Biomedical subjects

R H Foster

Publications and source records attributed to R H Foster.

30 records · Page 2Linked to original sources

PubMed1998

Abciximab. An updated review of its use in ischaemic heart disease.

UNLABELLED: Abciximab is a glycoprotein IIb/IIIa receptor antagonist that has proven to be of significant clinical value in improving patient outcome after percutaneous coronary revascularisation. Primarily, the drug inhibits platelet aggregation, but it may also have anticoagulant activity and other beneficial effects, such as inhibiting migration and promoting apoptosis of smooth muscle cells. Large well designed studies have found administration of abciximab (as an adjunct to heparin and aspirin) during percutaneous coronary revascularisation to significantly reduce the incidence of ischaemic complications occurring in the 30 days after the procedure. Significant benefit, particularly on the incidence of myocardial infarction, was still evident after 6 months in 2 of 4 major trials. Abciximab provides particular benefit in patients with unstable angina or myocardial infarction who are undergoing percutaneous coronary revascularisation. The benefits of the drug are additive to those achieved with coronary stenting. Very preliminary data suggest that abciximab may improve coronary blood flow after myocardial infarction and allow reperfusion to be achieved with reduced thrombolytic doses. Caution is required to minimise the risk of bleeding complications with the use of abciximab in combination with heparin and aspirin. Careful patient selection, use of an appropriate heparin regimen, early vascular sheath removal and meticulous femoral artery access site care are recommended. Thrombocytopenia can occur with abciximab treatment, but severe cases are uncommon (< 2% of patients) and can be treated with platelet transfusions. The high acquisition cost of abciximab may be partly or fully offset by the costs averted by the reduced incidence of ischaemic complications and need for urgent and/or repeat revascularisation in high risk patients who receive the drug. However, if bleeding complications occur, this adds to treatment costs. Cost effectiveness analyses generally support the use of abciximab in high risk patients. CONCLUSIONS: Abciximab can be recommended for the prevention of acute ischaemic events in most patients undergoing percutaneous coronary revascularisation, but careful patient selection and strict adherence to the recommended treatment protocol are required to reduce the risk of bleeding complications and thrombocytopenia. Its use in high risk patients is largely supported by pharmacoeconomic data. Further pharmacoeconomic information is needed to establish the drug as a standard of care for all patient groups. The indications for abciximab are likely to expand as more data on its use in acute coronary syndromes become available.

Abciximab↗

PubMed1998

Dienogest.

The progestogen dienogest exhibits highly selective binding to the progesterone receptor. It has high progestational and significant antiandrogenic activity, but only moderate antigonadotrophic activity. Dienogest inhibits ovulation, produces secretory transformation of the endometrium and has antiproliferative effects. Oral dienogest 2 mg/day plus ethinylestradiol 30 micrograms/day provides effective contraception (Pearl Index approximately 0.2). Cycle stability is good during long term use of this combination; irregular vaginal bleeding was evident in 6% of women after 12 months' use. Androgenic symptoms (including hirsutism, seborrhoea, alopecia, acne vulgaris and hair and skin greasiness) improved in women treated with dienogest plus ethinylestradiol. The adverse events associated with dienogest are typical of those expected of a progestogen. The drug does not produce androgenic adverse effects and has little clinically significant effect on metabolic, lipid and haemostatic parameters.

Androgen Antagonists↗

PubMed1998

Cefotaxime. A pharmacoeconomic review of its use in the treatment of infections.

Cefotaxime is a parenterally administered third generation cephalosporin with a broad spectrum of antimicrobial activity. After more than a decade of use, cefotaxime continues to play an important role in the treatment of patients with serious infections, particularly those caused by Gram-negative bacteria. Clinical trials of cefotaxime have demonstrated clinical and/or bacteriological success rates usually between 75 and 100% in hospitalised patients with infections such as pneumonia, complicated urinary tract infections and bacteraemia. In general, comparative trials have shown that cefotaxime has equivalent clinical efficacy to ceftriaxone. Although cefotaxime was traditionally administered at 6- or 8-hourly intervals, evaluations of twice daily regimens have demonstrated the feasibility of using this extended dosage interval in selected patients. Like other parenterally administered cephalosporins, cefotaxime is well tolerated. Cefotaxime does not cause a significant incidence of coagulopathies, as observed with some cephalosporins (e.g., cefamandole and cefoperazone), nor is it associated with the development of pseudocholelithiasis as seen with ceftriaxone. Some hospitals have achieved significant cost savings by implementing programmes or policies involving replacement of prescriptions for ceftriaxone with those for cefotaxime; however, other institutions have shown cost savings when cefotaxime is replaced by ceftriaxone. Similarly, conflicting results were seen in studies that assessed only the drug acquisition and administration supply costs (with or without inclusion of labour costs), highlighting the difficulty in applying pharmacoeconomic data from one clinical setting to another. A limited number of detailed pharmacoeconomic analyses of cefotaxime have been conducted. One analysis, in patients with pneumonia or other serious infections, incorporated published clinical trial data as well as published or estimated cost data (from 1992 or earlier) for the US healthcare setting. Total treatment costs per patient-day were $US25.21 for cefotaxime 1 g twice daily and $US37.23 for cefotaxime 1 g 3 times daily, compared with $US69.97 for ceftriaxone 2 g once daily and $US74.57 for ceftriaxone 1 g twice daily. Costs included those associated with drug acquisition, administration and preparation, laboratory monitoring and adverse events. A large retrospective analysis was conducted between 1989 and 1993 in a US hospital. Patients treated with cefotaxime twice daily had similar clinical outcomes, including duration of hospital stay (7.21 vs 7.24 days), to those receiving antimicrobials other than cefotaxime. However, when a model was applied to determine attributable differences, a trend was demonstrated towards reduced length of hospitalisation (mean reduction 0.5 days) and total cost of hospitalisation (mean reduction $US623 per patient) with cefotaxime. In a Canadian clinical decision-analysis model of initial empirical monotherapy for an average infectious disease state (costs for serious lower respiratory tract infection, urinary tract infection, sepsis, skin/soft tissue infection and febrile neutropenia were weighted according to the incidence of each infection and combined to give a single value), the average total cost per patient for cefotaxime was $Can4099 (1994 dollars). This was lower than that for ceftriaxone ($Can4257) but higher than that for cefepime ($Can3945), ciprofloxacin ($Can4008) and ceftazidime ($Can4086). Costs included those related to drug acquisition, preparation and administration, bacterial culture and sensitivity testing, hospitalisation and adverse events. An analysis conducted in France demonstrated that cefotaxime 1 g 3 times daily was associated with total treatment costs equal to or lower than those for ceftriaxone 2 g once daily. The study also evaluated total costs of cefotaxime 1 g twice daily and ceftazidime 1 g 3 times daily; treatment costs associated with cefotaxime were less than on

Bacterial Infections↗

PubMed1998

Risperidone. A pharmacoeconomic review of its use in schizophrenia.

UNLABELLED: The availability of new atypical antipsychotics, such as risperidone, that have higher acquisition costs than conventional treatments has promoted pharmacoeconomic evaluation of their costs and benefits. Risperidone is reported to have superior efficacy to haloperidol and similar efficacy to other atypical antipsychotics. At dosages < or = 8 mg/day, risperidone is generally associated with a lower risk of extrapyramidal symptoms than conventional antipsychotics and may have a more favourable effect on cognitive function and quality of life. Overall treatment costs during the first year of risperidone treatment were lower than in the previous year in a number of studies in patients with schizophrenia, reflecting a reduction in hospitalisation, although costs slightly increased after risperidone initiation in 2 studies. Total treatment costs were not significantly different with risperidone or conventional antipsychotics in a large, prospective naturalistic study. The use of risperidone in preference to conventional antipsychotics in patients with chronic schizophrenia has been supported by several modelled studies, including a cost-effectiveness analysis that compared risperidone and haloperidol in chronic schizophrenia and a cost-utility study that compared the drug with oral haloperidol, depot haloperidol decanoate and depot fluphenazine decanoate for 1 year's treatment of an initially hospitalised chronic schizophrenic patient with moderate symptoms. In another study, the cost-utility ratio for risperidone versus haloperidol was 24,250 Canadian dollars per quality-adjusted life year (year of costing not stated), but only drug costs were considered. Risperidone had favourable cost-benefit ratios relative to conventional antipsychotic treatment in a study that investigated a scenario in which all patients hospitalised with newly diagnosed schizophrenia received conventional antipsychotic therapy for 6 months, and then those who did not respond received a 6-month trial of risperidone or clozapine. The results of 2 limited decision-analytical models did not favour risperidone. One study compared risperidone with oral haloperidol or depot haloperidol decanoate for the outpatient treatment of a schizophrenic patient with a history of relapse and rehospitalisation. The other compared risperidone, olanzapine and oral haloperidol for the treatment of schizophrenia. CONCLUSIONS: Despite its high acquisition cost, risperidone does not increase, and may even reduce, overall treatment costs of schizophrenia by reducing hospitalisation compared with standard treatment regimens. While further pharmacoeconomic evaluation of risperidone as a first-line agent is required, pharmacoeconomic data overall support its use in patients with chronic schizophrenia.

Antipsychotic Agents↗

PubMed1997

Recent progress in understanding aldosterone secretion.

1. The synthesis and secretion of aldosterone in the adrenal zona glomerulosa in physiologic conditions is controlled by adrenocorticotropin (ACTH), angiotensin II (AII), and extracellular (K+). 2. ACTH effects on aldosterone output are explained by cyclic AMP-(cAMP)- and Ca(2+)-dependent mechanisms. 3. All effects on aldosterone secretion are initiated by an increase in Ca2+ influx through hormone-operated Ca2+ channels and G-protein- and phospholipase C-(PLC) dependent hydrolysis of phosphoinositides leading to the generation of inositol 1,4,5 trisphosphate (IP3) and DAG that induce intracellular Ca2+ release and PKC activation, respectively. 4. ACTH increases DAG formation with marginal or undetectable IP3 generation. The effect of ACTH on DAG levels is discussed. 5. The requirement of external Ca2+ in PLC activation and aldosterone secretion also is discussed.

Adrenal Cortex↗

PubMed1997

Estradiol and dydrogesterone. A review of their combined use as hormone replacement therapy in postmenopausal women.

The focus of this review is hormone replacement therapy (HRT) with continuous oral 17 beta-estradiol (herein referred to as estradiol) 2 mg/day plus sequential oral dydrogesterone 10 or 20 mg/day for 14 days of each 28-day cycle. According to data from nonblind trials, this regimen relieves climacteric symptoms, preserves bone mineral density (BMD) and improves the cardiovascular risk profile in postmenopausal women. Increases in mean BMD in the lumbar spine of 2.4 to 6.4% have been reported after 2 years' treatment. The effect on BMD of oral estradiol plus sequential dydrogesterone was similar to that achieved with transdermal estradiol plus sequential oral dydrogesterone or with oral tibolone. Good protection against endometrial hyperplasia and cancer is provided by the dydrogesterone component. Cyclical vaginal bleeding occurs in most treatment cycles, but is generally light to moderate and the time of onset is highly predictable. Noncyclical bleeding occurs in < 10% of cycles. Mean serum high density lipoprotein-cholesterol levels are increased and low density lipoprotein-cholesterol levels are decreased during treatment with oral estradiol plus sequential dydrogesterone. Insulin resistance appears to be improved. Blood pressure and bodyweight are not generally affected to any clinically important extent. Serum homocysteine levels were reported to decrease in postmenopausal women with high pretreatment levels. No data are available on the general tolerability profile of this regimen. However, the adverse events that most commonly led to discontinuation of treatment in clinical trials were typical of those associated with HRT, including vaginal bleeding headache, bloating and breast tenderness. Although the risk of breast cancer has not been specifically assessed for this regimen, it is unlikely to carry a greater risk than that of other HRT regimens. In summary available data indicate that treatment with continuous oral estradiol plus sequential dydrogesterone is effective in relieving climacteric symptoms and preserving BMD in postmenopausal women. The dydrogesterone component provides good endometrial protection and cycle control without negating the cardiovascular benefits of estradiol. Comparisons with other standard HRT regimens and long term data (including clinical end-points) are needed. In the meantime, this regimen can be regarded as an acceptable HRT option.

Aged↗

PubMed1997

Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation.

Ibutilide is the first 'pure' class III antiarrhythmic drug to become available. Its predominant action is prolongation of the myocardial action potential duration. This appears to be achieved by a unique ionic mechanism of action that involves activation of a late inward sodium current and possibly blockade of the rapidly activating component of the cardiac delayed rectifier potassium current. Intravenous ibutilide 0.01 to 0.025 mg/kg or 1 to 2 mg successfully converted atrial flutter or fibrillation to sinus rhythm in 33 to 49% of patients in 2 placebo-controlled trials involving 439 patients with sustained arrhythmia. In a third trial in 300 patients who developed atrial flutter or fibrillation after cardiac surgery, ibutilide 2 mg successfully converted the arrhythmia in 57% of patients. The mean times to conversion were < or = 30 minutes in these trials. In 3 comparative trials, ibutilide was significantly more effective than racemic sotalol or procainamide in terminating atrial flutter or fibrillation. The pretreatment duration of the arrhythmia is an important predictor of the success of ibutilide treatment; the greatest conversion rates are achieved when the arrhythmia is of recent onset (i.e. < or = 30 days' duration). Ibutilide is more effective in terminating atrial flutter than atrial fibrillation. Adverse events associated with ibutilide are predominantly cardiovascular. Sustained polymorphic ventricular tachycardia developed in 1.7%, and non-sustained polymorphic ventricular tachycardia in 2.7%, of 586 patients treated with ibutilide in clinical trials. However, no proarrhythmia-related deaths have been reported with the use of ibutilide. The drug has minimal haemodynamic effects and is associated with few noncardiovascular adverse events. Thus, ibutilide is a useful agent for the pharmacological cardioversion of recent-onset atrial fibrillation or flutter, provided that adequate steps are taken to monitor for proarrhythmic events. The drug causes few noncardiovascular adverse events and has minimal haemodynamic effects. Furthermore, it appears to be more effective than procainamide (especially in patients with atrial flutter) and racemic sotalol.

Anti-Arrhythmia Agents↗

PubMed1995

Adrenocorticotropin activates glycerol-3-phosphate acyltransferase in bovine adrenal glomerulosa cells.

1. The mechanism whereby ACTH activates the synthesis of diacylglycerol (DAG) in isolated adrenal glomerulosa cells was investigated. 2. ACTH activates glycerol-3-phosphate acyltransferase (G3PAT) in intact and cell-free preparations of adrenal glomerulosa cells. Whereas activation of G3PAT by ACTH was observed in homogenates and membrane fractions, no activation was observed by angiotensin II (AII) at the same concentration. 3. ACTH effects were mimicked by nonspecific phospholipase C (PLC). 4. Our preliminary results suggest that ACTH activation of G3PAT may account for ACTH-induced increases in DAG via de novo synthesis of phosphatidic acid (PA).

Acyl Coenzyme A↗

PubMed1990

External calcium is required for activation of phospholipase C by angiotensin II in adrenal glomerulosa cells.

Previous studies have shown that external calcium (Ca2+) is required for the effects of angiotensin II (AII) on aldosterone secretion in adrenal glomerulosa zone. Using bovine adrenal glomerulosa cells prepared by collagenase dispersion, we examined whether external Ca2+ is required for the activation of phospholipase C by AII. Adrenal glomerulosa cells were exposed to Ca-EGTA buffered media to provide accurate estimates of external free Ca2+ concentrations. Phospholipase C activation was evaluated by measurement of inositol phosphates production. At 0.1 microM Ca2+ and less, sustained AII effects on inositol monophosphate (IP), inositol bisphosphate (IP2) and inositol trisphosphate (IP3) were markedly inhibited. Increasing the Ca2+ concentration to 50 microM or greater fully restored AII-induced inositol phosphates production. AII-induced increases in cytosolic Ca2+ measured by Quin-2 fluorescence, were diminished at lower external Ca2+ concentrations. Treating adrenal glomerulosa cells with Chelex-100, a strong Ca2+ binding resin, blocked early activation of phospholipase C by AII. Inhibition of IP3 production was also observed when inhibitors of Ca2+ movement across the plasma membrane were used, viz., La2+, TMB-8 and nifedipine. The requirement for Ca2+ during AII-induced activation of phospholipase C may be explained, at least partly by a requirement for Ca2+ at a site between the AII receptor and Phospholipase C.

Aldosterone↗

PubMed1989

Angiotensin II increases diacylglycerol in calf adrenal glomerulosa cells by activating de novo phospholipid synthesis.

Effects of angiotensin II (AII) on diacylglycerol (DAG) synthesis were examined in calf adrenal glomerulosa cells. AII provoked rapid increases in [3H]glycerol-labeling and content of DAG. Effects on [3H]glycerol-labeling of DAG were observed both in cells prelabeled with [3H]glycerol for 60 minutes, and when AII and [3H]glycerol were added simultaneously. Increases in [3H] DAG labeling were associated with increases in total glycerolipid labeling, and in simultaneous addition experiments, were preceded by increased [3H] phosphatidic acid (PA) labeling. Labeling of glycerol-3-PO4, on the other hand, was not increased by AII, suggesting that increases in lipid labeling were not due to prior increases in precursor specific activity. ACTH, which does not increase the hydrolysis of inositol-phospholipids appreciably in this tissue, provoked increases in content and [3H]glycerol-labeling of DAG, which were only slightly less than those provoked by AII. Thus, part of the AII-induced increase in DAG may also be derived from sources other than inositol-phospholipids. Moreover, AII-induced increases in DAG appear to be at least partly derived from increased de novo synthesis of PA.

Adrenocorticotropic Hormone↗

PubMed1988

A rapid decline in external Ca2+ induces Ca2+ mobilization in bovine adrenal glomerulosa cells.

Bovine adrenal glomerulosa cells perifused with M 199 containing 1 mM Ca2+ showed a transient increase in 45Ca2+ when the external Ca2+ was decreased. The efflux observed in the presence of 100 nM angiotensin II was similar to that observed when the external Ca2+ was changed from 1 mM to 50 microM. This efflux is the result of the transient activation of the PIP2 hydrolysis with the subsequent production of inositol-trisphosphate.

Animals↗

PubMedDate not supplied

Alitretinoin.

Alitretinoin is a retinoid receptor pan-agonist, which has been investigated in the treatment of Kaposi's sarcoma (KS). Binding with high affinity to all known retinoid receptors, alitretinoin is thought to regulate proliferation, differentiation, and apoptosis of KS cells. Significantly more patients experienced complete or partial responses [according to the AIDS Clinical Trials Group (ACTG) criteria for topical treatment of cutaneous KS] with alitretinoin 0.1% gel 2 to 4 times daily than with vehicle gel in 2 phase III, multicenter, 12-week, randomized, double-blind clinical trials of patients with AIDS-related KS (35 vs 18%, p = 0.002 and 37 vs 7%, p = 0.00003, respectively). Responses were also observed in patients refractory to prior systemic or topical anti-KS therapies. In an intent-to-treat analysis in a phase II trial, 37% of patients with AIDS-related KS receiving alitretinoin capsules 60 to 100 mg/m2/day demonstrated either complete or partial responses (determined by ACTG criteria). The majority of adverse events associated with alitretinoin 0.1% gel were classified as either mild or moderate, occurred at the site of application and were reversible. In both phase III trials, rash was the most common adverse event. The most common adverse events in patients taking alitretinoin capsules included headache, dry skin, rash, alopecia, exfoliative dermatitis, and hyperlipidemia.

Alitretinoin↗