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Biomedical subjects

D M Cocchetto

Publications and source records attributed to D M Cocchetto.

At least 37 records · Page 2Linked to original sources
PubMed1984

Initial slope technique for estimation of the apparent volume of distribution during constant-rate intravenous infusion.

A new technique is presented for estimating the apparent volume of distribution of drugs during constant-rate intravenous infusion. It is based on the initial slope of the plasma drug concentration versus time profile during the infusion. Equations are derived to provide estimates of the apparent volume of distribution for a one-compartment drug and for the central compartment of a two-compartment drug. The utility of the technique is illustrated by data obtained during constant-rate infusion of metronidazole in 11 healthy subjects. The average estimated value of the volume of the central compartment of metronidazole was 12% higher than the average value obtained by conventional pharmacokinetic analysis. The systematic error associated with this volume estimation procedure was assessed through the use of dimensionless concentration versus dimensionless time plots. The initial slope technique should prove useful in providing initial estimates of volume terms.

Half-Life↗
PubMed1983

Relationships between several pharmacokinetic parameters and psychometric indices of subjective effects of delta 9-tetrahydrocannabinol in man.

This study explored the relationships in man between various pharmacological effect of delta 9-tetrahydrocannabinol (THC), plasma THC concentration, and pharmacokinetic parameters of THC. Three male and three female experienced marihuana users smoked two standard marihuana cigarettes. The relationships between heart rate, subjective "high" rating, Linear Mood Scale factors, and plasma THC concentration were assessed. Significant correlations were observed between various Linear Mood Scale factors and pharmacokinetic parameters reflecting the magnitude of drug intake and the degree of temporal dissociation between the time courses of plasma THC concentration and pharmacological effects (tachycardiac effect, "high"). In particular, the disturbed/weird and sensitive/aware mood factors correlated positively with pharmacokinetic measures of drug intake and time lag to effect. A more reliable index of intoxication with THC may be provided by the global subjective "high" rating, rather than other ratings more specific for particular moods.

Dronabinol↗
PubMed1983

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.

Adult↗
PubMed1983

Antibiotic efficacy against Vibrio vulnificus in the mouse: superiority of tetracycline.

Seven antimicrobial agents, all effective against Vibrio vulnificus in vitro, were compared for in vivo efficacy in mice experimentally infected with V. vulnificus strain B3547. Mice were injected s.c. with 1 X 10(8) cells, and i.p. injection of antimicrobials was begun 1.5 hr later when mice were bacteremic and had edematous lesions at the injection site. The study was done in two phases. Phase I was a dose-ranging experiment, using single injections within the range (on a body weight-adjusted basis) clinically useful in humans. Of 12 mice treated with tetracycline (4 mg/kg), 12 survived at 24 hr, compared to 0 of 21 saline-treated controls, 3 of 10 given ampicillin (32 mg/kg) and 2 of 3 given cefotaxime (20 mg/kg). There were no survivors at 24 hr in groups of 5 to 10 mice treated with cefazolin (32 mg/kg), carbenicillin (80 mg/kg), erythromycin (8 mg/kg) or gentamicin (8 mg/kg). Phase II was designed to simulate clinical conditions using multiple dosing for 30 hr and scoring for survival at 96 hr. Of 12 mice given tetracycline (3 mg/kg every 12 hr), 12 survived, compared to 1 of 10 given cefotaxime (20 mg/kg every 6 hr), 0 of 12 given carbenicillin (40 mg/kg every 6 hr) and 0 of 12 given saline every 6 hr. Tetracycline thus appears to be the agent of choice among those tested for in vivo efficacy against V. vulnificus in the mouse model.

Animals↗
PubMed1982

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.

Antithrombin III↗
PubMed1982

Dipyridamol kinetics.

The kinetics of the antiplatelet drug dipyridamole were studied in six normal subjects (three men and three women) who were ages 22 to 34 yr old. Each received 20 mg IV and four also took a 50-mg oral dose. Blood samples were collected after each dose for a period of 3 days and concentrations of dipyridamole were measured by a sensitive and specific high-performance liquid chromatographic assay. Concentrations after the intravenous dose showed a triexponential decline with a terminal half-life of 11.6 +/- 2.2 hr (x +/- SD). Total plasma clearance was 8.27 +/- 1.82 1/hr and the apparent volume of distribution was 141 +/- 51 1. Concentrations rose 6 to 10 hr after intravenous dipyridamole in each female subject, but not in the male subjects. Dipyridamole blood/plasma concentration ratio changed from an average of 0.7 over the first hour to 1.2 after 5 hr after the intravenous dose. There was an absorption lag time ranging from 34 to 75 min after the oral dose; concentrations peaked at about 2 to 2.5 hr after the dose. The percentage of unbound drag in plasma was 0.88 +/- 0.24%. Systemic availability of the end oral dose was 43 +/- 13%. These results suggest widely varying concentrations in patients receiving the drug, and raise questions about the current clinical practice of using empirical dosage schedules.

Administration, Oral↗
PubMed1981

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.

Acute Kidney Injury↗
PubMed1981

Absorption of orally administered sodium sulfate in humans.

Sodium sulfate can be used to enhance the conjugation of phenolic drugs with sulfate and to treat hypercalcemia. It is thought that sulfate in is absorbed slowly and incompletely from the digestive tract. The purposes of this investigation were to determine the absorption of large amount of sodium sulfate (18.1 g as the decahydrate, equivalent to 8.0 g of the anhydrous salt) and to compare the bioavailability when this amount is administered orally to normal subjects as a single dose and as four equally divided hourly doses. The 72-hr urinary recovery of free sulfate following single and divided doses was 53.4 +/- 15.8 and 61.8 +/- 7.8%, respectively (mean +/- SD, n=5, p greater than 0.2). The single dose produced severe diarrhea while the divided doses caused only mild or no diarrhea. Thus, a large amount of sodium sulfate, when administered orally in divided doses over 3 hr, is well tolerated and is absorbed to a significant extent. Orally administered sodium sulfate may be useful for the early treatment of acetaminophen overdose.

Administration, Oral↗
PubMed1981

Relationship between plasma delta-9-tetrahydrocannabinol concentration and pharmacologic effects in man.

The relationship between each of two pharmacologic effects (tachycardia and psychological "high") of delta-9-tetrahydrocannabinol (THC) and plasma THC concentration was investigated in three male and three female experienced marihuana smokers. Each subject smoked 1% THC cigarette on two occasions separated by 2 h. Heart rate and subjective psychological self-rating were determined frequently throughout the 4 h study period. Data were analyzed by calculating the area under the parameter versus time curves, constructing hysteresis plots, and calculating the decay rate constants from pharmacologic effect versus time plots. In both males and females, dose inhaled and psychological response were apparently equivalent for the first and second cigarettes. While all subjects exhibited marked tachycardia in response to the first cigarette, heart rate in both male and female subjects was not increased as markedly during the second cigarette. Interestingly, female subjects had less tachycardiac response than males during the second cigarette. Hysteresis plots revealed that both heart rate and subjective psychological effect were elicited in an effect compartment which was "deep" relative to the reference plasma compartment. The time courses of tachycardiac and psychological responses lagged behind the plasma THC concentration-time profile. Zero-order decay rate constants for subjective psychological rating did not change substantially from the first to second cigarette. This study suggest that plasma THC concentration is a poor predictor of simultaneously occurring physiological and psychological pharmacologic effects.

Adult↗
PubMed1981

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.

Benzopyrans↗
PubMed1981

A critical review of the safety and antiemetic efficacy of delta-9-tetrahydrocannabinol.

Over the past six years, both government 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.

Animals↗
PubMed1980

Pitfalls and valid approaches to pharmacokinetic analysis of mean concentration data following intravenous administration.

Pharmacokinetic analysis fo arithmetic mean concentration data can lead us to selection of an inappropriate deterministic compartmental model and biased pharmacokinetic parameter estimates. The terminal phase disposition rate constant estimated by fitting a deterministic model to mean data is in all cases an underestimate of the expected value of this rate constant. The area under the mean data curve calculated via the linear trapezoidal rule from time zero to the last detectable concentration sampling point is equal to the mean of the individual subject areas under the curve for the same time span. This equality supports the use of mean data for determination of model-independent pharmacokinetic parameters.

Humans↗
PubMed1979

Acyclovir kinetics after intravenous infusion.

The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1-hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (+/- SEM), determined by radioimmunoassay, were 6.4 +/- 0.7, 12.1 +/- 2.3, 14.9 +/- 2.7, and 33.7 +/- 7.1 microM. The plasma concentration-time profiles could be described by a biexponential equation. The half-life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose-independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse-phase high-performance liquid chromatography revealed the presence of the metabolite 9-carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.

Aged↗
PubMedDate not supplied

Benefit-risk assessment of investigational drugs: current methodology, limitations, and alternative approaches.

Development of investigational drugs is a process integrated traditionally into four overlapping phases. The goal is to introduce new therapies to clinical medicine by assessing benefits and risks associated with administering the new drug. Benefit assessment is performed with respect to the disease for which the drug may comprise an effective treatment. In contrast, safety assessment is relatively standardized across many pharmacologic classes of agents. For purposes of benefit-risk assessment, investigational drugs are developed to provide benefit in three major disease categories: acute, episodic, and chronic. Benefit assessment is the major focus of conventional methodologies. Inherent limitations of risk assessment produced by conventional approaches are illustrated by the historical inability to detect toxicities of various drugs until large patient populations have been treated, typically after the drug is marketed. Alternative approaches to overcome these limitations include assessment of safety in studies specifically designed to optimize such evaluation and more extensive safety testing of investigational drugs in patient subgroups at higher risk. Such approaches serve the interest of patients, physicians, and developers by facilitating the development of new therapies by providing a more complete benefit-risk assessment prior to initial marketing of the drug.

Acute Disease↗