Besipirdine
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Besipirdine (besipirdine hydrochloride, or HP749), an indole-substituted analog of 4-aminopyridine, is a nootropic drug developed for the treatment of Alzheimer's disease (AD).[1][2]
History
Besipirdine was first considered for the treatment of obsessive-compulsive disorder (
Mechanism of action
As a member of the
Medical uses
Alzheimer's disease
The most successful treatments for AD have been strategies targeting the
Other
Besipirdine was originally suggested as a treatment for OCD due to its effects on the adrenergic and serotonergic systems.[11] "In vitro" studies of besipirdine indicated its potency in inhibiting serotonin reuptake in addition to norepinephrine reuptake.[9][11] "In vivo", besipirdine showed efficacy in reducing schedule-induced polydipsia (SIP) in rats.[12] The drug's anticonvulsant properties ultimately led Hoechst AG to pursue it as a treatment for Alzheimer's disease. After its discontinuation in the mid-1990s, besipirdine was re-evaluated as an oral treatment for
Pharmacology
Besipirdine primarily acts to enhance both cholinergic and adrenergic neurotransmission in the central nervous system. It is administered orally[2][3][4] at a maximum tolerated dose (MTD) of 50 mg BID.[1][2][3][16] In Phase II clinical trials, patients were administered 5 mg or 20 mg BID doses of besipirdine.[1][2][3] Its N-despropyl metabolite, P86-7480, exhibits transient vasoconstrictor effects, producing a pressor effect of 16 ± 4 mm Hg after intravenous administration of 0.1 mg/kg, in monkey, rat and dog models.[3][4][17]
Pharmacokinetics
The pharmacokinetics of besipirdine have been studied in conscious monkey. The calculated elimination half-life (t1/2) of besipirdine and P86-7480 after oral administration of 10, 20, and 40 mg/kg doses is 7.4 ± 2.1 hours. The t1/2 after intravenous administration of 10 mg/kg is 1.5 hours. Besipirdine is cleared through the kidneys at 0.13 ± 0.04 mL/min/kg; only 1% of the administered dose is excreted unused via the kidneys.[4] In humans, using doses up to 30 mg, the t1/2 of besipirdine and P86-7480 were calculated as 3 hours, and 5.5–7 hours, respectively. Peak plasma concentrations of besipirdine and P86-7480 were calculated as 1.5–2 hours, and 2–3 hours, respectively.[3]
Adverse effects
Besipirdine is reported to be well tolerated. More severe adverse effects, such as bradycardia and postural hypotension, may have been a result of a high ratio of adrenergic to cholinergic potency caused by the metabolite P86-7480, which has direct vasoconstrictor effects.[1][3] Some studies suggest that the effects of besipirdine on cognition are reversible after withdrawal from treatment, indicating that the efficacy of the drug is primarily symptomatic and not neuroprotective.[1]
General
- Nausea and vomiting[3]
- Dry mouth[3]
- Headache[3]
- Rash[3]
- Eye disorder[3]
- Urinary frequency[3]
- Mouth ulceration[3]
- Loss of appetite[1]
- Dizziness[1]
- Paresthesia[3]
- General pain[3]
Cardiovascular
- Bradycardia[3]
- Postural hypotension[3]
- Premature ventricular contractions[3]
- Angina[3]
- Arrhythmia[3]
Gastrointestinal
Sleep
Psychological
See also
References
- ^ S2CID 34854267.
- ^ PMID 1818073.
- ^ PMID 7674813.
- ^ S2CID 24557891.
- ^ PMID 8558529.
- ^ PMID 8741167.
- PMID 10071091.
- PMID 1909035.
- ^ S2CID 54646.
- PMID 8581286.
- ^ PMID 8879677.
- S2CID 26113146.
- ^ S2CID 23506523.
- ^ Sacco E, Bientinesi R (April 2012). "Future Perspective in Pharmacological Treatment Options for Overactive Bladder Syndrome". European Urological Review. 7 (2): 120–6.
- ^ Haab F, Vela-Navarrete R, Perez-Martinez F, Castilla-Reparaz C, Ferte J, Bienayme H, Attali P (January 2006). "Effects of besipirdine on acetic acid-induced bladder irritation in rabbits. Comparison with duloxetine" (PDF). Neurology and Urodynamics. 25 (6): 586–587.
- S2CID 54239722.
- PMID 9103515.