Special warnings and precautions for use

Inosine pranobex may cause a transient elevation of baseline serum and urinary uric acid, usually remaining within the normal range (using 8 mg % as the upper limit), particularly in males and in the ageing population of both sexes. The elevation of uric acid levels is due to the catabolic metabolism of the inosine moiety in this product in humans to uric acid. It is not due to a fundamental drug-induced alteration of enzyme or renal clearance function. Therefore, Inosine pranobex may be administered with caution in patients with a history of gout, Hyperuricemia, urolithiasis, or to patients with impaired renal function. During treatment, uric acid levels in these patients should be monitored closely.^[10]

In the case of long term treatment (3 months or longer), the serum and/or urine uric acid levels, liver function, blood count and renal functions should be checked on a regular basis in all patients. There is a possibility that ureteric and biliary calculi may occur when patients receive long term treatment. In some people acute hypersensitivity reactions (urticaria, angioedema, anaphylaxis and anaphylactic shock) may occur. Treatment with Inosine pranobex should be withdrawn in these cases.^[11]

Controlled trials monitoring fetal risk and impairment of fertility in humans are not available. It is not known if inosine pranobex is excreted in human milk. Therefore, inosine pranobex should not be administered during pregnancy or lactation unless the physician decides the benefits outweigh the potential risk. Although animal tests have shown no teratogenic effect, the use of inosine pranobex in women where pregnancy is suspected or confirmed should be avoided.^[12]

Mechanism of Action

The broad spectrum antiviral activity of Inosine pranobex in vivo is due to its immunomodulating effect. It positively impacts 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. It has been shown that it can affect viral RNA levels and hence inhibit growth of several viruses.^[6]

Pharmacodynamics

Inosine pranobex is a synthetic purine derivative with immunomodulatory and antiviral properties, which result from an apparent in vivo enhancement of host immune responses due to the drug.

In clinical studies Inosine pranobex has been shown to normalize (to the patient's baseline) a deficient or dysfunctional cell-mediated immunity by evoking a Th1 type response which initiates T lymphocyte maturation and differentiation and potentiation of induced lymphoproliferative responses, in mitogen or antigen-activated cells. Similarly, the drug has been shown to modulate T lymphocyte and natural killer cell cytotoxicity, T8 suppressor and T4 helper cell functions and also to increase the number of IgG and complement surface markers.^[18]

Inosine pranobex increases cytokine IL-1 production and enhances IL-2 production, up regulating the expression of the IL-2 receptor in vitro. It significantly increases endogenous IFN -γ secretion and decreases the IL-4 production in vivo. It has also been shown to potentiate neutrophil, monocyte and macrophage chemotaxis and phagocytosis.^[20]

In vivo, inosine acedoben dimeparanol enhances potentiation of depressed lymphocytic mRNA protein synthesis and translational ability while inhibiting viral RNA synthesis achieved by yet-to-be-clarified degrees of (1) incorporation of inosine-mediated orotic acid into polyribosomes; (2) inhibition of polyadenylic acid attachment to viral messenger RNA and (3) molecular reorganization of lymphocyte intramembrane plasma particles (IMP) which take part in emitting signals via specific T cells receptor (TcR) that results in a nearly threefold increase in density. Inosine pranobex inhibits cGMP phosphodiesterase only at high concentrations in vitro and at levels not involved in the in vivo immunopharmacological effects. In vitro, inosine pranobex exhibits inhibitory activity on the replication of herpes virus type 1 (HSV-1).^[21][22]

Pharmacokinetics

Each moiety of the drug exhibits separate pharmacological properties.

Absorption: When administered orally in man, inosine pranobex is rapidly and completely absorbed (≥ 90%) from the gastrointestinal tract and appears in the blood. Similarly, 94-100% of IV values of DIP [N,N-dimethylamino-2-propanol] and PacBA [p-acetamidobenzoic acid] components are recovered in urine after oral administration in Rhesus monkeys.^[23]

Distribution: Radiolabelled material was found in the following tissues in order of decreasing specific activity when drug was administered to monkeys: kidneys, lung, liver, heart, spleen, testes, pancreas, brain and skeletal muscle.

Metabolism: In human subjects following a 1 g oral dose of inosine pranobex, the following plasma levels were found for DIP and PAcBA, respectively: 3.7μg/ml (2 hours) and 9.4μg/ml (1 hour). In human dose tolerance studies, peak post-dose elevation of uric acid levels as a measurement of drug-derived inosine are not linear and can vary±10% between 1–3 hours.

Excretion: The 24-hour urinary excretion of PAcBA and its major metabolite under steady-state conditions at 4g per day amounted to approximately 85% of the administered dose. 95% of the DIP-derived radioactivity in urine was recovered as unchanged DIP and DIP N-oxide. The elimination half-life is 3.5 hours for DIP and 50 minutes for PAcBA. The major metabolites in humans are the N-oxide for DIP and the o-acylglucuronide for PAcBA. Because the inosine moiety is degraded by the purine degradation pathway to uric acid, radiolabelled experiments in humans are inappropriate. In animals up to about 70% of the administered inosine can be recovered as urinary uric acid following oral tablet administration and the remainder as the normal metabolites, xanthine and hypoxanthine.

Bioavailability/AUC: Urinary recoveries under steady state conditions of the PAcBA moiety and its metabolite were found to be > 90% of the expected value from solution. The recovery of the DIP moiety and its metabolite was >76%. The plasma AUC was >88% for DIP and > 77% for PAcBA.^[24]