Systemic osmotherapy for ophthalmic disease in dogs and cats.
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Animals↗
Biomedical subjects
S M Roberts
Publications and source records attributed to S M Roberts.
Antagonism of bromobenzene-induced hepatotoxicity by the alpha-adrenoreceptor blocking agents phentolamine and idazoxan: role of hypothermia.
A recent study from our laboratory revealed that cotreating mice with the alpha-adrenoreceptor antagonists phentolamine and idazoxan markedly diminished bromobenzene-induced hepatotoxicity. Subsequent studies also revealed that such cotreatment does not alter the pharmacokinetic disposition of bromobenzene in mice nor its bioactivation to reactive metabolites. In the present study, the possible role of hypothermia in the phentolamine antagonism of bromobenzene-induced hepatotoxicity was investigated. Bromobenzene alone caused a significant, dose-related hypothermia. The high dosage regimen (10 mg/kg per dose) of phentolamine or idazoxan that had been found to be hepatoprotective in earlier studies potentiated this hypothermia and more than doubled the net decrease in core body temperature experienced by the animals. Placing mice receiving bromobenzene in an environment with an ambient temperature of 10 degrees C likewise increased the hypothermia experienced by animals receiving bromobenzene. The magnitude of the net change in core body temperature elicited by exposure to cold was similar to but slightly less than the net change produced by cotreatment with either alpha-adrenoreceptor antagonist and the magnitude of the hepatoprotection this procedure provided against bromobenzene hepatotoxicity was equivalent to that observed with phentolamine cotreatment. In contrast, a lower dosage regimen of either adrenoreceptor antagonist (2.5 mg/kg per dose) resulted in no additional hypothermia yet still produced a near maximal antagonism of bromobenzene-induced hepatotoxicity. Further, increasing the ambient temperature to 30 degrees C completely reversed the phentolamine-induced (10 mg/kg per dose) increase in hypothermia, but did not affect phentolamine's antagonism of the bromobenzene-induced changes in hepatic glutathione levels, serum alanine aminotransferase activity, or 24-hr mortality. Therefore, we conclude that while the hepatoprotective intervention of phentolamine can be mimicked by an exposure to cold that results in hypothermia, it is clear that alpha-adrenergic antagonists diminish the hepatotoxicity induced by bromobenzene by a mechanism that is independent of hypothermia.
Adrenergic alpha-Antagonists↗
Procainamide hydroxylamine lymphocyte toxicity--I. Evidence for participation by hemoglobin.
A number of lines of evidence suggest that the lupus-like symptoms associated with procainamide therapy may be caused by products of metabolic N-oxidation. In the present study, the perfusion of the isolated rat liver with a hemoglobin-free solution containing procainamide (100 microM) resulted in the rapid appearance of the N-oxidation metabolite procainamide hydroxylamine in the perfusate. Addition of procainamide hydroxylamine in vitro to whole rat blood (1-40 microM) resulted in a concentration-dependent loss of proliferative response among mononuclear cells isolated from the treated blood and cultured with mitogens (phytohemagglutinin, PHA-P: concanavalin A, Con A; and pokeweed mitogen, PWM), as well as a loss of viability. Similar effects on lymphocyte mitogen responsiveness were observed when procainamide hydroxylamine (1-40 microM) was added to rat whole splenic cell populations. Carbon monoxide or ascorbic acid pretreatment inhibited the toxicity of procainamide hydroxylamine to lymphocytes in whole blood, but only carbon monoxide pretreatment inhibited procainamide hydroxylamine-induced methemoglobin formation. These observations are consistent with the participation of hemoglobin in a redox cycle with procainamide hydroxylamine, generating products which are primarily responsible for its cytotoxicity in blood.
Acecainide↗
Perturbation of glutathione by a central action of morphine.
A series of studies were conducted in order to further characterize the previously reported effect of morphine to diminish hepatocellular concentrations of glutathione (GSH) in mice. Naive ICR mice administered morphine (i.p.) in doses up to 1000 mg/kg had diminished hepatic GSH concentrations, with a maximum depletion of approximately 50% occurring at doses of 250 mg/kg or greater. No such effect from an acute challenge with morphine was observed in morphine-tolerant mice. The intracerebro-ventricular administration of the opioid receptor antagonist naltrexone (250 micrograms) completely blocked the hepatic GSH depression resulting from the systemic (i.p.) administration of morphine (100 mg/kg). When morphine (100 micrograms) was administered by the i.c.v. route, GSH concentrations in liver and plasma were significantly altered while heart and kidney were unchanged. Variable responses to i.c.v. morphine were obtained in spleen, stomach and lung. The depression of hepatic GSH was found not to be a consequence of morphine-induced hypoxia or hypothermia, and could not be attributed to intracellular oxidation of GSH.
Animals↗
Immunomodulatory effects of procainamide metabolites: their implications in drug-related lupus.
Evidence suggests that N-oxidized metabolites of procainamide may be responsible for the development of lupus-like symptoms associated with procainamide therapy. The human hepatic microsomal metabolism of procainamide has been previously reported to result in formation of the N-hydroxylamine derivative of procainamide (procainamide hydroxylamine [PAHA]). The objective of this study was to examine the effects of PAHA on human lymphocytes and adherent cells (monocytes and macrophages). When incubated with lymphocytes in whole blood, PAHA enhanced the response to mitogen and immunoglobulin secretion at lower concentrations (less than or equal to 4 mumol/L) but suppressed these functions at higher concentrations. The cytotoxic effects were nonselective for T lymphocytes and B lymphocytes and appeared to involve an interaction between PAHA and hemoglobin. When erythrocytes were removed or when hemoglobin was converted to carboxyhemoglobin, the suppressive effects of PAHA on lymphocytes were reduced. PAHA stimulated interleukin-1 production by adherent cells at 25 mumol/L but had no effect at lower concentrations. Superoxide anion release was unaffected by PAHA in "resting" adherent cells. Pretreatment with PAHA (2 mumol/L) diminished superoxide release in response to stimulation by phorbol myristate acetate (PMA) or latex bead phagocytosis but augmented superoxide release when coincubated with PMA or latex. These observations indicate that PAHA produces complex, concentration-dependent interactions with human immunoregulatory cells, and they suggest that the effects of PAHA on lymphocyte function may result from the further oxidation of PAHA by hemoglobin, perhaps to the nitroso form.
Adult↗
An assay for phentolamine using high performance liquid chromatography with electrochemical detection.
A new method is presented for the detection of phentolamine by high performance liquid chromatography with electrochemical detection. The electrochemical detector was used in the oxidative mode at +900 mV potential versus Ag/AgCl reference. The on-column detection limit for phentolamine using this method was 3 ng, and detector response was linear for 3-1000 ng injected on column. The coefficient of variation for replicate injections was 2.4%. The measurement of phentolamine in biological samples was accomplished using yohimbime as the internal standard; retention time for yohimbine was 3.0 min while phentolamine eluted at 4.75 min. Biological samples were buffered to pH 9.2 and extracted with diethyl ether, followed by back extraction into 0.1 N HCl. The extraction efficiency for this method was 99.4% for phentolamine in serum and 59.3% in liver tissue. The detection limit for phentolamine was 5 ng/ml for 1.0-ml serum samples, and was 10 ng/ml for 1.0-ml liver homogenate samples. The disappearance of phentolamine from serum and liver after administration of a single ip dose of phentolamine to mice was determined using this method. Absorption from the ip route was rapid, with peak phentolamine concentrations achieved in 15 min or less. The elimination half-life of phentolamine in serum was approximately 50 min and was paralleled by disappearance of phentolamine in the liver.
Animals↗
Diazotised [125I]iodosulphanilic acid is not a marker for the outer bilayer of the tegument of adult Schistosoma mansoni.
Diazotised [125I]iodosulphanilic acid (DISA), has been used to label the tegument surface of adult male Schistosoma mansoni in vitro. In a surface membrane fraction prepared by freeze-thaw, only a negligible amount of lipid material was labelled by DISA, and 15 labelled protein bands were detected, ranging in apparent molecular weight from 21,000 to 175,000. As a result of experiments using digitonin to extract surface material, DISA has been described as a marker for the outer bilayer of the schistosome tegument surface. However, we found that two surface membrane fractions obtained by digitonin extraction, which were expected to be enriched in either outer or inner bilayer, yielded almost identical sodium dodecyl sulphate-polyacrylamide gel electrophoresis autoradiographic patterns, with 13 labelled protein bands (21 to 64 kDa) detected in each. In addition, a large proportion of the label was not bound firmly to the worm surface, and although the intact worm surface restricted the access of the label to membrane proteins, nevertheless proteins of the inner bilayer were labelled. Thus, we conclude that DISA is not a marker for the outer bilayer.
Alkaline Phosphatase↗
Effects of piperonyl butoxide on halothane hepatotoxicity and metabolism in the hyperthyroid rat.
A series of experiments were conducted to examine the potential role of phase I metabolism in halothane-induced liver injury in the hyperthyroid rat. The metabolism of halothane was determined in both hyperthyroid (triiodothyronine, 3 mg/kg per day, for 6 days) and euthyroid rats and in animals pre-treated with the cytochrome P-450 inhibitor piperonyl butoxide (75-100 mg/kg, i.p.). It was found that the hyperthyroid state, which is associated with a substantial increase in sensitivity to the hepatotoxic effects of halothane, decreases both oxidative and reductive routes of halothane metabolism in the rat. The production of trifluoroacetic acid (TFA), an oxidative metabolite, as well as that of chlorodifluoroethylene (CDF) and chlorotrifluoroethane (CTF), 2 reductive metabolites, was significantly reduced in hyperthyroid animals. Consistent with these findings serum and urinary bromide levels resulting from the formation of TFA, CDF or CTF were significantly reduced. The only route of halothane metabolism significantly increased by the hyperthyroid condition was the defluorination of halothane. Piperonyl butoxide administration did not render euthyroid animals sensitive to the halothane-induced hepatotoxicity and had no effect on the defluorination of halothane in euthyroid animals. However, piperonyl butoxide markedly increased the hepatotoxicity of halothane in hyperthyroid rats and, except for a modest increase in debromination reactions, decreased all measured indices of halothane metabolism including the defluorination of halothane. Thus, none of the observed changes in halothane metabolism produced by triiodothyronine or piperonyl butoxide treatment could be consistently correlated to the increases in hepatotoxicity linked to these 2 treatments. Based on these studies we suggest that the halothane hepatotoxicity induced in the hyperthyroid rat results from effects produced by either the parent compound or an as yet unidentified metabolite. In addition, these studies further demonstrate that considerable mechanistic differences exist for halothane-induced hepatotoxicity when comparing euthyroid and hyperthyroid animal models.
Administration, Inhalation↗
Centrally mediated opioid induced depression of hepatic glutathione: effects of intracerebroventricular administration of mu, kappa, sigma and delta agonists.
It has recently been demonstrated that morphine produces a loss of hepatocellular glutathione in mice by virtue of its action within the central nervous system. The ability of opioid receptor antagonists to abolish morphine's effect on hepatic glutathione suggests that this action is opioid-receptor mediated. The involvement of opioid receptors in this phenomenon is confirmed in the present study in mice by the ability of naltrexone, 100 micrograms administered intracerebroventricularly (i.c.v.), to completely block the decrease in hepatic glutathione induced by an i.c.v. injection of 100 micrograms of morphine. Intracerebroventricular administration of the selective mu (mu) opioid receptor agonist, (D-Ala2,N-MePhe4,Gly-ol5)enkephalin (DAGO; 25-50 micrograms), or the selective delta (delta) opioid agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE; 3-50 micrograms), like morphine, produced significant decreases in hepatic glutathione 3 h after administration. The selective kappa (kappa) opioid receptor agonists, ethylketocyclazocine (1-30 micrograms) and trans-(+/-)3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide-methane sulfonate (U50 488; 10-300 micrograms), as well as the selective sigma (sigma) opioid agonists, phencyclidine (PCP; 50-300 micrograms) and N-allylnormetazocine (SKF 10,047; 1-30 micrograms), had no effect on the concentrations of glutathione in the liver. It appears from these data that stimulation of mu- or delta-, but not kappa- or sigma-opioid receptors within the central nervous system results in a loss of hepatocellular glutathione.
Animals↗
Antagonism of bromobenzene-induced hepatotoxicity by the alpha-adrenergic blocking agents, phentolamine and idazoxan.
The coadministration of phentolamine, an alpha-adrenoreceptor antagonist, was found to be effective in antagonizing the hepatotoxicity produced by bromobenzene in B6C3F1 mice. Multiple doses of phentolamine, administered in dosages of 10 mg/kg, attenuated almost completely the acute lethality resulting from a 0.5 ml/kg dosage of bromobenzene. Consistent with this decline in lethality, the coadministration of phentolamine significantly altered the magnitude of hepatocellular necrosis, the elevation of serum alanine aminotransferase activity, and the glutathione depression normally produced by this dose of bromobenzene. These protective effects were not limited to phentolamine. Idazoxan, an adrenergic antagonist more specific for alpha 2-receptors, was equally effective in antagonizing the bromobenzene-induced hepatotoxicity. Measurements of serum catecholamine levels revealed that the administration of hepatotoxic doses of bromobenzene elevates serum epinephrine levels. Furthermore, the phentolamine antagonism of the bromobenzene hepatotoxicity could be correlated to elevated serum epinephrine levels in both a temporal and dose-dependent manner. Although the mechanism of the phentolamine antagonism remains to be established, one promising hypothesis involves its prevention of an epinephrine-mediated compromise in the glutathione-dependent detoxification of bromobenzene.
Adrenergic alpha-Antagonists↗
Antagonism of bromobenzene-induced hepatotoxicity by phentolamine: evidence for a metabolism-independent intervention.
A previous study has revealed that phentolamine markedly antagonizes the bromobenzene-induced hepatotoxicity and lethality in B6C3F1 mice. One potential mechanism by which phentolamine may diminish the bromobenzene-induced hepatotoxicity is by a direct or indirect interference with the metabolism of bromobenzene to toxic metabolites. In the present study, phentolamine cotreatment failed to alter the elimination of bromobenzene from serum or the distribution of bromobenzene to liver. This suggests that phentolamine cotreatment does not indirectly interfere with bromobenzene bioactivation secondary to changes in bromobenzene absorption, distribution, or elimination. Further, a phentolamine concentration 10- to 20-fold greater than those measured in vivo failed to alter the in vitro metabolism of bromobenzene to its ortho- and para-phenolic metabolites. It is believed that para-bromophenol represents the rearrangement product of the hepatotoxic 3,4-epoxide and that ortho-bromophenol is a product of the nonhepatotoxic 2,3-epoxide pathway. Thus, it appears that phentolamine does not antagonize bromobenzene-induced hepatotoxicity by inhibiting the formation of hepatotoxic intermediates, nor by enhancing metabolism via the nonhepatotoxic pathway. On the basis of these studies, we conclude that phentolamine antagonism of bromobenzene-induced hepatotoxicity occurs through a mechanism independent of bromobenzene bioactivation.
Adrenergic alpha-Antagonists↗
Antibody responses of rodents to a tegument membrane preparation from adult Schistosoma mansoni.
A preparation highly enriched in tegument membranes from adult worms has been used to probe rodent responses to schistosome surface antigens. All exposure regimens in mice stimulated levels of anti-tegument IgG, measurable by ELISA. Plateau levels of circulating antibody attained were similar after mixed-sex and male-only infections, and vaccination with tegument membranes. Female-only infections and exposure to irradiated cercariae stimulated lower levels of anti-tegument antibody. Responses in rats were similar, but occurred more rapidly, probably due to the large initial parasite exposure. Although both mice and rats could be stimulated to produce high levels of anti-tegument antibody by multiple vaccination, consistent protection against a challenge was not obtained. Paradoxically, rats and mice vaccinated with irradiated cercariae developed low levels of antibody to tegument membrane antigens but were highly resistant to challenge. It was concluded that, in the range of sera examined, antibody responses to schistosome tegument membranes did not correlate with the immune status of the host.
Animals↗
Comparison of covalent binding from halothane metabolism in hepatic microsomes from phenobarbital-induced and hyperthyroid rats.
1. Hepatic microsomal suspensions from rats pretreated with saline, phenobarbital or triiodothyronine were incubated with 14C-halothane under aerobic and anerobic conditions. 2. Metabolism of halothane by microsomes from phenobarbital-induced rats under anaerobic conditions resulted in covalent binding of 14C to microsomal lipids, and to a lesser extent, microsomal proteins, as seen in previous studies. Covalent binding was decreased with incubation under aerobic conditions. 3. Metabolism of halothane by microsomal suspensions from hyperthyroid rats produced much less covalent binding to microsomal lipids and proteins, with binding similar to, or less than, that observed with microsomes from saline-treated rats. The covalent binding of halothane to protein of microsomes from hyperthyroid rats was dependent upon metabolism, and was inhibited by SKF 525A, reduced glutathione, or cytosol. 4. The in vitro observations with respect to covalent binding are inconsistent with previous reports on halothane hepatotoxicity in hyperthyroid rats in vivo. This inconsistency and the relatively small extent of covalent binding with microsomes from hyperthyroid rats observed, suggests that covalent binding is not an important mechanism of halothane hepatotoxicity in the hyperthyroid rat model.
Animals↗
A centrally-mediated effect of morphine to diminish hepatocellular glutathione.
Morphine administration has been associated with a decrease in hepatic glutathione (GSH) and an increase in the hepatotoxicity of compounds dependent upon GSH for detoxification. In this study, intraperitoneal administration of 100 mg/kg morphine in mice resulted in approximately a 25% decrease in hepatic GSH. The same magnitude of GSH depletion was also observed following intracerebroventricular (i.c.v.) injection of 100 micrograms of morphine, but no effect was observed when 100 micrograms of morphine was administered intravenously. Pretreating animals with either yohimbine (5 mg/kg, i.p.) or prazosin (5 mg/kg, i.p.) resulted in a partial blockade of i.c.v. morphine-induced change in hepatic glutathione concentrations. Adrenalectomy prior to i.c.v. morphine treatment completely prevented morphine-induced changes in hepatic GSH concentrations; however, the morphine response was restored in adrenalectomized mice supplemented with hydrocortisone (2.5 mg/kg). No effect on the ability of i.c.v. morphine to diminish GSH concentrations in the liver was observed following pretreatment with either propranolol (20 mg/kg, i.p.), atropine (1 mg/kg, i.p.), hexamethonium (15 mg/kg, s.c.), or destruction of peripheral adrenergic nerve terminals with 6-hydroxydopamine (30 mg/kg, i.p.). It is concluded that hepatocellular GSH concentrations may be diminished as a consequence of a central action of morphine. The response by liver GSH to this action does not appear to be mediated through adrenal medullary release of catecholamines or by autonomic stimulation of the liver. While corticosteroids are a necessary component of this response, their role is probably permissive. The ability of both prazosin and yohimbine to antagonize the effect of i.c.v. morphine on hepatic GSH, coupled with the apparent absence of a peripheral catecholaminergic mechanism, suggests that the adrenergic interaction with the i.c.v. morphine effect is also of central origin. Thus, the results of this study show that the central effects of morphine can result in a decrease in hepatic GSH, and that this effect is not mediated by a peripheral catecholaminergic mechanism.
Adrenalectomy↗
Histamine and hepatic glutathione in the mouse.
A number of histamine receptor agonists and antagonists were utilized to study the effects of histamine on hepatocellular reduced glutathione (GSH) concentrations and the potential role of histamine as a mediator of morphine-induced hepatic GSH depression. Administration of histamine, the H1-histamine receptor agonist thiazolylethylamine, the H2-histamine receptor agonist impromidine, or the histamine-releasing substance compound 48/80 resulted in no significant change in hepatic GSH concentrations. The H1-histamine receptor antagonist chlorpheniramine and the H2-histamine receptor antagonist ranitidine were also without significant effect on hepatic GSH and did not antagonize morphine-induced GSH depression. These observations indicate that histamine release following morphine administration does not play a significant role in the subsequent depletion of hepatic GSH.
Animals↗
Ophthalmic complications following megavoltage irradiation of the nasal and paranasal cavities in dogs.
Megavoltage x-radiation was used to treat orbital nasal, and paranasal cavity malignant neoplasia in 29 dogs. In each instance, the globe and adnexal tissues were within the treatment portals (entry and/or exit). Doses administered to tumors ranged from 3,680 to 5,000 cGy. Ocular reactions after irradiation were classified as mild in 5 of 29 cases (17.2%) and severe in 17 of 29 cases (58.6%). No ocular complications were noticed in 7 of 29 cases (24.1%). Complications frequently noticed included severe keratitis (41%), mild conjunctivitis (34%), severe conjunctivitis (28%), cataract (28%), and keratoconjunctivitis sicca (24%). Ocular complications that developed were not life threatening, but posed a threat to visual function and patient quality of life. Treatment for the complications included control of bacterial infection, reduction of tissue inflammation, and ocular surface protection when tear film deficiencies were noticed. Mild complications represented acute effects of irradiation, and typically resolved. Severe complications developed both acutely and as late irradiation effects. Those attributed to late irradiation effects were more vision threatening and altered the quality of life more than did the early effects.
Animals↗
Immunity after treatment of human schistosomiasis mansoni quantitative and qualitative antibody responses to tegumental membrane antigens prepared from adult worms.
Quantitative antibody responses of individual Kenyan children to a tegument membrane preparation from adult schistosomes have been studied by enzyme-linked immunosorbent assay. Qualitative differences between patients were examined by electrophoretic fractionation of the membrane preparation followed by Western blotting analysis. All individuals had antibodies to the preparation, the level increasing twofold shortly after chemotherapy and declining to pre-treatment levels by 6 months. Susceptible children had significantly higher levels of antibody than resistant individuals at 12 and 18 months after chemotherapy. Antibody levels were positively associated with patient age (particularly over the range 8-12 years at the first bleed after chemotherapy) and the logarithm of pre-treatment egg excretion. The strongest association was observed between initial antibody level and subsequent levels. A total of 47 distinct antigens was detected in the membrane preparation. The major antigens were detected equally strongly by sera from both susceptible and resistant groups of children. At the outset the resistant group responded more strongly to 35%, and more weakly to 15%, of the antigens than the susceptible group. At the end of the study the figures were reversed, being 21% and 38% respectively, probably reflecting the reflecting the reinfection of the susceptible group. 3 antigens of molecular mass 100, 50 and 27 kDa were exceptions to the trend, being detected more strongly by the resistant than the susceptible group at one or more later times. It was concluded that the differences in total antibody level to the tegument membrane preparation were insufficient to account for the resistant or susceptible status of the children.
Animals↗
Immunodiagnosis of leptospiral uveitis in two horses.
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Animals↗