Slow-release Verapamil Research Articles

PS-R01-9: THE PERILS OF GRAPEFRUIT: A POTENTIALLY LETHAL INTERACTION WITH VERAPAMIL

Objective: Hereby we describe a case of severe toxicity induced by a standard dose of slow-release verapamil Design and Methods: Review of the patient's records and of the relevant literature. Results (Case Description): A 57-year old woman had been diagnosed with hypertension by her family physician, but her management had been complicated with intolerance to multiple antihypertensive drugs. On the occasion of a family conflict, she developed a hypertensive crisis, with a holocranial headache, tremor and palpitations, but no symptoms of ischemia on the EKG. After discharge from the Emergency Room she was referred to our Outpatient Hypertension Clinic in order to rule out secondary hypertension. For the workup, and in order to avoid interference with the renin-angiotensin-aldosterone system she was switched to slow-release verapamil 120 mg twice a day. One month afterwards the workup was completed: primary aldosteronism, pheochromocytoma/paraganglioma, renovascular hypertension and Cushing's syndrome had been ruled out. Her BP was adequately controlled with verapamil, with ABPM confirmation, and her tolerance was good. Considering her multiple drug intolerances, we decided to keep her on verapamil. Four months afterwards, the patient was brought back to the Emergency Room with severe hypotension and bradycardia, extreme asthenia, generalized rubor and diaphoresis, with normal lab tests except for mild creatinine elevation in the context of dehydration. Her SBP was 74 mmHg, with DBP not measurable, and HR 39 lpm; the EKG showed Wenckebach 2:1 AV block. After 48 hr in the Emergency Room with saline infusion and basic support measures the patient was discharged and referred again to our Clinic for reevaluation. A verapamil overdose was suspected, but the patient was adamant that she had always taken verapamil exactly as prescribed. A detailed anamnesis revealed that the patient had put on some weight the previous month and decided to lose it with a novelty diet based on the intake of about 2 liters of grapefruit fruit daily plus protein. She was switched to indapamide 2.5 mg daily with good tolerance and adequate BP control. Conclusions: Grapefruit juice contains 6’-7’dihydrohybergamottin, a powerful inhibitor of the key drug metabolizing enzyme CYP3A4, potentially causing accumulation of many common drugs such as verapamil, statins, ticagrelor, sildenafil, amiodarone or cisapride, and related toxicity. We need to remember that prescription drugs do not only interact among themselves but also with herbal remedies and common foodstuffs such as grapefruit.

Can Screening and Confirmatory Testing in the Management of Patients with Primary Aldosteronism be Improved?

Widespread application of the plasma aldosterone/renin ratio (ARR) as a screening test has led to the recognition that primary aldosteronism (PA) is the most common specifically treatable and potentially curable form of hypertension, accounting for 5-10% of patients. Maximal detection requires accurate diagnostic approaches and awareness and control of factors that confound results, including most antihypertensives, posture, time of day, dietary salt, and plasma potassium. Recent studies have revealed potential for false positives in patients on beta-adrenoceptor blockers, and, when direct renin concentration (but not plasma renin activity) is used to measure renin, in women during the luteal phase of the menstrual cycle or receiving estrogen-containing contraceptives or hormonal replacement therapy. In addition to verapamil slow release, hydralazine and prazosin, moxonidine has minimal effects on the ARR and can be used to control hypertension during work-up. Fludrocortisone suppression testing, while probably the most reliable means of definitively confirming or excluding PA, is time consuming and expensive, requiring a five day inpatient stay. A novel approach, upright (seated) saline infusion suppression testing (SST), has shown excellent reliability with much greater sensitivity than conventional recumbent SST in a recent pilot study, and requires only a day visit. Accurate measurement of aldosterone is essential for each step of PA workup: introduction of new, highly reliable high-throughput mass spectrometric methods into clinical practice has represented a major advance. In response to concerns raised about accuracy of renin assays, new mass spectrometric methods for measuring angiotensin II are currently being assessed in the clinical setting.

Acute Respiratory Distress Syndrome Associated with Intravenous Lipid Emulsion Therapy for Verapamil Toxicity, Successfully Treated with Veno-Venous ECMO

Calcium channel blocker (CCB) overdose is a potentially fatal poisoning. The use of intravenous lipid emulsion (ILE) therapy for CCB poisoning has emerged in the past few years. In 2017, the American College of Medical Toxicology published interim guidance for the use of ILE resuscitation in these cases. We report an uncommon complication of ILE, acute respiratory distress syndrome, treated with veno-venous extracorporeal membrane oxygenation (ECMO). Case report: A 40-year-old hypertensive woman presented with shock (blood pressure 62/34 mmHg, pulse 86/ min) following ingestion of 4,800 mg verapamil slow release and 1,500 mcg clonidine during a suicide attempt. She was treated with calcium gluconate, sodium bicarbonate, IV high dose insulin, IV glucagon, cardiac amines and vasopressors without response (blood pressure 69/37 mmHg, pulse 78/min). ILE was initiated, and two hours later, she developed acute respiratory failure necessitating intubation and mechanical ventilation. Due to poor oxygenation (pO2 44 mmHg; FiO2 100%) emergent veno-venous ECMO was instituted. After one hour her blood pressure increased to 104/50 mmHg (pulse 80, pO2 75 mmHg), and continued so until weaning from ECMO and ventilation. Conclusion: Acute respiratory distress syndrome can be a major life threating complication following ILE; venovenous ECMO is suggested for its treatment.

Treatment of hypertension in peripheral arterial disease

Peripheral arterial disease (PAD) causes considerable morbidity and mortality. Hypertension is a risk factor for PAD. Treatment for hypertension must be compatible with the symptoms of PAD. Controversy regarding the effects of beta-adrenoreceptor blockade for hypertension in patients with PAD has led many physicians to stop prescribing beta-adrenoreceptor blockers. Little is known about the effects of other classes of anti-hypertensive drugs in the presence of PAD. This is the second update of a Cochrane review first published in 2003. To determine the effects of anti-hypertensive drugs in patients with both raised blood pressure and symptomatic PAD in terms of the rate of cardiovascular events and death, symptoms of claudication and critical leg ischaemia, and progression of atherosclerotic PAD as measured by ankle brachial index (ABI) changes and the need for revascularisation (reconstructive surgery or angioplasty) or amputation. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Cochrane Peripheral Vascular Diseases Group Specialised Register (last searched March 2013) and CENTRAL (2013, Issue 2). Randomised controlled trials (RCTs) of at least one anti-hypertensive treatment against placebo or two anti-hypertensive medications against each other, with interventions lasting at least one month. Trials had to include patients with symptomatic PAD. Data were extracted by one author (DAL) and checked by the other (GYHL). Potentially eligible studies were excluded when the results presentation prevented adequate extraction of data and enquiries to authors did not yield raw data. Eight RCTs were included with a total of 3610 PAD patients. Four studies compared a recognised class of anti-hypertensive treatment with placebo and four studies compared two anti-hypertensive treatments with each other. Studies were not pooled due to the variation of the comparisons and the outcomes presented. Overall the quality of the available evidence was unclear, primarily as a result of a lack of detail in the study reports on the randomisation and blinding procedures and incomplete outcome data. Two studies compared angiotensin converting enzyme (ACE) inhibitors against placebo. In one study there was a significant reduction in the number of cardiovascular events in patients receiving ramipril (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.58 to 0.91; n = 1725). In the second trial using perindopril (n = 52) there was a marginal increase in claudication distance but no change in ABI and a reduction in maximum walking distance. A trial comparing the calcium antagonist verapamil versus placebo in patients undergoing angioplasty (n = 96) suggested that verapamil reduced restenosis (per cent diameter stenosis (± SD) 48.0% ± 11.5 versus 69.6% ± 12.2; P < 0.01), although this was not reflected in the maintenance of a high ABI (0.76 ± 0.10 versus 0.72 ± 0.08 for verapamil versus placebo). Another study (n = 80) demonstrated no significant difference in arterial intima-media thickness (IMT) in men receiving the thiazide diuretic hydrochlorothiazide (HCTZ) compared to those receiving the alpha-adrenoreceptor blocker doxazosin (-0.12 ± 0.14 mm and -0.08 ± 0.13 mm, respectively; P = 0.66). A study (n = 36) comparing telmisartan to placebo found a significant improvement in maximum walking distance at 12 months with telmisartan (median (interquartile range (IQR)) 191 m (157 to 226) versus 103 m (76 to 164); P < 0.001) but no differences in ABI (median (IQR) 0.60 (0.60 to 0.77) versus 0.52 (0.48 to 0.67)) or arterial IMT (median (IQR) 0.08 cm (0.07 to 0.09) versus 0.09 cm (0.08 to 0.10)). Two studies compared the beta-adrenoreceptor blocker nebivolol with either the thiazide diuretic HCTZ or with metoprolol. Both studies found no significant differences in intermittent or absolute claudication distance, ABI, or all-cause mortality between the anti-hypertensives. A subgroup analysis of PAD patients (n = 2699) in a study which compared a calcium antagonist-based strategy (verapamil slow release (SR) ± trandolapril) to a beta-adrenoreceptor blocker-based strategy (atenolol ± hydrochlorothiazide) found no significant differences in the composite endpoints of death, non-fatal myocardial infarction or non-fatal stroke with or without revascularisation (OR 0.90, 95% CI 0.76 to 1.07 and OR 0.96, 95% CI 0.82 to 1.13, respectively). Evidence on the use of various anti-hypertensive drugs in people with PAD is poor so that it is unknown whether significant benefits or risks accrue. However, lack of data specifically examining outcomes in PAD patients should not detract from the overwhelming evidence on the benefit of treating hypertension and lowering blood pressure.

Junctional bradycardia with verapamil in renal failure - care required even with mild hyperkalaemia

Treatment for hypertension with verapamil has a favourable renoprotective effect and is generally considered safe in patients with mild to moderate renal failure. In this report, we highlight the vulnerability of patients with mild to moderate renal failure to verapamil side effects especially in the presence of hyperkalaemia. We report two cases of junctional bradycardia with slow release (SR) verapamil therapy in the presence of mild hyperkalaemia in patients with mild to moderate chronic renal failure. Verapamil and hyperkalaemia may synergistically increase the vulnerability to atrioventricular conduction delay. Renal failure patients with baseline mild hyperkalaemia are particularly liable to bradyarrhythmias with SR verapamil. In such cases, we would recommend verapamil dose reduction and avoidance of SR formulation. In cases of verapamil toxicity, actively treating any level of hyperkalaemia is recommended.

Factors Affecting the Aldosterone/Renin Ratio

Although the aldosterone/renin ratio (ARR) is the most reliable screening test for primary aldo-steronism, false positives and negatives occur. Dietary salt restriction, concomitant malignant or renovascular hypertension, pregnancy and treatment with diuretics (including spironolactone), dihydropyridine calcium blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor antagonists can produce false negatives by stimulating renin. We recently reported selective serotonin reuptake inhibitors lower the ratio. Because potassium regulates aldosterone, uncorrected hypokalemia can lead to false negatives. Beta-blockers, alpha-methyldopa, clonidine, and nonsteroidal anti-inflammatory drugs suppress renin, raising the ARR with potential for false positives. False positives may occur in patients with renal dysfunction or advancing age. We recently showed that (1) females have higher ratios than males, and (2) false positive ratios can occur during the luteal menstrual phase and while taking an oral ethynylestradiol/drospirenone (but not implanted subdermal etonogestrel) contraceptive, but only if calculated using direct renin concentration and not plasma renin activity. Where feasible, diuretics should be ceased at least 6 weeks and other interfering medications at least 2 before ARR measurement, substituting noninterfering agents (e. g., verapamil slow-release±hydralazine and prazosin or doxazosin) were required. Hypokalemia should be corrected and a liberal salt diet encouraged. Collecting blood midmorning from seated patients following 2-4 h upright posture improves sensitivity. The ARR is a screening test only and should be repeated once or more before deciding whether to proceed to confirmatory suppression testing. Liquid chromatography-tandem mass spectrometry aldosterone assays represent a major advance towards addressing inaccuracies inherent in other available methods.

Extracorporeal Albumin Dialysis in Three Cases of Acute Calcium Channel Blocker Poisoning With Life-Threatening Refractory Cardiogenic Shock

We describe 3 patients admitted to the medical-surgical ICU in a university hospital with life-threatening cardiogenic shock after the ingestion of high doses of calcium channel blockers (8.4 g sustained-release diltiazem, 4.2 g sustained-release diltiazem, and 14.4 g slow-release verapamil). Cardiovascular failure and cardiac conduction disturbances were unresponsive to the usual therapy (eg, intravenous injection of high doses of calcium, glucagon, hyperinsulinemia-euglycemia therapy, fluid resuscitation) and to increasing doses of simultaneous infusions of adrenergic agonists. Albumin dialysis with Molecular Adsorbents Recirculating System (MARS) therapy was performed because of its unique ability to selectively remove from circulation protein-bound toxins (and potentially drugs) that are not cleared by conventional hemodialysis. A single procedure was successfully performed in each patient, which was followed by rapid weaning of adrenergic agonist agents and full recovery of the life-threatening cardiovascular failure. At 2-year follow-up, patients were asymptomatic. Albumin dialysis with MARS therapy may be effective when used as a rescue procedure in patients presenting with sustained, life-threatening cardiogenic shock as a result of massive calcium channel blocker poisoning.

TREATMENT OPTIMIZATION IN PATIENTS WITH STABLE ANGINA PECTORIS: FOCUS ON VERAPAMIL SR

Possibilities of angina pectoris pharmacotherapy are analyzed. Achievement of target heart rate (HR) 55-60 beats per minute in these patients is possible due to three classes of antianginal medications that slow down HR: beta blockers (BB), If-channel inhibitors, nondihydropyridine calcium channel blockers (CCB). Nondihydropyridine CCB verapamil in slow release (SR) formulation is focused. The main results of randomized clinical trials (APSIS, VHAS, CRIS, EVERESTH, VAMPHYRE, INVEST, VESPA, DAVIT-1, DAVIT-2), which have proven efficacy and safety, are presented. Verapamil SR is indicated for the treatment of angina pectoris in patients without history of myocardial infarction (MI); angina patients experienced MI without systolic heart failure and with contraindications to BB; angina with arterial hypertension; left ventricular diastolic dysfunction; peripheral arteries obliterating atherosclerosis; silent myocardial ischemia; vasospastic angina; angina associated with supraventricular cardiac arrhythmias (especially in permanent atrial fibrillation) except Wolff-Parkinson-White and Lown-Ganong-Levine syndromes; after coronary angioplasty and the placement of bare metal stents.

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Treatment of Polypharmacy Overdose with Multimodality Extracorporeal Life Support

A 45-year-old woman presented to the emergency department of a tertiary referral hospital after taking an overdose of verapamil, doxepin, quetiapine, diazepam, temazepam, and clonazepam. She rapidly developed shock refractory to pharmacological support and was placed on percutaneous venoarterial extracorporeal membrane oxygenation (ECMO). She had a severe metabolic acidosis from a combination of shock and drug intoxication that improved with continuous venovenous haemodialysis. Forty-eight hours after presentation, while still on ECMO, the patient had complete cardiac standstill for three and a half hours, attributable to slow-release verapamil, that resolved after the commencement of plasmapheresis. The role of plasmapheresis in verapamil overdose requires further study.

Evaluation of the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention: The randomized, double-blind, placebo-controlled, multicenter verapamil slow-release for prevention of cardiovascular events after angioplasty (VESPA) trial

Evaluation of the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention: The randomized, double-blind, placebo-controlled, multicenter verapamil slow-release for prevention of cardiovascular events after angioplasty (VESPA) trial

Evaluation of the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention: The randomized, double-blind, placebo-controlled, multicenter verapamil slow-release for prevention of cardiovascular events after angioplasty (VESPA) trial

ObjectivesWe investigated the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention (PCI). BackgroundThus far, there is no established systemic pharmacologic approach for the prevention of restenosis after PCIs. Five small studies reported encouraging results for calcium channel blockers. MethodsOur randomized double-blind trial included 700 consecutive patients with successful PCI of a native coronary artery. Patients received the calcium channel blocker verapamil, 240 mg twice daily for six months, or placebo. Primary clinical end point was the composite rate of death, myocardial infarction, and target vessel revascularization (TVR) during one-year follow-up; the angiographic end point was late lumen loss at the six-month follow-up angiography. ResultsWe obtained complete clinical follow-up in 95% of the patients, and scheduled angiography was performed in 94%. The proportion of patients treated with stents was 83%. The primary clinical end point was reached in 67 (19.3%) patients on verapamil and in 103 (29.3%) patients on placebo (relative risk [RR] 0.66 [95% confidence interval (CI) 0.48 to 0.89]; p = 0.002). This difference between the groups was driven by TVR (17.5% with verapamil vs. 26.2% with placebo; RR 0.67 [95% CI 0.49 to 0.93]; p = 0.006). Late lumen loss was 0.74 ± 0.70 mm with verapamil and 0.81 ± 0.75 mm with placebo (p = 0.11). Compared with placebo, verapamil reduced the rate of restenosis ≥75% (7.8% vs. 13.7%; RR 0.57 [95% CI 0.35 to 0.92]; p = 0.014). ConclusionsVerapamil compared with placebo improves long-term clinical outcome after PCI of native coronary arteries by reducing the need for TVR. This was caused by a reduction in the rate of high-grade restenosis.

Effects of Verapamil Slow Release Plus Trandolapril Combination Therapy on Essential Hypertension

Background: Fixed-dose combination antihypertensive therapy has been recommended for patients with essential hypertension who are unresponsive to monotherapy or as a first-line treatment. Objective: We investigated the effects of a fixed-dose combination of the phenylalkylamine-type calcium channel blocker verapamil slow release (SR)plus the angiotensin-converting enzyme inhibitor trandolapril on blood pressure (BP), serum lipid profile, urinary albumin excretion (UAE), left ventricular mass (LVM), and LVM index (LVMI), as well as the adverse events associated with this treatment. Methods: Patients aged 30 to 65 years with mild to moderate essential hypertension were included in the study. All of the patients received capsules containing combination treatment with verapamil SR 180 mg plus trandolapril 2 mg orally, daily for 12 weeks. Mean arterial pressure (MAP), systolic BP (SBP), diastolic BP (DBP), and heart rate (HR) were measured at baseline and at 4, 8, and 12 weeks of treatment. Serum lipid profile, UAE, LVM, LVMI, and body mass index (BMI) were determined at baseline and at the end of the study period. All patients underwent electrocardiography and echocardiography at baseline and week 12. The primary end point of the study was to achieve an SBP/DBP ≤140/≤90 mm Hg (ie, normotensive) during week 12. All adverse events were assessed as mild, moderate, or severe at each visit. According to the response rate at week 12, patients were divided into 2 groups: those who became normotensive ( responders) or those who remained hypertensive (SBP/DBP >140/>90 mm Hg; nonresponders). Results: Forty-one patients (29 women, 12 men; mean [SD] age, 47.7 [7.8] years; mean [SD] BMI, 29.4 [3.5] kg/m 2) were enrolled. The median durationof hypertension prior to enrollment was 5 months. Mean MAP, SBP, DBP, UAE, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), LDL-C/highdensity lipoprotein cholesterol (HDL-C) ratio, LVM, LVMI, and BMI decreased significantly after 12 weeks of combination treatment; HR and triglyceride level did not change significantly. Treatment-related adverse events occurred in 31.7% of patients, and none were severe or caused any patient to withdraw from the study. The most common adverse events were cough, constipation, headache, and dryness in the throat. Microalbuminuria, which may be a marker of endothelial dysfunction, was found in 7 (17.1%) patients at baseline and regressed significantly after 12 weeks. Conclusions: In this study population, the fixed-dose combination of verapamil–trandolapril was an effective and well-tolerated antihypertensive therapy. This combination significantly reduced MAP, BP, TC, LDL-C, LDL-C/HDL-C ratio, UAE, LVM, and LVMI. Also, microalbuminuria decreased after this treatment. Verapamil–trandolapril may be useful in preventing microalbuminuria and left ventricular hypertrophy in patients with essential hypertension.

Antihypertensive effects of six calcium antagonists: evidence from Fourier analysis of 24-hour ambulatory blood pressure recordings

Background: Blood pressure is characterized by a circadian rhythm, with lower values during sleep and periods of minimal activity, and higher values during the day and periods of mental and physical activity. An increased blood pressure variability has been reported to contribute independently to the higher cardiovascular risk of hypertensive patients; reducing this variability has therefore become an important goal of antihypertensive treatment. Objective: The aim of this study was to assess the ability of various calcium channel antagonists to reduce 24-hour average blood pressure and to study the effect of these agents on blood pressure variability, particularly on the blood pressure variations between day and night and the slope of the blood pressure increase that typically occurs in the morning at awakening. Methods: A total of 110 patients with grade 1 or grade 2 essential hypertension (diastolic blood pressure 90–109 mm Hg) were randomly assigned to receive nifedipine slow release (SR) 20 mg BID (n = 20), nifedipine gastrointestinal therapeutic system 60 mg QD (n = 20), amlodipine 10 mg QD (n = 20), felodipine extended release (ER) 10 mg QD (n = 15), verapamil SR 240 mg QD (n = 20), or lercanidipine 10 mg QD (n = 15) for 4 months. Each patient's blood pressure was monitored in ambulatory conditions over 24 hours before treatment and after 2 and 4 months of treatment. The 24-hour, daytime, nighttime, and hourly average values and trough-to-peak ratios were computed. Original data series were also analyzed by means of a Fourier model with 4 harmonics, and the blood pressure increase per time unit in the morning was computed. Results: The study sample included 60 men and 50 women (mean age ± SD, 53.2 ± 1.9 years). Based on the Fourier analysis, all patients in each treatment group experienced improvement in their blood pressure profile. With the exception of felodipine ER, all the compounds studied induced a significant ( P < 0.01) and uniform blood pressure reduction versus baseline throughout the 24-hour period. None of the drugs caused major alterations in the 24-hour blood pressure profile, although individual drugs had slightly different effects on the nocturnal blood pressure decrease. Trough-to-peak ratios were ≥0.50 in all groups. A significant decrease in the slope of blood pressure rise in the morning hours ( P < 0.05) was observed after treatment with amlodipine, nifedipine SR (twice daily), and lercanidipine. This finding may be relevant since it is well known that the slope of blood pressure increase at awakening is related to an increase in cardiovascular risk. Conclusions: Given the link between blood pressure fluctuations and cardiovascular risk, all new antihypertensive drugs should be tested for their ability not only to reduce 24-hour mean blood pressure levels, but also to maintain physiologic 24-hour blood pressure profiles and to prevent excessive blood pressure fluctuations.

Less Adrenergic Response to Mental Task During Verapamil Compared to Amlodipine Treatment in Hypertensive Subjects

We compared the effects of amlodipine and verapamil slow release on autonomic responses to a 5-min mental arithmetic test (MST) in patients with mild to moderate hypertension. Twenty subjects received 8 weeks of verapamil slow release 240 mg or amlodipine 10 mg in a double-blind crossover design, both after 4 weeks' placebo. Heart rate (HR) and blood pressure (BP) were continuously monitored. Venous plasma catecholamines were analysed by a radioenzymatic assay. Baroreflex sensitivity (BRS) was estimated with the transfer function technique. Calculations of the area under the curve (AUC) were used to estimate average HR, BP and catecholamine concentrations. The reactivity to MST was estimated as percent change from the basal AUC. A paired t

Fixed-dose combination therapy with trandolapril and verapamil SR is effective in primary hypertension

We assessed the efficacy of monotherapy with trandolapril, an angiotensin converting enzyme (ACE) inhibitor, and of verapamil slow-release (SR), a calcium antagonist, each in a range of three doses as monotherapy, and in the nine possible combinations of therapy in patients with stage I to III diastolic hypertension. After 4 weeks of single-blind placebo, 746 patients in 39 study centers were randomized to one of the 16 double-blind treatments for 6 weeks (placebo; verapamil SR monotherapy 120, 180, or 240 mg; trandolapril monotherapy 0.5, 2, or 8 mg; and trandolapril/verapamil SR combinations 0.5/120, 0.5/180, 0.5/240, 2/120, 2/180, 2/240, 8/120, 8/180, or 8/240 mg. Both mono- and combination therapies achieved the primary efficacy parameters: lowered supine diastolic blood pressure (at trough) more than placebo, P < .01 (except 0.5 mg trandolapril, 0.5/180 and 2/120 combinations, P < .05, and the 120 mg verapamil SR, P = NS). The therapies yielded a trough to peak ratio of >0.52 and had higher percentages of responders as compared with placebo ( P < .01, < .05). Supine systolic blood pressures were lowered more by combination therapy than the respective monotherapies, P < .05, P < .01, except the 8/120 combination. Combination therapy was more effective than monotherapy for sitting diastolic blood pressure, P < .05. The percentage of patients with adverse reactions were similar for mono- and combination therapy. Trandolapril had a greater “apparent” incremental effect on the systolic blood pressure reductions than verapamil SR.

Combination treatment in hypertension the VeraTran Study

In the past few years, the combination of two antihypertensive drugs has become a popular approach to hypertension treatment, because this procedure allows one to obtain satisfactory blood pressure control when monotherapy is partially ineffective and also to improve a patient's adherence to the therapeutic regimen, thereby enhancing the tolerance/effectiveness ratio of the treatment. This paper will briefly review the theoretical background and the requirements for an effective combination treatment. It will also discuss the results of the VeraTran Study, a multicenter study performed according to a double-blind parallel group design and aimed at assessing the antihypertensive efficacy of the fixed combination verapamil slow release (SR) and trandolapril, administered for 8 weeks, on clinic and 24-h ambulatory blood pressure. The results of the study demonstrate that the fixed combination of a calcium antagonist and an angiotensin converting enzyme (ACE) inhibitor allows one to obtain an effective and balanced blood pressure control throughout the 24 h.

Trandolapril and verapamil slow release in the treatment of hypertension: a dose-response assessment with the use of a multifactorial trial design

In this multicenter, multifactorial placebo-controlled, double-masked trial, we assessed the tolerability and antihypertensive efficacy of monotherapy with trandolapril, an angiotensin-converting enzyme inhibitor, monotherapy with verapamil slow-release (SR) formulation, or combination therapy with the two drugs, all at various doses. After a 4-week, placebo run-in period, 726 patients with mild-to-moderate hypertension (sitting diastolic blood pressure [DBP], 95 to 114 mm Hg) were randomized to receive 1 of the 16 treatment combinations of placebo, trandolapril alone, verapamil SR alone, or varying combinations of trandolapril and verapamil SR for 6 weeks. Sitting DBP and systolic blood pressure were monitored during the trial. Satisfactory response was defined as a posttreatment sitting DBP <90 mm Hg or a ≥10-mm Hg decrease from baseline. Three trandolapril/verapamil SR combinations—2 mg/180 mg, 2 mg/240 mg, and 8 mg/240 mg—were significantly more effective in decreasing sitting DBP than monotherapy with either drug. Trandolapril alone, verapamil SR alone, and trandolapril combined with verapamil SR administered once daily were well tolerated in patients with mild-to-moderate hypertension.

Nausea and Malaise During Treatment of Coccidioidomycosis

A 48-year-old man with cough, fever, and malaise was found to have disseminated Coccidioides immitis infection. He had a history of rheumatic heart disease with mitral valve stenosis and paroxysmal atrial fibrillation. A porcine mitral valve replacement had been performed one year earlier. His daily medications included warfarin, 5 mg; hydroxyzine, 10 mg; digoxin, 0.25 mg; and slow-release verapamil, 480 mg.Therapy was started with amphotericin B, 2.5 gm given intravenously, followed by itraconazole, 200 mg twice a day. Four weeks later the patient complained of malaise and nausea. On examination, he appeared to be in no acute distress. Blood pressure was 121/54 mm Hg; pulse, 55 beats per minute and regular; respirations, 18 per minute; temperature, 37.0°C. Examination of the skin, head, ears, eyes, nose, throat, and neck were unremarkable. The chest was clear. There was a grade 2 systolic ejection murmur, with no rub or gallop. The remainder of the examination was unremarkable.The complete blood cell count and serum levels of electrolytes, blood urea nitrogen, creatinine, and glucose were normal. The ECG is shown.

Activated Charcoal for Slow-Release Verapamil

Verapamil, a widely used calcium channel blocker, is usually absorbed rapidly after ingestion. Because of verapamil's relatively short half-life and need for frequent dosing, slow-release preparations have gained popularity. The potentially delayed absorption of these preparations may have implications for activated charcoal therapy in …