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PubMed1993

Viability and function in primary culture of adult hepatocytes from various animal species and human beings after cryopreservation.

Cryopreserved hepatocytes from various animal species and human beings were tested for their ability to survive and function in primary culture. The freeze/thaw protocol primarily designed for rat hepatocytes was used with slight modifications for the cells of all other species; it consisted of suspending parenchymal cells in the Leibovitz L15 medium containing 10% fetal calf serum and 10% to 16% dimethyl sulfoxide. After transient storage at 4 degrees C cell suspensions were transferred to -20 degrees C and then to -70 degrees C before being plunged in liquid nitrogen. Hepatocytes were stored for a few weeks to 4 yr. Prolonged storage did not augment loss of cell viability and function. Cell viability after thawing was estimated by the trypan blue exclusion test, and attachment efficiency to plastic was estimated by measuring intracellular lactate dehydrogenase content. Similar values were obtained for most species tested; after cryopreservation cell viability and attachment were decreased by 10% to 25% and by 40% to 50%, respectively. A lower attachment rate was found with dog hepatocytes. Total cytochrome P-450 and protein synthesis were compared in fresh and cryopreserved cells from four species after 4, 24, 48 or 72 hr of culture. Similar values were found in both cells after 24 or 48 hr of culture. In addition, drug-metabolizing activities were measured in human hepatocytes from five donors. In most cases phenacetin deethylation activity was decreased whereas procainamide N-acetylation and paracetamol sulfoconjugation and glucuronidation were increased in cryopreserved cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Clinical trials with antiemetic agents in cancer patients receiving chemotherapy.

Vomiting accompanied by nausea is a serious acute toxicity which occurs after chemotherapy with virtually every class of cancer chemotherapeutic agents. The inability to adequately alleviate this toxicity may lead to serious complications such as general malaise, weight loss, and electrolyte imbalance. We have reviewed 34 studies in which more than 2200 cancer patients were administered 25 different antiemetics for treatment of chemotherapy-induced vomiting. All patients received a variety of cancer chemotherapeutic agents given either as single agents or in combination. The antiemetic agents included phenothiazines, antihistamines, anticholinergics, benzoquinolizines, barbiturates, butyrophenones, procainamides, cannabinoids, steroids, and benzodiazepines. It is apparent from these studies that the use of conventional antiemetic agents for treating cancer chemotherapy-induced vomiting is of marginal value, and the use of investigational antiemetic agents show conflicting results as to efficacy. More quantitative measures for evaluating emesis need to be defined, and the implications that a particular antiemetic therapy may be efficacious for some but not all classes of cancer chemotherapeutic agents need to be evaluated.

Antiemetics↗

PubMedDate not supplied

Pharmacology and clinical use of mexiletine.

Mexiletine is an antiarrhythmic agent with structural and electrophysiologic properties similar to those of lidocaine. Mexiletine decreases ventricular automaticity while shortening both action potential duration and effective refractory period. The drug may be administered orally or intravenously. Hepatic metabolism is the major route of elimination. The elimination half-life is approximately 10 hours, but longer in patients with acute myocardial infarction, chronic congestive heart failure or hepatic insufficiency. Mexiletine suppresses ventricular ectopy in the acute phase of myocardial infarction. The drug is effective for some patients in whom lidocaine has failed. It suppresses chronic ventricular ectopy and is well tolerated in approximately two-thirds of stable outpatients treated with this agent. In that population, mexiletine is comparable in efficacy to quinidine, procainamide and disopyramide. It is effective in 30-50% of patients with ventricular arrhythmias refractory to other antiarrhythmic drugs. In patients with refractory arrhythmias, the efficacy of mexiletine may be enhanced by combination with propranolol, quinidine or amiodarone. Adverse reactions limit use of mexiletine in approximately 20% of patients. Gastrointestinal and central nervous system side effects are the most common. Mexiletine does not depress myocardial function. Aggravation of arrhythmias is uncommonly observed. The usual intravenous dose of mexiletine is 150-250 mg over at least 10 minutes. Long-term oral dosages are usually 200-300 mg 3 or 4 times daily.

Arrhythmias, Cardiac↗

PubMed1985

Treatment of fetal supraventricular tachyarrhythmias.

Supraventricular tachyarrhythmia has been encountered in 18 fetuses at the Yale-New Haven Medical Center during the past 4 years. Fourteen of these fetuses had supraventricular tachycardia and underwent in utero antiarrhythmic therapy with maternally administered digoxin either alone, or on combination with verapamil, propranolol, or procainamide. Thirteen of the 14 fetuses had successful in utero conversion of cardiac rhythm to normal sinus rhythm. The 14th patient underwent successful therapy after birth. All 14 fetuses survived despite severe fetal hydrops at the time of diagnosis in 13 of 14. The four remaining fetuses had either atrial flutter (3) or fibrillation. Two of the fetuses with atrial flutter died at birth, the 3rd survived after electrical cardioversion at birth. The fetus with atrial fibrillation converted to normal sinus rhythm and survived after maternal administration of digoxin. Using M-mode and pulsed Doppler echocardiography, the nature and electrophysiologic mechanism of the arrhythmia may be deduced. The latter information is reviewed along with the fetomaternal pharmacology of various antiarrhythmic agents to devise a rational antiarrhythmic treatment program.

Anti-Arrhythmia Agents↗

PubMed2005

Validated method for determination of bromopride in human plasma by liquid chromatography--electrospray tandem mass spectrometry: application to the bioequivalence study.

A simple, sensitive and specific liquid chromatography-tandem mass spectrometry method for the quantification of bromopride I in human plasma is presented. Sample preparation consisted of the addition of procainamide II as the internal standard, liquid-liquid extraction in alkaline conditions using hexane-ethyl acetate (1 : 1, v/v) as the extracting solvent, followed by centrifugation, evaporation of the solvent and sample reconstitution in acetonitrile. Both I and II (internal standard, IS) were analyzed using a C18 column and the mobile-phase acetonitrile-water (formic acid 0.1%). The eluted compounds were monitored using electrospray tandem mass spectrometry. The analyses were carried out by multiple reaction monitoring (MRM) using the parent-to-daughter combinations of m/z 344.20 > 271.00 and m/z 236.30 > 163.10. The areas of peaks from analyte and IS were used for quantification of I. The achieved limit of quantification was 1.0 ng/ml and the assay exhibited a linear dynamic range of 1-100.0 ng/ml and gave a correlation coefficient (r) of 0.995 or better. Validation results on linearity, specificity, accuracy, precision and stability, as well as application to the analysis of samples taken up to 24 h after oral administration of 10 mg of I in healthy volunteers demonstrated the applicability to bioequivalence studies.

Chromatography, High Pressure Liquid↗

PubMed1980

Fluorometric high-performance liquid chromatographic determination of sotalol in biological fluids.

A high-performance liquid chromatographic (HPLC) method for sotalol in biological fluids is presented. Sample preparation involves a simple acid-base double-extraction procedure, and analysis is carried out on a reversed-phase chromatographic system using a muBondapak C18 column. Procainamide was used as the internal standard. As little as 20 ng of sotalol/ml can be detected with good precision by a fluorometric detector. HPLC, which allows more rapid analysis of plasma sotalol levels than does GLC, appears suitable for pharmacokinetic studies as well as for therapeutic drug monitoring.

Chromatography, High Pressure Liquid↗

PubMed1988

Interactions of antiarrhythmics with artificial phospholipid membranes.

Binding of antiarrhythmics to phospholipids has been quantified by measuring the drug-induced fluorescence increase in 8-anilino-1-napthalenesulfonate (ANS)-treated phosphatidylcholine membranes. The ability of test compounds to increase fluorescence intensity to 50% varies between 1.3 and 88 X 10(-6) M, exhibiting a potency ratio of 1.8 log units. The antiarrythmics tested in this study exhibited a wide spectrum of lipophilicity ranging between sigma f = 6.66 for the most lipophilic compound asocainol, to sigma f = 1.21 for the most hydrophilic compound procainamide. The pKa values ranged from 10.80 for quinacainol to 6.26 for ethmozine. Consequently, the test compounds are 99.9 to 6.8% protonated at physiological pH. Binding of antiarrythmics to phosphatidylcholine membranes appears to be determined mainly by their lipophilicity (r = 0.91), irrespective of the pKa, as demonstrated for ethmozine and lidocaine which showed an excellent fit to the regression line. Binding of a variety of antiarrhythmics (n = 8) to phosphatidylcholine appeared to correlate significantly with the mean daily dosage for these drugs (r = 0.97).

Anti-Arrhythmia Agents↗

PubMed1986

The temperature dependence of halothane-induced contractures of skeletal muscle.

Frog muscles bathed in solutions equilibrated with 0.5%-2.0% halothane develop large contractures when cooled to 2-4 degrees C. These halothane-cooling contractures (HCC) are dose dependent and reproducible; they are potentiated by lidocaine (5 mM), abolished by procaine (5 mM), and partially inhibited by procainamide (5 mM) or sodium salicylate (2 mM). The HCC provides a simple model system for investigating the effects of low halothane concentrations on Ca homeostasis and contractility in skeletal muscle.

Anesthetics, Local↗

PubMed2001

Early cellular events in systemic autoimmunity driven by chromatin-reactive T cells.

In vivo exposure of the thymus of normal mice to procainamide-hydroxylamine, a lupus-inducing drug, causes development of chromatin-reactive T cells. Autoantibodies subsequently appear, but their origin and significance are unknown. The current studies were undertaken to determine the specificities of B cells that respond to chromatin-reactive T cells at the initiation of this autoimmune process. Three days after adoptive transfer of 6 x 10(6) chromatin-reactive T cells, B cells with the capacity to secrete IgM anti-chromatin antibodies were detected in 1/10(6) splenocytes, and these became 10- to 50-fold more numerous if either the donor T cells or the recipient had defective Fas due to the lpr allele. Five days later these mice developed IgG anti-chromatin-secreting B cells at a precursor frequency of 3-6 x 10(-5). B cells with dDNA-binding activity isolated from mice primed in vivo to a complex of methylated pigeon cytochrome c and dDNA could stimulate naive, cytochrome c-reactive T cells in vitro, demonstrating that B cells can internalize dDNA-bound proteins through their dDNA immunoblobulin receptor and can functionally present a T cell epitope. However, no capacity of chromatin for binding anti-dDNA antibodies was detected, and IgM dDNA-specific B cells did not expand when challenged with chromatin-reactive T cells in vivo. The rapid and robust expansion of anti-chromatin-secreting B cells indicates that the normal immune repertoire includes nontolerant autoreactive B cells that respond to strong T cell drive and are readily manifested if Fas-mediated activation-induced cell death is inhibited.

Animals↗

PubMed1994

Immunotoxicological investigation using pharmaceutical drugs: in vivo evaluation of immune effects.

Traditional methods for toxicological assessment have indicated that the immune system is a frequent target of toxic insult following subchronic or chronic exposure to xenobiotics. However, most of the xenobiotics evaluated in standardized protocols were environmental chemicals and correlation with available clinical data was not possible. The purpose of this work was to evaluate the potential immunosuppressive effects of pharmaceutical drugs using a standardized protocol developed for immunotoxicological assessment. Two groups of pharmaceutical drugs were utilized: (a) drugs without known immunosuppressive effect linked to their utilization in human therapy (cimetidine, furosemide, indomethacin, amoxicillin, and procainamide) and (b) immunosuppressive drugs (azathioprine, cyclosporine A, and dexamethasone). Ex vivo tests using B6C3F1 mice were performed after a 28-day repeat dose regimen and assessed: (a) immunopathology, (b) cell-mediated immunity, (c) humoral immunity, and (d) nonspecific immunity. Host resistance to Listeria monocytogenes was also assessed following exposure to immunosuppressive drugs. The results showed that (a) immunopathology and immune function assays were necessary to detect all immunotoxicants and (b) the effects observed with nonimmunotoxic drugs were sometimes statistically significant but the biological significance of these effects is unlikely.

Animals↗

PubMed2000

Effects of local anaesthetics on the activity of the Na,K-ATPase of canine renal medulla.

The purpose of this study is to characterize the effects of local anaesthetics on Na,K-ATPase activity. The ATPase activity of Na, K-ATPase-enriched membranes from canine renal medulla was determined in the absence and in the presence of lidocaine, procaine, tetracaine, benzocaine, bupivacaine, prilocaine, and procainamide at 37 and 25 degrees C. All of these local anaesthetics, except benzocaine, inhibit the activity of the Na,K-ATPase of canine renal medulla at both 25 and 37 degrees C. Benzocaine inhibits Na,K-ATPase activity at 37 degrees C, but stimulates activity at 25 degrees C. The influence of lidocaine on stimulation of Na,K-ATPase activity by Na(+) and K(+) was investigated. Lidocaine increases the apparent K(0.5) of the Na,K-ATPase for both Na(+) and K(+) and decreases the V(max) values for both ions. IC(50) values for lidocaine increase with increasing concentrations of both Na(+) and K(+). The data indicate that lidocaine diminishes the affinity of the Na,K-ATPase for Na(+) and K(+) and that binding of Na(+) or K(+) decreases the potency of lidocaine as an inhibitor of the Na,K-ATPase. Lidocaine markedly decreases the affinity of the Na,K-ATPase for ouabain, but only slightly diminishes the maximum amount of ouabain bound. Unprotonated lidocaine is apparently a more potent inhibitor than is the protonated form.

Anesthetics, Local↗

PubMed1998

Stabilization of recombinant Drosophila acetylcholinesterase.

The uses of pure and stable acetylcholinesterase can range from simple basic research to applications in environment quality assessment. In order to satisfy some of these needs its recombinant expression is routinely performed. Affinity-purified recombinant Drosophila melanogaster acetylcholinesterase proved to be instable; an apparent cause of this seemed to be the presence of contaminants with protease activity as evidenced by SDS-PAGE. The elimination of these accompanying products was achieved by anion-exchange, hydrophobic interaction, and cibacron blue affinity chromatography applied downstream from procainamide affinity chromatography. The utilization of a parallel affinity acting via an engineered histidine tail permitted the elimination of the copurified proteases as well. Despite the elimination of the contaminants, the apparently pure extracts were still unstable. It is shown that such instability can be counterbalanced by provoking protein-protein interactions, either between enzyme molecules or with other molecules such as bovine serum albumin. Another way to reduce instability is the addition of a reversible inhibitor or polyethylene glycol 3350.

Acetylcholinesterase↗

PubMed1997

The use of reporter antigens in the popliteal lymph node assay to assess immunomodulation by chemicals.

Various drugs and other chemicals can induce T-cell-dependent B-cell activation which may lead to allergic or autoimmune-like diseases. Because the nature of the relevant (neo-) antigens is generally not known and probably depends on the chemical, we have explored the potential use of reporter antigens to determine T-cell-dependent B-cell activation by chemicals. TNP-Ficoll and TNP-OVA were used for this purpose because they are recognized by the same TNP-specific B cells, but these cells require distinct costimulation for specific antibody production. It was found that HgCl2, phenytoin, nitrofurantoin, and D-penicillamine stimulated IgG1 production to both antigens, incomplete Freund's adjuvant, silica, and dimethylsulfoxide to TNP-OVA only, and LPS and hydroxyl-amino procainamide to TNP-Ficoll alone. The diabetogene streptozotocin did not enhance IgG1 production, but may enhance a cellular response instead. Tolerogens and a T-cell antigen without intrinsic adjuvant activity did not influence the responses. The IgG1 production to TNP-Ficoll was local and transient, and did not always require T cells. In contrast, responses to TNP-OVA could be measured in serum, led to specific memory, and were strictly T-cell dependent. These results demonstrate that specific antibody production to reporter antigens indicates immunostimulatory effects of chemicals more sensitive than PLN cell count and provides important mechanistic information. Moreover, with TNP-OVA as reporter antigen the kinetics and regulation of chemically enhanced immune responses can be studied without the need to know the relevant neo-antigens for each individual compound.

Adjuvants, Immunologic↗

PubMed1997

Long-term maintenance of drug-metabolizing enzyme activities in rat hepatocytes after cryopreservation.

Recent studies have demonstrated that freshly isolated adult hepatocytes from various species can be hypothermically preserved for a short period or cryopreserved for a prolonged period before seeding in primary culture. This study was designed to determine whether rat hepatocytes could be maintained functional for a prolonged period after either hypothermic preservation or cryopreservation. Cold storage was carried out in University of Wisconsin solution (UW) and freezing in Leibovitz medium added with 10% fetal calf serum and 16% dimethyl sulfoxide. Rat hepatocytes were then set up either in pure conventional culture or in coculture with rat liver epithelial cells. Various functions were measured over 4- and 15-day periods, i.e., albumin secretion rate, deethylation of ethoxyresorufin and phenacetin, dealkylation of pentoxyresorufin, glucuronidation and sulfoconjugation of paracetamol, and N-acetylation of procainamide. No major differences were observed between unfrozen, frozen, and UW-preserved cells. While in pure culture all the functions tested were markedly decreased after 3 or 4 days, they remained high over the 15-day period in coculture, being either maintained or increased after 7-12 days compared to initial values. These results clearly demonstrate that when maintained under suitable culture conditions, rat hepatocytes can fully recover after hypothermic preservation or cryopreservation and therefore represent a suitable in vitro model system for pharmacotoxicological studies.

Acetaminophen↗

PubMed1983

Studies on slow cardiac action potentials occurring in potassium-rich media as a simulation of the early phase of myocardial infarction. Influence of potassium-conductance blockers and antiarrhythmic drugs.

In the acute phase of myocardial infarction, a marked intracellular potassium loss and the lack of intact coronary circulation are known to result in extracellular hyperpotassemia partially depolarizing the damaged cells. To simulate these conditions, isolated guinea pig papillary muscles were superfused with K+-rich Tyrode solution, the minimal norepinephrine concentration required to trigger slow action potentials (SR) was measured, and the characteristics of SR were studied with glass microelectrodes. The threshold norepinephrine concentration was found to be about 1.04 x 10(-6)M. This threshold concentration was decreased by substances inhibiting the outward potassium currents (4-aminopyridine, tetraethylammonium, cesium); the SR duration and the maximal rate of depolarization were increased by them. Lidocaine and procainamide have no influence on these parameters. Phenytoin and the Mg2+ ion were found to have a marked inhibitor effect by increasing the threshold norepinephrine concentration and decreasing the maximal rate of depolarization of SR.

Action Potentials↗

PubMed1986

Triphenyl tin hepatotoxicity in rats.

Hepatic microsomal aniline hydroxylase and aminopyrine N-demethylase in vitro activities and the biliary excretion of sulfobromophthalein (BSP) were significantly reduced in rats treated with triphenyl tin (TPT) in daily doses of 1 mg/kg i.p. for 3 days. Bile flow, liver weight, serum enzyme activities, and hepatic sulfhydryl groups and thiobarbituric reactant levels were unaffected in TPT-treated animals. Moreover, TPT failed to induce any appreciable change in the biliary excretion of both the organic base procainamide ethobromide and the organic acid amaranth which is excreted into the bile in the unmetabolized form. TPT has been shown to be an effective inhibitor of rat liver glutathione-S-transferase activity. Reduced conjugation with glutathione may play a role as a factor determining the low rate of biliary BSP excretion in the TPT-treated rats.

Aminopyrine N-Demethylase↗

PubMed1990

Extraneuronal noradrenaline transport (uptake2) in a human cell line (Caki-1 cells).

This study describes for the first time an experimental system for the extraneuronal transport mechanism of noradrenaline (uptake 2) which is based on a clonal cell line (Caki-1). Caki-1 cells were originally derived from a human renal cell carcinoma. The conclusion that these cells express uptake 2 is supported by several experimental findings. (1) The initial rate of 3H-noradrenaline uptake in Caki-1 cells is saturable, the Km being 450 mumol/l. (2) Inhibitors of uptake 2 such as corticosterone (1 mumol/l) and O-methyl-isoprenaline (100 mumol/l) largely inhibit 3H-noradrenaline uptake in Caki-1 cells. Whereas inhibitors of the neuronal transport mechanism for noradrenaline (uptake 1) such as desipramine (1 mumol/l) and cocaine (10 mumol/l) do not reduce it. (3) Depolarization of Caki-1 cells by the elevation of extracellular potassium inhibits 3H-noradrenaline uptake. (4) There is a highly significant correlation between the Ic50's of various compounds for the inhibition of 3H-noradrenaline uptake in Caki-1 cells and rabbit aorta known to possess uptake2. Interestingly enough, uptake 2 in Caki-1 cells and rabbit aorta is inhibited by cimetidine, quinidine and procainamide which are substrates of the renal transport mechanism for organic cations. Moreover, 3H-cimetidine is shown to be a substrate of uptake 2 in the isolated perfused rat heart. These results indicate a striking similarity between uptake 2 and the renal transport mechanism for organic cations.

Animals↗

PubMed1996

Autoantibody to the nucleosome subunit (H2A-H2B)-DNA is an early and ubiquitous feature of lupus-like conditions.

Chromatin, a huge polymer of nucleosomes, has been implicated as an important target of autoantibodies in idiopathic and drug-induced lupus for decades, but the antigenicity of chromatin has only recently been dissected. IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, is present in the majority of patients with systemic lupus erythematosus, in > 90% of patients with lupus induced by procainamide and in individual patients with lupus induced by a variety of other drugs, but is not seen in people taking these medications who are clinically asymptomatic. Anti-[(H2A-H2B)-DNA] accounted for the bulk of the anti-chromatin activity in drug-induced lupus. The earliest detectable autoantibody in lupus-prone mice recognized similar epitopes in the (H2A-H2B)-DNA subnucleosome complex; as the immune response progressed, native DNA and other constituents of chromatin became antigenic. The importance of chromatin-reactive T cells in the anti-[(H2A-H2B)-DNA] response is suggested by the presence of somatic mutations in antibody VH and VL regions, their predominant IgG isotype and the similarity in kinetics of their production to that of conventional T cell dependent antigens. Together with the serologic data from human lupus-like disease, these results are consistent with chromatin being a common stimulant for both B and T cells. While chromatin-reactive antibodies are closely associated with systemic disease and have recently been implicated in glomerulonephritis in SLE, the absence of renal disease in drug-induced lupus indicates that additional abnormalities are required to manifest the serious pathogenic of anti-[(H2A-H2B)-DNA] antibodies.

Animals↗