The safety of osteoporosis medication.

Osteoporosis is a common, costly and serious disease, which is still too often regarded as an inevitable part of the normal ageing process and therefore sub-optimally treated, especially in the elderly--in fact, only two out of every 10 patients who sustain a hip fracture receive any form of assessment or prophylactic therapy for osteoporosis. One out of five patients die within 1 year after a hip fracture, and < 50% are capable of leading an independent life. Yet very effective anti-fracture therapy, capable of reducing fracture risk by 35 - 60%, is available. A number of publications have recently questioned the safety of drugs routinely used to treat patients with osteoporosis. This paper attempts to put the situation into perspective and expresses the National Osteoporosis Foundation of South Africa's view on the safety of these drugs. Their efficacy in preventing skeletal fractures and their cost-effectiveness are not addressed in any detail. The paper emphasises the fact that all osteoporosis medications have side-effects, some of which are potentially life-threatening.

Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study.

AIM: To assess the efficacy and safety of adding alogliptin versus uptitrating pioglitazone in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone. METHODS: In this randomized, double-blind, active-controlled, parallel-group study, patients with type 2 diabetes and A1c ≥7.0 and ≤10.0% on metformin (≥1500 mg or maximum tolerated dose; Met) and pioglitazone 30 mg (Pio30) received alogliptin 25 mg (Alo25; n = 404) or pioglitazone 15 mg (n = 399) added to Met+Pio30 for 52 weeks. The primary endpoint was change from baseline (CFB) in A1c at weeks 26 and 52, with sequential testing for non-inferiority of Met+Pio30+Alo25 at weeks 26 and 52 and then for superiority at week 52. RESULTS: Met+Pio30+Alo25 showed superior glycaemic control versus Met+Pio45 at week 52 [least squares (LS) mean CFB in A1c, -0.70 vs. -0.29%; p < 0.001]. At week 52, Met+Pio30+Alo25 resulted in greater CFB in A1c regardless of baseline A1c (p < 0.001); higher proportions of patients achieving A1c ≤7.0 (33.2 vs. 21.3%) and ≤6.5% (8.7 vs. 4.3%; p < 0.001); greater CFB in fasting plasma glucose (FPG; LS mean CFB, -0.8 vs. -0.2 mmol/L; p < 0.001); and greater improvements in measures of ß-cell function (p < 0.001). Hypoglycaemia incidence was low (Met+Pio30+Alo25, 4.5%; Met+Pio45, 1.5%), mostly mild to moderate, but with two severe events in the Met+Pio30+Alo25 group. No meaningful differences in incidences of individual adverse events were observed between treatments. CONCLUSIONS: Adding alogliptin to an existing metformin-pioglitazone regimen provided superior glycaemic control and potentially improved ß-cell function versus uptitrating pioglitazone in patients with type 2 diabetes, with no clinically important differences in safety.

Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study.

AIMS: To evaluate the efficacy and safety of alogliptin, a new dipeptidyl peptidase-4 inhibitor, for 26 weeks at once-daily doses of 12.5 and 25 mg in combination with metformin in patients whose HbA(1c) levels were inadequately controlled on metformin alone. METHODS AND PATIENTS: Patients with type 2 diabetes and inadequate glycaemic control (HbA(1c) 7.0-10.0%) were randomised to continue a stable daily metformin dose regimen (> or = 1500 mg) plus the addition of placebo (n = 104) or alogliptin at once-daily doses of 12.5 (n = 213) or 25 mg (n = 210). HbA(1c), insulin, proinsulin, C-peptide and fasting plasma glucose (FPG) concentrations were determined over a period of 26 weeks. RESULTS: Alogliptin at either dose produced least squares mean (SE) decreases from baseline in HbA(1c) of -0.6 (0.1)% and in FPG of -17.0 (2.5) mg/dl [-1.0 (0.1) mmol/l], decreases that were significantly (p < 0.001) greater than those observed with placebo. The between treatment differences (alogliptin - placebo) in FPG reached statistical significance (p < 0.001) as early as week 1 and persisted for the duration of the study. Overall, adverse events (AEs) observed with alogliptin were not substantially different from those observed with placebo. This includes low event rates for gastrointestinal side effects and hypoglycaemic episodes. There was no dose-related pattern of AE reporting between alogliptin groups and few serious AEs were reported. CONCLUSION: Alogliptin is an effective and safe treatment for type 2 diabetes when added to metformin for patients not sufficiently controlled on metformin monotherapy.

The nonmuscle myosin regulatory light chain gene mlc-4 is required for cytokinesis, anterior-posterior polarity, and body morphology during Caenorhabditis elegans embryogenesis.

Using RNA-mediated genetic interference in a phenotypic screen, we identified a conserved nonmuscle myosin II regulatory light chain gene in Caenorhabditis elegans, which we name mlc-4. Maternally supplied mlc-4 function is required for cytokinesis during both meiosis and mitosis and for establishment of anterior-posterior (a-p) asymmetries after fertilization. Reducing the function of mlc-4 or nmy-2, a nonmuscle myosin II gene, also leads to a loss of polarized cytoplasmic flow in the C. elegans zygote, supporting models in which cytoplasmic flow may be required to establish a-p differences. Germline P granule localization at the time of cytoplasmic flow is also lost in these embryos, although P granules do become localized to the posterior pole after the first mitosis. This result suggests that a mechanism other than cytoplasmic flow or mlc-4/nmy-2 activity can generate some a-p asymmetries in the C. elegans zygote. By isolating a deletion allele, we show that removing zygotic mlc-4 function results in an elongation phenotype during embryogenesis. An mlc-4/green fluorescent protein transgene is expressed in lateral rows of hypodermal cells and these cells fail to properly change shape in mlc-4 mutant animals during elongation.

Location and methylation pattern of a nuclear matrix associated region in the human pro alpha 2(I) collagen gene.

Using both a 25 mM Lithium di-iodosalicylic acid (LIS) and a 2M NaCl extraction procedure to extract nuclear matrices from white cells we have identified a 0.9 kb nuclear matrix associated region (MAR) in the human pro alpha 2(I) collagen gene. The MAR is located towards the 3' coding end of the gene, it is completely associated with the matrix in transcriptionally inactive white cells but is incompletely associated with the matrix in transcriptionally active fibroblasts. Furthermore the methylation state of the fibroblast gene in the region coinciding with the MAR showed unique differences when compared to adjacent sites in the fibroblast gene and corresponding sites of the white cell gene.

Holter monitoring at Tygerberg Hospital, 1979-1983--an appraisal.

Over a period of 4 years Holter monitoring was performed on 607 patients in the Division of Cardiology at Tygerberg Hospital. Indications for monitoring were broadly grouped into four categories: (i) evaluation of symptoms suggestive of disorders of cardiac rhythm (210 patients); (ii) evaluation of arrhythmias associated with a specific underlying cardiac condition (139 patients); (iii) evaluation of a previously documented or suspected arrhythmia (233 patients); and (iv) miscellaneous reasons (25 patients). Findings are presented and aspects of Holter monitoring are discussed. Finally, some recommendations for improving the clinical value of our Holter analyses are made.

Hypertrophic cardiomyopathy complicated by complete heart block. Case report and review of the literature.

A 48-year-old man with symptoms of presyncope and congestive cardiac failure had hypertrophic cardiomyopathy (HCM) without obstruction. Complete heart block (CHB), a rare complication of this disease, was preceded by complete left bundle-branch block. Right ventricular (RV) heart failure was a dominant clinical feature but improved dramatically after temporary transvenous RV pacing prompting the insertion of a permanent RV inhibited pacemaker. Repeated ventricular fibrillation was successfully controlled by amiodarone. This is the seventh case of HCM complicated by CHB reported in the literature, and the first in which RV endomyocardial biopsies were undertaken. Two other patients reported in the literature had RV inhibited permanent pacemakers implanted, and a further 2 had atrioventricular sequential pacemakers.

Ergometrine-provoked coronary vasospasm on angiography without angina or ischaemia on ECG. A case report.

A 32-year-old White man suffered a large transmural inferoposterior myocardial infarction (MI). Coronary vasospasm is strongly suspected of having caused this MI since the ergometrine maleate provocation test gave rise to severe coronary vasospasm resulting in total occlusion of the dominant right coronary artery, without angina or ECG or haemodynamic features of myocardial ischaemia. This is a most unusual response to ergometrine maleate. Possible explanations are suggested and the implications are briefly discussed.

Fever and pulmonary thromboembolism.

Fever patterns associated with pulmonary thromboembolism have not been well characterized. Upon review of 35 consecutive patients with angiographically documented pulmonary emboli, fever was present in 24 patients; and in 20, it was attributed solely to pulmonary thromboembolism. Analysis of these cases indicates that high fever (temperature greater than 39 degrees C) due to pulmonary thromboembolism may occur early, and low-grade fever may continue for a week or more. Fever persisting beyond six days, however, especially with temperatures over 38.5 degrees C, should not be ascribed to pulmonary thromboembolism unless other causes have been carefully excluded. If the clinical setting and patient's findings are consistent with pulmonary thromboembolism, one should not be deterred from presumptively making this diagnosis and initiating therapy because of the presence of high fever.