Screening of stabilizers for LC-MS/MS analysis of clevidipine and its primary metabolite in dog whole blood.

BACKGROUND: Clevidipine is an ester-containing antihypertensive agent that undergoes rapid hydrolysis in blood. A reliable stabilizer cocktail containing citric acid and ascorbic acid was established and the LC-MS/MS method was validated for simultaneous determination of clevidipine and its major metabolite in beagle dog whole blood. RESULTS: The stabilizer could nearly completely inhibit the esterase activity. Both analytes were extracted from whole blood by toluene and detected by MS/MS in positive ESI mode. The linearity range was 0.1-100.0 ng/ml for clevidipine and 1.0-1000.0 ng/ml for the primary metabolite. CONCLUSION: The stabilizer cocktail was able to effectively suppress the activity of esterase in blood. The method was successfully applied to a PK study of clevidipine in beagle dogs.

Quality of compounded topical 2% diltiazem hydrochloride formulations for anal fissure.

AIM: To investigate the quality of topical 2% diltiazem formulations extemporaneously compounded by retail pharmacies openly offering drug-compounding services. METHODS: A participating healthcare professional wrote 12 prescriptions for compounded 2% diltiazem cream, with 2 refills allowed per prescription. The 12 sets of prescriptions were filled, at intervals of 1-2 wk between refills, at 12 different independent retail pharmacies that openly offer drug-compounding services in a major metropolitan region. The 36 resultant preparations, provided as jars or tubes, were shipped, as soon as each was filled, at ambient temperature to the study core laboratory for high-performance liquid chromatography (HPLC) analysis, within 10 d of receipt. For the HPLC analysis, 8 different samples of the topical diltiazem, each approximately 1 g in weight, were taken from prespecified locations within each container. To initiate the HPLC analysis, each sample was transferred to a 100 mL volumetric flask, to which methanol was added. The HPLC analysis was conducted in accordance with the laboratory-validated method for diltiazem in cream, ointment, and gel formulations. The main outcome measures were potency (percentage of label claim) and content uniformity of the compounded topical 2% diltiazem formulations. RESULTS: Of the 36 prescriptions filled, 30 were packaged in jars and 6 were packaged as tubes. The prescriptions were specifically for cream formulations, but 6 of the 12 pharmacies compounded 2% diltiazem as an ointment; for another pharmacy, which had inadequate labeling, the dosage form was unknown. The United States Pharmacopoeia (USP) standard for potency is 90%-115% of label claim. Of the 36 preparations, 5 (13.89%) were suprapotent and 13 (36.11%) were subpotent. The suprapotent prescriptions ranged in potency from 117.2% to 128.5% of label claim, and the subpotent prescriptions ranged in potency from 34.8% to 89.8% of label claim. Fourteen (38.9%) preparations lacked content uniformity according to the USP standard of 90%-110% potency and < 6% relative standard deviation. Of the 30 formulations packaged in jars, 12 (40%) lacked content uniformity, while of the 6 formulations packaged in tubes, 2 (33.3%) lacked content uniformity. Nine of the 12 pharmacies (75%) failed USP potency or content-uniformity specifications for at least 1 of the 3 prescription fills. For 5 of the 12 pharmacies (41.7%), the mean potency across all three prescription fills was < 90% of label claim. CONCLUSION: Patients prescribed topical 2% diltiazem for treatment of anal fissure frequently receive compounded formulations that are misbranded with respect to potency and that lack content uniformity.

Pharmacopoieal quality of non-expired and expired nifedipine formulations from Estonian and Russian Federation medicinal products market.

The pharmacopoeial quality of non-expired and expired nifedipine tablets of the same batches purchased from the Estonian and Russian Federation medicinal product markets was evaluated. The IR spectroscopy, HPLC analysis for quantitative content and purity of the active pharmaceutical ingredient (API), and dissolution test techniques were applied. In the experiments with non-expired nifedipine tablets, in all Estonian (n = 8, label claims 10, 20, and 40 mg) and Russian Federation (n = 4, label claim 10 mg) registered formulations the API was identified and quantified as nifedipine in amounts set by the European Pharmacopoeia and without exceeding the tolerance limits for the impurities. The dissolution rate was variable but all 10 and 20 mg non-expired nifedipine tablets released at least 80% of API in 12 h. The expiration of the nifedipine tablets led to somewhat increased dissolution rate while only traces of the nifedipine degradation products were discovered in the dissolution medium. In conclusion, our present study shows that with minor variations the Estonian and Russian Federation registered nifedipine tablets are comparable, the API preserves well beyond the expiration date but the expired nifedipine tablets may release the API faster than the non-expired tablets.

Postmortem femoral blood concentrations of amlodipine.

Postmortem femoral blood concentrations of the calcium blocker amlodipine were determined by LC-MS-MS and compiled for the years 2003-2010. The cause of death was classified as unrelated to amlodipine in 38 cases in which the concentration ranged from 0.006 to 0.13 mg/kg (median 0.048 mg/kg), a range that exceeds published in vivo therapeutic serum levels by several-fold. In three cases, amlodipine was judged to be a contributing factor to death and concentrations ranged from 0.29 to 0.44 mg/kg. This concentration range is of the same order of magnitude as published serum levels for clinical toxicity cases. One fatality was ascribed to amlodipine poisoning with a concentration of 0.90 mg/kg, which is similar to values observed in previously published fatality cases. One suspected drug-drug interaction case in which the amlodipine level (0.17 mg/kg) was considered elevated due to inhibition of the cytochrome P450 3A4 enzyme by the azole antifungal drug, fluconazole, was detected. In conclusion, it is important to establish postmortem reference concentrations rather than relying on in vivo therapeutic serum levels, which may be too low and lead to false conclusions in postmortem cases.

Nifedipine capsules may provide a viable alternative to oral powders for paediatric patients.

BACKGROUND AND OBJECTIVE: To compare content uniformities between different sizes of extemporaneously compounded nifedipine oral powders and capsules, in order to find out if capsules could be used instead of oral powders as paediatric medications. METHODS: Actual content and content uniformity of extemporaneously compounded 1-mg nifedipine oral powders and capsules were evaluated by a high performance liquid chromatographic assay. Capsules and powders were prepared by triturating 10-mg nifedipine tablets with different amounts of lactose or microcrystalline cellulose with a mortar and pestle using a standard geometric dilution technique. Oral powders were weighed individually and capsules were filled by a hand-operated capsule-filling machine. Four different sizes of powders (500, 300, 100 and 50 mg) and three different sizes of capsules (numbers 1, 3 and 4) were prepared. Ten oral powders and 10 capsules from each batch were randomly selected and individually assayed for nifedipine amount. RESULTS AND DISCUSSION: The extemporaneously prepared nifedipine oral powders and capsules were within acceptable limits for content uniformity, as defined by the European Pharmacopoeia, but the results indicate that the loss of nifedipine during the preparation process may be considerable for both preparations. The concentration on nifedipine decreased while the total mass of the oral powder decreased. These results demonstrate that nifedipine oral powders can be replaced by capsules, whose contents are emptied for use, in paediatric medications. Compounding small capsules, such as size number 3 or 4, is acceptable when considering the average drug content. The total weight of the oral powder should be at least 300 mg. CONCLUSION: The preparation of nifedipine in all studied capsule sizes was safe with either lactose monohydrate or microcrystalline cellulose as excipients. Thus, emptied capsules seem to be a good choice for delivering a paediatric medication. The loss of nifedipine was considerable in oral powders with low total weight.

Assessing individual bioequivalence using the structural equation model.

The structural equation model (SEM) is introduced as a useful approach for assessing individual bio-equivalence. SEM parameters are estimated using a partial likelihood analysis and the hypotheses of individual bioequivalence is evaluated in a disaggregate way, testing separately the hypothesis concerning SEM parameters, and assessing the overall hypothesis of individual bioequivalence using the intersection-union principle. Limits of bioequivalence for SEM parameters are proposed and a power analysis is carried out.

Development and validation of a near infrared method for the analytical control of a pharmaceutical preparation in three steps of the manufacturing process.

A near infrared diffuse reflectance spectroscopy (NIRS) procedure for the quantitative control analysis of the active compound (otilonium bromide) in a pharmaceutical preparation in three steps of the production process (blended product, cores and coated tablets) and a methodology for its validation are proposed. The analytical procedure is composed by two consecutive steps. First, the sample is identified by comparing its spectrum with a second derivative spectral library. If the sample is positively identified, the active compound is quantified by using a previously established partial least squares (PLS) calibration model. The procedure was validated by studying repeatability, intermediate precision, accuracy and linearity. To this end, an adaptation of ICH (International Conference on Harmonisation) validation methodology to an NIR multivariate calibration procedure is proposed. The relative standard error of prediction (RSEP) was < or = 1% and the suitability of the procedure for control analysis was confirmed by the results obtained analysing new production samples produced over a three-month period.

Treatment of systemic hypertension in cats with amlodipine besylate.

Amlodipine besylate, a calcium channel blocker, was used to treat (mean +/- standard deviation [SD], 127 +/- 68 days) 12 cats with systemic hypertension. Amlodipine was administered orally at a dosage of 0.625 mg per cat (range, 0.08 to 0.23 mg/kg body weight; mean dose +/- SD, 0.17 +/- 0.04 mg/kg body weight) once daily as a single agent. Average indirect systolic blood pressure measurements in the 12 cases decreased significantly from 198 to 155 mmHg during amlodipine treatment. Significant changes in body weight and serum creatinine and potassium concentrations were not detected. Amlodipine appears to be a safe and effective oral treatment for systemic hypertension in cats when used chronically once daily as a single agent.

Safety and tolerability of fluvastatin with concomitant use of antihypertensive agents. An analysis of a clinical trial database.

The coexistence of hypercholesterolemia and hypertension often requires concomitant drug treatments. Thus, it is interesting to evaluate the efficacy, safety, and tolerability of the new lipid-lowering agent fluvastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)-reductase inhibitor, in patients receiving concomitant antihypertensive/cardiovascular drug treatments. A retrospective analysis was based on data from controlled clinical trials in which 1815 patients were treated with fluvastatin and 783 patients received placebo. The daily dose of fluvastatin was > or = 20 mg. At least one of the following drug treatments was taken by 445 of the fluvastatin-treated patients (24.5%) and 181 of those receiving placebo (23.1%): beta-adrenergic-receptor blockers (fluvastatin: n = 182; placebo: n = 84); diuretics (fluvastatin: n = 168; placebo: n = 72); calcium antagonists (fluvastatin: n = 161; placebo: n = 69); and angiotensin-converting enzyme (ACE) inhibitors (fluvastatin: n = 101; placebo: n = 30). The majority of patients received monotherapy with one of the above-mentioned antihypertensive agents (fluvastatin: 69%; placebo: 65%). The efficacy of fluvastatin in modifying low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol and triglyceride levels was not consistently different in patients taking a given antihypertensive compared with the overall group and the patients not taking the antihypertensive agent. In patients taking fluvastatin and antihypertensives, confirmed (measured at two consecutive occasions) increases more than three times the upper limit of normal in aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) occurred in only two patients. One case involved the concomitant use of a beta-blocker (ASAT and ALAT) and the other a diuretic (ALAT).(ABSTRACT TRUNCATED AT 250 WORDS)

An evaluation of self-measured blood pressure in a study with a calcium-channel antagonist versus a beta-blocker.

In recent years self-measurement of blood pressure at home has gained increasing importance but there have been only a few studies comparing casual, ambulatory, and self-measured blood pressure determinations during a single clinical trial. We therefore compared treatment-induced blood pressure-reductions in a double-blind, placebo-controlled, parallel study design with a single morning dose of either 10 mg bisoprolol (n = 26) or 20 mg nitrendipine (n = 27) with casual blood pressure readings in the morning before the dose, ambulatory 24-h monitoring, and self-recorded measurements in the morning before the dose and in the evening. Mean reductions for systolic and diastolic blood pressure after 4 weeks of therapy were significantly greater for bisoprolol than for nitrendipine. The treatment-induced blood pressure reductions were most pronounced as assessed by casual readings but showed good agreement between casual, ambulatory, and self-measured blood pressure for group comparisons. In some patients, however, marked individual differences between the three methods were observed. Correlation coefficients between ambulatory and self-measured blood pressure were 0.4 for systolic blood pressure (P less than .05) and 0.6 for diastolic blood pressure (P less than .0005). Under the conditions of this parallel study design and the usual statistical risks, a difference of 5 mm Hg in diastolic blood pressure can be detected in 118 patients at the clinic, in 70 patients if ambulatory blood pressure is used, or in 56 patients if self-measured blood pressure is used. In conclusion, bisoprolol was more effective over 24 h than nitrendipine at the doses studied.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized comparison of isradipine slow release given once daily with isradipine twice daily on 24 hour blood pressure in hypertensive patients.

Isradipine, a new calcium channel blocker, was given to 32 patients with mild to moderate essential hypertension. After a run-in period of three weeks, 32 patients were randomized double-blindly to six weeks' treatment with either isradipine 2.5 mg twice daily or isradipine 5.0 mg once daily in a modified release formulation. Based on conventional 'clinic' BP measurements 12 or 24 hours postdose, the two treatments resulted in clinically relevant BP reduction (16/11 and 19/15 mmHg) without reflex tachycardia. No differences were seen between the groups. Efficacy increased throughout the study period. By determination of the 24 hour BP profile with a noninvasive method, the two groups were comparable during the placebo period, and no differences were seen between the two treatments. Both treatments resulted in satisfactory BP reduction during 24 hours (daily reduction of 4/6 and 12/9 mmHg twice daily and once daily dosing respectively). One third of the patients had 'white-coat' hypertension based on ambulatory daytime mean BPs, compared with conventional measurements. No relationship was found between the initial BP lowering effect and the effect after long-term treatment with isradipine in either dose.

Effect of isradipine on 24-h blood pressure profile demonstrated by repeated monitoring.

The antihypertensive effect of isradipine was assessed by repeated 24-h ambulatory blood pressure monitoring. Using an SPS device (Sandoz Pharma, Basel, Switzerland), monitoring was carried out in 10 male patients with mild essential hypertension (1) after a placebo period, (2) after six months, and (3) after 12 to 13 months of treatment with isradipine (average dose 2.5 mg twice daily). Mean 24-h blood pressure decreased significantly after both periods 2 and 3 (from 148/93 mm Hg to 137/87 and 130/85 mm Hg, respectively). The total number of hypertensive systolic and diastolic blood pressure values also decreased. The normal circadian blood pressure curve was preserved, showing the reduction throughout the 24-h period, and the early morning rise in blood pressure was markedly blunted. These results indicate that isradipine has a favorable effect on the 24-h blood pressure profile that persisted throughout six and 12 months of antihypertensive therapy.