Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Probenecid”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 469 records · Page 26Linked to original sources
PubMed1986

Effect of dexamethasone, indomethacin, ibuprofen, and probenecid on carrageenan-induced brain inflammation.

A model of brain inflammation has recently been developed in mice using intraventricular injection of carrageenan (CAR). This model is characterized by increased brain water and vascular permeability, by neutrophil extravasation, and by evidence of increased pro-inflammatory arachidonic acid metabolites. The purpose of the current experiments was to determine the mechanism(s) by which CAR induces brain inflammation and to determine the utility of the CAR model in testing systemically administered therapeutic agents for their capacity to inhibit brain inflammation. Dexamethasone inhibited the increased brain water but not the increased vascular permeability produced by CAR. Indomethacin, an inhibitor of prostaglandin formation, suppressed peripheral inflammation produced by local injection of CAR but not brain inflammation produced by intraventricular CAR injection. Subsequent studies with carbon-14-labeled indomethacin showed that indomethacin penetrates peripheral tissues but is excluded from normal brain or brains inflamed by injection of CAR. Ibuprofen, another prostaglandin synthesis inhibitor, also had no effect on brain inflammation. Probenecid, an organic acid transport inhibitor, completely inhibited CAR-induced brain inflammation and also slowed brain elimination of intraventricularly administered prostaglandins. These experiments suggest, but do not conclusively prove, that increased prostaglandin formation contributes to brain inflammation. Also, the results with indomethacin and CAR-induced brain inflammation indicate that CAR-induced inflammation may be a useful model for screening for the ability of anti-inflammatory agents to cross the blood-brain barrier and exert their effect on brain inflammation.

Animals↗
PubMedDate not supplied

Effect of pyrazinamide and probenecid on peritoneal urate transport kinetics during continuous ambulatory peritoneal dialysis.

OBJECTIVE: We administered pyrazinamide (PZA) and probenecid (PB) --two well-known modulators of urate transport via the proximal tubules - to evaluate their impact on urate transport through the peritoneal membrane and to clarify mechanisms affecting peritoneal transport. SETTING: A continuous ambulatory peritoneal dialysis (CAPD) unit in 2nd Hospital of IKA (Social Services Institute), Greece. PATIENTS: In 20 stable CAPD patients, on the study day, a 4-hour, 2-L, 1.36% glucose exchange was performed (control exchange). Pyrazinamide 3 g was given orally and another identical exchange was performed (study exchange). The same protocol was repeated with 2 g PB. KtN, peritoneal clearances of urea, creatinine, and urate for each exchange, and mass transfer area coefficients (MTAC) for the three solutes and their dialysate-to-plasma concentration (D/P) ratios were used to estimate peritoneal transport. RESULTS: Administration of PZA resulted in decreased clearances and MTAC values for the three solutes. The D/P ratio decreased significantly only for urate, indicating a more intense influence of PZA on urate. After PB administration, clearances of urea, creatinine, and urate were increased. MTAC and DIP ratio increased significantly only for urate (p < 0.05), demonstrating an action similar to that exerted on renal tubules. CONCLUSIONS: These findings provide evidence that unrestricted diffusion is not the only transport mechanism in the case of urate, and demonstrate the existence of an active mechanism in peritoneal urate transport with a reabsorptive and, probably, a secretive component that resembles that of renal tubule urate transport. Attention should be given in the case of CAPD patients undergoing antituberculous (PZA) treatment: it might have a negative impact on urea, creatinine, and urate peritoneal transport rates.

Female↗
PubMed2000

Co-administration of probenecid, an inhibitor of a cMOAT/MRP-like plasma membrane ATPase, greatly enhanced the efficacy of a new 10-deazaaminopterin against human solid tumors in vivo.

Earlier studies from this laboratory have shown that the uricosuric agent probenecid (PBCD) will inhibit the extrusion of folate analogues from tumor cells mediated by a plasma membrane ATPase resembling the canicular multispecific organic anion transporter/multidrug resistance-related protein (MRP) family of ATP binding cassette transporters. This inhibition of this outwardly directed membrane ATPase has been shown to have a favorable impact upon the cellular pharmacokinetics, cytotoxicity, and efficacy of methotrexate in vivo. In an extension of these earlier studies, which had focused only on murine ascites tumors, we now report that parental co-administration of PBCD will also enhance net intracellular accumulation in vitro and intracellular persistence in vivo of a new folate analogue, 10-propargyl-10-deazaaminopterin (PDX) in tumor cells. This resulted in marked enhancement of the efficacy of PDX against murine and human lung neoplasms and human prostate and mammary neoplasms growing as solid tumors in mice. As possible ATPases targeted by PBCD, all of these tumors expressed MRP-1, -4, and -7 genes, with expression of MRP-4 being greatest in each case. Four other MRP genes were expressed to a variable extent in some tumors but not others. The therapeutic enhancement of PDX by PBCD was manifested as tumor regression, where PDX alone was only growth inhibitory (A549 NSCL tumor), or as a substantial increase (3-4-fold) in overall regression and/or number of complete regressions (Lewis and LX-1 lung, PC-3 and TSU-PR1 prostate, and MX-1 mammary tumors) compared to PDX alone. Also, only in the case of PDX with PBCD, a significant number of mice transplanted with LX-1 or MX-1 tumors that experienced complete regression did not have regrowth of their tumor. In view of these results, clinical trials of this therapeutic modality appear to be warranted, especially in the case of new more efficacious folate analogues that are also permeants for this canicular multispecific organic anion transporter/MRP-like plasma membrane ATPase.

ATP-Binding Cassette Transporters↗
PubMed2000

Probenecid-associated alterations in valproic acid pharmacokinetics in rats: can in vivo disposition of valproate glucuronide be predicted from in vitro formation data?

Previous investigations have suggested that probenecid (PRB) alters the in vivo disposition of valproic acid (VPA), perhaps by inhibiting hepatic formation of valproate glucuronide (VG). Because VPA and PRB bind moderately to plasma proteins, protein binding also is a potential locus of interaction. The purpose of this investigation was to determine whether in vitro systems could accurately predict PRB-associated perturbations in the hepatobiliary disposition of VPA and VG in vivo. VPA and PRB were coadministered to rats for 60 min at various infusion rates to examine steady-state VPA disposition. PRB did not alter the binding of VPA in serum or hepatic cytosol. However, PRB decreased the apparent intrinsic clearance of VPA (1.81 +/- 0.58 versus 1.23 +/- 0.23 ml/min; P =.025) by competitively inhibiting VPA elimination. In a separate study, rat hepatic S9 fractions were incubated with VPA (7.2-721 microg/ml) and PRB (0-2850 microg/ml). VG formation (V(max) = 0.80 +/- 0.06 microg/min/mg of protein; K(m) = 173 +/- 28.8 microg/ml) was impaired by PRB in a competitive manner (K(i) = 876 +/- 559 microg/ml), consistent with the in vivo data. Despite inhibition of phase II metabolism of VPA to VG by PRB, the VG biliary excretion rate at similar unbound VPA concentrations in hepatic cytosol was not lower in PRB-treated rats. These results indicate that VG disposition in the presence of PRB cannot be predicted accurately based solely on in vitro inhibition of glucuronidation and emphasize the complexity of processes associated with the hepatobiliary system.

Algorithms↗
PubMed2001

Probenecid-associated alterations in valproate glucuronide hepatobiliary disposition: mechanistic assessment using mathematical modeling.

The complexity of processes associated with the hepatobiliary disposition of xenobiotics may require a multiexperimental approach, including pharmacokinetic modeling, to assess mechanisms of drug interactions. The objective of this study was to examine the disposition of valproate glucuronide (VG) in the rat isolated perfused liver (IPL), and to determine the mechanisms of interaction with probenecid (PRB). Livers were isolated and perfused with standard techniques, and valproate (VPA) (20 mg) was administered in the absence and presence of PRB (approximately 75 microg/ml). Concentrations of VPA and VG in perfusate and bile were determined at timed intervals. In the absence of PRB, total recovery of VPA and VG in perfusate and bile was approximately 80%; PRB significantly increased this recovery to approximately 100%, suggesting a decrease in oxidative VPA metabolism. Similarly, pharmacokinetic modeling of the IPL data indicated that PRB competitively inhibited formation of oxidative VPA metabolites. PRB also significantly inhibited formation, biliary excretion, and sinusoidal egress of VG. These observations suggest a competitive interaction between PRB and VG for transport across the canalicular and sinusoidal membranes. Despite PRB-associated impairment of VG formation, mathematical modeling of the data revealed that hepatocyte VG concentrations were increased by PRB, presumably due to simultaneous inhibition of VG biliary excretion and sinusoidal egress by PRB. These results demonstrate the utility of pharmacokinetic modeling in elucidating the mechanisms of alteration in the hepatobiliary disposition of xenobiotics.

Animals↗
PubMed1992

[Solid-phase extraction and RP-HPLC screening procedure for diuretics, probenecid, caffeine and pemoline in urine].

A solid-phase extraction and reversed phase high performance liquid chromatographic method (RP-HPLC) was developed for the rapid determination of 13 diuretics (belonging to five different pharmacological groups), probenecid, caffeine and pemoline in urine. Two ml urine sample was first adsorbed on a XAD-2 column, then eluted with ether-ethyl acetate (1:1). The eluate was evaporated to dryness and reconstituted in methanol. The methanolic solution was injected into a HP LiChrosorb RP-18 column, using phosphate buffer (pH 3) and acetonitrile as the mobile phase and monitored at 216 nm, 230 nm, and 275 nm on a diode array ultraviolet detector. The extraction recoveries of 16 drugs were above 75%. The limits of detection ranged from 0.3-3.0 micrograms/ml of urine. All drugs were separately administered to healthy volunteers, positive urine samples were collected, and urinary excretion-time curves of some drugs were reported.

Adult↗
PubMed1991

Severe pancytopenia in a patient taking low dose methotrexate and probenecid.

A patient with rheumatoid arthritis developed life-threatening pancytopenia resulting from low dose oral methotrexate (MTX) toxicity potentiated by probenecid. Clinically significant drug interactions are not frequently cited as risk factors for MTX hematologic toxicity. As low dose MTX is gaining increasing popularity in rheumatologic practice, these potentially serious interactions should be considered.

Aged↗
PubMed1989

Ciprofloxacin versus amoxycillin and probenecid in the treatment of uncomplicated gonorrhoea.

In a randomized study 100 patients, 78 males and 22 females, with uncomplicated gonorrhoea were treated with either a single oral dose of 250 mg of ciprofloxacin or a single oral dose of 3 g of amoxycillin and 1 g of probenecid. Three of the gonococcal strains produced penicillinase and, in addition, nine strains had MIC-values of amoxycillin ranging between 0.6 and 1.2 mg/l and five other strains MIC-values higher than 1.2 mg/l. Twenty-two patients had a concomitant infection due to Chlamydia trachomatis. All patients treated with ciprofloxacin were cured, while two patients treated with amoxycillin had treatment failures. Neither treatment regimen had any effect on the chlamydial infections. No adverse effects were observed. It was concluded that ciprofloxacin is the drug of choice in the treatment of uncomplicated infections due to Neisseria gonorrhoeae.

Adolescent↗
PubMed1989

Covalent binding of diflunisal and probenecid to plasma protein in humans: persistence of the adducts in the circulation.

Acyl glucuronide conjugates of carboxylic drugs have been shown over the past decade to be potentially reactive metabolites, undergoing hydrolysis, intramolecular rearrangement and intermolecular transacylation reactions. The present report describes the covalent binding of diflunisal (D) and probenecid (P) to plasma protein of five healthy volunteers who took a 6-day course of oral D with oral P co-administered during the last 2 days. Maximum concentrations of the D- and P-adducts were achieved within one day of cessation of dosing, and were 35 +/- SE 1 and 17 +/- SE 1 ng/mg protein respectively. The D-protein adduct was eliminated from plasma in a biphasic manner, with a terminal half-life of 10.0 +/- SE 0.9 days. In contrast, elimination of the P-protein adduct was monophasic with a half-life of 13.5 +/- SE 0.3 days. The adducts were still measurable in plasma at least one month after the parent reversibly-bound drugs were undetectable. It is not known whether such covalent binding of the drugs, presumably via their acyl glucuronides, could have any biological consequences, such as induction of hypersensitivity reactions.

Adult↗
PubMed1978

Diflunisal renal clearance in anesthetized dogs: effect of probenecid, urine flow, and urine pH.

Using conventional clearance technique, the net renal clearance of diflunisal is very low, about 1% of glomerular filtration rate. Although net renal secretion is not demonstrable, probenecid significantly decreased renal clearance of the drug. Also, the renal clearance was increased by increases in urine flow or urinary pH. However, in contrast to acetylsalicylic acid, these effects would be expected to be minor, on the one hand to conserve drug or on the other hand in facilitating drug elimination in cases of overdosage.

Anesthesia↗
PubMed1986

Aspirin and probenecid pretreatment influences the potency of thiopentone and the onset of action of midazolam.

The effects of pretreatment with aspirin and probenecid, two drugs which are highly bound to albumin, on an induction dose of thiopentone and time to onset of action of a fixed dose of midazolam were investigated. Both drugs significantly potentiate thiopentone and shorten the induction time with midazolam. The importance of individual variations in plasma proteins in influencing the action of highly bound drugs is stressed.

Adult↗
PubMedDate not supplied

Women at risk for gonorrhea: comparison of rosaramicin and ampicillin plus probenecid in the eradication of Neisseria gonorrhoeae, Chlamydia trachomatis and genital mycoplasmas.

Rosaramicin is a macrolide antibiotic with activity against Neisseria gonorrhoeae, Chlamydia trachomatis, and the genital mycoplasmas Ureaplasma urealyticum and Mycoplasma hominis. Its efficacy in the treatment of genital infections was evaluated and compared with that of single-dose ampicillin plus probenecid in women with known, or suspected, uncomplicated gonococcal infection. Isolation rates for N. gonorrhoeae, C. trachomatis, U. urealyticum, and M. hominis were 72%, 44%, 95%, and 65%, respectively. Rosaramicin cured 24 (89%) of 27 gonococcal infections and 11 (92%) of 12 chlamydial infections. It transiently reduced the carriage of U. urealyticum but had little effect on carriage of M. hominis. Rosaramicin may be of value in the treatment of concurrent gonococcal and chlamydial infections when tetracycline is contraindicated.

Adolescent↗
PubMedDate not supplied

Further observations showing the impact of the probenecid test in movement disorders.

Two patients with movement disorders are described and neurochemically studied. The first subject concerns a central anticholinergic syndrome in a 83 years old man treated with l-dopa and amantadine for red nucleus tremor. The second one is an association of parkinsonism and chorea in a 76 years old woman presenting with FAHR's syndrome. In both cases, CSF HVA levels were measured before and after oral probenecid load. The observations confirm the usefulness of this neurochemical strategy in order to classify aging patients with parkinsonism into dopasensitive and doparesistant groups.

Aged↗
PubMed1983

The probenecid test.

A critical evaluation of the probenecid test is given. It is concluded that as presently performed in humans this test probably does not measure central dopaminergic or serotoninergic activities.

Blood-Brain Barrier↗
PubMed1980

[Use of the probenecid test for the diagnosis and treatment of Parkinsonism. Review of the literature and personal experience (author's transl)].

After describing the clinical picture of Parkinsonism, other Parkinson and depressive syndromes, the authors clarify ascending dopaminergic and serotoninergic pathways in the central nervous system as well as current knowledge on the nigro-striatal pathway. They also underline the interest of the probenecid test in the diagnosis of Parkinsonsism with or without depression. Neurochemical criteria of dopa-sensititivy and dopa-resistance are proposed as well as criteria aimed at serotoninergic therapy. Finally, the use of this neurochemical test in treatment and follow up is illustrated by a clinical case report.

Aged↗
PubMed1984

Studies on the metabolism of D-penicillamine and its interaction with probenecid in cystinuria and rheumatoid arthritis.

Four patients with recurrent cystine stones and 5 with rheumatoid arthritis (RA) were studied. After a single dose of D-penicillamine to cystinuric patients, cystine excretion decreased considerably. Cysteine-penicillamine mixed disulfide (CSSP) and penicillamine disulfide (PSSP) metabolites appeared within 1-2 h (CSSP/PSSP approximately equal to 4.8-8.6). In RA, cystine excretion remained negligible (CSSP/PSSP approximately equal to 1.4-2.9). With daily D-penicillamine in RA (CSSP/PSSP ratios were usually greater than 7 in those with favorable clinical response. CSSP/PSSP ratios may help to predict prognosis and adjust penicillamine dosage. Coadministration of probenecid is contraindicated in hyperuricemic cystinuric patients because of increased cystine and decreased CSSP and PSSP excretion.

Arthritis, Rheumatoid↗
PubMed1994

Probenecid inhibits transforming growth factor-beta 1 induced pyrophosphate elaboration by chondrocytes.

OBJECTIVE: The elaboration of excess extracellular inorganic pyrophosphate (ePPi) by cartilage contributes to calcium pyrophosphate dihydrate (CPPD) crystal deposition disease. Transforming growth factor-beta 1 (TGF beta 1) is the only defined physiologic stimulant of cartilage ePPi elaboration. The mechanism of ePPi generation by chondrocytes is unknown, but current evidence suggests that TGF beta 1 induced ePPi is made intracellularly. An active transport mechanism such as an anion transporter would then be necessary to export ePPi to the matrix where crystals form. We determined the effect of probenecid (PB), an anion transport inhibitor, on TGF beta 1 induced ePPi elaboration. METHODS: Porcine hyaline articular chondrocytes in high density monolayer cultures were exposed to serum-free media with and without TGF beta 1 and/or PB. ePPi was measured in the media after 48-96 h of exposure. Cell injury was measured by examining the release of 3H-deoxyglucose from chondrocytes. The activity of the ePPi generating ectoenzyme nucleoside triphosphate pyrophosphohydrolase (NTPPPH) and media lactate concentrations were measured with standard colorimetric assays. As PB may inhibit phosphodiesterase (PDE), its effects on ePPi generation were compared with isobutylmethylxanthine (IBMX), a specific PDE inhibitor. RESULTS: PB inhibited TGF beta 1 induced ePPi elaboration by chondrocytes. PB did not cause membrane injury or decrease NTPPPH activity. Lactate production was decreased by PB but did not correlate with the effects of PB on ePPi elaboration. IBMX did not inhibit TGF beta 1 effect on ePPi elaboration. CONCLUSION: PB blocks TGF beta 1 induced ePPi elaboration. This effect is independent of cell membrane injury, decreased NTPPPH activity, or PDE inhibition. Our data implicate a role for anion transport in TGF beta 1 induced ePPi elaboration, and suggest a potential therapy for CPPD disease.

1-Methyl-3-isobutylxanthine↗
PubMedDate not supplied

Pharmacokinetics of the neuroprotective glutamate antagonist NBQX (6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione) in mice, rats, and dogs. Interactions with probenecid.

NBQX [6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione] has proven effective in protecting against cerebral ischemic insult in rodents. The preclinical development included pharmacokinetic and toxicological investigations in mice, rats, and dogs. For these purposes, NBQX was given as an intravenous bolus dose (in mice, rats, and dogs) or as a constant infusion for up to 4 weeks in rats and dogs. In NMRI mice t1/2, CL, and V2 were 1-4 hr, 0.6-1 liter/kg/hr, and 1-4 liters/kg following 3, 10, or 30 mg/kg. In Wistar and Sprague-Dawley rats, the mean +/- SD values of t1/2, CL, and Vz were 0.8 +/- 0.35 hr, 3.2 +/- 1.0 liters/kg/hr, and 4.0 +/- 1.1 liters/kg, respectively. About 33 +/- 5.2% of the dose was excreted unchanged in urine. The CLR was 0.90 +/- 0.20 liter/kg/hr. The pH of the urine samples ranged from pH 6.2 to 8.8, with a mean of 7.9 +/- 0.72. The plasma concentrations were proportional to the dose rate in the dose range 0.3-10 mg/kg/hr, independent of sex, and did not change during 4 weeks of infusion. CL and CLR were decreased to half their value when NBQX was administered in combination with probenecid. In beagle dogs, t1/2 and Vz were 1-3 hr and 1-3 liters/kg, respectively. The CL was determined to be 1.5 +/- 0.4 liters/kg/hr (N = 18) following 2 days of infusion (0.2-1 mg/kg/hr), but after 1 month CL had decreased significantly (p < 0.0001) to 1.0 +/- 0.1 liter/kg/hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗