inosine-pranobex and HIV-Infections

Inosine pranobex (IP), commonly known as inosine acedoben dimepranol, isoprinosine and methisoprinol, has been proven to positively impact the host's immune system, by enhancing T-cell lymphocyte proliferation and activity of natural killer cells, increasing levels of pro-inflammatory cytokines, and thereby restoring deficient responses in immunosuppressed patients. At the same time, it has been shown that it can affect viral RNA levels and hence inhibit growth of several viruses. Due to its immunomodulatory and antiviral properties, and its safety profile, it has been widely used since 1971 against viral infections and diseases, among which subacute sclerosis panencephalitis, herpes simplex virus, human papilloma virus, human immunodeficiency virus, influenza and acute respiratory infections, cytomegalovirus and Epstein-Barr virus infections. Following an analysis of almost five decades of scientific literature since its original approval, we here summarize in vivo and in vitro studies manifesting the means in which IP impacts the host's immune system. We also provide a synopsis of therapeutic trials in the majority of which IP was found to have a beneficial effect. Lastly, positive results from limited studies, suggesting the putative future use of IP in new therapeutic indications are briefly described. In order to support use of IP against viral infections apart from those already approved, and to establish its use in clinical practice, further well-designed and executed trials are warranted.Funding: Ewopharma International.

Topics: Adjuvants, Immunologic; Antiviral Agents; HIV Infections; Humans; Inflammation Mediators; Influenza, Human; Inosine Pranobex; Noncommunicable Diseases; T-Lymphocytes; Virus Diseases

Inosine pranobex (InPx) could prove a valuable and innovative approach to the treatment of HIV-infected patients, since InPx administration has been shown in two multicenter trials to effectively delay the progression of HIV infection to overt AIDS. However, further studies are strongly required to optimize both the dosage of inosine pranobex and the administration schedules. Furthermore, clinical trials evaluating combination therapy of HIV infection with both InPx and zidovudine should ultimately provide an important advance in the management of HIV-infected patients. Our finding that concomitantly administered InPx to zidovudine-receiving patients increased the plasma levels of zidovudine as well as prolonged zidovudine mean half-life during InPx treatment suggests several potential advantages of the combination treatment with both InPx and zidovudine, such as a need for lower zidovudine dosage and a longer interval period between administering zidovudine to obtain sustained plasma levels as well as a potential to enhance residue immune function resulting from inosine pranobex treatment.

Topics: Drug Therapy, Combination; HIV Infections; Humans; Inosine Pranobex; Zidovudine

Local application of rabies immune serum and isoprinosine, an immunomodulator with antiviral activity was effective in mice infected with a sylvatic rabies virus. In this way, a single medical or veterinary treatment is only required, which is particularly important for developing but also for developed countries. The importance of using a post-exposure potency test to monitor rabies vaccines is emphasized. The same principle could be applied to other emerging viral infections of humans (for example, human immunodeficiency virus infection) and animals, for which no effective vaccines are available at this moment.

Topics: Animals; Antiviral Agents; Female; HIV Infections; Humans; Immune Sera; Inosine Pranobex; Mice; Rabies; Rabies Vaccines

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.

Topics: Acquired Immunodeficiency Syndrome; Denmark; Double-Blind Method; HIV Infections; Humans; Inosine Pranobex; Sweden

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Age Factors; Aged; HIV Infections; Humans; Inosine Pranobex; Middle Aged

We evaluated the clinical, immunologic, and virologic effects of oral treatment with ribavirin and isoprinosine for up to 3 months in asymptomatic, HIV-culture-positive homosexual men. Fifteen consecutive men received isoprinosine 4 g/day (1 g q.i.d.), and 800 (9 men) or 1,200 mg/day (6 men) of ribavirin. Five men in each ribavirin dosage group completed at least 2 months of treatment. No unexpected toxicities were observed. Eight minor HIV-related events occurred in six men while on study. All men remained HIV-positive, and time to positive culture decreased by at least 4 days in three men from each treatment group. Serum p24 levels did not change in two men who were p24 antigenemic and received 800 mg/day of ribavirin. Treatment was associated with a generalized lymphopenia affecting all lymphocyte subsets including CD4, which was partially reversible 1 month after stopping treatment. Most of the men remained anergic on DTHS skin testing. No improvements were noted in in vitro lymphoproliferative responses to antigens or in NK cell activity (which decreased significantly in the 1,200 mg/day ribavirin group). Although well tolerated at the doses employed, the combination of ribavirin and isoprinosine produced an unexpected generalized lymphopenia and did not exhibit HIV-suppressive or immunorestorative effects.

Topics: Adult; Antiviral Agents; CD4-Positive T-Lymphocytes; HIV; HIV Infections; Humans; Inosine; Inosine Pranobex; Killer Cells, Natural; Leukocyte Count; Male; Ribavirin; Ribonucleosides; T-Lymphocytes, Regulatory

We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of inosine pranobex (Isoprinosine) [corrected] in the treatment of patients with human immunodeficiency virus (HIV) infection but without manifest acquired immunodeficiency syndrome (AIDS). A total of 866 patients were enrolled in 21 centers in Denmark and Sweden. The patients were stratified in three groups according to their CD4+ cell count and randomly assigned to receive either inosine pranobex (1 g three times a day) (n = 429) or matching placebo (n = 437) for 24 weeks. Of the 831 patients who could be evaluated, AIDS developed in 17 in the placebo group as compared with 2 in the inosine pranobex group (P less than 0.001; odds ratio, 8.6 [95 percent confidence limits, 2.2 and 52.6]). There were no significant differences between the groups with respect to changes in CD4+ cell count or the development of other HIV-related conditions, with the exception of thrush, which developed in fewer patients in the inosine pranobex group (P = 0.05). No serious side effects were observed. We conclude that treatment with inosine pranobex delays progression to AIDS in patients with HIV infection. The duration of this beneficial effect, the optimal dose, and the mode of action of inosine pranobex remain to be clarified.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; CD4-Positive T-Lymphocytes; Double-Blind Method; HIV Infections; Humans; Inosine; Inosine Pranobex; Leukocyte Count; Middle Aged; Randomized Controlled Trials as Topic; T-Lymphocytes, Regulatory

Topics: Acquired Immunodeficiency Syndrome; Drug Evaluation; HIV; HIV Infections; Humans; Inosine; Inosine Pranobex; Randomized Controlled Trials as Topic

Topics: Carrier State; Ditiocarb; Drugs, Chinese Herbal; Glycyrrhetinic Acid; Glycyrrhizic Acid; HIV Infections; Humans; Immunotherapy; Inosine Pranobex; Lentinan; Poly I-C; Poly U

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.

Topics: 4-Aminobenzoic Acid; Animals; Dihydropteroate Synthase; Dose-Response Relationship, Drug; Escherichia coli; Folic Acid Antagonists; HIV Infections; Humans; Immunocompromised Host; Inosine Pranobex; para-Aminobenzoates; Pneumocystis; Rats; Rats, Sprague-Dawley; Saccharomyces cerevisiae; Toxoplasma

Topics: AIDS-Related Complex; CD4 Antigens; HIV Infections; Humans; Inosine Pranobex; Lymphocytes

To investigate a possible potentiation of Azidothymidine activity by immunomodulators, two in vitro models of HIV infection were analyzed. Peripheral blood lymphocytes on one hand, and cells from the CEM line on the other hand, were infected in vitro with HIV1 and reverse transcriptase activity was monitored daily in the cultures. When Azidothymidine was added, reverse transcriptase activity was significantly reduced. When Isoprinosine or Diethyldithiocarbamate was added in vitro, the reverse transcriptase was only slightly decreased (to a much less significant degree). When Azidothymidine was added together with either Isoprinosine or Diethyldithiocarbamate, a synergistic effect was observed with a very potent inhibition of reverse transcriptase activity. Before a possible application of such a combined therapy to patients, the pharmacokinetics of Azidothymidine was analyzed after the compound had been given alone or in combination with Isoprinosine. No alteration of pharmacokinetics was observed, suggesting that the immunomodulator will not alter the metabolism of the antiretroviral therapy in vivo, and may even enhance its biological activity, as it does in vitro.

Topics: Cells, Cultured; Ditiocarb; Drug Therapy, Combination; HIV Infections; Humans; Inosine Pranobex; Male; RNA-Directed DNA Polymerase; Zidovudine

Topics: HIV Infections; Humans; Inosine Pranobex