Antihypertensive drugs (AHTs) are associated with lowered risks of neurodegenerative diseases and stroke. However, the relative risks associated with different AHT classes are unclear. Using an electronic health record network with 34 million eligible patients, we compared rates of these disorders over a 2-year period, in propensity score-matched cohorts of people taking calcium channel blockers (CCBs) compared with those taking other AHT classes. CCBs were associated with a higher incidence of all disorders compared with renin-angiotensin system agents, and a higher incidence of dementia and cerebrovascular disease compared with diuretics. CCBs were associated with a lower incidence of movement disorders and cerebrovascular disease compared with beta-blockers. The data show that AHT classes confer differential risks of neurodegenerative and cerebrovascular diagnoses.

We sought to examine the potential modifiers in the association between long-term low-dose folic acid supplementation and the reduction of serum total homocysteine (tHcy) among hypertensive patients, using data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 16 867 participants who had complete data on tHcy measurements at both the baseline and exit visit. After a median treatment period of 4·5 years, folic acid treatment significantly reduced the tHcy levels by 1·6 μmol/l (95 % CI 1·4, 1·8). More importantly, after adjustment for baseline tHcy and other important covariates, a greater degree of tHcy reduction was observed in certain subgroups: males, the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, higher baseline tHcy levels (≥12·5 (median) v. <12·5 μmol/l), lower folate levels (<8·0 (median) v. ≥8·0 ng/ml), estimated glomerular filtration rate (eGFR) <60 ml/min per 1·73 m2 (v. 60–<90 and ≥90 ml/min per 1·73 m2), ever smokers and concomitant use of diuretics (P for all interactions <0·05). The degree of tHcy reduction associated with long-term folic acid supplementation can be significantly affected by sex, MTHFR C677T genotypes, baseline folate, tHcy, eGFR levels and smoking status.

There is significant unmet need for more effective treatments for bipolar disorder. The drug discovery process is becoming prohibitively expensive. Hence, biomarker clues to assist or shortcut this process are now widely sought. Using the publicly available data from the whole genome association study conducted by the Wellcome Trust Case Control Consortium, we sought to identify groups of genetic markers (single nucleotide polymorphisms) in which each marker was independently associated with bipolar disorder, with a less stringent threshold than that set by the original investigators (p⩽1×10−4). We identified a group of markers occurring within the CACNA1C gene (encoding the alpha subunit of the calcium channel Cav1.2). We then ascertained that this locus had been previously associated with the disorder in both a smaller and a whole genome study, and that a number of drugs blocking this channel (including verapamil and diltiazem) had been trialled in the treatment of bipolar disorder. The dihydropyridine-based blockers such as nimodipine that bind specifically to Cav1.2 and are more penetrant to the central nervous system have shown some promising early results; however, further trials are indicated. In addition, migraine is commonly seen in affective disorder, and calcium channel antagonists are successfully used in the treatment of migraine. One such agent, flunarizine, is structurally related to other first-generation derivatives of antihistamines such as antipsychotics. This implies that flunarizine could be useful in the treatment of bipolar disorder, and, furthermore, that other currently licensed drugs should be investigated for antagonism of Cav1.2.

The benzodiazepine Ro 11-3128 (methyl-clonazepam) presents several similarities with praziquantel with regard to its anti-schistosomal mode of action, since both drugs cause spastic paralysis, calcium influx and tegumental disruption in the parasites. In order to know whether the two compounds share the same binding sites in the schistosomes, we performed in vivo and in vitro competition experiments. We took advantage of the fact that Ro 11-3128 is active against immature Schistosoma mansoni (whereas praziquantel is inactive), and praziquantel is active against S. japonicum (which is insensitive to Ro 11-3128). An excess of praziquantel did not inhibit the activity of Ro 11-3128 against immature S. mansoni and an excess of Ro 11-3128 did not inhibit the activity of praziquantel against S. japonicum, suggesting that the schistosome binding sites of the two drugs are different. On the other hand, cytochalasin D, an agent known to perturb – among other things – calcium channel function, was capable of inhibiting the schistosomicidal activity of both praziquantel and Ro 11-3128, thus adding another element of similarity between the two anti-schistosomal agents. A similar, albeit partial, inhibition of the schistosomicidal activity of the two drugs was exerted by some of the classical calcium channel blockers. Taken together, these results suggest that praziquantel and Ro 11-3128, although binding to different schistosome receptor sites, may use the same basic anti-schistosomal effector mechanisms.

Clevidipine is a new lipophilic, ultra-short acting 1,4-dihydropyridine calcium channel antagonist for intraoperative use. Because sarcolemnal calcium currents are involved in the mechanism of action of anaesthetics we questioned whether clevidipine alters the potency of volatile anaesthetics. We studied the effects of clevidipine on minimal alveolar concentration and the time to awaken from isoflurane anaesthesia. Sprague-Dawley rats were anaesthetized with isoflurane, and were allocated to one of four treatments prior to minimal alveolar concentration determination: (a) saline control; (b) clevidipine 20 nmol kg−1 min−1; (c) clevidipine 40 nmol kg−1 min−1; (d) clonidine 1 μg kg−1 – positive control. Ten mongrel dogs were anaesthetized with isoflurane and received a continuous infusion of clevidipine 6 nmol kg−1 min−1 or the solvent (Intralipid 20% – control). After 2 h of steady-state anaesthesia, minimal alveolar concentration awake and the time to awakening were recorded. Clevidipine reduced minimal alveolar concentration to a small but statistically significant extent (from 1.40±0.16 control to 1.23±0.13 vol% with 20 nmol kg−1 min−1 and to 1.27±0.12 vol% with 40 nmol kg−1 min−1; mean±SD; P < 0.05) in rats. Clonidine reduced minimal alveolar concentration to 0.90±0.17 vol% (mean± SD; P < 0.05). Minimal alveolar concentration awake and the duration of sleep were not affected by clevidipine in dogs. Clevidipine mildly reduces miinimal alveolar concentration of isoflurane but does not prolong the duration of sleep and does not affect minimal alveolar concentration awake after a 2-h steady-state isoflurane anaesthesia.

Nimodipine, a calcium channel blocking drug, is used in the treatment of cerebral arterial spasm after subarachnoid haemorrhage due to bleeding from an intracranial aneurysm. The purpose of this study was to evaluate the effects of nimodipine on neuromuscular blockade after vecuronium had been given to facilitate tracheal intubation and maintenance of muscle paralysis in patients undergoing clipping of intracranial aneurysm. Twenty patients were divided into two groups: a control group (n = 10) who received no calcium channel blocking drug, and a nimodipine group (n = 10) consisting of patients treated with nimodipine at clinically used doses of 0.03 mg kg−1 h−1 pre- and perioperatively. Anaesthesia was induced with atropine 10 μg kg−1, dehydrobenzperidol 5 mg, fentanyl 5 μg kg−1, thiopental 5 mg kg−1 and maintained with a mixture of N2O and isoflurane (0.5–1% inspired concentration) in O2, and additional doses of fentanyl 2.5 μg kg−1. Neuromuscular responses were monitored by acceleromyograpy. The first twitch of the train-of-four response (T1) was considered as twitch height.After a stabilization period, an intubating dose of vecuronium 0.1 mg kg−1 was administered. The onset of action, the time of first appearance of T−1 and clinical duration of action were recorded. Then, maintenance doses of vecuronium 0.03 mg kg−1were administered twice more when T1 had recovered to 25% of control twitch height. The study ended when the recordings of the 3rd 25% T1 recovery had been obtained. There were no statistical differences in the onset time (120±44 s in the control group, 141±33 s in the nimodipine group), in the first appearance time of T1 (28±6 min in the control group, 30±8 min in the nimodipine group), and in the times for 25% recovery in T1 (41±11, 32±2, 40±13 min in the control group, respectively, and 44±16, 36±15, 38±15 min in nimodipine group, respectively) between the groups studied. The time between the injection of the intubating dose of vecuronium and the third recovery of T1–25% of control was not significantly different between the control group (113±34 min) and the nimodipine group (117±42 min). This study indicates that nimodipine does not have any significant effect on the time course of action of vecuronium including the onset time and its clinical duration of action after the initial and the two maintenance doses in these patients.

Therapeutic drug monitoring of tricyclic antidepressants is a controversial issue. A case is reported in which a patient with recurrent depression developed asymptomatic tricyclic toxicity while on trimipramine, a tricyclic antidepressant, and diltiazem, a calcium channel blocker. A metabolic interaction involving cytochrome P450 3A (CYP3A) is postulated. It is suggested that routine therapeutic drug monitoring of tricyclic levels should be an essential part of the management of depression.