David M. Cocchetto

A Comparison of Salmeterol with Albuterol in the Treatment of Mild-to-Moderate Asthma

BACKGROUND An effective, long-acting bronchodilator could benefit patients with asthma who have symptoms not controlled by antiinflammatory drugs. We compared a new long-acting, inhaled beta 2-adrenoceptor agonist, salmeterol, with a short-acting beta 2-agonist, albuterol, in the treatment of mild-to-moderate asthma. METHODS We randomly assigned 234 patients (150 male and 84 female patients 12 to 73 years old) to one of three treatment groups: one group received 42 micrograms of salmeterol twice daily, one received 180 micrograms of albuterol four times daily, and one received placebo. Treatment was assigned in a double-blind fashion, and all patients could use supplemental inhaled albuterol as needed during the 12-week treatment period. RESULTS Measurements of the forced expiratory volume in one second, performed hourly for 12 consecutive hours, showed that a single dose of salmeterol produced a greater mean area under the curve than two doses of albuterol taken 6 hours apart (6.3 vs. 4.9 liter.hr, P < 0.05). The difference was significant on day 1 and at week 4 of the study, but not at week 8 or 12. Salmeterol was also more effective than albuterol or placebo (with albuterol taken as needed) in increasing the morning peak expiratory flow rate: salmeterol induced a mean increase of 24 liters per minute over the pretreatment values, as compared with a decrease of 6 liters per minute with albuterol (P < 0.001) and an increase of 1 liter per minute with placebo (P = 0.002). The mean overall symptom score was improved most by salmeterol treatment (P < 0.05), with the number of days with symptoms and of nights with awakenings decreasing by 22 percent and 52 percent, respectively; there were no differences in results between albuterol treatment and placebo administration. We found no evidence of tolerance to the bronchodilating effects of salmeterol, and adverse reactions to all the treatments were infrequent and mild. CONCLUSIONS For the management of mild-to-moderate asthma, salmeterol given twice daily is superior to albuterol given either four times daily or as needed.

Hemodialysis Using Prostacyclin Instead of Heparin as the Sole Antithrombotic Agent

Anticoagulation during hemodialysis is necessary to prevent clotting of the blood on contact with the dialysis membrane. Heparin is the usual anticoagulant used, but systemic anticoagulation may persist for hours, and hemorrhage is common. We successfully used an infusion of prostacyclin, which has an in vitro half-life of three to five minutes, as the sole anticoagulant in 10 patients on long-term hemodialysis and in one patient undergoing dialysis for acute renal failure (this patient bled severely on three occasions when heparin was used). Prostacyclin was infused intravenously for 10 minutes before dialysis and into the arterial line of the dialyzer during dialysis. We adjusted the rate of infusion into the dialyzer to prevent prostacyclin-induced hypotension. Each patient completed 240 minutes of dialysis and received a total of 423 +/- 91 ng of prostacyclin per kilogram of body weight (mean +/- S.E.M.; range, 56 to 780). Prostacyclin caused no clinically important changes in the intrinsic clotting system, and there were no hemorrhages or clotting of the coil. We conclude that prostacyclin can safely replace heparin as the sole antithrombotic agent during hemodialysis and may be more advantageous if anticoagulation is contraindicated.

Decreased rate of creatinine production in patients with hepatic disease: implications for estimation of creatinine clearance.

Serum creatinine concentration is commonly used in conjunction with individual patient characteristics (e.g., age, sex, and body weight) in order to estimate creatinine clearance. Such estimates of creatinine clearance are widely used as a parameter for individualization of dosages of drugs excreted primarily via the kidneys in patients with diminished renal function. However, estimation of creatinine clearance in patients with concurrent hepatic disease tends to result in substantial overprediction of observed creatinine clearance in this patient population. This report suggests that a diminished rate of creatinine production in patients with hepatic disease is a likely explanation for this anomaly. This postulated mechanism is based on a presentation of the biology of creatinine formation.

Nomogram for Estimating Creatinine Clearance

SummarySeveral methods have been published for estimating creatinine clearance from serum creatinine concentrations. Such estimates of creatinine clearance are widely used for dosage adjustments of drugs which are primarily eliminated through the kidneys in patients with reduced renal function. Most of these methods involve the use of equations, requiring a few steps of calculations. A simple and easy-to-use nomogram is presented for estimating creatinine clearance from serum creatinine concentration, plus the age, sex, and bodyweight of the individual patient. This nomogram is based on the linear relationship between creatinine clearance and the reciprocal value of the serum creatinine concentration, where the slope of this relationship is determined by the rate of creatinine production. The rate of creatinine production, however, is related to age, sex, and bodyweight. These physical characteristics are therefore used to scale the slopes of the relationships between creatinine clearance and serum creatinine concentration.The validity of the nomogram was tested in 50 consecutive hospitalised patients for which creatinine clearance was measured. There was an excellent correlation (r = 0.903) between predicted and observed creatinine clearance values.

Effect of Synthetic Cannabinoids on Elevated Intraocular Pressure

Two chemical derivatives of delta-1-tetrahydrocannabinol were evaluated in a randomized, double-masked study, administered as a single oral dose to a group of ocular hypertensive patients. One of the compounds (BW146Y) was found to have a significant intraocular pressure lowering effect that was independent of orthostatic blood pressure changes, although such changes did occur in some patients. The other compound (BW29Y) was ineffective in lowering intraocular pressure at the doses tested. Psychological and performance parameters were measured, and except for a time production test among the BW29Y group, these parameters were not significantly affected by the test drugs. Patients receiving both drugs experienced mild subjective side effects.

A Critical Review of the Safety and Antiemetic Efficacy of Delta-9-Tetrahydrocannabinol

Over the past six years, both governmental institutions and private enterprise have expressed great interest and activity in the isolation of chemical constituents from the Cannabis sativa plant and synthesis of novel cannabinoid compounds with potential medicinal uses. Evaluation of the safety and antiemetic efficacy of delta-9-tetrahydrocannabinol, the primary psychoactive cannabinoid component of marijuana, comprises one of several very active areas of cannabinoid clinical research. The results of clinical studies of the safety and antiemetic efficacy of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy are critically evaluated. Deficiencies in current knowledge of the clinical pharmacology of delta-9-tetrahydrocannabinol are discussed in the context of antiemetic drug evaluation.

Simulation: An underutilized approach to coagulation system model evaluation

Simulation and mathematical modeling have proven useful in evaluating diverse physiological and biochemical systems. However, simulation methods have had extremely limited application in the formulation and evaluation of models of the blood coagulation system. The utility of this tool is illustrated via a mathematical model of the interactions of thrombin with fibrinogen, antithrombin III, and heparin-antithrombin III complex. This model provides exemplary simulations consistent with several empirical characteristics of the anticoagulant effect of heparin. Simulation methods provide a powerful tool with which to characterize the dynamic nature of hemostatic process and its responsiveness to endogenous perturbations or pharmacological interventions.

Studies in Rats on in vitro Inhibition and in vivo Activity of Vitamin-K-Dependent Carboxylation

Vitamin-K-dependent procoagulant activity was studied in vitro by characterizing vitamin-K-dependent carboxylation and in vivo by assessing prothrombin complex activity (PCA). The kinetics of endogenous substrate carboxylation were apparently first order. Inhibition of vitamin-K-dependent carboxylation versus antagonist concentration was determined for 2,3,5,6-tetrachloropyridin-4-ol (TCP), phenindione, 2,6-dichloroindophenol sodium (2,6-DIP), 2-chloro-1,4-naphthoquinone (chloro-K3), 2-chloro-3-phytyl-1,4-naphthoquinone (chloro-K1) and warfarin. These compounds represent different chemical classes of anticoagulants that exert their effects via vitamin K antagonism. The percent inhibition versus concentration plots exhibited a sigmoidal shape and were described by the logistic function. The following concentrations were associated with 50% inhibition of vitamin-K-dependent carboxylation: TCP = 1.23 +/- 0.238 microM (mean +/- SD), phenindione = 19.0 +/- 11.2 microM, 2,6-DIP = 116 +/- 39.2 microM, chloro-K3 = 146 +/- 62.1 microM, chloro-K1 = 285 +/- 89.3 microM and warfarin = 6.63 +/- 2.82 mM. The slope parameters of the percent inhibition versus concentration plots for chloro-K1 and phenindione were different from those for the other antagonists, suggesting a mechanism of action consistent with other data in the literature, i.e. competitive antagonism of the vitamin-K-dependent carboxylase. The relationships between in vitro parameters of vitamin-K-dependent carboxylation of precursor proteins and in vivo indices of rate of production of vitamin-K-dependent coagulation factors were studied in control animals and animals pretreated with compounds perturbing hepatic function. The in vivo rate of synthesis of prothrombin complex activity and the circulating levels of PCA were correlated with the in vitro first-order rate constant of vitamin-K-dependent carboxylation, but not with the amount of precursor proteins present. The results of these studies suggest that the rate of vitamin-K-dependent carboxylation is intimately involved in the regulation of levels and activity of vitamin-K-dependent coagulation factors.

Bimodal frequency distribution of rat hepatic vitamin K-dependent carboxylation rate

The time course of vitamin K-dependent carboxylation was studied in an in vitro rat hepatic microsomal system. This method is based on incorporation of radiolabelled CO2 into endogenous substrate proteins. Forty rats were studied in order to characterize the intrinsic formation rate (V/KM) of carboxylated vitamin K-dependent proteins and the maximum amount of endogenous substrate available for vitamin K-dependent carboxylation (P infinity; normalized for the total amount of microsomal protein harvested). The frequency distributions of V/KM and P infinity values were both well described as the sum of two Gaussian components, each representing about 40% and 60% of the populations.