A Phase II, double-blind, randomized, parallel group, dose-finding study of the safety and tolerability of darexaban compared with warfarin in patients with non-valvular atrial fibrillation: the oral factor Xa inhibitor for prophylaxis of stroke in atrial fibrillation study 2 (OPAL-2).

BACKGROUND: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa. OBJECTIVES: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF). METHODS: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability. RESULTS: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity. CONCLUSIONS: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.

Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes.

AIM: To assess the efficacy and safety of a range of doses of a systemic, partial, glucokinase activator, PF-04937319, as add-on therapy to metformin, in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients were randomized to once-daily PF-04937319 doses of 10, 50, 100 mg, or matching placebo (Study B1621002); or PF-04937319 doses of 3, 20, 50, 100 mg, or matching placebo (Study B1621007). Titrated glimepiride (Study B1621002) or sitagliptin (Study B1621007) were included in a double-dummy manner. The primary measure was change from baseline in glycated haemoglobin (HbA1c) at week 12. Key secondary measures included other glycaemic variables and safety and tolerability. RESULTS: In the 639 patients randomized, the minimally efficacious PF-04937319 dose was identified as 50 mg once daily. At the highest PF-04937319 dose tested (100 mg), on average, a clinically significant reduction in HbA1c [-4.94 or -5.11 mmol/mol (-0.45 or -0.47%), placebo-adjusted], which was similar to that achieved with sitagliptin [-4.69 mmol/mol (-0.43%)] but lower than that achieved with titrated glimepiride [-9.07 mmol/mol (-0.83%)], was observed. At this dose, the effect on fasting plasma glucose was not consistent between the two studies (Study B1621002 vs Study B1621007: placebo-adjusted mean change of -0.83 vs +0.50 mmol/l). PF-04937319 was well tolerated at doses up to 100 mg. Hypoglycaemia was reported in 2.5% of patients (on placebo), 5.1% of patients (on PF-04937319 100 mg), 1.8% of patients (on sitagliptin) and 34.4% of patients (on titrated glimepiride). CONCLUSIONS: In patients on metformin monotherapy, the addition of a 100-mg dose of PF-04937319 improved glycaemic control and was well tolerated.

Impaired cerebral vasoreactivity in white coat hypertensive adolescents.

BACKGROUND AND PURPOSE: Although its incidence is not high, adolescent hypertension may predict hypertension and increased cardiovascular risk in adulthood. Therefore, the aim of the present study was to assess whether cerebrovascular reactivity is altered in adolescent white coat and sustained hypertensive patients compared to healthy teenagers. METHODS: Fifty-nine normotensive, 47 white coat hypertensive (WCH), and 73 sustained hypertensive (SH) adolescents were studied. WCH and SH were differentiated by ambulatory blood pressure monitoring. Cerebrovascular reactivity was assessed by transcranial Doppler breath-holding test and was expressed in percent (%) change to the resting cerebral blood flow velocity value. RESULTS: The percent increase in middle cerebral artery mean blood flow velocity after 30 s of breath holding was lower in both WCH (5.3 ± 3.1%) and SH (9.5 ± 2.6%) groups indicating lower vasodilatory reactivity compared to healthy adolescents (12.1 ± 2.2%). Additionally, serum nitric oxide (NOx) concentrations were lower in both WCH (30.6 ± 11 µM) and SH (30.7 ± 22.4 µM) groups compared to controls (38.8 ± 7.6 µM). CONCLUSIONS: Both white coat and sustained hypertension result in decreased vasodilatory reaction to CO(2) in adolescents, suggesting involvement of the cerebral arterioles. The present study underlines the importance of early recognition and proper treatment of adolescent hypertension in order to prevent long-term cardiovascular complications.

The epidemiology of hypertension and its associated risk factors in the city of Debrecen, Hungary.

The purpose of this work was to estimate the prevalence of hypertension and cardiovascular risk factors and its association with sociodemographic, behavioural and lifestyle characteristics among the adult population of the city of Debrecen, Hungary.A cross-sectional study was conducted in 1996. Amongst 21 800 inhabitants aged 30-65 y risk screening for cardiovascular disease (CVD) was estimated by a questionnaire that included sociodemographic, lifestyle characteristics, family history of CVD and results of self-reported data of body weight, height and blood pressure. Of the total of 19 961 surveyed sample, 37.02% were considered to be hypertensive, 53.73% were overweight, 32.18% were current smokers and 58.85% were physically inactive. Hypertensives were older than normotensives (50.81+/-9.01 vs 44.78+/-8.97 y, P<0.001). The prevalence of various risk factors amongst hypertensives as compared to normotensives were overweight (68.49 vs 45.06%, P<0.0001), current smoking (28.38 vs 34.41%, P<0.0001), physical inactivity (64.78 vs 55.36%, P<0.001), and high alcohol consumption (1.91 vs 1.06%, P<0.01). Of the hypertensives 37.11% were on drug therapy. Of those on therapy, only 17.03% had normal blood pressure. Being overweight and having low physical activity was positively associated with hypertension (OR=2.25, CI=2.11-2.40) and (OR=1.26, CI=1.15-1.38). Manual work, a family history of CVD, low education, and the male gender were also associated with hypertension and more CVD risk factors. These findings illustrate a very high prevalence of hypertension and CVD risk factors in Debrecen, indicating the importance of the need for more effective prevention programmes and control of hypertension in Hungary.

Breath holding test in preeclampsia: lack of evidence for altered cerebral vascular reactivity.

Twenty-five healthy and thirty-one preeclamptic pregnant women were assessed by means of transcranial Doppler sonography. Resting cerebral blood flow velocities in the middle cerebral arteries were measured followed by a repeat measurement 30 s after breath holding. Absolute blood flow velocities and per cent changes after breath holding procedure were compared between the groups. Absolute blood flow velocities were higher in preeclamptic pregnant women both at rest and after breath holding. The percent increase in cerebral blood flow velocity after breath holding (cerebral vascular reactivity) was similar in the two groups. Our data suggest that cerebral vascular reactivity is preserved in pregnant women with preeclampsia.

[Epidemiology of hypertension in adolescence and factors influencing blood pressure]. / A serdülókori hypertonia epidemiológiája és a vérnyomást befolyásoló tényezók.

The authors summarize the determining and influencing factors of adolescent hypertension. An overview of the definition and prevalence of hypertension in adolescence is given and the predictive role of the adolescent hypertension on the incidence of adult cardiovascular diseases is pointed out. According to the previous literature data, adult hypertension is more frequent in those people who have had hypertension in their adolescence. There are no widely used, population-based nomograms of adolescent hypertensives available. According to the opinion of the authors, a population-based hypertension screening program would help in delineating the factors influencing adolescent blood pressure, and the most frequent risk factors for hypertension in Hungary. With the follow-up and appropriate treatment of the hypertensives the reduction of target-organ damages may be possible.

Comparison of cerebral blood flow velocity as measured in preeclamptic, healthy pregnant, and nonpregnant women by transcranial Doppler sonography.

AIM: To test the hypothesis that the middle cerebral artery blood flow velocity (MCAV) is altered in preeclamptic pregnant women as compared with healthy pregnant and nonpregnant women. METHODS: Preeclamptic (n = 21) and healthy pregnant (n = 17) as well as healthy nonpregnant (n = 29) women underwent transcranial Doppler MCAV measurements. The mean MCAV values were compared between the different groups. Anova combined with Bonferroni correction was used for statistical analysis. RESULTS: The MCAV was significantly higher in nonpregnant women (mean +/- SE 73.0 +/- 2.12 cm/s) as compared with healthy pregnant women (67.0 +/- 1.8 cm/s, p = 0.0356). Preeclamptic women showed significantly higher MCAV values (83.5 +/- 2.1 cm/s) as compared with nonpregnant females (73.0 +/- 2.12 cm/s, p = 0.0014). Similar to nonpregnant women, healthy pregnant women showed lower MCAV values (67.0 +/- 1.8 cm/s) as compared with preeclamptic women (83.5 +/- 2.1 cm/s, p = 0.001). After Bonferroni correction the MCAV values in patients suffering from preeclampsia were still statistically significantly higher as compared with the two other groups. CONCLUSIONS: We detected increased resting MCAV values in pregnant women with preeclampsia. In our opinion, this finding refers to arteriolar dilation of the resistance vessels of the brain. Further studies are needed to prove altered vasoreactivity responses of the brain resistance arterioles in preeclampsia.

Effect of hyperventilation on cerebral blood flow velocity in preeclamptic pregnancies: is there evidence for an altered cerebral vasoreactivity?

The purpose of this study was to investigate cerebral arteriolar vasoreactivity function in preeclampsia. Preeclamptic (n = 26) and healthy pregnant (n = 22) women underwent transcranial Doppler sonography of the middle cerebral artery at rest and after 60 seconds of hyperventilation (HV). Systolic, diastolic, and mean blood flow velocities were recorded. The percentage change of the blood flow velocities after HV was calculated. Mean blood flow velocity of the middle cerebral artery was higher in preeclamptic women as compared with healthy pregnant women. No difference could be detected in percentage change of middle cerebral artery blood flow velocities after HV between the two groups. There is no evidence of a small-vessel vasoconstriction among preeclamptic patients. The role of vasoconstriction of the large cerebral arteries and vasodilation of the resistance arterioles, as well as a combination of these 2 pathomechanisms, in determining cerebral blood flow in preeclampsia and eclampsia should be investigated in further studies.

Prevalence of cardiovascular risk factors of the smokers and non-smokers in the city of Debrecen, Hungary.

The aim of our study was to compare the major cardiovascular disease (CVD) risk factors of smokers and non-smokers. Risk screening of CVD was estimated by a questionnaire, via interview. Random samples of 20 000 inhabitants of Debrecen, Hungary, aged 30-65 y, took part in the study. 19 922 questionnaires were considered appropriate for further evaluation. 32.2% of the participants (n=6410) were smokers, whose data were compared to those of the 68.8% of non-smokers (n=13 512). There were more male smokers than female (39.3% vs 27.7%), (P<0.001). 36.5% of males and 58.9% of females had not previously smoked regularly (P<0.001). 24.2% of males and only 13.3% of females were able to stop smoking (P<0.001). 8.7% of the participants smoked more than 20 cigarettes per day (14.8% of males, 5.0% of females), (P<0.001). Smokers were younger, with a mean age of 43.4 y vs 47.1 y for non-smokers (P<0.01). The ex-smokers and non-smokers had a higher body mass index than light, moderate and heavy smokers (26. 75+/-4.1 kg/m2 and 26.09+/-4.3 kg/m2 vs 24.87+/-3.9 kg/m2 and 24. 89+/-4.2 kg/m2 and 25.32+/-4.3 kg/m2, respectively), (P<0.001). The results of the last measured blood pressures did not differ between the two groups. 94.8% of smokers and 93.6% of non-smokers did not perform any regular leisure time exercises (P<0.01). 39.8% of smokers regularly ate fatty food, in comparison to 28.0% of non-smokers (P<0.001). 30.6% of smokers vs 28.6% of non-smokers were factory workers while 69.4% of smokers vs 71.4% of non-smokers did sedentary jobs (P<0.001). 2.3% of smokers vs 0.9% of non-smokers admitted regular consumption of alcohol (P<0.001). Amongst the parents and brothers/sisters of smokers the prevalence of heart attack was higher 19.7% vs 18.7%, than for those of non-smokers (P<0. 05). We observed an accumulation of cardiovascular risk factors in the case of smokers, which indicates the higher susceptibility of smokers to CVD.

[Efficacy of benazepril monotherapy in moderate essential hypertension studied by automatic ambulatory blood pressure monitoring]. / Benazepril monoterápia hatékonyságának vizsgálata automata ambuláns vérnyomás-monitorozással enyhe és középsúlyos essentialis hypertoniában.

Authors examined the effects of benazepril, regarding the length of effectiveness by ambulatory blood pressure monitoring (ABPM), drug tolerable, and the compliance of patients in mild to moderate essential hypertension. 14 patients were treated with benazepril monotherapy. Six of them were newly diagnosed, and the rest had already been treated for hypertension. At the start, after six and 12 weeks, 24-hour monitoring was performed. Casual blood pressure (BP) measurements and detection of side-effects were also performed at 3rd and 9th-week. Prior the study the average daytime BP measured by ABPM was 149.1 +/- 7.7/96.6 +/- 4.7 mmHg. 10 mg of benazepril was first administered in the morning. By the end of the sixth week the average BP was significantly decreased (daily average: 139.1 +/- 9.9/88.2 +/- 7.6 mmHg). The daytime diastolic average BP of 8 patients was lower than 90 mmHg and the other's daily dose was raised to 20 mg. During the 12th-week we found optimal tension in 11 patients, while in two others there was also a significant decrease. The daily average BP was 134.7 +/- 7.5/85.6 +/- 6.6 mmHg. In comparison the data at the beginning of the study here was significant decrease in the 24-hour, daytime and night-time BP, in the hypertension time-index and the hyperbaric impact, both in systolic and diastolic levels. During the 12th-week period the diurnal index was unchanged. The early morning BP decreased by the end of the 3rd month from 148.6 +/- 14.1/98.5 +/- 11.7 mmHg to 135.2 +/- 13.5/93.4 +/- 11.2 mmHg. Sustained side-effect did not occur. The patient's compliance to benazepril was excellent. Authors conclude that benazepril monotherapy lowered in 92.8%, and normalized in 78.5% the blood pressure of patients suffering from mild to moderate essential hypertension. The unchanged diurnal index, and the decrease in the early morning blood pressure suggest the 24-hour effect of benazepril.

Depletion of white cells from platelet concentrates with a new adsorption filter.

Removal of white cells (WBCs) from platelets may reduce alloimmunization to WBC antigens, prevent febrile reactions, and improve platelet increments in multiply transfused patients receiving HLA-matched platelets. A new surface-modified fibrous polyester filter was evaluated; it requires no special processing of pooled platelet concentrates and can be used at the patient's bedside. The studies were designed to measure WBC removal, platelet function, in vitro platelet recovery, and in vivo platelet survival. WBC mean removal was 99.8 percent +/- 0.56 (n = 37) when a pool similar in volume to 6 platelet concentrates was tested. The mean number of residual WBCs after filtration was 5.6 x 10(5). In vitro mean platelet recovery was 86.9 percent for a pool size of 6 units (n = 37). Clot retraction and platelet aggregation were unaffected by filtration. Survival studies of 111Indium-labeled platelets done with filtered autologous platelets showed no reduction in the normally expected survival. These studies indicated that the filter efficiently removes WBCs without substantially decreasing platelet number, survival, or function. This device offers the potential of considerably improving platelet transfusion therapy.