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C A Hunt

Publications and source records attributed to C A Hunt.

72 records · Page 4Linked to original sources
PubMed1981

Liposome disposition in vivo. III. Dose and vesicle-size effects.

The effect of lipid dose (4,3-512.8 mumol total lipid/kg body weight), administered intravenously as liposomes encapsulating radioactive inulin, upon the ability of mouse organs to bind and/or take-up the radioactive label has been studied in vivo. Three different liposome diameters were investigated: 0.46 micrometers (L), 0.16 micrometers (M) and 0.058 micrometers(S). All liposomes were negatively charged with lipid composition of phosphatidylcholine/phosphatidic acid/cholesterol/alpha-tocopherol in the molar ration 4 : 1 : 5 : 0.1 or 4 : 1 : 1 : 0.05. Overall radioactive label disposition after 2 h was consistent with localization predominantly in the reticuloendothelial system. A saturation of liver with increasing lipid dose was demonstrated for all three sizes, together with a corresponding increase in blood levels. Spleen radioactivity increased with increasing dose of L- and M-liposomes, but decreased for increasing doses of S-liposomes. Levels in residual carcass exhibited no trend. It was noted that by adjusting liposomal lipid dose and vesicle diameter the percentage of administered dose present in blood could be varied 733-fold, that in spleen 9-fold, liver 4-fold. Stability in vivo was ranked L greater than M greater than S-liposomes. Correction for differences of in vivo stability reduced the differences in organ accumulation between the three liposome sizes. The organ accumulation pattern suggested a dose- and diameter-dependent mechanism for liposome disposition. It was expected that when doses of fixed liposome composition were expressed as number of liposomes or their total surface area, organ saturation patterns would be similar. However, re-plotting the percent dose values for liver and spleen versus the number of liposomes administered revealed a saturation pattern for L-, M- and S-liposomes which was different in each case. Plotting the data versus the total surface area of the dose revealed a similar disposition pattern for L-, M- and S-liposomes in liver and L- and M-liposomes in spleen. The data indicate that in addition to composition, the lipid dose, total liposomal surface area and effective mean diameter are important pharmacokinetic variables. Further, the optimization of the therapeutic index of an encapsulated agent or target-tissue delivery via liposomes will require consideration of both the surface area and diameter of the liposome doses together with liposome composition.

Animals↗
PubMed1981

Calculating number and surface area of liposomes in any suspension.

Simple formulas for calculating the total surface area and number of liposomes in any liposome population are presented. The necessary parameters for calculating these values are the encapsulation ratio (or efficiency) of the population. When tested on theoretical liposome populations, excellent results are obtained regardless of the heterogeneity of the population.

Lipids↗
PubMed1981

Evidence that cannabidiol does not significantly alter the pharmacokinetics of tetrahydrocannabinol in man.

The pharmacokinetics of delta 9-tetrahydrocannabinol (THC) administered intravenously was evaluated in four subjects after oral administration of placebo and 1500 mg of cannabidiol (CBD) according to a crossover design. The cannabidiol pretreatment had no apparent effect on THC pharmacokinetics, yet there may have been minimal effect on the formation and excretion of metabolites. The total (metabolic) blood clearance of THC averaged 17.4 ml/min/kg without CBD and 20.9 ml/min/kg with CBD, and was probably hepatic blood flow limited. The apparent steady-state volume of distribution averaged 9.86 (with CBD, 10.54) liters/kg. Irrespective of CBD pretreatment, the renal clearance of THC metabolites ranged from 17 ml/min after approximately 1 hr to 1.13 ml/min 3.5 days after dosing with THC. The apparent terminal halflife for metabolites averaged 8.2 days.

Adult↗
PubMed1980

Tolerance and disposition of tetrahydrocannabinol in man.

The hypothesis was tested that the development of tolerance in man to the pharmacological effects of delta 9-tetrahydrocannabinol (THC) is due in part to changes in metabolism and disposition. Tolerance developed in six subjects following p.o. administration of 30 mg of THC every 4 hr for 10 to 12 days. Evaluation of THC pharmacokinetics was based on plasma levels of unchanged THC following i.v. administration of [14C] THC before and after the chronic p.o. THC. Development of tolerance was paralleled by pharmacokinetic changes: 1) average total metabolic clearance and the initial apparent volume of distribution increased from 605 to 977 ml/min and from 2.6 to 6.4 liters, respectively; 2) steady-state volume of distribution, averaging 684 liters, was unaltered; 3) the majority of model-dependent pharmacokinetic parameters as well as the time course of total metabolites in plasma were unchanged; 4) the percent dose excreted in urine decreased from 23.2 to 17.5%, but total elimination (urine plus feces) was not significantly changed; and 5) metabolites were rapidly formed (t 1/2 = 2.8-4.4 min), but slowly eliminated (t 1/2 = 49-53 hours) because of extensive protein binding. Renal clearance values of total metabolites were surprisingly low (maximum of 18-20 ml/min) and decreased with time (approximately 1 ml/min after 4-5 days), indicating the accumulation of highly bound metabolites. We conclude that such pharmacokinetic and metabolic changes cannot account for the development of tolerance to the cardiovascular, psychological and skin hypothermic effects of THC.

Adult↗
PubMed1980

Liposome disposition in vivo: effects of pre-dosing with lipsomes.

The effect of a high, intravenous dose of extruded multilamellar liposomes (1.1 g lipid/kg body weight) upon the subsequent ability of mouse tissues to take-up or bind a second intravenous dose of similar liposomes encapsulating 14C-inulin has been studied in vivo. The first and second doses were separated by either 1,5 or 24 hours. All tissue levels were measured one hour after the second dose. Controls received only the second dose. When the two doses were separated by one hours, 14C-levels in liver were depressed 6-fold and blood levels rose 29-fold relative to controls. However spleen uptake of lipsomes increased to three times control levels. When the two doses were separated by 24 hrs, the first dose had only a minimal effect on the disposition of the second dose. The results are consistent with a reversible blockade of hepatic, but not spleenic uptake and/or binding sites, by the first dose and indicate that adjusting a liposome dose (i.e. number of lipsomes) or use of a drug-free liposome pre-dose may be a useful technique for reducing hepatic uptake, increasing the circulation life time and/or modifying the tissue disposition properteries of therapeutic liposomes without changing liposome composition or size.

Animals↗
PubMed1979

Preparation of liposomes of defined size distribution by extrusion through polycarbonate membranes.

Liposomes of defined size and homogeneity have been prepared by sequential extrusion of the usual multilamellar vesicles through polycarbonate membranes. The process is easy, reproducible, produces no detectable degradation of the phospholipids, and can double the encapsulation efficiency of the liposome preparation. Multilamellar vesicles extruded by this technique are shown by both negative stain and freeze-fracture electron microscopy to have mean diameters approaching the pore diameter of the polycarbonate membrane through which they were extruded. When sequentially extruded down through a 0.2 micron membrane, the resulting vesicles exhibit a very homogeneous size distribution with a mean diameter of 0.27 micron while maintaining an acceptable level of encapsulation of the aqueous phase.

Carbonates↗
PubMed1977

Separation and analysis of delta 9-tetrahydrocannabinol in biological fluids by high-pressure liquid chromatography and GLC.

High-pressure liquid chromatographic (HPLC) systems were developed to separate quantitatively delta 9-tetrahydrocannabinol from heptane-extractable lipoidal and other endogenous substances in biological fluids. These substances interfered with the quantitation by flame-ionization GLC of the unmodified compound and by electron-capture GLC of the pentafluorobenzoyl derivative. Reversed-phase HPLC elution, with 47% acetonitrile in water, and normal-phase HPLC with 25% chloroform in heptane separated delta 9-tetrahydrocannabinol from 11-hydroxy-delta 9-tetrahydrocannabinol and other monohydroxylated tetrahydrocannabinols. These systems also purified stock solutions of delta 9-tetrahydrocannabinol from accompanying contaminants. The various monohydroxylated tetrahydrocannabinols were resolved from each other in the normal phase, 80% chloroform in heptane. The delta 8- and delta 9-tetrahydrocannabinols were separable in the normal phase with 5% tetrahydrofuran in hexane. The GLC analysis of pentafluorobenzoylated delta 9-tetrahydrocannabinol had a sensitivity of 1 ng/ml of plasma, with an estimated 5% standard error with the developed extraction and GLC procedures. Radiochemical analysis of the HPLC-separated fraction had a sensitivity of 0.2 ng/ml of plasma, with an estimated 2% standard error. There was no significant difference between the liquid scintillation and electron-capture GLC assays of the HPLC-separated delta 9-tetrahydrocannabinol obtained from the plasma of dogs administered the drug. Radiolabeled compounds can be added to plasma samples as internal standards to determine the recovery efficiencies of the several procedures in the analysis of unlabeled tetrahydrocannabinol.

Animals↗
PubMed1977

Pharmacokinetics of delta9-tetrahydrocannabinol in dogs.

The pharmacokinetics of intravenously administered 14C-delta9-tetrahydrocannabinol and derived radiolabeled metabolites were studied in three dogs at two doses each at 0.1 or 0.5 and 2.0 mg/kg. Two dogs were biliary cannulated; total bile was collected in one and sampled in the other. The time course for the fraction of the dose per milliliter of plasma was best fit by a sum of five exponentials, and there was no dose dependency. No drug was excreted unchanged. The mean apparent volume of distribution of the central compartment referenced to total drug concentration in the plasma was 1.31 +/- 0.07 liters, approximately the plasma volume, due to the high protein binding of 97%. The mean metabolic clearance of drug in the plasma was 124 +/- 3.8 ml/min, half of the hepatic plasma flow, but was 4131 +/- 690 ml/min referenced to unbound drug concentration in the plasma, 16.5 times the hepatic plasma flow, indicating that net metabolism of both bound and unbound drug occurs. Apparent parallel production of several metabolites occurred, but the pharmacokinetics of their appearance were undoubtedly due to their sequential production during liver passage. The apparent half-life of the metabolic process was 6.9 +/- 0.3 min. The terminal half-life of delta9-tetrahydrocannabinol in the pseudo-steady state after equilibration in an apparent overall volume of distribtuion of 2170 +/- 555 liters referenced to total plasma concentration was 8.2 +/- 0.23 days, based on the consistency of all pharmacokinetic data. The best estimate of the terminal half-life, based only on the 7000 min that plasma levels could be monitored with the existing analytical sensitivity, was 1.24 days. However, this value was inconsistent with the metabolite production and excretion of 40-45% of dose in feces, 14-16.5% in urine, and 55% in bile within 5 days when 24% of the dose was unmetabolized and in the tissue at that time. These data were consistent with an enterohepatic recirculation of 10-15% of the metabolites. Intravenously administered radiolabeled metabolites were totally and rapidly eliminated in both bile and urine; 88% of the dose in 300 min with an apparent overall volume of distribution of 6 liters. These facts supported the proposition that the return of delta9-tetrahydrocannabinol from tissue was the rate-determining process of drug elimination after initial fast distribution and metabolism and was inconsistent with the capability of enzyme induction to change the terminal half-life.

Animals↗
PubMed1977

Acetaminophen.

Explore the source record for details and available documents.

Acetaminophen↗
PubMed1977

Synthesis and stereospecific antipsychotic activity of (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine.

The synthesis and resolution of 3-iodocyproheptadine [(+/-)-5a] and 1-cyclopropylmethyl-4-(3-iodo-5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidine [(+/-)-5b] are described. The resulting atropisomers undergo reaction with trifluoromethylthiocopper to give optically active products without extensive racemization. In this manner, optically pure (+)- and (-)-3-trifluoromethylthiocyproheptadine [(+)-6a and (-)-6a, respectively] and (+)- and (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine [(+)-6b and (-)-6b, respectively] have been prepared. The influence of a chiral europium shift reagent on the proton and fluorine resonance signals as a diagnostic tool for the determination of the optical purities of these atropisomers is discussed. The four compounds, (+)-6a, (-)-6a, (+)-6b, and (-)-6b, were studied in squirrel monkeys for their ability to block conditioned avoidance responding. All of the antiavoidance activity was found to reside solely in the levorotatory compounds (-)-6a and (-)-6b. Further comparison of the enantiomers (-)-6b and (+)-6b showed that the ability to antagonize apomorphine-induced stereotyped behavior is confined to the levorotatory isomer (-)-6b while weak central anticholinergic activity resides solely in the dextrorotatory isomer (+)-6b. Neither (-)-6b has significant peripheral anticholinergic activity.

Animals↗
PubMed1977

(+)- and (-)-3-Methoxycyproheptadine. A comparative evaluation of the antiserotonin, antihistaminic, anticholinergic, and orexigenic properties with cyproheptadine.

The synthesis and resolution of (+/-)-3-methoxycyproheptadine [(+/-)-4] are described. As a peripheral serotonin antagonist, (+/-)-4 was found to be one-half as potent as cyproheptadine (1b). The peripheral anticholinergic and antihistaminic activities as well as the orexigenic property of (+/-)-4 are less than those of 1b. A further comparison of the enantiomers (+)-4 and (-)-4 shows that all of the anticholinergic activity of (+/-)-4 resides solely in the dextrorotatory enantiomer, (+)-4, while the antiserotonin activity, which is similar to that of 1b, resides in the levorotatory enantiomer, (-)-4. Antihistaminic and orexigenic activity also resides in (-)-4 but these properties are reduced compared to those of 1b.

Animals↗
PubMed1976

Separation and sensitive assay of THC in biological fluids by HPLC and GLC.

HPLC systems were developed to permit quantitative separation of delta9-tetrahydrocannabinol from many of the heptane extractable lipoidal and other endogenous substances in biological fluids. These substances interfered with the quantification by flame ionization GLC of unmodified compound and by electron capture GLC of pentafluorobenzoylated compound. Reverse phase HPLC elution, with 47% acetonitrile in water, and normal phase HPLC with 25% chloroform in heptane, separated tetrahydrocannabinol from 11-hydroxy-delta9-tetrahydrocannabinol and other monohydroxylated tetrahydrocannabinols. These systems also purified stock solutions of tetrahydrocannabinol from accompanying contaminants. The various monohydroxylated tetrahydrocannabinols were resolved from each other in normal phase, 80% chloroform in heptane. The delta8 and delta9-tetrahydrocannabinols were separable in normal phase with 5% tetrahydrofuran in hexane. The GLC analysis of pentafluorobenzoylated tetrahydrocannabinol had a sensitivity of 1 ng/ml of plasma with an estimated 5% standard error of an assay with the extraction and GLC procedures given herein. Radiochemical analysis of the HPLC separated fraction had s sensitivity of 0.2 ng/ml of plasma with an estimated 2% standard error of an assay. There was no significant difference between the liquid scintillation and electron capture GLC assays of the HPLC separated delta9-tetrahydrocannabinol obtained from the plasma of dogs administered the drug. Radiolabelled compounds can be added to plasma samples as internal standards to determine the recovery efficiencies of the several procedures in the analysis of unlabelled tetrahydrocannabinol.

Animals↗
PubMedDate not supplied

A forecasting approach to accelerate drug development.

The clinical phase of drug development should be concluded sooner and at a lower cost if primarily only the pivotal and supportive studies were to be conducted. Such improved efficiency requires development of a decision support system that delivers five new capabilities: (i) it enables one to predict a result of a clinical study and to identify those studies that are expected to have an acceptable probability of success; (ii) it will allow one to optimally utilize available pharmacokinetic and pharmacodynamic (PK/PD) data and improve its predictive capability as more data become available; (iii) it will enable one to project useful population results, not just mean results; (iv) predictions will be accompanied by a measure of reliability; and (v) expected initial clinical results will be predictable from animal and related drug class data. With such a tool population targets could be specified very early in the drug development programme, challenged, and then rationally revised at each step during the development process. This report describes progress in developing and testing a clinical trials Forecaster, a prototype for such a system. The Forecaster generates estimates of the joint density for a population of combined PK/PD parameters. That population then serves as a surrogate for the population of individuals. When the resulting joint density is sampled, the obtained sets of parameters may be used to generate data that is statistically indistinguishable from the original experimental data. Such simulated data can be used to validate assumptions, and make inferences on specified population targets that are accompanied by a measure of prediction reliability. We demonstrate use of the forecaster by employing N = 22 PK/PD parameter sets for an orally administered analgesic.

Bias↗
PubMedDate not supplied

Retention of cytosine arabinoside in mouse lung following intravenous administration in liposomes of different size.

An extrusion technique was used to obtain multilamellar lipid vesicles (MLV, liposomes) of different size distribution. The larger MLV ranged in diameter from 0.1 to 2.6 mu and the smaller from 0.1 to 1.5 mu, and both were composed of phosphatidylserine/phosphatidylcholine/cholesterol in the molar ratio 1:4:5. After intravenous injection of large and small MLV containing encapsulated [3H]cytosine arabinoside (ara-C), their distribution in various organs showed that the fraction of the dose associated with lung was greater for large MLV relative to small MLV by factors of 3.6--10 after 1 hr, 5.3--14 after 4 hr, and 17--23 after 24 hr. For large MLV more than 50% of drug remaining in vivo after 24 hr was associated with the lung, compared with 2.5% for small MLV. Almost all of the 3H associated with lung at all times for both large and small MLV could be accounted for by unchanged ara-C. Differences in 3H levels between small and large MLV in other tissues were much less dramatic or were not significant. The apparent in vivo stability of the liposomes was not affected by size. The data are consistent with an initial trapping of large MLV during first passage in the lung, with subsequent binding and retention. Release of ara-C from large or small MLV in the lung is apparently slow relative to meatbolism.

Animals↗