Isoprinosine. Anti-Aging-Guide -- Your plan to stay young

No To Hattatsu. 2004 Jan;36(1):70-4.
Five patients with subacute sclerosing panencephalitis treated with intraventricular alpha-interferon and inosinpranobex.
Oshiro S, Minema H, Shiroma N, Hirayasu K, Nakada Y.
Department of Pediatrics, Okinawa Seishi Ryogoen, Naha, Okinawa.
We followed up 5 patients with subacute sclerosing panencephalitis (SSPE) for 14 to 81 months. They were treated with alpha-interferon (INF-alpha) and oral inosinpranobex (INP) in an early stage of Jabbour stage II and within 5 months after the onset. On admission, Ommaya reservoir was implanted for the intrathecal administration of INF-alpha. The dose was 1 x 10(5) U/m2 initially and daily increased to 1 x 10(6) U/m2. A total dose of 30 x 10(6) U/m3 was given to them over a 4-weeks to 6-weeks period. After discharge, a dose of 15 x 10(6) U/m2 in three patients was given weekly and a dose of 30 x 10(6) U/m2 in the other patients. In addition, all patients received oral INP. One patient showed mild progression and remained in early stage of Jabbour stage II. In the remaining 4 patients, the disease progressed to Jabbour stage III. Despite the small number of patients studied here, the results suggest that treatment with INF-alpha plus oral INP is ineffective in an early stage of SSPE.

J Helminthol. 2001 Sep;75(3):251-7.
In vitro effects of isoprinosine and a dipeptide methyl ester on Echinococcus multilocularis protoscoleces.
Lawton P, Walchshofer N, Sarciron ME.
Departement de Parasitologie et Mycologie Medicale, Faculte de Pharmacie, Lyon, France.
A protoscoleces/vesicles in vitro maintenance test with assessment of viability by eosin exclusion was used to evaluate the quantitative and qualitative activities of isoprinosine, its active component inosine and the dipeptide methylester L-Phe-Phe-OMe on isolated protoscoleces of Echinococcus multilocularis for 24 and 48 h. Isoprinosine and inosine showed dose- and time-dependent activity, the latter displaying a more rapid effect than the former. A high activity was shown with L-Phe-Phe-OMe, when compared to praziquantel. Ultrastructural alterations were much more striking with L-Phe-Phe-OMe, with an effect similar to that of praziquantel, whereas the chemotherapeutic activity of inosine and isoprinosine appeared to be directed against a metabolic target, with a lethal effect not immediately visible at the ultrastructural level. Thus, the previously reported in vivo activities of these drugs result largely from a direct effect on the parasite.

Int J Antimicrob Agents. 2000 Apr;14(3):181-91.
Immunomodulatory agents for prophylaxis and therapy of infections.
Masihi KN.
Robert Koch Institute, Nordufer 20, D-13353, Berlin, Germany.
The advent of the antibiotic era ushered in a shift towards non-pathogen-specific therapy of infectious diseases. This led to an overt emphasis on targeting microbial pathogens while strategies directed towards enhancing host immunity were neglected. In an effort to decrease sole reliance on antimicrobials, the time has come for a critical reappraisal of nonantibiotic, albeit immune response-enhancing substances. The diverse array of natural, synthetic, and recombinant immunomodulators discussed in this review succinctly demonstrate the potential of these agents to stimulate host defense mechanisms for prophylaxis and treatment of various microbial infections.

JAMA. 2000;284:1931-1938.
The June 21 issue of the New England Journal of Medicine

The June 21 issue of the New England Journal of Medicine reports a randomized, placebo-controlled trial of inosine pranobex (isoprinosine), an experimental immunomodulating agent. The study involved 866 persons infected with HIV, the AIDS virus, in Sweden and Denmark. The report suggests that patients in the isoprinosine arm of the trial were significantly less likely to progress to AIDS than those patients in the placebo arm of the trial. According to this report, during the 24-week trial, 17 patients in the placebo arm progressed to AIDS as opposed to 2 patients in the isoprinosine arm. Although the raw data from this study have not been submitted for review to FDA by the drug's sponsor, Newport Pharmaceuticals Inc. of Laguna Beach, Calif., the FDA's division of antiviral drug products has reviewed the report. The division prepared a response to the study report which also appears in the same issue of the journal. The division's response expresses a number of concerns about this study and other studies conducted on isoprinosine, and states its belief that more clinical investigation of this drug is needed before its value to patients can be well enough evaluated to decide whether, and on whom, it should be used. -MORE- Page 2, isoprinosine, T90-26 Isoprinosine has been under development as a treatment for HIV-infection for approximately 5 years. Previous studies of isoprinosine's effectiveness in delaying or preventing the onset of AIDS in HIV-infected patients conducted in the U.S. and other countries have not demonstrated that the drug had any significant effect in slowing disease progression in treated patients. For example, the company reported in November of 1988 that a multicenter trial of the drug involving 696 HIV-infected patients in the U.S. and the U.K. showed no significant benefit in those treated with isoprinosine as opposed to those given placebo. The sponsor is currently reanalyzing data from this study in order to evaluate why it produced a different result than the Scandinavian trial. There are also some issues concerning the design and analysis of this latest Scandinavian study of isoprinosine. For example, the classification system for determining endpoints was changed during the course of the study was one of a number of changes in the study's implementation and analysis that may have affected the study results, and may require additional, balanced assessment. An editorial in the journal written by members of FDA's division of anti-viral drug products also notes that the 24 weeks of the trial is a relatively short study period. FDA believes that additional clinical testing should be conducted. These could incorporate the use of pneumocystis prophylaxis and retroviral treatments that have recently been developed as standard therapies for HIV-individuals, in order to determine how isoprinosine therapy, if proven effective, could be maximized in today's current therapeutic scene.

J Neurol Neurosurg Psychiatry. 1994 Feb;57(2):164-8.
A placebo-controlled trial of isoprinosine in patients with multiple sclerosis.
Milligan NM, Miller DH, Compston DA.
Department of Neurology, University Hospital of Wales, Heath Park, Cardiff, UK.
Isoprinosine was used under double-blind, randomised, and placebo-controlled conditions in 52 patients with relapsing/remitting or progressive multiple sclerosis. All patients received pulsed treatment with methylprednisolone. There was no significant effect of treatment on clinical disability or the accumulation of MRI abnormalities, after correction of results for multiple comparisons. It is concluded that isoprinosine is not effective therapy for multiple sclerosis.

Ugeskr Laeger 1994 May 30;156(22):3314-8.
Controlled, clinical trial of isoprinosine administration to HIV-infected patients. Results of a Danish/Swedish multicenter study. The Scandinavian Isoprinosine Study Group.
Thorsen S, Pedersen C, Sandstrom E, Petersen CS, Norkrans G, Gerstoft J, Karlsson A, Christensen KC, Hakansson C, Pehrson PO, et al.
Infektionsmedicinsk afdeling, Hvidovre Hospital, Kobenhavn.
The safety and efficacy of isoprinosine in HIV-infected individuals were assessed in a multicentre, randomized, double-blind, 24-week study phase, followed by an optional 24-week open treatment phase. The results of the double-blind phase have been reported separately. Of 866 HIV-seropositive individuals randomized, 832 were eligible for efficacy analysis. On completion of the double-blind phase, 596 patients started open treatment. All patients were evaluated with regard to progression to AIDS. Within 48 weeks, 10/412 patients (2.4%) assigned isoprinosine and 27/420 (6.4%) assigned placebo progressed to AIDS (p = 0.005; odds ratio: 2.8, 95% CI: 1.3-6.2). Intention-to-treat analysis showed identical results. No severe adverse reactions or toxicities were observed. We conclude that HIV-infected individuals without AIDS may be safely and effectively treated with isoprinosine.

Antimicrob Agents Chemother. 1993 Jun;37(6):1227-31.
Inhibition of Pneumocystis carinii dihydropteroate synthetase by para-acetamidobenzoic acid: possible mechanism of action of isoprinosine in human immunodeficiency virus infection.
Kovacs JA, Powell F, Voeller D, Allegra CJ.
Critical Care Medicine Department, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Isoprinosine has been reported to decrease progression to AIDS, primarily by preventing Pneumocystis carinii pneumonia (PCP), in human immunodeficiency virus-infected patients, but the mechanism of action is unknown. para-Acetamidobenzoic acid (PAcBA), one component of isoprinosine, is structurally related to para-aminobenzoic acid (PABA), a precursor of de novo folate synthesis. This pathway is known to be important for P. carinii because sulfonamides, which are effective anti-P. carinii agents, inhibit incorporation of PABA into folate precursors by the enzyme dihydropteroate synthetase (DHPS). Inhibition of P. carinii DHPS by PAcBA was investigated by using two assays. In short-term cultures of P. carinii from rats, [3H]PABA incorporation into reduced folates was inhibited by both isoprinosine (mean +/- standard error 50% inhibitory concentration [IC50], 20 +/- 8.4 microM) and PAcBA free acid (IC50, 240 +/- 100 microM); a soluble PAcBA salt was more potent than PAcBA free acid alone (IC50, 29 +/- 48 microM). The activity of PAcBA free acid was confirmed in a cell-free DHPS inhibition assay (IC50, 120 +/- 120 microM). Inosine and dimethylaminopropanol, two other components of isoprinosine, were poor inhibitors of PABA incorporation (IC50, > 1,000 microM). PAcBA free acid also showed activity in inhibiting the DHPS of Toxoplasma gondii, but was a poor inhibitor of the DHPSs of Escherichia coli and Saccharomyces cerevisiae. In a rat model of PCP, the PAcBA salt administered intraperitoneally demonstrated no activity against established PCP either alone or when used in combination with trimethoprim; the lack of efficacy in this model may be due to the rapid metabolism of the drug. Prevention of PCP by PaCBA through inhibition of P. carinii DHPS may explain the activity of isoprinosine in decreasing the progression to AIDS in human immunodeficiency virus-infected patients.

Orv Hetil. 1993 May 9;134(19):1015-9.
Isoprinosine therapy in chronic hepatitis C (multicenter placebo-controlled double-blind prospective study).
Par A, Bero T, Brasch G, Gogl A, Kamaras G, Mehesfalvi E, Ozsvar Z, Paal M, Szipocs I, Telegdy L.
Pesci Orvostudomanyi Egyetem I. Belgyogyaszati Klinika, Pecs.
A placebo controlled clinical trial. Thirty two patients with chronic C hepatitis have been enrolled in a double blinded study to assess the therapeutic effect on an orally given antiviral-immunomodulatory drug, Isoprinosine. Seventeen patients were given Isoprinosine (3 g/day) and fifteen were on placebo. The treatment has been lasted for four months, when patients examined monthly. Clinical signs, liver function tests and side effects were evaluated. At the end of the trial, side effects and elevated serum alanine aminotransferase (ALT/GPT) levels occurred with higher frequency in Isoprinosine-treated patients. The results show that this antiviral drug has no beneficial effect in chronic C hepatitis.

J Intern Med. 1992 Jun;231(6):607-15.
One-year follow-up on the safety and efficacy of isoprinosine for human immunodeficiency virus infection. Scandinavian Isoprinosine Study Group.
Thorsen S, Pedersen C, Sandstrom E, Petersen CS, Norkrans G, Gerstoft J, Karlsson A, Christensen KC, Hakansson C, Pehrson PO, et al.
Department of Infectious Diseases, Hvidovre Hospital, Copenhagen, Denmark.
The safety and clinical impact of isoprinosine in HIV-infected individuals were assessed in a multicentre, randomized, double-blind, 24-week study phase, followed by an optional 24-week open treatment phase. The results of the double-blind phase have been reported. Of 866 HIV-seropositive patients randomized, 832 subjects were eligible for efficacy analysis. On completion of the double-blind phase, 596 patients started open treatment. All patients were evaluated with regard to progression to AIDS and/or death. Within 48 weeks, 10/412 (2.4%) patients assigned isoprinosine and 27/420 (6.4%) patients assigned placebo progressed to AIDS (P = 0.005). Intention-to-treat analysis showed identical results. Viewing the open treatment phase in isolation revealed no difference in progression rates between those treated and those not receiving the drug, perhaps reflecting the higher proportion of patients receiving zidovudine or PCP prophylaxis in the latter group. No severe adverse reactions or toxicities were observed. We conclude that HIV-seropositive patients without AIDS may be safely and effectively treated with isoprinosine.

Przegl Epidemiol. 1991;45(4):267-71.
Effect of isoprinosine and acyclovir on the clinical course of chickenpox and herpes zoster.
Janeczko J, Baranowska M, Romanowska B.
Klinika Chorob Zakaznych dla Doroslych Instytutu Chorob Zakaznych, Pasozytniczych Akademii Medycznej, Warszawie.
The therapeutic effect of isoprinosine and acyclovir have been studied in 352 and 284 patients with chicken-pox and herpes zoster respectively. The patients were divided into 4 groups: the first one was given palliative treatment only, the second--both palliative and isoprinosine ones, the third--palliative and acyclovir treatment, and the fourth group was given all these. The best therapeutic effect was achieved when acyclovir and isoprinosine was applied jointly, the one of acyclovir alone was less pronounced and that of isoprinosine only was the smallest. According to the authors acyclovir should be the treatment of choice in the very severe and severe cases of chicken-pox and herpes zoster; in the early stage of disease it should be supplemented with isoprinosine and passive immunotherapy.

Z Gesamte Inn Med. 1990 May 15;45(10):294-6.
Immune modulating effect of isoprinosine in patients with post-alcoholic liver cirrhosis.
Boron-Kaczmarska A, Boron P, Puch U, Hryniewicz A, Bobrowska E.
Institut fur Klinische Physiologie, Klinik fur Infektionskrankheiten, Medizinischen Akademie Bialystok.
Immunomodulating effect of isoprinosine was estimated in group of 10 patients with postalcoholic liver cirrhosis and compared with another group of 10 patients with postinflammatory liver cirrhosis with infection of hepatitis B virus. Disturbances of immunologic reactivity in the patients with postalcoholic liver cirrhosis mainly concerned increased immunoglobulin G, A concentrations in the blood serum, decreased percentage values of lymphocytes T and their subpopulations (lymphocytes T4 and T8) and increased percentage of lymphocytes B. Disturbances of the examined indices of the immunologic reactivity in the group of patient with postinflammatory liver cirrhosis concerned increased concentrations of circulating immunologic complexes, immunoglobulins A and M in the blood serum and decreased percentage of lymphocytes T and their subpopulation. Treatment with isoprinosine resulted in different immunologic effect in the examined patients concerning mainly increased concentrations of circulating immunologic complexes in the blood serum and increased percentage values of lymphocytes T, T4, T8, B in the course of postalcoholic liver cirrhosis. Patients with postinflammatory liver cirrhosis treated with isoprinosine mainly showed decreased concentrations of circulating immunologic complexes, immunoglobulins A, M the blood serum, increased percentage values of lymphocytes T4 and T8.

Scand J Infect Dis. 1990;22(6):645-8.
Isoprinosine in the treatment of chronic active hepatitis type B.
Cianciara J, Laskus T, Gabinska E, Loch T.
Department of Hepatology, Institute of Infectious and Parasitic Diseases, Warsaw, Poland.
1 patients with chronic active hepatitis B (CAH-B) were treated for 1-2 years with isoprinosine, while another 18 patients served as control group. All patients were initially DNA polymerase (DNAp) and HBeAg positive. Nine (43%) treated patients became persistently negative for DNAp, seroconverted to anti-HBe and showed histological remission on follow-up biopsy. Among simultaneously followed controls 5 (28%) lost DNAp and 4 (22%) also lost their HBeAg. However, only 2 (11%) seroconverted to anti-HBe. Histological improvement was seen in 5 (28%) controls. Thus, it seems that isoprinosine may exert a beneficial effect on the course and outcome of CAH-B.

Z Rheumatol. 1988 Mar-Apr;47(2):113-6.
Isoprinosine in the early pre-erosive stage of rheumatoid arthritis: a pilot study.
Sadowska-Wroblewska M, Wroblewska-Graff T, Werynska-Przybylska J, Rell-Bakalarska M, Kurdybacha J.
Institute of Rheumatology, Warsaw, Poland.
The etiology of rheumatoid arthritis is unknown. Virus infection is one of alleged factors initiating the disease process. In view of this, the authors undertook a trial of administration of an antiviral and immunostimulating preparation - isoprinosine, given in the early phase of the disease prior to the development of erosions. Isoprinosine was given to ten seropositive cases of rheumatoid arthritis (two males, eight females) aged 34-61 years, with disease duration from 6 months to 5 years treated previously only with non-steroidal anti-inflammatory drugs. Isoprinosine was administered for 4 weeks (2 weeks of 3.0 g daily and 2 weeks of 1.5 g daily). After the treatment, a statistically significant reduction was observed in the number of joints painful on pressure, the number of swollen joints, and the duration of morning stiffness. The grip strength of the left hand was increased. The ESR and serum uric acid level were not changed significantly. The titre of Waaler-Rose reaction in four patients was decreased, in two it was increased, and in four it remained unchanged. No side effects were observed during the treatment. In the light of these observations it seems worthwhile to continue further studies on the action of isoprinosine in early rheumatoid arthritis.

Clin Immunol Immunopathol 1988 Jun;47(3):363-7.
Pharmacologic immunoenhancement in the elderly: in vitro effects of isoprinosine.
Delafuente JC, Panush RS.
Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville.
The loss of immune competence that occurs with aging may be responsible for increased morbidity and mortality in elderly individuals. Pharmacologic modulation of the immune response might reverse the immunologic aberrations associated with aging. We, therefore, investigated the effects of isoprinosine, an immunoenhancing drug, on selected in vitro immune responses in elderly subjects. Subjects studied were 65 years of age or older, and all had chronic diseases. We chose this population since they were at greatest risk for morbid events. Isoprinosine significantly enhanced mitogen-stimulated mononuclear cell proliferation, did not affect unstimulated cell growth, and needed to be present for the entire culture period for maximum effect. Isoprinosine is a potent in vitro immunoenhancing agent in aged humans.

Cancer Detect Prev. 1988;12(1-6):497-501.
Isoprinosine in the treatment of genital warts.
ONeill BB, Robins DS.
Newport Pharmaceuticals International, Inc., Newport Beach, California.
Several modes of therapy are presently available for treatment of genital warts. These include use of keratolytics such as podophyllin or trichloroacetic acid, electrocoagulation, cryotherapy, and laser therapy. Responses have not been uniformly successful, however, and particularly in patients with resistant warts there is evidence of impairment of cell-mediated immunity (CMI). In the healing process both humoral and CMI responses are of importance, and indeed it has been reported that in patients with recalcitrant viral warts the lesions disappeared at the same time the CMI response returned to normal. Isoprinosine is an orally administered drug known to have both in vitro and in vivo immunopotentiating activity and has been shown previously to restore toward normal the depressed CMI responses of diverse etiology accompanying a variety of clinical conditions. Recent evidence implicating certain types of genital warts in later development of cervical cancer in females has led to the search for a more effective treatment of this condition. Clinical studies to date involving the use of isoprinosine alone or in combination appear to have established the role of this safe and easily administered oral drug in increasing the chances of total eradication of condylomatous lesions and sparing a high percentage of patients from having to undergo repeated and more traumatic therapies.

Cancer Detect Prev Suppl. 1987;1:597-609. Unique Identifier : AIDSLINE MED/88080280
Isoprinosine (inosine pranobex BAN, INPX) in the treatment of AIDS and other acquired immunodeficiencies of clinical importance.
Glasky AJ; Gordon JF.
Newport Institute for Medical Research, Newport Beach, CA.
The immunopharmacologic effects of Isoprinosine (INPX) have been associated with clinical benefit to the patient in a number of conditions characterized by immunodeficiency of diverse etiology. Immunodepressed homosexuals at risk of developing acquired immunodeficiency syndrome (AIDS) treated with placebo or INPX experienced an increase in the function and number of immunocompetent cells associated with clinical improvement. A multicenter trial designed to confirm these results has demonstrated that INPX produced an increase in natural killer (NK)-cell activity, total T cells, and T-helper cells, with certain effects persisting for months after completion of the 28-day treatment period. INPX-treated patients also experienced clinical improvement and decreased incidence of progression to AIDS. The administration of INPX for longer periods to patients with frank AIDS under a compassionate-use protocol has also proved useful. Clinical benefit associated with INPX treatment has been demonstrated in other patients with a depressed immune response, such as aged patients, cancer patients, severely burned patients, ill patients, and surgery patients. This program of clinical trials supports the therapeutic use of INPX in the treatment of AIDS and other acquired immunodeficiencies of clinical importance.

Cancer Detect Prev Suppl. 1987;1:377-83.
Immunosuppressive effects of isoprinosine in man: a comparison to chlorambucil effects in multiple sclerosis.
Pompidou A, Rancurel G, Delsaux MC, Meunier C, Telvi L, Cour V, Buge A.
Laboratoire dAnatomie-Pathologique, Hopital Saint-Vincent de Paul, Paris, France.
Immunological and clinical functions were studied over a 2 year period in conjunction with a placebo controlled trial of isoprinosine and chlorambucil in 21 patients with exacerbating remitting multiple sclerosis. Laboratory and clinical evaluations were performed at 3 month intervals and during relapses. In placebo-treated patients, the decrease in circulating T8+ cells was maximum during relapses, T lymphocyte function was impaired, and five of the six patients experienced clinical worsening. Chlorambucil treatment was responsible for a decrease in circulating T4+ and T8+ cells; nevertheless, T lymphocyte function was slightly improved during relapses. The alterations of delayed hypersensitivity responses were not accompanied by improvement in relapse rate or in intensity and major side effects: mainly infections with leukopenia and thrombocytopenia. During isoprinosine therapy, a regulation of circulating T lymphocytes and cell proliferation occurred. The higher level of circulating T cells was related to the increase in T4+ and T8+ cells, which did not decrease during relapses. The absence of Leu 7+ cell modifications suggest that NK were numerically unaffected by isoprinosine therapy and that in vivo regulation of circulating T suppressor cells was performed by this treatment. Four out of seven patients did not experience any relapse during the duration of the trial. In relapsing patients, the frequency and duration of the relapses were significantly different from that of other patients. A reduction of the disease progression was observed without any side effects. While no conclusion can be drawn on the long-term effectiveness, the results of this pilot study are consistent indicators of the immunological and clinical beneficial effects of isoprinosine therapy in patients with exacerbating remitting multiple sclerosis.

Int J Immunopharmacol. 1985;7(2):199-206.
In vitro restoration of immune responses in aging humans by isoprinosine.
Tsang KY, Pan JF, Swanger DL, Fudenberg HH.

The in vitro effects of isoprinosine (ISO) on the immune responses of aging humans were investigated. 64 healthy elderly humans (65 yr of age or over) were included in this study. Four immune parameters were measured, namely, Concanavalin A (ConA)-induced lymphocyte proliferation, natural killer cell (NK) activity, neutrophil chemotaxis, and interleukin-2 (IL-2) production. The ConA-induced lymphocyte proliferation was depressed in 55 of the 64 individuals (85.9%%), while the NK activity was depressed in 41 of the 64 individuals (64%). Neutrophil chemotaxis was depressed in 52 of the 64 individuals (81.1%) and IL-2 production was depressed in 35 of the 64 individuals (54.6%). In the presence of ISO, ConA-induced lymphocyte proliferation, NK activity, neutrophil chemotaxis, and IL-2 production were restored to normal or near normal levels in 50 of the 55 (90.0%), 35 of the 41 (85.3%), 44 of the 52 (84.6%), and 25 of the 35 (71.4%) aging humans, respectively. Our results indicate that ISO acts as an immune potentiator in these in vitro immune assays.