Economic evaluation of zuclopenthixol acetate compared with injectable haloperidol in schizophrenic patients with acute psychosis.

Zuclopenthixol acetate is a rapid-acting, injectable neuroleptic drug with a duration of action that allows for administration once every 2 to 3 days, in contrast to injectable haloperidol, which may require administration more than once daily. To assess the place of zuclopenthixol acetate in the treatment of acute episodes of schizophrenia, a cost-consequence analysis was performed comparing this new medication with short-acting, injectable haloperidol. The perspective of the Quebec health care system was adopted. The study population comprised patients diagnosed with schizophrenia who experienced an acute episode of psychosis and who were treated with intramuscular (i.m.) haloperidol. The study assessed patients for 9 days after the start of treatment. The literature was the principal source of comparative data about the clinical outcomes of the two treatments. The total cost associated with zuclopenthixol acetate i.m. or haloperidol i.m. was modeled using a decision tree built around the number of i.m. injections required to achieve stabilization. To establish costs, expert panels were consulted and patients' files were reviewed for a sample of schizophrenic patients who had been hospitalized in a large psychiatric or general hospital subsequent to a visit to the emergency department and had received a short-acting i.m. neuroleptic drug. Only a direct medical records costs were considered. Because zuclopenthixol acetate was not on the market at the time of the study, the file review did not allow for a direct estimate of its related costs but did provide an account of haloperidol use. The literature shows that zuclopenthixol acetate is similar to haloperidol with respect to the control of psychotic episodes; however, zuclopenthixol acetate is associated with increased sedation and a lower incidence of extrapyramidal symptoms. Using the base-case estimate for the number of injections required for stabilization, the incremental cost of zuclopenthixol acetate 50 mg over haloperidol was $25.00 (1995 Canadian dollars) per patient at the psychiatric hospital and $21.00 per patient at the general hospital. The results were sensitive to the estimate of the number of injections and the number of minutes of nursing care required by agitated patients. Zuclopenthixol acetate resulted in cost savings over haloperidol if it permits a reduction of 25% in minutes of nursing care or if 85% of patients require 2 injections or less (45% requiring 1 injection and 40% requiring 2). However, whichever drug is used, the cost of the injectable neuroleptic represents a small fraction of the cost of care for acutely psychotic patients.

Utilization of anti-asthma medications in two Quebec populations of anti-asthma medication users: a prescription database analysis.

This study describes the utilization of anti-asthma medications in two groups of users of such medications in the province of Quebec, Canada, during the year from June 1, 1990, to May 31, 1991. It is based on a secondary analysis of existing data banks recording the medications reimbursed by two government-funded ambulatory drug reimbursement programs that cover individuals aged 65 and over (seniors) and income security (welfare) recipients (ISRs). The study analyzed the use of the anti-asthma medications included in the list of medications eligible for reimbursement for program beneficiaries. Use was studied in two random samples of individuals who had at least one prescription filled for an anti-asthma medication (2566 seniors and 3695 ISRs). The most commonly used medication in both groups was inhaled salbutamol 100 mcg. Various forms of theophylline tablets were also used by a high proportion of the sample studied. Over 75% of the seniors and 68% of the ISR group used at least one form of theophylline during the course of the year. Inhaled corticosteroids were used by 43% of the seniors and by 36% of the ISR group, and sympathomimetics (beta 2-agonists), by 63% of seniors and 68% of ISRs.

Clearance by the liver in cirrhosis. II. Characterization of propranolol uptake with the multiple-indicator dilution technique.

We studied the steady-state hepatic extraction and single-pass hepatic uptake of propranolol in isolated perfused livers from normal rats and compared these values with those of rats with carbon tetrachloride-induced cirrhosis, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. The kinetics of propranolol transport in the liver were characterized by means of the multiple-indicator dilution technique, and estimates of cellular influx, efflux and sequestration rate constants were obtained with a computer fit to the model of Goresky. The outflow pattern of propranolol in the hepatic veins was then resolved into throughput material, which had swept past the hepatocytes along with albumin, and returning material, which had entered the cells but returned in the outflow after escaping metabolic sequestration. The steady-state extraction of propranolol was significantly decreased in the three experimental groups compared with that in controls, but the outflow profile differed within each group. In cirrhotic animals, influx was markedly decreased and the sequestration rate constant remained unchanged; most of the propranolol in the outflow consisted of throughput material. In rats treated with chlorpromazine, the sequestration rate constant was decreased, and propranolol in the outflow was mainly returning material. In rats with acute liver injury, both influx and sequestration rate constants were decreased. Indicator dilution curves for nonsequestered tracers showed a decreased transit time for red blood cells and abnormal diffusion of albumin and sucrose into the space of Disse in cirrhotic rats compared with the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of aging on the pharmacokinetics and pharmacodynamics of doxacurium.

Doxacurium (30 micrograms/kg) pharmacokinetics and pharmacodynamics were evaluated in nine elderly (age range, 70 to 83 years) and nine young (age range, 19 to 39 years) patients under nitrous oxide-isoflurane anesthesia. The force of contraction of the adductor pollicis was monitored and plasma samples were collected for an 8-hour period. In the elderly group, doxacurium elimination half-life was prolonged (119.7 versus 75.9 minutes) and plasma clearance was significantly reduced (1.75 versus 2.54 ml/min/kg) without any change in volume of distribution. Onset (12.9 versus 8.9 minutes) and recovery times (113.4 versus 48.1 minutes) were longer in the elderly group. The equilibrium rate constant to the effect compartment (kco) was decreased in the elderly (0.039 versus 0.051 min-1), whereas the effect compartment concentration at 50% block was similar in both groups (44.7 versus 54.1 ng/ml). An age-related reduction in muscle blood flow may be responsible for the decrease in kco. The pharmacokinetic changes observed in the elderly are consistent with a decreased function in the organs of elimination.

Clearance by the liver in cirrhosis. I. Relationship between propranolol metabolism in vitro and its extraction by the perfused liver in the rat.

To delineate the factors responsible for impaired clearance in cirrhosis, we examined propranolol disposition in rats with carbon tetrachloride-induced cirrhosis and compared it with that in control animals, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. We measured the extraction ratio of propranolol by the isolated perfused liver and related it to estimates of propranolol drug-metabolizing enzyme activity in homogenates of the same livers. In control animals, drug-metabolizing enzyme activity (measured as the ratio Vmax/Km) averaged 5,319 +/- 1,193 ml/min; the extraction ratio in the perfused liver was close to 1.0 (0.97 +/- 0.01). Important decreases of microsomal enzyme activity were observed in rats treated with chlorpromazine (30 +/- 27 ml/min, p < 0.001) and in rats with acute liver injury (724 +/- 401 ml/min, p < 0.001), accounting for the decrease in the hepatic extraction ratio by the perfused liver (0.33 +/- 0.09 and 0.71 +/- 0.04, respectively, p < 0.01). In cirrhotic livers, enzyme activity was not significantly different from that of controls (3,592 +/- 1,857 ml/min) and could not account for the observed decrease in extraction (0.66 +/- 0.14, p < 0.01). The extraction of antipyrine by the isolated perfused liver was also measured as an index of microsomal enzyme activity and related to propranolol extraction. Antipyrine extraction was decreased by 90% in acute liver injury, compared with 33% in cirrhosis, suggesting a much greater reduction of microsomal enzyme activity in the former group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of lignocaine on arginine-vasopressin plasma levels: baseline or induced by frusemide.

1. To assess whether or not lignocaine influences baseline and frusemide-induced (5 mg kg-1) plasma concentrations of arginine-vasopressin (AVP), 2 groups of rabbits received an infusion of lignocaine (130 micrograms min-1 kg-1) for 6 h. Lignocaine-induced changes in AVP plasma concentrations were substantiated by measurement of diuresis and natriuresis and hepatic plasma flow, by means of an infusion of indocyanine green (ICG) (249 micrograms min-1 kg-1). 2. Baseline plasma AVP levels were 4.9 +/- 0.9 pg ml-1 (+/- s.e.), and following lignocaine, these values were reduced to 0.7 +/- 0.1 pg ml-1 (P less than 0.01). Frusemide increased AVP levels to 134.1 +/- 73.6 pg ml-1 (P less than 0.05) and lignocaine totally prevented this increase, e.g. mean AVP levels of 2.7 pg ml-1. 3. Lignocaine enhanced baseline diuresis secondary to an increase in free water clearance; none of the experimental conditions affected the diuresis and natriuresis induced by frusemide. 4. Frusemide reduced the hepatic plasma flow and this decrease was not reversed by the infusion of lignocaine. 5. It is concluded that in healthy rabbits lignocaine reduces baseline secretion of AVP and its antidiuretic effect; in addition, lignocaine prevents the rise in AVP induced by frusemide.

Propranolol disposition in the rat: variation in hepatic extraction with unbound drug fraction.

The plasma protein binding of propranolol has been described as nonrestrictive for its hepatic extraction to explain the observation that propranolol is efficiently removed by the liver, in spite of extensive protein binding. The present study was designed to examine the relationship between propranolol protein binding, metabolism by isolated hepatocytes, and extraction by the isolated perfused rat liver. In isolated hepatocytes, the intrinsic clearance of free drug increased three- to fourfold as albumin and alpha 1-acid glycoprotein (AAG) concentrations increased, suggesting that albumin and AAG facilitate the elimination of propranolol by hepatocytes. In the isolated perfused liver, propranolol extraction was almost complete (E = 0.996) in the absence of albumin and AAG. With 40 g/L of albumin and 2 g/L of AAG in the perfusate, the free fraction of propranolol decreased to 0.031, but extraction remained high (E = 0.960). With 40 g/L of albumin and 10 g/L of AAG in the perfusate, the free fraction further decreased to 0.014 and extraction dropped sharply (E = 0.820). The observed relationship between propranolol extraction and the free fraction of propranolol was in good agreement with that predicted using estimates of intrinsic clearance measured in isolated hepatocytes suspensions. These data indicate that propranolol extraction is sensitive to changes in binding at very low free fraction values and suggest a facilitation of propranolol clearance by albumin and AAG.

Isolated perfused cirrhotic human liver obtained from liver transplant patients: a feasibility study.

Cirrhotic livers obtained from eight patients who underwent orthotopic liver transplantation were perfused through the portal vein and hepatic artery in a closed recycling system for periods ranging from 2 to 7 hr. An average perfusion flow of 451 ml/min was used, with about 80% coming from the portal vein and 20% from the hepatic artery. The livers appeared to remain viable as assessed by gross appearance, stable portal vein and hepatic artery pressures, oxygen consumption and bile production. The extraction ratio of indocyanine green by the perfused livers averaged 0.098 (range = 0.023 to 0.168); that of propranolol averaged 0.445 (range = 0.126 to 0.813). Using the multiple-indicator dilution-curve method, shunts greater than 15 microns in diameter were demonstrated between the portal and hepatic veins in six of eight cases, whereas shunts from the hepatic artery to the hepatic veins were absent. Perfusion of human livers obtained during hepatic transplantation is a fairly simple procedure that will allow researchers to gain new insights into cirrhosis in humans.

Propranolol metabolism by isolated hepatocytes from normal and cirrhotic rat livers: the effect of albumin.

Several recent reports have shown that the hepatic uptake and subsequent elimination of some substrates is faster in the presence of albumin than in its absence, as if some of the substrate bound to albumin was also available for uptake. In the present study, we examined the effect of albumin on the clearance of propranolol by isolated rat hepatocyte suspensions. The clearance of total drug decreased progressively as albumin concentration increased. There was also a progressive decrease in the free fraction of propranolol and the net result was an increase in the clearance of unbound drug (+50% at 40 g/L albumin). This increase was not due to an oncotic pressure effect of albumin, nor to the presence of fatty acids bound to albumin. The clearance of propranolol by isolated hepatocytes from cirrhotic rats was decreased compared with controls (-50%), and albumin also increased propranolol free clearance, albeit to a lesser extent than in control animals. Our results indicate that albumin facilitates the elimination of propranolol by hepatocytes, possibly because of surface-mediated catalysis of the albumin-propranolol complexes.

Predictive value of bronchoalveolar lavage cells and serum precipitins in asymptomatic dairy farmers.

In 1981 to 1982, we reported that many (19/43) asymptomatic dairy farmers, especially those with positive serum precipitins, had a lymphocytic alveolitis. We reevaluated, six and seven years later, 33 of the initial 43 farmers to verify their outcome. The restudied group included 31 men and 2 women between 24 and 67 years of age. In both studies, 24 were nonsmokers and 9 were exsmokers. Each farmer answered a questionnaire, had a physical examination, blood withdrawal for precipitin analysis, a chest roentgenogram, and pulmonary function tests (forced expiratory flows and diffusion capacity). At restudy, one subject had developed symptoms suggestive of sub-acute farmer's lung and now had inspiratory crackles; six had chronic morning cough and sputum production. Serum precipitins were positive in 10 subjects, whereas 16 had been positive at the initial study. Precipitins reverted from positive to negative in eight subjects and from negative to positive in six. Chest roentgenograms were normal in 23 subjects, while discrete interstitial abnormalities were noted in nine. One subject had significant pulmonary infiltrates. Results of current pulmonary function tests were (% predicted, mean +/- SEM) DL(CO) 114.8 +/- 3.0, FEV1 108.1 +/- 2.4, FVC 105.4 +/- 1.1. No correlations were found between these data and the lymphocytes or mast cells found in the bronchoalveolar lavage (BAL) at the initial study of 1981 and 1982. We conclude that bronchoalveolar lavage cell counts of asymptomatic farmers have no long-term clinical significance.

Lidocaine and indocyanine green kinetics: effect of hypoxemia and/or hypercapnia.

Patients with premature ventricular contractions are also frequently hypoxemic (HO) and/or hypercapnic (HC). The aims of the present study were to document the effect of HO and/or HC on the kinetics of lidocaine, a first choice drug for the i.v. treatment of premature ventricular contractions, and on indocyanine green (ICG), another flow-dependent drug. For this purpose, five groups of rabbits were used: a control group received 2.5 mg/kg i.v. of ICG followed, 30 min later, by 7.5 mg/kg of lidocaine as a bolus. Four other groups received lidocaine as an infusion (261 micrograms/min/kg) for 255 min and ICG (249 micrograms/min/kg) for 8 min, the latter beginning 180 min after the start of the lidocaine infusion. The controls and one test group receiving the lidocaine infusion were breathing air (PaO2 = 89 +/- 2 (S.E.M.) and PaCO2 = 20 +/- 1 mm Hg); the second test group had HO (PaO2 = 51 +/- 1 mm Hg), a third group HC (PaO2 = 68 +/- 1 mm Hg) and the fourth HO combined with HC (HOHC) (PaO2 = 53 +/- 1 and PaCO2 = 61 +/- 2 mm Hg). Multiple blood samples were drawn. Lidocaine and its metabolites and ICG were assayed by high-performance liquid chromatography. Lidocaine volume of distribution was not affected by HO and/or HC. Compared to control values, the clearance of infused lidocaine (CIL) tended to decrease from 65 +/- 2 to 53 +/- 3 ml/min/kg. In animals with HO, HC and HOHC, CIL was 49 +/- 6, 45 +/- 5 and 46 +/- 3 ml/min/kg, respectively, these values not being significantly different from CIL.(ABSTRACT TRUNCATED AT 250 WORDS)