Slow Channel Inhibitors Research Articles

Favorable combinations of antiseizure medication with vagus nerve stimulation to improve health-related quality of life in patients with epilepsy

BackgroundVagus nerve stimulation (VNS) is a non-pharmacological treatment of refractory epilepsy, which also has an antidepressive effect. The favorable combinations of VNS with specific mechanisms of action of antiseizure medication (ASM) on mood and health-related quality of life (HrQol) have not yet been studied. The objective was to identify favourable combinations of specific ASMs with VNS for the HrQoL and depression in refractory epilepsy. MethodsWe performed an observational study including patients with refractory epilepsy and an implanted VNS (N = 151). In the first 24 months after VNS implantation, all patients were on stable ASM therapy. We used the standardized questionnaires QOLIE10, EQVAS and EQ5D to evaluate HrQoL as well as the Beck Depression Inventory (BDI). Multiple regression analysis was performed to evaluate the synergistic combinations of ASM with VNS for HrQoL. ResultsAt the year-two follow-up (N = 151, age 45.2 ± 17.0 years), significant improvement (p < 0.05) in BDI scores was found for combination of VNS with SV2A modulators (58.4 %) or AMPA antagonists (44.4 %). A significant increase of HrQoL by at least 30 % (p < 0.05) was measured for a combination of VNS with SV2A modulators (brivaracetam, levetiracetam) or slow sodium channel inhibitors (eslicarbazepine, lacosamide). ConclusionThe results of our study suggests a favorable effect of the combination of SV2A modulators or slow sodium channel inhibitors with VNS on the HrQoL in comparison to other ASMs. Besides the possible synergistic effects on the seizure frequency, the amelioration of behavioral side effects of SV2A modulators by VNS is an important factor of HrQoL-improvement in these combinations.

Synergistic effects of vagus nerve stimulation and antiseizure medication

IntroductionVagus nerve stimulation (VNS) is an effective, non-pharmacological therapy for epileptic seizures. Until now, favorable combinations of different groups of antiseizure medication (ASM) and VNS have not been sufficiently addressed. The aim of this study was to identify the synergistic effects between VNS and different ASMs.MethodsWe performed an observational study of patients with epilepsy who were implanted with VNS and had a stable ASM therapy during the first 2 years after the VNS implantation. Data were collected from the Mainz Epilepsy Registry. The efficacy of VNS depending on the concomitantly used ASM group/individual ASMs was assessed by quantifying the responder rate (≥ 50% seizure reduction compared to the time of VNS implantation) and seizure freedom (absence of seizures during the last 6 months of the observation period).ResultsOne hundred fifty one patients (mean age 45.2 ± 17.0 years, 78 females) were included in the study. Regardless of the used ASM, the responder rate in the whole cohort was 50.3% and the seizure freedom was 13.9%. Multiple regression analysis showed that combination of VNS with synaptic vesicle glycoprotein (SV2A) modulators (responder rate 64.0%, seizure freedom 19.8%) or slow sodium channel inhibitors (responder rate 61.8%, seizure freedom 19.7%) was associated with a statistically significant better responder rate and seizure freedom than combinations of VNS and ASM with other mechanism of action. Within these ASM groups, brivaracetam showed a more favorable effect than levetiracetam, whereas lacosamide and eslicarbazepine were comparable in their effects.ConclusionOur data suggest that the combination of VNS with ASMs belonging to either SV2A modulators or slow sodium channel inhibitors could be optimal to achieve a better seizure control following VNS. However, these preliminary data require further validation under controlled conditions.

Slow Channel Inhibitor Verapamil in the Treatment of Arrhythmia

Slow Channel Inhibitor Verapamil in the Treatment of Arrhythmia

Analysis of the degradation products of diproteverine by moving belt LC/MS

AbstractMoving belt LC/MS has been used to identify the degradation products of the slow calcium membrane channel inhibitor, Diproteverine, after storage at elevated temperature and humidity. The major products observed result from oxidation. Two of these products, both ketones, yield [M  14 + H]+ ions by chemical ionization. These unusual ions also occur for some simple aromatic ketones used as model compounds and are shown to arise by reduction of the carbonyl group to a methylene by the reagent gas.

Slow channel inhibitor effects on brain function: tolerance to severe hypoxia in the rat

1. The protective effects of ten slow channel inhibitor drugs against severe progressive hypoxia were investigated in rats breathing spontaneously during light anaesthesia. Respiration, heart rate, electrocorticogram (ECoG) and/or electroencephalogram (EEG) were recorded. 2. Tolerance times were monitored from hypoxia onset until cessation of respiration, ECoG, EEG synchronization, and 'background-EEG'. Drugs were administered i.v. 5 min before the onset of hypoxia. 3. Verapamil, gallopamil, and nimodipine resulted in a significant increase of tolerance times; fendiline and bepridil showed a small increase (not significant); bencyclan and prenylamine were ineffective; cinnarizine and diltiazem slightly reduced tolerance times as did flunarizine at low doses. 4. At protective doses, verapamil, gallopamil, and nimodipine significantly raised the respiration rate but had little or no cardiac depressor effects. Bencyclan showed ventilatory drive but cardiocirculatory depression. A clear-cut ventilatory drive did not occur with the other ineffective slow channel inhibitors. 5. It is suggested that the protective actions observed were not due to slow channel inhibition per se, nor to spasmolytic potency or increased cerebral blood flow. Ventilatory drive associated with other cardiopulmonary actions which secondarily raise the brain oxygen supply are likely to be responsible for this effect.

Secondary prevention after myocardial infarction: effects of beta blocking agents and calcium antagonists.

Therapeutic interventions in patients with myocardial infarction, whether during the first hours after coronary occlusion or several days later, aim to reduce mortality and morbidity by several mechanisms: Prevention of fatal ventricular fibrillation, limitation of infarct size, and inhibition of platelet aggregation are some examples of such mechanisms. Results from early intervention trials with beta blocking agents, particularly from ISIS-I, suggest that 1-year mortality is significantly lower in selected patients randomized to active treatment. Late intervention studies also suggest a significant reduction in coronary mortality and morbidity with beta blockade, particularly when data are pooled. Studies with the calcium channel blockers nifedipine and verapamil were unable to demonstrate any beneficial effects of these drugs on mortality or reinfarction. In this review article, attention will be directed to the most recent information about the preventive value of beta adrenergic blocking drugs and slow calcium channel inhibitors.

Beta-adrenoceptor blocking drugs in primary and secondary prevention of myocardial infarction.

Beta-adrenoceptor blocking drugs reduce mortality by about 20% when used to treat patients in the first 1-3 years after a myocardial infarction. There is suggestive evidence of benefit, averaging about 14% reduction in mortality, when they are used acutely in the coronary crisis. The benefits of beta blockade in primary prevention in patients under treatment for hypertension are less clearly established. Two studies have suggested a benefit but only in non-smoking men, a third study has not confirmed the hypothesis. More evidence is needed. As there is little evidence of comparable benefit with other types of drug, e.g. calcium slow-channel inhibitors, it is reasonable to use beta-blocking drugs in male hypertensives (who should be encouraged to stop smoking in any case), unless there are specific contra-indications.

Twice-daily verapamil for hypertension: A comparison with propranolol

Recent reports have confirmed that some slow calcium channel inhibitors have useful antihypertensive properties because they produce dilatation of the peripheral arterioles without reflex tachycardia. Verapamil is such a drug, but its clinical role in the management of hypertension is not clear. An open crossover trial was performed to compare the 24-hour profiles of blood pressure reduction after long-term therapy with a standard β-adrenoceptor blocker, propranolol, and verapamil. Nineteen patients were studied by continuous ambulatory intraarterial recording and the order of drug administration was determined by random allocation. The drugs were administered 2 times a day and titrated according to casual clinic pressures (propranolol, 40 to 240 mg 2 times a day; verapamil, 120 to 240 mg 2 times a day). Mean hourly blood pressure and heart rate values were obtained over a 24-hour cycle and the responses to isometric and dynamic exercise were also examined. The drugs produced a uniform and comparable reduction in blood pressure throughout the day, together with a reduction in heart rate, which was greater with propranolol. Comparable effects were also seen on the pressor responses to exercise. Both drugs were equally well tolerated and caused no patient withdrawals. Thus, oral verapamil given 2 times a day shows a degree of efficacy similar to that of propranolol and provides 24-hour blood pressure control. This slow calcium channel inhibitor was well tolerated and may be used as initial therapy for hypertension.

Antiarrhythmic Effect of Diltiazem During Halothane Anesthesia in Dogs and in Humans

The antiarrhythmic effects of diltiazem (DL), a slow channel inhibitor, were evaluated in the presence of epinephrine-halothane-induced arrhythmias in dogs, of premature ventricular contractions (PVCs) during anesthesia in patients (n = 10), and of tachyarrhythmias with associated atrial fibrillation (AF) during anesthesia in patients (n = 9). The arrhythmogenic dose of epinephrine (ADE) during one MAC of halothane in dogs was increased from 1.13 +/- 0.21 to 3.14 +/- 0.89 microgram X kg-1 X min-1 by the administration of 0.3 mg/kg of DL. This suggests that DL significantly increases the threshold for the induction of arrhythmias associated with epinephrine and halothane. In 10 patients, PVCs that appeared spontaneously during halothane anesthesia were eliminated by the intravenous administration of DL (0.1 mg/kg). With an additional nine patients who had had AF preoperatively and suffered tachyarrhythmias during anesthesia, the intraoperative intravenous administration of DL significantly decreased heart rate (to less than 100 beats/min) within 10-15 min. Diltiazem is an effective means for the treatment of PVCs and AF-mediated tachyarrhythmias during anesthesia. Because of the pharmacologic properties of DL (e.g., depressing sinus and atrioventricular (AV) node function), DL should be used with caution in patients with a sick sinus syndrome or an AV block, or in the presence of beta-adrenergic antagonists.

Effects of oximes, diacetylmonoxime, pyridine-2-aldoxime, and pyridine-2-aldoxime methochloride, on the electrical and mechanical activities of guinea pig cardiac ventricular muscles.

Effects of 3 oximes, diacetylmonoxime (DAM), pyridine-2-aldoxime (PAM) and pyridine-2-aldoxime methochloride (2-PAM), on the normal electrical and mechanical activities and on the slow response action potentials were examined in the guinea pig ventricular muscles. DAM and long-term exposure to high concentrations of PAM produced decreases in contractile force, action potential duration and slow response action potentials, whereas 2-PAM and low concentrations of PAM tended to increase these parameters. Thus, these 3 oximes did not act uniformly on cardiac muscle. It was speculated that DAM and high concentrations of PAM may act as slow channel inhibitors, whereas 2-PAM and low concentrations of PAM may act as slow channel activators.

Prescription drug advertising: Trends and implications

Prescription drug advertisements which appeared in two leading American medical journals in 1972, 1977 and 1982 were analyzed to discover possible trends in advertising. The 5016 ads examined showed that ads for the diuretic-cardiovasculars, especially the beta-adrenergic blocking agents and the slow channel inhibitors, as well as the analgesics, had increased, while ads for the anti-infectives and tranquilizers had diminished. The average amount of space allocated for each ad had increased. On the average, most ads (69%) depicted neither male nor female patients in their graphics, and a trend of increased neutrality was observed. When the hormones were excluded, an average of 21% of the ads showed male patients and 10% showed females. Since a relationship was discerned between the leading drugs advertised and the leading prescriptions filled, it was concluded that advertising does have some effect on the prescribing behavior of practitioners. The findings suggest that great investment in advertising is necessary in order to achieve high levels of sales for such drugs as Valium ® (diazepam) which do not have a clear-cut ameliorative effect on a specific physiological condition. On the other hand, it was suggested that saturation advertising would not significantly enhance the sales of such drugs as Dyazide ® (triamterene and hydrochlorothiazide) because of its well established therapeutic value in the control of hypertension. Ten advertising companies, on the average, had purchased 67% of all advertising space and five had purchased almost half (47%). The same two pharmaceutical companies were among the top five advertisers and the same five were among the top ten for the three years studied.

Propranolol versus verapamil for the treatment of essential hypertension

Recent reports have confirmed that slow calcium channel inhibitors have useful antihypertensive properties because they produce dilatation of the peripheral arterioles without reflex tachycardia. Their clinical place in the management of hypertension has yet to be clearly defined, and thus we have performed an open crossover trial to compare the 24-hour profiles of blood pressure reduction after chronic therapy with propranolol and verapamil. Nineteen patients were studied by continuous ambulatory intraarterial recording and the order of drug administration was decided by random allocation. Drug dosage was twice daily and titrated according to casual clinic pressures (propranolol, 40 to 240 mg twice a day; verapamil, 120 to 240 mg twice a day). Mean hourly blood pressure and heart rate values were obtained over a 24-hour cycle, and the responses to isometric and dynamic exercise were also examined. Both drugs were shown to produce a uniform and comparable reduction in blood pressure throughout the whole day, together with a reduction in heart rate, which was greater with propranolol. Comparable effects were also seen on the pressor responses to exercise. Both drugs were equally well tolerated and caused no patient withdrawals. We conclude that oral verapamil given twice daily showed a similar degree of efficacy to propranolol and provided 24-hour blood pressure control. This slow calcium channel inhibitor may be useful as initial therapy for hypertension, particularly for those patients in whom beta-adrenoreceptor blockers are contraindicated.

The role of a slow channel inhibitor, verapamil, in the management of hypertension.

The 'Oxford' system for continuous monitoring of the ambulatory blood pressure was used to assess the changes in blood pressure following therapy with the slow channel inhibitor, verapamil. Sixteen patients were studied on no therapy and following a minimum of 6 weeks therapy (dose range 120-160 mg t.d.s.). During each study patients underwent standardized physiological tests including tilt, isometric handgrip and dynamic bicycle exercise. Verapamil was demonstrated to produce a consistent reduction of blood pressure over most of the 24 h period studied but this was most marked during the day. Heart rate was also reduced. There was no postural hypotension and the absolute responses to dynamic and isometric exercise were reduced. The results demonstrate the antihypertensive efficacy of 'slow channel inhibitors' as represented by verapamil.

Nifedipine or verapamil as sole treatment of hypertension. An intraarterial study.

Intraarterial ambulatory blood pressures were recorded prior to and during therapy with two different calcium ion antagonists, nifedipine and verapamil, in two separate groups of patients. In the first group, nine patients were studied off therapy and following a minimum of 6 weeks of nifedipine treatment (dose range, 20 to 60 mg twice daily). A second group of 16 patients followed the identical protocol but were prescribed verapamil (120 to 160 mg, three times daily). During both studies, patients underwent standardized physiological tests including tilt, isometric handgrip, and dynamic bicycle exercise. Both verapamil and nifedipine caused a reduction in blood pressure over most of the 24 hours studied. Nifedipine did not affect heart rate whereas verapamil caused a reduction of approximately 10 bpm. Nifedipine and verapamil did not induce postural hypotension, and the absolute responses to dynamic and isometric exercise were reduced. These results show the efficacy of slow channel inhibitors in the management of essential hypertension.

Calcium antagonists. Pharmacodynamic effects and mechanism of action.

Calcium antagonistic drugs (also called slow channel or calcium channel inhibitors or calcium entry blockers) represent a major development in cardiovascular pharmacology. Their main site of action is at the slow channels where they inhibit Ca2+ influx into the cells. This characteristic distinguishes them from other drugs such as sodium nitroprusside, papaverine, hydralazine and diazoxide which interfere with the availability of calcium ions for their physiological functions by acting at sites other than the 'calcium channels'. There is considerable evidence, however, that calcium antagonistic drugs act at an intracellular site(s) as well as the 'calcium channels'. At present, verapamil, nifedipine and diltiazem are the most important representatives of this new class of drugs. Their chemical structures are quite different but their pharmacological characteristics are similar. The action of these drugs is primarily confined to the cardiovascular system. In the heart they depress cardiac contractions and heart rate and protect the ischaemic myocardium from calcium injury. Furthermore, verapamil and diltiazem (but not nifedipine) prolong AV conduction and refractoriness, which is important for their use as antiarrhythmic agents. All 3 drugs are powerful dilators of the coronary and peripheral arteries. These in vitro effects can be substantially altered by activation of baroreceptor reflexes in vivo, as is expected with vasodilators that cause little or no inhibition of noradrenaline release from sympathetic nerve endings. The combination of coronary dilatation with decreased oxygen demand of the myocardium and with decreased preload explains their value in the treatment of vasospastic and effort angina.

Prevention of DOCA-salt hypertension with the calcium blocker nitrendipine.

Mononephrectomized female rats on a high sodium intake developed hypertension, hypokalemia, enlarged hearts and kidneys and slight adrenal involution under deoxycorticosterone treatment. Simultaneous administration of nitrendipine (5 mg/kg twice daily) completely prevented hypertension and reduced but did not abolish cardiac enlargement. There was no effect of the calcium slow-channel inhibitor on kidney enlargement, adrenal atrophy or hypokalemia. The ability of the steroid to produce cardiomegaly in the absence of an elevated blood pressure to account for it, tends to confirm the suggestion of other investigators that the steroid may have that effect by a mechanism not involving blood pressure elevation.

Protective effects on isolated hearts with developing infarction: Slow channel blockade by diltiazem versus beta-adrenoceptor antagonism by metoprolol

Slow channel inhibitors (calcium antagonists) and beta-adrenoceptor antagonists may theoretically protect the infarcting myocardium by different mechanisms. Thus, beta-receptor antagonism reduces the oxygen demand by the combined effects of bradycardia, decreased arterial pressure, and reduced contractility, whereas slow channel inhibition chiefly increases coronary blood flow and decreases the afterload by peripheral vasodilation. The present study was designed to assess and compare the effects of the beta-receptor antagonist metoprolol with those of the calcium channel inhibitor diltiazem on cellular damage and mechanical function in the isolated working rat heart subject to coronary artery ligation. We compared the highest concentrations of both agents that could be tolerated in this preparation: diltiazem 4 × 10 − 7 M and metoprolol 10 −4 M. These concentrations were equally effective in reducing enzyme release, which was taken as an index of cellular damage, and in preserving high energy phosphate contents in the infarcting myocardium. However, the 2 agents exhibited opposite effects on coronary flow rates and mechanical function. Compared with diltiazem metoprolol reduced total coronary flow, cardiac output, and left ventricular work and efficiency immediately after coronary artery ligation. However, diltiazem even favorably influenced the mechanical performance of the isolated heart compared with that of untreated control hearts during the 60 minutes of regional myocardial ischemia. These benefits were similarly apparent when the hearts were paced to the rate of control hearts. The presumed mechanism was coronary vasodilation, because afterload increased as left ventricular power production increased in this model. These results suggest that slow channel inhibition by diltiazem has advantages over beta-receptor antagonism by metoprolol in protecting the infarcting myocardium and that further evaluation of diltiazem in other preparations is warranted.

Greater Antihypertensive Efficacy of the Calcium Channel Inhibitor Verapamil in Older and Low Renin Patients

1. The calcium slow channel inhibitor verapamil was administered as monotherapy (240-270 mg; mean 427 mg/day) on the average for 93 days to 43 patients with essential hypertension; 11 with low, 24 with normal and eight with high renin sodium index. 2. Verapamil reduced blood pressure from 171 ± 16/108 ± sd 6 mmHg to 152 ± 14/93 ± 9 (both P &amp;lt; 0.001); in 25 of the 43 patients a diastolic pressure ≤95 mmHg was achieved. Two patients each reported vertigo, sleeplessness and constipation. 3. The fall in mean blood pressure after verapamil was directly related to age (r = 0.759, P &amp;lt; 0.001), pretreatment mean blood pressure (r = 0.701, P &amp;lt; 0.01) and plasma noradrenaline concentration (r = 0.400, P &amp;lt; 0.05), and inversely related to plasma renin activity (r = −0.551), P &amp;lt; 0.001). These correlations were also significant for diastolic blood pressure. Accordingly, the antihypertensive response to verapamil was greatest in older and low renin patients. 4. This greater blood pressure decrease with verapamil in older and low renin patients suggests a greater calcium influx-dependent vasoconstriction in these patients, which seems to be directly related to the activity of the sympathetic nervous system.

Electrophysiologic and hemodynamic effects of slow-channel blocking drugs

T HE last decade has witnessed an intense clinical and experimental investigation of the pharmacologic properties and the therapeutic applications of the class of drugs which now have come to be known as “calcium antagonists, ” “slow-channel inhibitors”, or “calcium influx blockers.“i-3 Although the prototype agent of such compounds, verapamil, has been known since 1 962,4 it is only recently that the concept of the selective slow-channel inhibition has been clearly delineated and has gained widespread recognition.5,6 Such an appreciation has followed closely in the wake of numerous developments which have provided a rational basis for the use of slow-channel inhibitors in a very large and increasing number of cardiocirculatory disorders.‘x7 An important advance was made when it was found that the inward depolarizing current in heart muscle had two components, one having fast kinetics and the other slow, each capable of being blocked selectively by specific antagonists.8-‘0 It was aIso found that certain fibers in the normal heart were dependent almost exclusively on slow-channel potentials.” For example, the selective inhibition of such potentials in the middle of the AV node provided a highly effective and predictable method for terminating reentrant paroxysmal supraventricular tachycardias which utilize anterograde conduction through the AV node as part of the re-entrant circuit.‘2,13 Although not all slow-channel antagonists block AV conduction in this manner, the selective inhibition of the slow-channel in cardiac muscle in general has become the main basis for identifying slow-channel inhibitors.236,‘4 The fact that the transport of calcium through the slowchannel during an action potential is responsible for excitation-contraction coupling in heart muscle, a major consequence of the inhibition of this process is a reduction in myocardial contractility, most clearly evident15*16 in isolated cardiac muscle. However, if such a negative inotropic propensity of this class of agents were not modulated favorably by their associated extracardiac effects, it is unlikely that they could be employed “safely” in clinical therapeutics. It so happens that slow-channel blocking compounds also inhibit calcium movements in smooth muscle;‘7*‘8 in so doing they reduce contraction thereby producing vasodilatation in the peripheral vessels and in the coronary circulation.4”7”9-2’ The peripheral vasodilator effect is of particular significance insofar as it may reflexly increase heart rate, AV conduction, and myocardial contractility while improving ventricular performance indirectly by reducing ventricular afterload. In this atricle, the electrophysiologic and hemodynamic effects of slow-channel blockade are discussed relative to the overall pharmacologic properties of the most significant compounds (Fig. 1). Since the precise delineation of their cardiocirculatory and electrophysiologic actions in intact animals and man is critically dependent on their fundamental effects on isolated cardiac and smooth muscle cells, the role of the slow channel in excitation-contraction coupling in these tissues will first be discussed in brief.

Electropharmacology of the slow-channel inhibitors in the management of cardiac arrhythmias: verapamil.

Electropharmacology of the slow-channel inhibitors in the management of cardiac arrhythmias: verapamil.