The Inhalation Toxicology, Genetic Toxicology, and Metabolism of Difluoromethane in the Rat

Difluoromethane (HFC32) is under development as a replacementfor chlorofluorocarbons (CFCs) in some refrigeration applications.It has been evaluated by standard studies of toxicity, developmentaltoxicity, and genotoxicity. In addition, the metabolism anddisposition of HFC32 was investigated and a physiologicallybased pharmacokinetic (PB-PK) model constructed. Inhalationof HFC32 (up to 50,000 ppm) caused no organ-specific effects,but resulted in slight maternal toxicity to the pregnant ratand rabbit and some fetotoxicity to the rat. HFC32 did not sensitizethe heart to adrenaline. The pharmacokinetics of [¹⁴C]difluoromethane(10,000 to 50,000 ppm/6 hr) revealed that about 2.1% of theinhaled HFC32 was absorbed and that steady state blood levelswere achieved within 2 hr and were proportional to dose. Carbondioxide was the major metabolite of HFC32 at all exposure levels.Carbon monoxide was not detected. The in vivo data were usedto validate a PB-PK model to describe the uptake and metabolismof HFC32. Absorption and distribution are adequately describedusing rat blood:air and tissue:air partition coefficients. Metabolism,which was linear across the dose range, was described by a firstorder rate constant (K_f=8.98 hr^–1). Of the absorbed HFC32,about 63% was metabolized at all doses; however, when metabolismwas expressed as a percentage of the inhaled dose it was muchlower, being about 1.4% of the HFC32 entering the airways. Overall,the results indicate that HFC32 is of very low toxicity andshould be an acceptable alternative to CFCs.     

Is There Space for Surgery in the Treatment of Tachyarrhythmias?

Curative treatment of both supraventricular and ventricular tachyarrhythmias started with the introduction of surgical therapy. Surgical treatment modalities were often very successful and associated with low mortality and morbidity, especially in patients with various supraventricular tachyarrhythmias. However, results were acceptable in patients with ventricular tachyarrhythmias, with often a very complex and extended arrhythmogenic area associated with structural heart disease. Because of the development and proven effectiveness of catheter ablation and defibrillator implantation, the role of surgical therapy became limited. In the treatment of supraventricular arrhythmias, surgical therapy is an option after failure of catheter ablation. Since His-bundle catheter ablation is only a palliative treatment for atrial fibrillation, the potentially curative Maze operation may be an acceptable alternative. However, its potential against formation of intracavitary thrombi has not yet been proven. In the treatment of ventricular tachyarrhythmias, ischemia related polymorphic ventricular tachycardia and ventricular fibrillation can be treated very effectively by revascularization. Map-guided surgery is an appropriate treatment modality for patients with monomorphic ventricular tachycardia and an extended arrhythmogenic area. However, patients with very poor left ventricular function may have an unacceptable perioperative risk. In patients with congenital long QT syndrome who are refractory to beta blocking agents, left-sided sympathectomy is the most appropriate choice.     

Role of pentobarbitone anaesthesia and sympathetic tone in the haemodynamic effects of isosorbide dinitrate in rats with cirrhosis

The haemodynamic effects of nitrovasodilators and their mechanisms of action on portal hypertension remain unclear. The splanchnic and systemic haemodynamic response to the infusion of isosorbide dinitrate (100 μg/kg per min), a nitrovasodilator, was investigated in cirrhotic rats. The role of the conscious state in the haemodynamic response to isosorbide dinitrate was examined using rats that were anaesthetized with pentobarbitone. The role of sympathetic tone in the haemodynamic response to isosorbide dinitrate was examined using rats pretreated with the ganglion blocker hexamethonium. Isosorbide dinitrate had no haemodynamic effects in conscious, unblocked normal and cirrhotic rats. Isosorbide dinitrate had no haemodynamic effects in normal and cirrhotic rats treated with hexamethonium. In normal anaesthetized rats, isosorbide dinitrate significantly decreased systemic vascular resistance (414±25 vs 290±26 dyn.s/cm⁵ per 100 g). In cirrhotic anaesthetized rats, isosorbide dinitrate significantly decreased mean arterial pressure (98±6 vs 79±7 mmHg), systemic vascular resistance (318±30 vs 207±10 dyn.s/cm⁵ per 100 g), portal pressure (14.0±1.0 vs 11.3±0.9 mmHg) and portal territory vascular resistance (1362±163 vs 1031±182 dyn.s/cm⁵ per 100 g). In conclusion, this study shows that the portal hypotensive effects of isosorbide dinitrate depend upon the alterations of vascular tone by pentobarbitone.     

Efficacy of subcutaneous sumatriptan in the acute treatment of early-morning migraine: a placebo-controlled trial

Abstract. Objectives. To evaluate the efficacy of self-administered subcutaneous sumatriptan in the acute treatment of early-morning migraine attacks. Design. A double-blind, randomized, placebo-controlled, cross-over study. Setting. Thirteen neurology centres in France. Subjects. Patients of either sex, 18–65 years old, with two to six attacks of migraine (according to the International Headache Society (IHS) criteria, with or without aura) per month, of which at least two had to be early-morning migraine attacks. One-hundred-and-one patients were included, 96 being evaluable for the first attack and 81 for the cross-over design. Interventions. Two migraine attacks (grade 2/3) were treated with sumatriptan (6 mg) or placebo, with an optional second injection 1–24 h later. Main outcome measures. The primary end-point was headache relief: reduction in headache severity from grade 2/3 (moderate/severe) to grade 1/0 (mild/none) 2 h after treatment. Results. Sumatriptan was superior to placebo for headache relief (32 [78%] vs. 11 [28%] at the first attack; 29 [73%] vs. 8 [20%] at the second; P < 0.001). Because of a significant carry-over effect for some of the secondary end-points, a parallel-group analysis of the first attack was performed, which confirmed a significantly higher efficacy of sumatriptan for all end-points: pain-free rate (22 [46%] vs. 7 [15%]; P = 0.001) and use of a second injection (26 [53%] vs. 38 [81%]; P = 0.004). Sumatriptan was preferred by 74% of patients vs. 17% for placebo, and 9% expressed no preference (P < 0.0001). After complete relief, headache reappeared in 8/23 (35%) patients with sumatriptan and 3/7 (43%) with placebo. Adverse events were significantly more frequent with sumatriptan but they were minor and transient. Conclusion. Subcutaneous sumatriptan auto-injection is an effective and well-tolerated acute treatment of early-morning migraine attacks allowing earlier return to normal activity.     

Opiate and cocaine consumers attending Barcelona emergency rooms: a one year survey (1989)

Due la the limitations of standard epidemiological methods, indirect indicators have often been used to describe the characteristics of drug abusing populations and to assess prevalence trends in illegal drug use. In Barcelona (Spain), a study of emergency room (ER) attendance was carried out to describe the population of opiate/cocaine consumers across the whole city who use this service. Three thousand four hundred and five consumers of opiates and/or cocaine, aged 15-44 years, who attended ERs during 1989, were identified. They accounted for 6807 episodes in the hospitals surveyed. Their mean age was 26 years, men (73%) being 1 year older than women (25.2 years). The drug of abuse was specified in the clinical records of 60% of individuals, heroin being the most frequently specified (56%). The main reason for attendance was 'other medical condition'(OMC) (55% of episodes), followed by withdrawal (34%) and overdoses (6%). Seventy-one percent of individuals were residents of Barcelona city, yielding a rate of 3.2 opiate/cocaine consumers attending ERs per thousand Barcelona residents aged 15-44. The geographical distribution of the rates in the city showed a very large difference between districts, the most deprived ones having a higher rate of consumers attending ERs. ER data can provide valuable insights into the nature and dimensions of drug abuse problems.     

Species Differences in 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicity and Biotransformation in Fish

Species Differences in 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicityand Biotransformation in Fish. KLEEMAN, J. M., OLSON, J. R.,AND PETERSON, R. E. (1988). Fundam. Appl. Toxicol 10, 206-213.Rainbow trout, yellow perch, carp, bluegill, largemouth bass,and bullhead were treated with graded doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD; 1, 5, 25, or 125 µg/ kg) or vehicle, ip. The lethalpotency of TCDD tended to be greater in yellow perch, carp,and bullhead than in the other three species (LD50 80 days post-treatment,3-5 versus 10-16 µg/kg, respectively). All species treatedwith the highest dose of TCDD (125 µg/kg) displayed alatency period of 1-4 weeks prior to death; longer latency periodswere produced by lower lethal doses. Effects of TCDD treatmenton body weight were both species-dependent and dose-dependent.Fin necrosis was observed in all fish species; however, cutaneoushemorrhage was observed only in TCDD-treated perch, carp, andbluegill, and cutaneous hyperpigmentation only in TCDD-treatedcarp and largemouth bass. Gallbladder bile was analyzed forTCDD and its metabolites 7 days after fish were injected with[¹⁴C]TCDD (60 µg/kg, ip). At least three TCDD metabolitesin addition to the parent compound were found in the gallbladderbile of all six species. In addition, the retention time ofthe major biliary TCDD metabolite (determined by HPLC) was similarin all species except yellow perch. ß-Glucuronidasetreatment of the bile from largemouth bass and bluegill suggestedthat at least two of the TCDD metabolites were glucuronide conjugates.Thus, species differences exist in the lethal potency, signsof overt toxicity, and biotransformation of TCDD among freshwaterfish.     

Pulmonary Immunotoxicity of Inhaled Ammonium Metavanadate in Fisher 344 Rats

Male Fisher 344 rats were exposed to 2 mg vanadium(V)/m³ (asammonium metavanadate NH⁴VO³, 0.32 µm MMD) atmospheresfor 8 hr/day for 4 days in a nose-only exposure system. In exposedrats, lung V burdens increased in a time-dependent fashion.Analysis of lung cells and lavage fluid 24 hr after the finalexposure suggested that tissue damage and a strong inflammatoryresponse was elicited; numbers of neutrophil and small macrophages(M), as well as levels of lavageable protein and lactate dehydrogenase,were significantly elevated as compared with levels observedwith air-exposed rats. Vanadium also affected pulmonary alveolarM (PAM) capacities to produce and respond to immunoregulatingcytokines. Inducible PAM production of tumor necrosis factor-awas significantly inhibited, as was the ability to increasecell surface Class II/I-A molecule expression in response tointerferon- (rFN-). PAM from V-exposed hosts were also inhibitedin their ability to be primed by EFN- to produce superorideanion and hydrogen peroxide in response to stimulation withopsonized zy-mosan. These studies indicate that short-term repeatedexposure of rats to atmospheric V, at levels encountered inan occupational setting, can alter host pulmonary immunomocompetence,with one major effect occurring at the level of cytokine-relatedfunctions. These alterations may be underlying mechanisms forthe well-documented increases in bronchopulmonary infectionsand cancers in workers chronically exposed to V-containing atmospheres.     

Retinoid-Induced Hypertriglyceridemia in Rats Is Mediated by Retinoic Acid Receptors

Retinoids in clinical use today are known to induce hypertriglyceridemiaas one of their major side effects. The purpose of the presentstudy was to determine, in an appropriate animal model, if retinoid-inducedhypertriglyceridemia is mediated by retinoic acid receptors(RARs) and/or by retinoid X receptors (RXRs). Oral gavage ofmale Fischer rats with 13-cis-retinoic acid for 6 days causeda rapid and sustained increase in serum triglycerides that wasreversible within 4 days posttreatment In subsequent experiments,rats were treated by gavage once daily for 3 days with variousretinoids, and serum triglyceride levels were determined 24hr after the last treatment without fasting. All-trans-and 13-cis-retinoicacid, which can be converted to both RAR and RXR agonists, and9-cis-retinoic acid, an RAR/RXR pan-agonist, caused dose-dependentincreases in serum triglycerides at doses that did not causeweight loss or mucocutaneous toxicity. Ro 13–6298 andAGN 190121, two RAR-specific agonists, caused dose-dependentincreases in serum triglycerides, although Ro 13–6298only induced hypertriglyceridemia at weight-suppressive doses.Two RXR-selective agonists, LG100268 and AGN 191701, failedto induce hypertriglyceridemia or weight loss up to the highestdoses tested. A structural isomer of AGN 190121 that does notactivate RARs or RXRs, AGN 190727, did not induce hypertriglyceridemia.Hypertriglyceridemia induced by AGN 190121 was significantlyinhibited by co-treatment with an RAR-selective antagonist,AGN 193109. Taken together, these data provide strong evidencethat retinoid-induced hypertriglyceridemia is mediated, at leastin part, by RARs. These data also suggest that RXR-specificagonists may have reduced potential to induce hypertriglyceridemiarelative to RAR-active retinoids.