C-Glucuronidation of the acetylenic moiety of ethchlorvynol in the rabbit.

An acetylenic C-glucuronide of the sedative-hypnotic drug ethchlorvynol was isolated from rabbit urine as the major metabolite. The C-glucuronide represents a novel metabolic pathway for acetylenes and is a rare example of the formation of a carbon-glucuronide bond in mammalian systems.

Fixed-bed charcoal hemoperfusion. Treatment of drug overdose.

Fixed-bed activated charcoal cartridges were used for hemoperfusion in the treatment of 54 patients with overdose of one or more drugs, including barbiturate, glutethimide, ethchloryvnol, meprobamate, methyprylon, methaqualone, salicylate, and diazepam. The most dramatic improvement was noticed in patients with phenobarbitol intoxication; they were admitted in stage 3-4 coma and were either awake or arousable by verbal communication at the end of 1 1/2 to 3 1/2 hours of hemoperfusion. Other intoxications improved slowly and required longer duration of treatment. The clearance rates of the drugs with hemoperfusion were greater than those usually achieved with hemodialysis. The data demonstrate the efficacy and usefulness of charcoal hemoperfusion for the management of drug overdose.

Resin hemoperfusion in ethychlorvynol overdose.

An 18-yr-old male with a severe ethchlorvynol (ECV) overdose was treated with Amberlite XAD-4 resin hemoperfusion. Plasma ECV concentration declined 33% during a 3.5-hr hemoperfusion, but rebounded substantially, peaking 6 hr later. It was estimated that 16% of ECV in the body was removed. Following hemoperfusion, plasma ECV concentrations declined linearly at a rate of 13 mg/1/day. Hemoperfusion clearance was estimated by both the traditional method, using extraction ratios across the column and column blood flow (Cl = 270 ml/min), and an alternative method, using blood concentrations during hemoperfusion and recovery of drug from the resin (Cl = 184 ml/min). The latter may provide a better estimate of hemoperfusion clearance because it is not subject to error (which can be substantial) in measurement of column blood flow. The resin completely extracted ECV from plasma, resulting in a rate of elimination 10 times that expected from endogenous processes. To aid in kinetic analysis, blood:plasma partition and protein binding of ECV in 3 normal subjects were also examined. Blood:plasma ratio averaged 0.88 +/- 0.04 and fraction free in plasma, 0.38 +/- 0.02; neither changed as a function of blood concentration between 27 and 108 mg/1. Our data indicate that removal of ECV from the overdosed patient by hemoperfusion is limited by extensive distribution in and slow redistribution from body tissues, but because of the extremely slow rate of removal by the body and the severe nature of the ECV overdose, Amberlite XAD-4 hemoperfusion may be clinically useful.

Flexor and extensor postures in sedative drug-induced coma.

Flexor and extensor postural reflexes are most commonly seen in coma after structural brain lesions, but may also occur in metabolic coma. We report 10 patients who exhibited flexor or extensor posturing as an early and transient feature of coma resulting from sedative drug ingestion. In comatose patients with normal pupillary reactivity but no ocular movements, these postural responses suggest sedative drug overdose.

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.

Preliminary report on the effects of totigestational exposure to ethchlorvynol.

Ethchlorvynol, a sedative-hypnotic drug used clinically since 1955, has recently been the subject of renewed interest primarily because of its chemical relationship to vinyl chloride. In our totigestational studies, sperm-positive female rats were given a daily dose of ethchlorvynol dissolved in olive oil for 21 consecutive days. The dams were allowed to deliver and their offspring were observed for alterations in development by monitoring a number of gross behavioral, histological and biochemical parameters at newborn, weanling, puberty, adult and geriatric stages. Gross development appeared normal at time of weaning: however, offspring of treated dams showed increased behavioral activity in addition to alterations in a number of clinical chemistry parameters. The dose-response seen with most of the parameters suggests that the changes are drug related. However, the clinical pathological significance has not been ascertained.

Bilateral exudative pleural effusions following intravenous ethchlorvynol administration.

A 26-year-old man had bilateral alveolar infiltrates and exudative pleural effusions following self-administration of intravenous ethchlorvynol (ECV). The effusions and pulmonary edema resolved by 72 h with supportive therapy only. As no other etiology was established, we concluded that the pathogenesis of the pleural fluid was the transvisceral pleural leak of the increased extravascular lung water induced by ECV. Current experimental and clinical evidence support the concept that pleural effusions probably develop in most states of permeability pulmonary edema.

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.

Effects of ibuprofen on the hypoxemia of established ethchlorvynol-induced unilateral acute lung injury in anesthetized dogs.

Nonsteroidal anti-inflammatory agents, given prior to induction of unilateral acute lung injury with ethchlorvynol (ECV) in anesthetized dogs, prevent the decreases in systemic oxygen tension (PaO2) which are observed when ECV is given alone. We investigated whether ibuprofen, administered after acute lung injury, would result in improvement in arterial oxygenation. In animals not receiving ibuprofen after unilateral acute lung injury with ECV, PaO2 decreased and venous admixture increased significantly from control values at all experimental time-periods. In those animals receiving ibuprofen, significant decreases in venous admixture were noted. The decrease in PaO2 after ECV administration was significantly less than that observed in animals that did not receive ibuprofen after acute lung injury (p less than 0.05). Ibuprofen had no effect on extravascular lung water. These results demonstrate that in an ECV model of acute lung injury the administration of ibuprofen, after the acute lung injury, results in significant decreases in venous admixture.

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.

Cyclooxygenase inhibitors prevent ethchlorvynol-induced injury in rat and rabbit lungs.

The effect of three chemically dissimilar cyclooxygenase inhibitors on ethchlorvynol-(ECV) induced acute lung injury was studied in isolated buffer-perfused rat and blood-perfused rabbit lungs. ECV caused the microvascular fluid filtration coefficient (Kf) to increase by greater than threefold in the rat lungs and twofold in the rabbit lungs. ECV caused increased pulmonary vascular resistance (PVR) and microvascular pressure measured by the double occlusion technique (Pdo) compared with the vehicle control group in the rat experiments. However, ECV had no effect on PVR or Pdo in the rabbit experiments. Pretreatment with the cyclooxygenase inhibitors indomethacin, ibuprofen, and meclofenamate prevented the increase in microvascular permeability in both the rat and rabbit lung preparations. The cyclooxygenase inhibitors also prevented the ECV-induced PVR and Pdo increases in the rat lungs but had no effect on PVR or Pdo in the rabbit lungs. These results indicate that cyclooxygenase products of arachidonate metabolism mediate the ECV-induced Kf increase in both isolated rat and rabbit lungs.

Ibuprofen reduces ethchlorvynol lung injury: possible role of blood flow distribution.

The role of cyclooxygenase products in acute lung injury was determined by pretreatment of dogs with ibuprofen before injury with intravenous ethchlovynol (ECV). In animals given ECV only, lung injury resulted in extravascular lung water of 18.9 ml/kg after 2 h, which was significantly higher than the 14.8 ml/kg in the group pretreated with ibuprofen. The comparison of gravimetric and indicator-dilution measurements of edema fluid indicates that edema fluid could not be reliably detected after treatment with ibuprofen because of diversion of flow from injured areas. Venous admixture increased from 6% at baseline to 32% 120 min after ECV in the vehicle-pretreated group compared with an increase from 4% at baseline to 7% in the ibuprofen-pretreated group. The regression analysis of the relationship between venous admixture and extravascular lung water indicated that, at any level of edema, venous admixture was significantly less in the group treated with ibuprofen than in the untreated group. Measurement of plasma and bronchoalveolar lavage fluid indicated that ibuprofen inhibited cyclooxygenase activity without affecting lipoxygenase activity. These results suggest that in intact dogs ibuprofen has a protective effect on both pulmonary gas transfer and pulmonary edema formation in ECV-injured lungs, which is consistent with limiting blood flow to injured segments of the lung.

Increased leukotriene C4 in ethchlorvynol-induced acute lung injury in dogs.

We investigated whether ethchlorvynol (ECV)-induced acute lung injury (ALI) is associated with an increase in leukotriene C4 (LTC4) production. In six pentobarbital sodium-anesthetized dogs, ECV (15 mg/kg iv) introduced into the pulmonary circulation resulted in a 164 +/- 31% increase in extravascular lung water 120 min after ECV administration. Concomitantly, the mean (+/- SE) concentration of LTC4 in arterial plasma measured by radioimmunoassay following 80% EtOH precipitation, XAD-7 extraction and high-pressure liquid chromatography purification was 5.0 +/- 1.3 pg/ml, unchanged from control (pre-ECV) values. In contrast, in pulmonary edema fluid 120 min post-ECV, the LTC4 concentration was 35.2 +/- 10.8 pg/ml, sevenfold greater than those values found in the arterial plasma (P less than 0.01). In six additional dogs, 120 min after unilateral ALI had been induced with ECV (9 mg/kg iv), LTC4 in the bronchoalveolar lavage (BAL) of the uninjured lung was 12.1 +/- 1.5 pg/ml, unchanged from pre-ECV values, whereas, LTC4 in the BAL of the injured lung increased from a control value of 10.2 +/- 1.6 to 24.2 +/- 3.5 pg/ml (P less than 0.01) 120 min after ECV administration. These results demonstrate that, in ECV-induced acute lung injury, LTC4 concentrations in pulmonary edema fluid are considerably greater than those found in arterial plasma in the case of bilateral acute lung injury and significantly greater in the BAL of the injured lung compared with the uninjured lung in the case of unilateral acute lung injury. The results are a necessary first step in support of the hypothesis that leukotrienes participate in the altered permeability of ECV-induced acute lung injury.

Effect of tidal volume and PEEP in ethchlorvynol-induced asymmetric lung injury.

We examined the effects of positive end-expiratory pressure (PEEP) and tidal volume on the distribution of ventilation and perfusion in a canine model of asymmetric lung injury. Unilateral right lung edema was established in 10 animals by use of a selective infusion of ethchlorvynol. Five animals were tested in the supine position (horizontal asymmetry) and five in the right decubitus position (vertical asymmetry). Raising PEEP from 5 to 12 cmH2O improved oxygenation despite a redistribution of blood flow toward the damage lung and a consistent decrease in total respiratory system compliance. This improvement paralleled a redistribution of tidal ventilation to the injured lung. This was effected primarily by a fall in the compliance of the noninjured lung due to hyperinflation. The effects of higher tidal volume were additive to those of PEEP. We propose that the major effect of PEEP in inhomogeneous lung injury is to restore tidal ventilation to a population of alveoli recruitable only at high airway pressures.

Effect of cyclooxygenase inhibition on ethchlorvynol-induced acute lung injury in dogs.

In anesthetized dogs ethchlorvynol (ECV, 9 mg/kg) was selectively administered into the right pulmonary circulation to produce unilateral acute lung injury (ALI) characterized by nonhydrostatic pulmonary edema and systemic hypoxemia. To investigate the hypothesis that products of cyclooxygenase activity are mediators of the arterial hypoxemia, but not the edema formation in this injury, animals were pretreated with one of two chemically dissimilar cyclooxygenase inhibitors, indomethacin (5 mg/kg), or ibuprofen (12.5 mg/kg), or vehicle (0.1 M sodium carbonate) prior to the administration of ECV. Pretreatment with either inhibitor prevented the ECV-induced systemic hypoxemia observed in animals pretreated with vehicle (P less than 0.01). Despite this protection of systemic oxygenation, there was no redistribution of blood flow to the uninjured lung following unilateral ECV administration. Cyclooxygenase inhibition prior to ALI did not attenuate the accumulation of lung water. In the ibuprofen group, left atrial pressure increased significantly following ECV administration. We conclude that a product(s) of cyclooxygenase-mediated arachidonic acid metabolism is responsible for the altered vascular reactivity and consequent systemic hypoxemia in this model, but that the edema formation following ECV is not related to cyclooxygenase activity. In addition, ibuprofen, administered prior to the induction of ALI, exhibits properties not shared by indomethacin but is not different in its capacity to attenuate hypoxemia or in its failure to limit edema formation.

Delirium and stereotypy from anticholinergic antiparkinson drugs.

1. This report describes two cases of psychotic syndrome from benztropine (Cogentin), which was used to treat haloperidol-induced extrapyramidal side effects. The patients' symptomatology meets DSM III criteria for delirium. Both patients displayed repetitive motor automatisms (stereotypy). 2. Symptomatology appeared one-to-two days after the start of benztropine 2 mg b.i.d. and subsided one-to-several days after benztropine was stopped. Treatment consisted of administration of sedative hypnotic drugs. 3. The literature on anticholinergic-induced psychotic syndromes is surveyed. Particular attention is drawn to the occurrence of stereotypy. 4. It is proposed, on the basis of a review of animal and clinical data, that stereotypies in delirious patients are related to muscarinic blockade in the central nervous system. This model is used to explain repetitive motor automatisms which are seen in Alzheimer's disease. 5. The paper concludes with brief guidelines for the management of anticholinergic delirium.

Drug-induced pulmonary edema and acute respiratory distress syndrome.

Noncardiogenic pulmonary edema, and, to a lesser extent, acute respiratory distress syndrome (ARDS), are common clinical manifestations of drug-induced lung diseases. Clinical features and radiographic appearances are generally indistinguishable from other causes of pulmonary edema and ARDS. Typical manifestations include dyspnea, chest discomfort, tachypnea, and hypoxemia. Chest radiographs commonly reveal interstitial and alveolar filling infiltrates. Unlike pulmonary edema that is due to congestive heart failure, cardiomegaly and pulmonary vascular redistribution are generally absent in cases that are drug-related. Rare cases of drug-induced myocarditis with heart failure and pulmonary edema have been described. Results from laboratory evaluation and respiratory function tests are nonspecific.

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.

Quantitative analysis of ethchlorvynol in a capsule dosage form by NMR spectroscopy.

A quantitative 1H-NMR procedure is described for measuring ethchlorvynol in capsules. Deuterochloroform is used as the solvent, and hexamethylenetetramine as the internal standard; the analysis is based on the comparison of the area of the AB peak system of ethchlorvynol with the area of the hexamethylenetetramine singlet. The 1H-NMR method yields results that are precise to within 1% and agree well with results of the more cumbersome and less specific USP titrimetric procedure.