Effect of age and renal impairment on the pharmacokinetics and safety of trimetazidine: An open-label multiple-dose study.

This study evaluated the effect of age and renal impairment on pharmacokinetics of trimetazidine (TMZ) in healthy elderly and renally impaired subjects and assess safety and tolerability. In this open-label, multi-dose study, 73 subjects were divided into six treatment groups: (1) 55-65 years; (2) 66-75 years; (3) >75 years (dosing for groups 1-3 [healthy]: B.D. for 4 days), (4) mild renally impaired (dosed B.D. for 8 days); (5) moderate renally impaired (dosed O.D. for 8 days); and (6) severe renally impaired-no dialysis (dosed once every 48 h for 8 days). Blood and urine samples were collected and analyzed. The geometric least squares mean ratios for; Group 2 and 1 of AUC(0-τ)ss was 112.2 (90% CI; 92.0-136.8) and Cmax,ss was 109.9 (89.6-134.8), Group 3 and 1 of AUC(0-τ),ss was 140.5 (115.9-170.3) and Cmax,ss was 137.8 (112.9-168.2), Group 4 and 1 of AUC(0-τ),ss was 114.2 (90.3-144.4) and Cmax,ss was 120.8 (92.5-157.8), Group 5 and 1 of; AUC(0-τ),ss was 213.0 (153.1-296.3) and Cmax,ss was 123.3 (92.2-164.7) and Group 6 and 1 of AUC(0-τ),ss was 247.4 (197.8-309.6) and Cmax,ss was 95.6 (73.0-125.1). Significant increase in systemic exposure of TMZ was observed in subjects; over 75 year's age and renally impaired compared to healthy subjects. TMZ was safe and well-tolerated.

A drug utilization study to evaluate effectiveness of risk minimization measures for trimetazidine in France, Hungary, Romania and Spain.

WHAT IS KNOWN AND OBJECTIVE: The approved indication for trimetazidine (TMZ) was restricted to "add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies" in 2012 by the Committee for Medicinal Products for Human Use (CHMP). TMZ was no longer indicated for ophthalmology and otolaryngology (ENT) indications. This drug utilization study analysed actual utilization of TMZ before and after the restriction on its indications to evaluate the effectiveness of risk minimization measures (RMM). METHODS: This was a multi-national, cross-sectional, non-interventional drug utilization study using European databases: IMS Prescribing Insights (PI) for France and Spain, National Diagnostic Index (NDI) for Romania and National Prescription Audit (NPA) for Hungary. TMZ prescriptions issued by Ear-Nose-Throat (ENT) specialists, ophthalmologists, cardiologists and General Physicians (GPs)/others were analysed during the 24-month period before (reference period) and after RMM implementation (assessment period). RESULTS AND DISCUSSION: During the assessment period, most of the TMZ prescriptions for ENT and ophthalmology indications (un-authorized indications) were made by GPs/others followed by ENT specialists, ophthalmologists and cardiologists in most of the countries. The proportion of TMZ prescriptions for ENT or ophthalmological indications after the restrictions on indication was reduced in Hungary (by 0.4%) and Spain (by 11.8%), remained the same in Romania and increased in France (by 3.7%). WHAT IS NEW AND CONCLUSION: This study showed that a significant proportion of TMZ prescriptions was off-label for ENT or ophthalmological indications following the RMM implementation. More effective RMM strategies are required to reduce off-label prescriptions of TMZ.

Evaluation of the effectiveness of risk minimization measures for trimetazidine: A cross sectional joint PASS survey among physicians in selected European countries.

PURPOSE: In 2012, the Committee for Medicinal Products for Human Use (CHMP) restricted prescription of trimetazidine (TMZ) to "add-on therapy for patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line therapies." TMZ was no longer indicated for ophthalmology and otolaryngology. Risk minimization measure (RMM) was communicated to physicians. The survey presented here evaluated effectiveness of the RMM and assessed physicians knowledge and compliance with RMM. It also analyzed actual prescribing pattern of TMZ. METHODS: A cross sectional, web-based survey was developed and conducted among prescribing physicians of TMZ across 12 European countries. Physicians' samples were weighted to account for the actual proportion of specialties within and across countries. RESULTS: Using weighted samples, data from 1123 physicians and 8332 prescriptions were analyzed. Most (74.0%) of the physicians assumed stable angina pectoris to be an indication for TMZ. Three quarter of (75.7%) of these physicians were aware of the approved indication. Vertigo (62.1%), tinnitus (42.5%), declined visual acuity, and visual field disturbances (45.1%) were also presumed to be approved indications for TMZ, and physicians actually prescribed for these indications. Only 29.8% of the physicians remembered receiving RMM communications regarding TMZ. Most (90.5%) of the physicians expressed their interest to know and comply with the safety communications. Of all prescriptions, 33.9% were issued for add-on therapy for patients with stable angina pectoris. CONCLUSIONS: RMM for TMZ prescription have been moderately effective. Improvement in physician's compliance with safety information of TMZ is necessary for patient's safety.

Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects.

AIM: This study assessed the linearity of pharmacokinetics (PK) of trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on therapy for stable angina pectoris) and measured its renal elimination, safety, and tolerability in healthy subjects. METHODS: This was a randomized, open-label, single-ascending dose study in healthy subjects. Subjects were administered with a single dose of 35, 70, or 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic evaluations and safety analysis were performed before the first dose and till 48 h post-first dose. RESULTS: Following administration of 35, 70, and 105 mg TMZ-modified release; the Cmax (mean±SD) was 79.32 (±23.08), 153.17 (±23.08), and 199.67 (±23.08) ng/mL, the Tmax was 5.42 (±0.49), 4.51 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h, AUC(0-inf) was 1116.89 (±378.35), 1838.39 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24) L·h-1 and CL/F was 33.69 (±8.51), 38.85 (±6.15), and 42.74 (±7.10) L·h-1, respectively. Slope estimates for AUC(0-inf), AUC(0-t), and Cmax were less than 1. Corresponding 95% CI of the slope for the AUC parameters excluded 1, indicating that the deviation from dose-proportionality was statistically significant. Corresponding 95% CI of the slope for Cmax included 1, indicating that the less than dose-proportional increase in Cmax was not statistically significant. No significant adverse events were observed. CONCLUSION: Substantial deviation from a dose-proportional increase in AUC(0-inf) and AUC(0-t) suggested a non-linear PK for TMZ-modified release. Single dose of TMZ-modified release was well tolerated and safe.

Food allergies--leads from Ayurveda.

Food allergy being a common health problem needs attention. The experience of Ayurveda can be utilized to accelerate our understanding and management of food allergies and related phenomenon like allergic tension fatigue syndrome, intolerance and indigestion associated with certain foods. Prevention of food allergies by carefully selecting the foods in accordance with the individual's body constitution and seasonal alterations, is considered as the best strategy in Ayurveda. If possible, the concept of prakriti and properties of food as described in Ayurveda, should be interpreted in modern terminology. Moreover, to scientifically validate them, an appropriate correlation with modern concepts is required along with scientific studies on modern parameters. Rasayanas may also prove helpful in the management of food allergies. It is obvious that there, is an urgent need for multidimensional and planned investigations of these Ayurvedic rasayanas in management of food allergies. The clinical acceptability of rasayanas for the treatment of food allergies entirely rests on such studies. Food intolerance and allergies are common health problems which are difficult to diagnose and still more difficult to treat. This problem is well addressed in Ayurveda and guidelines are available for their management. This paper aims to present the Ayurvedic concepts in the management of food intolerance/ allergies and its correlation with the evidences available from modem scientific laboratories. The understanding of this ancient wisdom may prove to be of immense importance in patient care.

Rational use of ayurvedic literaature for drug development.

Research in Ayurveda for lead structures has continued to be an area of major scientific interest with investigators engaged in drug development. The exhaustive information available in Ayurvedic literature provides a drug researcher the opportunity to start with a well tested and safe botanical material. However, an inappropriate interpretation of Ayurvedic texts can lead to research in a wrong direction which may present as lack of effectivity or serious adverse effects with herb under investigation. The problems faced in the selection of medicinal plants, underlying cases and the possible solutions have been discussed in the following article.

Immunomodulating effects of rasayana drugs in diabetics - a clinical study.

Immune system plays an important role in pathogenesis of diabetes (DM). Besides hypoglycaemics, rasayanas are indicated in the management of DM. In several studies the immunomodulatroy potentials of rasayanas have been proved. A clinical trial of three rasayana drugs, Asparagus recemosus (AR). Bacopa monnieri (BM) and Centella asiatica (CA) was carried out in diabetics. In this study, diabetics were found to have significantly lower levels of serum IgG, increased serum IgA and comparable levels of IgM. All drugs reverted levels of serum IgG levels in diabetics, however, statistical significance was attained only with AR. Further the increased IgA levels were brought back towards normal. These drugs also increased serum protein levels.

Stress - management : leads from ayurveda.

The role of stress in the aetiology of several diseases is well recognized in Ayurvedic science and modern medicine. The stress is known as sahasa in Ayurveda. Sahasa by causing ojahksaya (loss of immunity) increases the susceptibility of the body to various diseases. Avoidance of stress is the best strategy for treatment and where it is not possible, the body should be well protected by taking appropriate care of the diet and sleep, sleep here indicates adequate rest required by the body. Further, regular intake of several rasayana herbs to increase the coping capacity of the body is advised. Several of these rasayanas have demonstrated significant stress attenuating effects in animal experimentation and scientific efforts are ongoing to logically utilize rasayana herbal formulation in stress management.