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PubMed1996

Inhibition of cytochrome P-450 attenuates hypoxemia of acute lung injury in dogs.

The intravenous administration of ethchlorvynol (ECV), in dogs, resulted in an acute lung injury (ALI) characterized by a 200 +/- 80% increase in venous admixture and a 142 +/- 30% increase in extravascular lung water (EVLW). Pretreatment with the cytochrome P-450 inhibitor 8-methoxypsoralen prevented the ECV-induced increase in venous admixture but not the increased EVLW. These findings parallel those reported for cyclooxygenase inhibition in ECV-induced ALI and suggest that an arachidonic acid (AA) metabolite of pulmonary cytochrome P-450 activity may mediate the increase in venous admixture of ALI. We demonstrate that canine pulmonary microsomes metabolize [1-(14)C]AA to a variety of products, including the cytochrome P-450 metabolites 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid (EET). In prostaglandin F2 alpha-contracted, isolated pulmonary venous rings, 5,6-EET induced relaxation in a concentration-dependent manner. This action of 5,6-EET was prevented by indomethacin (10(-5) M). These results suggest that may serve as the cyclooxygenase-dependent endogenous pulmonary vasodilator responsible for the increase in venous admixture of ECV-induced ALI.

8,11,14-Eicosatrienoic Acid↗

PubMed1979

Fixed-bed uncoated charcoal hemoperfusion in the treatment of intoxications: animal and patient studies.

We examined the efficacy of a new, fixed-bed, uncoated charcoal device in experimentally intoxicated dogs and in drug-intoxicated as well as chemically poisoned patients. In the animal studies, 4 h of hemoperfusion resulted in a significant decrease in the blood level of phenobarbital, salicylate, pentobarbital and glutethimide. The drug clearances varied between 97 +/- 10 and 129 +/- 6 ml/min. However, the total amount of drug removed was higher for phenobarbital and salicylate which have a small apparent volume of distribution (AVD) than for pentobarbital and glutethimide which have an AVD greater than total body water. We next treated 14 patients suffering from a wide variety of intoxications. Patients intoxicated with phenobarbital, methsuximide, chlordane and Amanita muscaria all showed a significant improvement in their clinical status. Patients intoxicated with ethchlorvynol, glutethimide, methaqualone, podophyllin and fluoroacetamide did not improve. Charcoal hemoperfusion may be useful in patients poisoned with drugs characterized by an AVD smaller than total body water. No major complications were encountered during the hemoperfusions.

Adolescent↗

PubMed1993

Effect of hydroxyethyl starch on alveolar flooding in acute lung injury in dogs.

The efficacy of hydroxyethyl starch (HES) in limiting alveolar flooding after acute lung injury was investigated using ethchlorvynol (ECV)-induced low pressure pulmonary edema in dogs. Harvested autologous plasma (PL) (control, n = 8) or 6% HES (n = 8) was infused (25 ml/kg) along with packed cells to result in an isovolemic, normochromic preparation before the administration of ECV. Extravascular thermal volume significantly increased after ECV administration in both groups of animals (6.6 to 13.4 ml/kg in PL, 6.5 to 15.0 ml/kg in HES). Systemic arterial PO2 decreased from 216 +/- 4 to 113 +/- 20 mm Hg, and venous admixture increased from 2.8 to 12.8% in the PL group but was not significantly changed in the HES group (219 +/- 5 to 203 +/- 8 mm Hg, and 2.9 to 4.4%, respectively). Epithelial lining fluid volumes after ECV administration increased in both groups but were elevated in the PL group to a greater extent than in the HES group (13.5 ml in HES versus 24.8 ml in PL). In the HES group there appeared to be no difference in the ability of plasma proteins to move across the alveolar epithelium. These results suggest that HES attenuates the flooding of the alveolar space and the resulting alterations in gas exchange during the development of low pressure pulmonary edema. The replacement of the plasma proteins with HES and the apparent inability of HES to cross the epithelial barrier into the alveoli may account for the protective effect of HES in these experiments.

Acute Disease↗

PubMed1979

Comparison of a new hypnotic (Finorgal) with placebo in a double-blind trial.

The hypnotic effects of Finorgal (ethchlorvynol with diphenhydramine) were compared with those of placebo in a double-blind study with crossover of treatments in thirty-five hospital in-patients. During the four-week period of Finorgal treatment there was a significant reduction in the mean time elapsing between the administration of the hypnotic and the onset of sleep, and a significant increase in the duration of sleep, compared with the four weeks of placebo treatment. There was also a significant increase in the proportion of nights when the patients felt they had slept well, and in the incidence of morning 'hangover' and nocturnal confusion during the Finorgal treatment periods. Patients had to be actively woken in the morning significantly more often following Finorgal administration. In patients experiencing pain in the night there was a significant reduction in the occurrence of pain during the nights when Finorgal had been given.

Adolescent↗

PubMed1988

Inhibition of endothelial cell retraction by ATP depletion.

To determine the relationship among endothelial cell (EC) retraction, cell adenosine triphosphate (ATP), and the status of cellular actin, ATP levels, F-actin content, and cytochemical redistribution in bovine pulmonary artery endothelial cells were assessed. EC monolayers 7 days after confluence were exposed to ethchlorvynol (ECV), histamine, or cytochalasin B (cyto B) for time intervals from 5-90 minutes. All 3 agents resulted in endothelial cell retraction without significant effect on cellular ATP content. Sixty-minute incubation of monolayers in glucose-free media containing antimycin A and 2-deoxyglucose depleted cellular ATP to less than 10% of control levels. ATP depleted monolayers failed to retract when incubated with ECV, histamine, or cyto B. ATP depletion resulted in loss of the prominent EC margins but only a rare gap between adjacent cells. When ATP levels were allowed to recover, the ability of EC monolayers to retract was restored. Actin filaments in control monolayers localized to a dense peripheral band of actin, a paranuclear complex, and bundles of microfilaments orientated parallel to the long axis of the cell. ECV induced complete loss of the dense peripheral band and other changes in the actin disposition. Monolayers exposed to histamine showed a retraction of the dense peripheral band of actin to a subcortical position. Cyto B caused loss of the dense peripheral band and the longitudinal microfilament bundles. Monolayers depleted of ATP lost their dense peripheral band and exhibited a disorganized, tangled web of microfilaments. Neither histamine nor ECV modified the actin distribution in ATP-depleted monolayers, whereas exposure to cyto B resulted in substantial change in actin with formation of a rim inside the cell membrane and considerable loss of actin filaments. ECV or histamine induced a small reduction in F-actin content while cyto B resulted in a 50% decline in 15 minutes. ATP depletion resulted in a 19% decrease in F-actin, with no further reduction on subsequent exposure to histamine or ECV. Cyto B treatment of ATP-depleted monolayers caused a drop in F-actin content equivalent to that observed in cells with normal ATP levels. These studies indicate that ATP is essential for changes in actin filament distribution and endothelial cell retraction produced by ECV, histamine or cyto B, and make it unlikely that any of these agents acts simply by depolymerization of actin filaments or modification of the dense peripheral band, although disruption of the dense peripheral band may facilitate retraction in the presence of adequate levels of cell ATP.

Actins↗

PubMedDate not supplied

Titrimetric and spectrophotometric determination of acetylenic hypnotics, using brominating agents.

Titrimetric and spectrophotometric titration methods are described for the quantitative determination of acetylenic hypnotics ethchlorvynol, ethinamate, and meparfynol carbamate as pure substances and in dosage forms. The methods involve the use of different brominating agents. A known excess of the reagent is added and, after the specified time, the residual reagent is determined iodometrically. These procedures permit semimicro determination (1-20 mg) of the drug. Recoveries ranged from 98.48 +/- 0.76 to 102.74 +/- 2.60%. The procedures have been successfully applied to pharmaceutical dosage forms; the results agree well with those for compendial methods.

Capsules↗

PubMed1982

Chiasmal optic neuritis.

Two patients exhibiting bitemporal hemianopia due to chiasmal optic neuritis with pathological confirmation of noncompressive lesions are presented; the first due to a chronic, idiopathic demyelinating process, and the second a result of ethchlorvynol (Placidyl) toxicity. The literature regarding chiasmal optic neuritis is reviewed, and a discussion of other noncompressive causes of bitemporal hemianopia is presented.

Adult↗

PubMed1983

The general toxicology unknown. I. The systematic approach.

The general toxicology unknown often presents challenges and interests to toxicologists. A systematic analytical approach to search for drugs or poisons is presented here. The preliminary screening analyses were as follows: alcohol by gas chromatography (GC), ethchlorvynol colorimetric analysis, enzyme multiplied immunoassay technique (EMIT), basic drug screening by GC, and neutral and weakly acidic drug screening by GC. Other additional analyses were performed depending on the special circumstance of each individual case and the results of these preliminary analyses. Positive findings were confirmed by computerized gas chromatography/mass spectrometry when practical. Quantitation was performed by GC whenever possible.

Alcohols↗

PubMedDate not supplied

The effect of activated charcoal on mouse sleep times induced by intravenously administered hypnotics.

The effect of orally administered activated charcoal (AC) on the sleep times of mice following intravenous injection of various hypnotics was investigated. Preliminary studies with phenobarbital (Pb) showed that a linear relationship exists between the Pb-induced sleep time and the logarithm of the Pb dose in both control and AC treated mice. Half-lives of Pb in the two groups were estimated to be 8.1 and 0.9 h, respectively. A linear decline in Pb-induced sleep time with increasing dose of AC was observed up to a maximum effective dose of AC beyond which dose increments caused no further reduction in sleep time. A similar relationship was observed between sleep time and the concentration of sodium sulfate in which the AC was suspended. AC treatment resulted in an 82-88 per cent reduction in sleep time induced by administration of phenobarbital, methyprylon, glutethimide, ethchlorvynol, and methaqualone. AC had no significant effect on sleep time following amobarbital or pentobarbital administration.

Administration, Oral↗

PubMed1976

A modified ultraviolet spectrophotometric method for the determination of theophylline in serum in the presence of barbiturates.

Ultraviolet spectrophotometry is the most commonly used technique for the determination of theophylline levels for therapeutic monitoring. Common interferences in most methods are barbiturates and xanthines. A modified method which eliminates interferences from barbiturates and most xanthines is presented. Theophylline is extracted from serum with chloroform/isopropanol at pH 7.4 back extracted into dilute hydrochloric acid and then the solution is made alkaline with sodium hydroxide. Barbiturate interferences are eliminated. Interference from caffeine, uric acid, 7-(2,3-dihydroxypropyl)theophylline, xanthine, and hypoxanthine are not observed. Theobromine, and the metabolite 3-methylxanthine interfere. Interference is not observed from quinidine, diazepam, salicylate, glutethimide, methylprylon, propranolol, methaqualone, dilatin and ethchlorvynol. Sulfanilamide, procainamide and chlordiazepoxide interfere.

Barbiturates↗

PubMed2000

Loxapine intoxication: case report and literature review.

Loxapine is a dibenzoxazepine tricyclic compound used to treat schizophrenia in the United States since 1976. Metabolism includes demethylation to its primary metabolite, amoxapine. There are few documented reports of the disposition of loxapine in deaths due to overdose. This report discusses the overdose suicide of a 69-year-old white female found dead in her home by her husband. A prescription for loxapine (50-mg capsules) was found near the body. An autopsy was performed and heart blood, bile, vitreous humor, and gastric contents were submitted for toxicological analysis. The blood specimen was subjected to comprehensive testing that included volatile analysis by headspace gas chromatography (GC); acidic/neutral and basic drug screening by GC; benzodiazepine screening by high-performance liquid chromatography; opiate screening by modified immunoassay; and acetaminophen, salicylate, and ethchlorvynol screening by colorimetry. Loxapine and amoxapine were detected in the basic drug screen. No other drugs were detected in the case specimens. The respective concentrations of loxapine and amoxapine in each specimen were as follows: heart blood, 9.5 and 0.6 mg/L; bile, 28.8 and 4.7 mg/L; gastric, 278 mg/L and negative; and vitreous, 1.5 mg/L and negative. A review of the literature showed that the heart blood concentration of loxapine measured in this case was the highest reported to date. Based on the autopsy findings, patient history, and toxicology results, the cause of death was determined to be acute intoxication of loxapine and the manner, suicide.

Aged↗

PubMedDate not supplied

Pharmacokinetics of drug overdose.

Pharmacokinetics of drugs taken in overdose may differ from those observed following therapeutic doses. Differences are due both to dose-dependent changes and to effects of drugs or pathophysiological consequences of the overdose on kinetics. Dose-dependent changes in rate and extent of absorption, bioavailability (saturation of first-pass metabolism), distribution (saturation of protein binding sites) and metabolism are discussed. Gastrointestinal motility is affected both by specific drug actions, such as delayed gastric emptying by anticholinergic drugs, and by general nervous system depression caused by many drugs. Drug-induced circulatory insufficiency may retard tissue distribution and reduce clearance. Disturbances in blood and urine pH may alter distribution and clearance of weak acids and bases. Drug-induced renal or hepatic failure can significantly decrease clearance. Hypothermia is a common complication of drug overdose and might retard distribution and also reduce clearance. The data concerning pharmacokinetics during overdose are usually incomplete and difficult to interpret. Doses and times of ingestion are uncertain, duration of blood and urine sampling is often inadequate to distinguish absorption from distribution and elimination phases, active metabolites are not measured, protein binding is not determined and clinical features of patients not adequately described. We have, however, reviewed available data for salicylate, paracetamol (acetaminophen), barbiturates, ethchlorvynol, glutethimide, chloral hydrate, tricyclic antidepressants, lithium, phenytoin, ethanol, theophylline, digoxin, amphetamine and phencyclidine.

Acetaminophen↗

PubMed1996

Hypotheses regarding the role of pericytes in regulating movement of fluid, nutrients, and hormones across the microcirculatory endothelial barrier.

A decade ago, we initiated studies to define relationship(s) between products of 5-lipoxygenase-mediated arachidonic acid metabolism and altered microvascular permeability. Patients with permeability (nonhydrostatic) pulmonary edema (adult respiratory distress syndrome) and intact animal models of permeability edema, produced with agents that required neutrophils (phorbol myristate acetate) and those that did not (ethchlorvynol), invariably revealed the presence of leukotrienes; in contrast, leukotrienes were not detected in cases of hydrostatic pulmonary edema. In isolated perfused canine lung, we identified increases in microvascular permeability coefficients in response to the injurious agent. Permeability coefficients were not increased when injurious agents were given in the presence of 5-lipoxygenase inhibitors. To define further the relationships between leukotriene generation and edema formation, we postulated that leukotrienes effected contraction of capillary pericytes, thereby increasing pore size of endothelial intercellular junctions and enhancing movement across the microvascular barrier. We isolated pericytes from bovine retinas, identified them morphologically and by staining characteristics, and, in preliminary experiments, found that they do not possess the 5-lipoxygenase enzyme; however, when cocultured with neutrophils, which possess 5-lipoxygenase but cannot synthesize sulfidopeptide leukotrienes because of their lack of glutathione S-transferase, sulfidopeptide leukotriene synthesis ensued. In view of the anatomic position of pericytes, evidence that they participate in endothelial transport, their ability to contract, and evidence of cell-to-cell communication, we propose that pericytes control the movement of fluid, solutes, hormones, and small and large molecules across the microvascular endothelium.

Animals↗

PubMed1992

The treatment of sleep disorders.

Narcolepsy is clinically associated with cataplexy, sleep paralysis and hypnagogic hallucinations. It is treated by reassurance (that there is no physical disease) and by stimulants such as ephedrine and amphetamine on an intermittent basis. The special tricyclic antidepressant clomipramine is also used, and mono-amine oxidase inhibitors (MAOIs) are useful in theory. Obstructive sleep apnoea is an important and often unrecognised cause of daytime somnolence. It is treated by weight reduction (pickwickian syndrome), hormones, or recently, with continuous positive pressure apparatus. Night terrors (pavor nocturnus) and sleepwalking typically occur during deep sleep (stage 3 and 4 throughout the episode) in children. In a night terror the child sits up with a scream, with eyes open, but inaccessible. He eventually falls asleep calmly. Sleepwalking, too, shows the features of inaccessibility and subsequent amnesia for the episode. Both conditions are normally treated with reassurance (to the parents) but may occasionally warrant benzodiazepines. Enuresis usually occurs in non-rapid eye movement (NREM) sleep, especially stages 3 and 4. The reason for the efficacy of tricyclic antidepressants is not precisely known. Delirium tremens (DT) is treated as a rebound excess of REM sleep, with benzodiazepines and other drugs. It is the withdrawal syndrome (with or without major seizures) to the barbiturate-alcohol group of drugs, which includes alcohol, chloral, paraldehyde, glutethimide, methylprylone, ethchlorvynol, meprobamate and meprobamate-diphenhydramine. Insomnia may be treated by the above drugs, by analgesics, antidepressants, major tranquillisers (neuroleptics) and miscellaneous other compounds. For the majority of patients, however, the most suitable group seems to be the benzodiazepines. The benzodiazepines are much safer than their predecessors, in both acute and chronic usage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Consequences of the 1989 New York State triplicate benzodiazepine prescription regulations.

OBJECTIVE: Comparison of psychoactive medication prescribing and Medicaid expenditures before (1987 through 1988) and after (1989 through 1990) institution of the New York State triplicate benzodiazepine regulations. DATA SOURCES: The National Prescription Audit (IMS America, Plymouth Meeting, Pa), New York State Medicaid, and Blue Cross/Blue Shield fo the Rochester (NY) Area. RESULTS: From 1988 to 1989, New York State benzodiazepine prescribing decreased by 44%, 60%, and 30% as assessed by IMS America, Medicaid, and Blue Cross/Blue Shield, respectively. Prescribing of the following alternative sedative-hypnotics increased in New York State compared with decreases nationally (IMS America data): meprobamate, +125% vs -9%; methyprylon, +84% vs -15%; ethchlorvynol, +29% vs -18%; butabarbital, +31% vs -15%; hydroxyzine, +15% vs -1.1%; and chloralhydrate, +136% vs -0.4%. Increased prescribing of alternatives was also seen in the Medicaid and Blue Cross/Blue Shield data. Medicaid benzodiazepine expenditures decreased 52% from 1988 to 1989 ($21.7 million to $10.4 million). Alternative sedative expenditures increased 115% ($3.9 million to $8.4 million). Total Medicaid psychoactive medication expenditures remained nearly constant ($46.7 million to $45.6 million). CONCLUSION: Although the triplicate regulations have decreased benzodiazepine prescribing, an undesirable increase has occurred in the prescribing of less acceptable medications. The wider public health, patient care, and financial implications of triplicate benzodiazepine regulations are of concern and require further study before other jurisdictions undertake similar programs.

Anti-Anxiety Agents↗

PubMed1991

Effect of alcohols and other hypnotics in mice selected for differential sensitivity to hypothermic actions of ethanol.

Mice selectively bred for resistance (HOT) and sensitivity (COLD) to the hypothermic effect of an acute dose of ethanol were tested twice during the course of genetic selection for their hypothermic response to other alcohols and sedative hypnotics. The drugs administered were ethanol, propanol, n-butanol, t-butanol, pentanol, diazepam, phenobarbital, pentobarbital, methyprylon and ethchlorvynol, all of which have sedative effects on the central nervous system, and hydralazine, a peripheral vasodilator. All drugs decreased body temperature of both HOT and COLD mice. In mice selected for seven to nine generations, COLD mice were more sensitive than HOT mice to all sedative drugs. The longer-chain alcohols were more potent than ethanol in inducing hypothermia, but the magnitude of the response difference between HOT and COLD mice appeared to be smaller. The difference between HOT and COLD mice in hypothermic sensitivity to an acute dose of ethanol was greater after 11-15 generations of selection than after seven generations. Similarly, the differential effect of the other alcohols, phenobarbital, pentobarbital, and methyprylon, on HOT and COLD mice increased with more generations of selection but to a lesser extent than ethanol. These data demonstrate that selecting for sensitivity to acute ethanol hypothermia has produced mice that are also differentially sensitive to other sedative hypnotic agents. They also support the hypothesis that the drugs used in the present study share a common mechanism of action for inducing hypothermia, which may be regulated by a common set of genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗

PubMed1978

Simultaneous liquid-chromatographic determination of 12 common sedatives and hypnotics in serum.

We present a method for simultaneously determining 12 hypnotics and sedatives (primidone, methyprylon, phenobarbital, butabarbital, butalbital, ethchlorvynol, pentobarbital, amobarbital, phenytoin, glutethimide, secobarbital and methaqualone) in 200 microliter of serum. Serum proteins are precipitated with an acetonitrile solution containing 5-(4-methylphenyl)-5-phenylhydantoin, the internal standard. The drugs are eluted from a reversed-phase column with a mobile phase consisting of an acetonitrile/phosphate buffer, at a flow rate of 3.0 ml/min. The eluted drugs are detected by their absorption at 195 nm; their quantities are estimated from their peak heights. Each analysis requires no longer than 30 min at the optimum column temperature of 50 degrees C. The lower limit of detection for all of these drugs is less than 10 ng/sample for drug standard. A sensitivity of 1.0 mg/liter of serum is attained routinely for each of the drugs. Analytical recoveries for the 12 drugs varied from 94 to 112%, with good day-to-day precision (CV between 3.8 and 10.4%). Of more than 35 drugs tested for possible interference, only ethotoin interferes with the analysis of phenobarbital.

Chromatography, Liquid↗

PubMed1986

Genetic differences in anticonvulsant sensitivity in mouse lines selectively bred for ethanol withdrawal severity.

WSP (withdrawal seizure-prone) mice exhibit approximately 10-fold more severe withdrawal convulsions than WSR (withdrawal seizure-resistant) mice after identical chronic ethanol exposure. Although WSP and WSR mice do not differ in threshold for seizures elicited by electroconvulsive shock (ECS), WSR mice are more sensitive to ethanol-induced elevation of ECS seizure thresholds. The current experiments demonstrated that WSR mice showed more ECS-induced seizure threshold elevation than WSP mice when tested after the administration of C1-C5 straight-chain alcohols. Whereas the brain concentrations of the C1 and C2 alcohols did not differ between the lines, WSP mice tended to have higher brain concentrations than WSR mice of the C3-C5 alcohols, even though they exhibited the smaller behavioral response in all cases. Thus, the difference between WSP and WSR mice was one of neurosensitivity and could not be attributed to pharmacokinetic differences. The WSR line was also more sensitive to ethchlorvynol, methyprylon, barbital, phenobarbital, pentobarbital, diazepam, valproic acid and phenytoin in this test. Examining loss of righting reflex (RR), we found that WSP and WSR mice did not differ in ED50, latency to lose RR or duration of loss of RR. Thus, the genetic anticonvulsant sensitivity difference is not simply a genetic difference in sensitivity to central nervous system depression between the lines. In summary, WSR mice were more sensitive to the anticonvulsant effects of a variety of compounds than WSP mice, suggesting that some genes influence both ethanol withdrawal seizures and ethanol's anticonvulsant effects.

Alcohol Withdrawal Delirium↗