Survey to Identify Substandard and Falsified Tablets in Several Asian Countries with Pharmacopeial Quality Control Tests and Principal Component Analysis of Handheld Raman Spectroscopy.

The World Health Organization has warned that substandard and falsified medical products (SFs) can harm patients and fail to treat the diseases for which they were intended, and they affect every region of the world, leading to loss of confidence in medicines, health-care providers, and health systems. Therefore, development of analytical procedures to detect SFs is extremely important. In this study, we investigated the quality of pharmaceutical tablets containing the antihypertensive candesartan cilexetil, collected in China, Indonesia, Japan, and Myanmar, using the Japanese pharmacopeial analytical procedures for quality control, together with principal component analysis (PCA) of Raman spectrum obtained with handheld Raman spectrometer. Some samples showed delayed dissolution and failed to meet the pharmacopeial specification, whereas others failed the assay test. These products appeared to be substandard. Principal component analysis showed that all Raman spectra could be explained in terms of two components: the amount of the active pharmaceutical ingredient and the kinds of excipients. Principal component analysis score plot indicated one substandard, and the falsified tablets have similar principal components in Raman spectra, in contrast to authentic products. The locations of samples within the PCA score plot varied according to the source country, suggesting that manufacturers in different countries use different excipients. Our results indicate that the handheld Raman device will be useful for detection of SFs in the field. Principal component analysis of that Raman data clarify the difference in chemical properties between good quality products and SFs that circulate in the Asian market.

The Circle of Female Sexual Desire-Have We Come a Long Way?

Ever since the release of sildenafil (Viagra) two decades ago to treat erectile dysfunction in men, there has been a conversation around whether there is a need for a "female Viagra." Last year's release of flibanserin (Addyi) was hailed by some as an achievement in women's sexual health. But how effective is this drug in affecting women's sexual desire? And are the things being labeled as women's sexual desire problems really problems to be fixed with a drug?

Dabigatran: patient management in specific clinical settings.

Dabigatran, a direct thrombin inhibitor, is licensed for the prevention of venous thromboembolism after knee and hip replacement, the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for the treatment of acute venous thromboembolism. As dabigatran has a favourable benefit-risk profile, it is being increasingly used. Dabigatran differs from vitamin K antagonists as regards its pharmacological characteristics and its impact on certain laboratory tests, and also in the lack of a direct antagonist that can reverse dabigatran-induced anticoagulation. In emergency settings such as acute bleeding, emergency surgery, acute coronary syndrome, thrombolysis for ischaemic stroke or overdosing, specific strategies are required. A working group of experts from various disciplines has developed strategies for the management of dabigatran-treated patients in emergency settings.

Evaluation of the membrane permeability (PAMPA and skin) of benzimidazoles with potential cannabinoid activity and their relation with the Biopharmaceutics Classification System (BCS).

The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying these molecules as very permeable, independent of their thermodynamic solubility, if and only if these have a Log P(oct) value <3.0. In contrast, transdermal permeability is conditioned on the solubility of the molecule so that it can only serve as a model for classifying the permeability of molecules that possess high solubility (class I: high solubility, high permeability; class III: high solubility, low permeability).

First automatic radiosynthesis of 11C labeled Telmisartan using a multipurpose synthesizer for clinical research use.

OBJECTIVE: Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist, is an antihypertensive drug. Positron emission tomography (PET) imaging with [(11)C]Telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as the transport function of hepatic OATP1B3. We developed a first automatic preparation system of [(11)C]Telmisartan to applicable clinical research using a new (11)C and (18)F multipurpose synthesizer. METHODS: Two milligrams of precursor (1) in 5 µl of 1 M KOH in 0.5 ml of dimethyl sulfoxide was reacted with [(11)C]CH(3)I for 5 min at 120°C. The resultant solution was hydrolyzed with 1 M NaOH at 100°C for 3 min. The neutralization was carried out with acetic acid, followed by purification with high-performance liquid chromatography. The desired radioactive fraction was collected and solvent was replaced by 10 ml saline containing 0.3 ml of EtOH and 0.5 ml of PEG400, and then passed through a sterile 0.22 µm filter (Millex-GV, Millipore) to a pyrogen-free vial as the final product. RESULTS: The yield of [(11)C]Telmisartan for clinical research use was 16.8 ± 2.9% EOB as decay corrected (n = 8, mean ± SD) in 32-36 min. The radiochemical purity of [(11)C]Telmisartan was >97%, and specific activity was higher than 86.3 MBq/nmol. CONCLUSIONS: We succeeded in the first synthesis of [(11)C]Telmisartan for clinical research use by appropriate quality tests.

Cardio classics revisited--focus on the role of candesartan.

Angiotensin II receptor blockers (ARBs) are antihypertensive agents with considerable evidence of efficacy and safety for the reduction of cardiovascular (CV) disease risk in numerous patient populations across the CV continuum. There are several agents within this class, all of which have contributed to various degrees, to this evidence base. The evidence with ARBs continues to accumulate, with ongoing trials investigating their role in additional patient populations, potentially expanding their efficacy across a broad spectrum of CV disease states. Cardiovascular disease (CVD) is a leading cause of death around the world, accounting for approximately 29.2% of total global deaths. Of all the deaths attributed to CVD, approximately 43% are due to ischemic heart disease, 33% to cerebrovascular disease, and 23% to hypertensive and other heart conditions. CVD has been represented as a "CV continuum". This continuum concept can be used to describe CVD in general or in specific vascular beds (eg, coronary artery disease or cerebrovascular disease). This review article will discuss the results of the landmark ARB candesartan clinical trials published over the past decade. The evidence presented spans the entire CV continuum, including the effects of ARBs in at-risk patients, stroke, myocardial infarction (MI), and heart failure (HF), as well as a brief discussion of ongoing trials.

Telmisartan is more effective than losartan in reducing proteinuria in patients with diabetic nephropathy.

In patients with diabetic nephropathy, lowering blood pressure and reducing proteinuria by over 30% correlates with a slower progression to kidney failure. We compared two different angiotensin receptor-blockers in a double blind, prospective trial of 860 patients with type 2 diabetes whose blood pressure levels was over 130/80 mmHg or who were receiving antihypertensive medication(s) and who had a morning spot urinary protein to creatinine ratio of 700 or more. Patients were randomized to telmisartan (a highly lipophilic agent with a long half-life) or losartan (with low lipophilicity and short half-life). The primary endpoint was the difference in the urinary albumin to creatinine ratio between the groups at 52 weeks. The geometric coefficient of variation and the mean of the urinary albumin to creatinine ratio fell in both groups at 52 weeks but both were significantly greater for the telmisartan compared to the losartan cohort. Mean systolic blood pressure reductions were not significantly different between groups at trial end. We conclude that telmisartan is superior to losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, despite a similar reduction in blood pressure.

Should the results of TROPHY affect the JNC 7 definition of prehypertension?

In the Trial of Preventing Hypertension (TROPHY), volunteers with "high normal blood pressure" were randomized to 4 years of placebo (n = 381) or 2 years of 16 mg/d of candesartan (n = 391) followed by 2 years of placebo. At 2 years, there was a 26.8% absolute and a 66.3% relative risk reduction (P < 0.0001) of hypertension in the candesartan group. At study end, the former candesartan group had a 9.8% absolute and a 15.6% relative risk reduction (P < 0.007) of hypertension. The treatment was well tolerated. The Seventh Joint National Committee (JNC 7) changed the nomenclature from "high normal blood pressure" to "prehypertension" and widened the range to 120 to 139 and/or 80 to 89 mm Hg. Our results support the term "prehypertension" only for the 130 to 139 and/or 85 to 89 mm Hg group; in 4 years two thirds of the placebo group developed hypertension. We suggest stratifying the JNC classification into "prehypertension" (130-139 and/or 85-89 mm Hg) and "high normal blood pressure" (120-129 and/or 80-84 mm Hg). By the present JNC definition, only one quarter of adult men have normal blood pressure. Removing the disease label from another 28% would appropriately focus attention on high-risk prehypertension.

Use of ambulatory blood pressure monitoring to evaluate the selective angiotensin II receptor antagonist, telmisartan, and other antihypertensive drugs.

Telmisartan (Micardis (R)) is a new, orally active, long-acting angio-tensin (Ang) II receptor antagonist that is effective in the treatment of hypertension. Ambulatory blood pressure monitoring (ABPM) has emerged as an important method for evaluating the consistency of the antihypertensive effects of a drug throughout the dosing interval. ABPM was used to evaluate the antihypertensive efficacy of telmisartan in several placebo-controlled, double-blind, multicenter studies. Patients with mild-to-moderate hypertension were allocated randomly to groups to receive telmisartan 40 or 80 mg, losartan 50 mg, or placebo, once daily in a 6-week, fixed-dose study, or telmisartan 40-120 mg, amlodipine 5-10 mg, or placebo, once daily in a 12-week, dose-titration study. Patients treated with telmisartan 40 and 80 mg or placebo in a separate 4-week, fixed-dose study were included in an additional analysis. Telmisartan 40 and 80 mg significantly decreased mean ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP) relative to placebo for the entire 24 h period and in the following intervals: day (6 a.m. to 10 p.m.), morning (6 a.m. to noon), night (10 p.m. to 6 a.m), and the last 4 h of the dosing interval (P<0.01). Notably, telmisartan 40 or 80 mg was more effective than losartan, especially during the last 4-6 h of the dosing interval (P<0.05). Telmisartan 40- 120 mg tended to be more effective than amlodipine 5-10 mg in reducing SBP and DBP in each time interval, with significant differences between treatments noted for DBP in the last 4 h of the dosing interval and in the morning (P < 0.05). ABPM also revealed that the magnitude of the blood pressure decreasing effect with telmisartan was consistent throughout the dosing interval. These results demonstrate that telmisartan maintains a normal circadian blood pressure pattern and provides full 24 h blood pressure control with once-daily dosing.

The efficacy of levamisole, and a mixture of oxfendazole and levamisole, against the arrested stages of benzimidazole-resistant Haemonchus contortus and Ostertagia circumcincta in sheep.

Sheep were allowed to graze pasture that had been seeded with benzimidazole-resistant Haemonchus contortus and Ostertagia circumcincta in order to acquire a burden of arrested larvae. Following housing, sheep were dosed orally with either oxfendazole at a dose rate of 4.7 mg/kg (to confirm the benzimidazole-resistant status of the species of nematode), levamisole at a dose rate of 7.5 mg/kg, or an oxfendazole/levamisole mixture at a dose rate of 4.6 mg/kg oxfendazole and 8.1 mg/kg levamisole. The efficacies of the treatments were assessed by estimation of the arrested larval burden in the abomasum of each sheep, either at 10 or 11 days (oxfendazole and oxfendazole/levamisole mixture), or 12 or 13 days (levamisole), after treatment. Compared to the untreated controls, the protection afforded by a single dose of either levamisole or the oxfendazole/levamisole mixture was >99% against the arrested stages of both Haemonchus contortus and Ostertagia circumcincta. Treatment with oxfendazole confirmed the benzimidazole-resistance status of the two species.

Fasciolicides: efficacy, actions, resistance and its management.

The modes of action of fasciolicides are described. Closantel and other salicylanilides interfere with energy metabolism by uncoupling oxidative phosphorylation in the fluke. Other fasciolicides are believed to have a metabolic action-halogenated phenols (via uncoupling) and clorsulon (via inhibition of glycolysis)-but direct evidence is lacking. Benzimidazoles (in particular, triclabendazole) bind to fluke tubulin and disrupt microtubule-based processes. Diamphenethide inhibits protein synthesis in the fluke. Other potential drug actions may contribute to overall drug efficacy. In particular, a number of fasciolicides-salicylanilides, phenols, diamphenethide-induce a rapid paralysis of the fluke, so their action may have a neuromuscular basis, although the actions remain ill-defined. Resistance to salicylanilides and triclabendazole has been detected in the field, although drug resistance does not appear to be a major problem yet. Strategies to minimize the development of resistance include the use of synergistic drug combinations, together with the design of integrated management programmes and the search for alternatives to drugs, in particular, vaccines.

Comparative evaluation of several DNA binding dyes in the detection of apoptosis-associated chromatin degradation by flow cytometry.

Mouse thymocytes readily undergo apoptosis-associated DNA degradation upon exposure to glucocorticoids or ionizing radiation. It has been previously shown that flow cytometric cell cycle analysis of propidium iodide-stained apoptotic thymocytes results in the appearance of a distinct cell cycle region (the A0 region) below the G0/G1 region. Cells in this region were shown to be undergoing apoptosis, and determination of apoptosis by flow cytometric analysis was proposed as a superior method for evaluating thymocyte apoptosis. In this study, a variety of DNA binding dyes with diverse primary binding mechanisms were evaluated for their ability to detect glucocorticoid and ionizing radiation-induced apoptosis in mouse thymocytes. Apoptotic thymocytes stained with DNA binding dyes from the phenanthridinium, acridine, actinomycin, chromomycinone, anthracycline, and bisbenzimidazole groups all demonstrated clearly defined A0 regions with percentages comparable to those obtained for propidium iodide. These results indicate that the appearance of the A0 region is not dependent on a particular dye binding characteristic and may be the consequence of extensive changes in chromatin structure resulting in a significant degree of dye exclusion.

Multicentre clinical trials of benzimidazole-carbamates in human cystic echinococcosis (phase 2).

A multicentre study which constituted the second phase of trials of the efficacy of albendazole and mebendazole in human cystic echinococcosis was coordinated by WHO. A total of 112 patients from four clinical centres in Beirut, Paris, Rome and Sofia completed standardized dosage of regimens of each drug and 68 patients were followed up for at least 12 months after treatment. Albendazole was more effective than mebendazole and adverse reactions were comparable with both treatment regimens. At least 12 months is needed after treatment for an objective evaluation of the efficacy of benzimidazoles. At present, treatment with albendazole or mebendazole should be reserved for inoperable cases of cystic echinococcosis (under strict medical supervision) and individualized according to the patient's response and the occurrence and severity of adverse reactions.

Multicentre clinical trials of benzimidazole-carbamates in human cystic echinococcosis

A multicentre study which constituted the second phase of trials of the efficacy of albendazole and mebendazole in human cystic echinococcosis ws coordinated by WHO. A total of 112 patients from four clinical centres in Beirut, Paris, Rome and Sofia completed standardized dosage regimens of each drug and 68 patients were followed up for at least 12 months after treatment

Albendazole was more effective than mebendazole and adverse reactions were comparable with both treatment regimens. At least 12 months is needed after treatment for an objective evaluation of the efficacy of benzimidazoles

At present, treatment with albendazole or mebendazole should be reserved for inoperable cases of cystic echinococcosis (under strict medical supervision) and individualized according to the patient's response and the occurrence and severity of adverse reactions(AU)

Efficacy and safety of astemizole, a long-acting and nonsedating H1 antagonist for the treatment of chronic idiopathic urticaria.

The efficacy and safety of astemizole (AST), a new long-acting H1 antagonist with minimal sedative or anticholinergic side effects, were studied in an 8-week double-blind trial of 51 patients with chronic idiopathic urticaria. Patients with chronic idiopathic urticaria were randomized to AST-treated (10 mg every day) or placebo-treated groups. Patients were followed at weekly intervals and evaluated for pruritus, erythema, extent of wheals, frequency of urticarial episodes, and total control of urticaria. Only three of 27 AST-treated patients stopped the double-blind phase before 8 weeks because of inadequate response as compared to 11 of 24 placebo-treated subjects (p = 0.027). On the last evaluable visit of the double-blind phase of the study, 85% of the AST-treated patients reported an excellent or good response compared to 30% of the placebo-treated group (p = 0.0001). AST-treated patients also reported significant improvement compared to placebo-treated patients in pruritus (p = 0.0001), erythema (p = 0.0001), and extent of wheals (p = 0.003). Mild sedative effects were observed in only two of 27 patients receiving AST. It was concluded that AST is a potent and safe drug for symptomatic control of chronic idiopathic urticaria.