Biomedical subjects

C S Cook

Publications and source records attributed to C S Cook.

At least 37 records · Page 2Linked to original sources

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↗

PubMed1994

Effect of salicylic acid on the plasma protein binding and pharmacokinetics of misoprostol acid.

The in vitro serum protein binding and erythrocyte uptake of [3H]misoprostol acid ([3H]MPA; SC-30695), an active metabolite of the prostaglandin E1 (PGE1) analogue misoprostol, was determined in the blood of young (20-40 years) and elderly subjects (64 years or older) at concentrations ranging between 20 and 5000 pg/mL. The effect of selected other drugs on the displacement of [3H] MPA from the binding sites was also investigated. [3H]MPA serum binding (between 81 and 89 %) was similar and concentration independent in the young and elderly subjects and the erythrocyte partitioning coefficient was about 1, indicating the absence of a significant accumulation of MPA in red blood cells. Both the plasma and serum protein binding of [3H] MPA were substantially reduced in the presence of high (> 100 microg/mL) concentrations of salicylic acid. In an in vivo study, the single-dose pharmacokinetics of MPA did not change significantly when misoprostol (200 microg) was given alone or concomitantly with 975 mg of aspirin. These findings indicate that MPA is displaced from its protein binding sites only by high concentrations of salicylic acid and that this displacement is unlikely to be of clinical significance with the usual therapeutic doses of aspirin.

Adult↗

PubMed1993

Pharmacokinetics of a novel antiarrhythmic drug, actisomide.

The pharmacokinetics of a novel antiarrhythmic drug, actisomide, were examined in the rat, dog, monkey, and human. The terminal half-life of actisomide was similar (1.15-1.89 hr) across species, regardless of dose. The total plasma clearance was higher in the monkey (13.5-16.4 mL/min/kg) than in the dog (9.01-9.32 mL/min/kg), rat (8.6-9.8 mL/min/kg), or human (6.79 +/- 1.07 mL/min/kg). Excretion of the parent drug was higher in urine than in feces in the dog and rat, whereas in the monkey and human, urinary and fecal excretions of actisomide were similar. In humans, atypical plasma concentration-time curves with double peak concentrations were observed following oral doses. Systemic availability of actisomide was higher in the dog than in the rat, monkey, and human. Further, the systemic availability appeared to increase with dose in the rat and monkey. The species-dependent systemic availability appeared to be due primarily to species-dependent absorption of actisomide, and not to species-dependent first-pass metabolism, biliary excretion, and/or renal elimination. The absorption of actisomide in the rat and its in vitro uptake in CaCo-2 cells were pH dependent. The higher systemic availability of actisomide observed in the dog may be due partly to the higher pH in the gastrointestinal (GI) tract of the dog. However, the pH differences in the GI tract of the different species alone did not appear to be enough to explain the difference in systemic availability of actisomide.

Administration, Oral↗

PubMed1993

Absorption and disposition of a new antiarrhythmic agent bidisomide in man.

Absorption and disposition of bidisomide were studied in 12 healthy male subjects after a 20-min iv (1 mg/kg; N = 6) infusion and oral (2 mg/kg; N = 6) administration of the 14C-labeled drug. The oral absorption profile of unlabeled bidisomide was also studied after administration of a solution by a nasoenteric tube to different sites of the gastrointestinal tract (stomach, duodenum, jejunum, and ileum). The systemic availability was 61%. Absorption was slow initially and then rapid, achieving peak plasma concentrations between 2 and 4 hr. Less than complete systemic availability was attributed to incomplete absorption rather than first-pass metabolism. When the drug solution was delivered directly to the stomach, two distinct peak plasma levels were found. This was attributed to the more rapid absorption of bidisomide in the duodenum and ileum (and/or possibly colon). Following an iv dose, plasma levels of the drug declined with mean half-lives of 0.11, 2.0, and 12 hr for alpha, beta, and gamma phases, respectively, and a plasma clearance of 380 mL/min. The percentages of the dose recovered as bidisomide in urine and feces were 19 +/- 1 and 29 +/- 4 for the iv dose and 9.1 +/- 0.9 and 48 +/- 5 for the oral dose. Bidisomide did not exhibit substantial enantioselective pharmacokinetics in plasma regardless of the route of administration. The mean urinary excretion of the (-) enantiomer was, however, slightly higher than that of the (+) enantiomer, with (-)/(+) enantiomeric ratios of 1.2 and 1.3 after iv and oral administration, respectively. The enantiomeric ratio of bidisomide recovered in the feces was approximately 1.

Absorption↗

PubMed1993

Importance of pharmacokinetic and physicochemical data in the discovery and development of novel anti-arrhythmic drugs.

1. The importance of pharmacokinetics and physicochemical data in the discovery and development of a new mono-cationic antiarrhythmic agent, bidisomide (pKa 9.3), structurally related to the di-cationic anti-arrhythmic disobutamide (pKa of 8.6 and 10.2) and a mono-cationic drug disopyramide (pKa 10.4), is described. 2. In man, the di-cationic disobutamide was slowly eliminated with a mean terminal phase half-life of 54 +/- 18 h, a value > 7 times longer than disopyramide. The long terminal phase half-life of disobutamide is attributed to high accumulation of the drug in the tissues, a phenomenon attributed to the di-cationic nature. 3. Structural modification of disobutamide resulted in the mono-cationic agent bidisomide, designed to minimize drug accumulation in the tissues. Human studies with bidisomide confirmed that the terminal phase elimination of this drug was much faster than that of disobutamide, with a half-life of about 11h. The absolute bioavailability of bidisomide was 45-62% which is lower than that of disopyramide (60-90%). 4. Unlike disopyramide, absorption of bidisomide was complex, characterized by a lag period (0.75-1.5 h) before absorption, followed by occurrence of two peaks in the plasma concentration-time curves. 5. The characteristic double peaks found with bidisomide was attributed to two rapid absorption sites of the drug in the gastrointestinal tract.

Adolescent↗

PubMed1993

Involvement of cytochrome P-450IIIA in metabolism of potassium canrenoate to an epoxide: mechanism of inhibition of the epoxide formation by spironolactone and its sulfur-containing metabolite.

In vitro metabolism studies of potassium canrenoate (PC) were conducted to examine whether spironolactone (SP) and/or its sulfur-containing metabolites inhibit the PC metabolic pathways to mutagenic metabolites and to elucidate the mechanism for any observed inhibitory effect. The mechanistic study was conducted using liver microsomes prepared from male and female rats with and without pretreatment of a cytochrome (Cyt) P-450IIIA inducer [pregnenolone-16 alpha-carbonitrile (PCN) or dexamethasone (DEX)] and with and without a Cyt P-450IIIA inhibitor, triacetyloleandomycin (TAO). The present study demonstrates that SP and its sulfur-containing metabolite 7 alpha-thio-spirolactone substantially inhibited the formation of promutagen 6 beta, 7 beta-epoxycanrenone (6 beta, 7 beta-epoxy-CAN) from PC. The sulfur-containing metabolite of SP that inhibit promutagen formation were not formed from PC, although a glutathione conjugate of PC was formed. The formation rate of 6 beta, 7 beta-epoxy-CAN was greater in liver microsomes prepared from rats pretreated with a Cyt P-450IIIA inducer (PCN or DEX) than in liver microsomes prepared from the untreated rats. The formation rate of the epoxide metabolite was lower after in vitro addition of TAO. Pretreatment of animals with TAO 4 hr before sacrifice produced similar results. Erythromycin, which is N-demethylated by Cyt P-450IIIA, also reduced the formation rate of 6 beta, 7 beta-epoxy-CAN. Inhibition of PC metabolism to 6 beta, 7 beta-epoxy-CAN by TAO and erythromycin, and its induction by DEX and PCN, suggest involvement of Cyt P-450IIIA, which is in turn inhibited by SP and 7 alpha-thio-spirolactone.

Animals↗

PubMed1992

Fetal alcohol syndrome and fatty acid ethyl esters.

Fetal alcohol syndrome is the leading known cause of mental retardation. The syndrome, defined as growth retardation, midface hypoplasia, and neurologic dysfunction, represents only part of the spectrum of fetal alcohol effects. The biochemical mechanism of teratogenesis is unknown. In adults, metabolites of ethanol, FAEE, are known to accumulate in major organs. The formation of FAEE is catalyzed by a family of enzymes, FAEE synthases. Our hypothesis is that accumulation of FAEE in the embryo results in fetal alcohol syndrome. We have developed assays for FAEE and FAEE synthase activity using mg of tissue. Using these assays, we have shown the following: Human placenta, mouse placenta, heart, and liver are active in catalyzing the formation of FAEE. One h after maternal ethanol administration on gestational d 14, mouse placenta and fetuses accumulated significant quantities of FAEE. The fatty acid incorporated into FAEE was tissue dependent. Tissues from pregnant animals given ethanol on gestational d 7 showed persistence of FAEE on gestational d 14. We conclude that: 1) human and mouse placentas have significant FAEE synthase activity, 2) mouse heart, liver, placenta, and fetal tissues accumulate significant amounts of FAEE after maternal ethanol exposure, 3) there is tissue specificity for the fatty acid incorporated into FAEE, and 4) FAEE may persist for 7 d in placentas. These results provide a basis for further research into the role of FAEE in the development of fetal alcohol syndrome.

Acyltransferases↗

PubMed1991

RPE dysplasia with retinal duplication in a mutant mouse strain.

An autosomal dominant mutation was produced by quadruple gonadal exposure of a male (C3H x 101)F1 mouse to 500 rad of X-irradiation. This mutation is maintained by the mating of affected heterozygous males to normal (C3H x C57B1)F1 females. Clinically apparent abnormalities were limited to the eyes and, in the affected adults, ranged from apparent anophthalmia to globes that were enlarged and exhibit large uveoscleral colobomas. Sequential evaluations of the embryogenesis of this condition have identified abnormal differentiation of the outer layer of the optic cup (presumptive retinal pigment epithelium-RPE) into a second layer of neural retina. The abnormality is identified as early as day 10 of gestation, during invagination of the optic cup and lens placode. The area of RPE dysplasia may be diffuse or regional with an abrupt transition from normal RPE and often demonstrates excessive and uncontrolled proliferation. The two symmetrical, apposed layers of photoreceptors fail to differentiate and begin to degenerate prenatally. Absence of normal RPE leads to failure of induction of adjacent choroid and sclera, resulting in a posterior segment consisting of a large neuroepithelial-lined cyst. Radiation-induced ocular malformations of this type have not been previously described. In addition, this model presents a unique opportunity to examine the processes leading to differentiation of a single, continuous epithelial layer into tissues as anatomically and functionally distinct as neural retina and RPE.

Animals↗

PubMed1991

Use of biometry and keratometry for determining optimal power for intraocular lens implants in dogs.

Axial length and corneal curvature were determined by use of A-scan ultrasonography and keratometry on both eyes of dogs of various breeds, sizes, and ages. Mean axial length was 20.43 +/- 1.48 mm; axial length was not related to age or sex, but was significantly greater (P = 0.047) in dogs of larger breeds. Mean corneal curvature was 39.94 +/- 2.61 diopters. Dogs of large breeds had significantly (P less than 0.001) flatter corneas. Mild, roughly symmetric astigmatism was detected in a majority of dogs. Use of mean values in a theoretic artificial intraocular lens power equation suggests that aphakic dogs require an implant of approximately 40 diopters to achieve emmetropia.

Animals↗

PubMed1990

Metabolism and pharmacokinetics of nufenoxole in animals and humans: an example of stereospecific hydroxylation of an isoquinuclidine ring.

1. Nufenoxole, a novel antidiarrhoeal agent, was well absorbed in rat, monkey and human after oral administration. Systemic availability of nufenoxole was 85% in monkey and 102% in man. 2. The elimination rate was much faster in rat (t1/2 of 1.8 h) and monkey (t1/2 of 4.9 h) compared with human (t1/2 of 35.8 h). 3. After oral and i.v. 14C-nufenoxole, concentrations of 14C in human erythrocytes and saliva were approx. 3- and 4-fold lower, respectively, than plasma concentrations. 4. Nufenoxole was metabolized to metabolites hydroxylated on the methyl substituent and isoquinuclidine ring in rat and monkey. The isoquinuclidine ring hydroxylation, a major pathway in human, was stereospecific. 5. Following oral doses of 14C-nufenoxole the urinary excretion of radioactivity (about 8%) was less than the faecal excretion (66.6%) in rat, while urinary excretion was the major route of drug elimination (about 60%) in man. In monkey, urinary and faecal excretion were equally important.

Adult↗

PubMed1990

Spontaneous, asymmetrical microphthalmia in C57B1/6J mice.

An investigation was undertaken to evaluate ocular size and shape by objective and subjective criteria to establish the incidence and laterality of spontaneous microphthalmia in the C57B1/6J mouse strain. The purpose was to provide useful information of normal and abnormal ocular development in a laboratory strain frequently used for teratogenic studies. Ten-week-old C57B1/6J mice were time mated and sacrificed at gestational day 14. Eye normality was evaluated subjectively using veterinary ophthalmology methods, and objectively by a computer derived method. A distinct laterality was noted in the right eye when compared to the left eye. Degree of laterality varied with assessment methodology (19.0% vs. 6.9% and 8.9% vs. 4.0% for the subjective and objective methods respectively). Mean eye area and histogram distributions for the right eye were consistently smaller than the left eye for all anatomical rating groups, thereby suggesting that asymmetry found in the C57B1/6J may be due to an inherent discrepancy in eye size in the strain. The data from this study suggest that when C57B1/6J mouse eyes are used as end points for teratological testing each eye should be treated as an independent unit of measure.

Animals↗

PubMed1990

Laminin and fibronectin in retinoid-induced keratolenticular dysgenesis.

Acute embryonic exposure to isotretinoin during gastrulation (gestational day 7) in the mouse results in delay or failure of separation of the lens vesicle from the surface ectoderm. During normal lens vesicle detachment, laminin is localized within the lens, keratolenticular stalk and adjacent surface ectoderm. The mesenchyme surrounding the stalk stains positively for fibronectin. In contrast, isotretinoin-exposed embryos at the same stage of gestation exhibit reduced staining for both extracellular matrix components. Persistent keratolenticular attachment observed later in gestation in the exposed embryos is associated with increased production of laminin by the keratolenticular stalk and anterior lens epithelium. A delay in the sequence of production of extracellular matrix may be causally associated with persistence of the keratolenticular stalk.

Abnormalities, Multiple↗

PubMed1989

Experimental models of anterior segment dysgenesis.

Normal anterior segment embryogenesis is summarized followed by a review of syndromes of spontaneous and inherited conditions of abnormal development in humans and animals. The study of teratogen-induced malformations in animal models has provided valuable information about critical periods during gestation for the initiation of anterior segment dysgenesis. Although the major developmental events leading to iridocorneal angle formation occur during the third trimester, it appears that embryonic insult much earlier in human gestation (during the first three to five weeks post fertilization) can induce an abnormal sequence of events leading to anterior segment dysgenesis.

Abnormalities, Drug-Induced↗

PubMed1988

Difference in metabolic profile of potassium canrenoate and spironolactone in the rat: mutagenic metabolites unique to potassium canrenoate.

The metabolic fates of potassium canrenoate (PC) and spironolactone (SP) were compared for the rat in vivo and in vitro. Approximately 18% of an in vivo dose of SP was metabolized to canrenone (CAN) and related compounds in the rat. In vitro, 20-30% of SP was dethioacetylated to CAN and its metabolites by rat liver 9000 g supernatant (S9). Thus, the major route of SP metabolism is via pathways that retain the sulfur moiety in the molecule. PC was metabolized by rat hepatic S9 to 6 alpha, 7 alpha- and 6 beta, 7 beta-epoxy-CAN. The beta-epoxide was further metabolized to its 3 alpha- and 3 beta-hydroxy derivatives as well as its glutathione (GSH) conjugate. Both 3 alpha- and 3 beta-hydroxy-6 beta, 7 beta-epoxy-CAN were shown to be direct acting mutagens in the mouse lymphoma assay, whereas 6 alpha, 7 alpha- and 6 beta, 7 beta-epoxy-CAN were not. These mutagenic metabolites, their precursor epoxides and their GSH conjugates were not formed from SP under identical conditions. The above findings appear to be due to inhibition of metabolism of CAN formed from SP by SP and/or its S-containing metabolites, since the in vitro metabolism of PC by rat hepatic microsomes was appreciably reduced in the presence of SP. The hypothesized mechanism(s) for this inhibition is that SP and its S-containing metabolites specifically inhibit an isozyme of hepatic cytochrome P-450 or SP is a preferred substrate over PC/CAN for the metabolizing enzymes. Absence of the CAN epoxide pathway in the metabolism of SP provides a possible explanation for the observed differences in the toxicological profiles of the two compounds.

Animals↗

PubMed1988

Teratogens and craniofacial malformations: relationships to cell death.

Environmental agents including ethanol, 13-cis retinoic acid (RA, Accutane), the antimetabolite methotrexate, periods of hypoxia, ionizing radiation or hyperthermic stress, when administered acutely to pregnant experimental animals, induce stage-dependent craniofacial malformations comparable to those in corresponding human teratogen syndromes. Acute treatment regimens have allowed analysis of cell populations initially affected and subsequent dysmorphogenetic sequences as well as speculation relative to mechanisms of teratogenesis. In rodent models, ethanol and RA appear to affect similar cell populations and comparable malformations can be induced by both agents. When administered during gastrulation they cause a major insult to the anterior neural plate which results in characteristic ocular, brain and facial malformations comparable to those seen in the fetal alcohol syndrome. Exposure to these drugs at a time just prior to and during neural crest cell migration into the craniofacial and cervical regions results in malformations comparable to those seen in the Di-George sequence and/or retinoic acid embryopathy. Slightly later, at the time that the epibranchial placodes are active, insult results in mandibulofacial dysostosis-like syndromes. We propose that the pattern of these malformations is related to the particular vulnerability of cells in the vicinity of normal programmed cell death. Cell death is also associated with ionizing radiation and hyperthermia-induced malformations. Both of these teratogens are particularly damaging to the early development of the eye and central nervous system. Teratogenic temperature elevations result in arrest of mitotic activity and death of cells in mitosis. Hypoxia is also associated with cell death in specific regions and subsequent malformation. For example, death of cells in the invaginating olfactory placode has recently been associated with cleft lip formation. The relationship of hypoxia-induced cell death to energy requirements is being explored. Acute treatment with methotrexate results in frontonasal dysplasia (median facial clefts). Combined effects of fluid imbalance, lack of proliferation or death of frontonasal mesenchyme appear to be involved. Although the mechanisms of craniofacial malformation are complex, a common feature for many is excessive cell death for which the embryo may be unable to compensate. Excessive cell death in regions of programmed cell death represents an important, yet little appreciated, mechanism of teratogenesis.

Animals↗

PubMed1987

Fetal alcohol syndrome. Eye malformations in a mouse model.

Acute maternal ethanol administration on gestational day 7 (gastrulation stage) in C57Bl/6J mice results in a spectrum of ocular malformations. A deficiency in the anterior neural plate observable within 24 hours of exposure results in corresponding defects in the optic sulcus and subsequent optic vesicle. Deficiency in the size of the lens vesicle induced by a small optic vesicle is demonstrable as microphakia in older embryos. Delayed detachment of the lens vesicle from the surface ectoderm manifests in the live offspring as progressive corneal opacification and vascularization related to defects in corneal endothelium and Descemet's membrane. Anterior segment dysgenesis results in persistent iridocorneal adhesions, dyscoria, and abnormal formation of the anterior chamber. In contrast, ethanol exposure on day 8 of gestation did not result in eye malformations. Thus, it appears that many of the ocular abnormalities associated with fetal alcohol syndrome may result from an acute insult to the optic primordia during a very specific period that corresponds to the third week after fertilization in the human.

Animals↗

PubMed1986

Copper exchanges and toxicity in the rabbit lens in vitro.

Lenses (in vitro) exposed to 10(-4) M Cu for 24 hr gained an excess of Na and lost K. Incubation for 7 days with 10(-5) M Cu had a similar toxic effect. Threonine, which is present in aqueous humor, increased sensitivity of lenses to Cu, and also uptake of 64Cu. Uptake of 64Cu commenced reaching tissue saturation levels in 5 hr at 10(-7) M Cu. At higher concentrations, uptake was greater (1263 X for a 1000-fold rise in concentration from 10(-7) -10(-4) M) and saturation was not seen in this time. Autoradiography of sections of such lenses suggested that accumulation of the 64Cu occurred principally within the region of the cells of the anterior epithelium and capsule and lens bow. Efflux of accumulated 64Cu occurred more rapidly when copper was present in the external media suggesting the presence of 'specific' binding sites for copper. Percentage retention of accumulated 64Cu was greater in lenses loaded in 10(-6) M than 10(-5) M Cu. It is suggested that copper can enter lenses, possibly facilitated by threonine, and can bind to two types of sites: one with a high affinity but low capacity for the metal ion, the other with a lower affinity but larger capacity. The former may be concerned with the physiological roles and normal metabolism of copper and the latter with its toxic actions.

Animals↗

PubMed1986

Clinical and pathologic evaluation of a flexible silicone posterior chamber lens design in a rabbit model.

Flexible silicone posterior chamber intraocular lenses made of a proprietary formulation were implanted in rabbits following planned extracapsular lens extraction. The lenses were of three designs: unfenestrated, partially fenestrated, and fully fenestrated haptics. Biostability and tissue reactivity of the silicone lenses and another manufacturer's polymethylmethacrylate lenses appeared equivalent as evaluated clinically by slitlamp biomicroscopy and by light microscopy. The frequency and distribution of lens precipitates were evaluated grossly and by scanning electron microscopy and appeared notably less prominent on the surfaces of the hydrophobic silicone lenses.

Animals↗