Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Tumor necrosis factor (TNF) enhances leukocyte adherence to vascular endothelium and increases procoagulant activity in the endothelial cells. Thus it may be implicated in the pathogenesis of acute vascular occlusions. To study the role of TNF in the early stages of acute myocardial infarction (MI), the authors measured circulating TNF levels in the sera of patients with acute MI and unstable angina pectoris. Blood samples were obtained within six hours after onset of chest pain and stored at -70 degrees until tested. A sensitive sandwich enzyme-linked immunosorbent assay (ELISA) test was used for TNF measurement. C-reactive protein (CRP) levels were determined semiquantitatively. Immediate complications such as heart failure, arrhythmia, and shock were also noted. Twenty-four patients with electrocardiographically and biochemically confirmed acute MI and 14 patients with unstable angina pectoris were included in the study. TNF levels were serially assessed at the time of admission and at hours 6, 24, 48, 72, and 96 after onset of chest pain in 2 patients with acute MI. Detectable TNF was found in 13 sera of the acute MI group (range; 10-1510 pg/mL) and 4 sera of the angina pectoris group (range; 15-240 pg/mL). There was no correlation between the serum TNF levels and the occurrence of complications and the extent of myocardial damage. CRP response was unrelated to TNF levels. Contrary to previous reports, serial measurement of TNF revealed that peak values were reached within six hours and disappeared after twenty-four hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Grapefruit juice has been reported to markedly improve the bioavailability of triazolam, midazolam, terfenadine, cyclosporine and several dihydropyridine calcium channel blockers including felodipine, nifedipine, nitrendipine and nisoldipine. Because these drugs are metabolized by the hepatic cytochrome P450 isozyme (CYP) 3A4, the inhibitory effect of grapefruit juice is thought to results from inhibition of CYP3A4. In this study, our aim was to investigate the effects of grapefruit juice on plasma concentrations of diazepam. Eight healthy male and female subjects participated in this study. Oral (5 mg) diazepam was administered with either 250 ml water and grapefruit juice. Blood samples were collected for a 24 h period, and whole blood concentrations of diazepam were measured enzyme immunoassay. The mean AUC(0-24) of diazepam was increased 3.2-fold (P < 0.001) and Cmax was increased 1.5-fold (P < 0.05) by the grapefruit juice. Grapefruit juice postponed the tmax of diazepam from 1.50 h to 2.06 h (P < 0.01).

Drug/metabolite ratios (MRs) are used as in vivo markers of enzyme activity. The ratios are potentially confounded by the renal clearance of the drug (urine-based MRs) or metabolite (plasma-based MRs). The authors have investigated the relative sensitivity of urinary MR of 3 in vivo probe substrates of CYP2D6 debrisoquine (DB), dextromethorphan (DM), and metoprolol (MP) to changes in urine pH. Three groups of healthy volunteers each comprising 12 individuals were given DB (10 mg), DM (25 mg), or MP (100 mg) on 3 occasions. In 1 study arm, urine was acidified by the oral intake of ammonium chloride; in another, it was alkalinized by intake of sodium bicarbonate; and in the third, urine pH was uncontrolled. Urinary MP/alpha-hydroxy-MP, DM/dextrorphan, and DB/4-hydroxy-DB ratios were calculated. The mean(geo) MR for DB was not significantly different in any of the study arms, whereas those for MP and DM were significantly different under acidified and alkalinized urine conditions compared to uncontrolled urine pH (P < .01) and were correlated with urine pH (P < .001). Without control of urine pH, in vivo estimates of CYP2D6 metabolic activity are likely to be less precise using DM or MP as probe substrates compared to DB. Although this is unlikely to cause any problem in distinguishing the large functional differences in CYP2D6 in poor metabolizer (PM) and extensive metabolizer (EM) phenotypes, this may contribute to difficulties in differentiating in vivo metabolic activity among allelic variants within the overall CYP2D6 EM phenotype using MP or DM. However, because DB is not available in many countries (eg, United States), alternative in vivo markers of CYP2D6 with low sensitivity to urine pH should be sought.

The PRP seems to be better for pain relief and functionality in the short and mid-term periods.

AimIn this study, we investigated the relationship of increased inflammatory parameters (C-reactive protein – CRP), oxidative stress markers (serum uric acid – SUA) and red blood cell distribution width (RDW) with non-dipper hypertension (NDHT).Material and methodsAmong the individuals who presented to the cardiology clinic, 40 patients (32.5% male, 67.5% female; mean age: 54.4 ±7.1) who had hypertension and were diagnosed with NDHT through ambulatory blood pressure monitoring, 40 age- and sex-matched dipper hypertension (DHT) patients (25% male, 75% female, mean age: 54.2 ±7.0), and 40 normotensive individuals (42.5% male, 57.5% female, mean age: 51.9 ±9.0) were enrolled in the study. Peripheral venous blood samples were collected from all the patients in order to evaluate the hematological and biochemical parameters. All the assessed parameters were compared among the groups.ResultsThe CRP, RDW and uric acid levels were observed to be significantly higher in the non-dipper hypertension group in comparison to the dipper hypertension patients and the normotensive population (p < 0.05). These parameters were also significantly higher in the dipper HT group compared to the normotensive population (p < 0.05).ConclusionsWe found in our study that increased CRP, uric acid and RDW levels, which are indicators of increased inflammation and oxidative stress, are significantly higher in the non-dipper HT patients in comparison to the dipper HT patients and control group.

The impact of different single oral doses of ketoconazole (KTZ) (100, 200 and 400 mg) and of staggering its dosage (400 mg at -12, -2, 0, 2 and 4 h), with respect to the administration of a single 5 mg oral dose of midazolam (MDZ) on the extent of inhibition of the metabolism of the latter, was evaluated in healthy subjects in two separate studies. Escalation of the ketoconazole dosage resulted in 2.3 (1.9), 2.7 (1.7) and 4.2 (2.5) -fold increases in the mean AUC (and C ) values of midazolam. Dose-staggering was associated with 3.9 (2.5), 4.9 (2.9), 5.4 (2.8), 2.0 (1.3) and 1.2 (0.9) -fold increases in the mean AUC (and C ) of midazolam. These findings could be predicted by physiologically based pharmacokinetic (PBPK) modelling using the ADAM (advanced dissolution absorption and metabolism) model within the Simcyp Simulator (Version 12 Release 2) to characterize the absorption kinetics of ketoconazole with respect to disintegration time, supersaturation ratio and precipitation rate. This study also emphasizes a need to account for inter-individual variability in the gut wall and systemic exposure of inhibitors with physicochemical properties similar to ketoconazole, in particular in their rate of oral absorption and when using different pharmaceutical formulations, in designing and evaluating the extent of drug-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.

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