Incidence of virological failure and emergence of resistance with twice-daily vs every 8-h administration of telaprevir in the OPTIMIZE study.

The OPTIMIZE study demonstrated noninferior efficacy between telaprevir (TVR) twice daily (bid) vs every 8-h (q8h) administration. This analysis compared the selective pressure of both dosing regimens by characterisation of the hepatitis C virus (HCV) variants emerging in genotype 1 (G1) HCV-infected patients who did not achieve sustained virological response (SVR). HCV NS3•4A population sequencing was performed at baseline and time of failure (viral breakthrough, stopping rule or relapse). TVR-resistant variants were classified by fold change in inhibitory concentration (IC50 ). Baseline TVR-resistance was low (<5%) and did not preclude achieving SVR in either arm. The proportion of patients with TVR-resistant variants at time of failure was similar in the bid (15%) and q8h (17%) dosing arms. The majority of variants and virological failures occurred in G1a patients, and mutations V36M, R155K and R155T (G1a), and V36A, T54A and A156S (G1b) were significantly enriched in both treatment arms. The number and type of emerging TVR-resistant variants in non-SVR patients were comparable between treatment arms and were consistent with previous observations. No differences in viral resistance profiles were observed between TVR-based treatment arms in non-SVR patients, indicating a similar selective pressure of TVR bid and q8h dosing.

Analysis of genotype 2 and 3 hepatitis C virus variants in patients treated with telaprevir demonstrates a consistent resistance profile across genotypes.

Study C209 evaluated the activity of telaprevir in treatment-naïve patients with genotypes 2 or 3 (G2, G3) hepatitis C virus (HCV) infection. Telaprevir monotherapy showed potent activity against HCV G2, but limited activity against G3. This analysis was performed to characterize HCV viral variants emerging during telaprevir-based treatment of G2/G3 HCV-infected patients. Patients were randomized to receive 2 weeks of treatment with telaprevir (telaprevir monotherapy), telaprevir plus peginterferon alfa-2a and ribavirin (triple therapy), or placebo plus peginterferon alfa-2a and ribavirin (control), followed by 22-24 weeks of peginterferon/ribavirin alone. Viral breakthrough was defined as an increase >1 log10 in HCV RNA from nadir, or HCV RNA >100 IU/mL in patients previously reaching <25 IU/mL. Twenty-three patients (47%) had G2 and 26 (53%) had G3 HCV. Viral breakthrough occurred during the initial 2-week treatment phase in six G2 patients (66.7%; subtypes 2, 2a and 2b) and three G3 patients (37.5%; all subtype 3a), all in the telaprevir monotherapy arm. Four breakthrough patients (three G2, one G3) subsequently achieved sustained virologic response (SVR). In all patients with breakthrough and available sequence data, mutations associated with reduced susceptibility to telaprevir in genotype 1 (G1) HCV were observed. No novel G2/G3-specific mutations were associated with telaprevir resistance. The telaprevir resistance profile appeared consistent across HCV genotypes 1, 2 and 3. Although viral breakthrough with resistance occurred in patients receiving telaprevir monotherapy, half of these patients achieved an SVR upon addition of peginterferon/ribavirin highlighting the importance of combination therapy.

Long-chain polyunsaturated fatty acids at birth and cognitive function at 7 y of age.

OBJECTIVE: During the central nervous system (CNS) growth spurt, rapid accretion of long chain polyunsaturated fatty acids (LCPUFA) takes place. This particularly concerns docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6), which are thought to play important roles in CNS development and function. The aim of this study was to investigate the relationship between cognitive performance at 7 y of age and LCPUFA levels in umbilical venous plasma phospholipids, representing the prenatal fatty acid availability, and in plasma phospholipids sampled at 7 y. DESIGN: As part of a follow-up study, the cognitive performance of 306 children, born at term, was assessed at 7 y of age with the Kaufman Assessment Battery for Children. Backward stepwise regression analysis was used to study the relationship between the outcomes and LCPUFA status. Social class, maternal intelligence and parenting skills were included as covariables, among others. RESULTS: Results show no significant association with either DHA or AA at birth and the cognitive performance at 7 y of age. The LCPUFA levels at 7 y were not associated with these outcomes either. Consistent with the literature, significant relationships were found between cognitive outcome measures and maternal education, maternal intelligence and the child's birthweight. CONCLUSIONS: In conclusion, our results do not provide evidence for a positive association between cognitive performance at 7 y and LCPUFA status at birth or at 7 y of age.

Red blood cell and plasma phospholipid arachidonic and docosahexaenoic acid levels at birth and cognitive development at 4 years of age.

OBJECTIVE: The long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) have biophysical properties that may mediate behavioral outcome, especially cognitive development. This study examined the relationship between the LCPUFA-status at birth and cognitive development at 4 years of age. METHODS: Cognitive development of 128 full-term neonates, whose umbilical venous plasma and/or red blood cell phospholipid DHA and AA levels were known, was assessed at 4 years of age. Pearson correlation coefficients were calculated between cognitive development and DHA, AA, maternal intelligence, birth weight, duration of breast-feeding and paternal educational attainment. Multiple linear regressions were employed with cognitive development as the dependent variable and whereby the above-mentioned covariables were entered in step one while each of the four LCPUFAs was entered in step two. RESULTS: In bivariate analysis, maternal intelligence, birth weight, maternal smoking habits during pregnancy, paternal education and duration of breast-feeding showed significant correlations with cognitive development (p<0.01). The association of cognitive development with DHA and AA measured zero in bivariate analysis (plasma levels: r=0.03 and r=-0.03, respectively; erythrocyte levels: r=0.01 and r=0.05) and in multiple regression analysis (plasma DHA r=0.01, p=0.88; plasma AA r=0.02, p=0.80; erythrocyte DHA r=-0.01, p=0.95) except for erythrocyte AA (r=0.15, p=0.09). CONCLUSION: No evidence was found for an association of the DHA or AA-status at birth with cognitive development at 4 years of age.

Factor analyses of WISC-R and K-ABC in a Dutch sample of children referred for learning disabilities.

This study examined correlations between WISC-R and K-ABC subtests in a sample of 101 children referred for learning disabilities. A considerable overlap between the two instruments was found. Separate factor analyses of the WISC-R and K-ABC were conducted. By and large, the WISC-R factor structure was similar to that found for standardization samples. Three factors emerged, namely Verbal Comprehension, Perceptual Organization, and Freedom From Distractibility. In line with earlier findings, the K-ABC factor analysis resulted in two factors: Simultaneous and Sequential Processing. A shorter battery combining subtests from both instruments is discussed.

Quality of spontaneous general movements in full-term small for gestational age and appropriate for gestational age newborn infants.

Quality of spontaneous movements was studied in 15 healthy full-term appropriate for gestational age (AGA) and in 15 full-term small-for gestational age (SGA) newborn infants. All general movements with a minimal duration of 20 seconds were judged on different aspects of movement quality. From the general movements in each group (AGA: n = 106; SGA: n = 187), dominant patterns were isolated. In the AGA Group 3 dominant patterns of general movements were present. In the SGA Group 5 dominant patterns of general movements were found. Three of those were identical to the movement patterns in the AGA group, the remaining two patterns were unique for the SGA infants. Our results indicate that the three different types of general movements which constitute the major part of the normal repertoire of healthy full-term infants can be used as a reference for normal spontaneous motor behaviour. The two different types of general movements in the SGA infants might be used to discriminate between healthy and neurologically suspect newborn infants. The difference in movement pattern between AGA and SGA infants might be explained by the effect of intrauterine malnutrition on CNS development.

Pharmacological properties of the new potent diuretic torasemide in rats and dogs.

Torasemide, a pyridine-3-sulfonylurea derivative, has potent diuretic activity in rats and dogs. In both species urinary volume and electrolyte excretion increased linearly with the logarithm of the dose, thus resembling the profile of a high ceiling diuretic. The minimum effective dose by oral route was 0.2 mg/kg in the rat and less that 0.1 mg/kg in the dog. Maximal effect was obtained with about 10 mg/kg. Experiments by oral and i.v. routes in the rat indicated that torasemide was equally potent by both oral and parenteral administration. In both rats and dogs, urinary excretions induced by torasemide were similar to those obtained with furosemide. However, for the same natriuretic effect, potassium losses with torasemide were significantly less than with furosemide. On a weight basis, torasemide was 9-40 times more potent than furosemide in the rat and about 10 times in the dog. After oral administration the diuretic effects of torasemide started within 20 min and lasted approximately 2 h in the rat and more than 8 h in the dog. The activity of torasemide was not decreased after a repeated daily oral dose of 10 mg/kg for 15 days in the rat. Torasemide at a daily oral dose of 5 mg/kg for 12 days effectively reduced the arterial blood pressure in desoxycortone induced hypertension in the rat. Besides the diuretic and antihypertensive effects no other significant pharmacological effects were observed with torasemide in the different in vitro and in vivo experiments. Torasemide was practically fully absorbed by the gastrointestinal tract, its bioavailability by oral route ranged from 80 to 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal effects of the high ceiling diuretic torasemide in rats and dogs.

The mode of action of torasemide was investigated by clearance experiments in dogs and rats. In the dog, torasemide (1 mg/kg i.v.) had no significant effect on glomerular filtration rate (GFR) but increased p-aminohippuric acid (PAH) clearance by 16% (p less than 0.01). In the rat both GFR and PAH clearance were significantly decreased, on an average 8-17%, by torasemide infused in the dose range of 1 to 20 mg/kg i.v. After i.v. injection the onset of diuresis was observed within 5 to 10 min and peak effect within 20 to 40 min in the rat and within 40 to 60 min in the dog. Fractional water and sodium excretions of nearly 25% were obtained in the rat with a dose of 8 mg/kg i.v. At equipotent doses, torasemide and furosemide induced similar diuretic and natriuretic effects in function of time in the rat. In the dog the effects lasted much longer with torasemide than with furosemide. This difference can be related to the longer half-life (about 8 h) of torasemide in the dog. In both species significant differences could be noted between torasemide and furosemide with respect to the time course of their effects on the urinary excretion of potassium. From the first experimental hour on, torasemide proved to be significantly less kaliuretic than furosemide as shown by increased Na/K ratios, during the third experimental hour they reached 20.5 vs 9.9 in the dog and 11 vs 7.5 in the rat with torasemide and furosemide, respectively. In hydropenic dogs, free water reabsorption was significantly reduced with torasemide and osmolar clearance significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the diuretic torasemide on p-aminohippuric acid transport in the rat.

The effect of torasemide, a new diuretic, on p-aminohippuric acid (PAH) transport (TPAH) was studied using renal clearance and micropuncture techniques in anaesthetized rats. In clearance experiments, TPAH and TPAH/glomerular filtration rate (GFR) did not significantly change after i.v. administration of torasemide or furosemide but decreased after probenecid injection. In order to enhance the possibility to demonstrate torasemide and PAH interference, small volumes of [3H]-PAH + [14C]-inulin solutions were directly injected into the peritubular capillary system using calibrated micropipettes. When the concentration of microinjected PAH was less than or equal to 0.6 mmol/l, fractional recovery of [3H]-PAH from the micropunctured kidney was not significantly decreased by the diuretics in contrast to probenecid. When the concentration of microinjected PAH was greater than or equal to 5 mmol/l, fractional recovery of [3H]-PAH from the micropunctured kidney was significantly decreased by torasemide from 252% (control) to 210% (P less than 0.005), by furosemide to 217% (P less than 0.005), and by probenecid to 205% (P less than 0.01). Under these conditions, differential transit times between [3H]-PAH and [14C]-inulin in the micropunctured kidney were decreased from -15 to -4 s in the presence of torasemide (P less than 0.05). They were slightly but not significantly reduced by furosemide and probenecid. These findings suggest interference, at least to some extent, between torasemide and PAH secretion in the rat kidney.

[In vivo assay of antisomatotropic activity of somatostatin and two of its analogs]. / Dosage in vivo de l'activité antisomatotrophine de la somatostatine et de deux de ses analogues.

Somatostatin (Growth hormone release inhibiting hormone or somatotrophin-release inhibiting factor) and its analogues can be measured in vivo by inhibiting the pentobarbital induced growth hormone release in male rats. Experimental conditions must be carefully defined to become optimal.