The bioequivalence of a new amitriptyline tablet formulation in comparison with a reference preparation

An investigation of the bioequivalence of a new tablet formulation (amitriptylin 25 von ct) with 28.3 mg amitriptyline hydrochloride (CAS 549-18-8) was performed in a two-way cross-over study with 18 subjects. The relative bioavailability with respect to a reference preparation for AUC related to amitriptyline (CAS 50-48-6) was 99.3% and for Cmax 100.4%. A positive decision for bioequivalence derived from the usual confidence intervals for both parameters related to amitriptyline and the metabolite nortriptyline (CAS 72-69-5), respectively tmax showed no difference. The new formulation was bioequivalent to the reference.     

The bioequivalence of a new allopurinol tablet formulation in comparison to a reference formulation]

Recent studies have shown that there are distinct genetic pathways leading to the most malignant astrocytic neoplasm, the glioblastoma. Primary (de novo) glioblastomas are characterized by amplification/overexpression of the EGF receptor (EGFR) and, less frequently, of the MDM2 gene. Another pathway, operative in the progression of low-grade or anaplastic astrocytomas to secondary glioblastomas, is characterized by the frequent occurrence of p53 mutations. In this study, we assessed p53 mutations and EGFR expression in the giant cell glioblastoma. This rare variant is characterized by unusually large, multinucleated giant cells, but tends to be more confined and has been reported to carry a somewhat more favorable prognosis. We analyzed biopsies from 16 patients (mean age at clinical manifestation, 40 years). DNA sequencing revealed that 12 of 16 (75%) giant cell glioblastomas contained a p53 mutation. In 7 patients with two or more surgical interventions, the p53 mutation was already detected in the first biopsy. Focal EGFR overexpression, including multinucleated giant cells, was observed immunohistochemically in 9 of 16 (56%) tumors. However, most tumor areas lacked immunoreactivity, indicating that EGFR overexpression does not play a significant role in the evolution of this glioblastoma variant. These results suggest that giant cell glioblastomas develop de novo with a short preoperative history (mean, 47 +/- 40 days), but contain genetic alterations similar to those observed in secondary glioblastomas.     

Bioequivalence of a new tablet formulation of sotalol hydrochloride in comparison to a standard preparations

Bioequivalence of a New Sotalol Hydrochloride Tablet Formulation Compared with a Standard Preparation An investigation on the bioavailability of a new tablet with 80 mg sotalol hydrochloride (Rentibloc mite, CAS 959-24-0) was performed in a two-way cross-over study with 16 persons. The relative bioavailability with respect to a reference preparation for AUC0-infinity was 101.9% and for Cmax 104.5%. A positive decision for bioequivalence derived from the usual confidence intervals for both parameters. The difference in tmax showed no clinical relevance. The new formulation is bioequivalent to the reference.     

Treatment of chronic anal fissure with isosorbide dinitrate: long-term results and dose determination

Individuals with a genetic predisposition to pemphigus will develop the disease only when one or more additional factors are present. The nature of these factors is as yet unknown, but our starting point was that certain drugs (penicillamine, captopril, and rifampicin) are recognized as such factors. Since some nutrients have chemical compositions similar to these known causative drugs, these nutrients may act similarly and, therefore, nutritional factors should also be suspected. As when drugs are involved, elimination of the inciting ingredients may be crucial for management of the disease. This article discusses the possible role of nutritional ingredients in the disease process of pemphigus, including fruit, leaves, roots, seeds, and even water. Possible causative candidates are thiol, thiocyanate, phenols, and tannins.     

Mefenamic acid bioequivalence assessment with a new statistical procedure

The bioequivalence of three different formulations of mefenamic acid was tested using the index zeta 2 previously defined by Rescigno. This index is a measure of the distance in Hilbert space of two concentration vs time functions; unlike the approach of Westlake which assumes a multiplicative model for the AUC and Cmax characteristics, this approach does not imply any hypotheses on the structure of the data and no particular model of the absorption or of the elimination processes. The index zeta 2 is simply an indication of how similar two formulations are. Results for this new test were compared with those obtained with two other tests, namely 90 and 95% symmetrical confidence intervals of Westlake and two one-sided t-tests of Shuirmann through the 90% confidence intervals in the ranges 80-125% for AUC and 70-143% for Cmax. Results of the new test are fully comparable with those obtained using the other two tests.     

Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding

BACKGROUND: Patients who have bleeding from esophageal varices are at high risk for rebleeding and death. We compared the efficacy and safety of endoscopic sclerotherapy with the efficacy and safety of nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding. METHODS: Eighty-six hospitalized patients with cirrhosis and bleeding from esophageal varices diagnosed by endoscopy were randomly assigned to treatment with repeated sclerotherapy (43 patients) or nadolol plus isosorbide-5-mononitrate (43 patients). The primary outcomes were rebleeding, death, and complications. The hepatic venous pressure gradient was measured at base line and after three months. RESULTS: Base-line data were similar in the two groups, and the median follow-up was 18 months in both. Eleven patients in the medication group and 23 in the sclerotherapy group had rebleeding. The actuarial probability of remaining free of rebleeding was higher in the medication group for all episodes related to portal hypertension (P = 0.001) and variceal rebleeding (P = 0.002). Four patients in the medication group and nine in the sclerotherapy group died (P = 0.07 for the difference in the actuarial probability of survival). Seven patients in the medication group and 16 in the sclerotherapy group had treatment-related complications (P = 0.03). Thirty-one patients in the medication group underwent two hemodynamic studies; 1 of the 13 patients with more than a 20 percent decrease in the hepatic venous pressure gradient had rebleeding, as compared with 8 of the 18 with smaller decreases in the pressure gradient (P = 0.04) for the actuarial probability of rebleeding at two years). CONCLUSIONS: As compared with sclerotherapy, nadolol plus isosorbide mononitrate significantly decreased the risk of rebleeding from esophageal varices.     

Multiple testing to establish superiority/equivalence of a new treatment compared with kappa standard treatments

In this paper we develop multiple hypotheses testing procedures to compare a new treatment with a set of standard treatments in a clinical trial. The aim is to classify the new treatment with respect to each of the standards, by specifying those to which the new treatment is superior, those to which the new treatment is equivalent and those to which one can establish neither superiority nor equivalence. We propose several stepwise procedures and compare them with respect to their familywise error rates and power. The step-down methods SD1 and SD2 test for superiority first, followed by tests for equivalence for those comparisons where we cannot establish superiority. The step-up methods SU1 and SU2 test for equivalence first, followed by tests for superiority for those comparisons where we can establish at least equivalence. The methods SD3 and SU3 apply the tests for superiority and equivalence in pairs. All the methods require that we specify a threshold value delta > 0 in advance for defining equivalence. In applications where it is not possible to specify a value delta, we can use the method SD1 by testing for superiority first, followed by one-sided confidence limits on the efficacy differences for those comparisons where we cannot establish superiority.     

Modeling the effects of hydroxypropylcellulose in acetaminophen tablet formulation

The objective of the research described here was to develop a set of predictive models that would be used to show the performance of hydroxypropylcellulose as a pharmaceutical tablet binder. A statistically designed set of experiments was used to relate tablet formulation to functionality. It was found that the binder level affected both hardness and dissolution time. Useful predictive models were generated for tablet hardness and dissolution time as a function of the binder or binder-drug ratio. The optimal formulation can be predicted from this study, and will depend upon the combination of desired hardness and the dissolution time for a particular drug.     

Molsidomine and isosorbide dinitrate: a comparative trial of tolerance in long-term intake by IHD patients with stable angina of effort

Potential tolerance to isosorbide dinitrate (ID) and molsidomine (M) was studied in 18 ischemic heart disease (IHD) patients with stable angina of effort entered in a double blind cross-over trial. Each drug was administered for 3 weeks 4 times a day in individual effective dose. Single doses of ID and M were similar by effectiveness, but after 3 weeks of regular intake their efficacy fell, ID becoming less potent than M. For ID, tolerance after long-term intake manifested in 7 out of 18 patients, for M--in 5 out of 18. Complete tolerance was registered in 3 of 18 and 1 of 18 patients, respectively. Thus, tolerance is possible for the two drugs, but for M it is less pronounced.     

钢筋混凝土用热轧带肋钢筋国内外标准对比分析(下)

为配合GB14 99- 1998钢筋混凝土用热轧带肋钢筋标准的修订 ,收集了国外主要发达国家的钢筋标准 ,对其进行对比分析 ,以利于对我国标准的不断改进 ,为标准的修订工作提供有用的数据和信息     

钢筋混凝土用热轧带肋钢筋国内外标准对比分析(上)

为配合GB14 99- 1998钢筋混凝土用热轧带肋钢筋标准的修订 ,收集了国外主要发达国家的钢筋标准 ,对其进行对比分析 ,以利于对我国标准的不断改进 ,为标准的修订工作提供有用的数据和信息。     

Effects of amlodipine and isosorbide dinitrate on exercise-induced and ambulatory ischemia in patients with chronic stable angina pectoris

This study was designed to compare once-daily administration of 5-10 mg amlodipine with two daily doses of 40 mg sustained-release isosorbide dinitrate in 59 patients with stable angina using a randomized, double-blind, crossover study design. Anginal episodes, nitroglycerin consumption, and possible adverse events were recorded in a diary. A maximal symptom-limited bicycle exercise test and 48-hour ambulatory ECG monitoring were performed at baseline and at the end of each 5-week period of therapy. Exercise time, time to angina, time to ST depression, and maximal ST depression were measured during exercise. During ambulatory monitoring, the number of ischemic episodes and the duration per hour of ST depression were assessed. Amlodipine significantly reduced anginal episodes (P < 0.001) when compared with isosorbide dinitrate. Furthermore, amlodipine prolonged time to ST depression (P < 0.001) and time to angina (P < 0.05) when compared with isosorbide dinitrate. The number and duration of ischemic episodes during ambulatory monitoring were significantly reduced with amlodipine when compared with baseline values (P < 0.05), whereas no differences were found between isosorbide dinitrate and baseline. Adverse events were reported more frequently with isosorbide dinitrate than with amlodipine (P < 0.02). Amlodipine appears to be more effective and tolerable than sustained-release isosorbide dinitrate as monotherapy for chronic stable angina.     

Influence of combination therapy (isosorbide dinitrate and molsidomine) on the incidence of angina pectoris in patients with coronary heart disease

Angina pectoris in patients with severe 3-vessel-disease refractory to treatment is a challenge for the treating physician. We have therefore tested the treatment efficacy of isosorbide dinitrate combined with molidomine on the frequency of angina pectoris in patients with symptoms refractory to treatment. PATIENTS AND METHODS: 15 patients with severe coronary heart disease were included in the study. The protocol included a 2-weeks stabilisation phase, followed by a 4-weeks treatment phase with 100 mg isosorbide dinitrate in the morning as well as 8 mg slow-release molsidomine at 6 p.m. RESULTS: Initially all of the 15 patients reported about daily angina pectoris attacks. After 4 weeks of treatment 4 out of 15 patients became free of symptoms. From the other 11 patients 6 reported an improvement, 5 an unchanged frequency of attacks. DISCUSSION: Combination treatment with isosorbide dinitrate with molsidomine in a slow-release form (in the nitrate free interval) showed a distinct improvement in patients with angina pectoris refractory to treatment with reduction of complaints. The effect of the combination is possibly based on a prolonged vasodilatation of the stenosed vessels and a prolonged reduction of filling pressure (reduction of preload).     

High performance liquid chromatographic method for the determination of lobenzarit disodium in a sustained release tablet formulation

A rapid and simple high performance liquid chromatographic method is described and validated for the determination of lobenzarit disodium (CAS 64808-48-6) in a sustained release tablet formulation. The calibration graph was linear over the range 20-105 micrograms/ml. The sensitivity (discriminator capacity) was 2.079 micrograms/ml. The coefficient of variations for repeatability and reproducibility were less than 1.60% and 1.30%, respectively. The accuracy of the method did not depend on lobenzarit concentration in tablets. The mean recovery was found to be 100.62%. The method was selective, even when degradation products were present.     

Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration-time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the Cmax of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found.     

Hemodynamic effects of combined treatment with somatostatin analogue (SMS 201-995) and low-dose isosorbide dinitrate on portal hypertension in conscious cirrhotic rats

The authors investigated whether combined treatment with the somatostatin analogue, SMS 201-995, and low-dose isosorbide dinitrate enhanced the hemodynamic effects of the individual agents on rats with thioacetamide-induced cirrhosis. Four groups of cirrhotic rats received SMS 201-995 (0.1 microgram.min-1.kg-1), isosorbide dinitrate (10 micrograms.min-1.kg-1), both agents, or placebo, respectively. Hemodynamics were measured serially in conscious rats, using a radioactive microsphere method. SMS 201-995 reduced portal venous inflow 21 +/- 4% and portal pressure 17 +/- 3%. Isosorbide dinitrate decreased portal venous inflow 20 +/- 4%, by inducing splanchnic vasoconstriction mediated by low pressure baroreflexes, and this agent also decreased portal pressure, by 14 +/- 2%. Portal venous resistance rose 7.6 +/- 3% with isosorbide dinitrate alone, but decreased 18 +/- 4% with combination therapy. This effect may have been induced by the pronounced vasodilatory effect of isosorbide dinitrate on the venous vasculature, since the reflex splanchnic vasoconstriction that occurs with low-dose isosorbide dinitrate disappears when this agent is combined with SMS 201-995. The decrease in portal pressure was more marked (22 +/- 4%) and changes in systemic hemodynamics were milder with the combined treatment. It was concluded that combination therapy with SMS 201-995 and low-dose isosorbide dinitrate may be beneficial for portal hypertension in liver cirrhosis.