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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 109 records · Page 6Linked to original sources
PubMed1988

Carbaryl metabolism is inhibited by cimetidine in the isolated perfused rat liver and in man.

The potential for cimetidine to alter the metabolism of carbaryl has been investigated in the isolated perfused rat liver and in man. In the isolated perfused rat liver, carbaryl was removed by a high intrinsic clearance process, which was inhibited in a dose dependent fashion by cimetidine in the concentration range of 60-240 micrograms/ml. The pharmacokinetic profile in one subject for orally administered carbaryl was altered following administration of cimetidine (200 mg every eight hours for three days). The peak carbaryl level occurred 25 minutes later and was increased by twofold, due to a 46% reduction in apparent oral clearance. The observations indicate that cimetidine can inhibit the metabolism of carbaryl in both rat and man. These data suggest that administration of cimetidine to individuals exposed to carbaryl could result in enhanced toxicity.

Adult↗
PubMed1988

Liver volume measurements and three-dimensional display from MR images.

A method was investigated for measuring the volumes of human livers in vivo from magnetic resonance images and subsequently displaying these livers in three dimensions. Volumetric image sets of phantoms, healthy volunteers, and patients with cirrhotic livers were processed. Two image-processing approaches were compared for accuracy of liver measurements, intrasubject and interobserver variation, and speed of processing. Results indicated that both processing methods had a high degree of volume-measuring accuracy (within 8%), the interobserver measurements had a high coefficient of correlation (r = .9994), the intrasubject measurements had a low coefficient of variation (1.8%), and one method was four to five times faster than the other. The faster and easier of the two image-processing approaches provided satisfactory results for measuring liver volumes, but the slower approach provided more realistic-looking three-dimensional images of the liver.

Humans↗
PubMed1988

Adenosine in renin-dependent renovascular hypertension.

Our previous studies support the hypothesis that activation of the renin-angiotensin system by renal ischemia elevates adenosine levels and that adenosine acts in a negative feedback loop to limit renin release and to mitigate some of the hypertension-producing effects of angiotensin II. To further test this hypothesis, we compared the time course of caffeine-induced increases in plasma renin activity with the time course of changes in plasma levels of adenosine in two models of renin-dependent renovascular hypertension. Also, we compared the effects of caffeine on plasma renin activity and arterial blood pressure in renin-dependent versus renin-independent renovascular hypertension. In comparison to sham-operated rats, plasma levels of adenosine in the left and right renal veins and aorta were elevated severalfold in two-kidney, one clip rats (2K1C) 1 week after left renal artery clipping. However, adenosine levels declined during the second and third weeks after clipping. In 2K1C rats treated chronically with caffeine, plasma renin activity was markedly elevated during the first week after operation as compared to non-caffeine-treated 2K1C rats. However, during the second and third weeks after clipping, caffeine had lesser effects on plasma renin activity. A temporal relationship between plasma adenosine levels and caffeine-induced hyperreninemia was also observed in rats with aortic ligation. Caffeine accelerated hypertension in 2K1C rats and rats with aortic ligation (renin-dependent renovascular hypertension), but it had no effect on plasma renin activity or blood pressure in one-kidney, one clip rats (renin-independent renovascular hypertension). These results lend further support to the hypothesis that adenosine functions to mitigate the renin-angiotensin system in renin-dependent renovascular hypertension.

Adenosine↗
PubMed1988

Prevention of amphotericin B-induced renal impairment. A review on the use of sodium supplementation.

Amphotericin B is the treatment of choice for most deep-seated mycoses; however, doses may have to be limited because of concern over adverse effects such as nephrotoxicity. Evolving evidence suggests that the extent of amphotericin B-induced renal impairment may be modified via alteration of a normal physiologic feedback response that further contributes to changes due to direct nephrotoxicity. As such, renal impairment has a substantial theoretically preventable and reversible element. In animals exposed to amphotericin B, sodium loading interferes with this response. Mounting clinical evidence also supports the usefulness of sodium supplementation to prevent as well as to reverse amphotericin B-induced nephrotoxicity. At this time, the use of sodium supplementation (eg, intravenous saline and/or ticarcillin disodium, which contains 5.2 mEq of sodium per gram of drug) along with avoiding dehydration appears to be a safe and effective means of reducing the risk of nephrotoxicity associated with amphotericin B administration; however, it is not known whether renal changes can be entirely prevented. These preliminary observations merit confirmation in a prospective, randomized clinical trial.

Amphotericin B↗
PubMed1988

Brain uptake of benzodiazepines: effects of lipophilicity and plasma protein binding.

The rapid intracarotid injection technique was used to determine the unidirectional brain uptake of a number of benzodiazepines in the rat. The drugs varied considerably in their lipophilicity and, within the series oxazepam, lorazepam, chlordiazepoxide, desmethyldiazepam and diazepam, brain extraction of unbound moiety was enhanced as the octanol-water (pH = 7.4) partition coefficient increased. However, with flunitrazepam and midazolam, two fluorine-containing benzodiazepines, extraction was more and less extensive, respectively, than predicted from their lipophilicities. Importantly, the uptake findings were consistent with the characteristic onsets of central effects of the drugs established clinically in humans. The effects of reversible protein binding on uptake also were investigated by the addition of albumin (0-8 g.dl-1) to the injectate. This affected markedly the unbound fraction, determined in vitro by equilibrium dialysis, and also the brain uptake of all drugs. As the unbound fraction was reduced, the unidirectional brain extraction ratio decreased in a curvilinear fashion toward zero. However, attempts to describe the data were unsuccessful using a conventional model based on transcapillary uptake of only unbound drug whose binding kinetics with albumin were assumed to be the same as those indicated by equilibrium dialysis. The observed brain extraction was greater than predicted, and the discrepancy became more apparent as binding and albumin concentration increased. The data for all of the benzodiazepines could be fitted, however, if the equilibrium association constant was assumed to be smaller in vivo than in vitro, so that the effective unbound fraction in the brain capillaries was substantially higher (5- to 25-fold, dependent on the particular drug) than that estimated in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Genetic predisposition to bladder cancer: ability to hydroxylate debrisoquine and mephenytoin as risk factors.

The hypothesis that the frequency distribution of indices of oxidative drug-metabolizing activity is different between patients with bladder cancer (n = 98) and age, sex-matched control subjects (n = 110) has been investigated. Urinary recovery ratios of debrisoquine and R/S ratios of mephenytoin have been measured in an 8-h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg). In addition, alcohol consumption, smoking habit, and acetylation phenotype (using 100 mg dapsone as a substrate) have been measured. Patients with bladder cancer were classified on histological criteria as having aggressive (Stage III) (34%) or nonaggressive (Stages I and II) (66%) disease. The median of the frequency distribution of the debrisoquine urinary recovery ratio in patients with aggressive bladder cancer was greater than in control subjects, and only four patients had recovery ratios lower than the mean of the control group. Using logistic regression analysis, efficient debrisoquine metabolism and a synergistic interaction between smoking and ethanol consumption were significant, independent risk factors, while S-mephenytoin hydroxylation and acetylation phenotype were not significant risk factors. In contrast, patients with non-aggressive bladder cancer had a significant, but weaker, association with rapid hydroxylation of S-mephenytoin, which was independent of a significant synergistic interaction between smoking and alcohol consumption. Acetylation phenotype and debrisoquine urinary recovery ratio were not associated with increased risk of nonaggressive cancer. These results are consistent with the concept that oxidative isozymes might be responsible for conversion of environmental agents to proximate bladder carcinogens in nonindustrial-related bladder cancer. They also suggest that different etiological factors are involved in the pathogenesis of aggressive and nonaggressive bladder cancer.

Acetylation↗
PubMed1987

Amphotericin-B nephrotoxicity in humans decreased by sodium supplements with coadministration of ticarcillin or intravenous saline.

Previous observations suggest that salt loading can help reverse amphotericin-B induced nephrotoxicity. Evidence is presented indicating that sodium supplements provide prophylaxis against the development of amphotericin-B nephrotoxicity. In a retrospective study at Vanderbilt University, 14/21 patients receiving amphotericin B (target dose, 25 mg/day) without salt supplements developed impaired renal function; in 10 instances amphotericin B was temporarily withdrawn. In contrast, only 2/17 patients who received amphotericin B with ticarcillin (with its obligatory sodium supplement) developed nephrotoxicity (P less than 0.01). All four patients, who were receiving the combination of amphotericin B and ticarcillin and who had their ticarcillin therapy stopped, developed nephrotoxicity in the subsequent week. In a prospective observational study at Essen, 20 patients had 24 courses of amphotericin B (target dose, 40 mg/day) with routine supplementation of 1 liter of 0.9% sodium chloride daily. Only two patients showed evidence of nephrotoxicity and no dosage modification of amphotericin B was required in any patient. Four patients with initial evidence of mildly impaired renal function received full supplements without adverse effects or the development of nephrotoxicity. These observations suggest that routine parenteral administration of sodium supplements can help minimize the nephrotoxic potential of amphotericin B.

Amphotericin B↗
PubMed1987

S-mephenytoin 4-hydroxylase is inherited as an autosomal-recessive trait in Japanese families.

The 4-hydroxylation of S-mephenytoin exhibits polymorphism in both whites and Japanese such that the populations can be divided into extensive and poor metabolizers. To determine whether genetic constitution is a primary determinant in the expression of such metabolism, four extended Japanese families containing 13 sets of parent/offspring relationships were phenotyped for their mephenytoin 4-hydroxylation activity using the 8-hour urinary ratio of unchanged R- and S-mephenytoin as the trait measurement. The incidence of the poor metabolizer phenotype in these families was 2.2 times greater than that in an unrelated Japanese population. In three families in which both parents were poor metabolizers of mephenytoin, all six children also exhibited the poor metabolizer trait. The phenotype distribution for each family studied was consistent with the hypothesis that mephenytoin 4-hydroxylation activity is under diallelic, monogenic control, with the poor metabolizer phenotype being the autosomal recessive homozygous genotype and the extensive metabolizer phenotype including both the autosomal dominant and heterozygous genotypes.

Alleles↗
PubMed1987

Intrarenal hypertonic saline infusions in dogs with thoracic caval constriction.

Intrarenal artery infusions of hypertonic saline can activate tubuloglomerular feedback (TGF), decreasing renal blood flow (RBF) and glomerular filtration rate (GFR). The response to infusion of hypertonic saline is enhanced by salt depletion and attenuated by salt loading, but has not previously been investigated in pathophysiological states where expanded extracellular fluid volume due to salt retention is associated with avid, renal sodium reabsorption. The renal response following intrarenal infusions of hypertonic saline was investigated in five control dogs and eleven dogs with partial constriction of the thoracic portion of their inferior vena cava, which resulted in salt retention and the formation of ascites. Intrarenal infusion of hypertonic saline induced significant reductions in RBF and GFR in both control and caval constricted dogs. The extent of these reductions were positively correlated with baseline renal function. An intravenous infusion of 50 ml/kg of 0.9% sodium chloride, which abolished the vasoconstrictor response in normal dogs, failed to abolish the decrease in RBF and GFR in response to intrarenal hypertonic saline infusion in dogs with ascites which had an initial vasoconstrictor response. We conclude that the potential for TGF is preserved in early stages of caval constriction syndrome in dogs, but that this potential activity decreases when basal renal function decreases.

Animals↗
PubMed1987

Vancomycin entry into lung lymph in sheep.

The distribution of antibiotics into target tissues is a crucial factor in therapeutic efficacy. To estimate the availability of systemically administered vancomycin to the interstitial fluid in the lung, we have used a sheep model with a chronic pulmonary lymph fistula to collect simultaneously series of plasma and pulmonary lymph specimens during a 6-h period after an intravenous dose of vancomycin (7 mg/kg). After a minor delay in transit from blood to lymph, vancomycin was completely distributed to pulmonary lymph with a ratio of free drug in lymph to free drug in plasma of 0.9. This suggests that vancomycin is an excellent choice for treating pulmonary infections by susceptible organisms.

Animals↗
PubMed1987

Adenosine inhibits beta-adrenoceptor but not DBcAMP-induced renin release.

The purpose of these studies was to assess the direct effect of adenosine on the renin release response to beta-adrenoceptor activation in vivo in the canine kidney. In an initial study, innervated, intrarenal beta-adrenoceptors were activated selectively via renal nerve stimulation in kidneys in which the alpha-adrenoceptor response to renal nerve stimulation had been blocked with phentolamine. Adenosine, infused directly into the renal artery (10 and 30 micrograms/min), significantly blunted the renin release response to renal nerve stimulation. However, adenosine also caused significant reductions in base-line glomerular filtration rate, sodium excretion rate, and filtration fraction. To eliminate these confounding effects of adenosine on renal function and to prevent changes in norepinephrine release due to prejunctional inhibition by adenosine, we also studied the effect of intrarenal infusions of adenosine on norepinephrine-induced renin release in the nonfiltering, alpha-adrenoceptor-blocked, canine kidney. In this model of beta-adrenoceptor activation, adenosine abolished the renin release response to intrarenal infusions of norepinephrine. In a final series of experiments, the effect of adenosine on the renin response to dibutyryl-adenosine 3',5'-cyclic monophosphate (cAMP) was examined in the nonfiltering, beta-adrenoceptor-blocked, canine kidney. In this model of cAMP-induced renin release, adenosine was ineffective in attenuating the renin release response. These data demonstrate that in vivo adenosine directly inhibits beta-adrenoceptor-mediated renin release by a mechanism that does not involve a reduction in the ability of cAMP to activate intracellular mechanisms leading to renin release.

Adenosine↗
PubMed1987

Effects of atrial natriuretic factor on hormone-induced renin release.

The purpose of this study was to determine whether or not atrial natriuretic factor can act directly on the juxtaglomerular cell in vivo to inhibit hormone-induced renin release. To achieve this objective the interaction between synthetic atrial natriuretic factor and two different renin secretagogues was examined. To exclude any indirect effect of atrial natriuretic factor on renin release due to changes in sodium delivery to the macula densa, all studies were conducted in nonfiltering, canine kidneys. In one series of studies renin release was stimulated by intrarenal infusions of norepinephrine (3 micrograms/kg/min), and in a second series of studies renin release was induced by intrarenal infusions of prostacyclin (0.1 micrograms/kg/min). In both studies intrarenal infusions of atrial natriuretic factor (0.3 micrograms/kg/min), which provided supraphysiological levels of atrial natriuretic factor in the renal arterial plasma, failed to attenuate hormone-induced renin release. In contrast, adenosine, a well-known inhibitor of renin release, abolished the renin release response to both hormones. These data indicate that, at the dose used in this study, synthetic atrial natriuretic factor does not act directly on the juxtaglomerular cell to attenuate hormone-induced renin release. Further, these results imply that circulating endogenous atrial natriuretic factor cannot directly attenuate juxtaglomerular cell responsiveness.

Adenosine↗
PubMed1987

Caffeine enhances the slow-pressor response to angiotensin II in rats. Evidence for a caffeine-angiotensin II interaction with the sympathetic nervous system.

The purpose of this study was to determine if caffeine augments the slow-pressor response to chronic low-dose infusions of angiotensin II (AII) or the rapid-pressor response to acute infusions of AII. AII was infused (125 ng/min i.p.) for 12 d via mini-osmotic pumps in four groups of rats: group I, intact rats not treated with caffeine (n = 9); group II, intact rats treated with caffeine (0.1% in drinking water, n = 9); group III, rats previously sympathectomized with 6-hydroxydopamine, but not treated with caffeine (n = 10); and group IV, rats previously sympathectomized with 6-hydroxydopamine and treated with caffeine (n = 10). Chronic low-dose AII infusions slowly elevated systolic blood pressure in all groups. Caffeine greatly augmented this slow-pressor response to AII in intact animals; however, caffeine failed to enhance AII-induced hypertension in sympathectomized rats. Caffeine pretreatment did not enhance the rapid-pressor response to acute intravenous infusions of AII. We conclude that caffeine augmented the slow-pressor effect of chronic low-dose infusions of AII via a mechanism that involved the sympathetic nervous system.

Angiotensin II↗
PubMed1987

Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes.

The in vivo metabolism in humans of the anticonvulsant mephenytoin exhibits stereoselectivity as well as genetic polymorphism of the 4-hydroxylation pathway. The characteristics of the involved cytochrome P-450 isozyme are, however, not known completely. Accordingly, the ability of human liver microsomes to metabolize mephenytoin and its enantiomers was investigated in vitro, and the ability of related anticonvulsants and other compounds to inhibit 4-hydroxylation was studied. Marked stereoselectivity was observed in the conversion of S-mephenytoin to its 4-hydroxy metabolite, but N-demethylation was essentially similar for both enantiomers. The intrinsic clearance (Vmax/Km) for 4-hydroxymephenytoin formation showed an almost 10-fold range in five livers and was 150- to 1000-fold greater than that for N-demethylation. Competitive inhibition of 4-hydroxylation was observed with ethotoin, mephobarbital, methsuximide and phensuximide, but not other commonly used anticonvulsants such as ethosuximide, phenobarbital, phenytoin and primidone. However, synthetic N-alkyl analogs of the latter compounds were found to be inhibitory. An aryl residue alpha to the carbonyl carbon of an N-alkyl lactam in a 5- or 6-membered ring, therefore, appears to be a minimal requirement for strong interaction with the 4-hydroxylase. Warfarin, but not diazepam, ketoconazole or iodochlorohydroxyquin, were also competitive inhibitors, but at much higher concentrations than the anticonvulsants. Competitive inhibition at concentrations similar to the Km of 4-hydroxymephenytoin formation (30-350 microM) may indicate that the isozyme is involved in the metabolism of the substrates under consideration and, therefore, their in vivo metabolism may be regulated to some extent by the same genetic factor(s) that determine mephenytoin's biotransformation.

Anticonvulsants↗
PubMed1987

Effect of cyclooxygenase and thromboxane synthase inhibition on the response to angiotensin II in the hypoperfused canine kidney.

The potential for endogenous prostaglandin production to modulate the renal vascular response to intrarenal infusions of angiotensin II (AII) was investigated in the canine kidney at varying renal perfusion pressures (RPP), using suprarenal aortic constriction to vary RPP. AII, infused to achieve increments in renal arterial plasma concentrations of 300 pg/ml, induced reductions in renal blood flow (RBF) and glomerular filtration rate (GFR) when RPP was 80 mm Hg or above. When RPP was reduced to 60 mm Hg, AII decreased RBF, but GFR failed to change. The vasoconstrictor response to AII was enhanced by indomethacin (8 mg/kg) at all perfusion pressures, but was not modified by the thromboxane (Tx) A2 synthase inhibitor, UK 38,485 (1 mg/kg). In contrast, the lack of change in GFR in response to AII at a RPP of 60 mm Hg was converted to a significant reduction by both indomethacin and UK 38,485. These observations are consistent with the hypothesis that the effect of AII on RBF is attenuated by renal release of vasodilator prostaglandins at all RPP. However, at low RPP, AII infusion also induces the release a factor that increases GFR. As this response can be prevented by both TxA2 synthase and cyclooxygenase inhibition, it is possible that this factor is TxA2.

Angiotensin II↗
PubMed1987

[Prevention of nephrotoxicity of amphotericin B during the treatment of deep candidiasis].

Previous observations suggest that tubulo-glomerular feedback could be involved in amphotericin B nephrotoxicity. We then investigated the influence of sodium status on the occurrence of renal damage during amphotericin B therapy. A retrospective survey demonstrated that impaired renal function occurred during therapy in 67 per cent of the patients who received amphotericin B alone and in 12 per cent of the patients who received amphotericin B and ticarcillin (parenteral sodium supplement of 100-150 meq per day). Prospective studies were then undertaken both in adults and children. Intravenous sodium supplement was given intravenously as routine prophylaxis with amphotericin B therapy. In all courses amphotericin B was successfully administered without deterioration in renal function. These results support the hypothesis that parenteral sodium supplementation reduces the frequency of developing impaired renal function during amphotericin B therapy.

Adult↗