 4 14% ~

-<
(1980) w/zoster mg/kg (7 -1 0) o·
~
P 14 5.8 7.2 43%

Catania et al. n Normal IP 70-100 27 10.2 IP .;; control

(1982) w/varicella mg/kg (8-12)
untreated 8 14.0
controls

n Normal and IP 4g (7-10) 9 4.4 4.2

immuno- untreated 9 8.9 5.5
compromised controls
w/zoster
Feldman et al. db, r Paediatric IP 1.8-2.7 6 3.5 50%
(1978) cancer pts g/m 2 (5)
w/zoster P 7 4.0 43%

Lento et al n Normal IP 4gc 5 5-6 .;;3 0

(1981) w/zoster symptomatic 5 10-15 4-5 20%
meds

Lesourd et al. db, r Normal IP 50 mg/kg (5) 18 94% ~ day 5-6 71% ~ day 7-8 0
(1982) w/zoster P 18 61% (p .;; 0.03) 69% (NS) 0

a Mean or median values are given except for Lento et al. (1981) which gives a range of times.
b Analgesics, large doses of vitamin B, rondomycin and more or less inert topical preparations.
c Until symptoms disappeared.
Abbreviations: '" = non-significant trend; NS = not significantly different; P = placebo; m = multicentre; n = non-blinded; r = randomised; db = double-blind. ~
00
Inosine Pranobex: A Preliminary Review 409

tween 1971 and 1980. Hoehler et al. (1984) deter- Table X. Pros and cons of using historical controls in thera-
mined that a survival analysis of 2 independent peutic drug trials (after Hoehler et a!. 1984)
groups would require over 100 deaths to yield an Pros Cons
80% chance of detecting a 40% reduction in hazard
rate with an a level of 0.05. Smaller sample size Lack the assurance of randomisation
required that there is no systematic bias in the
Three studies compared the clinical course of
assignment of patients·
inosine pranobex-treated patients with that of his- No ethical dilemma
torical controls in the treatment of patients with due to withholding Ethical dilemma of failing to establish
SSPE (table XI). Jones et al. (1982) compared sur- potentially effective the efficacy of a potentially valuable
vival data of 98 inosine pranobex-treated SSPE treatments treatment

patients with a group ofSSPE patients derived from Lack of control over the adequacy or
national registries in the US, Lebanon and Israel. uniformity of diagnostic criteria and
clinical follow-up of historical controls
Based on life table analyses the investigators con-
cluded that the probability of survival was signifi- Problem of guaranteed survival of
cantly higher in treated patients (fig. 4). Care and treatment group inherent in the time
lag between diagnosis and treatment
attention were paid to the possible fallacies of the
use of historical controls (e.g. guaranteed survival) Possibility that treatment group might
have more extensive or adequate
and the investigators determined that the cases and
overall medical care or nutrition
controls were comparable and were treated at a
similar stage of the disease. A re-analysis of the a By randomising the selection of subjects and using enough
data using an additional 163 US registry patients, subjects 'chance' will usually 'correct' for sampling errors
and refined statistical procedures was reported to and render the groups comparable despite the inability to
know all relevant variables.
confirm the beneficial effects of inosine pranobex
compared with results in untreated patients from
either the US (p = 0.(01) or Israel (p = 0.001)
[Hoehler et al. 1984J. However, the possibility re- discussed. Additionally, the use of 'recovery' as an
mains that the treated patients might have received end-point is questionable in a disease such as SSPE;
better nutrition or medical care in other ways and 'remission' would have been more appropriate
so the 2 groups might not be strictly comparable given the relatively short term follow-up.
despite careful attempts to match them, particu- In a subgroup of patients with slowly progres-
larly given the geographic heterogeneity of the con- sive SSPE, DuRant and colleagues determined that
trol group (Editorial 1982). both survival (DuRant & Dyken 1983) and neu-
There was no statistically significant difference rological disability (DuRant et al. 1982) were im-
in the rate of recovery of 18 Middle Eastern SSPE proved in patients treated with inosine pranobex
patients treated with inosine pranobex 50 to 100 compared with untreated controls followed be-
mg/kg daily (in divided doses) for a mean duration tween 1964 and 1975 (figs. 5 and 6). There was no
of 12 weeks and 96 historical controls from the significant difference between treated and un-
same geographic area (Haddad & Risk 1980). treated patients with rapidly progressive disease.
However, although among the subgroups of patients However, in the assessment of survival, neither the
in stages Ua and lIb of the disease more inosine effect of the time lag between diagnosis and onset
pranobex-treated patients recovered (p P:l 0.(075), of treatment nor the comparability of the treat-
the investigators concluded that the clinical course ment and control groups were clearly discussed. In
of the improvements indicated little likelihood of the analysis of neurological disability the compar-
an association with inosine pranobex therapy. Un- ability of the treatment and control groups is also
fortunately, neither statistical methods nor com- in question, particularly the difference in the level
parability of control and treatment groups were of neurological disability at the mean time of treat-
Table XI. Design of studies comparing Inosine pranobex (Ip}-traated patients with subacute sclerosing panencephalltis (SSPE) to historical controls

References IP patients e patients Group Interval from Statistical design Total dally IP
(e)
Assessed
-
g
5'
n
comparability diagnosis to dosage
traatment
(months)
lg.
~
DuRant & Dyken 19 treated between 13 followed pre-1975 History of measles Ufe table analysis 100 mgJkg until Survival (fig. 5)
(1983) 1975 and 1982 (6 rd SSPE; 7 sd Infection: NS death
>
(10 rd SSPE; 9 sd SSPE) Age of onset of ~
t::
SSPE) SSPE: IP > e· a
DuRant et al.
(1982)
12 treated between
1975 and 1981
13 followed pre-1975
and 2 othars·
Age of onset of
measles: NS
4-32:
rapid group 9
Maen disability
analysed by two-
100 mgJkg until
death
Neurological
disability (fig. 6)
l
(6 rd SSPE; 6 sd (7 rd SSPE; 8 sd Age of onset of (mean) way covariance ~
SSPE) SSPE) SSPE: IP > e· slow group 12.5
(mean)
i'
Haddad & Risk 18 of 118 evaluated 96 of 118 evaluated 1-68 50-100 mgJkg x Recovaries
(1980) 2-27 wks (mean
12 wks)b

Jones et al. 98 150 US, 94 Age at onset of Ufe table analysis 100 mg/kg x Survival (fig. 4)
(1982) Lebanese, and 89 SSPE: IP 12.4y, e 1mo-9y
Israelie 9.5y

a Two patients in whom inosine pranobex treatment was not Initiated until 58 months and 82 months after diagnosis. Data obtained after the Initiation of traatment was
excluded.
b Umiting factors to continued treatment were death (4 pts), continued daterloratlon (7 pts) and lack of Improvement resulting in patient withdrawal (remainder).

-.,.
c Derived from national registries.
=
Abbreviations: rei rapidly deteriorating; sd= =
slowly deteriorating; NS non-significant difference; • '" p < 0.001.
o
Inosine Pranobex: A Preliminary Review 411

100 100
~ 90
(U 80 .?,,;
>
'~ 70
~ 80
,: .-\
r: '......
:::J
'" 60 If I: ........ ....
'0 50
:0
<0
'"
,.,,:: .... .
~ 40
:0 30
'0
(U 60 ,:
,:
'"
.0 20
e
o
'0,
o
,:
0.. 10 '0 ':
~~~~~~~~nn~~ ~ 40
1224 3648 6072 84 96108 20 132 220 c
C
Time since onset (months) 1 144 <0
Q)
~ 20

Fig. 4. Life table profiles for 98 inosine pranobex·treated sub-

acute sclerosing panencephalitis (SSPE) patients (e) and 333 o 12 24 36 48 60 72 84 96 108
untreated SSPE controls (Israeli, Lebanese and US Registry
patients; .) [after Jones et al. 1982).

Fig. 6. Mean neurological disability for rapidly developing [6 in-

osine pranobex-treated (---) and 7 non-treated patients (....))
and slowly developing [6 inosine pranobex-treated ( - - ) and
8 non-treated patients (-)) subacute sclerosing panencephalitis
'" 100
c
':; - \.'1 \
1.._--, (SSPE) by months of follow-up; • = onset of treatment (after
.~

:::J
eo ~, \
DuRant et a!. 1982),
en

L',___ ~+\
c
0 60
t:
-
beneficial clinical effects in patients with SSPE, the
8.0 problems inherent in historically controlled studies
C. 40 -
Q) . . . . . . . . ·. ·1·\1':\ J (in particular the inability to know and therefore
,2;
t; 20
"5
E
:::J
:. '-----1 to match treatment and control groups for all rel-
evant variables which might affect response to
U 0
0 20 40 60 80 100 120 140 160 treatment) casts doubt on the genuineness of this
Time since onset of SSPE (months) apparent result. Despite the great difficulties which
would be entailed in conducting a randomised
comparative trial in this rare disease it is the only
Fig. 5. Cumulative proportion (± standard error) of patient way that this doubt can be resolved.
survival for rapidly developing [10 inosine pranobex-treated
(_._ .) and 6 non-treated patients (....... )) and slowly developing
[9 inosine pranobex-treated (-) and 7 non-treated patients
3.3 Acquired Immunodeficiency Syndrome
(---)) subacute sclerosing panencephalitis (SSPE) (after DuRant and Persistent Generalised Lymphadenopathy
& Dyken 1983).
For a definition of the clinical characteristics of
the various manifestations of LAV/HTLV-III in-
ment onset (12.5 months after diagnosis); the mean fection (persistent generalised lymphadenopathy,
disability at this time was approximately 40% AIDS-related complex and frank AIDS) see FDA
among the inosine pranobex group but was greater Drug Bulletin (1985).
than 55% in the control patients. Treatment with inosine pranobex may improve
Thus, although inosine pranobex appears to have the immune function of immunodepressed patients
Inosine Pranobex: A Preliminary Review 412

Inosine pranobex 3 g/day has been used in 75

patients with AIDS who were included in a 'com-
passionate use' protocol in the US, the preliminary
findings of which are presented in table XIII. How-
ever, the lack of a control group or even a sub-
stantial body of evidence on the natural history of
the disease make interpretation of these results dif-
ficult.

3.4 Genital Warts

The efficacy of both orally and topically ad-

Fig. 7. Percentage of immunologically depressed male patients
with persistent generalised lymphadenopathy experiencing im-
ministered inosine pranobex has been assessed in
provement or deterioration in clinical symptoms and well-being the treatment of genital warts. In open studies en-
among those administered inosine pranobex 1 or 3g daily (43 couraging cure rates have been reported for the 20%
patients; _) or placebo (18 patients; II) for 28 days and then topical cream applied 4 times daily for 8 to 10 days
assessed 1 and 6 months after initiation of treatment (Bekesi
(3 of 5 patients cured) [Zagni & Cannarozzo 1982]
1984; Wallace 1984; unpublished data on file, Newport Phar-
maceuticals). Related cumulated data available in Wallace & Be-
and for a 5-day oral course, in a total daily dose
kesi (1986). of 3g, repeated monthly for 1 to 6 months (24 of
31 women cured) [Malgouyat 1983]. However, the
with the AIDS-related complex or persistent gen- results of open studies must be interpreted with
eralised lymphadenopathy, but has not been shown caution because the natural history of genital warts
to influence the immunological status of patients is unpredictable and a considerable number of
with AIDS (see section 1.2.5). patients will show spontaneous regression.
In a placebo-controlled study in immunologi- Three studies have compared inosine pranobex
cally depressed homosexual males with persistent with conventional treatments (podophyllin,
generalised lymphadenopathy, a total oral daily cryotherapy, electrocautery, CO 2 laser and surgery)
dosage of inosine pranobex 1 or 3g administered in the treatment of genital warts (table XIV). In
for 28 days also appeared to stimulate positive non-pregnant women, inosine pranobex Ig admin-
clinical effects (Bekesi et al. 1984; Wallace & Be- istered orally 4 times daily for 30 days (24 women)
kesi 1986; unpublished data on file, Newport Phar- appeared to be more effective than the application
maceuticals; Wallace 1984). A greater percentage of of 20% inosine pranobex ointment topically 4 times
drug-treated patients than placebo patients had an daily for 30 days (24 women), similar in efficacy
improvement in qualitatively assessed clinical to the coadministration of oral and topical inosine
symptoms and sense of wellbeing (fig. 7). However, pranobex for 30 days (24 women) and less effective
while 'cumulative' clinical improvement scores than surgical removal of the warts (12 women)
(based on weight gain, fever, night sweats and [Signorelli et al. 1982]. The authors concluded that
lymphadenopathy) were significantly (p < 0.05) the advantage of oral or topical treatment over
greater for drug-treated than for placebo-treated hospitalisation and anaesthesia make inosine pra-
patients, these results included patients lost to fol- nobex a valid therapy. However, the statistical sig-
low-up who were assumed to have had no further nificance of the results of the study was not re-
change in clinical condition. Additionally, the ac- ported. In heterosexual men and non-pregnant
tual clinical benefit was only slight and was not women Mohanty and Scott (1985, 1986) found that
statistically significant (table XII) and there were the cure rate for inosine pranobex Ig administered
no statistically significant effects on bodyweight or orally thrice daily for 4 weeks was not significantly
lymph node size when assessed separately. different from the rate for conventional treatments
Inosine Pranobex: A Preliminary Review 413

Table XII. Clinical improvement scores (CIS) and 'cumulative' clinical improvement scores (CCIS) in a double-blinded placebo-con-
trolled study of inosine pranobex (IP) 3g or 1g daily in immunologically depressed homosexual male patients with persistent gen-
eralised lymphadenopathy (Bekesi & Wallace. unpublished data on file, Newport Pharmaceuticals; Wallace & Bekesi 1986)

Interval" Results b
(days)
IP 3g daily IP 19 daily placebo

CIS CCIS CIS CCIS CIS CCIS

28 0.43 0.43" 0.18 0.18 0.00 0.00

90 0.00 0.43 0.18 0.36 0.00 0.00

180 0.61 0.95"" 0.25 0.59 0.00 0.00

360 0.16 1.09 -0.31 0.36 0.22 0.20

a Active drug or placebo was administered for the first 28 days.

b Clinical improvement was characterised by an increased sense of well-being and appetite, and a reduction of lymph node pain,
night sweats, weight loss, skin rashes and thrush-associated discomfort. Scores were defined as: 2 = improved; 1 = slightly
improved; 0 = same or no data; -1 = slightly worse; -2 = worse. The apparent discrepancy between the values for CIS and
CCIS is due to the fact that it was assumed that there was no further change in patients who were lost to follow-up and so
these patients are included in the cumulative data.
Key: " = p < 0.05; "" = P < 0.01.

Table XIII. Preliminary clinical findings of the open use of inosine pranobex 3g daily in patients with AIDS (unpublished data on file,
Newport Pharmaceuticals)

Number of patients (duration of treatment)

28 days 60 days 90 days 180 days

Improved" 2 (3%) 7 (15%) 6 (16%) 3 (30%)

Stable b 48 (78%) 33 (69%) 24 (65%) 6 (60%)
Worse 12 (19%) 8 (16%) 7 (19%) 1 (10%)

Total 62 48 37 10

a Improvement was defined as the reduction of Kaposi's Sarcoma lesions, weight gain or the return of skin anergy.
b Stabilisation was defined as no additional weight loss, no opportunistic infections and no further advancement of Kaposi's Sar-
coma.

(usually podophyllin or cryotherapy). In the patients that obtained with the conventional treatment alone
cured by inosine pranobex the warts had been pre- (41%). Similarly, Sadoul and Beuret (1984) re-
sent for a significantly (p < 0.001) longer duration ported a greatly increased cure rate with the com-
(mean 39 weeks) than in the patients who failed to bination of oral inosine pranobex plus a single
respond to the drug (14 weeks); the reverse was course of CO 2 laser treatment (94%) versus the cure
true of patients who were cured by (13 weeks) or rate with the single CO 2 laser treatment alone (55%).
failed to respond to (31 weeks) conventional treat- Unfortunately, these 3 comparative studies were
ments. Importantly, the combined use of oral in- not blinded, lacked placebo controls and discussed
osine pranobex, plus podophyllin or cryotherapy neither compliance to therapy and to the preven-
treatment, greatly increased the cure rate (94%) over tion of reinfection nor the comparability of treat-
Inosine Pranobex: A Preliminary Review 414

Table XIV. Studies comparing the clinical efficacy of oral (po) and topical inosine pranobex (IP) with that of conventional treatments
[podophyllin (P), cryotherapy (C), electrocautery (E), CO2 laser (C02 L) and surgery (S)] in patients with genital warts

References Treatment No. of pts Results

interval to no. of pts no. of pts other (%)

assessment cured (%) failed (%)
(months)

Mohanty & Scott IP 19 po tid x 4 wks 36 6 14 (39)1 13 (36) 9 pts relapsed

(1985); unpublished (17M/19F) NS (25)
data on file, Conventional 91 6 37 (41) 48 (52) 6 pts relapsed (7)
Newport Pharma- therapy (P, C or E) (48M/43F)
ceuticals· IP 19 po tid x 4 wks 38 6 36 (94) 1 (3) 1 pt relapsed (3)
plus P, C or E (20M/18F)

Sadoul & Beuret IP 3g po daily x 5d 64F 6 1 C02 L: 60 (94) 0

(1984) monthly for 3 mo + 2 C02 L: 2 (3)
1-3 C02 L treatments 3 CO 2: 4 (6)

1-3 C02L treatments 64F 6 1 C0 2L: 34 (55) 10 (16)

2 C02 L: 16 (26)
3 C02L: 4 (6)

Signorelli et al. IP 19 po qid x 30d 24F 10 (42) 4 (17) 10 pts improved

(1982) (42)
IP 20% ointment qid 24F 4 (17) 6 (25) 14 pts improved
x 30d (58)
IP 19 po plus IP 20% 24F 11 (46) 2 (8) 11 pts improved
ointment qid x 30d (46)
Conventional 12F 11 (92) 0 1 pt improved (8)
therapy (5)

a The first 65 patients were treated with conventional therapy and then an additional 165 patients were randomised to receive
either inosine pranobex, conventional therapy or both.
Abbreviations: M = male; F = female; tid = 3 times daily; qid = 4 times daily; d = day; wk = week.

ment groups as to age and duration and severity virus, inosine pranobex 4 to 5 gjday altered neither
of infection (except for the analysis by Moh~nty & the incidence of illness nor seroconversion (table
Scott of the relationship of duration of infection to XV). However, in 2 of the 4 studies viral shedding
cure rate). The high cure rates obtained with the was significantly (p < 0.05) decreased in the drug-
combined use of oral inosine pranobex plus con- treated volunteers (Betts et al. 1978; Longley et al.
ventional non-surgical treatment of genital warts 1973), and 3 of the studies reported significantly
are highly encouraging; their confirmation in well (p < 0.05) reduced symptomatology amoBg the in-
designed comparative trials will be awaited with osine pranobex group (Betts et al. 1978; Khakoo et
interest. al. 1981; Schiff et al. 1978).
While treatment with inosine pranobex in a total
3.5 Influenza and Rhinovirus Infections daily dose of 6g had no significant effect on the
clinical course and serology of experimental infec-
In double-blind placebo-controlled studies in tion due to rhinovirus 44 or rhinovirus 32, a total
volunteers challenged intranasally with influenza daily dose of 4g effected a significantly lower in-
Table XV. Results of double-blind placebo (P)-controlled trials of inosine PJanobex (IP) in volunteers with experimental Influenza infection ....::s
0
!!J.
References Challenge virus No. of Total inosine pranobex daily Results ::s
tD
volun- dosage (duration, in days)
teers no. ill signs and viral antibody titres or ~
::s
symptoms shedding seroconversion
(%) [
Influenza
>
Betts et al. (1978) A/Victoriaf74 33 4g (6) starting 24h post- IP < p. IP < p. IP = P ~
~
challenge (days 3 + 4) (nasal) 8
S·
~
Khakoo et al. A/Dunedinf73 26 4g (9) starting 48h pre- IP (PR) = IP (T) [IP (PR) = IP (T)] IP (PR) = IP (T) IP (PR) = IP (T)
(1981) challenge [prophylactic (PR)] =P < p. =P =P
or 48h post-challenge (days 4, 5 + 6) (throat) ~
[therapeutic (T)] ~.

Longley et al. A/Hong Kong/58 30 5g (10) starting IP = P IP = P IP < p. IP = P

(1973) 48h pre-challenge (throat)

Schiff et al. (1978) A/Dunedinf73 <3oa 4g (6) starting liP> l p.

24h post-challenge (days 2, 3 + 4)

Rhinovirus
Pachuta et al. Rhinovirus 44 17 6g (9) starting IP" P IP" P IP = P IP = P
(1974) 48h pre-challenge (nose)

Rhinovirus 32 20 6g (9) starting IP = P IP" P IPOI> P IP 01> P

48h pre-challenge (nose)

Waldman & Rhinovirus 21 39 4g (7) starting on [IP (e) = IP (T)] [IP (C) = IP (T)] IP (C) = IP (T) IP (C) = IP (T)
Ganguly (1977) challenge day (C) or 48h < p •• < p. =P =P
post-challenge (T)

a 30 volunteers were challenged but only those diagnosed as 'ill' by clinical assessment were included in the trial which assessed the comparative reduction in symp-
tomatology.
Key: d = days; h = hours; >, < statistically significant difference; " non-significant trend; = not significantly different;· p < 0.05;·· P < 0.01.
-
"..
VI
Inosine Pranobex: A Preliminary Review 416

cidence (p < 0.01) and severity (p < 0.05) of rhi- bran 1983; Bonvoisin et al. 1983; Bouvier et al.
novirus 21 infection (vs placebo) [table XV]. 1983; Segond et al. 1982; Wybran et al. 1981).

3.6 Viral Hepatitis 3.8 Other Diseases and Infections

In a double-blind study, patients with HBsAg- In a double-blind placebo-controlled study, the

positive acute hepatitis were administered either mortality rate was significantly lower among 100
inosine pranobex 6 g/day for a mean duration of patients with tropical measles who were admini-
28 days (30 patients) or placebo (29 patients) stered inosine pranobex 100 mg/kg daily for 1 to
[Scasso et al. 1983]. The 2 groups were comparable 12 days compared with patients administered pla-
as to clinical symptoms and signs, and haemato- cebo (6% vs 15%; p < 0.025). There was no statis-
logical and immunological parameters. After 4 tically significant difference in the clinical course
weeks of therapy the inosine pranobex group had between the groups (Gallais et al. 1981). Similar
significantly (p < 0.05) less asthenia, anorexia and results were obtained in a non-blinded compara-
splenomegaly, lower total bilirubin, AST, ALT and tive study against untreated controls in 200 patients
alkaline phosphatase concentrations, and greater in a tropical area who had simple or complicated
well-being. There was no statistically significant measles (Samba-Lefebvre 1981). In contrast, a
difference in abdominal malaise, nausea or hepa- double-blind study of ordinary measles found no
tomegaly. 90 days after the start of therapy a sig- significant difference in the clinical course or mor-
nificantly (p < 0.05) greater number of inosine pra- tality rate between 40 patients administered ino-
nobex-treated patients were HBsAg-negative (see sine pranobex 50 mg/kg per day and 30 patients
section 1.2.7). administered placebo (Onoura et al. 1982).
Other double-blind studies compared inosine A double-blind placebo-controlled study re-
pranobex with placebo in acute viral hepatitis. Two ported no statistically significant therapeutic ef-
of these found that inosine pranobex-treated fects when 25 patients with well substantiated
patients had a more rapid decrease in AST and amyotrophic lateral sclerosis were administered in-
ALT values (Zola et al. 1982; unpublished data on osine pranobex 3 to 6g daily for 3 months (Fareed
file, Newport Pharmaceuticals), but Lam et al. & Tyler 1971). Similar results were reported in a
(1978) found no statistically significant advantage second double-blind placebo-controlled study as-
of inosine pranobex over placebo. Unfortunately, sessing 14 patients given inosine pranobex 4 to 6g
the results for patients with various forms of hep- daily for 4 to 6 months (Percy et al. 1971).
atitis (A, B or non-A/non-B), having different prog- Inosine pranobex has been reported to lower the
noses, were not reported separately in these 3 stud- incidence of infection in elderly, seriously ill, sur-
ies. gical and burn patients. 50 elderly institutionalised
patients were included in a double-blind placebo-
3.7 Autoimmune Diseases controlled assessment of inosine pranobex 4g daily
for 90 days. The 2 groups of patients were com-
In open studies inosine pranobex 25 to 50 mg/ parable as to age and sex, and appeared compar-
kg and 1.5 to 3g daily has been reported to be as- able as to underlying diseases and pathology. Dur-
sociated with positive clinical effects in a few ing the third month of therapy the treated patients
patients with psoriatic arthritis, Reiter's syndrome showed a significant reduction in the mean num-
(Appleboom & Wybran 1983), aphthous stomatitis ber (0.2 vs 0.52; p < 0.05) and duration (4 vs 6.7
(Wybran & Schandene 1984) and alopecia (Gal- days; p < 0.01) of respiratory and/or urinary tract
braith et al. 1984; Lowy et al. 1985). Conflicting infectious episodes (Meroni et al. 1984). In a
results have been reported as to the efficacy of the double-blind study of surgical patients, inosine
drug in rheumatoid arthritis (Appelboom & Wy- pranobex 4g daily for 14 days (n = 23) resulted in
Inosine Pranobex: A Preliminary Review 417

a lower incidence of infection than that among 23 pranobex in patients with recurrent Herpes sim-
placebo-treated patients (13 vs 39%) [Nanni et al. plex genitalis, 34 drug-treated patients received a
1982]. In addition, 23 seriously ill patients admin- total daily dosage of 3g for 5 days for each recur-
istered inosine pranobex 8g daily for 14 days had rent episode of the disease. A prophylactic dosage
a lower incidence of infection (52.5 vs 76.8%) and of Ig daily (in 2 divided doses) was given between
mortality (34.7 vs 61. 7%) than 34 placebo-treated episodes. There was a statistically significant (p =
patients (Delogu et al. 1982). However, statistical 0.003) increase in the serum uric acid concentra-
analyses of the results of the latter 2 studies were tion of male patients treated with the drug, but the
not provided. Among 10 severely burned patients increase of uric acid in female patients was not sta-
administered inosine pranobex 70 to 100mg daily tistically significant. There were no significant ab-
for 8 days mortality was 10% and septic compli- normalities of purine metabolism, hepatic function
cations occurred in 4 patients; among 10 un- or haematological indices (Wickett et al. 1984).
matched severely burned control patients the mor-
tality rate was 30% and septic complications 5. Dosage and Administration
occurred in 9 patients (Donati et al. 1983).
Case studies of patients with progressive rubella The recommended adult oral dosage of inosine
panencephalitis have been reported describing pranobex is Ig (2 tablets) 4 times daily. In children
beneficial clinical effects in 1 patient (Laszlo et al. the usual oral dosage is 50 mgjkg per day, given
1984) and continued deterioration in 3 other in divided doses throughout the normal waking
patients (Jan et al. 1979; Wolinsky et al. 1979) ad- hours. Dosages up to a maximum of 100 mg/kg
ministered inosine pranobex. daily administered in 4 to 6 equally divided doses
Clinical benefits from treatment with inosine may be administered.
pranobex have also been suggested in patients with Caution should be observed in treating patients
tuberculosis (Tanphaichitra & Panupornprapongs with gout, urolithiasis or kidney dysfunction be-
1981), mollusca contagiosa (Gross et al. 1986) and cause of the slight transient increases in serum uric
multibacillary leprosy (Saint-Andre et al. 1982), but acid concentration that the drug may produce.
not in patients with Paget's disease of bone (Kanis Monitoring of serum uric acid concentrations is
et al. 1985). recommended in these patients.

4. Side Effects 6. Place of Inosine Pranobex in Therapy

Human tolerance studies both in healthy indi- Inosine pranobex has been assessed most exten-
viduals and patients have uniformly shown that in- sively in Herpes simplex genitalis and labialis, and
osine pranobex is free from serious side effects encouraging clinical results have been reported. The
(Glasky et al. 1975). Continued drug administra- drug has been reported to be clinically useful in
tion for periods of up to 7 years, in doses ranging subacute sclerosing panencephalitis, but the use of
from 1 to 8 g/day has produced only occasional historical controls indicates the need for caution in
transient nausea. This nausea has been associated interpreting the validity of these results. In the
with the large number of tablets ingested. In ad- treatment of genital warts the combined use of oral
dition, a transient rise of serum and urinary uric inosine pranobex plus conventional non-surgical
acid concentrations has been reported. This is due treatment resulted in greatly increased cure rates
to the degradation of inosine to uric acid as occurs versus the rates for conventional treatment alone;
in the metabolism of the natural purine (see sec- confirmation in well designed comparative trials
tion 2). will be awaited with interest. Individual double-
In a double-blind placebo-controlled study of the blind placebo-controlled studies in immunologi-
short to long term (10 to 90 days) safety of inosine cally depressed homosexual men with persistent
Inosine Pranobex: A Preliminary Review 418

Facteurs inhibant Ie chimiotactisme au cours des maladies im-

generalised lymphadenopathy, in patients with munoproliferatives: antagonisme in vivo de I'isoprinosine.
zoster or type B viral hepatitis and in elderly in- Medicine et Hygiene 42: 136, 1984
stitutionalised patients subject to respiratory and/ Azzara A, Vatteroni ML, Petrini M, Polidori R, Bruschi F, et al.
Methisoprinol (viruxan): restoration of leukocyte chemotaxis
or urinary tract infections have reported statisti- inhibited by sera from patients with Hodgkin's disease. In Per-
cally significant clinical benefits with the use of in- itti P & Grassi GO (Eds) Current Chemotherapy and Immu-
notherapy. Proceedings of the 12th International Congress of
osine pranobex. No therapeutic benefit has been Chemotherapy, Florence, July 1981, pp. 1193-1194, American
obtained in patients with amyotrophic lateral scle- Society for Microbiology, Washington DC, 1982a
Azzara A, Margelli M, Caracciolo F, Petrini M, Carulli G, et al.
rosis and conflicting results have been reported in Methisoprinol restoration of chemotactic functions in neutro-
controlled comparative studies in patients with phils from patients with recurrent infections: in vitro and in
vivo observations. Recent Advances on Immunomodulators,
measles or experimentally induced rhinovirus in- Viareggio, Italy, May 14-16, 1982b
fection. In patients with experimentally induced Balestrino C, Montesoro E, Nocera A, Ferrarini M, Hoffman T.
Augmentation of human peripheral blood natural killer activ-
influenza the drug improved symptomatology but ity by methisoprinol. Journal of Biological Response Modifiers
generally neither the incidence of illness nor sero- 2: 577-585, 1983
Ballet JJ, Morin AM, Agrapart M. Modulation of isoprinosine of
conversion was affected. the activation, differentiation, and antigen specific responses
Thus, while inosine pranobex may prove to be of human lymphocytes in vitro. 4th International Congress of
Immunology, Paris, July 21-26, 1980
a valuable and innovative therapy for a number of Ballet JJ, Morin A, Schmitt C, Agrapart M. Effect of isoprinosine
diseases and infections for which currently no sat- on in vitro proliferative responses of human lymphocytes stim-
ulated by antigen. International Journal of Immunopharrna-
isfactory therapies exist, the data available at pre- cology 4: 151-157, 1982
sent needs confirmation with additional well de- Bekesi JG, Wallace 11, Roboz JP, Tsang PH, O'Brien EO. In vitro
and in vivo immunorestorative effects of isoprinosine in hom-
signed studies which have been subjected to the osexual subjects with prodromata of AIDS. Abstract. 6th Euro-
critical review of publication in full. The tempta- pean Immunology Meeting, Interlaken, 1984
Bene MC, Faure G. Immunomodulatory effect of isoprinosin in
tion can be strong to use a non-toxic drug of pos- vitro. 3rd International Conference on Immunopharrnacology,
sible therapeutic benefit in a fatal and/or debili- Florence, May 6-9, 1985. Abstract no. 67. International Con-
ference on Immunopharrnacology 7: 317, 1985
tating disease, such as SSPE or AIDS, or even in Benedetti M, Amanti C, Midiri G. Comparative evaluation be-
a merely painful, recurring and/or psychologically tween total parenteral nutrition and methisoprinol as
immunomodulating agents in cancer patients. Drugs Under
traumatic disease, such as herpes genitalis or la- Experimental and Clinical Research 10: 471-478, 1984
bialis, against which the practitioner feels power- Berkman N, LeGoix H, Moubri M, de Saxe E. Action favorable
de I'isoprinosine au cours des affections oculaires virales et
less. However, the interests of the patients would inflammatoires. Nouvelle Presse Medicale 8: 3829-3830, 1979
be better served by inclusion into well-designed and Betts RF, Douglas Jr RG, George SO, Rinehart CJ. Isoprinosine
reported randomised studies which would resolve in experimental influenza A infection in volunteers. Abstract.
78th Annual Meeting of the American Society for Microbio-
the doubts and firmly establish the place of the drug logy, Las Vegas, May 14-19, 1978
in therapy. Binderup L. Effect of isoprinosine in animal models of depressed
T-cell function. International Journal of Immunopharrnacol-
ogy 7: 93-101, 1985
Bonvoisin B, Sidot C, Touraine JL, Touraine F, Bouvier M. Mod-
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