Species differences in blood-mediated nitrosocimetidine denitrosation

Nitrosocimetidine (NC) is the nitrosated derivative of cimetidine (Tagamet), a p.o. administered drug used widely in the treatment of stomach ulcers. NC is capable of methylating DNA in vitro and in cultured cells in a manner similar to that of the laboratory carcinogens 1-methyl-2-nitro-1-nitrosoguanidine and methylnitrosourea (MNU) and gives positive indications in short-term in vitro tests for genotoxicity, generally held to be prognostic of compound carcinogenic potential. Nevertheless NC has been found to be a weak or non-carcinogen in the rat and mouse model systems and to produce minimal levels of tissue DNA alkylation when dosed p.o. or i.v. to rats. The results from our earlier experiments (D. E. Jensen, Cancer Res., 43: 5258-5267, 1983) indicated that compound denitrosation is the primary fate of NC in the rat and suggested that denitrosation is the blood, mediated by hemoglobin sulfhydryl residues, is perhaps the major detoxification mechanism. We now report that whole blood and hemoglobin isolated from various mammalian species differ in their capacity for NC degradation rate enhancement and for compound denitrosation. The observed whole blood activity in the degradation reaction (rat greater than mouse/guinea pig greater than human/hamster) paralleled the hemoglobin activity. The NC half-life in isolated rat blood, 37 degrees C, was found to be about 2 min and in hamster or human blood 27 min. For reference, the MNU half-life in isolated blood is 8 min. Compound denitrosation accounted for at least 75% of the degradation in rat blood and 40 to 55% in human and hamster blood. Parallel NC denitrosation activity was found in the various hemoglobin preparations. The NC degradation rates in the presence of the several hemoglobin species were roughly proportional to the number of sulfhydryls on the hemoglobin tetramers available for reaction with p-chloromercuribenzoate and approximated the rates observed in solutions containing equivalent concentrations of L-cysteine. The percentage of total decomposition due to compound denitrosation in the presence of rat hemoglobin, 95%, was found to be unique relative to the L-cysteine-mediated reactions (about 35%) and the reactions studied over the pH range 6 through 10, the denitrosation process never accounted for more than 50% of the total degradation. Chemically blocking the sulfhydryls on human hemoglobin using iodoacetamide deleted the NC degradation rate enhancement. We found no evidence for nitrosylhemoglobin formation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Gastroduodenal mucosal hemodynamics by endoscopic reflectance spectrophotometry

The reflectance spectrophotometric technique measures an index of mucosal hemoglobin concentration and an index of oxygen saturation by spectral analysis of light reflected from the mucosal surface. Using a commercially available unit, a technique for obtaining reproducible endoscopic measurements with acceptable intraobserver and interobserver variability was developed in the anesthetized dogs. The reflectance spectrophotometric finding that experimentally induced prehepatic portal hypertension did not affect gastric mucosal blood flow was confirmed by hydrogen gas clearance measurements. Endoscopic studies in patients with active duodenal ulcer disease revealed a higher index of mucosal hemoglobin concentration and a normal index of oxygen saturation (i.e., an increase in blood flow) at the margin of the ulcer compared with the adjacent normal appearing mucosa.     

Age and immune response to a surgical stress

We studied the effects of age and a relatively standardized stress (elective inguinal herniorrhaphy) on immune response. The patients included 20 men, ten at least 60 years old and ten younger, who were free of infection and illness and had not had prior surgery. Immune responses were measured one day before and five and 30 days after operation. We determined immunoglobulin levels, performed three delayed-hypersensitivity skin tests and a test for neutrophil chemotaxis, and measured lymphocyte responses to autologous cells, phytohemagglutinin-P (PHA), concanavalin A (Con A), and pokeweed. We also studied responses in 40 controls matched for age and sex. The responses to PHA and Con A were significantly lower in older patients than in controls at five days after operation; responses to Con A were still significantly lower at 30 days. Morbidity correlated with depressed immune responses in both age groups, even when there was no difference between older and younger patients.     

The effects of peripherald-amphetamine, 4-OH amphetamine, and epinephrine on maintained discharge in the locus coeruleus with reference to the modulation of learning and memory by these substances

d-Amphetamine, 4-OH amphetamine, and epinephrine have been shown in many behavioral studies to facilitate memory when given post-training. The effect of these drugs on the maintained discharge of cells in the locus coeruleus (LC) was investigated using a route of administration (intraperitoneal) and a log-dose range of these drugs comparable to those used in the behavioral experiments.d-Amphetamine profoundly suppressed maintained discharge: an inhibitory effect was observed at every dose (0.1, 1.0, 10.0 mg/kg). In contrast, only the highest dose of 4-OH amphetamine (8.2 mg/kg) inhibited activity in the LC, and this effect was a modest one. Unlike the amphetamines, epinephrine (500 μ/kg) elevated maintained discharge. These results are discussed in the contex of the hypothesized involvement of the LC in the enhancement of memory by these drugs.     

Early operation or conservative management of patients with small bowel obstruction?

OBJECTIVE: To evaluate the outcome after initial non-operative treatment in patients with small bowel obstruction (SBO). DESIGN: Prospective study. SETTING: University hospital, Norway. PATIENTS: One hundred and fifty-four patients with 166 episodes of SBO admitted during the period (1994-1995). Patients younger than 10 years as well as patients with large bowel obstruction, paralytic ileus, incarcerated hernia or SBO caused by cancer were excluded from the study. INTERVENTIONS: Patients with signs of strangulation were operated on early. The rest were given a trial of conservative treatment. MAIN OUTCOME MEASURES: Need of operative treatment. Incidence of bowel strangulation, complications and death. RESULTS: There were 166 cases of SBO. Twenty patients were operated on early among whom bowel was strangulated in 9. Among the 146 patients initially treated conservatively 93 (64%) settled without operation, 9 (6%) had strangulated bowel and 3 (2%) died. Of the 91 patients with partial obstruction but no sign of strangulation, 72 (79%) resolved on conservative treatment. CONCLUSIONS: Patients with partial obstruction with no sign of strangulation should initially be treated conservatively. When complete obstruction is present, it may settle on conservative management, but the use of supplementary diagnostic tools might be desirable to find the patients who will need early operative treatment.     

Increasing Maternal Blood Pressure with Ephedrine Increases Uterine Artery Blood Flow Velocity during Uterine Contraction

Background: During labor, ephedrine is widely used to prevent or to treat maternal arterial hypotension and restore uterine perfusion pressure to avoid intrapartum fetal asphyxia. However, the effects of ephedrine on uterine blood flow have not been studied during uterine contractions. The purpose of the study was to assess the effects of ephedrine on uterine artery velocities and resistance index using the Doppler technique during the active phase of labor.

Methods: Ten normotensive, healthy parturients with uncomplicated pregnancies at term received intravenous ephedrine during labor to increase mean arterial pressure up to a maximum of 20% above their baseline pressure. Peak systolic and end-diastolic Doppler flow velocities and resistance indices were measured in the uterine artery before and immediately after administration of bolus intravenous ephedrine and after ephedrine washout. Umbilical and fetal middle cerebral arterial resistance indices and fetal heart rate were also calculated.

Results: After ephedrine administration, mean arterial pressure increased by 17 +/- 4%. End-diastolic flow velocity in the uterine artery at peak amplitude of uterine contraction was restored to 74% of the value observed in the absence of contraction. The systolic velocity was totally restored, and the uterine resistance index was significantly decreased, compared with the values in the absence of contraction. Between uterine contractions, ephedrine induced similar but less marked effects. Fetal hemodynamic parameters were not altered by ephedrine administration.     

Effect of high hematocrit and high blood flow rates on transmembrane pressure and ultrafiltration rate in hemodialysis.

Removal of prescribed ultrafiltration volumes in hemodialysis requires knowledge of both the ultrafiltration coefficient of the dialyzer and the average transmembrane pressure (TMP) in the dialyzer. While it has been a fairly common practice to assume that the TMP is constant along the length of the dialyzer, it actually decreases linearly from a maximum value at the blood inlet to a minimum value at the blood outlet. In the past, ignoring the difference between arterial and venous TMPs when calculating the dialysate pressure setting did not result in significant errors in ultrafiltration volume. However, with the introduction of erythropoietin therapy and the trend toward high-efficiency dialysis, increases in hematocrit and blood flow rate have led to axial variations in TMP which, if ignored, can lead to inaccurate fluid removal. The goals of this paper are to provide an understanding of how high hematocrits and high blood flow rates affect TMP and ultrafiltration rate, and to provide simple guidelines for ensuring accurate fluid removal. Sample calculations are given on the last page for easy reference.     

Application of fluorescence in situ hybridization techniques in clinical genetics: use of two alphoid repeat probes detecting the centromeres of chromosomes 13 and 21 or chromosomes 14 and 22, respectively

Two cloned DNA fragments, one derived from an alpha satellite subfamily common to chromosomes 13 and 21, and the other derived from a similar subfamily common to chromosomes 14 and 22, have been used as biotinylated probes in in situ hybridization studies. Under high stringency conditions, chromosome specific centromeric labelling can be obtained. The applications of this technique in clinical situations are illustrated on metaphases from a fetus with trisomy 21, a fetus with trisomy 13, and a child with clinical features of cat-eye syndrome.     

Single-dose and steady-state pharmacokinetics of diltiazem administered in two different tablet formulations.

Single-dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assessed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in tmax was observed (2.9 +/- 1.9 and 6.8 +/- 2.6 hr respectively) whereas differences in AUC, t1/2 and Cmax were not significant. The AUC (mean +/- S.D.) values following single dose administration of Cardil and Cardizem were 678.4 +/- 321.5 and 948.6 +/- 580.6 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.89 and 0.44-1.34 respectively. At steady-state a significant difference between Cmax/Cmin and tmax was seen Cmax/Cmin being 4.9 and 3.2 respectively and Tmax being 2.7 +/- 2.0 and 6.0 +/- 2.8 hr respectively, whereas Cmax and AUC did not differ significantly. The AUC (mean +/- S.D.) values in steady state of Cardil and Cardizem were 880.1 +/- 399.8 and 1056.8 +/- 509.8 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.96 and 0.66-1.26 respectively. Although the observed ratios AUCCardil/AUCCardizem in both the single-dose and the steady-state study do not differ significantly from 1.0, the confidence limits exceed the acceptable values given by Poulsen & Juul (personal communication 1990) (a 20% decrease or increase of the ratio to 0.8 or 1.2).