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PubMed2002

Reduction of cisplatin hepatotoxicity by procainamide hydrochloride in rats.

In preceding papers, we proposed that procainamide hydrochloride, a class I antiarrhythmic agent, was able to protect mice and rats from cisplatin-induced nephrotoxicity and that it could exert its action through accumulation in kidneys followed by coordination with cisplatin (or its hydrolysis metabolites) and formation of a less toxic platinum compound similar to the new platinum(II) triamine complex cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate, obtained by the reaction of cisplatin with procaine hydrochloride. Hepatotoxicity is not considered as a dose-limiting toxicity for cisplatin, but liver toxicity can occur when the antineoplastic drug is administered at high doses. Here, we report that procainamide hydrochloride, at an i.p. dose of 100 mg/kg, reduces cisplatin-induced hepatotoxicity, as evidenced by the normalization of plasma activity of glutamic oxalacetic transaminase and gamma-glutamyl transpeptidase, as well as by histological examination of the liver tissue. Twenty-four hours after i.p. treatment with the combination of 7.5 mg/kg cisplatin and 100 mg/kg procainamide, a significant increase of procainamide (+56%, P<0.05), total platinum (+31%, P<0.05), platinum-DNA adducts (+31%, P<0.05) and percent DNA-DNA interstrand cross-links (+69%, P<0.02) was found in liver tissue, as compared to animals treated with cisplatin alone. Moreover, in accordance with these findings, we also observed a slightly lower concentration and cumulative excretion of platinum in the feces. Since mitochondrial injury is considered a central event in the early stages of the nephrotoxic effect of cisplatin, the distribution of platinum in these subcellular organelles obtained from hepatocytes was determined after treatment with cisplatin with or without procainamide hydrochloride, together with platinum concentration in their cytosolic fraction. Our data show that the coadministration of procainamide hydrochloride produced a rearrangement of subcellular platinum distribution in hepatocytes with a slight decrease in mitochondria (-15%, P<0.10) and a slight increase in the cytosolic fraction (+40%, P<0.10) of platinum content, compared to the treatment with cisplatin alone. In analogy with our previous results in the kidney, confirmed here by our data in vitro, we suggest that the hepatoprotective activity of procainamide hydrochloride is linked to the formation of a less toxic platinum complex, which leads to inactivation of cisplatin itself and/or its highly toxic hydrolysis metabolites and to a different subcellular distribution of platinum.

Animals↗
PubMed2000

Determination of trimebutine and desmethyl-trimebutine in human plasma by HPLC.

A simple and sensitive HPLC method has been developed to measure trimebutine (CAS 39133-31-8, maleate: CAS 34140-59-5) and its main metabolite desmethyl-trimebutine in human plasma. The method was validated according to the Washington Consensus Conference on the Validation of Analytical Methods. It involved extraction of the plasma with n-hexane containing 2-pentanol, followed by reversed-phase HPLC using a Partisil ODS2 10 microns column and UV detection at 265 nm. The retention times of the internal standard (procaine), desmethyl-trimebutine and trimebutine were 2.4, 4.3 and 6.5 min, respectively. The standard curves were linear from 20 ng.ml-1 (limit of quantitation) to 5000 ng.ml-1 for both compounds. The coefficient of variation for all the criteria of validation were less than 15%. The extraction recoveries obtained for trimebutine and desmethyl-trimebutine were about 90%. Both compounds were very stable upon storage in plasma. The method was tested by measuring the plasma concentrations following oral administration to humans during a bioequivalence study and was shown suitable for pharmacokinetic studies.

Calibration↗
PubMed1976

Mechanism of action of some bitter-tasting compounds on frog taste cells.

Effects of some bitter-tasting compounds on frog taste receptors were examined by recording glossopharyngeal nerve responses. The order of effectiveness of the compounds was quinine greater than brucine greater than formanilide greater than caffeine greater than urea. When the effects of quinine, brucine and caffeine on electrical responses in taste cells were examined, they all produced a depolarization associated with an increased input resistance. The action of the three compounds on taste receptors therefore, operates with a similar mechanism. The electrical responses in cells, produced by quinine, progressed slowly with time. Such effects with quinine are similar to those with procaine. After adaptation to quinine, the nerve responses to various chemical stimuli were gradually reduced in magnitude, while the electrical responses in taste cells during stimulation by chemicals became smaller. The mechanism of the effects of bitter stimuli are discussed in light of recent findings on the interaction of bitter stimuli with lipid monolayers and the extraction of lipid from bovine taste papillae by bitter stimuli.

Animals↗
PubMed1970

Effects of some drugs on the responses of the rat isolated, innervated urinary bladder to indirect electrical stimulation.

1. The effects of some drugs known to inhibit transmission in the superior cervical ganglion and at the neuromuscular junction were investigated on the cholinergic nerve-smooth muscle junction, using the rat isolated innervated urinary bladder preparation.2. HC-3 and Win 4981 inhibited the indirectly evoked contractions; the block was typically slow in onset, depended on the rate of stimulation and was partially reversed by choline. The moderate coincident inhibition of acetylcholine-responses disappeared after washing the tissue, while the block of the neuronally evoked contractions persisted.3. Morphine, methylpentynol carbamate, chloral hydrate and strychnine inhibited indirectly evoked contractions without inhibiting the responses to acetylcholine. Paraldehyde inhibited both types of response.4. Hexamethonium, mecamylamine and tubocurarine had no effect on either type of response. Tetraethylammonium augmented both types of response; the augmentation due to lower concentration was followed by a moderate block of the neuronally evoked contractions.5. Small concentrations of procaine markedly inhibited responses to acetylcholine and produced a partial block of the neuronally evoked contractions.6. None of the drugs affected conduction in the isolated phrenic nerve.7. All the drugs other than paraldehyde and procaine appeared to act at the nerve terminals. The results are generally consistent with the view that HC-3 and Win 4981 act by limiting transport of choline across nerve membrane and that the other drugs act by inhibiting the release of acetylcholine. A reduction in sensitivity of the effector cell membrane may account, wholly or in part, for the action of paraldehyde and procaine.

Animals↗
PubMed1975

Local anesthetic activity of 1-(morpholino or piperidino)-2-propanol derivatives.

The local anesthetic activities of 1-(morpholino or piperidino)-2-propanol derivatives were investigated. These activities were observed with nerve trunk anesthesia, rabbit's corneal anesthesia and intradermal injection anesthesia. Among these propanol derivatives, No. 24 and No. 25 which possess thioether-type sulfur were the most active and the effective potency was enhanced by increasing the dissociation constant (pKa) value in a series of the compounds. Effects on cat spinal reflex were also observed. These propanol derivatives revealed no selective depression of presynaptic depression or depression of the potential of monosynaptic reflex (MSR) and polysynaptic reflex (PSR). Procaine and lidocaine had similar actions. Effects on axonal membrane potential and interaction of the calcium on these derivatives were also investigated. These derivatives decreased the action potential without altering the resting membrane potential and when antagonized with calcium, sciatic nerve action potential was decreased. Procaine and idocaine also showed the same results.

1-Propanol↗
PubMed1985

Sensorineural hearing loss in experimental purulent otitis media due to Streptococcus pneumoniae.

Sensorineural hearing loss (SNHL) has been described clinically following chronic otitis media with effusion, but to the best of our knowledge, no studies have demonstrated SNHL in an animal model of otitis media. Using the chinchilla model of pneumococcal otitis media, significant SNHL was demonstrated after purulent otitis media, especially at higher frequencies. Animals with otitis media received penicillin G procaine treatment for five days after otitis media with effusion (OME) was first documented; resolution of middle ear infection was confirmed by middle ear effusion culture in all animals. Both the inoculated and uninoculated ears were examined by tone burst-elicited compound action potential at threshold. The inoculated ear showed a marked hearing loss of 13 to 36 dB three to four days after OME was first documented; a hearing loss up to 24 dB persisted two to five weeks after inoculation. The change in the compound action potential was highly significant at all frequencies studied. Conductive losses were largely ruled out because there was no middle ear effusion at death and the tympanogram was normal. Purulent labyrinthitis was ruled out by histopathological study. These results indicate that purulent pneumococcal otitis media in the chinchilla model causes significant SNHL and suggest that the pathogenesis of SNHL associated with chronic OME in humans may be studied in this model.

Animals↗
PubMed1986

Separation and identification of illicit heroin samples by liquid chromatography using an alumina and C18 coupled column system and photodiode array detection.

The analysis of illicit heroin and opium samples on a coupled alumina and C18 column system is described. The compounds to be analysed can be divided into two groups: those with low pKa values, such as caffeine, papaverine and noscapine, and those with high pKa values, such as heroin, acetylcodeine, O6-monoacetylmorphine, procaine, codeine, morphine and strychnine. The first group can best be separated on a C18 column, whereas alumina is more suitable for the second group. Previously reported criteria for choosing proper buffer systems for ion-exchange separations on alumina were used together with an iterative regressive optimization procedure developed in our laboratory. The system can be used with and without valve-switching, depending on the sample type. The peak purity of the judicially important components heroin and O6-monoacetylmorphine has been checked with a photodiode array detector and by use of advanced software.

Chromatography, Liquid↗
PubMed2004

Cross-reactivity among p-amino group compounds in sulfonamide fixed drug eruption: diagnostic value of patch testing.

We studied 28 patients with fixed drug eruption (FDE) caused by sulfonamide antibiotics to investigate cross-reactivity between sulfonamide derivatives and p-amino compounds and to explore the usefulness of patch testing, as an alternative to controlled oral challenge testing (COCT), in diagnosis within this clinical area. COCT with sulfamethoxazole (SMX), sulfadiazine (SDZ), sulfamethizole (SMZ), furosemide (FU), procaine (PRO) and glipizide (GPZ) was performed. Patch testing (PT) with SMX and SDZ was carried out. In all patients, the diagnosis of FDE was confirmed by positive COCT and allergy to trimethoprim ruled out by COCT. 42.8 and 31.8% of the SMX-induced FDE patients reacted to SMZ and SDZ, respectively. All patients (n = 28) tolerated FU, PRO and GPZ. COCT performed with the 3 sulfonamide antibiotics in 12 patients was positive in 2 subjects with the 3 drugs, in 2 patients only with SMX and SMZ and in the remaining 8, SMX was the only causative drug. PT was positive in 5 of 25 patients positive on COCT. The probability of obtaining a positive PT was higher among patients who had a residual lesion than that among those who lacked this. Cross-reactivity between different sulfonamide antibiotics is thus variable, being most likely between SMX and SMZ. We have found no cross-reactivity between sulfonamide antibiotics and other sulfonamide derivatives or p-amino drugs in FDE. PT is a useful tool in the diagnosis of FDE, especially if there are residual lesions, because it avoided the need for COCT in 20% of patients.

Administration, Oral↗
PubMedDate not supplied

Common solvent toxicity: autoxidation of respiratory redox-cyclers enforced by membrane derangement.

Unspecific biological effects of chemically diverse solvents strikingly reveal the unifying motif of oxidant toxicity both in higher organisms and in aerobic bacteria. In a few spectacular cases, solvent metabolites with oxidant properties were demonstrated, which however cannot explain extrahepatic toxicity, e.g. in muscle and nerve cells. A common source of solvent-inducible oxidants, by contrast, is suggested to be located in mitochondria or, more general, in membranes where the respiratory chain operates. Orderly respiration depends on membrane integrity, which is invariably compromised by exposure to most solvents and many other lipophils. In rat mitochondria, toluene-induced membrane derangement has been directly implicated with superoxide production, resulting from autoxidation of the membrane-located respiratory redox-cycler ubisemiquinone. A related mechanism may occur in bacteria: Exposure of Escherichia coli to lipophils such as ethanol, tetralin, indole, chlorpromazine and procaine, or to heat shock, induces anti-oxidant proteins, which are reliable indicators of increased oxidant levels. Although many molecular details remain to be elucidated, this review documents that oxidant toxicity of lipophilic compounds is a common physiological phenomenon correlated with derangement of membranes where respiratory processes take place. Subjective consequences of acute oxidant injury are probably the hangover from alcohol and nicotine consumption, and the sudden death from recreational solvent abuse. Suggestions concerning oxidants as major contributors to ageing remain unchallenged.

Animals↗
PubMedDate not supplied

The search for new antiarrhythmics in the group of chirally 1,2-aminoalcohols. I. 3',4',5'-trimethoxybenzoic acid esters of optically active N,N'-dimethyl-N,N'-bis-(1-hydroxybutyl-2) ethylenediamines.

Both enantiomeric (2S, 2'S) and (2'R) N, N'-dimethyl-N, N-bis (1-hydroxybutyl-2)-ethylenediamines (Table 1) were obtained by methylation of the corresponding N,N'-ethylene-bis-2-aminobutanols-1. The esterification of the former aminoalcohols with 3, 4, 5-trimethoxybenzoic acid gave the both enantiomeric in title named esters (Table 2). The isomer with S configuration at both chirally center (C2 and C2), has a particularly strong antiarrhythmic properties (about 10-20 greater than quinidine or procaine amide in different experimental arrhythmia models in animals. The 2R,2'R enantiomere is 10-100 times less active one. It seems that the antiarrhythmic activity of this new group of antiarrhythmically active compounds, derivatives of chirally 1, 2-aminoalcohols is connected with spatial configuration.

Amino Alcohols↗