Novel antagonists of the 5-HT3 receptor. Synthesis and structure-activity relationships of (2-alkoxybenzoyl)ureas.

A series of benzoylureas derived from bicycle amines were prepared and evaluated for 5-HT3 antagonist activity on the rat isolated vagus nerve. From among these compounds, those analogues which were ortho substituted by an alkoxy group on the benzoyl function were shown to be potent 5-HT3 antagonists with similar or greater potency than the standard agent ondansetron. NMR and X-ray crystallography studies showed these o-alkoxy compounds to exist as a planar, hydrogen-bonded, tricyclic ring system. In molecular modeling studies on endo-N-[[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl-amino] carbonyl]-2-(cyclopropylmethoxy)benzamide (30) the central hydrogen-bonded ring was able to mimic an aromatic ring present in previously reported 5-HT3 antagonists.     

Inhibition of dapsone-induced methaemoglobinaemia in the rat isolated perfused liver

We have investigated the disposition of dapsone (DDS, 1 mg) in the rat isolated perfused liver in the absence and the presence of cimetidine (3 mg). After the addition of DDS alone to the liver there was a monoexponential decline of parent drug concentrations and rapid formation of DDS-NOH (within 10 min) which coincided with methaemoglobin formation (11.7 +/- 3.0%, mean +/- s.d.) which reached a maximum (22.6 +/- 9.2%) at 1 h. The appearance of monoacetyl DDS (MADDS) was not apparent until 30-45 min. Addition of cimetidine resulted in major changes in the pharmacokinetics of DDS and its metabolites. The AUC of DDS in the presence of cimetidine (1018.8 +/- 267.8 micrograms min mL-1) was almost three-fold higher than control (345.0 +/- 68.1 micrograms min mL-1, P less than 0.01). The half-life of DDS was also prolonged by cimetidine compared with control (117.0 +/- 48.2 min vs 51.2 +/- 22.9, P less than 0.05). The clearance of DDS (3.0 +/- 0.55 mL min-1) was greatly reduced in the presence of cimetidine (1.03 +/- 0.26 mL min-1 P less than 0.01). The AUC0-3h for DDS-NOH (28.3 +/- 21.2 micrograms min mL-1) was significantly reduced by cimetidine (8.1 +/- 3.40 micrograms min mL-1, P less than 0.01). In contrast, there was a marked increase in the AUC0-3h for MADDS (32.7 +/- 25.8 micrograms min mL-1) in the presence of cimetidine (166.0 +/- 26.5 micrograms min mL-1 P less than 0.01). The methaemoglobinaemia associated with DDS was reduced to below 5% by cimetidine. Hence, a shift in hepatic metabolism from bioactivation (N-hydroxylation) to detoxication (N-acetylation) caused by cimetidine, was associated with a fall in methaemoglobinaemia. These data suggest that the combination of DDS with a cytochrome P450 inhibitor might reduce the risk to benefit ratio of DDS.     

The disposition of quinine in the rat isolated perfused liver: effect of dose size

We have investigated the pharmacokinetics of both free and total quinine in the rat isolated perfused liver at three doses, 6.25, 12.5 and 25 mg. The plasma concentrations of free and total quinine decayed biexponentially over 4 h. However, on increasing dose, the terminal half-life of free and total quinine showed marked increases ranging from 12.4 +/- 3.7 min at 6.25 mg to 176.0 +/- 153 min at 25 mg (total quinine). Quinine clearance was reduced approximately by half as the dose was doubled. At 10 min post dosage, quinine extraction at the 6.25 mg dose (56 +/- 16.3%) was more than twice that of the highest dose (25 mg, 25.0 +/- 6.5%). Free quinine at the 6.25 mg dose was cleared at approximately 100% of perfusate flow, whereas at 25 mg, clearance was less than one fifth of that value. Unchanged quinine elimination in bile was low, with less than 1% of the parent drug being detected at the 12.5 and 25 mg doses. Relatively little parent drug was recovered from the liver at 4 h. At the 25 mg dose, less than or equal to 6% was recovered as parent drug. HPLC analysis revealed some polar metabolites of quinine in the bile and in the liver homogenates. Dose dependent kinetics of quinine were demonstrated in this study, as hepatic extraction of quinine decreased with increasing dose and input concentration.     

Deprivation and survival from breast cancer.

We studied the association between deprivation and survival from breast cancer in 29,676 women aged 30 and over who were diagnosed during the period 1980-89 in the area covered by the South Thames Regional Health Authority. The measure of deprivation was the Carstairs Index of the census enumeration district of each woman''s residence at diagnosis. We studied the impact of stage at diagnosis, morphology and type of treatment on this association, with the relative survival rate and the hazard ratio as measures of outcome. There was a clear gradient in survival, with better survival for women from more affluent areas. At all ages, women in the most deprived category had a 35% greater hazard of death than women from the most affluent areas after adjustment for stage at diagnosis, morphological type and type of treatment. In younger women (30-64 years), the survival gradient by deprivation category cannot be explained by these prognostic factors. In older women (65-99 years), part of the unadjusted gradient in survival can be explained by differences in the stage of disease: older women in the most deprived category were more often diagnosed with advanced disease. Other factors, so far unidentified, are responsible for the gradient in breast cancer survival by deprivation category. The potential effect on breast cancer mortality of eliminating the gradient in survival by deprivation category is substantial (7.4%). In women aged 30-64 years, 10% of all deaths within 5 years might be avoidable, while in older women this figure is 5.8%.     

Reappraisal of the baseline bone scan in breast cancer

Baseline staging bone scans in 1,267 consecutive women with breast cancer attending a single clinic between 1980 and 1986 were reviewed. 0.3% of patients with T1, 3% with T2, 8% with T3, 13% with T4 tumors and none of those with Stage 1, 3% with Stage 2, 7% with Stage 3, and 47% with Stage 4 disease had a positive scan due to bone metastases. Two hundred eight-nine (23%) had bone scan abnormalities secondary to radiologically confirmed benign bone disease. In 20 patients, no cause for a bone scan abnormality could be found after a median follow-up of 3.50 yr, a false-positive frequency of 1.6%. The false-negative rate was 0.08%. It is concluded that patients with tumors less than 2 cm are most unlikely to have a positive scan. In this instance, scans are not required routinely. However, we recommend a baseline scan in all patients with Stage 2, 3, or 4 disease.     

Characterization of a YAC containing part or all of the Norrie disease locus

It has been shown from pulsed-field gel electrophoresis (PFGE)that the monoamine oxidase genes A and B (MAOA & MAOB) andDXS7 loci are physically very close. We have therefore extendedstudies on their relationship through the characterisation ofa 650 kb YAC isolated using L1.28 (recognising the DXS7 locus)as a probe. Restriction mapping of the YAC indicates that itcontains both MAOA and MAOB genes in addition to the DXS7 locus.The map derived from the YL1.28-YAC is compatible both withthe map from an independently derived YAC carrying MAOA andB genes and with the long range genomic map for the region.A series of subclones prepared from a 'phage library (lambdaDASH II) of the YAC have been characterised and have been employedto determine the end point of the deletion of a Norrie disease(NDP) patient who has been shown to lack both DXS7 and MAO codingsequences. The pattern of retention of subclones in the deletionpatient place the end point of the deletion within 30–130kb of the proximal end of the YAC. By combining the data withestablished recombination analysis, we provide evidence thatall or part of the NDP lies in the interval of approximately250kb within the YAC.     

A study of the freeze-drying conditions of calixarene based solid lipid nanoparticles.

In this note, we report a study of cryoprotectant carbohydrate (glucose, fructose, mannose and maltose) effects on the reconstitution of calixarene based solid lipid nanoparticle (SLN) suspensions after freeze-drying, studied by atomic force microscopy and photon correlation spectroscopy. All carbohydrates tested showed excellent cryoprotection and redispersion properties with the calixarene based SLNs.     

Epidemiologists in the United States: an assessment of the current supply and the anticipated need

We provide 1985 estimates of the work force of epidemiologists in the United States, the number of graduates from training programs in epidemiology, and a projection of the future need for these health professionals. Our methods included a search of mailing lists from professional organizations, mail contact with graduate training programs, telephone interviews with experts, and a review of job announcements in professional journals. The study indicates that the current work force of epidemiologists in the United States is estimated to include 4,600 persons, more than half of whom are physicians; most epidemiologists are located in either a state with a major federal public health agency or one with a large population; and programs in epidemiology graduate an average of 475 persons with one or two years of master's level education and approximately 80 with doctoral-level education each year. After considering the factors that influence the supply of epidemiologists, we project a substantial need for more epidemiologists in the future than current sources will provide.