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The direct-acting antiviral regimen of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r)±dasabuvir (DSV)±ribavirin (RBV) demonstrated high rates of sustained viral response at post-treatment week 12 (SVR12) in clinical trials for treatment of hepatitis C virus (HCV) genotypes (GT) 1 and 4. To confirm the effectiveness of this regimen in the real world, we conducted meta-analyses of published literature on 30 April 2016. Freeman-Tukey transformation determined the SVR rate within GTs 1a, 1b and 4, as well as specific SVR rates by cirrhosis or prior treatment experience status. Rates of virologic relapse, hepatic decompensation, drug discontinuation and serious adverse events were also analysed. In total, 20 cohorts across 12 countries were identified, totalling 5158 patients. The overall SVR12 rates were 96.8% (95% CI 95.8-97.7) for GT1 and 98.9% (95% CI 94.2-100) for GT4. For GT1a patients, the SVR rates were 94% and 97% for those with or without cirrhosis, and 94% overall. For GT1b patients, the SVR rates were 98% and 99% for those with or without cirrhosis, and 98% overall. The virologic relapse rate of GT1 patients was 1.3%, across 3524 patients in nine studies that reported this parameter. The rate of hepatic decompensation was less than 1% across five studies, including 3440 patients, 70% of which had cirrhosis. CONCLUSIONS: Real-world SVR12 rates for OBV/PTV/r±DSV±RBV were consistently high across HCV GT1 and four irrespective of cirrhosis status or prior HCV treatment experience, confirming effectiveness within a diverse patient population across multiple cohorts and countries.

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BACKGROUND: Thrombolysis in Myocardial Infarction (TIMI) flow grading is limited by subjectivity and imprecision. The corrected TIMI frame count (cTFC) has been proposed to obviate these problems. We sought to validate the utility of the cTFC in predicting adverse clinical outcomes after reperfusion therapy. METHODS AND RESULTS: We used angiographic core laboratory data from the Intravenous nPA for Treating Infarcting Myocardium Early Study (lanoteplase versus alteplase) to assess the predictive capacity of both final TIMI flow and cTFC on 30 day-composite adverse outcome (death, reinfarction, and new or worsening congestive heart failure). Only 390 angiograms of 586 were analyzable for cTFC; 33.4% of angiograms could not be analyzed for cTFC because filling of distal landmarks was not visualized for technical reasons such as inadequate panning. The interobserver correlation for determination of the cTFC was 0.99 and the intraobserver correlation was 0.97. The cTFC in the group with adverse outcomes was 49 +/- 34; in the group without adverse outcomes, it was 44 +/- 31 (P =.27). Of note, the TIMI flow correlated with adverse outcome in the overall group of patients (P =.018, area under the receiver-operator characteristic curve [c] = 0. 590) as well as in the group of patients with cines analyzable for cTFC (P =.025, c = 0.600). The independent correlates of adverse outcomes were age (P <.001), heart rate (P =.001), TIMI flow grade (P =.027), and infarct location (P =.038) but not cTFC. CONCLUSIONS: The cTFC did not predict adverse outcomes in this population of patients but did show excellent reproducibility within our core laboratory.

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BACKGROUND: Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase. METHODS AND RESULTS: InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P<0. 001). Similar results were observed at 90 minutes (26.1% to 57.1%, P<0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase. CONCLUSIONS: Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.

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Carvedilol is an antihypertensive agent which displays unselective beta-blocking, alpha 1-blocking and antioxidant properties. It is primarily metabolized by the liver and excreted via the biliary system. The compound is highly lipophilic and strongly bound to plasma proteins. Consequently, there is no elimination during hemodialysis. The efficacy, safety, and pharmacokinetic profile of carvedilol titrated to effect were investigated in an open clinical trial in 15 long-term hemodialysis patients with arterial hypertension over a period of 12 weeks. The drug was administered only on days without dialysis. After a wash-out phase of one week, carvedilol was started in a dose of 12.5 mg per day. All 15 patients were titrated according to the antihypertensive effect to a daily dose of 25 mg of carvedilol. Carvedilol was effective in lowering blood pressure in hemodialysis patients (RR systolic: 170 +/- 11 vs. 144 +/- 9 mmHg; RR diastolic: 98 +/- 10 vs. 85 +/- 10 mmHg). The pharmacokinetic parameters of carvedilol and its active metabolite M2, assessed in 12 of the 15 patients, were not influenced by the lack of renal function or intermittend haemodialysis. In particular, there was no accumulation of carvedilol or its metabolite M2. In terms of side effects, three patients had to be withdrawn from the trial, because of hypoglycemia (n = 1), insufficient blood pressure control (n = 1) and prolonged hypotension (n = 1). Taken together, these results indicate that carvedilol is a safe and efficacious antihypertensive agent which can be used in patients maintained by maintenance dialysis treatment.

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Pineal adrenergic receptor numbers show circadian variations in both rat and Syrian hamster. In the rat pineal beta-adrenergic receptor density reaches peak values either late in the light phase or at middark; the differences in the circadian phase seem related to the light:dark cycle to which the animals are exposed. No circadian rhythm of pineal alpha-adrenergic receptors is documented in intact rats. In the Syrian hamster pineal beta-adrenergic receptor density is high throughout the light phase and drops to minimal values at the time of the nocturnal peak of melatonin production. The circadian rhythm of pineal alpha-adrenergic receptor numbers runs parallel to the beta-adrenergic receptor variation, but is less pronounced. In the rat, pineal melatonin production is rapidly induced by beta-adrenergic agonists at any time during a 24-hour period, even when the pinealocyte beta-adrenergic receptor number is lowest (early in the light phase). In contrast, the Syrian hamster pineal seems most responsive to beta-adrenergic agonists in the late night while being less responsive during the day when beta-adrenergic receptor density is high. Interestingly, the human pineal gland is also not especially responsive to adrenergic stimulation during the light phase, possibly making the Syrian hamster pineal a better model than the rat pineal for determining neural/pineal interactions in humans. Comparison of the circadian variations in pineal adrenergic receptors leads to the conclusion that the functional differences between rat and hamster pineal are probably not explicable in terms of the adrenergic receptors, but are caused most likely by (a) intracellular mechanism(s) beyond the adrenergic receptors.

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1. Adult male Syrian hamsters were killed at nine intervals during a 24 hr period in the autumn, after 2 months either indoors in controlled conditions or in natural outdoor conditions. 2. Harderian glands were taken for determination of N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) activities and melatonin and porphyrin concentrations. 3. Mean 24 hr Harderian NAT and melatonin values were lower outside than inside. 4. Twenty-four hour melatonin rhythms were detected with similar daytime (afternoon) acrophases in both environmental conditions. 5. An NAT rhythm was seen only in animals kept inside, with a circadian maximum in the late dark phase. 6. Mean 24 hr HIOMT activity was slightly higher outdoors than indoors, and 24 hr rhythms were not detected in either condition. 7. Mean porphyrin concentrations were higher outdoors, with 24 hr rhythms detected in both conditions and a significantly earlier nocturnal circadian maximum outdoors.

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A naturally occurring compound, 6-methoxybenzoxazolinone (6-MBOA), present in grasses, has been shown to induce sexual maturation in a number of rodent species. The structural similarity of 6-MBOA and melatonin has led researchers to suspect that 6-MBOA might induce its progonadal effects by directly altering pineal function. Previous studies have shown that 6-MBOA has the properties of a weak beta-adrenergic agonist capable of stimulating rat pineal N-acetyltransferase (NAT) activity at pharmacological concentrations of 10(-3) M. In the present study we have examined the effect of 6-MBOA on both the pineal melatonin synthesizing enzymes, namely, NAT and hydroxyindole-O-methyltransferase (HIOMT) as well as on melatonin production, in organ cultured rat pineal glands. In addition, we have also examined the ability of 6-MBOA to displace a ligand from rat brain alpha- and beta-adrenoceptors. Our results confirm that 6-MBOA stimulates NAT activity and melatonin production at the high concentration of 10(-3) M. It appears to have no effect on HIOMT activity. A competition study shows that 6-MBOA is able of displacing ligands at the alpha- and beta-adrenoceptors but only at concentrations greater than 10(-4) M. Whether such high concentrations of 6-MBOA reach the pineal of rodent in their natural habitat is unknown. However, if 6-MBOA does mediate progonadal effects by altering pineal function it would be expected that 6-MBOA would ultimately inhibit the effects of melatonin. The possibilities are that the high melatonin levels induced by 6-MBOA cause desensitization of melatonin receptors or that 6-MBOA is an antagonist at the level of the melatonin receptor, thus restricting the inhibitory effects of melatonin on the reproductive system.

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Specific binding of [125I]iodo-[beta-(4-hydroxyphenyl)-ethylaminomethyl]tetralone ([ 125I]HEAT) was used to assess alpha 1-adrenergic receptors on pineal gland membranes of male Syrian hamsters (Mesocricetus auratus) housed under a 14:10 h light-dark cycle (lights on at 06.00 h). Saturation experiments with pooled pineal membrane preparations showed the presence of alpha 1-adrenergic receptor sites (dissociation constant Kd approx. 0.1 nM). Analysis of 4 time points indicated no significant change in Kd, but significant (P less than 0.01) changes of receptor density (Bmax) with a minimum recorded at night. Binding of a constant amount of [125I]HEAT (200 pM) to pineal membranes at 8 time points exhibited a circadian variation (P less than 0.001) of receptor density with lowest values around midnight and highest levels during daytime.

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Radioreceptor assays with (-) [125I]-iodopindolol (IPIN) were used to describe circadian variations of beta-adrenoceptors in the pineal gland of male Syrian hamsters (Mesocricetus auratus). Single-point experiments (200 pM IPIN, 8-9 pineals pooled per time point) showed a significant circadian variation (p less than 0.01) with maximal values (28.9 +/- 1.8 fmol/mg protein, means +/- SEM, n = 7) between 07:00 and 02:30 h, and minimal values at 04:00 (7.2 +/- 2.9 fmol/mg protein, n = 3), 8 h after darkness onset. Either exposure of animals to light at night or treating dark exposed hamsters with a beta-adrenergic receptor blocker, propranolol, prevented the nocturnal drop in the number of beta-adrenoceptors. Scatchard analysis of saturation isotherms at 02:30, 04:00 and 08:00 h (30-600 pM IPIN, one saturation experiment with 25 pineals pooled per time point) confirmed the circadian variation.

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Scatchard analysis of saturation isotherms of [125I]-iodopindolol was used to characterize beta-adrenoceptor density (Bmax) and affinity constant (Kd) in female and male hamster Harderian glands. Single-point experiments were also completed in intact females, intact males, and castrated or superior cervical ganglionectomized males. Scatchard analysis described a single population of binding sites with a Bmax of 292.2 +/- 45.1 fmol/mg protein (X +/- SEM, n = 6) in females and 18.2 +/- 3.0 fmol/mg protein (n = 6, P less than .001) in males. The affinity also varied significantly (P less than .05) with a Kd of 1.08 +/- 0.18 versus 0.26 + 0.05 nM (n = 6) in the Harderian gland of females and males, respectively. Single-point [125I]-IPIN (400 pM) binding values in females were 67.3 +/- 4.0, in intact males were 12.8 +/- 3.2, and in castrated males were 31.2 +/- 4.2 fmol/mg protein (n = 7-9). Superior cervical ganglionectomy induced no significant changes in receptor binding. The results indicate pronounced sexual differences in the density and affinity of beta-adrenoceptors in the hamster Harderian gland, which may be sex hormone dependent.

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The Harderian glands in Syrian hamsters exhibit a striking sexual dimorphism. Male Harderian glands show two cell types and low levels of porphyrins and melatonin. Of the enzymes involved in the synthesis of melatonin, N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) show high and low activity levels, respectively. Female Harderian glands show but one cell type and have high porphyrin and melatonin levels, low NAT activity, and high HIOMT activity. In castrated males, the Harderian glands exhibit a female pattern of morphology, porphyrin levels, and indoleamine metabolism. In an attempt to determine whether prolactin in involved in this sexually dimorphic response of the Harderian glands, intact and castrated male and intact female hamsters were injected daily with 500 micrograms of bromocriptine, a dopamine agonist. Bromocriptine led to reduced serum prolactin levels in all groups. It had no apparent effect on the Harderian glands of intact males. In contrast, in castrated males bromocriptine prevented the postcastrational rise in porphyrin levels but had no effect on NAT or HIOMT activities. In females, bromocriptine treatment had no effect on porphyrin concentrations or HIOMT activity; it led to a statistically significant increase in NAT activity. We propose that testosterone inhibits Harderian porphyrin synthesis while dopamine or prolactin stimulates it.

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Saturation and competition experiments with the radiolabeled beta-adrenergic antagonist (--)-[125I]-iodopindolol were used to characterized beta-adrenoceptor density (Bmax) and receptor affinity in the extraorbital lacrimal gland of male and female Syrian hamsters. Specific binding to the receptor was saturable. Scatchard analysis of saturation isotherms revealed a single population of receptor sites. Male glands had a significantly higher Bmax (38.9 +/- 5.0 vs. 23.3 +/- 2.1 fmol/mg protein, means +/- SEM, p less than 0.02) and receptor affinity (expressed in a lower dissociation constant Kd: 0.065 +/- 0.013 vs. 0.120 +/- 0.015 nM, p less than 0.02) than female glands. Binding of the radiolabeled ligand in competition with various adrenergic antagonists showed the receptor to be stereospecific and of the beta 2-subtype.

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Peripheral mononuclear leukocytes (MNLs) are widely used as a tissue model in studies of beta-adrenoceptor disturbances in hypertension and asthmatic diseases. The beta 2-adrenoceptor density (Bmax), however, depends not only on the gender of the person under study and on the time of day the blood specimens are obtained. Evidence is now reported for a circannual variation in the expression of beta 2-adrenoceptor sites on peripheral MNLs. In male volunteers the 24-h mean was found to be highest in the men studied in April/May (1135 +/- 10 sites/cell) and decreased to 891 +/- 16 sites/cell in August and to 712 +r90 sites/cell in December (means +/- SE, P less than 0.01 April/May compared to December). Concomitantly the circadian amplitude increased from 17.3% +/- 6.4% of 24-h mean in April/May to 28.2% +/- 1.4% of 24-h mean in August and to 34.2% +/- 4.2% of 24-h mean in December (means +/- SE, P less than 0.05, April/May compared to December). The circadian acrophase remained constant (190 degrees +/- 30 degrees equivalent to 12 h 40 min +/- 2 h 00 min, means +/- SE).

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