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At least 307 records · Page 17Linked to original sources
PubMed2006

Intermediate-dose cidofovir without probenecid in the treatment of BK virus allograft nephropathy.

BK virus allograft nephropathy (BKVAN) is a rising complication in kidney transplant recipients. Reducing immunosuppression has been the initial form of therapy in most cases, but is not always associated with improvement in graft function. Anti-viral therapy with low-dose cidofovir (0.25-0.42 mg/kg/dose) has been used successfully in some patients, but dose-related nephrotoxicity has limited its use. We present our experience with 3 kidney transplant recipients diagnosed with BKVAN who received intermediate-dose cidofovir (0.75-1.0 mg/kg/dose) without probenecid, and without concomitant nephrotoxicity. Three female patients, ages 8, 19 and 20 yr, presented with elevated serum creatinine (SCr) values, BK virus stain positive on renal biopsy and high plasma BK viral loads. As a result of viral loads being >2 million copies/ml in two patients and a lack of response to reduction in immunosuppression in the third, we initiated therapy with low-dose cidofovir. Because of persistent positive BK stain and positive plasma viral load, we then administered intermediate-dose cidofovir, without probenecid, for several subsequent doses (seven to 15 infusions till date). All patients tolerated the intermediate-dose cidofovir with no significant rise in SCr during the course of the infusions. The most recent SCr values in all three patients were improved from those at the initial diagnosis of BKVAN. All three patients showed a marked drop in BK viral loads when on intermediate-dose cidofovir, with complete clearing of viremia in two patients. In our experience, intermediate-dose cidofovir without probenecid, used judiciously, is not associated with additional nephrotoxicity and may provide an additional alternative for treatment.

Adult↗
PubMed1994

Probenecid inhibition of the outward transport of fluorescein across the human blood-retina barrier.

The effect of probenecid on the outward transport of fluorescein from vitreous to blood was studied in 13 insulin-dependent diabetic patients with background retinopathy in a randomised double-masked placebo controlled cross-over study. Fluorescein and fluorescein glucuronide was separated in the vitreous and in plasma by differential spectrofluorometry. The data for fluorescein were analysed using a simplified mathematical model of the eye. The inward permeability was estimated from data obtained 1 h after injection and the outward transport from data obtained 7 h after injection. During placebo treatment the mean inward permeability was 3.75 x 10(-7) cm/sec and the mean outward permeability was 2.25 x 10(-5) cm/sec. During probenecid treatment the mean inward permeability was 3.34 x 10(-7) cm/sec and the mean outward permeability was 1.44 x 10(-5) cm/sec. Thus, we found no significant change in inward permeability (p = 0.5879), whereas a significant decrease of 36% was found in the outward permeability of fluorescein (p = 0.0171). The demonstration that the outward permeability, which is more than 100-fold higher than the inward permeability in the healthy eye, is significantly decreased by probenecid, demonstrates that active transport is involved in movement of fluorescein across the blood-retina barrier from the vitreous to the plasma.

Adult↗
PubMed1987

Probenecid inhibition of the renal excretion of dyphylline in chicken, rat and man.

The effect of probenecid on the renal excretion of dyphylline was studied in chicken, rat and man. Dyphylline was found to be actively excreted when measured by the Sperber preparation in hens, the isolated perfused kidney of the rat and clearance studies in man. In each study probenecid significantly decreased dyphylline excretion demonstrating that dyphylline occupied the renal organic anion transport system. This same drug interaction, at the level of the renal excretory system, in these three species occurred at comparable concentrations of dyphylline and probenecid.

Adult↗
PubMed2004

Human udp-glucuronosyltransferases: isoform selectivity and kinetics of 4-methylumbelliferone and 1-naphthol glucuronidation, effects of organic solvents, and inhibition by diclofenac and probenecid.

The glucuronidation kinetics of the prototypic substrates 4-methylumbelliferone (4MU) and 1-naphthol (1NP) by human UDP-glucuronosyltransferases (UGT) 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17 were investigated. Where activity was demonstrated, inhibitory effects of diclofenac, probenecid, and the solvents acetone, acetonitrile, dimethyl sulfoxide, ethanol, and methanol were characterized. All isoforms except UGT1A4 glucuronidated 4MU, whereas all but UGT 1A4, 2B15, and 2B17 metabolized 1NP. However, kinetic models varied with substrate (for the same isoform) and from isoform to isoform (with the same substrate). Hyperbolic (Michaelis-Menten), substrate inhibition, and sigmoidal kinetics were variably observed for both 4MU and 1NP glucuronidation by the various UGTs. K(m) or S(50) (sigmoidal kinetics) and V(max) values varied 525- (8-4204 microM) and 1386-fold, respectively, for 4MU glucuronidation, and 1360- (1.3-1768 microM) and 37-fold, respectively, for 1NP glucuronidation. The use of a two-site model proved useful for those reactions exhibiting non-Michaelis-Menten glucuronidation kinetics. The organic solvents generally had a relatively minor effect on UGT isoform activity. UGT 2B15 and 2B17 were most susceptible to the presence of solvent, although solvent-selective inhibition was occasionally observed with other isoforms. Diclofenac and probenecid inhibited all isoforms, precluding the use of these compounds for the reaction phenotyping of xenobiotic glucuronidation pathways in human tissues. Diclofenac and probenecid K(i) values, determined for selected isoforms, ranged from 11 to 52 microM and 96 to 2452 microM, respectively. Overall, the results emphasize the need for the careful design and interpretation of kinetic and inhibition studies with human UGTs.

Acetone↗
PubMed1977

Effect of probenecid on the blood levels and urinary excretion of cefamandole.

Two oral 0.5-g doses of probenecid given 7 and 1 h before a single 1-g intramuscular dose of cefamandole resulted in higher serum levels of cefamandole than when cefamandole was given alone: 37 versus 20 mug per ml of serum, respectively. Cefamandole was not measurable (<0.3 mug/ml) at 8 h when it was given alone, whereas an average 8-h value of 2.9 mug/ml was obtained after pretreatment with probenecid. By prolonging the duration of these high cefamandole levels, probenecid should permit the treatment of more serious clinical infections, including those due to relatively resistant organisms, or permit a reduction in either the dosage of cefamandole or the frequency of administration.

Adult↗
PubMed1985

Effects of urinary pH on renal interactions between probenecid and cefsulodin in rabbits.

The effect of urinary pH on renal interaction of cefsulodin and probenecid was tested in rabbits. Probenecid was reabsorbed in acidic urine (fractional excretion [FE] = 8 +/- 4%) and secreted in alkaline urine (FE = 492 +/- 258%). Renal excretion of cefsulodin alone was not affected by the urinary pH (FE = ca. 100%). In acidic urine, probenecid significantly reduced tubular secretion of cefsulodin (FE = 74 +/- 8%). An inverse pattern was observed in alkaline urine (FE = 122 +/- 18%).

Animals↗
PubMed1986

Comparative trial of single-dose ciprofloxacin and ampicillin plus probenecid for treatment of gonococcal urethritis in men.

In a double-blind comparative trial, 100 men with uncomplicated gonorrhea caused by beta-lactamase-negative Neisseria gonorrhoeae were treated with a single 0.25-g dose of ciprofloxacin administered orally or with 3.5 g of ampicillin plus 1.0 g of probenecid administered orally. Urethral infection was eradicated in all 49 men treated with ciprofloxacin and in 47 (92%) of 51 men treated with ampicillin-probenecid (P = 0.12). The geometric mean MICs for pretreatment isolates were 0.008 microgram of ciprofloxacin per ml, 0.09 microgram of penicillin G per ml, 0.52 microgram of tetracycline per ml, and 23.5 micrograms of spectinomycin per ml. Chlamydia trachomatis infection persisted in 10 of 11 men treated with ciprofloxacin and in 11 of 14 men treated with ampicillin-probenecid. A single 0.25-g dose of ciprofloxacin was effective for treatment of uncomplicated urethral gonorrhea in men, but it did not eradicate coinfection with C. trachomatis.

Adolescent↗
PubMed1989

Multicenter randomized study of single-dose ofloxacin versus amoxicillin-probenecid for treatment of uncomplicated gonococcal infection.

The safety and efficacy of ofloxacin, 400 mg orally, were compared with those of amoxicillin, 3.0 g, plus probenecid, 1.0 g orally, as single-dose therapy in 201 heterosexual patients (101 men and 100 women) with uncomplicated gonococcal infection. Treatment groups were comparable in age, duration of symptoms, number of sexual partners within the previous month, and number of previous episodes of sexually transmitted diseases. The cure rate for men treated with ofloxacin was 98% (47 of 48), and that for women was 100% (52 of 52). Cure rates for both men and women treated with amoxicillin-probenecid were 96% (51 of 53 men; 46 of 48 women). All 13 patients with positive rectal cultures and 7 of 8 patients with positive pharyngeal cultures treated with ofloxacin were cured. Neither regimen reliably eradicated coexistent infection with Chlamydia trachomatis. The MIC of ofloxacin for all but two of 198 pretreatment isolates was 0.3 microgram/ml or less. The MIC of amoxicillin for 90% of isolates tested was 1.0 microgram/ml. Single oral doses of ofloxacin and of amoxicillin plus probenecid were equally effective for treatment of urethral and cervical gonorrhea. Ofloxacin appears promising as treatment for rectal and pharyngeal infection, but studies with larger numbers of patients with rectal or pharyngeal infection or both are required for confirmation. Relative contraindications in children and possibly pregnant women plus the potential for single-step, high-level resistance may limit the usefulness of quinolone therapy for gonorrhea.

Adult↗
PubMed1978

Prolongation and enhancement of serum methotrexate concentrations by probenecid.

The disappearance of methotrexate (MTX) from the serum after an intravenous bolus injection and intravenous infusion was studied over 24 hours in eight and four patients respectively. Probenecid given at the same time as the bolus injection delayed the disappearance of MTX from the serum and resulted in enhanced concentrations throughout the 24 hours studied. At 24 hours the mean concentration was four times higher than in patients not given probenecid. Overall serum concentrations were even greater than those in patients who had received MTX by intravenous infusion. We suggest that smaller doses of MTX may be given and treatment costs thereby reduced if probenecid is given in addition.

Adult↗
PubMed1999

Demonstration of a probenecid-inhibitable anion exchanger involved in the release of cortisol and cAMP and in the uptake of p-aminohippurate in bovine adrenocortical cells.

Recently we provided evidence for the involvement of a probenecid-inhibitable anion exchanger in cortisol release from primary cultures of bovine adrenocortical cells. In the present study, we further characterized this exchange transporter. Adrenocorticotropic hormone stimulated 3H-p-aminohippurate (3H-PAH) uptake into as well as cortisol release from the cells about two- and tenfold, respectively. Probenecid inhibited both 3H-PAH uptake and cortisol release by about 55 and 63%. Preincubation of the cells with 1 mM PAH trans-stimulated 3H-PAH uptake by 30%, whereas cortisol release was inhibited by 30%. 3H-PAH uptake was cis-inhibited by 1 mM glutarate or by 1 mM cortisol in the medium, while cortisol release was trans-stimulated by glutarate. PAH in the incubation medium showed saturable cis-inhibition of 3H-PAH uptake. The release of cyclic adenosine monophosphate, a substrate of the renal PAH exchanger, was also inhibited by probenecid and trans-stimulated by glutarate. In summary, the trans-stimulation and cis-inhibition experiments support the concept of an anion exchanger involved in cortisol and cyclic adenosine monophosphate release from and PAH uptake into adrenocortical cells.

Adrenal Cortex↗
PubMed1984

Interaction of probenecid with the protein binding of methotrexate.

The effect of probenecid on the plasma protein binding of methotrexate (MTX) has been examined in vitro. At concentrations greater than or equal to 5 x 10(-4) M, probenecid caused a significant reduction (greater than 30%) in the plasma binding of MTX. It is suggested that in vivo this would lead to a greater dispersion into the tissues and a larger volume of distribution, and may be partly responsible for the longer MTX elimination half-life observed with concurrent administration of probenecid.

Drug Interactions↗
PubMed1992

Effect of probenecid on the pharmacokinetics of DQ-2556, a new 3-quaternary ammonium cephalosporin antibiotic, in humans.

A total of 5 healthy volunteers were enrolled in a crossover study on the dose dependency and the effect of probenecid on pharmacokinetics of DQ-2556. They were administered intravenously 0.5 and 1.0 g of DQ-2556, and 1.0 g of DQ-2556 with oral administration of probenecid. The linearity in pharmacokinetics of DQ-2556 was confirmed up to the dose of 1.0 g. In the case of 1.0 g of DQ-2556 with probenecid treatment, the area under the serum concentration-time curve was larger, and total and renal clearances were less than those in the case of 1.0 g of DQ-2556 alone (by approximately 15% for each parameter, p < 0.01). These results demonstrated that DQ-2556 is secreted in the renal tubule, although it is excreted mainly by the glomerular filtration.

Administration, Oral↗
PubMed1980

Single oral dose of epicillin combined with probenecid in the treatment of gonorrhoea.

Two hundred and sixty male patients with gonorrhoea, allocated to 4 unequal groups, were treated with one single oral dose of: (a) 2 g epicillin plus 1 g probenecid, (b) 2 g epicillin alone, (c) 1 g epicillin, 1 g cephradine plus 1 g probenecid, and (d) 1 g epicillin and 1 g cephradine. The last 3 groups acted as controls. Follow-up, with cultures of urethral discharge, was carried out over a 2-week period in all patients. The most satisfactory results were in the group of patients receiving epicillin plus probenecid, a 97% cure rate being achieved, with urethral discharge disappearing within 24 hours of treatment.

Adolescent↗
PubMed1983

Probenecid inhibits the secretion of nephrogenous adenosine 3',5'-monophosphate in normal man.

Nephrogenous cAMP, that fraction of urinary cAMP secreted by the kidney, is PTH dependent and is used clinically as a measure of parathyroid function. To clarify the nature of secretion of nephrogenous cAMP, probenecid, an inhibitor of organic anion transport, was administered to eight healthy young males. Nephrogenous cAMP decreased after probenecid treatment (P less than 0.001), and plasma cAMP increased reciprocally (P less than 0.01) so that urinary cAMP did not change. There was no change in serum PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, or urinary clearance of calcium or phosphate. These results suggest that secretion of nephrogenous cAMP may be a carrier-mediated process in normal man. The effect of probenecid to increase plasma cAMP is consistent with other observations suggesting that cAMP is cleared from plasma in part by a carrier-mediated process.

25-Hydroxyvitamin D 2↗
PubMed1983

Probenecid increases dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in rat adrenal gland.

Although norepinephrine and epinephrine are the predominant catecholamines (CAs) in peripheral tissues, peripheral dopamine (DA) systems are also physiologically significant. The DA is present both in the sympathetic ganglia and in the adrenal gland. We attempted to determine the possible presence of it in individual adrenal cells. We found increments in adrenal 3,4-dihydroxyphenylacetic acid (DOPAC) levels produced by probenecid, an inhibitor of anionic secretory mechanisms. Small amounts of DA and DOPAC were detected in the rat adrenal gland by using the high-performance liquid chromatographic electrochemical detection method. Two hr after probenecid treatment (200 mg/kg, i.p.), the concentration of striatal homovanillic acid approximately doubled compared with those of control rats, and the levels of striatal DOPAC remained much the same. Conversely, the adrenal DOPAC was markedly increased with no change in the levels of CAs. The existence of DOPAC and the increase of DOPAC by probenecid indicate that the adrenal DA may be independently granulated.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Enantiomer-enantiomer interaction of a uricosuric antihypertensive diuretic (DBCA) in renal tubular secretion and stereoselective inhibition by probenecid in the cynomolgus monkey.

1. Enantiomer-enantiomer interaction of 5-dimethylsulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyl ic acid (DBCA), a uricosuric, diuretic and antihypertensive agent, was studied from the pharmacokinetics of the enantiomers following intravenous injection of individual enantiomers and racemate into male cynomolgus monkeys. Also studied was the involvement of the anion transport system in the renal excretion of DBCA by comparison of the pharmacokinetics in probenecid-treated and non-treated animals. 2. Separate administration of individual enantiomers showed higher plasma concentrations of (S)(-)-DBCA than those of the antipode, at an early period after dosing. Both enantiomers disappeared rapidly from plasma with an elimination half-life (t1/2 beta) of 0.35-0.38 h. Unbound fractions were 18.9% for the (R)(+)-enantiomer and 10.2% for the (S)(-)-enantiomer. The major portion of both enantiomers was excreted by 6 h after dosing and 77-78% of the dose was recovered within 48 h, principally as the unchanged drug. Tubular secretion contributed significantly to the renal excretion of DBCA, because tubular secretion clearance values of unbound drug (CLrf,s) were 14- to 29-fold greater than creatinine clearance. 3. The presence of the antipode decreased the tubular secretion clearance (CLrf,s) value of unbound (S)(-)-enantiomer by 30%, and tended to decrease that for the unbound (R)(+)-enantiomer, although not significantly. This indicates the occurrence of enantiomer-enantiomer interaction in the process of renal tubular secretion, and the inhibition of (S)(-)-DBCA renal excretion in the presence of the antipode. 4. Probenecid treatment significantly decreased the CLrf,s of both enantiomers, and the extent of inhibition for the (S)(-)-enantiomer (53%) was significantly higher than that for the antipode (14%). These results show that renal tubular secretion of DBCA involves an anion transport system which prefers the (S)(-)-enantiomer, and that probenecid can preferentially inhibit (S)(-)-enantiomer secretion.

Animals↗
PubMed1976

Inhibition of methotrexate transport from cerebrospinal fluid by probenecid.

In rabbit, the efflux of intraventricularly injected methotrexate from the cerebrospinal fluid was retarded by pretreatment with 200 mg/kg of ip probenecid. In vitro, the ability of the isolated choroid plexus to concentrate methotrexate was depressed by the inclusion of probenecid in the incubation medium. These experimental results are consistent with the hypothesis that probenecid depresses the clearance of methotrexate from the cerebrospinal fluid by blocking the transport of methotrexate from cerebrospinal fluid to blood via the choroid plexus.

Animals↗
PubMed1976

Probenecid and the rat kidney: investigations by renal enzyme excretion technique.

Probenecid in doses of 640 mg/kg was administered to rats by the oral route, and the changes in five important enzymatic activities of urine were recorded thereafter for two days. The resluts exclude that probenecid impairs tubular reabsorption of low molecular weight protein, as urinary muramidase activity was not found increased. On the other hand, increased activities were encountered in those enzymatic activities in urine which derive from the renal tubular cells (ALD, G-6-PDH, LDH). These observations point towards a nephrotoxic effect of probenecid, which, however, is only of very low degree, as other "standard" enzymatic activities of urine, such as alkaline phosphatase, remained unchanged.

Animals↗