Pharmacokinetics and Dose Proportionality of Betahistine in Healthy Individuals

Betahistine dihydrochloride is widely used to reduce the severity and frequency of vertigo attacks associated with Ménière’s disease. Betahistine is an analogue of histamine, and is a weak histamine H1 receptor agonist and potent histamine H3 receptor antagonist. The recommended therapeutic dose for adults ranges from 24 to 48 mg given in doses divided throughout the day. Betahistine undergoes extensive first-pass metabolism to the major inactive metabolite 2-pyridyl acetic acid (2PAA), which can be considered a surrogate index for quantitation of the parent drug due to extremely low plasma levels of betahistine. The aim of the present investigation was to assess the pharmacokinetics and dose proportionality of betahistine in Arabic healthy adult male subjects under fasting conditions. A single dose of betahistine in the form of a 8, 16, or 24 mg tablet was administered to 36 subjects in randomized, cross-over, three-period, three-sequence design separated by a one week washout period between dosing. The pharmacokinetic parameters Cmax, AUC0–t, AUC0–∞, Tmax, and Thalf were calculated for each subject from concentrations of 2-PAA in plasma, applying non-compartmental analysis. The current study demonstrated that betahistine showed linear pharmacokinetics (dose proportionality) in an Arabic population over the investigated therapeutic dose range of 8–24 mg.

Generalised tonic–clonic seizures on the subtherapeutic dose of olanzapine

Olanzapine is a second-generation antipsychotic. Incidence of olanzapine-induced seizures (OIS) is low with monotherapy. Combination therapy with another antipsychotic, drug metabolism and old age are risk factors for OIS. Our patient was a 71-year-old man, admitted to the psychiatry unit. He was managed on the lines of bipolar affective disorder current episode depression and dementia. He was started on olanzapine 1.25 mg two times/day. The patient developed generalised tonic–clonic seizure that lasted for around two and a half minutes within 24 hours of olanzapine treatment. His electroencephalogram showed findings that were suggestive of mild slowing. Our case discusses the incidence of OIS on the subtherapeutic dose. This presentation involves multiple risk factors for OIS: a history of stroke, poststroke seizure, old age and cognitive impairment. Due to scarcity of evidence of OIS; mostly with recommended therapeutic dose range physicians may underestimate seizure risk at subtherapeutic doses.

Citalopram–induced delusions in an older adult

IntroductionSelective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants worldwide. In older adults, citalopram is generally well tolerated and safe in the therapeutic dose range of 20 to 40 mg/day. In literature, there are cases of SSRI-induced psychosis, but mainly with fluoxetine. There are only three reported cases of citalopram-induced delusions, however, these case-reports did not involve an older adult.Objectives and aimsTo provide a case of citalopram–induced psychosis in an older adult, followed by the review of available literature.MethodsA case report is presented and discussed followed by a literature review.ResultsA 64-year-old woman without somatic illnesses was referred by a general practitioner with depressive symptoms. One week after initiation of citalopram 10 mg/day she suddenly developed delusions, predominantly in the early morning. No other medical evidence was found that could explain her delusions. After discontinuation of citalopram her delusions quickly resolved.ConclusionThis is the first case report of a SSRI-induced delusion in an older adult. Citalopram has been reported to be one of the safest SSRIs. Although most SSRI's have a mild side-effect profile, care should be taken when initiating SSRIs since unpredictable adverse effects may occur.Disclosure of interestThe authors have not supplied their declaration of competing interest.

PEG-Immobilized Keratin for Protein Drug Sequestration and pH-Mediated Delivery

Protein drugs like growth factors are promising therapeutics for damaged-tissue repair. Their local delivery often requires biomaterial carriers for achieving the therapeutic dose range while extending efficacy. In this study, polyethylene glycol (PEG) and keratin were crosslinked and used as sponge-like scaffolds (KTN-PEG) to absorb test proteins with different isoelectric points (pI): albumin (~5), hemoglobin (~7), and lysozyme (~11). The protein release kinetics was influenced by charge at physiological pH 7.4. The keratin network, with pI 5.3, electrostatically attracted lysozyme and repulsed albumin generating the release rate profile: albumin > hemoglobin > lysozyme. However, under acidic conditions (pH 4), all proteins including keratins were positively charged and consequently intermolecular repulsion altered the release hierarchy, now determined by size (MW) diffusion: lysozyme (14 kDa) > hemoglobin (64 kDa) > albumin (66 kDa). Vascular endothelial growth factor C (VEGF-C), with properties comparable to lysozyme, was absorbed into the KTN-PEG scaffold. Endothelial cells cultured on this substrate had significantly larger numbers than on scaffolds without VEGF-C suggesting that the ionically bound and retained growth factor at neutral pH indirectly increased acute cell attachment and viability. PEG and keratin based sequestrations of proteins with basic pIs are therefore a feasible strategy with potential applications for selective biologics delivery.