Effect of low versus conventional dose cyclopenthiazide on platelet intracellular calcium in mild essential hypertension.

Platelet free intracellular calcium levels were measured during a double-blind, placebo-controlled parallel study to investigate the antihypertensive activity of 50 micrograms, 125 micrograms, and 500 micrograms cyclopenthiazide, in mild essential hypertension. Cytosolic free calcium levels were significantly higher in established hypertensive patients (135 +/- 28 nmol/l, P less than 0.001) but not in borderline hypertensive patients (123 +/- 26 nmol/l) compared with normotensive controls (111 +/- 9 nmol/l). A positive correlation between platelet free calcium level and systolic and diastolic blood pressure was confirmed (n = 68; r = 0.309 P = 0.01; r = 0.405 P less than 0.001, respectively). The 125-micrograms and 500-microgram doses of cyclopenthiazide produced mean decrements in blood pressure of 18/10 mmHg and 23/8 mmHg, respectively, (P less than 0.05 for both), after 8 weeks of therapy. The 50-microgram dose displayed no useful antihypertensive activity. Platelet free calcium levels fell by a similar amount in the four groups. The fall in blood pressure produced by the 125 and 500-microgram doses of cyclopenthiazide did not correlate with changes in platelet [Ca2+]i (r = 0.166 systolic and r = 0.169 diastolic). These findings do not support the hypothesis that changes in platelet cytosolic calcium levels are determined by the same factors that control blood pressure.

Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia.

Rosuvastatin is a new, synthetic, orally active statin, with marked low-density lipoprotein (LDL) cholesterol-lowering activity. We conducted 2 dose-ranging studies. In the first study, after a 6-week dietary run-in, 142 moderately hypercholesterolemic patients were randomized equally to receive double-blind placebo or rosuvastatin 1, 2.5, 5, 10, 20, or 40 mg or open-label atorvastatin 10 or 80 mg once daily for 6 weeks; in the second study, conducted to extend the rosuvastatin dose range, 64 patients were randomized to double-blind, once-daily placebo or rosuvastatin 40 or 80 mg (1:1:2 ratio) for 6 weeks. Data from both studies were combined for analysis of lipid effects. No statistical comparison of atorvastatin arms with placebo or rosuvastatin was performed. Rosuvastatin was associated with highly significant dose-dependent reductions in LDL cholesterol compared with placebo (p <0.001); decreases ranged from 34% (1 mg) to 65% (80 mg). Linear regression analysis indicated an additional 4.5% LDL cholesterol reduction for each doubling of the rosuvastatin dose. Across the dose range, approximately 90% of LDL cholesterol reduction occurred within the first 2 weeks of treatment. Significant, dose-dependent reductions in total cholesterol and apolipoprotein B with rosuvastatin were also observed (p <0.001). High-density lipoprotein cholesterol increases and triglyceride reductions were consistently observed and statistically significant at some dose levels. All lipid ratios were significantly reduced at all rosuvastatin dose levels (p <0.001). Adverse events were similar across placebo and active treatments. No significant increases in alanine aminotransferase or creatine kinase were seen in any patient. Over 6 weeks, rosuvastatin produced large, rapid, dose-dependent LDL cholesterol reductions and was well tolerated in hypercholesterolemic patients.

The MYSTIC (meropenem yearly susceptibility test information collection) programme.

The primary objective of the MYSTIC study is to monitor the performance of meropenem over a period of at least 3 years during which this carbapenem is prescribed in different hospital units thus allowing profiles to be established within individual hospitals. Monitoring is being carried out by assessing the antibiotic susceptibility of bacterial pathogens isolated from patients with a predominate problem of intraabdominal infections (IAI) and/or lower respiratory tract infections (LRTI), treated in specialist centres (haematology wards, the Intensive Care Unit [ICU], cystic fibrosis units) and non-specialised centres. Samples will be collected over each year and tested against meropenem and a set of comparators. The data obtained from the first year of the study (1997) come from 33 centres spread mainly throughout Europe but also in Israel and Mexico. The results shows that meropenem retains its broad spectrum and potency whilst there is evidence that the activity of comparator antibiotics is being eroded by a variety of resistance mechanisms. Data from subsequent years of the programme will determine whether these trends continue and will allow a series of individual centre profiles to be compiled and presented.

Some statistical considerations in the development of new quality of life (QoL) scales in schizophrenia.

Assessing the effect of novel pharmaceutical treatments on the quality of life (QoL) of a patient, or group of patients, has been approached in numerous ways over the last 20 years. Techniques as diverse as single questions to multidimensional scales requiring trained assessors to devote several hours to each assessment; from generic questions about how life might have changed to specific issues such as the ability to use a toothbrush. In the pharmaceutical industry, the emphasis is on the registration of a product with national licensing bodies. Each body has tended to see the issue from a different perspective, which has driven study designs to be different in different countries; even different over time within one country. This paper emphasises the basic statistical steps necessary to ensure that a measure of QoL is appropriately recorded, while retaining sufficient flexibility to support the registration in several countries. Aspects about possible study design are included to assist with developing some simple concepts about analysing and then interpreting the results. It is not the intention of the paper to provide the answer, merely to provide the tools to develop the answer robustly. Put briefly, with the right approach generic solutions are feasible and these solutions will have greater utility. The challenge is to recognise exactly what QoL is, and not to deviate from it.

Angiotensin II in the management of excision of phaeochromocytoma.

The management of a patient with an unusual combination of anaesthetic problems, namely phaeochromocytoma and difficult intubation is described. Angiotensin II is discussed in the management of hypotension after excision of the tumour.

Morphine at gramme doses: kinetics, dynamics and clinical need.

The MS Contin tablet 200 mg (controlled release morphine sulphate) provides an equivalent rate and extent of absorption to two MS Contin tablets 100 mg. The characteristics of controlled release from this higher strength formulation are also consistent with those of the 100 mg tablet. The level of analgesia provided during the early post-dosing period, at the end of the dosing period and overall over the twelve hour interval were also equivalent between the preparations. The addition of the MS Contin tablet 200 mg to the existing range will facilitate oral dosing in patients requiring large doses of morphine. This extension to the range will increase the choice available to the clinician and provide a natural progression for those patients requiring a step-up in the dose titration procedure.

Photochemistry of tetrachlorosalicylanilide and its relevance to the persistent light reactor.

The photochemistry of 3,5,3',4'-tetrachlorosalicylanilide has been studied in solution under carefully controlled conditions. When irradiated in a buffered solution of pH 7.4 (physiological pH), three atoms of chlorine are liberated from the molecule instead of one as suggested by earlier photochemical work. From this observation a mechanism is proposed to explain the long-term photobiological effect of this compound in skin i.e. that of the persistent light reactor.

Patient satisfaction and acceptability of long-term treatment with quetiapine.

Satisfaction with, and subjective tolerability of, antipsychotic medication have emerged as important factors in determining treatment compliance and eventual outcome in the management of psychotic disorders. The acceptability of long-term treatment with quetiapine, an atypical antipsychotic agent with a lower incidence of extrapyramidal effects than standard therapy, was examined in this open-label, multicentre study of patient satisfaction. One hundred and twenty-nine patients with major psychiatric disorders, who had each been receiving quetiapine for at least 6 months in open-label extension studies, were asked to complete a 7-item questionnaire concerning subjective experience and satisfaction with treatment. Over 75% of respondents indicated that they were either "very" or "extremely" satisfied with their antipsychotic medication while 73.7% indicated that, over the last month, they regarded their antipsychotic medication to have been "very" or "extremely" helpful. Subjectively reported side-effects were uncommon, with 74.4% of patients reporting no side-effects, 23.3% mild side-effects and only 2.3% moderate side-effects. There were no unambiguous reports of extrapyramidal symptoms. An overwhelming majority of patients (114/118; 96.6%) reported that they preferred quetiapine to previous antipsychotic medications, the predominant reasons being their perceptions of better tolerability and greater efficacy. Patients also identified improvements in quality of life and their activities of daily living. These positive evaluations appeared to be reflected in the high proportion of respondents who indicated a readiness to continue quetiapine treatment. This study indicates that the combination of efficacy and a favourable tolerability profile shown by quetiapine may result in benefits that are evident to the patient and may be reflected in high levels of patient satisfaction and acceptance of treatment. By improving compliance with treatment, these benefits may also enhance clinical outcome.