Cinoxacin (Cinobac, Eli Lilly & Co.)

Cinoxacin, a synthetic organic acid antibacterial agent, related structurally to nalidixic and oxolinic acid, has been approved for the treatment of initial and recurrent urinary tract infections (UTIs) caused by susceptible gram-negative microorganisms. The role of cinoxacin in the treatment of UTIs, compared with the usual first-line agents, is uncertain at this time. The efficacy of cinoxacin in the treatment of pyelonephritis, compared with these proven agents, has been examined in only small numbers of patients, and cinoxacin is more expensive than these agents. Cinoxacin may prove valuable in the treatment of prostatitis and in the prophylaxis of recurrent UTIs; further study in these areas is warranted. In the routine treatment of acute UTIs, cinoxacin perhaps should be reserved only for those patients with organisms resistant to usual first-line agents or those who fail to respond to therapy with these agents. In this respect, cinoxacin may, in the future, replace nalidixic acid.     

Kinetics of p-aminohippurate transport in renal cortical slices from neonatal and adult rats

PAH accumulation in renal cortical slices of rats is age-related different. Kinetic parameters were quantified using the Lineweaver-Burk analysis. The Michaelis constant for PAH uptake is 0.50 mM in all age groups, i.e., the affinity of PAH for the transport sites is the same. The maximum PAH concentrations (steady-state) in renal cortical slices from 5-, 20-, 33-, and 55-day-old rats are 0.91, 1.72, 2.57, and 1.72mM, respectively. This finding suggests that the number of transport sites is increasing during the postnatal development of the kidney.     

Cinoxacin. A review of its pharmacological properties and therapeutic efficacy in the treatment of urinary tract infections

Cinoxacin is a urinary antibacterial drug closely related structurally to nalidixic acid. It has a spectrum of in vitro antibacterial activity which qualitatively resembles that of the latter agent, covering most common Gram-negative pathogens, excluding Pseudomonas. In acute or recurrent urinary tract infections it has been shown to be at least as effective as nalidixic acid or co-trimoxazole, and in a few studies was as effective as amoxycillin or nitrofurantoin. Cinoxacin appears to be well tolerated and may have a low propensity to induce bacterial resistance during clinical use, although the latter needs further confirmation. Thus, cinoxacin is an effective alternative for treating urinary tract infections due to common Gram-negative pathogens, and its apparently low incidence of adverse effects may offer worthwhile advantages over the related compounds nalidixic and oxolinic acids. Its use as prophylactic therapy in patients with recurrent urinary tract infections is not yet well established, although this appears a worthwhile area for further study.     

The acute toxic effects of hexachloro-1 : 3-butadiene on the rat kidney

A single intraperitoneal injection of hexachloro-1 3-butadiene (HCBD) at 100 mg/kg or above produced renal tubular necrosis in the rat by 24 h. Histological examination of the kidneys indicated damage to the straight portion of the proximal tubules. Urinary analysis showed diuresis, increased proteinuria and an increase in the excretion of N-acetyl--d-glucosaminidase, and alkaline phosphatase at doses above 100 mg/kg. At doses below 100 mg/kg only a mild increase in protein excretion was observed. Twenty-four hours after 200 mg/kg HCBD, i.p., there was a marked decrease in the glomerular filtration rate (inulin clearance) and in the clearance of the organic anion (p-aminohippuric acid, PAH) and the organic cation (tetraethylammonium bromide, TEA) by the kidney. HCBD did not affect the accumulation of PAH or TEA by renal cortical slices when added in vitro at a concentration up to 0.1 mM. However, a decrease in PAH, but not TEA accumulation, was seen in renal cortical slices from rats treated with HCBD 24 h previously. Mercuric chloride (HgCl₂, a known nephrotoxin, was used as a positive control for these studies.HCBD appears to specifically damage the straight portion of the proximal renal tubule and thereby selectively damage the organic anion transport system.     

The acute toxic effects of paraquat and diquat on the rat kidney.

The bipyridyls, paraquat and diquat, cause mild renal tubular damage in the rat. A marked diuresis, albuminuria, glucosuria, and an increased plasma urea concentration occurred 6–24 hr after paraquat (680, po, or 108 μmol/kg, sc) and an increased urinary excretion of N-acetyl-β-d-glucosaminidase occurred 6–24 hr after paraquat (680 μmol/kg, po). Diquat (680 μmol/kg, po) produced proteinuria and glucosuria 6–24 hr after dosing. Histological examination of the kidneys showed there was mild hydropic degeneration of the proximal convoluted tubules. Mercuric chloride (HgCl₂), a nephrotoxic agent, was used as a positive control in these studies dosed at 7.4 μmol/kg, sc, and produced marked tubular necrosis. Biochemical studies showed that both paraquat and diquat decrease N′-methylnicotinamide (NMN) but not p-aminohippurate (PAH) accumulation by renal cortical slices when added in vitro, suggesting competition for the base transport system. However, no decrease in NMN or PAH accumulation was seen in renal cortical slices from rats treated with paraquat or diquat. Both bipyridyls stimulated pentose phosphate pathway and inhibited fatty acid synthesis when added in vitro to renal cortical slices. However, neither of these parameters were affected in renal cortical slices prepared from rats treated with paraquat or diquat. We conclude that both bipyridyls cause renal tubular damage but this damage is mild compared with that seen after HgCl₂. And that biochemical indicators of paraquat damage in the lung are not altered in renal cortical slices from bipyridyl-treated rats. These minimal changes observed using histological and biochemical techniques contrast sharply with the effects these compounds have on renal excretory function.     

Renal handling of nourseothricin

Nourseothricin 1 is preferentially excreted via kidney and signs of nephrotoxicity can be observed after its administration. Renal handling of 1 was characterized in experiments on renal cortical slices under various experimental conditions. Following administration in vivo or in vitro the renal tubular transport system for organic anions (p-aminohippurate, PAH) is not influenced by 1. There is a high degree of accumulation of 1 in renal cortical slices. In contrast to PAH accumulation there is no influence of nitrogen atmosphere, simultaneous administration of PAH, probenecid or trishydroxyaminomethane on 1 accumulation. Age dependent differences in 1 accumulation does not exist. Our data show a distinct uptake of 1 in kidney tissue. Accumulation of 1 in renal cortical slices is caused by binding; an active tubular transport of 1 in renal cortical slices could be excluded.     

Peroxidative damage and nephrotoxicity of dichlorovinylcysteine in mice

Male NMRI mice were treated i.p. with dichlorovinylcysteine (DCVC) in a dosage of 2.5-500 mg/kg-1 and renal cortical slices from naive mice were incubated with 0-125 micrograms/ml-1 DCVC. The effects of DCVC on blood urea nitrogen (BUN), reduced glutathione (GSH) content, malondialdehyde (MDA) production, p-aminohippuric acid (PAH)- and tetraethylammonium (TEA)-accumulation and glucose synthesis (gluconeogenesis) were measured. DCVC depleted GSH in a time- and dose-dependent manner. Depletion of renal cortical GSH by DCVC was more pronounced in the kidney cortex than in the liver. DCVC caused a dose-dependent increase of ethane exhalation and of MDA production in the renal cortex. When animals were kept in a closed system, decrease in oxygen concentration increased the peroxidative damage. No increase of MDA concentration was observed in the liver. Treatment of mice with DCVC induced a dose-dependent increase in BUN and decreased the accumulation of PAH and TEA in renal cortical slices. Pretreatment of mice with aminooxyacetic acid (AOAA) and (+) cyanidanol-3 (CY) caused a significant reduction in DCVC-induced lipid peroxidation and nephrotoxicity. In vitro incubation of renal cortical slices of naive mice with DCVC resulted in a concentration-dependent increase in MDA and a concentration-dependent decrease in the accumulations of PAH, TEA and of gluconeogenesis. In conclusion, the interaction of DCVC and/or its metabolites with membrane lipids may be responsible for lipid peroxidation and nephrotoxicity. The formation of lipid peroxidation products was greater under hypoxic conditions and appeared to be related to the DCVC-induced nephrotoxicity. This data suggests lipid peroxidation as a possible mechanism of DCVC-induced nephrotoxicity.     

Enhancement of gentamicin nephrotoxicity by glycerol

Gentamicin nephrotoxicity was evaluated in normal rats and in rats in which renal damage had also been induced by glycerol treatment. Daily gentamicin injections for 1–3 weeks caused kidney weight to increase, while glucose synthesis, oxygen consumption and organic base uptake by renal cortical slices were inhibited. Gentamicin did not inhibit organic acid transport by renal cortical slices. Concomitant treatment of some rats with glycerol at weekly intervals enhanced the increase in kidney weight produced by glycerol, and caused a further decrease in organic base transport and gluconeogenesis by kidney slices. The combined treatment also decreased body weight, caused enhanced histologic damage and inhibited organic acid transport. The results indicate that gentamicin nephrotoxicity is increased in rats with impaired renal function.     

Protective effect of resveratrol against 6-hydroxydopamine-induced impairment of renal<Emphasis Type="Italic"> p</Emphasis>-aminohippurate transport

In the present study, the effects of resveratrol on 6-hydroxydopamine (6-OHDA)-induced p-aminohippurate (PAH) transport impairment were investigated in vitro using rat renal cortical slices. Cisplatin and cephaloridine (CPH), known nephrotoxins, were used as positive controls. In one series of experiments, renal cortical slices were incubated in a cisplatin-containing medium or a cisplatin-free medium. In another series of experiments, renal cortical slices were incubated in a CPH-containing medium, in a CPH- and probenecid-containing medium, or in a CPH-free medium. Subsequently, for each series of experiments kidney slices were incubated in a media containing PAH or tetraethylammonium. In a further series of experiments, renal cortical slices were incubated in a 6-OHDA-containing medium and in a 6-OHDA-free medium. In another series of experiments, renal cortical slices were incubated in a medium containing 50 µM 6-OHDA, in a 6-OHDA- and resveratrol-containing medium or in a 6-OHDA- and resveratrol-free medium. Subsequently, for each series of experiments kidney slices were incubated in media containing PAH. The results of this study in which slices were incubated in 6-OHDA-containing media indicate that 6-OHDA induced a time- and concentration-dependent decrease in PAH accumulation by renal cortical slices. Resveratrol inhibited the 6-OHDA-induced time-dependent decrease of PAH accumulation in a concentration-dependent manner. Therefore, 6-OHDA causes functional injuries of renal proximal tubule cell membrane, thus leading to impairment of transport processes across the cell membrane and to nephrotoxicity. Resveratrol has a nephroprotective effect.     

p-Aminohippurate (PAH) transport and Na-K-ATPase activity in rat renal cortical slices during postnatal maturation and drug-induced stimulation

PAH transport and Na-K-ATPase activity markedly increase during the first month of postnatal life. Pretreatment of rats with PAH or cyclopenthiazide induces a stimulation of in vitro PAH accumulation in renal cortical slices, whereas Na-K-ATPase activity is unchanged in comparison to saline-pretreated controls. 5 mM ouabain in the incubation medium reduces PAH accumulation. Developmental pattern and stimulation effects are pronounced as in controls. The ouabain-insensitive component of net PAH accumulation progressively increases with age and is significantly enhanced following drug pretreatment, whereas the ouabain-sensitive component of net PAH accumulation shows relatively slight modifications. Consequently, Na-K-ATPase seems not to be linked with postnatal maturation or drug-induced stimulation in tubular PAH transport.     

Cinoxacin: Mechanism of Action,Spectrum of Activity,Pharmacokinetics, Adverse Reactions,and Therapeutic Indications

Cinoxacin, a chemotherapeutic agent that inhibits bacterial DNA synthesis, has recently been approved for the treatment of initial and recurrent bacterial urinary tract infections. Although closely related to nalidixic acid, cinoxacin possesses some distinct characteristics: rapid attainment of therapeutic urinary concentrations and greater activity against strains of Enterobacteriaceae that cause urinary tract infections. Biopharmaceutical properties include serum protein binding of approximately 70%, 50–60% excretion of intact drug in the urine of patients with normal renal function, and an elimination half-life of approximately one hour. The elimination half-life is increased in patients with decreased renal function and when probenecid is coadministered. Adverse events occur infrequently and consist of nausea, vomiting, headache, dizziness, and hypersensitivity reactions. The drug compares favorably with standard therapies for the treatment of bacterial cystitis and recurrent urinary tract infections. Initial studies demonstrate that cinoxacin has substantial efficacy as a prophylactic agent for those women who experience recurrent, symptomatic urinary tract infections.     

Hemodynamic parameters and renal blood flow following stimulation of renal tubular transport processes by treatment with thyroid hormones

In adult rats, renal excretion of p-aminohippurate (PAH) can be stimulated by repeated administration of thyroid hormones. Data on renal cortical slices show clearly that a stimulation of active, carrier-mediated tubular transport processes is the most important cause. In vivo experiments also show an influence of treatment with thyroid hormones on various hemodynamic parameters. The diminution of vascular resistance in cortical and medullary regions of the kidney might contribute to the increased PAH excretion in thyroid hormone-treated rats.     

Evidence for in vivo effect of lithium on p-aminohippurate transport in rat kidney, preliminary study

We examined the effect of lithium on rat renal handling of p-aminohippurate (PAH) and accumulation of organic ions by rat kidney cortical slices. When infused intravenously with lithium at the rate of 0.13 mmoles/kg/min, decreased renal clearance of PAH as well as no significant changes in glomerular filtration rate and plasma PAH level was observed at the first clearance period during lithium infusion. As we expected, tubular secretion of PAH also was decreased significantly by the infusion of lithium. Therefore, it is suggested that the decrease in the clearance of PAH was due to the decrease in the tubular secretion of PAH. After four days of injections with lithium (4 mmoles/kg, i.p., once a day), a significant decrease in PAH accumulation in the slices was detected. No inhibition of tetraethylammonium accumulation was observed. Lithium pretreatment did not alter water content and extracellular space of the slices. The results suggest that lithium selectively inhibits the organic anion transport system in kidney with the in vivo treatment and follows our previous work in which we showed the in vitro effect of lithium on organic anion accumulation in the slices.     

Possible nephrotoxic effect of carbon tetrabromide and its interaction with chlordecone

The hepatotoxic and nephrotoxic effects of CBr4 were studied in male Sprague-Dawley rats following a single i.p. administration in a dose range of 25 to 125 microliter/kg to animals maintained for 15 days either on normal diet or a diet containing 10 ppm chlordecone (CD). At these doses, CBr4 did not cause hepatotoxic effects when given alone or in combination with prior exposure to CD. CBr4 caused renal dysfunction characterized by oliguria, aciduria and hypo-osmolality, and these effects were abolished by dietary CD pretreatment. In vitro incubation of renal cortical slices obtained from CBr4-treated animals revealed a significant depression of organic anion transport, i.e., decreased transport of p-aminohippurate (PAH). Organic cation transport was unaffected as judged by accumulation of tetraethylammonium (TEA). CBr4-induced renal dysfunction appeared unrelated to depressed PAH transport since CD pretreatment which abolished renal dysfunction failed to restore PAH transport. These results show that CD does not potentiate CBr4 hepatotoxicity and the nephrotoxic effects of this halomethane are abolished by prior exposure to CD.     

Effects of different nickel compounds on the transport of para-aminohippurate ion by rat renal cortical slices

In vitro rat renal cortical slice uptake of para-aminohippurate ion (PAH) expressed as tissue slice-to-medium ratio was used as a model to predict nephrotoxicity of different nickel compounds. Pretreatment with nickel compounds for a period of up to 4 h was followed by an incubation with 74 microM PAH for 2 h. The PAH uptake by renal cortical slices was reduced by nickel compounds in both concentration- and time-dependent manner. Furthermore, the extent of such reduction of PAH uptake was found to depend on the chemical form (speciation) of nickel. Thus, slice-to-medium ratios were 41, 49, 48, and 66% of control values after a 4-h pretreatment with 0.378 mM nickel carbonate hydroxide, 1.5 mM nickel subsulfide, 4 mM nickel sulfate and 2.98 mM nickel oxide, respectively. Such an inhibition of PAH transport was not due to cytotoxicity. The results suggest that the nephrotoxic potency decreases in the following order: nickel carbonate hydroxide>nickel subsulfide>nickel sulfate>nickel oxide. Treatment of renal cortical slices with high concentrations of either mannitol, a hydroxyl radical scavenger, or glutathione significantly reduced the inhibition of PAH uptake by soluble form of nickel subsulfide, with concomitant reduction of nickel ion uptake by cortical slices. But no such oxidative stress seems to be involved in nickel carbonate hydroxide-induced inhibition of PAH uptake.     

Effect of cisplatin on in vitro production of lipid peroxides in rat kidney cortex

Cisplatin (cis-diamminedichloroplatinum II), an antitumor agent with a dose-limiting adverse effect of nephrotoxicity, increased lipid peroxidation in a time- and concentration-dependent manner in rat renal slices incubated in vitro. The addition of an antioxidant, N-N'-diphenyl-p-phenylenediamine (DPPD), to the incubation medium completely inhibited this increase. We also studied the in vitro effects of agents that modify cisplatin nephrotoxicity on lipid peroxidation in the slices caused by cisplatin. Mannitol, which protects against cisplatin nephrotoxicity, almost completely inhibited the increase in lipid peroxidation caused by cisplatin. Methionine, which potentiates cisplatin nephrotoxicity, made the slices more susceptible to peroxidation. The decrease with cisplatin in p-aminohippurate (PAH) accumulation in incubated kidney cortical slices, the accumulation being a representative biochemical process in the transport ability of renal cells, was partially inhibited when DPPD was in the medium. The results suggested that cisplatin directly affected renal tissues in which free radicals generated by cisplatin may interact with membrane lipids to cause the production of lipid peroxides that damage membrane function. Compounds that modify cisplatin nephrotoxicity such as mannitol and methionine may act by affecting the production of renal lipid peroxides by cisplatin.     

Effect of chronic lead treatment on renal function

When rats were fed diets containing 1% or 2% lead acetate for 10–40 weeks, the kidney weight: body weight ratio was increased. Renal tissue water content was not changed. Accumulation of PAH and TEA by renal cortical slices from treated rats was not altered, but the capacity of kidney slices to synthesize glucose and metabolize pyruvate was decreased. Doses of 200 ppm lead or less had no effect on these parameters. Rats treated with 1% or 2% lead acetate showed an increase in the percentage of an injected dose of PAH excreted in 2 hr. Treatment of dams at parturition with 2% or 4% lead acetate resulted in an increase in the kidney weight: body weight ratio in the offspring at 30 days of age, an increase in PAH uptake by renal cortical slices, and a decrease in renal gluconeogenesis. Histologic examination of kidneys after lead treatment showed varying degrees of vacuolar degeneration and cellular necrosis, and the presence of some lead inclusion bodies.     

Studies on the nephrotoxicity of ochratoxin A in rats.

Administration of ochratoxin A (5 or 15 mg/kg/day, po) to rats daily for 3 days decreased the accumulation of p-aminohipuuric acid (PAH) in renal cortical slices. PAH clearance (C_PAH) was more depressed than inulin clearance (C_IN) in ochratoxin A-treated rats (5 mg/kg/day, po). The filtration fraction was increased by ochratoxin A treatment. Ochratoxin A, ochratoxin α, and citrinin inhibited the accumulation of PAH by renal tissue in vitro. These results reflected, at least in part, a cytotoxic action of ochratoxin A on renal cortical tissue.     

In vitro uptake of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) by renal cortical tissue of rabbits and rats

The active transport of 2,4-D and 2,4,5-T by renal cortical slices of rats and rabbits has been characterized with in vitro techniques. Renal cortical slices, prepared from both species, accumulate 2,4-D and 2,4,5-T, although greater uptake, was noted with rabbit tissue. Nitrogen and various metabolic inhibitors reduced the uptakes. This indicates that these processes are energy dependent. The enhancement of accumulation by the addition of certain metabolic substrates, e.g. acetate, lactate, provides evidence that both organic acid herbicides are transported by the renal organic anion mechanism. Potassium-ion stimulation also supports this concept. It is concluded that the renal tubular transport by the organic anion mechanism may account for the relatively rapid disappearance of these compounds, which in turn may contribute to their low toxicity.     

Pharmacokinetics and tissue distribution of uraemic indoxyl sulphate in rats

The purpose of the present study was to examine the pharmacokinetic properties of indoxyl sulphate, a harmful uraemic toxin that accumulates during chronic renal failure. The pharmacokinetics and tissue distribution of indoxyl sulphate were examined in normal and 5/6 nephrectomized (CRF) rats. The uptake process of indoxyl sulphate by rat renal cortical slices in vitro was also investigated. Endogenous indoxyl sulphate was found to be mainly distributed in the kidney. The rate of elimination of indoxyl sulphate from plasma was lower in CRF rats compared with sham-operated rats. The majority of intact indoxyl sulphate was excreted in the urine. In renal cortical slice experiments, uptake of indoxyl sulphate was a saturable process with a K(m) of 43.0 microm. Furthermore, sulphate conjugates, such as oestrone sulphate and dehydroepiandrosterone sulphate, inhibited the uptake of indoxyl sulphate to a greater extent than PAH. Thus, indoxyl sulphate is primarily eliminated from the plasma via the kidney by active tubular secretion, and renal uptake of indoxyl sulphate appears to be mediated by an organic anion transport system with a high affinity for oestrone sulphate and dehydroepiandrosterone sulphate.