Long-acting Calcium Channel Antagonist Research Articles

AMLOPIDINE AND DRESS SYNDROME: UP TO DATE WITH MY KNOWLEDGE?

Objective: Drug hypersensitivity syndrome or “Drug Reaction with Eosinophilia and Systemic Symptoms” (DRESS) is a severe form of cutaneous drug eruptions that combines skin manifestations and systemic damage. More than 50 drugs have been associated with this syndrome. Amlodipine is a long-acting calcium channel antagonist of type L (DHP), used as an antihypertensive drug. Peripheral edema remains one of the most common side effects of this drug, while dermatological events are very rare (1/100,000). We report a patient with DRESS syndrome who appeared under amlodipine treatment. Design and method: An 84-year-old hypertensive patient with eradicated chronic hepatitis C, chronic renal failure, idiopathic thrombocytopenia and dyslipidaemia was hospitalized with a febrile rash. Treatment with amlodipine 5 mg/d is prescribed for hypertension and then stopped by the patient after 15 days. Resumption of treatment is an accompanied at 4 weeks by a diffuse and infiltrated erythematous skin rash (initially suggestive of a large mesh livedo), associated with facial edema and fever at 39°. EKG is normal. The biological parameters: progressive hypereosinophilia up to 9 G/l, lymphopenia at 0,9 G/l with hyperbasophilic activated T lymphocytes (TL), hepatic cytolysis, HHV6 PCR is positive. The autoimmune test remains negative. The skin biopsy shows an inflammatory infiltrate, rich in eosinophils, with a few rare necrosis areas leading to cutaneous drug eruption. There is no vasculitis. The RegiSCAR score was 4. The discontinuation of amlodipine and high-dose dermocorticoids allowed the rash and hypereosinophilia is reduced within a few weeks until complete disappearance. The pharmacovigilance survey retained this diagnosis with proscription from this drug class. Results: The pathogenesis of DRESS syndrome is still very controversial. A hypersensitivity cytokine mediation of TL, and the reactivation of HHV6 are involved. The RegiSCAR score (European register of Serious Adverse Skin Reactions) is used to categorize the imputability to a drug. Amlodipine remains an exceptional cause but should be known because of the very common frequency of prescribing this treatment. Conclusions: DRESS syndrome is a rare but serious side effect of calcium channel blockers. Lack of knowledge can leaf to diagnostic errors and unnecessary additional examinations.

Combination Therapy as First-Line Treatment for Hypertension

Systemic hypertension is a long-term risk factor for the development of atherosclerotic vascular disease and when uncontrolled is a short-term trigger of acute vascular events such as acute coronary syndromes and stroke. Thus, rapid reduction in BP is desirable. Patients at high risk for vascular disease, such as those with diabetes mellitus, have aggressive goal BP targets because studies have shown that achieving these targets reduces events. Given the dual goals in high-risk patients of reducing BP quickly and to aggressively low targets, the classic 'step therapy' of one drug titrated at a time to reduce BP is inadequate. Combination therapy with at least two potent medications makes more sense, and manufacturers are now increasing their offerings of single-pill combinations for hypertension. Combination pills are popular with patients and increase compliance with therapy. Many believe that renin-angiotensin aldosterone system (RAAS) blockers are the cornerstone of hypertension treatment in patients at high risk for vascular disease. The newer combination pills include a RAAS blocker and diuretics or a long-acting calcium channel antagonist (CCA). Recent studies have shown that a RAAS blocker plus a dihydropyridine CCA is superior to older diuretic-based combinations for preventing cardiovascular events. These considerations support a new approach to the higher risk hypertensive patient: effective doses of RAAS blocker/CCA combination pills to rapidly lower BP to <130/80 mmHg.

Comparison of effect between nitrates and calcium channel antagonist on vascular function in patients with normal or mildly diseased coronary arteries

The comparative long-term antianginal efficacy of long-acting nitrates versus calcium channel antagonists remains unclear. The goal of the present study was to compare the coronary endothelial cell function and coronary artery vasoconstriction between patients with normal or mildly diseased coronary arteries treated with long-acting nitrates or calcium channel antagonists. Forty-two patients suspected to have angina pectoris and with normal or mildly diseased coronary arteries underwent Doppler flow study of the left anterior descending coronary artery. All patients were suspected to have angina pectoris and were receiving either long-acting nitrates (n = 18; Nitrates group) or calcium channel antagonists (n = 24; Ca-antagonists group) for at least 1 year. Vascular reactivity was assessed by intracoronary administration of papaverine, acetylcholine (Ach), and nitroglycerin using a Doppler guidewire. Segments that showed the greatest constrictive response to Ach were used for assessment of vasoconstriction. The percent increase in coronary blood flow (CBF) and coronary artery diameter (CAD) induced by Ach was significantly smaller in the Nitrates group than in the Ca-antagonists group (33% +/- 74% vs 83% +/- 77%, P < 0.05; -3% +/- 16% vs 11% +/- 12%, P < 0.01, respectively). The percent diameter reduction in the region of greatest constrictive response to Ach was significantly greater in the Nitrates group than in the Ca-antagonists group (44% +/- 39% vs 15% +/- 32%, P < 0.02). Long-term treatment with long-acting nitrates may produce less favorable effects on coronary endothelial function and the constrictive response to Ach when compared with long-acting calcium channel antagonists in patients with normal or mildly diseased coronary arteries.

Comparative Effects of Pranidipine with Amlodipine in Rats with Heart Failure

The aim of the present study was to compare the cardioprotective properties of long-acting calcium channel antagonist pranidipine with amlodipine in rat model of heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were randomized for the oral administration of low-dose amlodipine (1 mg/kg/day), high-dose amlodipine (5 mg/kg/day), pranidipine (0.3 mg/kg/day) or vehicle (0.5% methylcellulose). After oral administration for 1 month, the animals underwent echocardiography and hemodynamic analysis. Histopathology, immunohistochemistry, and Western immunoblotting were carried out in the heart samples. Both pranidipine and high-dose amlodipine increased survival rate. Although the heart rate did not differ among the four groups, left ventricular end-diastolic pressure was significantly decreased and ±dP/dt was increased in the pranidipine- and high-dose amlodipine-treated rats, but not in low-dose amlodipine-treated rats. In comparison to amlodipine treatment, pranidipine treatment significantly reduced myocyte size and central venous pressure. Furthermore, both pranidipine and high-dose amlodipine treatment significantly reduced myocardial protein levels of atrial natriuretic peptide and inducible nitric oxide synthase, whereas pranidipine only significantly decreased tumor necrosis factor-α, and improved sarcoplasmic reticulum Ca²⁺ATPase2 protein levels. We conclude that pranidipine ameliorates the progression of left ventricular dysfunction and cardiac remodeling in rats with heart failure after autoimmune myocarditis in a lower dose when compared to amlodipine and which may be a clinically potential therapeutic agent for the treatment of heart failure.

Impact of Therapy Initiation with Amlodipine or Losartan on Hemodynamic Endpoints and JNC-VI Blood Pressure Stage

The relative efficacy of long-acting calcium channel antagonists and angiotensin II receptor blocking agents has been described in clinical trials; however, their effectiveness in an actual practice setting has not been well studied. This study assessed the effectiveness of 2 commonly prescribed antihypertensives, amlodipine and losartan, either as monotherapy or as add-on for patients insufficiently controlled on beta-blocker or diuretic therapy. This was a retrospective, observational study that utilized electronic medical records. Hypertensive patients more than 40 years old who were new users of amlodipine or losartan were included in the study. Patients with congestive heart failure or those using antihypertensives other than diuretics or beta-blockers were excluded. Blood pressure (BP) readings were followed up to 6 months after enrollment. Univariate and multivariate regression models were used to assess the impact of amlodipine or losartan therapy on hemodynamic end points and on JNC-VI BP stage. A total of 346 patients met the entry criteria. Of these, 275 (79.5%) amlodipine and 71 (20.5%) were prescribed losartan. Mean changes in systolic and diastolic blood pressure were greater for patients receiving amlodipine in univariate and multivariate analyses (reduction of 20/8 and 11/4 mm Hg, respectively; P<0.05). Mean change in pulse pressure trended strongly in favor of amlodipine (11.8 mm Hg vs. 7 mm Hg, P = 0.08). Univariate analysis indicated that amlodipine-treated patients were more likely to move to a better JNC-VI BP stage, where as losartan-treated patients, on average, moved to a worse stage. Amlodipine therapy was superior to losartan therapy among this population of hypertensive patients.

A controlled trial of amlodipine for cocaine dependence: A negative report

Preclinical models of cocaine dependence have shown favorable reductions in cocaine use using dihydropyridine calcium channel antagonists. This is one of the first reports testing the efficacy of the long-acting calcium channel antagonist, amlodipine, for the treatment of cocaine dependence. This was a 12-week, double-blind, randomized, placebo-controlled, parallel patient group trial of amlodipine vs. placebo for the treatment of cocaine dependence. One hundred and sixteen subjects participated in a 12-week medication trial in which 60 subjects received medication and 56 received placebo. Subjects in both groups received up to 12 standard manual-driven cognitive behavioral therapy sessions. Overall, drop-out rate for both groups was high, with only about 20% of subjects completing all 12 weeks of treatment. Both groups showed comparable levels of medication compliance and therapy attendance. In the end, amlodipine was no more effective than placebo in reducing craving or measured levels of cocaine use.

Effect of an Angiotensin II Type 1 Receptor Blocker, Valsartan, on Neurohumoral Factors in Patients with Hypertension: Comparison with a Long-Acting Calcium Channel Antagonist, Amlodipine

This study compared the effects of amlodipine and valsartan on the sympathetic nervous system, the renin-angiotensin-aldosterone system, and brain natriuretic peptide, which are considered important parameters of the long-term prognosis. Seventy-three elderly patients, who had received antihypertensive treatment for more than 6 months with amlodipine, participated in this study. They were randomized to the V group (n = 36) and switched to valsartan from amlodipine, or to the A group (n = 37), which continued treatment with amlodipine. The dose of valsartan was set as that which controlled the blood pressure to the same extent as before switching. Blood samples were measured before and after 6 months of therapy. Data were analyzed by two-way analysis of variance with the Newman-Keuls test. In the V group, norepinephrine (from 597.0 +/- 52.9 to 475 +/- 43.8 pg/ml, p < 0.05) and aldosterone (from 74.5 +/- 7.0 to 53.9 +/- 5.3 pg/ml, p < 0.001) were decreased significantly after 6 months, although norepinephrine and aldosterone levels were unchanged in the A group. However, brain natriuretic peptide did not show a difference between the two groups. These findings suggested that valsartan is probably superior to amlodipine with respect to less activation of the sympathetic nervous system and preventing upregulation of the renin-angiotensin-aldosterone system.

Update on calcium antagonists and the kidney

PURPOSE OF REVIEW The treatment of hypertension has been proven to reduce cardiovascular and renal risk. The role of long-acting calcium channel antagonists in the management of hypertension has been confused in the past because of a lack of controlled clinical trials on people with hypertension and in subpopulations including those with diabetes and renal disease. The year 2002 saw the publication of the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the largest ever prospective drug-treatment trial, which involved 33 357 people with hypertension and included a calcium-antagonist group of 9048 individuals. Major publications on blood pressure control in people with kidney disease include the African American Study of Kidney Disease and Hypertension, and publications on people with diabetes include the results of the normotensive arm of the Appropriate Blood Pressure Control in Diabetes trial. RECENT FINDINGS The main finding, from the studies reported in the last year, is that blood pressure control can be achieved using one or more of the first-line agents, including diuretics, calcium antagonists and angiotensin-converting enzyme inhibitors. On the basis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, diuretics make clinical and economic sense as initial therapy for those with hypertension. Calcium antagonists are well tolerated and effective and should be considered as the initial drug therapy when diuretics are not tolerated or when multiple drug therapy is indicated. Angiotensin-converting enzyme inhibitors should be used in people with nephropathy, and, in these patients, will nearly always need to be part of multiple drug therapy to achieve blood pressure control. When blood pressure control can be achieved in largely non-nephropathic populations, there is further evidence that the drug class used as initial therapy may not be important. One of the main themes coming from the literature in the last year is that renal function is increasingly being recognized as an important outcome measure and marker of cardiovascular risk. SUMMARY The focus in blood pressure management must now be on identifying those with hypertension and bringing their blood pressure to target. For the majority of those with hypertension and renal disease, multiple drug therapy will be required, and, to achieve blood pressure targets, calcium antagonists are an appropriate part of this regimen. Particular attention is needed for nephropathic patients because of their higher risk of progression and the need for combination therapy; this group is likely to be the focus of future research and publications.

Update on calcium antagonists and the kidney.

The treatment of hypertension has been proven to reduce cardiovascular and renal risk. The role of long-acting calcium channel antagonists in the management of hypertension has been confused in the past because of a lack of controlled clinical trials on people with hypertension and in subpopulations including those with diabetes and renal disease. The year 2002 saw the publication of the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the largest ever prospective drug-treatment trial, which involved 33 357 people with hypertension and included a calcium-antagonist group of 9048 individuals. Major publications on blood pressure control in people with kidney disease include the African American Study of Kidney Disease and Hypertension, and publications on people with diabetes include the results of the normotensive arm of the Appropriate Blood Pressure Control in Diabetes trial. The main finding, from the studies reported in the last year, is that blood pressure control can be achieved using one or more of the first-line agents, including diuretics, calcium antagonists and angiotensin-converting enzyme inhibitors. On the basis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, diuretics make clinical and economic sense as initial therapy for those with hypertension. Calcium antagonists are well tolerated and effective and should be considered as the initial drug therapy when diuretics are not tolerated or when multiple drug therapy is indicated. Angiotensin-converting enzyme inhibitors should be used in people with nephropathy, and, in these patients, will nearly always need to be part of multiple drug therapy to achieve blood pressure control. When blood pressure control can be achieved in largely non-nephropathic populations, there is further evidence that the drug class used as initial therapy may not be important. One of the main themes coming from the literature in the last year is that renal function is increasingly being recognized as an important outcome measure and marker of cardiovascular risk. The focus in blood pressure management must now be on identifying those with hypertension and bringing their blood pressure to target. For the majority of those with hypertension and renal disease, multiple drug therapy will be required, and, to achieve blood pressure targets, calcium antagonists are an appropriate part of this regimen. Particular attention is needed for nephropathic patients because of their higher risk of progression and the need for combination therapy; this group is likely to be the focus of future research and publications.

Current treatment of patients with hypertension: therapeutic implications of INSIGHT.

When planning treatment for patients with hypertension, current guidelines emphasise the importance of risk stratification, based on blood pressure, the presence of end-organ damage and other cardiovascular risk factors. Because the beneficial effect of antihypertensive therapy seems to be linked to the degree of blood pressure reduction, guidelines recommend reducing blood pressure below 140/90mm Hg, with a lower target in patients who are young or who have diabetes mellitus (with or without nephropathy) or non-diabetic nephropathy. Blood pressure reduction can be achieved with several classes of drugs, including diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists and calcium channel antagonists. Calcium channel antagonists have been shown to reduce the risk of stroke and major cardiovascular events. However, it is still controversial whether different treatment regimens based on different drug classes can offer advantages beyond similar degrees of blood pressure control in preventing cardiovascular morbidity and mortality. The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) was a controlled clinical trial aimed at comparing the efficacy of a long-acting calcium channel antagonist, nifedipine gastrointestinal-transport-system (GITS), versus co-amilozide, a combination of the diuretics hydrochlorothiazide (HCTZ) and amiloride, on morbidity and mortality in high-risk hypertensive patients. Nifedipine GITS and HCTZ/amiloride were equally effective at reducing blood pressure and the risk of primary outcomes (a composite of death from any cardiovascular or cerebrovascular cause, non-fatal stroke, myocardial infarction and heart failure). Results from other studies indicate that there may be greater benefits for stroke and smaller benefits for coronary artery disease with calcium channel antagonist-based regimens than with diuretic or beta-blocker-based regimens. However, there is at present insufficient evidence to recommend a specific drug choice based on patient risk profile. Thus, the choice of antihypertensive drug(s) should be according to efficacy and tolerability. In addition to the reductions in cardiovascular risk, two substudies of INSIGHT showed that nifedipine GITS was able to prevent the progression of intima media thickness in the common carotid artery and slow the progression of coronary calcification. The clinical significance of this effect in the prevention of cardiovascular events still remains to be established.

Long-acting calcium channel antagonist pranidipine prevents ventricular remodeling after myocardial infarction in rats.

The purpose of this study was to examine the effects of the long-acting calcium channel antagonist pranidipine on ventricular remodeling, systolic and diastolic cardiac function, circulating humoral factors, and cardiac mRNA expression in myocardial infarcted rats. Myocardial infarction (MI) was produced by ligation of the coronary artery in Wistar rats. Three mg/kg per day of pranidipine was randomly administered to the infarcted rats. Hemodynamic measurements, Doppler echocardiographic examinations, analyses of the plasma levels of humoral factors, and myocardial mRNA expression were performed at 4 weeks after myocardial infarction. Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) increased to 24.2 +/- 1.2mmHg and 5.4 +/- 0.6 mmHg. Pranidipine reduced LVEDP and CVP to 13.6 +/- 1.4mmHg (P < 0.01) and 2.5 +/- 0.4mmHg (P < 0.01). The weight of the left and right ventricles in MI was significantly higher than in the sham-operated rats (sham, 2.02 +/- 0.04 and 0.47 +/- 0.02g/kg; MI, 2.18 +/- 0.05 and 0.79 +/- 0.04g/ kg; P < 0.01). Left ventricular end-diastolic dimension (LVDd) in MI increased to 10.3 +/- 0.3mm (P < 0.01) (sham, 6.4 +/- 0.3mm). Pranidipine prevented an increase in the weight of the left and right ventricles (2.02 +/- 0.04 and 0.6 +/- 0.03g/kg, P < 0.01) and LVDd (7.9 +/-0.2mm, P < 0.01 to MI). Plasma renin activity (PRA), and plasma epinephrine, norepinephrine, and dopamine concentrations in MI were higher than those of the sham-operated rats. Pranidipine decreased the PRA and plasma cathecolamine levels of the myocardial infarcted rats to the level of the sham-operated rats. Moreover, the rats in MI showed systolic dysfunction, shown by decreased fractional shortening (sham, 31 +/- 2% vs MI, 15 +/- 1%; P < 0.01) and diastolic dysfunction shown by the E-wave deceleration rate (sham, 12.8 +/- 1.1 m/s2; MI, 32.6 +/- 2.1 m/s2; P < 0.01). Pranidipine significantly prevented systolic and diastolic dysfunction. The increases in beta-myosin heavy chain (MHC), alpha-skeletal actin, and atrial natriuretic polypeptide mRNAs in the noninfarcted left ventricle and right ventricle at 4 weeks after the myocardial infarction were significantly suppressed by the treatment with pranidipine. On the other hand, depressed alpha-MHC was restored to normal levels by pranidipine in both regions. In conclusion, pranidipine prevents the left ventricular remodeling process accompanied by systolic and diastolic dysfunction, and inhibits abnormal cardiac gene expression after myocardial infarction.

Possible linkage between renal injury and cardiac remodeling in Dahl salt-sensitive rats treated with the calcium channel antagonist benidipine.

Interest in cardiovascular protection by calcium channel antagonists has grown over the past decade. We investigated the prevention of cardiac remodeling and renal injury by the long-acting calcium channel antagonist benidipine using 12 week-old Dahl salt-sensitive (Dahl S) rats fed a high-salt (4% NaCl) diet. Six-week benidipine treatment (10 mg/kg chow) decreased systolic blood pressure by 22% in Dahl S rats. This blood pressure reduction was associated with decreases in cardiac mass and weight of the aortic wall. Collagen content in the left ventricle tended to decline with benidipine treatment. In addition, glomerular filtration rate increased by 33% and arterial and glomerular lesions improved morphologically with this treatment. Regression of cardiac mass and collagen content in the left ventricle was due mainly to blood pressure reduction; however, collagen content in the low-pressure right ventricle was not only related to systemic blood pressure but to the severity of renal lesions. These data suggest that the calcium channel antagonist benidipine attenuates cardiac and renal injury in hypertensive Dahl S rats, and that part of the cardiac hypertrophy is due to a non-hemodynamic mechanism that might be responsible for, or be a consequence of, the lesions in the kidney.

New dihydropyridine calcium channel antagonist, pranidipine, attenuates hypertensive renal injury in Dahl salt-sensitive rats.

Interest in the cardiovascular protective effects of calcium channel antagonists has increased in the past decade. We investigated prevention of vascular wall remodeling by the long-acting calcium channel antagonist pranidipine in 12-week-old Dahl salt-sensitive (SS) rats with high-salt-induced (4% NaCl) hypertension. Six-week pranidipine treatment (60 mg/kg chow) decreased systolic blood pressure (SBP) by 22% in SS rats. This BP reduction was associated with decreases in cardiac mass and weight of the aortic wall. Glomerular filtration rate (GFR) was increased by 33%, but this did not lead to a decrease in urinary protein or NAG excretion. Morphologic investigation demonstrated striking resolution of arterial injury (medial necrosis and/or hyperplasia, inflammatory cell infiltration, and thrombus formation) by 87% after pranidipine treatment. Glomerular sclerosis was also attenuated by 61%, whereas tubular injury was improved by only 28%. These morphologic changes were reflected in the findings that the capacity of kidney homogenate for generating lipid peroxides was significantly decreased and that collagen levels and pattern type became similar to those of normotensive salt-resistant (SR) rats. Pranidipine also attenuated hypertensive vasculopathy in small arteries of the middle cerebral arteries. Thus, the calcium channel antagonist pranidipine can attenuate the vascular injury that occurs in salt-induced hypertension, a promising property that implicates its clinical usage, particularly in essential hypertension with cardiovascular complications.

Saturable metabolism of perhexiline maleate: Correlations with long-term toxicity

VERAPAMIL IN THE TREATMENT OF PRINZMETAL'S VARIANT ANGINA: A LONG-TERM, DOUBLE-BLIND, RANDOMIZED TRIAL. SM Johnson, MD, DR Mauritson, MD, LD Hillis, MD, FACC, JT Willerson, MD, FACC, U of Texas Health Science Center, Dallas, TX. This study was performed to assess the efficacy of verapamil (V) in patients (pts) with variant angina pectoris (VAP). 1n 13 pts (8 men, 5 women, mean age 52 yrs) with VAP, V (38&76 mg/day, meanfSD) was compared to placebo (P) in a double-blind, randomized, double-crossover trial of 9 months duration: 1 month of open-label V followed by four 2-month periods of blinded therapy (V-P-V-P or P-VP-V). Ten of 13 pts were maintained on stable doses of isosorbide dinitrate (128*55 mg/day) throughout the study. During each Z-month period, the following were quantitated: (1)chest pains/week (wk). (2)nitroglycerin (NTG) used/wk, and (3)required hospitalizations (HOS) for clinical instability. During the 4 months of V, the number of chest pains/wk (2.0f3.5) and the number of NTG/wk (2.5* 4.5) were less (pcO.01) than during P (12.1*27.8 pains/wk, 15.7f37.5 NTG/wk). None of 13 required HOS during V, but 4/13 required a total of 5 HOS during P (pcO.05). Of the 13 pts, 6 had clinical activity throughout the study, but the other 7 (54X) had prolonged periods of inactivity which, in 6/7, lasted the entire 8 months. In the 6 active pts V had a marked salutary effect (3.8f3.1 pains/wk, 4.645.7 NTG/wk) h w en compared to P (24.7f36.2 painslwk, 3O.lf49.8 NTG/wk, p<O.Ol). V was well tolerated, causing only minor constipation not requiring a change,of dosage. Thus, (1)many patients with variant angina have prolonged periods of clinical quiescence even without calcium antagonists, emphasizing the need for properly-designed studies of potential therapeutic agents; and (2)in a long-term, double-blind, randomized study, verapamil is safe and efficacious in the treatment of variant angina and is especially beneficial in those with clinically-active disease. SATURABLE HETABOCISH OF PERHEXILINE MALEATE: CORRELATIONS WITH LONG-TERM TOXICITY John D. Horowitz, MB; Pamela M. Morris, BSc; Olaf Drummer, MSc; Alan J. Goble, MD; and William J. Louis, MD, Departments of Cardiology and Clinical Pharmacology,Austin Hospital, Heidelberg, Victoria, Australia. Perhexiline maleate (Px) is a calcium channel antagonist which is an effective prophylactic anti-angina1 a‘gent, with minimal cardiovascular adverse effects. However, the chronic administration of Px may cause hepatitis or peripheral neuropathy, limiting the clinical usefulness of Px, which is cleared largely by hepatic hydroxylation. The current investigation examines the possibility of a pharmacokinetic basis for these adverse effects. Single-dose pharmacokinetic studies were performed in six patients with severe angina pectoris using oral Px doses of 150 and 300 mg. A sensitive (threshold 5 ng/ml) and specific high performance liquid chromatographic assay was used. Doubling of the Px dose was associated with a prolongation of mean elimination half-life (from ll.Zf2.1 S.E.M. to 19.1 k-2.8 hours; p<O.Ol) and a disproportionate increase (mean 5.3-fold)in area under the plasma concentration-time curve suggesting saturable hepatic hydroxylation of Px. Steadystate studies in 17 patients treated with Px indicated a therapeutic plasma concentration range of approximately 150 to 600 ng/ml. Five cases of Px toxicity (2 of peripheral neuropathy, one each of hepatitis, blurred vision and nausea) were all associated with Px levels above 700 ng/ml (mean 15702370 ng/ml), and were reversible with readjustment of Px dosage. We conclude that Px is a longacting calcium channel antagonist which is prone to accumulate in some patients due to limited capacity for hepatic Px metabolism. Monitoring of plasma Px concentrations at regular intervals will permit optimization of long-term therapy with Px. BENEFITS OF ADDED NIFEDIPINE IN UNSTABLE ANGINA PERSISTING DESPITE BETA BLOCKADE AND ISOSORBIDE DINITRATE Frans Hagemeijer, MD, FACC, Sint Franciscus Gasthus and Thoraxcenter, Erasmus University, Rotterdam, The Nether-