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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 55 records · Page 3Linked to original sources
PubMed1995

Potassium depletion potentiates amphotericin-B-induced toxicity to renal tubules.

Hypokalemia and potassium depletion are frequent complications of amphotericin B therapy. Both ischemic and gentamicin-induced renal failure is potentiated by potassium depletion; it is, therefore, possible that amphotericin B nephrotoxicity is similarly influenced. This study evaluated whether the acute nephrotoxic response to amphotericin B is potassium sensitive. Potassium-depleted and control rats were subjected to an acute intravenous infusion of either amphotericin B (AmB-K; AmB, n = 10 in each) or its vehicle (V-K, V; n = 6 in each). Potassium-depleted rats had both lower urinary daily excretion and lower plasma levels of potassium than control animals (0.1 +/- 0.0 vs. 2.1 +/- 0.2 mEq/day, p < 0.001, and 3.8 +/- 0.2 vs. 1.9 +/- 0.1 mEq/l, p < 0.001, respectively). In AmB and AmB-K groups, there were equivalent falls in glomerular filtration rate and renal blood flow, and a rise in renal vascular resistance, compared with V and V-K. In contrast, the AmB-K group showed a higher urinary excretion of sodium (AmB-K vs. AmB: 2.9 +/- 0.7 vs. 1.1 +/- 0.3 microEq/min; p < 0.05) and fractional excretion of Na (AmB-K vs. AmB: 1.6 +/- 0.4 vs. 0.6 +/- 0.1%; p < 0.05) in comparison to the AmB group. Neither of these parameters changed in either amphotericin B or vehicle-treated groups. These results suggest that potassium depletion does not influence the acute renovascular effects of amphotericin B but potentiates its tubular toxicity. This may have clinical implications since hypokalemia and potassium depletion are frequent complications of amphotericin B therapy.

Amphotericin B↗
PubMed1995

Relationship between oxidative hepatic metabolism, urinary sodium excretion and sympathetic nerve activity in experimental cirrhosis in the rat.

This study investigated the relationship between changes in renal sympathetic activity as assessed by renal norepinephrine spill-over and the onset of renal sodium retention in the phenobarbital/carbon tetrachloride model of experimental cirrhosis in rats. In this model, sodium retention occurs when hepatic function, assessed by the aminopyrine breath test (ABT), falls below a critical threshold. Three groups of rats, studied on a constant salt diet, included a group with cirrhosis and sodium retention, a group with cirrhosis of similar duration and no sodium retention and a time-control phenobarbitaltreated group. ABT, renal plasma flow (RPF), glomerular filtration rate (GFR) and mean arterial pressure (MAP) were measured at the time of catecholamine sampling in anesthetized rats. Cirrhosis was associated with reductions in MAP, no change in RPF and GFR, and an ABT below the threshold in rats with sodium retention. In contrast, rats without sodium retention had liver function above the threshold. Renal norepinephrine spill-over increased continuously from controls to non-sodium retaining and sodium retaining animals. The difference between sodium retaining animals and controls was significant. Norepinephrine spill-over correlated to ABT and MAP but not urinary salt excretion. The data suggest that, under these experimental conditions, increased sympathetic activity may contribute to the onset of sodium retention. A plausible explanation for the continuous increase is that catecholamines are released as a compensatory mechanism in response to a primary yet undefined vasodilator.

Aminopyrine↗
PubMed1994

Frequency distribution of dapsone N-hydroxylase, a putative probe for P4503A4 activity, in a white population.

Phenotypic trait values in 166 healthy white subjects (age range, 18 to 88 years) were determined for dapsone N-hydroxylation, dapsone N-acetylation, debrisoquin 4-hydroxylation, and S-mephenytoin 4'-hydroxylation after single oral dose administration of the probe drugs dapsone (100 mg), debrisoquin (10 mg), and mephenytoin (100 mg). No associations or evidence of cosegregation were found between the individual routes of metabolism. Dapsone N-hydroxylation exhibited a unimodal distribution, with marked (tenfold) intersubject variability, and aging was associated with reduced N-oxidation. However, the other measured routes of metabolism were age independent, but intersubject variability in all of the trait measurements increased with age. In subjects younger than 50 years, S-mephenytoin 4'-hydroxylation was modestly (34%) less in men than in women. In contrast, dapsone N-acetylation, dapsone N-hydroxylation, and debrisoquin 4-hydroxylation were not influenced by gender. Previous smoking habit and alcohol consumption were not associated with a difference in any of the four routes of metabolism. Accordingly, the measured phenotypic traits of drug oxidation and N-acetylation appear to be quite robust in regard to some common demographic variabilities present in population studies, with the exception of dapsone N-hydroxylase, which is affected by aging.

Acetylation↗
PubMed1994

Correlation of polymorphic expression of CYP2D6 mRNA in bladder mucosa and tumor tissue to in vivo debrisoquine hydroxylase activity.

Debrisoquine hydroxylase activity has been attributed to CYP2D6 and poor metabolizers of debrisoquine have a reduced relative risk of developing aggressive bladder cancer. Production of a proximate carcinogen could occur in liver or bladder mucosa. However, it is not known if CYP2D6 is expressed in human bladder mucosa. In vivo whole body debrisoquine hydroxylase activity was measured as the debrisoquine recovery ratio (DBRR) following single dose oral administration of debrisoquine (10 mg) in 10 normal subjects and 20 patients with bladder cancer prior to diagnostic cystoscopy. Semi-quantitative PCR was used to measure mRNA for CYP2D6 in bladder tissue obtained at cystoscopy. Of the 30 subjects, three were phenotypically and genotypically poor metabolizers. Among the extensive metabolizers, there were extensive intersubject variations in DBRR. A 10-fold variation in CYP2D6 mRNA levels was observed in bladder tissue. There was a highly significant association between DBRR and CYP2D6 mRNA expression (r2 = 0.702, P < 0.001). These results demonstrate the presence of CYP2D6 mRNA in bladder mucosa. Furthermore, they are consistent with debrisoquine hydroxylation being mediated by CYP2D6 and suggest that differences in mRNA concentration are rate limiting for enzyme activity and that bladder mucosal regulation reflects total body regulation for this enzyme. The expression of CYP2D6 in bladder mucosa suggests that this enzyme could be involved in the local production of a proximate carcinogen in this tissue and contribute to the pathogenesis of bladder cancer in man.

Base Sequence↗
PubMed1994

Low activity of dapsone N-hydroxylation as a susceptibility risk factor in aggressive bladder cancer.

N-arylamines involved in the pathogenesis of bladder cancer, require metabolic activation via N-hydroxylation. The efficiency of in vivo N-hydroxylation of dapsone, a non-carcinogenic arylamine, may, therefore, provide a host susceptibility measure of risk of developing bladder cancer. To investigate this possibility, the dapsone recovery ratio, a phenotypic measure of the efficiency of dapsone hydroxylation, has been measured in a case control study in an urban UK population, comparing patients with aggressive bladder cancer (n = 33), non-aggressive bladder cancer (n = 60) and controls (n = 108). Dapsone recovery ratio in controls exhibited a unimodal distribution. Patients with aggressive bladder cancer had a similar distribution but significantly lower mean value (p < 0.005). Logistic regression analysis, controlling for sex, age, smoking habit and alcohol consumption confirmed a significant (p < 0.05) association between the dapsone recovery ratio and aggressive bladder cancer. Subjects in the lowest tertile of dapsone recovery ratio had a relative risk to 5.4-fold greater than subjects in the upper tertile (p < 0.009), and a trends test was significant (p < 0.001). There was no significant association between dapsone recovery ratio and non-aggressive bladder cancer. These results do not support the hypothesis that the drug metabolizing enzymes involved in dapsone N-hydroxylation are involved in causing bladder cancer. Instead, they suggest the opposite, the observation that low enzyme activity was associated with increased risk is consistent with this enzyme providing a detoxification mechanism for environmental procarcinogens.

Case-Control Studies↗
PubMed1993

Sensitive high-performance liquid chromatographic determination of chlorzoxazone and 6-hydroxychlorzoxazone in plasma.

A rapid and sensitive high-performance liquid chromatographic assay was developed for the quantitation of chlorzoxazone and its major metabolite 6-hydroxychlorozoxazone in plasma. These compounds, as well as the internal standard 5-fluorobenzoxazolone, were extracted from plasma (0.5 ml) using C18 solid-phase extraction columns. The extracts were analyzed on a 10-microns Waters C18 muBond-apak column with a mobile phase of acetonitrile-tetrahydrofuran-0.1 M ammonium acetate (22.5:5.5:72). The assay utilized ultraviolet detection (283 nm) which provided sensitivity and specificity sufficient to simultaneously quantify > or = 100 ng/ml chlorozoxazone and 6-hydroxychlorzoxazone in plasma. The mean correlation coefficient of the multi-level standard curves for each compound was 0.996 or greater over a concentration range of 100-3000 ng/ml. The inter-day and intra-day coefficients of variation were < 6%. This method has been used by our laboratory to provide the unattended overnight analysis of chlorozoxazone and 6-hydroxychlorzoxazone in plasma samples obtained from human study subjects.

Calibration↗
PubMed1993

Sodium retention and hepatic function following partial portal vein ligation in the rat.

Recent studies have suggested that the development of sodium retention in experimental cirrhosis in the rat occurs when hepatic function, measured by the aminopyrine breath test, decreases below a critical threshold. The present study evaluated the relationship between renal sodium handling and hepatic function and determined whether sodium retention occurs following partial portal vein ligation. Sodium balance, urine volume, creatinine clearance and the aminopyrine rate constant of elimination, on a constant sodium intake, were evaluated daily, from 1 day before surgery to 5 days after surgery, in both sham-operated (n = 6) and partially portal vein-ligated rats (n = 14). In the partially portal vein-ligated group, sodium retention occurred in 9 rats between 1 and 4 days after surgery, accompanied by a 45% reduction in the aminopyrine rate constant of elimination. Spontaneous natriuresis occurred within 5 days after surgery, and was associated with an increase in the aminopyrine rate constant of elimination from 0.94 +/- 0.07 x 10(-2) min-1 on the last day of sodium retention to 1.36 +/- 0.06 x 10(-2) min-1 on the day of diuresis (P < 0.05). In contrast, creatinine clearance did not change throughout the study. There was a negative curvilinear association between sodium balance and the aminopyrine rate constant of elimination (r = 0.70, P < 0.001). In the five rats without sodium retention, there was no change in the aminopyrine rate constant of elimination and creatinine clearance over the 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopyrine↗
PubMed1993

Interaction between thromboxane A2 and angiotensin II in postischemic renal vasoconstriction in dogs.

The kidney responds to periods of ischemia with vasoconstriction and a decrease in glomerular filtration rate (GFR) on reperfusion. The mediators of this response have not been fully identified. In this study, we examined the contribution of angiotensin II (AII), thromboxane A2 (TXA2) and the interaction between them to this response. Anesthetized dogs were subjected to 30 min of clamping of both renal arteries. Renal hemodynamics and function were followed from 60 min before and for 105 min after clamping. Dogs were divided into salt-depleted (AII-stimulated) and captopril-treated (AII-inhibited) groups. Each group included dogs that received either the TXA2 synthase inhibitor CGS 13080 or its vehicle (controls) starting 30 min before renal artery clamping and lasting to the end of the experiment. In captopril-treated control dogs, 30 min of ischemia induced a 25% fall in renal blood flow (RBF). GFR initially fell by 75%, but recovered to 64% of base-line value 60 to 90 min after release of the clamp. In captopril-treated dogs, CGS 13080 prevented the fall in RBF, but the GFR response was similar to vehicle-treated dogs. In control dogs, both GFR and RBF responses were enhanced in salt-depleted compared with captopril-treated dogs; the decrease in RBF (44%) was greater, and the recovery in GFR, which fell by 89%, less. In salt-depleted, CGS 13080-treated dogs, the 30% fall in RBF was less than its control, but greater than dogs treated with captopril and CGS 13080. The change in GFR was similar to the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1992

Effect of amphotericin B on intracellular calcium levels in cultured glomerular mesangial cells.

Amphotericin B induces a reduction in the glomerular filtration rate due, in part, to a decrease in the glomerular capillary ultrafiltration coefficient (Kf), possibly resulting from mesangial cell contraction. The present study has examined the effect of amphotericin B on intracellular free calcium concentrations ([Ca2+]i) in cultured glomerular mesangial cells, using the fluorescent probe, fura-2. Under control conditions, amphotericin B caused a concentration-dependent increase in [Ca2+]i with a 231 +/- 52 nM increase at a concentration of 10(-6) M. This increase was almost completely inhibited when Ca2+ ions were omitted from the cell medium (an increase of 34 +/- 7 nM, P less than 0.0001). Replacement of extracellular Na+ ions with N-methylglucamine caused a marked inhibition of the amphotericin B-induced rise in [Ca2+]i (28 +/- 5 nM, P less than 0.0001). Diltiazem (20 microM) also suppressed the rise in [Ca2+]i seen with amphotericin B (36 +/- 6 nM, P less than 0.0001). In contrast, theophylline (20 microM) enhanced the response to amphotericin B (351 +/- 51 nM rise, P less than 0.001). The results suggest that amphotericin B-induced mesangial cell contraction is secondary to Ca2+ entry from the extracellular space through voltage-dependent calcium channels. The dependence of the response on extracellular Na+ suggests that Na+ entry induces depolarization of the membrane and opening of voltage-dependent calcium channels.

Amphotericin B↗
PubMed1992

Activity of oxidative routes of metabolism of debrisoquin, mephenytoin, and dapsone is unrelated to the pathogenesis of vinyl chloride-induced disease.

The hypothesis, that cytochrome P4502D6, cytochrome P4502CMP, cytochrome P4503A4 or N-acetyl-transferase may form active intermediary metabolites that could be etiologically related to vinyl chloride-induced disease was investigated in 21 drug-free workers with previous development of vinyl chloride-induced disease and in 23 drug-free workers from the same plant who did not develop the syndrome. Each subject received simultaneous oral administration of debrisoquin (10 mg), mephenytoin (100 mg), and dapsone (100 mg). Measurement of the debrisoquin recovery ratio, the 8-hour recovery of 4-hydroxymephenytoin, and the dapsone recovery ratio in the subsequent 8-hour urine sample provided in vivo phenotypic indexes of cytochromes P4502D6, P4502CMP, and P4503A4 activity, respectively. An 8-hour blood sample was used to measure the acetylation ratio, a measure of N-acetyltransferase activity. The frequency distributions of each drug metabolizing activity were similar between groups. Within this small sample, there was no evidence to implicate cytochromes P4502D6, P4502CMP, and P4503A4 and N-acetyltransferase in the pathogenesis of vinyl chloride-induced disease.

Arylamine N-Acetyltransferase↗
PubMed1992

The disposition of dapsone in cirrhosis.

Acetylation and N-hydroxylation of dapsone were evaluated in drug-free, non-smoking, normal subjects and subjects with cirrhosis (n = 7 for each group) after oral administration of 100 mg dapsone. Acetylation was not correlated with oral dapsone clearance or reduced in cirrhosis (0.37 +/- 0.43 versus 0.52 +/- 0.32). Fractional metabolic clearance of dapsone to its hydroxylamine was associated with dapsone oral clearance (r = 0.96, p less than 0.001, n = 14). In patients with cirrhosis, liver disease was associated with a trend to reduction in oral clearance (22%) and metabolic clearance of dapsone (48%). Protein binding was minimally reduced by cirrhosis (73% +/- 1% versus 69% +/- 3% in patients with cirrhosis (p less than 0.02). The dapsone recovery ratio was validated as a phenotypic index of the metabolic clearance of dapsone (r = 0.74, p less than 0.05). In an extended comparison of 14 patients with cirrhosis to 70 control subjects, cirrhosis was associated with reductions of 28% in dapsone recovery ratio (p less than 0.001), and 37% in acetylation ratio (p less than 0.01). Neither dapsone recovery ratio nor acetylation ratio correlated with Pugh Score, conventional liver function tests, indocyanine green clearance, or phenotypic measures of S-mephenytoin hydroxylase or debrisoquin hydroxylase activity. We conclude that cirrhosis is associated with minor changes in dapsone disposition and that dosage modification is not required. In addition, there is evidence that cirrhosis has a selective influence on activity of individual isozymes of cytochrome P450.

Acetylation↗
PubMed1992

The ability to 4-hydroxylate debrisoquine is related to recurrence of bladder cancer.

Oxidative metabolism by cytochrome P450 enzymes is often involved in the activation of environmental procarcinogens. Debrisoquine, mephenytoin, and dapsone were used as in vivo probes for the activities of P4502D6, 2CMP, and 3A4, respectively, as well as dapsone for N-acetyltransferase, in order to assess the relationship between such activities and the relative risk of recurrence of bladder cancer. Urinary recovery ratios of debrisoquine and dapsone and the R/S ratio of mephenytoin were measured in an 0-8 h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg), and the administration of dapsone (100 mg) one week later, to patients undergoing local surgical resection of transitional cell bladder cancer of G-I, G-II, or G-III histopathology. In addition, plasma levels of dapsone and mono-acetyldapsone were determined in an 8 h plasma sample to determine the N-acetylation phenotype. Patients were followed for 3 years, to the time of tumour recurrence, or death. Three patients were lost to follow-up; of the remaining 95 patients, 55 had tumour recurrence. The debrisoquine recovery ratio was significantly greater in patients with recurrence than in individuals who remained disease-free. Among the 65 patients with non-aggressive (G-I and G-II) histopathology, two patients were lost to follow-up and 32 had tumour recurrence. In this subgroup, the debrisoquine recovery ratio was again found to be significantly greater in those individuals with tumour recurrence (p < 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Acute and chronic effects of flucytosine on amphotericin B nephrotoxicity in rats.

The combination of intravenous flucytosine (FC) in 0.9% saline (NaCl) and amphotericin B (AmB) provides synergistic antifungal activity and is associated with a lower incidence of nephrotoxicity than with AmB treatment alone. This study was conducted to examine whether flucytosine can influence renal function and whether it can modify the acute and chronic renal responses to AmB in the rat. In the in situ perfused rat kidney, FC at a concentration of 10 mg/kg/min for 15 min had a vasodilator effect, increasing renal blood flow by 2.5 +/- 0.7 ml/min, an effect not observed with vehicle. After the infusion of FC was stopped for 15 min, AmB induced a decrease in renal blood flow similar to that with both FC and vehicle. In a second series of studies, AmB (5 mg/kg/day intraperitoneally) was administered to four groups of rats for 7 days. In addition, the following groups received the intravenous daily interventions indicated: group 1, 5% dextrose in water (15 ml/kg/12 h); group 2, FC (150 mg/kg/12 h) in 0.9% saline (15 ml/kg/12 h); group 3, 0.9% saline (15 ml/kg/12 h); and group 4, FC (150 mg/kg/12 h) in 5% dextrose in water. Group 1 sustained a 77% decrease in creatinine clearance over the 7 days and a threefold increase in serum creatinine concentration (P of < 0.05). Groups 2, 3, and 4 sustained significantly less nephrotoxicity, with no change in serum creatinine concentration and only 38, 41, and 53% decreases in creatinine clearance, respectively (P of < 0.05), compared with that for group 1. AmB levels in renal tissue varied inversely to creatinine clearance (r of 0.57, P of < or = 0.005). However, no significant differences were found in levels in tissue between groups (P of 0.06). The results of this study suggest that FC has a small but significant effect in reducing chronic AmB-induced nephrotoxicity. This amelioration of renal injury is independent of saline administration. There was evidence that the extent of renal uptake of AmB related to the efficiency of renal function at the end of the experiment.

Amphotericin B↗
PubMed1992

Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. Part I: History, neuropsychological findings and chelator effects.

Mercury poisoning occurred after the acute, prolonged exposure of 53 construction workers to elemental mercury. Of those exposed, 26 were evaluated by clinical examination and tests of neuropsychological function. Patients received treatment with chelation therapy in the first weeks after exposure. Eleven of the patients with the highest mercury levels were followed in detail over an extended period. Observations included the evaluation of subjective symptoms of distress, using the 'Symptom Check List 90-Revised' (SCL-90R) and tests of visual-motor function such as 'Trailmaking Parts A and B', 'Finger Tapping', 'Stroop Colour Word Test' and 'Grooved Pegboard.' On day 85 +/- 11 (mean +/- s.d.) after exposure, these 11 men again received either 2,3-dimercaptosuccinic acid (DMSA) or N-acetyl-D, L-penicillamine (NAP) in a short-term study designed to compare the potential to mobilize mercury and the incidence of drug-induced toxicity of these two chelating agents. Rapidly resolving metal fume fever was the earliest manifestation of symptoms. CNS symptoms and abnormal performance on neuropsychological tests persisted over the prolonged period of follow-up. There were significant correlations between neuropsychological tests and indices of mercury exposure. Serial mercury in the blood and urine verified the long half-life and large volume of distribution of mercury. Chelation therapy with both drugs resulted in the mobilization of a small fraction of the total estimated body mercury. However, DMSA was able to increase the excretion of mercury to a greater extent than NAP. These observations demonstrate that acute exposure to elemental mercury and its vapour induces acute, inorganic mercury toxicity and causes long-term, probably irreversible, neurological sequelae.

Adult↗
PubMed1992

Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. Part II: Hyperchloraemia and genitourinary symptoms.

Exposure to elemental mercury vapour is known to influence renal function; however, severe renal disease has not been consistently identified. Eleven men were evaluated for renal disease after acute, massive mercury poisoning. Significant hyperchloraemia was identified in this group of patient and a reversible renal tubular defect was suggested by low normal serum bicarbonate, a normal serum anion gap and a positive urinary anion gap. The only other evidence of renal dysfunction was transient, mild proteinuria in one of the 11 patients. During this same time period, neuropsychological impairment was identified on a test of cognitive and visual-motor function, 'Trailmaking B', in seven of the 11 patients. Additionally, dysuria and ejaculatory pain occurred without evidence of urological disease. These complaints were more frequent in those patients with impairment on 'Trailmaking B' suggesting a neurological basis for these symptoms. The findings of this study support earlier observations that the brain rather than the kidney is the critical target organ after elemental mercury vapour exposure.

Adult↗
PubMed1992

Angiotensin II facilitates tricyclic antidepressant-induced changes in QRS-duration in the rat.

Experimental evidence indicates that angiotensin II can modulate sodium channel and gap junction function. This raises the possibility that variations in angiotensin II could alter the effect of drugs that act on these mechanisms. In this study, the influence of changing salt status and angiotensin II activity has been investigated by evaluating the QRS prolonging effects of the sodium channel blocking drug, desmethylimipramine. In control rats with a normal salt intake, intravenous infusion of desmethylimipramine (0.8 mg/kg/min) over 60 min increased QRS duration over time to 150% of control by 60 min; mean arterial blood pressure and pulse rate were decreased. In salt-deplete rats, the response to desmethylimipramine was similar to controls for 30 min. Thereafter, QRS duration increased more rapidly than controls. In rats on a high salt diet, the same desmethylimipramine infusion produced no change in QRS duration for 30 min, despite equivalent reductions in mean arterial blood pressure. Thereafter, QRS duration increased, reaching values similar to control by 60 min. In rats on a normal salt diet pretreated with captopril, there was a similar blunting of the QRS response to desmethylimipramine to that observed in salt-loaded rats. The QRS response to desmethylimipramine and salt-loaded rats on normal salt diets receiving captopril returned to the control pattern after a subpressor infusion of angiotensin II (3 ng/min), while a higher rate of angiotensin II (10 ng/min) further enhanced the QRS prolonging effect of desmethylimipramine. These data demonstrate that endogenous angiotensin II contributes to the regulation of the cardiac electro-physiological response to DMI.

Angiotensin II↗