Combination therapy with diltiazem plus CsA/MMF/Pred or CsA/Aza/Pred triple immunosuppressive regimens for use in clinical kidney transplantation in Northwestern China.

OBJECTIVE: The effects of diltiazem on 1692 kidney transplant recipients under the immunosuppressive regimen of cyclosporine A (CsA) in combination with either mycophenolate mofetil or azothioprine were assessed. The two treatment groups were compared for blood concentrations of CsA, the extent of acceptable dosage reduction for the maintenance of immunotherapy, potential effects of kidney protection, and promotion of graft function. METHOD: We monitored changes of blood concentrations of CsA in the two different patient treatment groups for post-transplant graft function, episodes of acute rejection, and hepatic and renal toxicity in 1640 renal transplant recipients after treatment with diltiazem. RESULTS: In patients treated with the triple immunosuppressive regimen consisting of CsA, azothioprine, and prednisolone (Pred), the sub-group of patients receiving the diltiazem treatment saw a significantly reduced CsA dosage in comparison to the non-diltiazem group (control group 1) (P < 0.05), but the blood concentrations of CsA of the diltiazem group were higher than those of control group 1 (P < 0.01). Of the patients treated with CsA, mycophenolate mofetil, and Pred, the sub-group of patients also treated with diltiazem showed similar effects: CsA dosage was reduced (P < 0.01) and the blood concentrations of CsA significantly increased (P < 0.01) in comparison with those of control group 2. In addition, recovery time of graft function decreased to 4.7 ± 1.8 days and 3.9 ± 1.4 days in the two diltiazem treatment groups, respectively (P < 0.05), and the rate of acute rejection decreased to 21 (p < 0.05) and 7.9% (P < 0.01), respectively. CONCLUSION: In our cohort of renal transplantation patients, co-administration of CsA and diltiazem increased CsA blood concentration, thereby resulting in a reduction in its required dosage treatment, which lightened the patients' economic burden while improving primary and long-term kidney function by promoting the recovery of graft function and decreasing hepatic and renal toxicity. The co-administration of diltiazem may also reduce the rate of acute rejection, especially in patients who also receive the triple immunosuppressive regimen consisting of CsA, mycophenolate mofetil, and Pred.

[Treatment of chronic anal fissures: diltiazem or isosorbide dinitrate as first choice?]. / Behandeling van chronische anale fissuren. Diltiazem of isosorbidedinitraat als middel van eerste keus?

Chronic anal fissures are a painful condition frequently seen in general practice, with an incidence of 2,5/1000 per year. According to the practice guidelines of the Dutch College of General Practitioners, isosorbide dinitrate 1% ointment (ISDN) is the treatment of first choice for chronic anal fissures. Systemic side-effects such as headache are reported in 27% of all cases. This side effect in combination with the frequent application of ISDN (4-6 times daily) leads to a low compliance for this therapy. A meta-analysis of the Cochrane Collaboration showed similar efficacy of diltiazem compared to ISDN. Diltiazem has several advantages: the application frequency is only twice daily, no systemic side-effects have been reported, the total costs of treatment are lower than the costs of ISDN and a standard preparation of diltiazem ointment is available. Therefore, diltiazem 2% ointment should be the first line treatment for chronic anal fissures.

Pharmacological advancements in the treatment of chronic anal fissure.

Chronic anal fissure is a tear in the lining of the anal canal that, if not treated appropriately at an early stage, causes considerable anal pain during defaecation. Surgery is no longer considered the first-line treatment of this common condition, as recent advancements in medical treatment has produced promising results in the healing of fissures, thus avoiding the unwanted complications that frequently occur following operative treatment. This review looks at those pharmacological agents used commonly in the treatment of chronic anal fissures and explores alternative therapies that may be of benefit in the future.

Diltiazem co-treatment in renal transplant patients receiving microemulsion cyclosporin.

BACKGROUND: Usage of cyclosporin (the Hong Kong Hospital Authority's single largest item of drug expenditure) continues to increase, mainly due to increasing numbers of renal allograft patients taking it as long-term antirejection therapy. Diltiazem, an antihypertensive agent, interferes with the first pass extraction of oral cyclosporin, thus serving to conserve its dosage. AIMS: In renal transplant patients, to assess whether diltiazem co-treatment could achieve worthwhile dosage conservation of Neoral (a relatively new microemulsified cyclosporin formulation), safely. METHODS: A randomized, placebo-controlled, double-blind clinical trial was undertaken at three local hospitals. Renal transplant recipients receiving Neoral as prophylactic immunosuppression were randomized to two treatment arms. Active treatment consisted of diltiazem tablets 30 or 60 mg twice daily for patients weighing < 60 or >or= 60 kg, respectively. One hundred and ten eligible patients gave their informed consent, and were followed up for at least six months. The mean difference in the dollar cost in the sixth month was the primary outcome. Secondary/ancillary outcomes included changes in cyclosporin dosage and blood level, and untoward clinical events including rejection. Outcomes were evaluated by intention to treat analyses. RESULTS: During weeks 23-26 (sixth month) post randomization, diltiazem co-treatment yielded an estimated average cost saving per patient on drugs of 15%[the 95% confidence interval (CI) of the difference being HK dollars 609 +/- 517 or pound 50 +/- 42], with no apparent excess of untoward or adverse events, complications, hospitalization, outpatient visits, or inferior quality of life. CONCLUSIONS: This diltiazem co-treatment regime applied to the nearly 1800 surviving renal allograft patients followed up in Hospital Authority hospitals could have saved approximately HK dollars 14.3 million ( pound 1.17 million) annually, without adverse sequelae.

Esmolol versus diltiazem in the treatment of postoperative atrial fibrillation/atrial flutter after open heart surgery.

BACKGROUND: Supraventricular tachyarrhythmias are common after open heart surgery. Possible causative factors for these arrhythmias include operative trauma, atrial ischemia, electrolyte imbalances, pericardial irritation, and excess catecholamines. Two agents commonly used to control ventricular rate in atrial fibrillation or atrial flutter (AF/AFL) are beta-blockers and calcium channel blockers. METHODS AND RESULTS: This randomized study was designed to compare the safety and efficacy of intravenous diltiazem versus intravenous esmolol in patients with postoperative AF/AFL after coronary bypass surgery and/or valve replacement surgery. A comparative cost analysis was also performed. Thirty patients received either esmolol (n = 15) or diltiazem (n = 15) for AF/AFL. During the first 6 hours of treatment, 66.6% of esmolol-treated patients converted to sinus rhythm compared with 13.3% of the diltiazem-treated patients (P <.05). At 24 hours, 66.6% of the diltiazem group converted to SR compared with 80% of the esmolol group (not significant). Drug-induced side effects, time to rate control (<90 beats/min), number of patients requiring cardioversion, and length of hospitalization were similar for the two groups. The drug cost/successfully treated patient for esmolol versus diltiazem was $254 versus $437 at 6 hours and $529 versus $262 at 24 hours. CONCLUSIONS: Although this is a small study, it suggests that esmolol is more effective in converting patients to normal sinus rhythm than diltiazem during the initial dosing period. No differences in conversion rates were observed between the two groups after 24 hours. Additional studies are needed to confirm whether esmolol is the initial drug of choice in patients with postoperative AF/AFL after coronary bypass surgery.

The use of other drugs to allow a lower dosage of cyclosporin to be used. Therapeutic and pharmacoeconomic considerations.

Since its discovery in 1970, and introduction into clinical practice in 1978, cyclosporin has become the most important immunosuppressive drug used to prevent organ transplant rejection. This has been achieved by virtue of the improved graft survival rates and adverse effect profiles in patients when compared with that of the older agents. Cyclosporin is substantially more expensive (both to provide and to monitor) however, and the magnitude of these costs may preclude its use, particularly where the transplant recipient is required to pay. Cyclosporin has a complex pharmacokinetic profile with poor absorption, extensive metabolism to more than 30 metabolites and considerable inter- and intrapatient variability. Many transplant centres routinely use drugs ("cyclosporin-sparing agents') to allow a reduction in the dosage of cyclosporin while maintaining therapeutic blood cyclosporin concentrations. The use of a second drug to affect the pharmacokinetic profile of a primary drug is not new, but the use of cyclosporin-sparing agents is a departure from previous practices in that this coprescription is primarily for economic reasons. The decision to use these agents (and the choice of agent) is based upon economic and other factors including the extent of the cyclosporin-sparing effect, the potential for additional therapeutic benefit and/or adverse effects. The coprescription of cyclosporin-sparing agents is ethically more acceptable where the transplant recipient is the economic beneficiary but where the savings accrue to a third party it is more difficult. Benefits to the community at large must be balanced against the risk of adverse effects to the patient. The use of cyclosporin-sparing agents may reduce compliance and hence, jeopardise transplant and/or recipient outcomes. The transplant recipient must be informed about the reasons for their use and advised to consult an experienced physician or pharmacist before altering the established drug regimen.

Reference-based pricing in British Columbia: implications for cardiologists--an analysis.

Under the reference-based pricing (RBP) policy, British Columbia will fund drug therapies based on the cost of the 'gold standard' therapy that meets the needs of the majority of patients with a specific condition. Hence, Pharmacare will pay for the lowest cost drug within a cluster of related but different drugs, regardless of the indication. When evaluating the impact of drugs on health care expenditure, one must consider that their costs are more than offset by the clinical and economic benefits they provide. Pharmaceutical expenditure accounts for a small proportion of health care expenditure and should be viewed as an essential and interactive component in the global health care budget rather than as an independent constituent. In that respect, insight should be gained from many countries in which RBP has been implemented A wealth of data converge to the same conclusion: price controls and restricted access to drugs do not reduce prescription drug expenditures but actually increase health care costs. Furthermore, cost containment being the main issue behind RBP in British Columbia, the contentious issue of therapeutic substitution has not been taken fully into consideration, nor has its impact on the quality of care of the patient. The case of diltiazem once-a-day versus diltiazem tablets for hypertensive and angina patients illustrates the important considerations that must be taken into account in writing the overall financial equation that drives the implementation of the RBP policy. If pharmacotherapy is to be an appropriate treatment to attain optimal cost effective health care, its benefit can only be optimized with a strategy that entails the right therapy, for the right patient, in the right dosage form and at the right time. Accordingly, RBP in British Columbia should be analyzed in light of patient welfare and appropriate use of collective resources.

Survey of cyclosporin-sparing agent use in Australasian transplant centres.

BACKGROUND: The co-prescription of drugs which elevate cyclosporin blood concentration has been advocated to reduce the costs associated with use of this expensive immunosuppressive drug. This is the first time that drugs have been widely prescribed for an economic purpose and while it is thought to be widespread, there are little published data on the extent of this practice in Australia and New Zealand. AIMS: To determine the extent to which cyclosporin sparing agents are used by Australian and New Zealand organ transplant centres, to determine which agents are used and why these agents are used by some but not all centres. METHODS: Organ transplant centres were surveyed via a questionnaire. RESULTS: Considerable variation in use of cyclosporin sparing agents exists both within and across organ transplant types by Australian and New Zealand transplant centres. Diltiazem use is more widespread than ketoconazole. CONCLUSIONS: Little of the variability in use of cyclosporin sparing agents can be explained by scientific considerations. While the central government benefits from the significant cost savings achieved by the use of cyclosporin sparing agents, individual transplant units may not. Transplant units may however be the major target in the event of litigation arising as a result of adverse effects. The availability of generic brands and improved formulations of cyclosporin may affect the viability of using cyclosporin sparing agents.

Treatment of supraventricular tachyarrhythmias with intravenous calcium channel blockers: are subtle differences worth the cost?

Verapamil and diltiazem are effective in terminating paroxysmal supraventricular tachycardias and slowing ventricular response during atrial fibrillation or flutter. Results from clinical trials for each individual drug demonstrate comparative efficacy rates, and both drugs share the same contraindications and relative precautions. Well-designed comparative clinical trials are needed to establish if either drug has any clinical advantages in a particular patient population.

Clinical and medicoeconomic impact of the cyclosporine-diltiazem interaction in renal transplant recipients.

The effect of the diltiazem-cyclosporine interaction on cyclosporine pharmacokinetics, pharmacodynamics, and pharmacoeconomics was studied in 10 recipients of renal allografts. Each subject was studied while receiving diltiazem 60 mg twice/day and while not taking the drug. After achieving steady-state conditions, cyclosporine and metabolite concentrations were determined in whole blood from samples drawn after the morning cyclosporine dose. After pharmacokinetic analysis, all patients were followed for 6 months during treatment with cyclosporine plus diltiazem or cyclosporine alone. Cyclosporine blood clearance decreased significantly after treatment with diltiazem (18.0-11.0 ml/min.kg; p = 0.008). The apparent volume of cyclosporine distribution also decreased significantly (4.26-2.62 L/kg; p < 0.05). After 6 months, diltiazem had no effect on renal function indexes, and no apparent effect on immunosuppression. Alterations in cyclosporine clearance and apparent volume of distribution secondary to diltiazem result in dosage reduction and potential cost savings in transplant pharmacotherapy. The mean decrease in cyclosporine dosage requirements would produce a cost saving of $1520 or 28% per patient per year.

Effect of pharmaceutical formulation for diltiazem on health care expenditures for hypertension.

A 1-year retrospective analysis was undertaken to discern the economic utility of providing prescription coverage for the sustained-release (SR) formulation of diltiazem, a calcium-channel antagonist, under the state of South Carolina's Medicaid program. Data for this analysis were derived from the state of South Carolina's Medicaid computer archive. The study population consisted of 347 ambulatory beneficiaries diagnosed with hypertension for whom either the SR or immediate-release (IR) formulation of diltiazem was prescribed. Multivariate regression analysis was used to discern the incremental influence of selected demographic characteristics, use of medical services prior to diagnosis for hypertension, and prescribed formulation of diltiazem on health care expenditures 1-year postdiagnosis. Patients for whom the SR formulation of diltiazem was prescribed achieved a significant (P < or = 0.05) increase in the medication possession ratio, an index of compliance (SR, 0.63 +/- 0.17) relative to patients for whom the IR formulation was prescribed (IR, 0.44 +/- 0.13). Results indicate that receipt of diltiazem in an SR formulation was associated with a significant decrease in aggregate health care expenditures over the 1-year study period ($258.80, P < or = 0.05). Receipt of the SR formulation was associated with an increase in expenditures for antihypertensive therapy ($109.26, P < or = 0.05), and a decrease in financial commitments for physician ($128.70, P < or = 0.05), hospital ($211.84, P < or = 0.05), and laboratory ($27.52, NS) services. At the managerial and policy levels, these data argue for an increased use of therapeutic alternatives that facilitate a reduction in the patient's daily dosing schedule for antihypertensive therapy.