BACKGROUND: The increasing prevalence of routine radial artery (RA) use in coronary artery bypass grafting (CABG) has rendered the pharmacologic prevention of spasm of this artery a critical consideration in the early postoperative period and in the long-term outcome. In this study, we compared the effects of iloprost and diltiazem on vasospasm. METHODS: Seventy patients who underwent CABG with the RA were randomized into 2 groups, and the vasodilator effects of iloprost and diltiazem were studied prospectively. RA flow was measured with Doppler ultrasonography. Following harvesting, a 5-mm piece was removed from the RA distally for pathologic examination. In group B, diltiazem was infused before removing the RA, whereas in group A, iloprost infusion was initiated 5 days before surgery. At the end of a 2-year follow-up, each patient underwent coronary angiography. RESULTS: Doppler flow measurements made during harvesting revealed a statistically significant reduction in flow, and a pathologic examination of the RAs revealed significant luminal narrowing in group B. A 2-year angiographic follow-up revealed all of the RA grafts in group A to be patent. CONCLUSIONS: Our evaluation of the results revealed the superior efficacy of iloprost over diltiazem in preventing RA spasm in the early period, and the 2-year angiographic findings showed that the use of iloprost produced superior mid-term patency.

BACKGROUND: Lovastatin is oxidized by cytochrome P4503A to active metabolites but pravastatin is active alone and is not metabolized by cytochrome P450. Diltiazem, a substrate and a potent inhibitor of cytochrome P4503A enzymes, is commonly coadministered with cholesterol-lowering agents. METHODS: This was a balanced, randomized, open-label, 4-way crossover study in 10 healthy volunteers, with a 2-week washout period between the phases. Study arms were (1) administration of a single dose of 20 mg lovastatin,(2) administration of a single dose of 20 mg pravastatin,(3) administration of a single dose of lovastatin after administration of 120 mg diltiazem twice a day for 2 weeks, and (4) administration of a single dose of pravastatin after administration of 120 mg diltiazem twice a day for 2 weeks. RESULTS: Diltiazem significantly (P <.05) increased the oral area under the serum concentration-time curve (AUC) of lovastatin from 3607 +/- 1525 ng/ml/min (mean +/- SD) to 12886 +/- 6558 ng/ml/min and maximum serum concentration (Cmax) from 6 +/- 2 to 26 +/- 9 ng/ml but did not influence the elimination half-life. Diltiazem did not affect the oral AUC, Cmax, or half-life of pravastatin. The average steady-state serum concentrations of diltiazem were not significantly different between the lovastatin (130 +/- 58 ng/ml) and pravastatin (110 +/- 30 ng/ml) study arms. CONCLUSION: Diltiazem greatly increased the plasma concentration of lovastatin, but the magnitude of this effect was much greater than that predicted by the systemic serum concentration, suggesting that this interaction is a first-pass rather than a systemic event. The magnitude of this effect and the frequency of coadministration suggest that caution is necessary when administering diltiazem and lovastatin together. Further studies should explore whether this interaction abrogates the efficacy of lovastatin or enhances toxicity and whether it occurs with other cytochrome P4503A4-metabolized 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin.

1. The effects of diltiazem and verapamil on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a double-blind randomized cross-over study of three phases. 2. Nine healthy volunteers were given orally diltiazem (60 mg), verapamil (80 mg) or placebo three times daily for 2 days. On the second day they received a 15 mg oral dose of midazolam, after which plasma samples were collected and performance tests carried out for 17 h. 3. The area under the midazolam concentration-time curve was increased from 12 +/- 1 microgram ml-1 min to 45 +/- 5 micrograms ml-1 min by diltiazem (P < 0.001) and to 35 +/- 5 micrograms ml-1 min by verapamil (P < 0.001). The peak midazolam concentration was doubled (P < 0.01) and the elimination half-life of midazolam prolonged (P < 0.05) by both diltiazem and verapamil treatments. 4. These changes in the pharmacokinetics of midazolam were also associated with profound and prolonged sedative effects. 5. If the administration of midazolam cannot be avoided, the dose of midazolam should be reduced during concomitant treatment with diltiazem and verapamil.

The pharmacokinetic and pharmacodynamic effects of diltiazem were studied in 8 patients after a short intravenous infusion (20 mg over 10 minutes), a single oral dose (60 or 90 mg), and repeated oral administration (60 or 90 mg every 6 hours for 16 doses). Diltiazem levels decreased in a triexponential manner after intravenous infusion. Terminal half-lives after intravenous, single oral, and repeated oral administration were not significantly different (4.5 +/- 1.3, 3.7 +/- 0.6, and 4.9 +/- 0.4 hours, respectively). The kinetic effects of oral diltiazem were nonlinear. With repeated oral administration, there was accumulation of both diltiazem and its metabolite, deacetyldiltiazem. The diltiazem area under the time versus concentration curve increased by a factor of 2.39 +/- 0.42 (p = 0.00002). Most patients showed a double peaked time versus concentration curve after oral administration, indicating possible enterohepatic recirculation. After intravenous administration, there was a substantial increase in the P-R interval (14.3 +/- 5.4%). Although only small changes in P-R interval were seen with a single oral dose, with chronic administration there was persistent P-R interval prolongation, peaking at 17.3 +/- 5.6% over control. Counterclockwise hysteresis was present in the P-R interval versus plasma diltiazem concentration curve after intravenous administration. Only small changes were seen in heart rate and blood pressure.

The long-term effects of different antihypertensive regimens were studied in uninephrectomized beagles with alloxan-induced diabetes mellitus. Mean arterial pressure (MAP) was elevated (P < 0.05) in untreated diabetic dogs. Treatment of diabetic dogs with an angiotensin converting enzyme inhibitor (ACEI; lisinopril), a calcium antagonist (CA;TA-3090), or both lowered MAP. At one year, the RBF, GFR, and SNGFR were similarly elevated (P < 0.05) in all groups of diabetic dogs. The increase in SNGFR present in untreated diabetic dogs was primarily attributable to an increased (P < 0.05) glomerular capillary pressure (PGC). Treatment with lisinopril lowered the PGC to a mean value that was indistinguishable from that for nondiabetic dogs. In contrast, diabetic dogs treated with TA-3090 had an elevated PGC. While untreated diabetic dogs exhibited marked increases in glomerular volume (P < 0.05 vs. nondiabetic dogs), treatment with lisinopril and TA-3090, either alone or in combination, blunted the extent of glomerular hypertrophy observed in diabetic dogs (P < 0.05 vs. untreated diabetic dogs). Proteinuria was similarly reduced (P < 0.05 vs. untreated diabetic dogs) in dogs treated with lisinopril and TA-3090. Combination therapy of diabetic dogs produced a further significant (P < 0.05) decrement in proteinuria. We conclude that although treatment of diabetic dogs with either lisinopril or TA-3090 results in differential effects on PGC; each produces a similar decrement in proteinuria. Further, combination therapy has a greater effect on proteinuria than either agent alone.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Topical nitrates lower anal sphincter pressure and heal anal fissures, but a majority of patients experience headache. The internal anal sphincter has a calcium dependent mechanism to maintain tone, and also receives an inhibitory extrinsic cholinergic innervation. It may therefore be possible to lower anal sphincter pressure using calcium channel blockers and cholinergic agonists without side effects. AIMS: To investigate the effect of oral and topical calcium channel blockade and a topical cholinomimetic on anal sphincter pressure. METHODS: Three studies were conducted, each involving 10 healthy volunteers. In the first study subjects were given oral 60 mg diltiazem or placebo on separate occasions. They were then given diltiazem once or twice daily for four days. In the second and third studies diltiazem and bethanechol gels of increasing concentration were applied topically to lower anal pressure. RESULTS: A single dose of 60 mg diltiazem lowered the maximum resting anal sphincter pressure (MRP) by a mean of 21%. Once daily diltiazem produced a clinically insignificant effect but a twice daily regimen reduced anal pressure by a mean of 17%. Diltiazem and bethanechol gel produced a dose dependent reduction of the anal pressure; 2% diltiazem produced a maximal 28% reduction, and 0.1% bethanechol a maximal 24% reduction, the effect lasting three to five hours. CONCLUSIONS: Topical diltiazem and bethanechol substantially reduce anal sphincter pressure for a prolonged period, and represent potential low side effect alternatives to topical nitrates for the treatment of anal fissures.

To test the hypothesis that calcium antagonists decrease the incidence and severity of delayed graft function, we conducted three separate, prospective, randomized trials. In these trials, we investigated the effects of diltiazem and those of the prostacyclin analogue iloprost. In the first study, 22 control patients and 20 diltiazem patients received grafts perfused with either vehicle or diltiazem 20 mg/liter in the Euro-Collins solution. Subsequently, the diltiazem subjects were given the drug as a bolus of 0.28 mg/kg, followed by a continuous infusion of 0.002 mg/min/kg for the following two days. Thereafter, diltiazem 60 mg was given to the treated subjects orally for up to four years. In the second study, 11 control subjects and 10 diltiazem subjects received the same postoperative regimen, but all grafts were harvested without addition of diltiazem to the perfusion solution. In the third protocol, four groups were studied as follows: 19 control subjects who received no specific treatment, 16 subjects who received diltiazem, 16 subjects who were given iloprost, and 14 subjects who received both iloprost and diltiazem. The donor kidney of treated patients was perfused with either diltiazem, iloprost, or both drugs. Primary graft function occurred more commonly in the groups receiving diltiazem. Further, in the first study the number of hemodialyses per patient was reduced in those patients with delayed graft function. Fewer rejection episodes occurred in patients receiving diltiazem. Plasma levels of soluble interleukin-2 receptors decreased significantly during diltiazem treatment. Moreover, renal biopsies showed less severe signs of Cyclosporin A (CsA) nephrotoxicity in diltiazem-treated patients compared to controls, even though these patients also exhibited higher CsA trough levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Gamma-scintigraphy is applied extensively in the development and evaluation of pharmaceutical drug delivery systems. It is used particularly for monitoring formulations in the gastrointestinal and respiratory tracts. The radiolabelling is generally achieved by the incorporation of an appropriate technetium-99m or indium-111 labelled radiopharmaceutical into the formulation. In the case of complex dosage forms, such as enteric-coated tablets, labelling is best undertaken by the addition of a non-radioactive tracer such as samarium-152 oxide or erbium-170 oxide followed by neutron activation of the final product. Systems investigated include tablets and multiparticulates for oral administration, enemas and suppositories, metered dose inhalers and nebulisers, and nasal sprays and drops. Gamma-scintigraphy provides information on the deposition, dispersion and movement of the formulation. The combination of such studies with the assay of drug levels in blood or urine specimens, pharmacoscintigraphy, provides information concerning the sites of drug release and absorption. Data acquired from the scintigraphic evaluation of pharmaceutical dosage forms are now being used increasingly at all stages of product development, from the assessment of prototype delivery systems to supporting the product licence application.

BACKGROUND: Chronic anal fissure has traditionally been treated surgically. Initial enthusiasm for chemical sphincterotomy has waned because of poor outcomes with glyceryl trinitrate ointment. In this study the use of topical 2 per cent diltiazem ointment has been investigated as an alternative method of chemical sphincterotomy. METHODS: A prospective assessment of 71 consecutive patients with a chronic anal fissure treated with 2 per cent topical diltiazem ointment for a median duration of 9 (range 2--16) weeks was performed. RESULTS: Fifty-one patients (75 per cent) experienced healing of the fissure after 2--3 months of treatment with topical diltiazem. Seventeen patients who did not heal were treated for a further 8 weeks with topical diltiazem. Eight of these patients subsequently healed with diltiazem. Fifty-nine of 67 patients who completed follow-up therefore healed on diltiazem ointment. Four patients experienced perianal dermatitis and one patient experienced headaches. No other side-effects were recorded. After a median of 32 (range 14--67) weeks' follow-up following completion of treatment, 27 of 41 patients available remain symptom free. Six of seven patients with recurrent fissure were treated successfully by repeat chemical sphincterotomy. CONCLUSION: Topical 2 per cent diltiazem ointment used as an agent for chemical sphincterotomy for chronic anal fissure offers significant healing rates but does not have a significant side-effect profile, which may aid compliance to treatment. Early recurrences are common but usually amenable to further chemical sphincterotomy.

BACKGROUND: The prevalence of gingival overgrowth induced by chronic medication with calcium channel blockers is uncertain. Although there have been several studies examining this question, the results are conflicting, with previous estimates ranging from 20% to 83%. There have been only 2 studies examining the prevalence of overgrowth induced by diltiazem and amlodipine, with estimates of 74% and 3.3%, respectively. METHODS: The current study aimed to address the problems associated with these studies by examining a sample of patients taking one of 3 calcium channel blockers, who were drawn from a community-based population in northeastern England. Nine hundred eleven (911) subjects were recruited from general medical practices in the area. Of these, 442 were taking nifedipine, 181 amlodipine, and 186 diltiazem. In addition, 102 control subjects were examined. Drug and demographic data for each subject were recorded. The periodontal condition of all subjects was assessed including plaque index, papillary bleeding index, and a photograph of the anterior gingivae for subsequent analysis of overgrowth severity. RESULTS: More than six percent (6.3%) of subjects taking nifedipine were seen to have significant overgrowth. This overgrowth was statistically greater than the amount of overgrowth seen in either of the other 2 drug groups or the control population. The prevalence of gingival overgrowth induced by amlodipine or diltiazem was not statistically significant when compared to the control group. The severity of overgrowth within the nifedipine group was found to be related to the amount of gingival inflammation and also to the gender of the subject, with males being 3 times as likely to develop overgrowth than females. CONCLUSIONS: The prevalence of clinically significant overgrowth related to chronic medication with calcium channel blockers is low, i.e., 6.3% for nifedipine. Males are 3 times as likely as females to develop clinically significant overgrowth. The presence of gingival inflammation is an important cofactor for the expression of this effect.