Isoprinosine
INN: Inosine acedoben dimepranol

Chemical structures of the three components of inosine pranobex (from top to bottom: inosine, acedoben and dimethylamino isopropanol)
Combination of
Inosine	Immunostimulant
Dimethylaminoisopropanol	Immunostimulant
Acedoben	Immunostimulant
Clinical data
Trade names	Imunovir, Delimmun, Isoprinosine, Isojol 500, Viruxan
Other names	Methisoprinol
AHFS/Drugs.com	https://www.drugs.com/international/isoprinosine-500mg.html
Routes of administration	Oral
ATC code	J05AX05 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
PubChem CID	135449284
ChemSpider	16736312
UNII	W1SO0V223F
KEGG	D01995
ECHA InfoCard	100.048.313
Chemical and physical data
Formula	C52H78N10O17
Molar mass	1115.249 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(CN(C)C)O.CC(CN(C)C)O.CC(CN(C)C)O.CC(=O)NC1=CC=C(C=C1)C(=O)O.CC(=O)NC1=CC=C(C=C1)C(=O)O.CC(=O)NC1=CC=C(C=C1)C(=O)O.C1=NC2=C(C(=O)N1)N=CN2C3C(C(C(O3)CO)O)O

Inosine pranobex (BAN; also known as inosine acedoben dimepranol (INN) or methisoprinol) is an antiviral drug that is a combination of inosine and dimepranol acedoben (a salt of acetamidobenzoic acid and dimethylaminoisopropanol) in a ratio of 1 to 3. Inosine pranobex has no effect on viral particles itself.^{[citation needed]} Instead, it acts as an immunostimulant, an analog of thymus hormones.^[1]

Inosine pranobex has been used in SSPE, herpes simplex virus, human papillomavirus, HIV, influenza virus, and airway virus infections, cytomegalovirus, and Epstein-Barr virus infections.^[2] The effect on SSPE is unclear, it is not a cure for it.

In a milestone move, Drugs Controller General of India approved inosine pranobex for the mild treatment of COVID-19.^[3] The drug is currently sold by Jolly Healthcare, from Jaipur, Rajasthan under the brand name “ISOJOL 500.”^[4]

Medical Uses

Inosine pranobex is an immunostimulant and antiviral drug indicated for^[5]:

● Mucocutaneous infections due to herpes simplex virus (type I and/ or type II).

● Genital warts as adjunctive therapy to podophyllin or carbon dioxide laser.

● Subacute Sclerosing Panencephalitis (SSPE).

● Influenza and other Acute Viral Respiratory Infections (AVRI).

● Restricted emergency use as add-on therapy for treatment of mild COVID-19 patients with co-morbidities and moderate COVID-19 patients.^[6]

Dosage and Administration

Before starting treatment with inosine pranobex your doctor will ask you, about your own medical history, if necessary he may perform physical examination and advice lab investigations. The drug can be taken orally and the dosage is prescribed by your doctor.^[7]

Contraindications

If there is a known hypersensitivity to product components, inosine pranobex should not be used. Also, it should not be prescribed in cases where the patient is presently suffering from gout or elevated uric acid blood levels. ^[8]

Special warnings and precautions for use

a. Inosine pranobex may cause a transient elevation of baseline serum and urinary uric acid, usually remaining within the normal range (using 8mg % 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, hyperuricaemia, urolithiasis, or to patients with impaired renal function. During treatment, uric acid levels in these patients should be monitored closely.^[9]

b. 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.^[10]

Adverse Effects

Common side effects include: nausea with or without vomiting, discomfort in the stomach, increased liver enzymes and blood urea nitrogen, itching, skin rashes, headaches, vertigo, fatigue or malaise (feeling unwell), and painful joints. Uncommon side effects include: diarrhoea, constipation, nervousness, drowsiness or insomnia.^[11][12][13]

Overdose

There has been no experience of overdose with inosine pranobex. However, serious adverse effects apart from increased levels of uric acid in the body, seem unlikely in view of the animal toxicity studies. Treatment should be restricted to symptomatic and supportive measures.^[14]

Drug interactions

It is not advisable take xanthine oxidase inhibitors drugs (drugs reducing production of uric acid), uricosuric agents (drugs which increase excretion of uric acid), diuretics (drugs which helps to excrete excess amount of water from body), immunosuppressive drugs (drugs which suppresses immune system) and zidovudine.^[15]

Use in special populations (such as pregnant women, lactating women)

Controlled trials monitoring foetal 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.^[16]

Pharmacology

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.^[5]

Pharmacodynamic properties

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 normalise (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.^[17]

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.^[18]

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 reorganisation 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).^[19][20]

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.^[21]

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.^[22]

References