Effects of vegetable oils on the biological disposition of ethchlorvynol. I. the effects on the distribution of ethchlorvynol in rat.
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Animals↗
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Effects of vegetable oils on the biological disposition of ethchlorvynol. II. The effects on the brain distribution of ethchlorvynol in rat.
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Animals↗
Indomethacin blunts ethchlorvynol-induced pulmonary hypertension but not pulmonary edema.
Ethchlorvynol (10 mg/kg) causes transient pulmonary hypertension and an increased permeability pulmonary edema in sheep. To determine the role of cyclooxygenase and its metabolites, histamine, and catecholamines in both phenomena, we studied five groups of sheep: group I, placebo; group II, ethchlorvynol; group III, indomethacin with ethchlorvynol; group IV, diphenhydramine with ethchlorvynol; group V, phentolamine with ethchlorvynol. Indomethacin, but not diphenhydramine or phentolamine, blunted the pulmonary hypertensive response seen immediately following the ethchlorvynol injection. However, none of the drugs had any effect on the increased permeability pulmonary edema. We conclude that cyclooxygenase or its metabolites partially mediates the hypertensive response but not the increased permeability pulmonary edema seen in sheep following ethchlorvynol injection.
Animals↗
Resin hemoperfusion for treatment of ethchlorvynol overdose.
Hemoperfusion has been increasingly used to treat drug intoxication. Although efficient extraction rates have been reported with hemoperfusion devices, simultaneous measurements of drug adsorption on the columns and endogenous clearance rates have not been made. We studied three patients who ingested 12 to 22 g of ethchlorvynol (Placidyl). In each patient saline diuresis was induced, and Amberlite XAD-4 resin hemoperfusion was done. Resin extraction of ethchlorvynol was calculated hourly, and the recovery of drugs from each column was measured. Renal clearance of ethchlorvynol was simultaneously measured. The resin removed 100% of perfused ethchlorvynol measured by gas chromatography. Ethchlorvynol recovery from the columns agreed well with calculated extraction. Renal clearance was 1 to 6 mL/min, and estimated metabolic clearance was 16% to 31% of resin extraction rate. Complications included anemia, thrombocytopenia, hypocalcemia, and pancreatitis. Resin hemoperfusion substantially supplements endogenous clearance of ethchlorvynol and is a valuable therapy in ethchlorvynol intoxication.
Adolescent↗
Pulmonary tissue concentrations of ethchlorvynol after intravenous injection.
Noncardiogenic pulmonary edema has been reported to follow the intravenous use of ethchlorvynol (Placidyl) in both human clinical and animal experimental situations. In a further attempt to define ethchlorvynol-pulmonary tissue inter-relations, we measured ethchlorvynol concentrations in venous and arterial blood and lung and liver tissue of dogs after intravenous injection of 15 to 25 mg of the drug per kg of body weight. In 10 dogs, the mean +/- SEM lung concentrations 1, 3, and 5 min after injection were 70 +/- 20, 50 +/- 13, and 24 +/- 9 mug per g of tissue, respectively. Simultaneous mean +/- SEM venous contrations were 75 +/- 40, 29+/-5, and 22 +/- 5 mug per ml of blood, respectively. During minutes 1 and 3, the liver concentrations were lower than those found in the lung. In an additional 3 dogs, injection of ethchlorvynol into the portal vein led to higher concentrations (at all sample times) in the liver when compared to the lung. In vitro lung slice studies using ethchlorvynol labeled with iodine-131 revealed no active energy-dependent uptake. Intravenously administered ethchlorvynol rapidly fluxes into and out of lung tissue, apparently following the laws of diffusion.
Animals↗
A comparative study of ethchlorvynol levels in blood versus bone marrow.
Bone marrow may be utilized as an alternative biological sample in cases where uncontaminated blood samples are not available for analyses. Bone marrow/blood ratios of ethchlorvynol as a function of time and dosage level were determined in 40 rabbits. A modified quantitative analysis that produced accurate and reproducible results was employed for the determination of ethchlorvynol levels. Further, ten blood and bone marrow samples containing ethchlorvynol were chosen to study the effects of storage for a period of 24 hours. Studies of blood and bone marrow ethchlorvynol levels with time showed no linear relationship. Bone marrow/blood ratios as a function of dose resulted in close mean averages with a wide range of values. Significant losses in both blood and bone marrow ethchlorvynol levels were evidenced in most of the samples subjected to the 24-hour storage study.
Animals↗
Alkylation of the prosthetic heme in cytochrome P-450 during oxidative metabolism of the sedative-hypnotic ethchlorvynol.
The clinically used sedative-hypnotic ethchlorvynol destroys hepatic microsomal cytochrome P-450 enzymes in a process catalyzed by the same hemoproteins. Abnormal porphyrins accumulate in the livers of phenobarbital-pretreated rats after administration of ethchlorvynol. The abnormal porphyrin fraction has been isolated and shown to consist of the four possible regioisomers of N-(5-chloro-3-ethyl-3-hydroxy-2-oxo-4-pentenyl)protoporphyrin IX. Cytochrome P-450 inactivation thus appears to result from alkylation of the prosthetic heme by the oxidatively activated acetylenic function in ethchlorvynol. The autocatalytic destruction of the hemoprotein is likely to alter the metabolism and elimination of ethchlorvynol and coadministered drugs and may be the cause of the porphyrinogenic properties of ethchlorvynol.
Alkylation↗
The role of leukocytes in ethchlorvynol-induced pulmonary edema.
Intravenous administration of ethchlorvynol (Placidyl) is known to produce noncardiogenic pulmonary edema in animals and humans. Since intrapulmonary sequestration of leukocytes has been observed to occur following injection of ethchlorvynol, we evaluated the role of these elements of the blood in producing pulmonary edema. In vivo studies in dogs showed intrapulmonary trapping of leukocytes, as evidenced by increasing leukocyte differences between blood from the pulmonary artery and arterial blood. In both animals with normal leukocyte counts and those depleted of leukocytes (less than 500 cells per millimeter), pulmonary edema occurred, as evidenced by increased pulmonary water after injection of ethchlorvynol. Preparations of isolated lung perfused with either whole blood or leukocyte-poor plasma had similar gains in weight following injection of ethchlorvynol, in spite of marked differences in leukocyte counts. We conclude that intrapulmonary sequestered leukocytes do not play a role in ethchlorvynol-induced pulmonary edema.
Animals↗
Determination of ethchlorvynol in body tissues and fluids after embalmment.
A 54 year-old female expired at her residence. Her husband, a physician, signed a certificate stating that her death was due to cerebrovascular accident (CVA) and released her body to a funeral home, where she was embalmed. Since the deceased had a long history of medical problems and drug abuse, an autopsy was performed and no evidence of CVA was found. Toxicological analyses of body fluids and tissues revealed the presence of ethchlorvynol in high concentration in the bile (112 mg/l). The bloody fluid collected from the heart contained a concentration of ethchlorvynol below the limit for quantitation. Other findings included phenobarbital (32.8 mg/l) in heart bloody fluid and methanol (an ingredient of embalming fluid). The significance of the findings is discussed in relation to embalmment prior to autopsy and toxicological analyses. Ethchlorvynol concentration in the bile is compared to other fatal cases due to ethchlorvynol overdose.
Bile↗
Pulmonary edema induced by intravenous ethchlorvynol.
The intravenous injection of ethchlorvynol is an uncommon cause of noncardiac pulmonary edema. Two cases of intravenous ethchlorvynol-induced pulmonary edema are presented. The patients fell asleep after injecting the liquid contents of Placydil capsules (ethchlorvynol) and awoke several hours later with severe dyspnea. Arterial blood gases demonstrated marked hypoxia. Chest radiographs revealed bilateral diffuse alveolar densities. The patients' symptoms and radiographic findings resolved after several days of supportive care. Changes in the lung caused by ethchlorvynol may be the result of direct effect of the drug on the lung.
Adult↗
Ethchlorvynol ingestion in San Diego County: a 14-year review of cases with blood concentrations and findings.
Cases of nonfatal (51) and fatal (38) ingestions involving ethchlorvynol over a 14-year period (1975 through 1988) were reviewed in order to evaluate the current status of ingestion of this drug. In both series of cases men and women were involved approximately equally. Sixty-three percent of cases in both series occurred during the period 1975 through 1980. Most (78% of nonfatal and 89% of fatal) ingestions involved other drugs in addition to ethchlorvynol. Physical findings for nonfatal ingestions and causes of death for fatal ingestions are presented. Blood ethchlorvynol concentrations are discussed, and a composite of the average patient for each series is presented. Although ethchlorvynol abuse appears to be decreasing with time, it still occurs, and a search for this sedative-hypnotic agent should be included in the so-called "toxicology screen."
Adolescent↗
Charcoal hemoperfusion for treatment of ethchlorvynol overdose.
Charcoal hemoperfusion is commonly employed to treat overdose of a number of drugs. There are varying reports of its efficacy in the treatment of ethchlorvynol overdose. Herein is reported a case of ethchlorvynol overdose successfully treated with charcoal hemoperfusion within 5 h of ingestion of 12.5 g of the drug. The patient was deeply comatose at that time but recovered consciousness at the end of 4 h of hemoperfusion. Ethchlorvynol clearance over the charcoal varied from 118 to 147 ml/min. There were no bleeding complications. Prompt charcoal hemoperfusion may be an effective mode of treatment in cases of ethchlorvynol intoxication.
Adult↗
Increases in lung lymph and albumin clearance with ethchlorvynol.
We studied anesthetized dogs with right lymph duct (RLD) preparations and measured lymph flow, albumin concentrations in lymph (L) and plasma (P), pulmonary artery pressure (PAP), and pulmonary capillary wedge pressure (PCWP). Intravenous (iv) injection of ethchlorvynol (15-25 mg/kg) was followed by significant (p less than 0.02) increases in right lymph duct flow from 0.9 +/- 0.3 to 5.4 +/- 1.6 ml/h with stable PAP, PCWP, and L/P albumin (0.8 +/- 0.05 and 0.9 +/- 0.1). Similar results in RLD flow were obtained in dogs given 1) diphenhydramine, 3 mg/kg iv loading dose and 1.5 mg.kg-1 .h -1 infusion; 2) indomethacin, 4 gm/kg iv loading dose and 4 mg.kg-1h-1 infusion; 3) methylprednisolone, 30 mg/kg iv; 4) cyclophosphamide (40 mg/kg iv) to induce leukopenia (900 WBC/mm3) prior to ethchlorvynol injection. Cardiac lymph flow increased also and cardiac L/P albumin remained stable. Total hemolytic complement remained normal. We conclude that lung vascular permeability is increased following ethchlorvynol injection. Ethchlorvynol may have a direct effect on lung vascular permeability since, unlike other experimental models, complement activation, leukocytes, prostaglandins, and histamine play insignificant roles. A "final common pathway" may not exist for all forms of increased permeability pulmonary edema.
Animals↗
The effects of ethchlorvynol on pulmonary alveolar membrane permeability.
Intravenous injection of ethchlorvynol (Placidyl) causes noncardiogenic pulmonary edema in humans and laboratory animals. We studied the effects of intravenous ethchlorvynol (15 to 25 mg per kg of body weight) on pulmonary alveolar membrane permeability to various endogenous and exogenous solutes in the in vivo saline-filled dog lung model. Baseline and postethchlorvynol times in minutes for 50 per cent equilibration between the blood and saline-filled alveoli were, respectively, for urea, 37.3 +/- 12.4 and 12 +/- 6.3; for albumin 8,160 +/- 4,400 and 267 +/- 93; for dextrans of molecular weight 10,400 daltons, 1,150 +/- 80 and 185 +/- 160; for dextrans of molecular weight 250,000 daltons, 24,000 +/- 800 and 1,120 +/- 900; for dextrans of molecular weight 500,000 daltons, 24,500 +/- 150 and 1,020 +/- 590. All of these pairs of values were significantly different (P less than 0.01). In addition, lung liquid histamine (but not blood histamine) concentrations increased significantly (P less than 0.001) after ethchlorvynol injection. Intravenous ethchlorvynol causes marked increases in alveolar membrane permeability.
Animals↗
Ethchlorvynol ingestion: interpretation of blood concentrations and clinical findings.
Thirty-eight patients who ingested ethchlorvynol were seen at our institution over an 8.7 year period. Eleven involved ethchlorvynol alone ("pure") while the remainder included at least one other drug ("mixed"). Twenty-three of the patients were women. Six patients required hospitalization. Five patients were chronic users of the drug. Admission ethchlorvynol blood concentrations ranged from 3 to 46 mg/L ("pure") and from 3 to 75 mg/L ("mixed"). For the "pure" cases the most common physical findings were depressed level of consciousness (10 cases), dysarthria (7), mydriasis (6), nystagmus (6), areflexia (4), tachycardia (4), and hypotension, ataxia, and respiratory depression (2 cases each). Following "pure" ingestion, ethchlorvynol concentrations greater than 19 mg/L were usually associated with dysarthria, mydriasis, nystagmus, and tachycardia. When concentrations exceeded 38 mg/L, coma, areflexia, hypotension, and respiratory depression were generally noted as well. All patients recovered with supportive care alone.
Adult↗
Rate of decrease in serum ethchlorvynol concentrations after extreme overdosage-a case study.
Ethchlorvynol is a commonly abused sedative hypnotic. I report here a seven-day study of serum ethchlorvynol concentrations in a patient who had received an extreme overdose. These concentrations were correlated with the patient's response to stimuli. Serum ethchlorvynol concentrations were logarithmically related to time, a fact that can be useful in predicting when a patient's serum ethchlorvynol concentration will return to a therapeutic concentration. In this case the decrease was about 35% per 24h.
Adult↗
Ethchlorvynol pharmacokinetics during long-term administration in a patient with hyperlipidemia and hypothyroidism.
A 33-year-old obese, hypothyroid, white male with several medical problems was admitted to University Hospital in September 1984 for treatment of drug intoxication. Admitting medications included ethchlorvynol in addition to other central nervous system depressants. Initial serum concentrations were reported at 70 micrograms/ml in this somnolent yet totally conscious adult. Established therapeutic concentrations are 2-8 micrograms/ml, with toxic exceeding 20 micrograms/ml. A tolerance phenomenon seemed evident. Serum ethchlorvynol concentrations were monitored daily during early hospitalization and continued to be substantially greater than reported toxic concentrations. Kinetic values were as follows: total body clearance 9.92 ml/min, volume of distribution 68.0 liters, and half-life 78 hours. These values are unique in that they were calculated from a patient who had not suffered an acute overdose, thereby differing markedly from previously published values. The influence of hypothyroidism and hyperlipidemia on these markedly different values appears to be significant. Ethchlorvynol should probably be added to the list of drugs influenced by thyroid disease.
Adult↗
Polygraphic evaluation of ethchlorvynol (14 days).
Ethchlorvynol 500 mg was administered to four young insomniacs for 14 days as part of a standard 22-day sleep laboratory protocol. Subjects slept more while receiving drug, but these benefits were not statistically significant. Ethchlorvynol impaired mood during both drug and withdrawal periods as compared to baseline, and serious side effects were reported. Stage REM and stage 1 were suppressed by ethchlorvynol, and stage 1 (but not stage REM) showed withdrawal rebound.
Adult↗