Oestrogen-dependent satellite cell activation and proliferation following a running exercise occurs via the PI3K signalling pathway and not IGF-1.

AIM: The purpose of this study was to determine whether 17ß-estradiol (E2) enhances the activation, proliferation and differentiation of muscle satellite cells (SC) following eccentric exercise either via insulin-like growth factor-1 (IGF-1) or through phosphatidylinositol 3-kinase (PI3K) signalling. METHODS: This study used 64, 9-week-old, ovariectomized Sprague-Dawley rats that were divided into eight treatments groups based on oestrogen status (0.25 mg oestrogen pellet or sham), exercise status (90 min run @ 17 m min(-1), -13.5° or unexercised) and PI3K signalling inhibition (0.7 mg wortmannin kg(-1) body weight or DMSO control). RESULTS: Significant increases in total SCs were found in both soleus and white gastrocnemius muscles (immunofluorescent co-localization of Pax7(+) nuclei) 72 h following eccentric exercise (P < 0.05). Oestrogen supplementation caused a further enhancement in total SCs in exercised rats (P < 0.05). In animals where the PI3K pathway was inhibited, regardless of oestrogen or exercise status, there was no significant enhancement of SC number in both the soleus or white gastrocnemius muscles. Interestingly, oestrogen supplementation lowered muscle levels of IGF-1 with this effect being most prominent in the soleus muscle. While IGF-1 was increased following exercise (P < 0.05), oestrogen supplementation abrogated this increase back to sedentary levels. CONCLUSION: These data suggest that the increase in SC population following exercise in oestrogen-supplemented females may be mediated via PI3K pathway signalling and not IGF-1.

A cost-effectiveness approach to drug subsidy and pricing in Australia.

The Australian government offers its citizens subsidies on a select list of pharmaceuticals. For a drug to qualify for inclusion on this list, its manufacturer must demonstrate that the drug is both clinically effective and cost-effective. In part, this measure, along with others, was introduced to improve clinical and economic outcomes. Although this evidence-based system has provided transparency and consistency in decision making about which drugs will be covered, it may not have contained the rate of increase in drug costs.

Problems with the interpretation of pharmacoeconomic analyses: a review of submissions to the Australian Pharmaceutical Benefits Scheme.

CONTEXT: Pharmacoeconomic analyses are being used increasingly as the basis for reimbursement of the costs of new drugs. Reports of these analyses are often published in peer-reviewed journals. However, the analyses are complex and difficult to evaluate. OBJECTIVE: To describe the nature of problems encountered in the evaluation and interpretation of pharmacoeconomic analyses used as a basis for reimbursement decisions. DATA SOURCES: All major submissions to the Department of Health and Aged Care (DHAC) by the pharmaceutical industry for funding made under the Australian Pharmaceutical Benefits Scheme. Specifically, the DHAC's database of submissions that were received between January 1994 and December 1997 were reviewed. STUDY SELECTION: Of a total of 326 submissions, 218 had serious problems of interpretation and were included in the analysis. The nature of the serious problems reviewed were classified as estimates of comparative clinical efficacy, comparator issues, modeling issues, and calculation errors. DATA EXTRACTION: All submissions in the DHAC's database were reviewed and data were extracted if both the DHAC evaluators and technical subcommittee considered problems to have a significant bearing on the decisions of the parent committee. DATA SYNTHESIS: Of a total of 326 submissions, 218 (67%) had significant problems and 31 had more than 1 problem. Of the 249 problems identified, 154 (62%) related to uncertainty in the estimates of comparative clinical efficacy, and 71 (28.5%) related to modeling issues, which included clinical assumptions or cost estimates, used in the construction of the economic models. There were 15 instances of disagreement over the choice of comparator, and serious calculation errors were found on 9 occasions. Overall, 159 problems (64%) were considered to be avoidable. CONCLUSIONS: Significant problems were identified in these pharmacoeconomic analyses. The intensive evaluation process used in the Australian Pharmaceutical Benefits Scheme allowed for identification and correction of pharmacoecomomic analysis problems, but the resources that are required may be beyond the capacity of many organizations, including peer-reviewed journals.

Lack of evidence for improvement in internal mammary graft flow by occlusion of side branch.

Coronary steal due to unligated side branches of an internal mammary artery graft has been reported previously. Embolization of these side branches has been shown to result in symptomatic improvement, but objective evidence of improved flow to the coronary artery has been lacking. We studied intracoronary Doppler flow in a patient presenting with symptoms thought to be due to a large unligated side branch of mammary graft. There was no significant change in the mammary flow after balloon occlusion of the side branch. More objective data may be required to routinely prescribe side branch embolization for symptomatic patients with unligated side branches of a mammary graft.

Profiles of antibacterial drug use in Australia and trends from 1987 to 1989. A report from the Drug Utilization Subcommittee of the Pharmaceutical Benefits Advisory Committee.

OBJECTIVE: To survey the use by Australian pensioners of orally administered antimicrobial agents supplied through the Pharmaceutical Benefits Scheme over the years 1987-1989. DATA SOURCES: Australian Pharmaceutical Benefits Scheme pensioner data for 1987-1989 and market research data from a private company. DATA EXTRACTION: The data were initially available as the number of prescriptions dispensed and were aggregated on a quarter year basis. These were converted to defined daily doses (DDDs) per 1000 pensioners per day (DDD/1000 per day). This conversion of the data allows comparisons across drug groups, and with prescribing patterns in other countries. The DDD/1000 per day also gives an indication of the proportion of individuals in the community receiving a drug at a particular time. DATA SYNTHESIS: There was a 26% increase in antibacterial drug use over this period. Comparison of prescribing profiles for particular indications with peer consensus guidelines revealed marked discrepancies, particularly for upper respiratory tract infections, urinary tract infections, otitis media and sinusitis. Upper respiratory tract infections accounted for 31% of instances of antibiotic prescribing. Dispensing of amoxycillin/potassium clavulanate relative to amoxycillin as a single agent, showed a marked increase in 1989 to the point where it represented 25% of all amoxycillin used. This could be considered excessive given the lack of evidence that amoxycillin resistance has substantially increased in infections presenting to general practice. The data presented here confirm previous suggestions that Australian antibiotic prescribing is heavily concentrated on the use of broad spectrum agents. By comparison with Norway or Sweden, there is a greater relative use of broad spectrum penicillins and tetracyclines and a lower relative use of phenoxymethylpenicillin and trimethoprim. CONCLUSIONS: Antibiotic prescribing practices in Australia continue to be often inappropriate and expensive, being directed too heavily towards the use of broad spectrum agents and newer more expensive drugs. Correction of such antibacterial drug use will require coordination of educational and regulatory activities that are sensitive to the context of general practice.

The effect of cardiac catheterization upon management of advanced aortic and mitral valve disease.

We assessed the incremental effect of cardiac catheterization upon the management of 93 adult patients with aortic and/or mitral valve disease, referred for surgical consideration. There were 52 patients with aortic valve disease, 29 with mitral valve disease and 12 with aortic and mitral valve disease. Prior to cardiac catheterization, a detailed unblinded ultrasound assessment of each valve was made utilizing 2D and Doppler ultrasound. Based upon the ultrasound result and the clinical assessment, the patient's cardiologist recorded a grading of valve severity and a management decision for each valve. Following catheterization and coronary angiography, the cardiologist repeated the gradings of valve severity and recorded a final management decision. After catheterization, management changed in nine patients and was unchanged in 84. Reasons for management change included differences between echocardiographic and catheterization assessment of valvular regurgitation (three patients), information on coronary anatomy (two patients), minor differences in assessed aortic valve area (one patient) and left ventricular function (one patient), and confirmation of ultrasound findings where clinical and ultrasound findings had been conflicting before catheterization (two patients). Both mitral and aortic valve disease were present in the three patients in whom management changed as a result of significant differences between echocardiography and catheterization assessment of valvular regurgitation. Management was unchanged in the 16 patients with isolated mitral stenosis. In this study, a combination of clinical and noninvasive assessment including Doppler echocardiography, resulted in a reliable evaluation of valvular disease in a large majority of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the long-term effects of estrogen and clomiphene citrate on pituitary and uterine function in ovariectomized rats.

The effects of estradiol-17 beta (E2) and clomiphene citrate (CC) on pituitary-uterine function in ovariectomized (OVX) rats were compared in two experiments. In experiment 1, CC completely blocked E2 stimulation of uterine weight when administered concurrently for 10 and 30 days. In experiment 2, content of total (occupied and unoccupied) uterine nuclear estrogen receptors was increased by E2, but not by CC, compared to OVX controls. Only a fraction of the nuclear receptors was occupied in E2-treated rats, whereas all of these receptor sites were occupied in CC-treated rats. In addition, uterine cytoplasmic estrogen receptors were increased by E2 and diminished by CC treatment. Both E2 and CC were effective in preventing the postovariectomy rise in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), although LH was always inhibited to a greater extent than FSH. After 30 days of treatment, pituitary gonadotropins were also substantially reduced by E2 and CC, suggesting that long-term treatment decreased both pituitary synthesis and release. An increase in pituitary weight observed in E2-treated rats only was due largely to the stimulation of lactotropes, as serum prolactin was increased. In summary, although CC and E2 similarly depressed pituitary gonadotropin secretion, they exhibited marked differences in the stimulation and occupancy of uterine estrogen receptors and the stimulation of pituitary prolactin secretion.

Effects of long-term treatment with estradiol or clomiphene citrate on bone maintenance, and pituitary and uterine weights in ovariectomized rats.

Long-term estrogen replacement therapy in postmenopausal women can bring relief to hot flushes and reduce loss of bone mass due to osteoporosis, however, such treatment often can cause uterine hyperplasia and other undesirable effects. This study compared changes in bone mineral content (BMC), uterine weight, pituitary weight and pituitary gonadotropin content in the ovariectomized rat model following treatment with estradiol (E2) or two levels of clomiphene citrate (CC), an estrogen agonist/antagonist. Groups (n = 8-12) of adult ovariectomized (OVX) rat were implanted with E2 pellets (5 micrograms/day) or injected subcutaneously with CC at 1 mg/kg body wt (CC-1) or 5 mg/kg body wt (CC-5) twice weekly for 12 months. Placebo implanted OVX and intact (INT) female rats served as negative and positive controls, respectively. Following treatment, the uterus, pituitary gland and right femur were collected from each animal. E2 treatment increased (P less than 0.05) uterine weight compared to all other treatment groups, while both CC doses increased uterine weight over the OVX group only (E2, 0.24 +/- 0.03; INT, 0.14 +/- 0.01; CC-1, 0.06 +/- 0.01; CC-5, 0.07 +/- 0.01; and OVX, 0.02 +/- 0.01 g per 100 g body wt). Pituitary weight was increased 15-fold (P less than 0.05) by E2 treatment over all other treatment groups (E2, 65.7 +/- 13.9; INT, 4.0 +/- 0.5; CC-1, 3.3 +/- 0.03; CC-5, 2.7 +/- 0.02; and OVX, 2.9 +/- 0.02 mg per 100 g body wt). Both E2 and CC treatments reduced pituitary luteinizing hormone and follicle stimulating hormone content (micrograms/pit) to INT levels and were lower (P less than 0.05) than OVX levels. Mean BMC of E2, CC-1- or CC-5-treated rats was greater (P less than 0.05) than that of either the INT or OVX groups, while INT animals had a higher BMC compared to OVX animals (E2, 0.027 +/- 0.003; CC-1, 0.026 +/- 0.001; CC-5, 0.028 +/- 0.001; INT, 0.021 +/- 0.001; and OVX, 0.017 +/- 0.001 g/cm per 100 g body wt). These data indicate that CC has the potential to reduce bone mineral loss without causing other undesirable effects, including uterine hyperstimulation, and thus needs to be further investigated.

Patients as a direct source of information on adverse drug reactions.

To determine whether patients should participate directly in detecting adverse reactions to drugs their ability to provide written reports of symptoms experienced during treatment with amoxycillin or trimethoprim-sulphamethoxazole was investigated. When compared with telephone interviews forms on which patients reported events were reliable (the observed agreement with the same statements posed during telephone calls was 85%, kappa = 0.56) and valid (sensitivity = 54%, specificity = 94%). Patients were also supplied with forms that invited them to report adverse reactions, and their perceptions were compared with those of a panel of experts, who were informed of all clinical events that had been reported during the detailed telephone interviews. Patients were more conservative than the experts in attributing clinical events to drug treatment. The extent of agreement varied and was notably poor for skin and bowel complaints (kappa = 0.13 in each case). The performance of event report forms and reaction report forms as instruments of detection was compared in a hypothetical situation in which the experts' views represented the "truth" about adverse reactions to a new drug. Event reporting had a higher sensitivity than reaction reporting (42% v 24%) but a lower specificity (58% v 98%). National centres monitoring adverse drug reactions should probably resist pressure to accept reports of reactions directly from the public, but a system based on large scale reporting of events might be valuable in aiding the early detection of symptomatic reactions to new drugs.

Combined use of prazosin and beta-blockers in hypertension.

Combined use of prazosin and beta-blockers in a hypertension clinic over a 3-year period was surveyed by means of a computerized record system. Of the 1,250 patients in the clinic, 171 (14%) had been treated with this combination for periods averaging 17 months. Prazosin was administered with a beta 1-selective beta-blocker in 94 cases and with a beta 1 + beta 2-blocker in 100 cases; 23 patients had received treatment with both combinations. Diuretics were given in 86% of cases and other antihypertensive drugs in 19%. The population treated had a high incidence of severe hypertension, with initial diastolic pressure greater than 120 mm Hg in 38% and between 100 and 120 mm Hg in 50%. The percentage of patients with diastolic pressure less than 100 mm Hg was 12% initially and 79% at the end of the treatment period. Side effects necessitated withdrawal of therapy in 35 cases. These were referable in 19 cases to prazosin and in 16 to beta-blockers. Prazosin was found to be more effective in lowering blood pressure in combination with beta 1-blockers than with beta 1 + beta 2-blockers, although there were fewer severe side effects with beta 1-blockers.

The assessment of an antiarrhythmic agent, sustained-release procainamide, with the aid of Holter monitoring.

A sustained-release preparation of procainamide (PAD) was evaluated in a double-blind cross-over study. The preparation was found to reduce ventricular ectopic activity in all seven patients who completed the investigation in five patients the effectiveness reached the defined level of significance. A larger clinical trial to assess the long-term use of this preparation in terms of efficacy, safety and convenience is recommended.