Synthesis and evaluation of some novel quinazolinone derivatives as diuretic agents

A new series of quinazolin-4(3H)-one derivatives containing either a thiazole or a 1, 3, 4-thiadiazole moiety were prepared in order to study the effect of such a heterocyclic combination on the expected diuretic activity. Synthesis of the target compounds (2, 4, and 6) has been achieved through an interaction of the starting 7-chloro-2-methyl-4H-3, 1-benzoxazin-4-one 1 with different heterocyclic amines. Alkylation of 3-(2-mercapto-1, 3, 4-thiadiazol-5-yl)quinazolin-4(3H)-one derivative 4 with different alkyl halides or chloroacetic acid afforded the corresponding thioethers 5 while interaction of 2-methyl-3-(1, 3, 4-thiadiazol-5-yl or thiazol-5-yl)quinazolin-4(3H)-ones (2 and 6) with various aromatic aldehydes resulted in the formation of the arylvinyl analogs 3 and 7, respectively. On the other hand, 2-morpholinomethyl-3-(2-sulfamoyl or mercapto-1, 3, 4-thiadiazol-5-yl)quinazolin-4(3H)-one derivatives 10 have also been synthesized through an interaction of the sulfonamide or thiol analog 9 with the appropriate amine. Biological evaluation of some of the target compounds as diuretic agents was carried out. The results showed that 2-[2-(4-chlorophenyl)vinyl]-7-chloro-3-(2-sulfamoyl-1, 3, 4-thiadiazol-5-yl)quinazolin-4(3H)-one 7b exhibited significant diuretic activity. The detailed synthesis, spectroscopic and biological data are reported.     

Automated 96-well liquid-liquid back extraction liquid chromatography-tandem mass spectrometry method for the determination of ABT-202 in human plasma

A high-throughput bioanalytical method using automated sample transferring, automated liquid-liquid back extraction and liquid chromatography-tandem mass spectrometry was developed in a GLP regulated environment for the determination of ABT-202 in human plasma. Samples of 0.30 ml were transferred into 96-well plate using an automatic liquid handler. Automated liquid-liquid extraction (LLE) was carried out on a 96-channel programmable liquid handling workstation using methyl tert-butyl ether as the extraction solvent. A dual-HPLC with single mass spectrometer configuration was utilized to provide a reliable and routine means to increase sample throughput. The standard curve range was 0.38-95.02 ng/ml. There was no interference from endogenous components in the blank plasma tested. The accuracy (% bias) at the lower limit of quantitation (LLOQ) was 7.7% and the precision (% CV) for samples at the LLOQ was 4.7%. The inter-day % CV and % bias of the quality control samples were < or = 6.8 and < or = 7.6%, respectively. Coefficients of determination, a measure of linearity, ranged from 0.994 to 0.997. The method was accurate and reproducible and was successfully applied to generate plasma concentration-time profiles for human subjects after low oral doses of the compound.     

Single photon emission tomography (SPECT) study of regional cerebral blood flow in normoalbuminuric children and adolescents with type 1 diabetes

Abstract: Cerebral damage in diabetes can be related to chronic hyperglycemia and recurrent severe hypoglycemia as well as due to the associated vasculopathy. The pattern of regional cerebral blood flow using cerebral single photon emission tomography (SPECT) was evaluated in normoalbuminuric type 1 diabetic children and adolescents and its relation to the metabolic control and cognitive functions. Thirty-one type 1 diabetics aged 10–18 yr (mean 14.7 ± 3.4) were included, 16 males and 15 females, divided into four groups: group I (n = 8) with history of recurrent severe hypoglycemia (≥ 3); group II (n = 8) with history of severe diabetic ketoacidosis (≥ 3); group III (n = 7) with recurrent minor hypoglycemia (≥ 3/week); and group IV (n = 8) with controlled diabetes. The control group (V) comprised seven healthy children, aged 10–18 yr (mean 14.2 ± 3.1). SPECT was done using technetium-99m hexamethyl propylene amine oxime. There was significant brain hypoperfusion in diabetics compared with controls, mainly in the basal ganglia (p < 0.01) and frontal regions (p < 0.01), with less changes in parietal and temporal regions. These changes were not related to the age, sex, diabetes duration, mean blood glucose or HbA1C. Basal ganglia hypoperfusion was significant in groups I (p < 0.01) and II (p < 0.01) compared with controlled diabetics. There was no correlation between cerebral SPECT changes and cognitive scores in type 1 diabetics.
Conclusion: Subclinical alterations in cerebral blood flow (hypoperfusion) are present in children and adolescents with type 1 diabetes mainly affecting the basal ganglia and frontal regions, usually not associated with measurable alterations of the cognitive functions     

Spectrophotometric determination of binary mixtures of pseudoephedrine with some histamine H1-receptor antagonists using derivative ratio spectrum method

A derivative spectrophotometric method is developed for the assay of three binary mixtures of pseudoephedrine with fexofenadine (mix I), cetirizine (mix II) and loratadine (mix III). The method is based on the use of the first derivative of the ratio spectrum. The ratio spectrum was obtained by dividing the absorption spectrum of the mixture by that of one of the components. The concentration of the other component was determined from its respective calibration graph treated similarly. Moreover, the influence of Deltalambda for obtaining the first derivative of the ratio spectra and the effect of the divisor concentration on the calibration graphs were studied. The described method was applied for the determination of these combinations in synthetic mixtures and dosage forms. The results obtained were accurate and precise.     

Esomeprazole vs pantoprazole effects on cyclosporine levels in kidney transplantation: A randomized clinical trial

Renal allograft survival requires multiple immunosuppressive drugs. This strategy may lead to gastric complications that necessitate gastro‐protective medications, notably, proton pump inhibitors (PPI). This study aimed to compare the influence of pantoprazole and esomeprazole on serum cyclosporine trough levels (C₀) in renal transplant recipients (RTR). A prospective, parallel, open‐label trial was conducted on 47 adult RTR receiving cyclosporine doses adjusted to attain trough concentrations of 100 to 150 μg/L, mycophenolate mofetil (MMF) 750 mg q12 hour and prednisolone at 5 mg daily at Nasser Institute, Cairo, Egypt from January to September 2016. Patients were randomized into the esomeprazole group (25) or pantoprazole group (22) receiving the same dose (40 mg once daily). The study outcomes included clinical signs of rejection and renal function decline, assessed by elevations in serum creatinine, caused by cyclosporine level variations in either of the two study groups. Renal function, C₀ and CBC measurements were measured at baseline and monthly for 6 months. The mean C₀ values were higher in the pantoprazole group than in the esomeprazole group in the sixth month only (P = .007). Serum creatinine level was lower in the sixth month than at baseline in the esomeprazole group (P = .004). There were no signs of rejection biochemical or clinical in any of the study groups. In conclusion, PPIs should be used with caution and doses should be titrated to reach the C₀ targets in RTR, which is of more importance in pantoprazole than esomeprazole to avoid C₀ level elevation or decline affecting the allograft function.     

Safety of frozen liver for human consumption

The objective of this study was to ensure and evaluate the safety of imported frozen beef liver traded in supermarkets of Kafr El-Sheikh Governorate, Egypt, through detection of Salmonella typhimurium, Salmonella enteritidies, Escherichia coli O157:H7, antibiotic residues, and aflatoxin B1 residue. Fifty samples of imported frozen liver were randomly collected from different shops at Kafr El-Sheikh Governorate for isolation of S. typhimurium, S. enteritidies, and E. coli O157:H7. The results revealed that for both microorganisms 4% of the examined samples presumed to contain Salmonella and E. coli O157:H7 organisms, according to the colonial character on Harlequin Salmonella ABC agar media and Harlequin SMAC-BCIG agar media. According to biochemical and serological identifications, both organisms could not be detected in the examined samples. A total of 29 (58%) samples were positive for antibiotic residues, using the Premi test (a broad-spectrum screening test for the detection of antibiotic residues in meat) at or below the maximum residue limits. In addition, aflatoxin B1 was detected in one (2%) samples with a concentration of 1.1 μg/kg. The results reflect that there was good hygiene practice for handling and preparation of frozen liver while selling to consumers. However, a high percentage of antibiotic residues reflect ignorance of withdrawal time before slaughtering of animals as well as misuse of antibiotics in veterinary fields. Furthermore, aflatoxin B1 residue was detected in examined frozen liver samples at a concentration below the maximum residual level, which is not enough to cause threat to humans, but it is enough to cause problem if it is eaten regularly reflect contamination of animal feed with aflatoxins.     

Early adult outcomes of adolescents who deliberately poisoned themselves

OBJECTIVE: To describe the early adult psychopathological and social outcomes of adolescents who deliberately poisoned themselves. METHOD: Prospective cohort study with a 6-year follow-up of 132 of 158 (84%) adolescents who, between ages 11 and 16 years, had taken part in a randomized trial of a brief family intervention after deliberate self-poisoning. Comparisons were made with a sample of participants matched for age, gender, and childhood social class. Both groups were assessed using standardized measures of psychopathology and social functioning. RESULTS: In most cases (93/132 or 70%) self-harm stopped within 3 years. Psychiatric disorders, particularly depression (74/132 or 56%), were prevalent, and self-harm in adulthood was restricted to this subgroup. There was a strong association between childhood adversity, in particular childhood sexual abuse, and self-harming risk in adulthood. Adulthood adversity also added to the risk, especially for those who had experienced index episode major depression. These associations were not mediated by childhood problem solving and hopelessness. CONCLUSIONS: For some young people, deliberate self-poisoning in adolescence seems to be part of a complex and continuing network of problems, marked by high rates of psychopathology, comorbidity, with other disorders and high psychosocial adversity.     

Evaluation of cerebrospinal fluid (CSF) C-reactive protein in the diagnosis of suspected meningitis

Cerebrospinal fluid C-reactive protein (CSF-CRP) was studied in 183 consecutive infants and children with suspected meningitis, using a nephelometric technique. Cerebrospinal fluid C-reactive protein was above an empirically chosen level of 1 mg/1 in seven of 19 children with culture-proven bacterial meningitis, in only one of 15 children with viral meningitis, and three of 139 children with no meningitis. All 10 children with partially treated meningitis had CSF-CRP levels below 1 mg/1. There was good correlation between CSF-CRP and total protein levels in children with bacterial meningitis (R value 0.4999 P less than 0.05). The test was not sensitive enough for early differentiation between bacterial and viral meningitis. The test also did not add extra information regarding aetiology in partially treated meningitis.     

A multivariate discrete failure time model for the analysis of infant motor development

We develop a multivariate discrete failure time model for the analysis of infant motor development. We use the model to jointly evaluate the time (in months) to achievement of three well-established motor milestones: sitting up, crawling, and walking. The model includes a subject-specific latent factor that reflects underlying heterogeneity in the population and accounts for within-subject dependence across the milestones. The factor loadings and covariate effects are allowed to vary flexibly across milestones, and the milestones are permitted to have unique at-risk intervals corresponding to different developmental windows. We adopt a Bayesian inferential approach and develop a convenient data-augmented Gibbs sampler for posterior computation. We conduct simulation studies to illustrate key features of the model and use the model to analyze data from the Nurture study, a birth cohort examining infant health and development during the first year of life.