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PubMed1978

The efficacy of cefuroxime for the treatment of acute gonorrhoea in men.

This is a report on a clinical trial in which cefuroxime was used for treating 110 men with uncomplicated urethral gonorrhoea. Twenty-three men were given 1 g cefuroxime intramuscularly and 1 g probenecid orally, and 87 were treated with 1.5 g cefuroxime intramuscularly with 1 g probenecid orally. All 18 patients treated with 1 g cefuroxime and 1 g probenecid and seen at least once after treatment, were cured. Sixty-six (98.5%) of 67 patients treated with 1.5 g cefuroxime and 1 g probenecid and seen at least once after treatment, were cured. No side effects were reported. The high cure rates compared favourably with other antibiotics now in regular use and cefuroxime should be of great value especially for patients infected with beta-lactamase producing gonococci.

Acute Disease↗
PubMed2005

Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter.

BACKGROUND: Soluble uric acid stimulates vascular smooth muscle cell (VSMC) proliferation by activating mitogen-activated protein kinases, and stimulating COX-2 and PDGF synthesis. The mechanism by which uric acid enters the VSMC is not known. We hypothesized that uric acid enters via transporters similar to that observed in the kidney. METHODS: We studied the uptake of uric acid into rat VSMC under polarized and depolarized conditions and in the presence of organic anion transport (OAT) inhibitors (probenecid and benzbromarone) or p-aminohippurate (PAH). We also examined the ability of probenecid to inhibit uric acid-induced VSMC proliferation and monocyte chemoattractant protein-1 (MCP-1) synthesis. RESULTS: (14)C-Urate uptake was shown in VSMC and was enhanced under depolarized conditions. (14)C-Uric acid uptake was inhibited by probenecid and benzbromarone, as well as by unlabelled urate and PAH. Probenecid blocked VSMC proliferation and MCP-1 expression in response to uric acid. VSMC did not express rOAT1-3, rOAT-5 or URAT-1 mRNA by PCR, but did express the voltage-sensitive transporter (UAT) by both PCR and RNase protection assay. CONCLUSIONS: Urate enters VSMC by both voltage-sensitive and OAT pathways, and the uptake, cell proliferation and MCP-1 expression can be blocked by OAT inhibitors. The specific transporter(s) responsible for the urate uptake remains to be determined.

Animals↗
PubMed1973

Origins of the uricosuric response.

The acute effects of intravenous (i.v.) probenecid and chlorothiazide on renal urate handling were investigated in paired studies in normal men. Uricosuric responses to these agents were compared in the same subjects, both without and with pyrazinamide (PZA) pretreatment. Assuming that PZA selectively inhibits the tubular secretion of urate and that uricosuric agents act by increasing the excretion of filtered urate, then the uricosuric responses (the increment in urate excretion or clearance) should have been unaffected by PZA. Defined in this manner, however, uricosuric responses to probenecid and chlorothiazide were significantly decreased after PZA pretreatment. In order to determine whether PZA diminished other renal actions of chlorothiazide, changes in sodium and inorganic phosphorus excretion were examined. Chlorothiazide produced equivalent natriuretic and phosphaturic responses after PZA pretreatment, indicating that PZA does not interfere with at least some of the renal actions of chlorothiazide. In separate studies, PZA depressed urate excretion by at least 68% during the maintenance of chlorothiazide-induced natriuresis and phosphaturia, suggesting that chlorothiazide does not diminish the anti-secretory action of PZA. The results suggest that probenecid and chlorothiazide may derive their uricosuric properties by facilitating the excretion of both filtered and secreted urate. Possibly, increased excretion of secreted urate might occur through modulation of urate reabsorption at a site distal to tubular secretion, rather than by the direct acceleration of secretory transport. However, PZA-induced interference with the actions of probenecid and chlorothiazide on renal urate transport mechanisms cannot be excluded as a possible explanation for the present results.

Adult↗
PubMed1975

Structural and functional studies of ligandin, a major renal organic anion-binding protein.

Sephadex gel filtration of the 1000,000 g supernate of homogenates of rat kidney revealed binding of various organic anions (penicillin, Bromsulphalein [BSP], bilirubin, phenolsulfonphthalein [PSP], phlorizin, glutathione [GSH], p-amino hippurate (PAH), probenecid, conjugated bilirubin, and BSP-GSH) to a nonalbumin-containing protein fraction (Y), which precipated on addition of monospecific anti-rat liver ligandin (Y protein)-IgG, but not control IgG. Quantitatively similar organic anion binding was observed in vivo after injection of BSP, BSP-GSH, phlorizin, probenecid, conjugated bilirubin, PAH, or penicillin. The binding protein was purified to apparent homogeneity and is a basic protein (pI 8.9) of 44,000 daltons with two apparently identical subunits of 22,000 daltons. Monospecific antibody was produced against the renal protein. The results of binding studies in vivo and in vitro and phsicochemical, immunologic, structural, and binding site investigations indicate that the renal protein is identical to hepatic ligandin. Immunofluorescent studies utilizing anti-ligandin IgG previously localized ligandin in the kidney to all proximal tubular cells. By quantitative radial immunodiffusion, the concentration of renal ligandin was 31.2 plus or minus 2.2 mug/mg supernatant protein and was increased 160% above basal values by pretreatment of rats with tetrachloro-dibenzo-p-dioxin. Pretreatment with phenobarbital, DDT, or pregnene-16alpha-carbonitrile did not increase renal ligandin concentration but doubled hepatic ligandin concentration. Circular dichroism studies of renal ligandin revealed percent helical structure similar to hepatic ligandin and primary association contrasts were derived for BSP (10-6 M-1) and PAH, probenecid, and penicillin (10-3 M-1). Administration of BSP or probenecid simultaneously with [C14] penicillin resulted in increased plasma retention and reduced kidney and urinary bladder content of [14C] penicillin and a correlation coefficient of -0.8 between total kidney/plasma radioactivity and percent of protein-bound radioactivity bound to ligandin in the kidney. These studies indicate that renal and hepatic ligandin are identical. Their response to drugs and chemicals varies. Competitive binding between several organic anions for ligandin correlated with their renal uptake from plasma, which suggests that ligandin may function in the proximal tubular cell as a component of the renal organic anion transport system.

Amino Acids↗
PubMed1980

CSF monoamine metabolites in depression and schizophrenia.

The authors report cerebrospinal fluid (CSF) concentrations of five monoamine metabolites before and after probenecid administration in normal subjects and patients with depression and schizophrenia. No differences were found in baseline metabolite concentrations among the three groups. CSF metabolite and CSF probenecid concentrations were significantly correlated in depressed patients for all metabolites, and there was decreased postprobenecid accumulation of homovanillic acid in the CSF of depressed patients compared with schizophrenic patients and with normal subjects. The authors propose a method for correcting for probenecid concentrations. Data from normal subjects should be of value for other investigators using the probenecid technique.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Secretory transport of p-aminohippuric acid across intestinal epithelial cells in Caco-2 cells and isolated intestinal tissue.

The intestinal transport of an organic anion, p-aminohippuric acid (PAH), was studied in Caco-2 cell monolayers and rat intestinal tissue mounted in Ussing chambers. In both experimental methods, PAH exhibited vectorial transport with significantly greater permeability in the secretory direction than the absorptive direction, indicating net secretion. This secretory transport required metabolic energy, but protons or hydroxyl ions were not involved as the driving force. In Caco-2 monolayers, secretory transport of [3H]PAH was decreased, and the intracellular accumulation of PAH was increased with increasing concentration of unlabelled PAH at the basolateral side. Addition of probenecid and genistein at the basolateral side decreased the secretory transport of [3H]PAH; the accumulation was not changed by probenecid, but was increased by genistein. In addition, the initial uptake rate of [3H]PAH from the basolateral side was decreased by both PAH and probenecid, but not by genistein. Therefore, it is suggested that the transport of PAH in Caco-2 cells is regulated by several transporters: a genistein-sensitive transporter on the apical membrane and probenecid-sensitive transporters on both the basolateral and apical membranes. In rat intestinal tissues, the transport rate of PAH showed regional variation (ileum > jejunum > duodenum), suggesting that secretory transporters with high activity exist predominantly in the lower region of the small intestine. The results suggest that PAH transport in both Caco-2 cells and rat intestinal tissues is regulated by multiple transporters on the apical and basolateral membranes, and these transporters have different characteristics.

Animals↗
PubMed1996

Renal handling of urate in a patient with familial juvenile gouty nephropathy.

We encountered a case of familial juvenile gouty nephropathy (FJGN) with an autosomal dominant transmission pattern. Hyperuricemia in the propositus was caused by renal underexcretion of urate although his erythrocyte purine enzyme was normal. A renal biopsy specimen from the propositus showed interstitial fibrosis with tubular atrophy. On pyrazinamide and probenecid tests, the tubular secretion of urate selectively decreased without changes in either presecretory or postsecretory reabsorption of urate when his renal function was normal. Probenecid increased the urinary urate excretion and Cur/Ccr. The serum urate concentration was poorly controlled by allopurinol. When his renal function deteriorated, the uricosuric effects of both probenecid and benzbromarone were attenuated. However, the combined administration of probenecid with allopurinol decreased the serum urate concentration. These data suggest that the tubular secretion of urate is selectively impaired in FJGN and at the stage of renal failure, the combination of an uricosuric agent with allopurinol might be effective in treating hyperuricemia in FJGN.

Adolescent↗
PubMed1977

The enhancement of beta-lactam antibiotic therapy by novobiocin.

Novobiocin demonstrates an effect similar to that of probenecid (the "probenecid effect") in enhancing the therapeutic efficacy of antibiotics excreted mainly by the renal tubules. The ability of cefoxitin, cephalexin, cephalothin and penicillin G to protect mice against infection with Salmonella schottmuelleri was enhanced 2- to 3-fold when the animals were given oral doses of either probenecid or of novobiocin. The efficacy of cephaloridine, excreted mainly by glomerular filtration, was not enhanced by either probenecid or by novobiocin.

Animals↗
PubMed1975

The origin of blood k-hydroxyindoleacetic acid following L-hydrazino-alpha-methyldopa (MK-486).

Blood 5-HIAA-14C levels derived from exogenous D,L-5-HTP-14C were investigated in normal, sham-operated and nephrectomized rats pretreated with MK-486 and probenecid (200 mg/kg i.p.). Blood 5-HIAA-14C levels decreased in nephrectomized rats following probenecid. Peripheral decarboxylase inhibition by MK-486 was enhanced by both probenecid and nephrectomy. Increased penetration of 5-HTP into brain occurred following probenecid. The results indicate that following MK-486 about 20% of the blood 5-HIAA-14C derived from 5-HTP-14C in rats originates in the CNS.

5-Hydroxytryptophan↗
PubMed1975

The origin of blood 5-hydroxyindoleacetic acid following L-hydrazine-alpha-methyldopa (MK-486).

Blood 5-HIAA-14C levels derived from exogenous D,L-5-HTP-14C were investigated in normal, sham-operated and nephrectomized rats pretreated with MK-486 and probenecid (200 mg/kg i.p.). Blood 5-HIAA-14C levels decreased in nephrectomized rats following probenecid. Peripheral decarboxylase inhibition by MK-486 was enhanced by both probenecid and nephrectomy. Increased penetration of 5-HTP into brain occurred following probenecid. Thr results indicate that the following MK-486 about 20% of the blood 5-HIAA-14C derived from 5-HTP-14C in rats originates in the CNS.

5-Hydroxytryptophan↗
PubMed1977

Renal excretion of a slauretic-uricosuric agent (MK-196) and interaction with a urate-retaining drug, pyrazinoate, in the chimpanzee.

The excretory pattern for MK-196 is ocmpatible with that of other weak organic acids such as salicylate and probenecid. Tubular secretion of MK-196 is strongly inhibitied by probenecid and high loads of p-aminohippurate. Urinary excretion of MK-196 is increased 10-fold when the urine is alkaline. Clearances of MK-196 were not corrected for plasma protein binding of the drug which is very high (greater than 99%). Bidirectional transport processes are operative in that MK-196 is secreted by the renal tubule and passively back diffuses across the tubular epithelium by a pH-dependent process. MK-196 is able to overcome pyrazinoate-induced urate retention, whereas probenecid is not when studied by conventional clearance techniques. The uricosuric activity of MK-196 appears to be somewhat less with pyrazinoate than in its absence. When MK-196 is administered prior to pyrazinoate an attenuated uricosuric response was observed. This finding cannot be ascribed to a temporal decline in uricosuric action. Diuresis and saluresis produced by MK-196 are not influenced by pyrazinoate. The interaction of MK=196 and pyrazinoate on urate excretion is in direct contrast to results obtained with probenecid and pyrazinoate. A model has been proposed to explain this unique finding.

Acetazolamide↗
PubMed1990

Microperfusion studies on the permeability of retinal vessels. A new model demonstrating organic anion transport and a reabsorptive fluid flux.

We developed an experimental model to study the permeability of individual retinal vessels in vitro using microperfusion techniques adapted from kidney tubule studies. The retinal vessels were isolated by freehand dissection and mounted on a microperfusion apparatus. When inulin was perfused luminally, it was diluted to 80.2 +/- 2.3% of its initial concentration. However, no radioactive leak into the bath side was observed, suggesting that the dilution was due to fluid flux from bath to lumen. The dilution of fluorescein (81.9 +/- 3.8%) was in the same range as that of inulin, the reference marker. The extremely low lumen-to-bath fluorescein flux, 0.5 +/- 0.9 X 10(-12) mol/min/mm, increased by 68% when probenecid was added to the perfusate and by 210% when probenecid was placed in the bath. The effect was concentration-dependent. When placed in the bath, fluorescein moved rapidly across the retinal vessel walls, accumulating in the lumen to concentrations 40 times higher than in the bath. This movement from bath to lumen, which was much higher (13.6 +/- 0.3 X 10(-12) mol/min/mm) than the lumen-to-bath fluorescein flux for the same fluorescein concentration, decreased by adding probenecid to the bath. The kinetics of this unidirectional movement of fluorescein were consistent with a saturable active transport process. The fluid flux from bath to lumen across the retinal vessels, which was 6.3 +/- 1.0 nl/min/mm for perfusion rates of 6.6 +/- 0.2 nl/min, was temperature-dependent and was coupled to the fluorescein transport. Fluorescein stimulated the fluid flux by 17% when added to the perfusate and by 60% when added to the bath, and this effect could be reversed by probenecid. Our results showed an active transport of fluorescein in the rabbit retinal vessels coupled with net fluid flux from outside the vessels into the lumen.

Animals↗
PubMed1978

Supersaturation of urine with uric acid and urate: response to a uricosuric diuretic.

In order to assess the possibility that treatment with the uricosuric diuretic ticrynafen (tienilic acid) could lead to UA or MSU crystalluria, the degree of urinary supersaturation with respect to these crystalloids was assessed in persons receiving the diuretic for 1 week, and the results were compared with similar data generated from the use of probenecid. Initially, only probenecid significantly increased the degree of urinary suspersaturation with respect to MSU, and after adjustment of urine pH values to 5.5, probenecid also increased the degree of urinary supersaturation with respect to nonionized UA. At a pH of 5.5, the urine was significantly more supersaturated with nonionized UA after a single dose of probenecid than after ticrynafen (tienilic acid). Ticrynafen never significantly affected the degree of urinary supersaturation with respect to UA or MSU. Neither agent affected small amounts of "colloidal" or "bound" urinary urate. Insofar as the degree of urinary supersaturation with these crystalloids predisposes to crystalluria and calculus formation, ticrynafen (tienilic acid) appears to present no increased risk.

Crystallization↗
PubMed1986

Characteristics of renal p-aminohippurate and urate excretion in rabbits.

Urate and p-aminohippurate (PAH) excretion was studied in New Zealand white rabbits to determine the extent to which the renal tubular handling of these organic anions by intact kidneys paralleled observations made in single isolated perfused tubules in vitro. At low plasma concentrations (less than 60 mumol/L) net reabsorption of urate was observed in the majority of animals; as plasma urate concentration was increased by infusing lithium urate, net urate secretion was demonstrated, the fractional excretion of urate (FE urate) reaching 270%, and net urate secretion (filtered urate minus urinary concentration of urate times volume flow rate) 1.8 mumol/min at mean plasma urate levels 200 and 310 mumol/L. A maximal urate secretion rate was not demonstrated. Probenecid (250 mumol/kg) reduced FE urate to 27%, thereby revealing concealed reabsorption despite high plasma urate levels. By contrast, net secretion of PAH at all plasma levels was achieved by infusing NaPAH. The highest secretory rate was 38.6 mumol/min at plasma PAH levels between 1000 and 1750 mumol/L. Probenecid reduced fractional excretion of PAH (FEPAH) from 796% to 265%, no evidence of PAH reabsorption being found after inhibition of secretion with probenecid. At comparable plasma levels (220 mumol/L), net PAH secretion exceeded net urate secretion (reflected by the decrement in urate and PAH excretion caused by probenecid) by a factor of 5.3:1. These experiments indicate that urate and PAH are filtered and secreted by the rabbit kidney; however, only urate is significantly reabsorbed over the range of plasma organic anion levels examined. The configuration of the relation between plasma levels and net secretion rates and the greater secretory rate for PAH for urate in the living rabbit are consonant with the characteristics of PAH and urate transport determined previously in studies of isolated perfused proximal tubules.

Aminohippuric Acids↗
PubMed1985

Effects of the diuretic torasemide on p-aminohippuric acid transport in the rat.

The effect of torasemide, a new diuretic, on p-aminohippuric acid (PAH) transport (TPAH) was studied using renal clearance and micropuncture techniques in anaesthetized rats. In clearance experiments, TPAH and TPAH/glomerular filtration rate (GFR) did not significantly change after i.v. administration of torasemide or furosemide but decreased after probenecid injection. In order to enhance the possibility to demonstrate torasemide and PAH interference, small volumes of [3H]-PAH + [14C]-inulin solutions were directly injected into the peritubular capillary system using calibrated micropipettes. When the concentration of microinjected PAH was less than or equal to 0.6 mmol/l, fractional recovery of [3H]-PAH from the micropunctured kidney was not significantly decreased by the diuretics in contrast to probenecid. When the concentration of microinjected PAH was greater than or equal to 5 mmol/l, fractional recovery of [3H]-PAH from the micropunctured kidney was significantly decreased by torasemide from 252% (control) to 210% (P less than 0.005), by furosemide to 217% (P less than 0.005), and by probenecid to 205% (P less than 0.01). Under these conditions, differential transit times between [3H]-PAH and [14C]-inulin in the micropunctured kidney were decreased from -15 to -4 s in the presence of torasemide (P less than 0.05). They were slightly but not significantly reduced by furosemide and probenecid. These findings suggest interference, at least to some extent, between torasemide and PAH secretion in the rat kidney.

Aminohippuric Acids↗
PubMed1974

Single-dose treatment of gonococcal urethritis in males: evaluation of procaine penicillin, ampicillin and spectinomycin.

Males with acute gonococcal urethritis were treated at random with 2.4 million units aqueous procaine penicillin G intramuscularly plus 1.0 g. probenecid orally, 3.5 g. ampicillin orally plus 1.0 g. probenecid orally, or 2.0 g. spectinomycin intramuscularly. The overall follow-up was 97%. All treatments were of equal efficacy, eradication of gonococcal disease being observed in 93 to 97% of treated patients. Treatment failures occurred in each drug group and pre-treatment isolates recovered from these cases showed decreased susceptibility to the agent used. Aqueous procaine penicillin G plus probenecid remains the preferred therapy for gonorrhea. For patients hypersensitive to penicillin, spectinomycin is currently a reasonable alternative drug. This agent, unlike procaine penicillin-probenecid, is probably ineffective against concurrent incubating syphilis, and future development of bacterial resistance is a definite possibility.

Administration, Oral↗
PubMed1983

Cyclic GMP efflux from liver slices.

Cyclic GMP efflux from liver slices was studied when the intracellular cyclic GMP levels were elevated by incubation with N-methyl-N'-nitro-N-nitrosoguanidine (0.1 mM) and 3-isobutyl-1-methylxanthine (0.25 mM). A probenecid-sensitive and a probenecid-insensitive efflux system for cyclic GMP was found. It is suggested that the former system operates a carrier, which is saturable, the capacity of which is increased by alkylation with N-ethylmaleimide. The rate of net efflux of cyclic GMP increases 20-fold in the temperature interval 18-37 degrees C. Probenecid (0.5 mM) gives 50% inhibition of this system. The probenecid-insensitive cyclic GMP efflux component probably corresponds to passive diffusion. It appears that efflux may be an important complement to cyclic 3':5'-nucleotide phosphodiesterase activity in reducing intracellular cyclic GMP levels.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Accumulation of cimetidine by kidney cortex slices.

The mechanisms involved in the excretion of the histamine H2-receptor antagonist cimetidine are as yet incompletely understood. The purpose of this study was to examine the interaction of cimetidine with incubated slices of dog kidney cortex. The results of time and concentration-dependent experiments by using 3H-labeled cimetidine demonstrated that the drug was accumulated without metabolism against a concentration gradient by a saturable process. Inhibition of uptake by cyanide and by incubation under a nitrogen atmosphere indicated energy dependence. Uptake of cimetidine by active cationic transport was likely inasmuch as both cyanine 863 and quinine blocked accumulation. However, a probenecid-sensitive component, accounting for about 20% of steady-state accumulation, also was identified. The lack of inhibitory action of p-aminohippuric acid and the cationic nature of the cimetidine molecule suggest the probenecid-sensitivity was not related to the renal organic anion mechanism. Further, probenecid inhibition was not due to a generalized cellular toxicity because maximally inhibitory concentrations of probenecid did not interfere with uptake of the cation tetraethylammonium.

Animals↗