An extreme magneto-ionic environment associated with the fast radio burst source FRB 121102.

Fast radio bursts are millisecond-duration, extragalactic radio flashes of unknown physical origin. The only known repeating fast radio burst source-FRB 121102-has been localized to a star-forming region in a dwarf galaxy at redshift 0.193 and is spatially coincident with a compact, persistent radio source. The origin of the bursts, the nature of the persistent source and the properties of the local environment are still unclear. Here we report observations of FRB 121102 that show almost 100 per cent linearly polarized emission at a very high and variable Faraday rotation measure in the source frame (varying from +1.46 × 105 radians per square metre to +1.33 × 105 radians per square metre at epochs separated by seven months) and narrow (below 30 microseconds) temporal structure. The large and variable rotation measure demonstrates that FRB 121102 is in an extreme and dynamic magneto-ionic environment, and the short durations of the bursts suggest a neutron star origin. Such large rotation measures have hitherto been observed only in the vicinities of massive black holes (larger than about 10,000 solar masses). Indeed, the properties of the persistent radio source are compatible with those of a low-luminosity, accreting massive black hole. The bursts may therefore come from a neutron star in such an environment or could be explained by other models, such as a highly magnetized wind nebula or supernova remnant surrounding a young neutron star.

Sex- and season-dependent differences in C-peptide levels at diagnosis of immune-mediated type 1 diabetes.

AIMS/HYPOTHESIS: The incidence of type 1 diabetes varies according to age, sex and season of diagnosis. We investigated whether these and other clinical, biological and anthropometric parameters were correlated with residual beta cell function in newly diagnosed patients, since it is possible that the nature of external and/or genetic disease accelerators may be (partly) reflected in the inaugural disease presentation. MATERIALS AND METHODS: The correlates of random C-peptide levels sampled shortly after diagnosis (median [interquartile range]: 3 [0-14] days) were studied by multivariate analysis in 1,883 islet-antibody-positive diabetic patients aged <40 years who were diagnosed between 1989 and 2000. RESULTS: Higher C-peptide levels (above percentile 50 of patients) were associated with older age at diagnosis, female sex, diagnosis in the high-incidence season (October to March), less-decreased BMI (expressed as a standard deviation score), lower insulin requirements after stabilisation, lower prevalence of ketonuria and a less-increased glycaemia at diagnosis (all p < 0.001). C-peptide levels were not correlated with calendar year at diagnosis, duration of symptoms prior to diagnosis, HLA-DQ2/DQ8 genotype or islet antibody status. CONCLUSIONS/INTERPRETATION: Sex- and season-dependent differences in residual functional beta cell mass and/or insulin resistance have been identified at diagnosis of type 1 diabetes. They may reflect differences in disease-precipitating external or lifestyle factors and should be further investigated longitudinally in prediabetes to further identify putative aetiological factors, which may provide targets for prevention.

The safety and tolerability of single intravenous doses of lubeluzole (Prosynap) in healthy volunteers.

The safety and tolerability of single escalating doses of lubeluzole were evaluated in healthy male volunteers in 2 studies. In the first of 2 randomized, single-blind, placebo-controlled, dose-escalation studies, 6 subjects received single 30-minute infusions of 2.5, 5, and 10 mg of lubeluzole, and 2 additional subjects received placebo. In the second study 6 different subjects received a 1-hour infusion of 15 mg of lubeluzole, 5 of whom received the 20-mg dose, and 2 received 25 mg of lubeluzole. Two additional subjects received placebo. Small increases and decreases in PQ, QRS, QT, QTc, and QTm intervals were noted after infusion of all lubeluzole doses and placebo, however, these changes were within the normal ranges for these values except for the QTc for the 25-mg dose of lubeluzole. Significant prolongation of the QTc interval was observed at the end of the 1-hour infusion in both subjects receiving the 25-mg dose of lubeluzole. No clinically relevant changes in systolic time intervals, heart rate, blood pressure, and clinical laboratory values were noted in subjects receiving 2.5-25 mg of lubeluzole or placebo. Adverse experiences, predominantly lightheadedness and dizziness, were reported by subjects receiving doses of lubeluzole greater than or equal to 10 mg. Lubeluzole, administered as single intravenous doses of 2.5-15 mg, is safe and well tolerated in healthy male volunteers.

Effect of food on the pharmacokinetics of a new hydroxypropyl-beta-cyclodextrin formulation of itraconazole.

STUDY OBJECTIVE: To compare the pharmacokinetics of a single 100-mg oral dose of itraconazole administered as 10 ml of a 10-mg/ml itraconazole solution in hydroxypropyl-beta-cyclodextrin under fasting versus postprandial conditions. DESIGN: Open-label, two-way, randomized, crossover study. SETTING: Janssen Research Foundation, Belgium. PATIENTS: Twelve healthy volunteers. INTERVENTIONS: Blood samples were obtained for pharmacokinetic analyses immediately before dosing and at regular intervals up to 96 hours after each dose. Blood and urine samples were obtained for hematologic, biochemical, and urinary safety analyses at baseline and at the end of the study. MEASUREMENTS AND MAIN RESULTS: The mean peak plasma concentrations of both itraconazole and its active metabolite hydroxy-itraconazole were significantly higher under fasting conditions than under postprandial conditions. The mean times to peak concentration for both the parent compound and its metabolite were significantly shorter under fasting than under nonfasting conditions. The mean areas under the curve (AUC0-infinity and AUC0-24 hrs) were also significantly higher under fasting than under postprandial conditions. CONCLUSIONS: Our findings suggest that the higher bioavailability of this new formulation of itraconazole may be of benefit in seriously ill patients who are not able to ingest adequate quantities of food. The fact that the solution was also well tolerated and was not associated with clinically significant changes in any laboratory value further underscores the potential utility of this dosing form.

Recurrent spontaneous abortion: histocompatibility between partners, response to immune therapy, and subsequent reproductive performance.

PROBLEM: Immunological factors may account for previously unexplained cases of recurrent abortion. METHOD: After screening 76 couples for causes of recurrent spontaneous abortion and measuring maternal antipaternal immunity, 23 primary spontaneous recurrent aborters were immunized once with their husbands' leukocytes. Testing for antipaternal cytotoxicity was repeated in 21 couples. Seroconversion was significantly less frequent in couples who shared more than one human leukocyte antigen [one of five (20%) versus 13 of 16 (81%), P < .02]. RESULTS: Twelve of 16 women (75%) who became pregnant had live children and five of those have had a second live child. All 12 women who achieved successful pregnancies had become antipaternal cytotoxic antibody-positive after immunization, whereas all four patients who had repeat abortions had failed to seroconvert (P < .001). However, this relationship is not necessarily causative, as the successful group also tended to have fewer previous abortions and less human lymphocyte antigen sharing. CONCLUSION: Except for transient illness after immunization, one moderately small for gestational age baby and one premature labor at 32 wk, no complications were observed after immunization.

Ridogrel inhibits systemic and renal formation of thromboxane A2 and antagonizes platelet thromboxane A2/prostaglandin endoperoxide receptors upon chronic administration to man.

The effects of ridogrel, a dual thromboxane A2 (TXA2) synthase inhibitor and TXA2/prostaglandin (PG) endoperoxide receptor antagonist, on systemic and renal production of prostaglandins and on platelet TXA2/PG endoperoxide receptors was evaluated upon chronic administration (300 mg b.i.d. orally, for 8 and 29 days) to man. Such a medication with ridogrel inhibits the systemic as well as the renal production of TXA2 as measured by the urinary excretion of 2,3-dinor-TXB2 and TXB2 respectively without inducing significant changes in systemic or renal PGI2 production. Simultaneously with the latter effects, the production of TXB2 by spontaneously coagulated whole blood ex vivo is inhibited (greater than 99%) while that of PGE2 and PGF2 alpha is largely increased. Administration of ridogrel causes a three- to five-fold shift to the right of concentration-response curves for U46619 in eliciting platelet aggregation; no tachyphylaxis is observed after 29 days of treatment in this respect. Apart from a reduction of serum uric acid levels with a concomitant increase in urinary uric acid excretion during the first days of treatment, no clinically significant changes in hematological, biochemical, hemodynamic and coagulation parameters occur during the 8 days or 29 days study. The study demonstrates that ridogrel is a potent inhibitor of the systemic as well as renal TXA2 synthase and an antagonist of platelet TXA2/PG endoperoxide receptor in man, covering full activity during 24 h at steady-state plasma level conditions without tachyphylaxis during 29 days of medication. The compound is well tolerated, at least during 1 month of administration.

The antihypertensive and cardiac hemodynamic effects of nebivolol.

Acute, subacute, and chronic treatment with nebivolol, a novel beta 1-selective adrenergic antagonist, significantly lowered systolic and diastolic blood pressure and heart rate in patients with essential hypertension. No orthostatism and bradycardia were reported. A comparison between a normal control group and 23 hypertensive patients revealed that the ratio between the preejection period (PEP) and the left ventricular ejection time (LVET) of the systolic time intervals (STI) was significantly increased in the hypertensive patients, owing to a prolongation of the PEPc (PEP corrected for heart rate). Treatment with nebivolol 5 mg once a day significantly improved the PEP/LVET, in acute conditions from 0.42 +/- 0.023 to 0.39 +/- 0.018, after one month of treatment from 0.40 +/- 0.013 to 0.36 +/- 0.013 and after one year of treatment from 0.41 +/- 0.012 to 0.36 +/- 0.010, owing to a significant shortening of the PEPc. There was no correlation between changes of blood pressure and changes of STI. Diastolic dysfunction is an early finding in hypertension and may well be reflected in the prolongation of the PEPc. The improvement of left ventricular performance, as measured with STI, suggests that treatment with nebivolol may favorably influence the underlying diastolic dysfunction and be of therapeutic value for hypertensive patients with left ventricular damage.

A multicentre trial of the aldose-reductase inhibitor tolrestat, in patients with symptomatic diabetic peripheral neuropathy. North European Tolrestat Study Group.

One hundred and ninety patients with symptomatic diabetic peripheral neuropathy took part in a double blind multicentre trial of either placebo or tolrestat 200 mg once daily for 6 months. Painful and paraesthetic symptoms, vibration sensory threshold, and nerve conduction velocity (NCV) were assessed as efficacy end-points during the trial. There was an equally marked improvement of painful symptoms during the trial in the tolrestat and placebo groups. A difference in the improvement of paraesthetic symptoms was found however in favour of the placebo group at 24 weeks (p less than 0.02). The deterioration in mean vibration threshold of the tolrestat group was less than placebo at 24 weeks at all 3 sites measured, and reached significance at the carpal site (p less than 0.05). Significant improvements in median motor NCV and in the mean NCV of the four motor nerves were also seen in tolrestat treated patients at 24 weeks compared to placebo (p less than 0.05). In addition, significant changes in favour of tolrestat were seen when the number of motor nerves per patient with NCV increased during the trial was analysed (p less than 0.001). Concordance analysis of patients with increased mean motor NCV and improvement in painful symptoms demonstrated a positive effect for tolrestat compared to placebo (p less than 0.02). Mild reversible elevations of hepatic transaminases were seen in a few patients treated with tolrestat, with no other significant adverse effects. Tolrestat may therefore be helpful in diabetic peripheral neuropathy, where there is little opportunity for therapeutic intervention apart from effort to achieve normoglycaemic control.

R 75251, a new inhibitor of steroid biosynthesis.

R 75251, a new imidazole derivative, inhibited the conversion of androgens to estrogens, of progestins to androstenedione and testosterone, and of 11-deoxycorticosterone to corticosterone in human placenta microsomes, subcellular fraction of rat testis, bovine adrenocortical mitochondria, in cultured rat granulosa, testicular and adrenal cells, respectively. In vitro, no effect on cholesterol synthesis and cholesterol side-chain cleavage was found at concentrations up to 10 microM. In rat granulosa cells, no effect on progesterone production was detected. In vitro, no effect on steroid radioligand binding was observed. In male volunteers, a single dose of 300 mg of R 75251 significantly lowered plasma testosterone and estradiol for 24 hours and increased plasma concentration of 17 alpha-hydroxyprogesterone and progesterone. As compared with ketoconazole high dose (600 mg b.i.d), R 75251 (300 mg b.i.d) was at least as efficacious as inhibitor of testosterone synthesis when studied during ACTH stimulation. In contrast to ketoconazole, R 75251 did not significantly affect circulating adrenal androgen levels in male volunteers. Precursors of gluco- and mineralocorticoids such as 11-deoxycortisol and 11-deoxycorticosterone accumulated more than after ketoconazole administration. The data show that the cytochrome P450-dependent aromatase, 17-hydroxylase/17,20-lyase, and 11-hydroxylase are the target enzymes for R 75251.

The clinical pharmacokinetics of itraconazole: an overview.

Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungal fluconazole. The pharmacokinetics of itraconazole in man are characterized by a good oral absorption, an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day and a biotransformation into a large number of metabolites. One of them, hydroxy-itraconazole, is antifungally active and explains why antifungal plasma levels, when measured by bioassay, are about three times the itraconazole levels measured by a specific HPLC-method. Distribution studies have shown that therapeutically active levels of itraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for 3 weeks in the stratum corneum of the skin after treatment has been stopped. Unlike fluconazole, itraconazole does not interfere with mammalian drug metabolizing enzymes, minimizing the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high efficacy and safety of itraconazole in patients with various mycotic infections. New pharmaceutical formulations are being explored in order to broaden the application field of itraconazole to intravenous and oral therapy of patients with malabsorption.

Aromatase inhibition by R 76713: experimental and clinical pharmacology.

R 76713 is a new non-steroidal compound which inhibits aromatase in vitro and in vivo with a potency of at least 1000-fold that of aminoglutethimide. In male cynomolgus monkeys peripheral conversion of labeled androstenedione to estrone is decreased by 85%, 4-5 h after a single intravenous dose of 0.003 mg/kg of R 76713, without altering steroid metabolic clearance rates. In rats fed a sodium-depleted diet for 3 weeks, plasma levels of aldosterone and plasma renin activity remain unchanged 2 h after a single oral dose of up to 20 mg/kg of R 76713. This confirms previous data on the selectivity of R 76713 for aromatase inhibition as compared to inhibition of other enzymes involved in steroid biosynthesis. In male volunteers, a single oral dose of 5 or 10 mg of R 76713 lowers median plasma estradiol levels from 70 pM to the detection limit of the assay (30 pM) 4 and 8 h after intake, whereas no important changes are detected after placebo administration. In 15 premenopausal female volunteers receiving a single oral dose of 20 mg of R 76713, mean plasma estradiol levels decrease from 415 pM (before) to 179, 149 and 185 pM respectively 4, 8 and 24 h after intake whereas they remain above 380 pM after placebo (n = 7).

Pharmacokinetic profile of orally administered itraconazole in human skin.

Itraconazole is an orally effective antifungal agent with a high affinity for tissues. The skin kinetics in human volunteers have been studied after administration of 100 and 200 mg of itraconazole daily. From day 7 onward, tissue levels in the beard region and on the back were consistently higher than the corresponding plasma levels. The levels in the palmar stratum corneum were lower than the corresponding plasma levels but persisted for 3 weeks after discontinuation of therapy. Stratum corneum levels in the beard area were still measurable 4 weeks after the end of therapy. With the 200-mg dose, sweat levels became detectable 24 hours after the first drug intake. The sweat levels were usually lower than the corresponding plasma levels and followed the same curve as the plasma levels. Sebum levels of itraconazole were 10 times as high as the corresponding peak plasma levels. Sebum levels were undetectable 14 days after discontinuation of therapy. The results indicate that oral intake of itraconazole will result in therapeutic levels in the skin and these levels vary, depending on the region of skin tested. There are at least three routes of delivery of itraconazole to the skin: (1) passive uptake by keratinocytes in the basal layer (as shown by the continued presence of the drug in the palmar stratum corneum at a moment when plasma, sebum, and sweat levels are again undetectable); (2) a less significant excretion through the sweat glands (as shown by the lower drug levels compared with the plasma levels); and (3) a massive excretion through the sebaceous glands (as shown by the sebum levels compared with the plasma levels).

Clinical experience with cyclandelate in insulin-dependent diabetic patients with neuropathy.

Previous trials have demonstrated a clinical and electrophysiological improvement of diabetic peripheral polyneuropathy in diabetic patients treated with cyclandelate at a dosage of 1600 mg/day. Hence, a double-blind randomised trial was started in 16 insulin-dependent diabetic patients presenting with symptoms of neuropathy, an increased vibration perception threshold (VPT), disturbed tendon reflexes at lower limbs and an EMG showing a significantly decreased motor nerve conduction velocity (MCV) of the peroneal nerves. The placebo-treated group and the cyclandelate-treated group were not significantly different regarding age, duration of diabetes and level of metabolic control (measured as total HbA1), which remained unchanged during the year of observation. In the cyclandelate-treated group, pathological sensation improved significantly in 7 of 8 patients. MCV, measured under standardised conditions, increased significantly during the first 6 months of treatment, while mean VPT did not change. In the placebo group 3 of 8 patients showed an improvement of sensation, 3 did not feel any change and 2 worsened. Neither mean MCV nor VPT changed significantly. No severe side effects were observed during the study period.

Serum and erythrocyte magnesium levels in type I and type II diabetics.

Serum and red blood cell magnesium (RBC-Mg) concentrations of 195 type I and 111 type II diabetic outpatients with different degree of control and 40 control subjects have been evaluated using atomic absorption spectrophotometry. In the total group, no significant difference in serum and RBC-Mg levels in type I and II diabetic outpatients could be found. However, poor control was often associated with lower serum magnesium levels. A negative correlation was found between serum magnesium levels and HbA1. A particular group of male patients with severe macroangiopathy showed high RBC-Mg levels; this finding was probably due to atherosclerotic and hypertensive renal involvement.

Evaluation of the effect of atenolol on the reaction time of healthy volunteers.

The effect of atenolol on visual reaction time was tested in 30 healthy subjects in a between-subject double-blind placebo-controlled trial. Visual reaction time was defined as the time between the display of a light signal and its extinction by the subject. Acute or chronic administration of atenolol had no effect on visual reaction time when compared with placebo.

Bone mass in obese, goldthioglucose-treated, hyperglycaemic mice.

In contrast to insulin-dependent diabetics, bone mass in obese non-insulin dependent diabetics seems to be greater than in normal subjects. Hyperglycaemic, obese goldthioglucose mice were studied as a model for this last type of diabetes. A significantly greater cortical bone mass (cortical surface: 1.32 mm2 vs 1.15 mm2 for controls, p less than 0.01) with enhanced bone apposition was found together with a significantly greater trabecular bone mass (trabecular surface 0.17 mm2 vs 0.13 mm2, p = 0.05) increasing bone solidity. The pathogenesis is unclear but hyperinsulinism and overnutrition may be contributory factors.