Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain.

Adenosine A(2A) receptors are found on striatal neurones projecting to the external pallidum. KW-6002 (istradefylline) is a potent and selective antagonist for the adenosine A(2A) receptors in the CNS and acts to inhibit the excessive activity of this pathway in the MPTP marmoset model of PD, thus relieving parkinsonism. The objectives of this study were to investigate the regional binding of the novel positron emission tomography tracer [(11)C]KW-6002 in the healthy human brain and the rat brain, along with receptor occupancy by cold KW-6002 at varying doses in human. The highest [(11)C]KW-6002 uptake in the rat brain was seen in striatum and lower levels in cortex and cerebellum. Brain [(11)C]KW-6002 uptake was well characterized in humans by a two-tissue compartmental model with a blood volume term, and the ED(50) of cold KW-6002 was 0.5 mg in the striatum. Over 90% receptor occupancy was achieved with daily oral doses of greater than 5 mg. In humans, blockable binding was present in all gray matter structures including the cerebellum, which has not been reported to express A(2A) receptors. MRS 1745, an A(2B) receptor selective antagonist, had no effect on the cerebellar binding of [(11)C]KW-6002 in rats, suggesting that this blockable signal is unlikely to result from an affinity for adenosine A(2B) receptors.

The bridging concept: optimizing dose for phase II/III in Alzheimer's disease.

Our research has shown that the tolerance of Alzheimer's disease (AD) patients for anti-dementia compounds is frequently higher but occasionally lower than the tolerance of healthy young or elderly populations. Such differences can either pose safety problems in later efficacy studies if patients cannot tolerate the dosages previously deemed 'safe' in healthy populations, or interfere with determining efficacy if inadequate doses are employed. We recommend use of a 'bridging study', which optimizes dosage early in development by determining the maximum tolerated dose of a compound in patients. Consecutive panels of patients each receive higher doses of study drug until a minimum intolerated dose is reached. The dose immediately below this one is then considered the maximum tolerated dose. Careful subject selection, adequate facilities, and highly qualified, experienced personnel, are critical to the successful implementation of a bridging study. Correctly done, bridging can streamline the overall drug development process while making Phase II and III trials safer for patients, and has immense potential for accelerating the search for compounds that have efficacy in AD.

Necrotizing cellulitis caused by Legionella micdadei.

Legionella micdadei is primarily considered a pathogen of the pulmonary tract of immunocompromised patients, the majority of whom have been renal transplant recipients. We report the case of a necrotizing soft tissue infection in a cadaveric renal transplant recipient resulting in amputation of the left arm. Only one other extrathoracic bacteriologically documented L. micdadei infection has been reported in the literature.

Treatment with pulsatile luteinizing hormone-releasing hormone modulates folliculogenesis in response to ovarian stimulation with exogenous gonadotropins in patients with polycystic ovaries.

Combined treatment with pulsatile LH-RH and hMG, given to eight patients who had anovulation associated with PCO and resistant to CC, significantly reduced the number of large follicles induced by hMG alone. A direct effect of pulsatile LH-RH on the ovary is postulated. This combined treatment eased the problems of multifollicular development, thereby increasing efficiency and reducing complications in patients with PCO stimulated by gonadotropins.

Combined luteinizing hormone releasing hormone analogue and exogenous gonadotrophins for the treatment of infertility associated with polycystic ovaries.

This study was designed to compare the results of treatment with, firstly, exogenous gonadotrophins, with (57 cycles) and without (65 cycles) pretreatment with a superactive analogue of luteinizing hormone releasing hormone (LHRH) and, secondly, pure follicle stimulating hormone (FSH) (50 cycles) with those of human menopausal gonadotrophin (HMG) (72 cycles) in 46 women with clomiphene-citrate-resistant anovulation associated with polycystic ovaries. Patients randomly allocated to the analogue group received buserelin (Suprefact, Hoechst, UK, Ltd, Hounslow, Middlesex), 800 micrograms/day by nasal insufflation and when hypogonadism was achieved, patients were again randomly allocated for ovarian stimulation with either FSH or HMG. Controls received FSH or HMG alone. Patients pretreated with the analogue had similar pregnancy and ovulation rates, needed larger doses and more days of gonadotrophin therapy and had more ovarian overstimulation than those receiving no pretreatment. The role of superactive LHRH analogues for induction of a single ovulation for in-vivo fertilization is thus uncertain. Pure FSH had no advantages over HMG, the LH content of HMG having no deleterious effect on the ovary.

Most women with acne have polycystic ovaries.

Out of 98 female referrals with acne vulgaris it was possible to define ovarian morphology by high resolution ultrasound imaging of the pelvis in 82 (84%). Sixty-eight (83%) were shown to have polycystic ovaries, compared with 19% in a control group without acne. The presence of polycystic ovaries in the acne patients did not correlate with acne severity, infertility, menstrual disturbance, hirsutes, or biochemical endocrinological abnormalities.

Guidelines for completion of the college of radiographers' D.M.U. logbook.

The College of Radiographers has recently released its guidelines for the diploma in medical ultrasound (DMU) logbook which cover many of its aspects. It has been our intention to concentrate on the images required for each section. We hope DMU students will find this guide useful when preparing for the scan and afterwards when writing up the case studies.

One hundred pregnancies after treatment with pulsatile luteinising hormone releasing hormone to induce ovulation.

OBJECTIVE: To review treatment with pulsatile luteinising hormone releasing hormone in infertile women who do not ovulate and are resistant to clomiphene after 100 pregnancies achieved with this treatment. DESIGN: Retrospective analysis of 146 courses of treatment over 434 cycles. SETTING: Infertility clinic. PATIENTS: 118 Women whose failure to ovulate was due to idiopathic hypogonadotrophic hypogonadism (n = 39), amenorrhoea related to low weight (n = 17), organic pituitary disease (n = 15), or polycystic ovaries (n = 47). INTERVENTIONS: Dose of 15 micrograms luteinising hormone releasing hormone/pulse subcutaneously every 90 minutes given with a miniaturised pump throughout cycle monitored by ultrasound. Women with hypogonadotrophic hypogonadism had 48 courses, women with amenorrhoea related to low weight 23, women with organic pituitary disease 18, and women with polycystic ovaries 57. END POINT: Follow up of 100 pregnancies achieved in 77 women during six years after introducing treatment. MEASUREMENTS and main results--One hundred pregnancies (seven multiple, 28 miscarriages). Cumulative rates of pregnancy were 93-100% at six months in women with idiopathic hypogonadotrophic hypogonadism, amenorrhoea related to low weight, and organic pituitary disease. In women with polycystic ovaries (cumulative rate of pregnancy 74%) adverse prognostic factors were obesity, hyperandrogenism, and high luteinising hormone concentrations, which were also associated with a high rate of early pregnancy loss. CONCLUSIONS: Treatment with pulsatile luteinising hormone releasing hormone is safe, simple, and effective, and the preferred method of inducing ovulation in appropriately selected patients. Compared with exogenous gonadotrophin treatment there is little need for monitoring, no danger of hyperstimulation, and a low rate of multiple pregnancies.

A retrospective study of infant mortality of cotton-top tamarins (Saguinus oedipus) in captive breeding.

Fifty of 156 (32%) colony bred cotton-top tamarins were stillborn, and 31 (20%) died within the first week after birth. The stillbirth rate was related to litter size and parity in captivity. A higher percent of single births were stillborn (69%) compared to those of twin births (26%) (p less than 0.005). A higher percent of infants born of the first litter in captivity (42%) were stillborn than those of subsequent litters (23%) (p less than 0.025). Stillbirths were not related to season of birth or sex of infant. Survival of live infants was unrelated to season of birth, sex, litter size, or number of litters.

The effect of non-selective and selective beta-1-blockade on the plasma potassium response to hypoglycaemia.

The effect of non-selective beta-blockade with propranolol, beta 1-selective blockade with betaxolol and of saline on the plasma potassium response to insulin induced hypoglycaemia was examined in six healthy subjects. Although propranolol retarded the recovery from hypoglycaemia, the degree of hypokalaemia was significantly (p less than 0.01) less than with saline or betaxolol, which had similar effects. Adrenergic mechanisms may modulate potassium disposal through a beta 2 receptor.

A comparison between propranolol, practolol and betaxolol (SL75212) on the circulatory and metabolic responses to insulin-induced hypoglycaemia.

1. Six healthy male volunteers received equivalent intravenous beta-blocking doses of propranolol, practolol and betaxolol (SL75212) or saline at weekly intervals Sixty minutes later 0.1 unit/kg insulin was given intravenously. 2. In all studies, maximum hypoglycaemia (mean 1.2 mmol/l) was reached thirty minutes after insulin. Recovery from hypoglycaemia was delayed with propranolol but practolol and betaxolol had no effect. 3. Propranolol blocked the tachycardia and widening of pulse pressure seen in saline treated subjects. It also blocked the rebound rise in free fatty acids (FFA) and glycerol concentrations that followed the nadir of hypoglycaemia. 4. Neither practolol nor betaxolol had significant effects on pulse rate or blood pressure but betaxolol resembled propranolol in blocking the rebound rise in FFA and glycerol, while practolol blocked the rise in glycerol alone. 5. The magnitude of the rise in growth hormone following hypoglycaemia was similar in all groups, but the peak was earlier after practolol and betaxolol.

Blood concentrations and pharmacodynamic effects of betaxolol (SL 75212) a new beta-adrenoceptor antagonist after oral and intravenous administration.

1 In normal subjects, intravenous betaxolol given in doses which inhibited the tachycardia of exercise failed to affect the peak expiratory flow rate. 2 From 2 to 48 h after administration of 150 micrograms/kg in four normal subjects, there was no significant difference between the blood levels, whether given orally or intravenously. 3 At all times, heart rate and blood pressure, at rest and during exercise, were reduced equally after administration by both routes, but the area under the curve of exercise heart rate against time was significantly smaller (P < 0.05) after intravenous drug. 4 The absolute bioavailability of betaxolol was 89 +/- 5%.

Cardiovascular effects of single oral doses of the new beta-adrenoceptor blocking agents betaxolol (SL 75212) in healthy volunteers.

1 The effects of betaxolol (SL 75212), a new beta-adrenoceptor blocking agent, on the cardiovascular response to exercise have been studied in six normal subjects after placebo and single oral doses of 5, 10, 20 and 40 mg given double-blind in a randomized sequence. 2 All doses reduced exercise heart rate, with a significant reduction persisting to 23 h after doses of 20 mg and 40 mg. Systolic blood pressure on exercise was reduced after all doses, with a reduction continuing to 23 h after doses of 10 mg and above. 3 The mean elimination half-life of SL 75212 was 17.5 +/- 3.9 h. The plasma clearance ranged from 0.15--0.48 1 kg-1 h-1 and the volume of distribution from 5.8--13 1 kg-1. 4 There was a significant correlation between the peak blood levels and change in exercise heart rate (r = 0.53, P less than 0.05) and between the area under the blood concentration curve and the effect of the exercise heart rate (r = 0.55, P less than 0.01).

Pharmacokinetics of the new beta-adrenoceptor blocking agent betaxolol (SL 75212) in man after repeated oral administration.

(+/-)-1-(Isopropylamino)-3-[p-(2-cyclopropyl-methoxyethyl)-phenoxy]-2-propanol HCl (betaxolol, SL 75212) was given to groups of healthy volunteers, 10 mg daily for 7 days followed by 20 mg daily 7 days in one group, and increasing daily doses up to 60 mg/day for a total of 15 days in the other group. The pharmacokinetics were studied during dosing and in the washout period. The pharmacokinetic characteristics were unchanged after repeated doses, T/2 16-22 h, Vd 7.7-8.8 l/kg; clearance 0.28-0.33 l/h/kg.