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T Balazs

Publications and source records attributed to T Balazs.

At least 19 recordsLinked to original sources
PubMed1999

Polymer structure and solubility of deoxyhemoglobin S in the presence of high concentrations of volume-excluding 70-kDa dextran. Effects of non-s hemoglobins and inhibitors.

Earlier observations indicated that volume exclusion by admixed non-hemoglobin macromolecules lowered the polymer solubility ("Csat") of deoxyhemoglobin (Hb) S, presumably by increasing its activity. In view of the potential usefulness of these observations for in vitro studies of sickling-related polymerization, we examined the ultrastructure, solubility behavior, and phase distributions of deoxygenated mixtures of Hb S with 70-kDa dextran, a relatively inert, low ionic strength space-filling macromolecule. Increasing admixture of dextran progressively lowered the Csat of deoxyHb S. With 12 g/dl dextran, a 5-fold decrease in apparent Csat ("dextran-Csat") was obtained together with acceptable sensitivity and proportionality with the standard Csat when assessing the effects of non-S Hb admixtures (A, C, and F) or polymerization inhibitors (alkylureas or phenylalanine). The volume fraction of dextran excluding Hb was 70-75% of total deoxyHb-dextran (12 g/dl) volumes. Electron microscopy showed polymer fibers and fiber-to-crystal transitions indistinguishable from those formed without dextran. Thus when Hb quantities are limited, as with genetically engineered recombinant Hbs or transgenic sickle mice, the dextran-Csat provides convenient and reliable screening of effects of Hb S modifications on polymerization under near-physiological conditions, avoiding problems of high ionic strength.

Anemia, Sickle Cell↗
PubMed1999

Reversal of propranolol blockade of adrenergic receptors and related toxicity with drugs that increase cyclic AMP.

An overdose of propranolol, a widely used nonselective beta-adrenergic receptor blocking agent, can result in hypotension and bradycardia leading to irreversible shock and death. In addition, the blockade of adrenergic receptors can lead to alterations in neurotransmitter receptors resulting in the interruption of the activity of other second messengers and the ultimate cellular responses. In the present experiment, three agents, aminophylline, amrinone, and forskolin were tested in an attempt to reverse the potential lethal effects of a propranolol overdose in dogs. Twenty-two anesthetized beagle dogs were given a 10-min infusion of propranolol at a dose of 1 mg/kg/min. Six of the dogs, treated only with intravenous saline, served as controls. Within 15-30 min all six control dogs exhibited profound hypotension and severe bradycardia that led to cardiogenic shock and death. Seven dogs were treated with intravenous aminophylline 20 mg/kg 5 min after the end of the propranolol infusion. Within 10-15 min heart rate and systemic arterial blood pressure returned to near control levels, and all seven dogs survived. Intravenous amrinone (2-3 mg/kg) given to five dogs, and forskolin (1-2 mg/kg) given to four dogs, also increased heart rate and systemic arterial blood pressure but the recovery of these parameters was appreciably slower than that seen with aminophylline. All of these animals also survived with no apparent adverse effects. Histopathologic evaluation of the hearts of the dogs treated with aminophylline showed less damage (vacuolization, inflammation, hemorrhage) than the hearts from animals given propranolol alone. Results of this study showed that these three drugs, all of which increase cyclic AMP, are capable of reversing the otherwise lethal effects of a propranolol overdose in dogs.

Adenylyl Cyclases↗
PubMed1996

Reversal of acute theophylline toxicity by calcium channel blockers in dogs and rats.

Theophylline, widely used in the treatment of pulmonary diseases, has a narrow therapeutic index; the recommended plasma levels being 10-20 micrograms/ml in humans. The misuse or abuse of theophylline can cause life-threatening central nervous system and cardiovascular effects. Increased intracellular Ca2+ levels are thought to play an important role in theophylline toxicity and death. The objective of this study was to determine whether Ca2+ channel blockers, e.g. verapamil, nifedipine, or diltiazem, prevent sudden death caused by theophylline treatment in rats and dogs. Groups of Sprague-Dawley rats were treated with theophylline alone (150 mg/kg i.p.) or with theophylline pretreatment followed by administration of verapamil (0.25 to 0.5 mg/kg i.p.), nifedipine (0.25 to 1.0 mg/kg i.p.), or diltiazem (0.5 to 1.0 mg/kg i.p.), 2.5 to 15 min later. The rats were observed for toxic signs and survival over a period of 15 days. All three calcium channel blockers significantly reduced the theophylline-induced sudden death in rats. In a separate study, neither verapamil (0.5 mg/kg i.p.) nor nifedipine (1.0 mg/kg i.p.) prevented the theophylline-induced myocardial necrosis in the rat. In beagle dogs, verapamil (0.5 mg/kg i.v.) prevented theophylline (15 mg/kg/min i.v. for 10 min)-induced hypotension, arrhythmias, and sudden death. Our results support previously reported findings that calcium plays a major role in theophylline-induced toxicity and death.

Animals↗
PubMed1994

Measurement of the hemoglobin concentration in deoxyhemoglobin S polymers and characterization of the polymer water compartment.

Biological polymers contain freely exchangeable water within intermolecular crevices with restricted access to large extrapolymer solutes. Our recent studies highlighted large osmotic effects of such polymer water compartments (PWCs), and their substantial physiological and pathophysiological relevance. The size and accessibility of the PWC are critical parameters determining the polymers' osmotic properties. We report here a new experimental approach to investigate these parameters in deoxyhemoglobin S polymers. The size of the PWC is inversely related to the deoxyhemoglobin S concentration in the polymer (CP). Only an approximation of CP (approximately 69 g/dl) was previously available. By analyzing the distributions of soluble hemoglobin and a large molecular weight (MW) marker (14C-dextran, MW approximately 70kDa) in the supernatant and pellet of centrifuged gels, we obtained a reproducible value of CP, 54.7 (+/- 0.7)g/dl. This indicates that 60% of the polymer is composed of a water compartment inaccessible to soluble Hb and other non-interactive macromolecules. The accessibility properties of this PWC to smaller molecules were explored with markers of different MW. Non-interactive markers with MW < 200 kDa diffused freely in the PWC, whereas those with 300 kDa < MW < 1000 kDa showed partial exclusion. Higher MW markers were generally excluded, except molecules with elongated (rather than spherical) shapes or possible interactivity with hemoglobin. These results predict that dense sickle cells would significantly dehydrate on deoxygenation, generating a PWC of up to 60% to 80% of the cell water. Soluble enzymes would concentrate in the residual cytosol. For osmotic equilibrium, most of the ions and low MW substrates would concentrate in the PWC. Oxygenation-deoxygenation would thus cause dynamic oscillations in cell hydration and between states of single and double cytoplasmic water phases, the latter with a substantially altered internal environment. The relevance of such oscillations to the membrane and metabolic abnormalities of dense sickle cells requires further investigation.

Anemia, Sickle Cell↗
PubMed1989

Cardiotoxic effects of the combined use of caffeine and isoproterenol in the minipig.

Beta agonists such as isoproterenol are widely used in the treatment of acute asthmatic attacks. It would not be unexpected that some patients receiving isoproterenol might have ingested caffeine as an over-the-counter drug or beverage. This study explores the possible interaction between these two drugs. Anesthetized minipigs were injected with 0.5 mg/kg caffeine iv followed by a 10-min infusion of 1 microgram/kg.min isoproterenol. Heart rate, EKG, respiration, and blood pressure were recorded continuously and the animals were sacrificed at 72 h. The two drugs in combination produced subtle changes in heart rate and blood pressure with significant alteration in the EKG tracing (premature ventricular contractions and extrasystoles). These changes persisted for 8 to 24 h. At autopsy both gross and microscopic lesions were noted in 10 of the 13 minipig hearts receiving the combination of drugs. This was not true of the six minipigs given only caffeine or the eight minipigs receiving only the infusion of isoproterenol. No changes in EKG tracings or pathologies were noted with caffeine and only two of eight animals infused with isoproterenol showed any lesions. Results indicate that doses of caffeine equivalent to that expected from drinking a cup of coffee appear to increase the toxicity of isoproterenol to a point that EKG changes and myocardial pathologies are observed.

Animals↗
PubMed1989

A comparative study of minoxidil-induced myocardial lesions in beagle dogs and miniature swine.

Minoxidil, a long-acting vasodilating antihypertensive agent, reduces arterial blood pressure by a direct action on arteriolar smooth muscle. The present studies examined the gross anatomic, histologic and ultrastructural myocardial alterations produced by 2 daily doses of minoxidil in beagle dogs (0.5, 1, or 3 mg/kg) and miniature swine (1, 3, or 10 mg/kg). Both myocardial necroses and hemorrhages were observed in dogs and pigs 24 hr after the last dose of minoxidil. In both species, the necroses were most frequent in the left ventricular papillary muscles, particularly the posterior one, but were less severe in swine. An ischemic origin of the necroses was suggested by the location of the lesions and by the pharmacologic effects of minoxidil. Gross epicardial or endocardial hemorrhages involving the atria and, to a lesser extent, the ventricles were observed in both species but were more severe in dogs. The atrial lesions were manifested grossly by diffuse redness and microscopically by interstitial edema, extravasated erythrocytes and infiltration of mononuclear cells. Hemorrhages, occurring on the epicardial surfaces, were often associated with lesions that involved small arteries having 3-6 layers of medial smooth muscle cells and were characterized by endothelial injury, intramural accumulations of erythrocytes and platelets, periadventitial hemorrhage, fibrin deposits and an inflammatory cell reaction. These lesions preferentially involved the right atrium in dogs and the left atrium in pigs. Pretreatment of beagle dogs with pyribenzamine (3 doses of 6 mg/kg every 8 hr), cimetidine (3 doses of 15 mg/kg every 8 hr), or both, had no effect on the incidence or severity of minoxidil-induced hemorrhagic lesions. The hemorrhagic lesions may be caused by overstretching of the vascular walls due to excessive, prolonged vasodilatation.

Animals↗
PubMed1989

Effects of non-psychotropic drugs on conditioned behavior of cats.

Cats were trained to obtain food pellets under a cycle reward condition in 4-6 weeks. These conditioned-behavior cats were then used for testing a group of non-psychotropic drugs, and any modification of the feeding cycle (FC) was considered as a side effect of the drug on conditioned behavior. All drugs were given orally. Of the 16 non-psychotropic drugs studied, only indomethacin caused a loss and irregularity in the FC. Antihistamines, acetylsalicylic acid, phenoxybenzamine and amantadine reduced the number of FC by about 50%. Studies of conditioned behavior in the cat appear to be useful for both the investigation of drug interactions and the detection of side effects of drugs not ordinarily considered to have central nervous system effects.

Administration, Oral↗
PubMed1989

The effects of chronic treatment and withdrawal of CNS depressants on aggressive behavior.

Young adult CD-1 male mice were housed in individual cages throughout the study. Groups of 10 to 20 mice were given gradually increasing doses of delta-9-tetrahydrocannabinol (THC) at 6.25 to 25 mg/kg i.p., trifluoperazine (TFP) at 6 to 12 mg/kg p.o., phenobarbital sodium (PS) at 20 to 35 mg/kg p.o., morphine sulfate (MS) at 5 to 20 mg/kg i.p., methaqualone (MQ) 10 to 20 mg/kg p.o. or chlordiazepoxide (CDP) 10 to 25 mg/kg p.o. over four to six weeks to develop tolerance of these drugs. Following the development of tolerance, the drugs were withdrawn. On the fourth day of withdrawal, a young (3-4 weeks old) male mouse was introduced into the cage. When the intensity of the attack was measured by the percentage of animals that killed the intruder within four hours. The results indicated 0 to 4 percent in the controls, 50-54 percent for THC, 50 percent for TFP, 42 percent for PS and 57 percent for MS. In contrast, no killing behavior was exhibited by these mice after treatment with MQ or CDP. These data suggest that enhanced aggressive behavior, elicited by withdrawal from certain psychotropic drugs, may be measured by the killing (muricidal) behavior of isolated mice.

Aggression↗
PubMed1989

Protection against isoproterenol-induced myocardial necrosis in rats by 6-mercaptopurine and 6-thioguanine or by irradiation.

Isoproterenol produces myocardial necrosis in rats. To investigate the possible role of oxygen free radicals generated by xanthine oxidase and neutrophils, we examined the effects of the xanthine oxidase inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG) combined and allopurinol, or of irradiation (to induce leukopenia) on isoproterenol-induced myocardial necrosis (ISOMN). The incidence and severity of ISOMN was significantly reduced by 6MP + 6TG but not by the specific inhibitor of xanthine oxidase, allopurinol, indicating that the protective effects of 6MP + 6TG may be due to its free radical scavenging activity rather than its xanthine oxidase inhibitory activity. Irradiation provided complete protection against ISOMN in all rats. Marked leukopenia or other radiation-induced protective factors could play a role in the mechanism of the protection.

Allopurinol↗
PubMed1988

Examination of minoxidil-induced acute cardiotoxicity in miniature swine.

Minoxidil, a vasodilating antihypertensive agent, was given orally in doses of 1, 3 or 10 mg/kg to miniature swine on 2 consecutive days. Mean arterial pressure decreased and heart rate increased most consistently after the 10 mg/kg dose. However, all 3 doses of minoxidil induced myocardial hemorrhages and/or left ventricular papillary muscle necrosis within 24 h after the second dose. Necrosis, characterized by hypercontraction of muscle cells and myofibrillar damage, occurred in 1 of 8 pigs given 1 mg/kg, 3 of 13 given 3 mg/kg and 7 of 14 given 10 mg/kg of minoxidil. The pharmacological effects of minoxidil, hypotension and reflex tachycardia, probably led to ischemia and necrosis in left ventricular papillary muscles. Gross hemorrhages involving the left atrium and to a lesser extent the left ventricle were found in 4 of 8 pigs given 1 mg/kg, 9 of 13 given 3 mg/kg and 11 of 14 given 10 mg/kg of minoxidil. The atrial lesions were manifested grossly by diffuse redness and microscopically by interstitial edema, extravasation of erythrocytes and infiltration of areas around small arteries and arterioles with acute and chronic inflammatory cells. The hemmorhagic areas were concentrated along the epicardial surfaces, and to a lesser extent along the endocardial surfaces. Atrial lesions induced by minoxidil preferentially involve the left atrium in pigs and the right atrium in dogs. These differences may be related to the anatomic patterns of coronary circulation in the 2 species.

Administration, Oral↗
PubMed1988

Procainamide induces a transitory impairment of B cell mitogenesis in beagle dogs.

Beagle dogs (3 to 6 years old) were treated with 100-150 mg procainamide HC1/kg/day. After 2, 5, and 9 months of treatment, peripheral blood lymphocytes were isolated and stimulated with pokeweed mitogen. The data demonstrated a suppression of mitogenesis only at 2 and 5 months after procainamide treatment. The lymphocytes from dogs treated for 9 months had a normal response to pokeweed mitogen. At no time during this experiment were any significant levels of serum antinuclear antibodies detected nor was any change in the number of cycling lymphocytes apparent in the experimental versus control groups. The resting membrane potential of both control and experimental groups was similar and pokeweed mitogen depolarized the cells from both groups.

Animals↗
PubMed1987

Reduced arachidonic acid levels in major phospholipids of heart muscle in the diabetic rat.

The fatty acid composition of phospholipids and triglycerides in heart muscle was examined in normal and alloxan-diabetic male Wistar rats. In diabetes the major phospholipids, phosphatidyl choline and phosphatidyl ethanolamine, showed significant changes in fatty acid composition, whereas cardiolipin and phosphatidyl serine + phosphatidyl inositol did not show marked changes in fatty acid profile. In phosphatidyl choline there was a significant diminution in arachidonic acid, 20 : 4(n-6) and palmitic acid, 16 : 0, and a corresponding increase in linoleic acid, 18 : 2(n-6), and stearic acid, 18 : 0. In phosphatidyl ethanolamine the level of 20 : 4(n-6) was significantly reduced. The diabetic heart had normal levels of individual phospholipids, whereas the triglycerides were increased by 90% and contained significantly higher levels of 18 : 2(n-6). The results confirm that diabetes is associated with a diminution in fatty acid desaturation, affecting the fatty acid composition of phosphatidyl choline in particular. These changes may be relevant to development of atherosclerosis and relative resistance to catecholamine-induced cardiac necrosis in diabetes.

Animals↗
PubMed1987

Immunogenetically controlled autoimmune reactions induced by mercury, gold and D-penicillamine in laboratory animals: a review from the vantage point of premarketing safety studies.

Mercury and gold salts as well as d-penicillamine can cause glomerulonephritis by an autoimmune mechanism in man. The susceptibility to this effect of these chemicals is controlled by the genes of the major histocompatibility complex (MHC). The presence of certain alleles confers sensitivity. The role of MHC-linked genes has been demonstrated also in the rat and mouse in the development of autoimmunity induced by these chemicals. While Brown Norway rats and ASW mice were sensitive, several other strains were resistant. Also an interaction of MHC with background genes has been shown in determination of the response to HgCl2. In conventional toxicity studies, use of a single inbred strain of laboratory animals obviously handicaps the detection of a reaction of this nature.

Animals↗
PubMed1987

Brain neurotransmitter receptor alterations in offspring of rats exposed to phenobarbital, phenytoin or their combination during pregnancy.

Neurotransmitter receptor binding was studied in the progeny of rats exposed to phenobarbital (80 mg/kg), phenytoin (80 mg/kg) or their combination daily from 5 to 20 days of gestation. At 22 days postnatally, female pups in all treated groups showed decreased binding of [3H]spiroperidol to striatal membranes. A decreased binding of [3H]diazepam to frontal cortical membranes was observed in the female pups of rats exposed to phenytoin or the combination. The Scatchard analysis of data from the affected groups revealed a decrease in the maximum number of dopamine and benzodiazepine receptor sites and no change in their affinities. The binding of [3H]spiroperidol or [3H]diazepam was not altered significantly in any of the drug-treated male pups. Also, no significant change in the binding of [3H]serotonin or [3H]quinuclidinyl benzilate to frontal cortical membranes was observed in any of the treated groups. At 60 days postnatally, no significant change in the binding of any of the above ligands was evident. The above prenatal drug exposures appear to cause transitory subsensitivity of dopamine and benzodiazepine receptors in rats.

Animals↗
PubMed1986

Cardiotoxicity mechanisms from the point of view of preclinical or premarketing safety evaluation.

The most commonly occurring cardiotoxic reactions in humans are due to over-exposure to chemicals that affect physiological function of the heart. These effects, which are usually receptor-mediated, are dose related and can generally be predicted from safety studies in animals. Direct chemical toxicity is initiated by an interaction of a reactive metabolite of the xenobiotic with cellular macromolecules. The incidence of such cardiotoxicity is low because few of these chemicals are metabolized in the heart. The concentration of cellular protective substances influences the development of such toxicity, and therefore species variation should be considered in safety studies. Chemically induced immune system-mediated reactions can develop in the heart, and may occur in anaphylaxis. Antibody mediated cytotoxic or immune complex reactions are rare events, and the predictability is poor. In some instances sensitivity is immunogenetically controlled. Cardiotoxic effects can also develop after prenatal exposure to chemicals, and thus consideration should be given to examining the offspring for those effects in teratology studies.

Adaptation, Physiological↗
PubMed1986

Mercuric chloride-, gold sodium thiomalate-, and D-penicillamine-induced antinuclear antibodies in mice.

Inducibility of antinuclear antibodies (ANA) by mercuric chloride (HgCl2) was studied in various strains of mice. High response to the treatment was observed in strains A.SW (H-2s), A.CA (H-2f), A.TH (H-2t2), B10.S (H-2s), DBA/1J (H-2q), and P/J (H-2p); strains A.BY (H-2b), B10.M (H-2f), and C3H/HeSnJ (H-2k) showed a low response, while strains A/WySn (H-2a), A/J (H-2a), A.TL (H-2tl), BALB/cJ (H-2d), C57BL/10SnJ (H-2b), B10.A (H-2a), and PL/J (H-2u) did not produce any detectable ANA. Thus, the H-2a haplotype determines resistance to the treatment regardless of the genetic background; the H-2s determines susceptibility, while the H-2b and H-2f are intermediate haplotypes whose effect depends on the interaction with the background genes. Our results with intra-H-2 recombinant strains indicate that the I region of the H-2 complex is the major genetic factor controlling this response. The function of the I region is to control cellular cooperation in the immune response that finally results in production of antibodies specific for a particular antigen. Therefore, we postulated that the I region controls the antibody response to a nuclear antigen released as a result of HgCl2 toxicity in mice. A genetic study of an A.SW X C57BL/10 cross confirmed this observation, showing that resistance to ANA induction by HgCl2 in this strain combination is determined by interaction of a semidominant H-2-linked gene and one or more unlinked genes. The two drugs tested, gold sodium thiomalate and D-penicillamine, also induced ANA in A.SW mice, while other strains tested resisted this treatment.

Animals↗