Uro-458

Uses

Methenamine is a urinary tract antiseptic and antibacterial drug used for the prophylaxis and treatment of frequently recurring urinary tract infections requiring a long-term therapy.

For prophylactic or suppressive treatment of frequently recurring urinary tract infections when long-term therapy is considered necessary. This drug is not used to treat infection and should only be used after appropriate eradication of infection with antimicrobial agents.

Methylene blue is an oxidation-reduction agent used for the treatment of pediatric and adult patients with acquired methemoglobinemia.

Indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia.

Other clinical applications of methylene blue include improvement of hypotension associated with various clinical states, an antiseptic in urinary tract infections, treatment of hypoxia and hyperdynamic circulation in cirrhosis of liver and severe hepatopulmonary syndrome, and treatment of ifofosamide induced neurotoxicity.

Pain and fever .

Uro-458 is also used to associated treatment for these conditions: Urinary Tract InfectionCystitis, Methaemoglobinaemia, Nephritis, Urethritis, Urinary tract inflammation, Diuresis

How Uro-458 works

Methenamine does not have antibacterial properties in an alkaline environment (pH≥6); however, in a more acidic environment (pH<6), methenamine is hydrolyzed to formaldehyde. (1) Formaldehyde is considered to be highly bactericidal. (1) Formaldehyde has nonspecific antibacterial activity and works by denaturing proteins and nucleic acid of bacteria. (1) Certain bacteria such as Proteus sp. can alkalize urine, inhibiting the beneficial activity of formaldehyde. (1) The key role of the salt component of the drug, for example hippuric acid, is to maintain the acidic state of the urine. (1)

• Main mechanism of action involves inhibition of nitric oxide synthase and guanylate cyclase.
• In Alzheimers Disease: a mechanistic study found that methylene blue oxidizes cysteine sulfhydryl groups on tau to keep tau monomeric. One preclinical treatment study in tauopathy mice reported anti-inflammatory or neuroprotective effects mediated by the Nrf2/antioxidant response element (ARE); another reported insoluble tau reduction and a learning and memory benefit when given early.
• In Methemoglobinemia: Methylene Blue acts by reacting within RBC to form leukomethylene blue, which is a reducing agent of oxidized hemoglobin converting the ferric ion (fe+++) back to its oxygen-carrying ferrous state(fe++).
• As antimalarial agent: Methylene Blue, a specific inhibitor of P.falciparum glutathione reductase has the potential to reverse CQ resistance and it prevents the polymerization of haem into haemozoin similar to 4-amino-quinoline antimalarials.
• For ifosfamide induced neurotoxicity: Methylene blue functions as an alternate electron acceptor. It acts to reverse the NADH inhibition caused by gluconeogenesis in the liver while blocking the transformation of chloroethylamine into chloroacetaldehyde. In addition, it inhibits various amine oxidase activities, which also prevents the formation of chloroacetaldehyde.

Inhibits the activity of the enzyme known as cyclooxygenase (COX) which causes the formation of prostaglandins, substances which cause inflammation, swelling, pain, and fever . For more information, refer to the drug entry Aspirin.

Toxicity

Less than 3.5% of patients treated with this drug will experience minor adverse events such as upset stomach, dysuria, nausea, and rash.

LD50 = 1180 mg/kg ( Rat ).

Oral LD50 in the rat is 3000 mg/kg

Adverse effects can be divided into several categories , :

Eyes: irritation

Skin: skin irritation

Cardiovascular: rapid pulse, flushing

Central Nervous System —blurred vision, dizziness

Respiratory —shortness of breath or troubled breathing , irritation of respiratory system

Genitourinary —difficult micturition, acute urinary retention

Gastrointestinal —dry mouth, nausea/vomiting

Overdosage may be managed by inducing emesis or gastric lavage. Slow intravenous administration of physostigmine in doses of 1 to 4 mg (0.5 to 1 mg in children) repeated as needed in 1-2 h to relieve severe antimuscarinic symptoms. Administration of small doses of diazepam to control excitement and seizures may be warranted. Artificial respiration with oxygen can be used if needed for respiratory depression. Adequate hydration is important, as well as symptomatic treatment, provided as necessary .

Volume of Distribution

10 mg/kg (in rats).

Steady-state plasma salicylate concentrations increase more than proportionally with increasing dosages; the time required to reach steady state increases with increasing daily dose. Dosage intervals of 8-12 h are sufficient to maintain plasma salicylate concentrations in the normal therapeutic anti-inflammatory concentration range .

Elimination Route

After oral administration, rapid absorption of methenamine occurs. (1)

Rapidly absorbed. Refer to Aspirin for detailed salicylate absorption information.

Half Life

Elimination half-life = 3-4 hours assuming normal renal function. (1)

5–6.5 hours (after IV dose).

Mean half-life of 1.1 h .

Clearance

70-90% of a single oral dose of methenamine is excreted unchanged in the urine within 24 hours. (1)

3.0 ± 0.7 L/min.

Please refer to Aspirin for more information.

Elimination Route

Methenamine is primarily eliminated via the kidneys. (1)

Excreted in urine and bile. About 75% of an oral dose excreted in urine, primarily as stabilized colorless leukomethylene blue.

Please refer to Aspirin for the route of elimination.

Innovators Monograph

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