Biomedical subjects

F G Russel

Publications and source records attributed to F G Russel.

At least 55 records · Page 3Linked to original sources

PubMed1996

Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: pharmacokinetic analysis and relationship to clinical response.

1. The influence of sulphasalazine (SASP) on the pharmacokinetics of low dose methotrexate (MTX) and the relation between pharmacokinetic variables and clinical response was studied in 15 patients with active rheumatoid arthritis despite > 6 months of SASP treatment. 2. SASP was stopped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was administered after a standard breakfast. Blood was sampled initially every 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks the same procedure was repeated supplemented with concomitant administration of 1000 mg SASP. Clinical measurements included Ritchie articular index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two-compartment model with first order absorption and lag time. Results are given as mean (s.d.). Paired t-test or signed rank test were applied in the statistical analysis. 3. Pharmacokinetics of MTX without vs with SASP, means +/- s.d. were follows: AUC: 673 +/- 179 vs 628 +/- 210 (95% confidence interval [CI] of the difference was -71 to 159) ng ml-1, MRT: 5.2 +/- 1.3 vs 5.2 +/- 1.1 (95% CI -0.4 to 0.4) h, t1/2,z: 4.3 +/- 1.1 vs 4.2 +/- 1.1 (95% CI -0.3 to 0.5) h, V/F: 59.3 +/- 29.3 vs 65.5 +/- 25.3 (95% -23.8 to 11.4) 1, CL/F: 12.3 +/- 5.0 vs 13.5 +/- 4.8 (95% CI -4.5 to 2.3) 1 h-1. CLR/F: 6.2 +/- 1.3 vs 6.3 +/- 2.1 (95% CI -1.3 to 1.1) l h-1. All P values were > or = 0.3. 4. A weak correlation existed between the change of ESR and the MRT, the t1/2,z and the V/F (Spearman correlation coefficients of 0.43, 0.50 and 0.50 respectively, 0.05 < P < 0.1). 5. There is no significant influence of chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consistently with some pharmacokinetic variables on MTX.

Antirheumatic Agents↗

PubMed1996

Effects of tolbutamide on vascular ATP-sensitive potassium channels in humans. Comparison with literature data on glibenclamide and glimepiride.

Sulfonylurea (SU) derivatives exert their hypoglycemic effect by blockade of adenosine-5'-triphosphate-sensitive potassium (KATP) channels in the beta-cell of the pancreas. Interestingly, KATP channels also occur in the cardiovascular system, where they are thought to play an important role in cardioprotective mechanisms against ischemia. We have recently shown that the classical second generation SU-derivative glibenclamide is able to block vascular KATP channels in man, whereas the newly developed second generation derivative glimepiride was devoid of this property. The aim of this study was to determine whether the first generation SU derivative tolbutamide has KATP channel blocking properties in humans. In a group of 12 healthy male non-smoking volunteers, we investigated whether therapeutic concentrations of tolbutamide were able to inhibit the forearm vasodilation in response to the infusion of the KATP channel opening drug diazoxide into the brachial artery. Changes in forearm blood flow were recorded by venous occlusion mercury-in-silastic strain-gauge plethysmography. Diazoxide alone increased the forearm blood flow ratio dose-dependently by ultimately 691 +/- 198%. A second diazoxide infusion in the presence of tolbutamide revealed a comparable vasodilator response with a percentage increase in forearm blood flow ratio of ultimately 542 +/- 111%. This response did not differ from the vasodilator response to diazoxide alone. The present study shows that therapeutic concentrations of tolbutamide are not able to attenuate the vasodilation caused by the KATP channel opener diazoxide in man. When compared with published data on second generation SU derivatives, tolbutamide shows an intermediate position between glibenclamide (with significant blockade of vascular KATP channels) versus glimepiride (with no blockade at all). It remains to be determined whether these acute effects of SU derivatives on pharmacological opening of forearm vascular KATP channels can be extrapolated to the chronic effects of these drugs on ischemia-mediated opening of myocardial KATP channels during treatment of NIDDM patients.

Adenosine Triphosphate↗

PubMed1996

Glomerular filtration and saturable absorption of iohexol in the rat isolated perfused kidney.

1. The renal handling of iohexol was examined in the rat isolated perfused kidney (IPK) over a perfusate concentration range of 5-20 micrograms ml-1. 2. At a concentration of 5 micrograms ml-1, a ratio of renal clearance over clearance by glomerular filtration (ClR/GF) of 0.63 +/- 0.06 could be determined. This ratio increased until 1.02 +/- 0.06 at 20 micrograms ml-1, indicating that a saturable mechanism is involved in the luminal disappearance of the drug. 3. Pretreatment of the kidneys with polylysine, probenecid or diatrizoate resulted in a significantly enhanced clearance of iohexol, probably due to inhibition of membrane binding. Renal clearance data were fitted to a kinetic model including filtration into the primary urine followed by saturable absorption at the luminal membrane. An absorption constant, KA, of 7.3 +/- 1.3 micrograms ml-1, and a maximum rate of absorption, VA,Max, of 1.4 +/- 0.1 micrograms min-1 were determined. 4. Iohexol accumulated in kidney tissue, reaching a concentration of 2 to 7.5 times the perfusate concentration. In freshly isolated proximal tubular cells and kidney cortex mitochondria, iohexol reduced the uncoupled respiratory rate at a concentration comparable to the highest tissue concentration found in the IPK. 5. In conclusion, iohexol is not only filtered by the kidney but also reabsorbed via a saturable mechanism, which results in tubular accumulation. Intracellularly sequestered iohexol may affect mitochondrial oxidative metabolism. Our results indicate that iohexol is not a true filtration marker.

Animals↗

PubMed1996

Renal excretion and accumulation kinetics of 2-methylbenzoylglycine in the isolated perfused rat kidney.

The effect of protein binding on kidney function has been studied by investigating the renal accumulation and secretion of the hippurate analogue 2-methylbenzoylglycine in the isolated perfused rat kidney in the absence and presence of bovine serum albumin (BSA). Experiments were performed with either 2.5% pluronic or a combination of 2.2% pluronic and 2% BSA as oncotic agents; a wide concentration range (1-190 micrograms mL-1) of 2-methylbenzoylglycine was studied. Tubular secretion appeared to be a function of the amount of unbound drug in the perfusate and was best described by a model consisting of a high and low affinity Michaelis-Menten term. Parameters obtained after the analysis of renal excretion data were maximum transport velocity for the high affinity site (TM,H) = 3.0 +/- 2.8 micrograms min-1, Michaelis-Menten constant for tubular transport for the high affinity site (KT.H) = 0.5 +/- 0.8 microgram mL-1, maximum transport velocity for the low affinity site (TM,L) = 250 +/- 36 micrograms min-1, and Michaelis-Menten constant for tubular transport for the low affinity site (KT,L) = 62 +/- 17 micrograms mL-1. The compound accumulated extensively in kidney tissue, ratios up to 175 times the perfusate concentration were reached. Accumulation data were best analysed by a two-site model similar to the model used to describe renal excretion. Calculated parameters were theoretical maximum capacity of the high affinity site (RM,H) = 26 +/- 23 micrograms g-1, affinity constant for renal accumulation at the high affinity site (KA,H) = 0.2 +/- 0.4 microgram mL-1, theoretical maximum capacity of the low affinity site (RM,L) = 1640 +/- 1100 micrograms g-1 and affinity constant for renal accumulation at the low affinity site (KA,L) = 60 +/- 58 micrograms mL-1. The very high accumulation in kidney tissue could be explained by active tubular uptake, mediated by the secretory mechanisms involved, and dependent on the amount of free drug in the perfusate. This study shows that anionic drugs, subject to active secretion, may reach high concentrations in tubular cells even at low plasma concentrations.

Animals↗

PubMed1996

Multiple pathways of organic anion secretion in renal proximal tubule revealed by confocal microscopy.

Previous studies with p-aminohippurate (PAH) and fluorescein (FL) have shown that cellular uptake and tubular secretion of organic anions is driven by indirect coupling to sodium. Here we used killifish proximal tubules and laser-scanning confocal microscopy to study the transport of a larger organic anion, fluorescein-methotrexate (FL-MTX, mol mass 923 Da). When tubules were incubated in medium containing 2 microM FL-MTX, dye accumulated in both cells and tubular lumens. At steady state, luminal fluorescence was 4-5 times higher than cellular fluorescence. Ouabain (0.1 mM) did not affect cellular or luminal fluorescence, and replacement of medium sodium by N-methylglucamine had only a modest effect; preincubation with glutarate had no effect. KCN did not affect cellular uptake but abolished secretion into the lumen. Uptake and secretion of FL-MTX were inhibited by micromolar concentrations of other organic anions (MTX, folate, probenecid, bromocresol green, bromosulfophthalein), but 1 mM PAH had a relatively small effect. FL-MTX secretion into the lumen was inhibited by leukotriene C4, cyclosporine A, and verapamil, none of which affected FL transport. Thus a substantial component of FL-MTX secretion is Na independent and ouabain insensitive. Both the basolateral and luminal steps in the Na-independent pathway differ from those usually associated with FL and PAH secretion.

Animals↗

PubMed1996

Uptake of cimetidine into syncytial microvillus membrane vesicles of human term placenta.

Uptake of the H2-receptor antagonist, cimetidine, into syncytial microvillus membrane vesicles of human term placenta was investigated to clarify whether an active transport mechanism can be responsible for the observed barrier of the human placenta for cimetidine. Imposition of an outwardly directed H(+)-gradient stimulated cimetidine uptake, resulting in a small transient overshoot. The H(+)-gradient-dependent peak uptake was decreased under voltage-clamped conditions by carbonyl cyanide p-trifluoromethoxy-phenylhydrazone, suggesting the presence of an organic cation-proton exchange mechanism. Uptake was partially, but significantly, inhibited by organic cation transport inhibitors, H2-receptor antagonists and several other cationic drugs, providing further evidence for mediated uptake. H(+)-gradient-dependent cimetidine uptake was saturable and characterized by a low-affinity (Km) of 6.3 mM and Vmax of 17.5 nmol/mg protein/10 sec. We conclude that the system cannot play an important role in the barrier function of the human placenta in the transport of cimetidine. Rather than active transport, other factors, as for instance the degree of ionization of cimetidine at physiological pH, seem to be a more likely explanation for the low clearance of cimetidine across the human placenta.

Biological Transport↗

PubMed1996

Interaction of fluorescein with the dicarboxylate carrier in rat kidney cortex mitochondria.

The interaction of the organic anion, fluorescein (FL), with mitochondria in renal proximal tubule cells was investigated. Confocal microscopy was used to demonstrate FL accumulation in mitochondria of intact cells. Phenylsuccinate inhibited the mitochondrial accumulation of the FL analog, carboxyfluorescein (CF) indicating that the dicarboxylate carrier may be involved in the intracellular compartmentation of organic anions. To characterize the interaction, radio-tracer uptake and respiration studies with renal mitochondria were carried out using succinate as a substrate. Respiration measurements in freshly isolated kidney cortex mitochondria revealed that FL inhibited ADP-stimulated and uncoupled respiratory rate, indicating that the organic anion inhibited the availability of succinate as a reducing agent. A similar effect on mitochondrial respiration was found for PAH and phenylsuccinate. FL inhibited 14C-succinate uptake concentration-dependently, and Dixon analysis revealed that the nature of interaction between FL and succinate was competitive, Ki values of 0.5 +/- 0.2 and 1.1 +/- 0.8 mM were calculated for respiration experiments and tracer uptake studies, respectively. The data demonstrate that FL competitively interacts with a mitochondrial dicarboxylate transporter.

Animals↗

PubMed1996

Pharmacokinetics and dosimetry of cobalt-55 and cobalt-57.

UNLABELLED: The isotopes 55Co and 57Co have been evaluated for PET and SPECT imaging in several clinical brain studies. For clinical application of cobalt, it is important to know the delivered radiation dose. The biodistribution of 55Co in both rat and humans after intravenous (bolus)-administration was studied. Based on pharmacokinetic data, radiation dose calculations according to the MIRD system are presented. By combining present measurements with literature data on 60CoCl2, the radiation dose delivered by 56CoCl2 (T1/2 78.8 days) and 57CoCl2 (T1/2 = 270 days) could be assessed. METHODS: Whole-body Co-PET was performed in two healthy volunteers and one rat after intravenous injection of 37 and 3.7 MBq (1 resp. 0.1 mCi) 55Co, respectively. Blood samples were withdrawn during 300 min in humans. In seven rats the 55Co-biodistribution was determined by postmortem analysis. The residence time of the liver (critical organ) was determined in rats and humans. Blood partition-data of 55Co were assessed resulting in basic pharmacokinetic data in humans. Based on these kinetic data, radiation dose was calculated using the MIRD protocol. RESULTS: In both the humans and the rat, the liver and bladder retained the highest fractions of 55Co (about 50% resp. 40% of the administered dose). The liver residence time in humans was 8.6 hr. The free fraction 55Co in the human plasma was at maximum 12%. The total-body mean transit time was 152 min. The volume of the central compartment = 2.8 liter and the steady-state distribution volume = 48 liter. CONCLUSION: From these results, according to the WHO recommendations for class II studies, 22.2 MBq (0.6 mCi) 55Co and 14.8 MBq (0.4 mCi) 57Co (excluding any radionuclide contamination) can be used.

Adult↗

PubMed1995

Inhibition of choline uptake in syncytial microvillus membrane vesicles of human term placenta. Specificity and nature of interaction.

The potency and nature of the inhibitory effect of various cationic drugs on the transport of choline across the placental syncytial microvillus membrane was investigated. Tetraethylammonium, a model substrate for organic cation transport, was a poor inhibitor. Enlarging the degree of alkylation of the quaternary ammonium increased the inhibitory effect, in proportion with increasing lipophilicity. Log concentration vs % control uptake curves showed marked differences in inhibitory potency for the different cationic drugs. Hemicholinium-3 inhibited mediated choline uptake in the micromolar range, whereas atropine and mepiperphenidol were less potent. The H2-receptor antagonists cimetidine, ranitidine, and famotidine inhibited choline uptake in the millimolar ranges. Dixon analysis revealed a competitive nature of inhibition for hemicholinium-3 and atropine (Ki = 40 microM and 1.2 mM, respectively). Cimetidine interacted noncompetitively (Ki = 3.4 mM). Since relatively high concentrations were needed to reach half maximal inhibition, impairment of fetal choline supply due to maternal drug use during pregnancy is not to be expected.

Atropine↗

PubMed1995

Pancuronium masks the prejunctional muscarinic autoreceptor in guinea pig tracheal smooth muscle.

The effect of pancuronium pretreatment on the function of the prejunctional muscarinic receptor in guinea-pig trachea was studied by using electrical field stimulation (EFS). The effects of cumulative doses of the muscarinic M2 receptor antagonist gallamine were investigated in tracheal smooth muscle strips from guinea-pigs after addition of pancuronium in vitro and in strips from guinea-pigs which had been pretreated with doses of pancuronium that caused 100% neuromuscular blockade. The results of both types of experiments were compared to those of control groups of the same size. In all strips a dose response curve with cumulative doses of methacholine was made before EFS was switched on. No differences were found between the mean pD2 value and slope of the concentration-response curves of untreated guinea-pigs and animals treated with anaesthetics and pancuronium. The animals showed variable responses to pancuronium. The bath concentration of pancuronium which decreased the EFS-induced contraction to half the original value varied between 14-61 microM. The intravenous dose necessary to paralyze the muscles, varied among the different guinea-pigs from 0.017-0.085 mg.kg-1. The EFS-induced contraction for the concentration range of gallamine 0.32 microM-0.32 mM was found to differ significantly between the strips treated with pancuronium in the organ bath and their control group. For the guinea-pigs anaesthetized and pretreated with pancuronium a significant difference with control was observed at gallamine concentrations ranging from 0.032-0.32 mM. These results show that pancuronium, added to the organ bath as well as administered intravenously to the guinea-pig, masked the inhibitory muscarinic receptor.

Animals↗

PubMed1995

Isolation of syncytial microvillous membrane vesicles from human term placenta and their application in drug-nutrient interaction studies.

The initial step in placental uptake of nutrients occurs across the syncytial microvillous membrane of the trophoblast. This study was designed to isolate syncytial microvillous membrane vesicles (SMMV) of human term placenta, to validate their purity and viability, and to investigate the interaction of several commonly used drugs with the transport of two essential nutrients: alanine and choline. SMMV were isolated according to an established procedure, but instead of homogenization the initial preparation step was replaced by mincing of placental tissue followed by gently stirring to loosen the microvilli. These modifications doubled the protein recovery and increased the enrichment in alkaline phosphatase, whereas no substantial contamination with basal membranes nor interfering subcellular organelles was found. The functional viability of the vesicles was evaluated through the transport of alanine. In accordance with literature, uptake was sodium-dependent, inhibitable by structural analogues, and saturable. A number of cationic drugs were were able to able to inhibit choline uptake, whereas no effect on alanine transport was observed. Anionic drugs, drugs of abuse, and catecholamines did not interfere with alanine transport either. In conclusion, our isolated SMMV provide a suitable tool for screening drug-nutrient interactions at the level of membrane transport. In view of the very low susceptibility of the alanine transporter to drug inhibition and the relatively high drug concentrations necessary to inhibit choline transport, it seems unlikely that clinically important drug interactions may occur with these nutrients.

Alanine↗

PubMed1995

Disposition of the bromosulfophthalein-glutathione conjugate in the isolated perfused rat kidney.

Renal elimination of the bromosulfophthalein-glutathione conjugate (BSP-GSH) after its i.v. administration in the rat in vivo is negligible. In our study we wanted to establish whether the high albumin-binding of BSP-GSH constitutes the major restrictive factor toward the urinary excretion of the compound. The renal disposition of BSP-GSH was studied in the isolated rat kidney during perfusions with or without albumin in the perfusate. The urinary clearance of BSP-GSH in the absence of albumin was very low (< 60 microliters/min) as compared to the inulin clearance (approximately 300 microliters/min). This indicates that albumin-binding is not the major reason for the low urinary clearance of BSP-GSH. Addition of albumin to the perfusate further decreased the urinary excretion by 60%. BSP-GSH is metabolized by the kidney into two major metabolites: the cysteinylglycine conjugate and the di-glutathione conjugate. Both metabolites appear in perfusate, which suggests that BSP-GSH undergoes tubular (re-)uptake. The di-glutathione conjugate is further metabolized to the di-cysteinylglycine conjugate. The di-glutathione conjugate and the di-cysteinylglycine conjugate are the major urinary components and the urinary elimination of BSP-GSH may depend on their formation. Inhibition of gamma-glutamyl transpeptidase activity with acivicin largely prevented the degradation to the cysteinylglycine and dicysteinylglycine conjugates of BSP. The total rate of urinary excretion, however, was only slightly lowered by acivicin. Apparently, cleavage of the gamma-glutamyl moiety is not relevant for the total urinary elimination of BSP-GSH.

Albumins↗

PubMed1995

Hydrochlorothiazide exerts no direct vasoactivity in the human forearm.

BACKGROUND: Recently, hydrochlorothiazide has been shown to relax vascular smooth muscle in vitro in clinically relevant concentrations by the opening of calcium-activated potassium channels, leading to hyperpolarization and consequent closing of voltage-operated calcium channels. Long-term administration of hydrochlorothiazide reduces peripheral vascular resistance in vivo in man. These results indicate that hydrochlorothiazide has hemodynamic activity, and we therefore examined the direct vascular action of this drug in vivo. SUBJECTS AND METHODS: Forearm vasodilator responses to the infusion of a placebo and five increasing doses of hydrochlorothiazide into the brachial artery were recorded by venous occlusion strain-gauge plethysmography (perfused forearm technique) in eight normotensive male volunteers. Venous samples were taken from an ipsilateral antecubital vein at the end of each infusion period to measure the hydrochlorothiazide concentration. RESULTS AND DISCUSSION: Plasma concentrations of hydrochlorothiazide averaged 3.5 +/- 0.3 mu g/ml at the highest infusion rate. This concentration leads to a 60 +/- 10% relaxation in vitro and is more than 10 times the therapeutic plasma concentration. Despite these supratherapeutic levels, we were unable to demonstrate a change in forearm blood flow and vascular resistance. Also, no significant changes were observed in blood pressure and heart rate. CONCLUSION: In contrast to in vitro results, hydrochlorothiazide does not exert any direct vasoactivity in the forearm vascular bed of healthy normotensive male volunteers at (supra)therapeutic plasma concentrations.

Antihypertensive Agents↗

PubMed1994

Ion-pair solid-phase extraction of cimetidine from plasma and subsequent analysis by high-performance liquid chromatography.

An improved method is described for the solid-phase extraction of cimetidine from plasma or serum with subsequent analysis by HPLC. New aspects of the method include protein precipitation with metaphosphoric acid (5%, w/v), followed by selective adsorption of cimetidine and the internal standard ranitidine on the surface of a solid-phase phenyl (PH Bond Elut) column, using octanesulfonate as an ion-pairing agent. Separation was achieved on a LiChrosorb RP-18 column with a mobile phase consisting of acetonitrile-0.01 M phosphate buffer pH 3.0 containing 0.005 M octanesulfonate (22:78, v/v). The intra-assay coefficient of variation varied between 0.7 and 4.0%. The procedure provides cleaner and more stable samples and a better recovery (90 +/- 2.3%) and sensitivity (limit of detection 5 ng/ml and limit of quantitation 25 ng/ml) as compared with previous methods.

Chromatography, High Pressure Liquid↗

PubMed1994

Uptake of choline into syncytial microvillus membrane vesicles of human term placenta.

The uptake of the quaternary ammonium compound choline was studied in syncytial microvillus membrane vesicles of human term placenta. Uptake was stimulated by an inside negative membrane potential and by loading the vesicles with unlabeled choline. Imposition of an inwardly directed Na+ or outwardly directed H+ gradient did not stimulate choline uptake. Several organic cations were able to inhibit choline transport in the following order: hemicholinium-3 > or = choline > or = mepiperphenidol > cimetidine > or = famotidine. The kinetics of uptake involved a saturable process for choline with high affinity (Km = 550 microM). Our results confirm the presence of a carrier mediated transport system in human placental syncytial microvillus membranes. The system appears to be electrogenic, and able to transport choline efficiently from the maternal circulation into the placenta.

Biological Transport↗

PubMed1994

p-aminohippurate uptake by syncytial microvillous membrane vesicles of human term placenta.

The mechanism of uptake of p-aminohippurate (PAH) by syncytial microvillous membrane vesicles of human term placenta was investigated. Initial PAH uptake and efflux were increased in the presence of a pH-gradient and a Cl(-)-gradient, respectively. Forced negative and positive membrane potentials did not influence the uptake, which indicated that the transport is not electrogenic. The pH-dependent increase is probably the result of a higher rate of diffusion due to a lower degree of dissociation of PAH. Because several organic anions failed to transstimulate PAH uptake and FCCP did not decrease the uptake in the presence of an inwardly directed H(+)-gradient, ruling out a PAH/OH- antiport, an anion exchange system does not appear to be present in these membranes. Since electrogenicity and anion exchange seem not to be involved in the Cl(-)-dependent increase, an allosteric effect of Cl- on the transporter might be possible. Various organic anions were able to inhibit pH-stimulated PAH uptake significantly. Kinetic analysis of the probenecid sensitive part of uptake provided further evidence for mediated transport of PAH (Km = 7.4 +/- 2.6 mM and Vmax = 2.0 +/- 0.4 nmol/mg/15 s). Non-inhibitable diffusion accounted for the main part of total transport. Concentration dependent inhibition of PAH transport by probenecid showed a Ki of 2.5 +/- 0.9 mM. It is concluded that human placental syncytial microvillous membrane vesicles possess a low affinity transport mechanism for PAH with low specificity. The importance of this system, for placental excretion of anionic drugs, will depend on the intrasyncytial concentration of these drugs, caused by the transport across the basal membrane.

Biological Transport↗

PubMed1994

Effect of substituted benzoylglycines (hippurates) and phenylacetylglycines on p-aminohippurate transport in dog renal membrane vesicles.

The effect of substituted benzoylglycines (hippurates) and phenylacetylglycines on the transport of p-aminohippurate (PAH) was studied in basolateral (BLMV) and brush border membrane vesicles (BBMV) isolated from dog kidney cortex. The probenecid-sensitive part of 100 microM [3H]PAH uptake into BLMV and BBMV was measured in the presence and absence of 5 mM glycine conjugate. The benzoyl- and phenylacetylglycines studied were substituted in the 2-, 3-, or 4-position with an H, CH3, OCH3 or OH group. Benzoylglycines were stronger inhibitors of PAH transport than phenylacetylglycines and the inhibitory potency of the conjugates was in general lower against the transporter in BBMV than BLMV. The specificities of the transporters in both membranes appear to be very similar. The inhibitory potency of the benzoylglycines, expressed as the apparent inhibition constant (logKi), did not show a linear relationship with their lipophilicity as determined by reversed phase HPLC. Deviation from linearity was caused mainly by the 3-OH and 4-OH analogs, which showed a greater inhibitory potency than expected from their lipophilicity. Phenylacetylglycines only showed a small variation in logKi values, indicating that insertion of a CH2 group between the ring and the carbonyl practically abolishes the influence of the ring and its substituents. In conclusion, both hydrophobic and electronic properties are important determinants of affinity for the PAH transport system. An additional partially negative hydroxyl group in the ring, located preferably at the 3- or 4-position, increases the interaction with the transport system.

Animals↗

PubMed1994

Continuous infusion of furosemide in the treatment of patients with congestive heart failure and diuretic resistance.

OBJECTIVES: To assess the value of treatment with continuous intravenous infusion of furosemide (F) in patients with refractory congestive heart failure. DESIGN: Open uncontrolled dose-response study. SUBJECTS: Patients with congestive heart failure (those with New York Heart Association (NYHA) classes III and IV with an assessed amount of oedema of more than 5 kg and diuretic resistance were included [n = 10]). Diuretic resistance was defined as: failure to lose weight and/or inappropriate urinary sodium excretion (50 mmol 24 h-1) despite bed rest for a period of 2-3 days, salt and water restriction, orally and intravenously administered furosemide in a dose of 250 mg day-1, digoxin, and when possible an ACE inhibitor. Included patients were treated with continuous F infusion at a delivery rate of 20 mg-1 over 24 h. The infusion rate was gradually heightened up to a maximum dose of 160 mg h-1. MAIN OUTCOME MEASURES: Daily physical examination, history of side-effects, determination of serum electrolytes and 24-h electrolyte excretion during treatment with furosemide. RESULTS: Weight loss (mean +/- SD; 12.5 +/- 5 kg) and relief of symptoms was achieved in all patients. Mean (+/- SD) 24-h sodium output rose from 19 +/- 16 mmol 24 h-1 (n = 10) on oral therapy with 250 mg F to 137 +/- 85 mmol 24 h-1 (n = 8) during 80 mg h-1 and to 268 +/- 124 mmol 24 h-1 (n = 3) on the maximal dose of 160 mg h-1. CONCLUSION: Continuous infusion of F under careful monitoring of the patient is a safe, controllable and efficient treatment in patients with severe congestive heart failure and diuretic resistance.

Aged↗