Biomedical subjects

C S Cook

Publications and source records attributed to C S Cook.

At least 19 recordsLinked to original sources

PubMed2001

Species difference in stereoselective involvement of CYP3A in the mono-N-dealkylation of disopyramide.

1. To determine which CYP isoenzyme is involved in the N-dealkylation of disopyramide (DP) metabolism in human and dog, and to determine the stereoselectivity of DP metabolism with human CYP and dog CYP isoenzymes, the following in vitro metabolism studies of DP were conducted: correlation between human CYP isoenzyme activities and DP metabolism with human liver microsomes; inhibition of DP metabolism in human and dog liver microsomes with chemical inhibitors of CYP isoenzymes; inhibition of DP metabolism in human microsomes with human CYP antibodies; inhibition of DP metabolism in dog liver microsomes with human and dog CYP antibodies; metabolism of DP with human (CYP3A4) and dog (CYP3A12) cDNA-expressed isoenzymes; determination of Km and Vmax of DP enantiomers by using cDNA-expressed CYP3A4 and CYP3A12. 2. In human liver microsomes, the formation of the mono-N-dealkylated disopyramide (MNDP) metabolite was best correlated with CYP3A4 activities. DP metabolism was substantially inhibited by ketoconazole, troleandomycin (TA) and human CYP3A4 antibody. DP was metabolized by cDNA-expressed CYP3A isoenzymes. In dog liver microsomes, DP metabolism was inhibited by ketoconazole, TA and dog anti-CYP3A12. DP was also metabolized by cDNA-expressed CYP3A12. 3. CYP3A4 and CYP3A12 are the principal isoenzymes involved in DP metabolism in human and dog respectively. There was no stereoselectivity in N-dealkylation of DP by human CYP3A4. However, there was notable stereoselectivity in the N-dealkylation by dog CYP3A12.

Amino Acid Sequence↗

PubMed2001

Eplerenone: a selective aldosterone receptor antagonist (SARA).

Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT(1)) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels--a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone--the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs)--is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.

Animals↗

PubMed2001

Pharmacokinetics of celecoxib after oral administration in dogs and humans: effect of food and site of absorption.

Celecoxib pharmacokinetics was evaluated after single and multiple oral dosing; after dosing in a solution and as a solid; with and without food; and after administration into different sites of the GI tract using dog. After oral dosing in a solution, celecoxib was rapidly absorbed and reached maximum concentrations by 1 h; absorption was delayed another 1 to 2 h when administered as a solid. The absolute bioavailability of celecoxib was higher when given as a solution (64--88%) compared with capsule (22--40%). The absorption of celecoxib given in a capsule was delayed by food, although systemic exposure increased by 3- to 5-fold. The systemic availability of celecoxib given intragastrically in solution was similar to that obtained following direct instillation into the duodenum, jejunum, or colon through a chronic intestinal access port. Collectively, these data suggest that celecoxib is a highly permeable drug that can be absorbed throughout the GI tract and that dissolution may be a rate-limiting factor for absorption from solid dosage forms. Unlike dogs, celecoxib given to humans with a high fat meal exhibits only a slight increase in AUC(0--infinity) (11%) that is not clinically significant with regard to safety or efficacy. In humans, a lower dose and a longer GI residence time may promote the opportunity for absorption of a poorly soluble drug such as celecoxib that can be absorbed throughout the GI tract. This would minimize the effect of food on absorption; as such, patients with arthritis can be given celecoxib with or without food.

Adult↗

PubMed2001

Morphology and immunohistochemistry of spontaneous chronic corneal epithelial defects (SCCED) in dogs.

PURPOSE: To determine the morphologic features of the epithelium and extracellular matrix in spontaneous chronic corneal epithelial defects (SCCED) in dogs. METHODS: Forty-eight superficial keratectomy specimens were obtained after confirmation of the presence of a superficial corneal erosion for longer than 3 weeks with no discernible underlying cause. Histologic samples were examined by light microscopy, scanning electron microscopy, and transmission electron microscopy. Immunolocalization of laminin, collagen IV, fibronectin, and collagen VII was performed. RESULTS: Epithelial cells adjacent to the defect were poorly attached to the underlying extracellular matrix. A prominent superficial stromal hyaline acellular zone composed of collagen fibrils in the area of the erosion was present in most specimens. Samples exhibited a varying degree of fibroplasia, vascularization, and leukocytic infiltrate. Laminin, collagen IV, and collagen VII were usually either not present or were present only in discontinuous segments on the surface of the erosion. Fibronectin usually coated the surface of the erosion, either as a continuous sheet or in discontinuous segments. Transmission electron microscopy of 15 samples revealed that the basement membrane was either absent in the area of the erosion or was present only in discontinuous segments. Scanning electron microscopy of eight of nine samples confirmed the absence of continuous basement membrane. Epithelial and extracellular matrix components in the peripheral cornea appeared normal. CONCLUSIONS: Most canine patients with spontaneous chronic corneal epithelial defects do not have a normal basement membrane structure in the region of the epithelial defect and have other abnormalities in the subjacent extracellular matrix that may reflect a part of the underlying pathophysiology of chronic and recurrent erosions.

Animals↗

PubMed2000

Absorption and disposition of a selective aldosterone receptor antagonist, eplerenone, in the dog.

PURPOSE: The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. METHODS: Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). RESULTS: After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. CONCLUSIONS: EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.

Administration, Oral↗

PubMed2000

Effect of diet and gavage on the dose- and dose-mode-dependent absorption and metabolism of bidisomide in rat.

1. The metabolism of bidisomide was investigated to examine how dose and mode of drug administration (i.e. diet admixture versus oral solution) affect the absorption and metabolism of bidisomide in the toxicity studies. 2. After dietary admixture, bidisomide was more absorbed and less metabolized at the higher doses. Reduced metabolism at the high doses resulted from saturation of stereo-specific formation of the N-desisopropyl-arylhydroxy bidisomide (NDABD) metabolite. 3. The rat-specific NDABD metabolite was formed only from (-)-bidisomide on incubation with rat liver microsomes. 4. After oral solution dosing, absorption was increased and metabolism reduced compared with the dietary admixture. 5. After 24-h infusion, plasma concentrations of radioactivity were approximately dose-proportional. However, the concentrations in the liver were similar at the 200 and 400 mg/kg doses due to saturation of liver uptake of the NDABD metabolite.

Administration, Oral↗

PubMed1998

Mechanism of compound- and species-specific food effects of structurally related antiarrhythmic drugs, disopyramide and bidisomide.

PURPOSE: To determine mechanism of food effects observed with bidisomide but not with the structurally similar drug, disopyramide. METHODS: Food effect studies of bidisomide and disopyramide were conducted with and without a standardized high fat meal in healthy subjects and in the dog. Intestinal metabolism of disopyramide and absorption of the metabolites were examined after oral administration of the drug to the dogs with portal vein canula implanted. Effects of food or a mixture of amino acids on metabolism of [14C]disopyramide were examined after intraportal infusion of the drug with and without high fat meal and after drug infusion into portal vein with the amino acid mixture, respectively. RESULTS: The systemic availability of bidisomide was markedly reduced with food in humans, whereas the systemic availability of disopyramide did not change notably. In the dog, the systemic availability of bidisomide was also reduced with food. The systemic availability of disopyramide did not change with food. This was due to the fact that reduction in absorption was compensated by reduction of metabolism. There was no evidence for reduction in hepatic and intestinal metabolism with food. CONCLUSIONS: The apparent reduction in disopyramide metabolism with food may be due to an increase in colonal and/or lymphatic absorption. Food effects on the apparent systemic availability of bidisomide and disopyramide in the dog were similar to those in the rat. However, there was substantial species difference in the mechanism of food effects.

Adult↗

PubMed1997

Characteristics of participants in domestic violence. Assessment at the scene of domestic assault.

OBJECTIVE: To evaluate the characteristics of victims and perpetrators of domestic assault. DESIGN AND SETTING: Consecutive-sample survey study conducted at the scenes of police calls for domestic assault in Memphis, Tenn, in 1995. PARTICIPANTS: A total of 136 participants (72 victims and 64 assailants) involved in 62 incidents of domestic violence and 75 adult family members at the scene. MAIN OUTCOME MEASURES: Participants' responses to a confidential survey and review of police records. RESULTS: Of 62 episodes of domestic assault, 42 (68%) involved weapons and 11 (15%) resulted in serious injury. Fifty-five (89%) of 62 assault victims reported previous assaults by their current assailants, 19 (35%) of them on a daily basis. Although nearly all assault victims had called the police for help on previous occasions, only 12 (22%) reported having ever sought medical care, counseling, or shelter because of domestic assault. Sixty (92%) of the 64 assailants reportedly used alcohol or other drugs on the day of the assault. Of the assailants, 28 (44%) had a history of arrest for charges related to violence, and 46 (72%) had an arrest for substance abuse. Eleven (15%) of the victims were children. Children directly witnessed 53 (85%) of the assaults. CONCLUSIONS: Most victims of domestic violence who had called the police rarely used medical or mental health facilities for problems related to family violence despite frequent assaults. Victims and assailants were willing to discuss their histories of family violence and undergo assessments at the scenes of police calls.

Adolescent↗

PubMed1997

Surgery for glaucoma.

Most cases of glaucoma in small animals ultimately require surgical treatment for long-term control of intraocular pressure. Surgical procedures that have the potential to preserve vision in acute cases are categorized into those that reduce aqueous production (cyclodestructive techniques). Salvage procedures for irreversibly blind eyes include enucleation, implantation of an intraocular prosthesis, and pharmacologic ciliary body ablation. The indications, surgical technique, and complications of these procedures are discussed in this article.

Animals↗

PubMed1997

Effects of SC-52458, an angiotensin AT1 receptor antagonist, in the dog.

We have previously reported on the basic pharmacologic properties of SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), a novel angiotensin (AII) receptor antagonist that binds potently to AT1 receptors in rat adrenal cortex and blocks AII-mediated contraction in isolated rabbit aorta. In the present study, the ability of SC-52458 to block AII pressor responses in conscious dogs was measured. In addition, we determined whether SC-52458 lowered mean arterial pressure in dogs with 2 kidney/1 clip renal hypertension when given daily for 4 days. In conscious, normotensive dogs, SC-52458 at 30 mg/kg orally, blocked the pressor response to AII (50 ng/kg, intravenously) with maximal inhibition (91%) observed 2 h after dosing. Plasma concentrations of SC-52458 measured by HPLC also were highest at the 2-h time point. After 24 h, the AII pressor response remained inhibited (by 35%) and SC-52458 was still measurable in plasma from treated dogs. In dogs made hypertensive by constriction of the left renal artery, SC-52458 lowered mean arterial pressure compared to vehicle treatment although heart rate was not different in the two groups. The maximal blood pressure lowering achieved with SC-52458 was similar to the maximal effect observed with the angiotensin converting enzyme inhibitor lisinopril. We conclude that SC-52458 blocks AII mediated pressor responses in normotensive, conscious dogs and SC-52458 is an efficacious antihypertensive agent in dogs with 2 kidney/1 clip renal hypertension.

Administration, Oral↗

PubMed1997

Mechanisms of food effects of structurally related antiarrhythmic drugs, disopyramide and bidisomide in the rat.

PURPOSE: To determine whether the rat is a good animal model for the food effects observed with bidisomide but not with the structurally similar antiarrhythmic drug, disopyramide in man and to explore a reason for the differences in the food effects of these compounds. METHODS: The following effects on the absorption of bidisomide and/or disopyramide were examined in the rat: Food effects, gastrointestinal transit time under fasting and nonfasting conditions, pH effects, hypertonic solution effect of NaCl and glucose, bile effects, permeability, inhibitory effects by Gly, Gly-Gly, Gly-Pro, glucose and mannitol and drug binding to food. RESULTS: Remarkable food effects were observed with bidisomide but not with disopyramide. There was no difference in the GI transit time with and without food. The pH effect with and without food was similar. Effect of salt concentrations on bidisomide and disopyramide was similar. There was no bile effect on absorption of both compounds. Binding of bidisomide and disopyramide to food was similarly low. The apparent permeability of bidisomide was much lower than disopyramide especially in the ileum and its absorption was more inhibited by Gly, Gly-Gly and Gly-Pro. CONCLUSIONS: In the rat, as previously seen in humans, the food effect was observed with bidisomide but not with disopyramide. This difference was in part due to both lower intestinal permeability of bidisomide compared to disopyramide and greater inhibition of absorption by the amino acid, Gly and the dipeptides, Gly-Gly and Gly-Pro.

Animals↗

PubMed1996

Measurement of muscle and tendon stiffness in man.

Human first dorsal interosseous muscle was stimulated tetanically using several levels of percutaneous electrical current which produced forces in the muscle-tendon complex of between 30% and 100% of maximum. During the tetanus the muscle was subjected to a small fast stretch. The ratio of the force response to the displacement of the muscle-tendon complex gave a measure of the stiffness of the total complex. An adaptation of the method of Morgan (1977) allowed the stiffness to be separated into two components the stiffness of the muscle fibres and the stiffness of the tendon. The results showed that at full activation the stiffness of the muscle fibres and the tendon are approximately the same. The normalised stiffness values obtained in the experiments compared well with animal data.

Adult↗

PubMed1996

Force responses to constant-velocity shortening of electrically stimulated human muscle-tendon complex.

Force-velocity curves in human muscle often have unexpectedly high forces at high velocities. If series elasticity is the cause, it should have less effect at lower activation levels and larger shortening amplitudes. The first dorsal interosseus muscle-tendon complex was shortened at different levels of activation and by different amplitudes. Force-velocity curves had high force well maintained at high velocities. With an actuator release of 4.21 mm at 80% of maximal activation, force was > 45% of isometric force (Po) for all actuator velocities > 200 mm/s (1.49 muscle lengths/s). At 30% activation, the force was > 25% of Po at these velocities. The smaller 2.46-mm releases produced higher forces than the 4.21-mm releases at these velocities. At 80% activation, force was > 65% of Po, and at 30% activation, it was > 50% of Po at these velocities. Corrections of these data for elasticity produced classic Hill-type force-velocity curves. A model incorporating the Hill force-velocity equation and a spring in series accounts for the results.

Adult↗

PubMed1995

Species dependent esterase activities for hydrolysis of an anti-HIV prodrug glycovir and bioavailability of active SC-48334.

PURPOSE: The in vitro fate of an ester prodrug, glycovir, was studied to determine if the species differences in the bioavailability of pharmacologically active SC-48334 observed after glycovir administration and not observed after SC-48334 administration is due to species differences in ester hydrolysis rate or species differences in absorption of the prodrug itself, and to determine the site(s) of ester hydrolysis which contributes most to species differences in the bioavailability of SC-48334 if any. METHODS: Glycovir was incubated with small intestinal mucosa, liver S9 fractions, whole blood, red blood cells (RBC) and plasma of the rat, dog, monkey (cynomolgus and rhesus) and man, and glycovir concentrations were determined by HPLC. RESULTS: The relative bioavailabilities of SC-48334 after prodrug administration to the rat, dog, monkey and man were 99, 15, 42 and 37%, respectively. After SC-48334 administration, SC-48334 was rapidly and similarly well absorbed in all species. The hydrolysis rate in the small intestinal mucosa was well correlated with the relative bioavailability of SC-48334 after prodrug administration. Among different species the hydrolysis rate of glycovir in liver S9 fractions, blood, RBC and plasma did not parallel those in the mucosa of the small intestine. CONCLUSIONS: The species differences in bioavailability of SC-48334 with the prodrug were due to species differences in hydrolysis rates of the prodrug in small intestinal mucosa. The monkey was a good animal model for prediction of esterase activity in human small intestine and relative bioavailability in man.

1-Deoxynojirimycin↗

PubMed1995

Force responses to controlled stretches of electrically stimulated human muscle-tendon complex.

Human first dorsal interosseus muscle was tetanized using percutaneous electrical stimulation. During the tetanus the muscle was subjected to constant velocity stretches. The stretch produced an enhancement of muscular force of up to 80% during the stretch. The size of the enhancement was dependent on both the amplitude and the velocity of the stretch. During an isometric hold phase after the stretch, the force decayed quickly for the first 100 ms and thereafter much more slowly, reaching a level 30% higher than the isometric force without pre-stretch. The force during this hold phase was dependent on amplitude of stretch but was independent of stretch velocity. The interaction of tendon elasticity and muscle fibre mechanics in producing these responses is discussed. Implications for normal human movements are also explored.

Adenosine Triphosphate↗

PubMed1995

Effects of SC-56525, a potent, orally active renin inhibitor, in salt-depleted and renal hypertensive dogs.

SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1 +/- 16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.

Administration, Oral↗

PubMed1995

Metabolism of a novel antiarrhythmic agent, bidisomide, in man: use of high resolution mass spectrometry to distinguish desisopropyl bidisomide from desacetyl bidisomide.

1. Metabolism of bidisomide, a novel antiarrhythmic agent, was studied in man, and was not extensive as evidenced by the fact that approximately 60 and 70% of the radioactive doses were recovered as the parent drug after i.v. and oral administration respectively. 2. The mass spectra of bidisomide metabolites indicate that the two major metabolic pathways of bidisomide were hydroxylation of the piperidine ring and N-dealkylation. The latter occurred on the side chain containing the piperidine ring or the isopropyl group. The N-dealkylated metabolite on the side chain containing the piperidine ring was cyclized to result in a pyrrolidone metabolite. 3. The N-dealkylated metabolite, desisopropyl bidisomide, was identified by comparing its high resolution mass spectrum to that of authentic desacetyl bidisomide. 4. In the hydroxylation pathway, both mono- and dihydroxylated metabolites of the piperidine ring were observed. The exact location of the hydroxyl groups on the piperidine ring was not determined.

Administration, Oral↗

PubMed1994

Testing reckless drivers for cocaine and marijuana.

BACKGROUND: Driving under the influence of intoxicating drugs other than alcohol may be an important cause of traffic injuries. We used a rapid urine test to identify reckless drivers who were under the influence of cocaine or marijuana. METHODS: We conducted a consecutive-sample study in Memphis, Tennessee, in the summer of 1993. Subjects arrested for reckless driving who were not apparently impaired by alcohol (did not have an odor of alcohol, tested negative on breath analysis, or both) were tested for cocaine and marijuana at the scene of arrest. The results of the drug tests were compared with clinical evaluations of intoxication made at the scene by a police officer. RESULTS: A total of 175 subjects were stopped for reckless driving, and 150 (86 percent) submitted urine samples for drug testing at the scene of arrest. Eighty-eight of the 150 (59 percent) tested positive: 20 (13 percent) for cocaine, 50 (33 percent) for marijuana, and 18 (12 percent) for both drugs. Ninety-four of the 150 tested drivers were clinically considered to be intoxicated, and 80 of them (85 percent) tested positive for cocaine or marijuana. The intoxicated drivers had a broad range of affects and appearances. Nearly half the drivers intoxicated with cocaine performed normally on standard sobriety tests. CONCLUSIONS: Over half of the reckless drivers who were not intoxicated with alcohol were found to be intoxicated with other drugs. Toxicologic testing at the scene is a practical means of identifying drivers under the influence of drugs and is a useful adjunct to standard behavioral sobriety testing.

Adult↗