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Biomedical subjects

C George

Publications and source records attributed to C George.

At least 55 records · Page 3Linked to original sources
PubMed2000

Conformational preferences of the potent dopamine reuptake blocker BTCP and its analogs and their incorporation into a pharmacophore model.

Molecular mechanics calculations using MM3-92 and ab initio quantum mechanical calculations using SPARTAN 5.0 were performed on the structurally similar PCP and BTCP, in which only the latter has a cocaine-like pharmacological profile as a dopamine reuptake blocker. Calculations were also performed on BTCP analogs with a methyl group in various positions of the cyclohexane ring. The results for the cis-2-methyl compound, which retains good pharmacological activity, allowed us to determine that an aryl-axial conformer is the biologically active form for at least some of the compounds in this series. However, an aryl-equatorial conformer presents the identical pharmacophore, as shown by superposition of the two conformers. X-ray crystallographic structures were also obtained for BTCP and related compounds with a 2-methyl group on the cyclohexane ring, with reasonable agreement between the computational and experimental results. Superposition studies were performed with two rigid analogs of cocaine which illustrate the optimal orientations of the ammonium hydrogen for monoamine transporters. There is excellent agreement between a 'back-bridged' cocaine analog that is optimal as a dopamine reuptake blocker and the previously proposed biologically active conformer of methylphenidate. However, BTCP is found to be a better fit to the 'front-bridged' cocaine analog that is optimal for a serotonin reuptake blocker.

Dopamine Uptake Inhibitors↗
PubMed1999

Effect of antidepressant drug counselling and information leaflets on adherence to drug treatment in primary care: randomised controlled trial.

OBJECTIVES: To evaluate two different methods of improving adherence to antidepressant drugs. DESIGN: Factorial randomised controlled single blind trial of treatment leaflet, drug counselling, both, or treatment as usual. SETTING: Primary care in Wessex PARTICIPANTS: 250 patients starting treatment with tricyclic antidepressants. MAIN OUTCOME MEASURES: Adherence to drug treatment (by confidential self report and electronic monitor); depressive symptoms and health status. RESULTS: 66 (63%) patients continued with drugs to 12 weeks in the counselled group compared with 42 (39%) of those who did not receiving counselling (odds ratio 2.7, 95% confidence interval 1.6 to 4.8; number needed to treat=4). Treatment leaflets had no significant effect on adherence. No differences in depressive symptoms were found between treatment groups overall, although a significant improvement was found in patients with major depressive disorder receiving drug doses of at least 75 mg (depression score 4 (SD 3.7) counselling v 5.9 (SD 5.0) no counselling, P=0.038). CONCLUSIONS: Counselling about drug treatment significantly improved adherence, but clinical benefit was seen only in patients with major depressive disorder receiving doses >/=75 mg. Further research is required to evaluate the effect of this approach in combination with appropriate targeting of treatment and advice about dosage.

Adult↗
PubMed1999

Determining the occurrence of a 3(10)-helix and an alpha-helix in two different segments of a lipopeptaibol antibiotic using TOAC, a nitroxide spin-labeled C(alpha)-tetrasubstituted alpha-aminoacid.

Trichogin GA IV is a 11-residue lipopeptaibol antibiotic exhibiting membrane modifying properties. We synthesized step-by-step by solution methods three trichogin analogues, each with a double Aib (alpha-aminoisobutyric acid)-->TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) replacement. The strict similarity in the conformational propensities of Aib and TOAC allowed us to exploit these analogues in a detailed investigation of the conformation of this lipopeptaibol in different organic solvents and in a membrane-mimetic environment using in particular the double spin labeling ESR technique. We conclude that the secondary structure in solution remains essentially unchanged if compared to that previously found in the crystal state for trichogin. More specifically, the N-terminal region of the peptide folds in a 3(10)-helix, while the central and C-terminal regions are mainly alpha-helical. An additional, significant proof for the modest plasticity of the trichogin structure was obtained by an X-ray diffraction analysis of the nOct-[TOAC4,8, Leu-OMe11] analogue. For the three analogues permeability measurements revealed membrane-modifying properties comparable to those of natural trichogin.

Aminoisobutyric Acids↗
PubMed1999

Level of care utilization system for psychiatric and addiction services (LOCUS): a preliminary assessment of reliability and validity.

The financing of mental health care services has undergone significant change in the past several years, with increasing emphasis on resource management. This emphasis has raised concerns among consumers and providers of services that needed resources are often withheld. In order to address this issue, the American Association of Community Psychiatrists (AACP) developed an instrument designed to maintain balance between quality care and the wise use of resources. The Level of Care Utilization System for Psychiatric and Addiction Services (LOCUS) evaluates clients along six dimensions and defines six levels of resource intensity. It also provides a methodology to facilitate rapid and consistent level of care recommendations. This paper describes the circumstances leading to the creation of LOCUS and the principles used to guide its development. It then describes preliminary reliability and validity testing design and outcome. This initial testing indicates that LOCUS can facilitate consistent placement of clients in psychiatric or addiction services and does so in a manner which trends in a pattern similar to the recommendations of clinicians who are naive to LOCUS assessment and placement methodology.

Health Care Rationing↗
PubMed1999

The development of attachment in separated and divorced families. Effects of overnight visitation, parent and couple variables.

This study represents the first systematic investigation of the effects on infant attachment to mother and to father of the increasingly common practice of overnight visitation (time-sharing) with the father in separated and divorced families. There were 145 infants (ages 12 to 20 months) and their mothers (and 83 fathers) who participated in the study. Parents completed questionnaires, were interviewed about their relationship with the baby, and were observed with their infants in the Strange Situation. Infants in separated/divorced families who had regular overnight visits with father (n = 44) were significantly less likely to be classified as secure and more likely to be classified as disorganized or unclassifiable in their attachment to mother than infants in a married comparison group (n = 52). Attachment classification to father was unrelated to visiting (time-sharing) arrangements, but infants were significantly more likely to be classified disorganized/unclassifiable with father in the separated/divorced groups (n = 39) than in dual-parent families (n = 44). Disorganized attachment to mother in the Overnight group was associated with maternal reports of low parent communication and high parent conflict, and with low maternal psychological protection of the infant, assessed from maternal interviews. Consistent with Bowlby's and Rutter's context-sensitive views of the effects of separation, the results suggest that repeated overnight separations from the primary caregiver are associated with disruption in mother-infant attachment when the conditions of visitation are poor, i.e. when parents are unable to provide adequate psychological support to the child.

Child Custody↗
PubMed1999

Abuse and violence in intimate adult relationships: new perspectives from attachment theory.

Previous attachment writing about violence between intimate adult partners has implicated the role of insecure attachment. This paper proposes that insecure attachment is not sufficient to explain intimate partner violence. Instead, it is suggested that recent evidence leads to the conclusion that such violent behavior is best explained in terms of attachment disorganization, a more profound form of relational insecurity. We discuss the contributions of this perspective to intervention.

Adult↗
PubMed1999

The caregiving system in mothers of infants: a comparison of divorcing and married mothers.

This study was designed to investigate (1) the construct validity of a measure of the mother's internal representation of herself as a secure base in samples of married and divorcing mothers and infants, and (2) the relative contribution to infant security of this measure and a second representational measure, termed Psychological Protection, which focused specifically on the mother's responsiveness to the infant in the context of father visitation. There were 144 mothers and their first-born infants, age 12 to 20 months, who participated in the study. Of these, 51 dyads were from intact families; 93 were from families who had never married, had recently separated, or were in the process of divorce. Divorcing families were further divided into those in which the infant was participating in overnight timesharing arrangements with the father (n = 44) and those in which the infant was not (n = 49). Mothers completed questionnaires, they participated with their infants in the Strange Situation, and an hour-long, semi-structured Caregiving Interview was administered to them. Ratings of mothers on the Secure Base and Psychological Protection scales were based on verbatim transcripts of this interview. As predicted, mothers of securely attached infants in all family groups were discriminated from mothers of insecurely attached infants on the basis of Secure Base scores. Within the group of divorcing mothers, Secure Base scores were correlated with a rating of the mother's Psychological Protection of the infant in the context of visitation and both measures made independent contributions to infant attachment security. These findings are interpreted in terms of a more general model of the caregiving system. The manner in which the divorce context can disrupt the mothers' caregiving behavioral strategies and representations is also discussed.

Child Custody↗
PubMed1999

Developmental vs. social personality models of adult attachment and mental ill health.

Both the developmental and social personality approaches to the study of adult attachment are concerned with understanding those factors that describe an individual's quality of relational adaptation and risk for mental ill health. This paper examines the theoretical and methodological assumptions of these alternative models and how these assumptions have markedly different implications for addressing clinical issues. It is suggested that recent evidence necessarily leads to the conclusion that mental and relational difficulties, such as partner violence and victimization, borderline personality, dissociation, suicidal behaviour and other clinical symptomology thought to be related to experiences of severe relationship distress, are best explained in terms of attachment disorganization rather than as normative forms of attachment insecurity or fearful avoidant adult romantic attachment.

Adaptation, Psychological↗
PubMed1998

Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton.

To discover agents that might be useful in the treatment of cocaine abuse, we have chosen to re-explore a class of molecules that was first reported by Clarke et al. in 1973 and that was and shown to lack locomotor stimulatory activity in mice. These compounds are piperidine-3-carboxylic acid esters bearing a 4-chlorophenyl group in position 4, and as such, these structures may be viewed as truncated versions of the WIN series compounds, i.e., they lack the two-carbon bridge of the tropanes. All members of this class were synthesized starting from arecoline hydrobromide and obtained in optically pure form through resolution methods using either (+)- or (-)-dibenzoyltartaric acid. Interestingly, we have found that these piperidines do, in fact, exhibit substantial affinity in both WIN 35, 428 binding at the dopamine transporter and in the inhibition of [3H]dopamine uptake. Of all of the compounds synthesized, the 3-n-propyl derivative (-)-9 was found to be the most potent with a binding affinity of 3 nM. This simple piperidine is thus 33-fold more potent than cocaine in binding affinity and 29-fold more potent in its inhibition of dopamine uptake. Although no efforts have presently been made to "optimize" binding affinity at the DAT, the substantive activity found for the n-propyl derivative (-)-9 is remarkable; the compound is only about 10-fold less active than the best of the high-affinity tropanes of the WIN series. As a further point of interest, it was found that the cis-disubstituted piperidine (-)-3 is only about 2-fold more potent than its trans isomer (+)-11. This result stands in sharp contrast to the data reported for the tropane series, for the epimerization of the substituent at C-2 from beta to alpha has been reported to result in a lowering of activity by 30-200-fold. This smaller spread in binding affinities for the piperidines may reflect the smaller size of these molecules relative to the tropanes, which allows both the cis and the trans isomers to adjust themselves to the binding site on the DAT. Our present demonstration that these piperidine structures do, in fact, possess significant DAT activity, taken together with their reported lack of locomotor activity, provides a compelling argument for exploring this class of molecules further in animal behavioral experiments. The present work thus broadens the scope of structures that may be considered as lead structures in the search for cocaine abuse medications.

Animals↗
PubMed1998

Synthesis and metabotropic glutamate receptor activity of a 2-aminobicyclo[3.2.0]heptane-2,5-dicarboxylic acid, a molecule possessing an extended glutamate conformation.

A photochemical approach to the synthesis of the aminobicycloheptane 6a is reported. This compound assumes an extended glutamate conformation, and for this reason was created to further probe the structural features relevant to achieving selectivity for the subtypes of the metabotropic glutamate family of receptors.

Animals↗
PubMed1998

Similarities between the uterine decidual reaction and the "mesenchymal lesion" of the urinary bladder in aging mice.

The histopathologic characteristics of the decidual reaction in the uterus of aging mice and the "mesenchymal lesion/tumor" in the urinary bladder of aging mice are compared and found to be very similar. Both lesions consist of spindle and epithelioid cells, may contain round eosinophilic granules and possess nuclear progesterone receptors and cytoplasmic desmin. The decidual reaction derives from endometrial stromal cells, while the "mesenchymal lesion" apparently develops from mesenchymal cells near the trigone area, carrying or developing progesterone receptors. If the hypothesis is accepted that in aging mice the uterine decidual reaction and the "mesenchymal lesion" in the urinary bladder represent an equivalent type of tissue reaction, then it follows that the typical "mesenchymal lesion" is not a tumor and could be called more specifically "decidual-like reaction".

Aging↗
PubMed1998

Mobilization and harvesting of peripheral blood stem cells: randomized evaluations of different doses of filgrastim.

The effects of different doses of filgrastim on yields of CD34+ peripheral blood stem cells were evaluated in patients with breast cancer. 55 were randomized to receive filgrastim 10, 20, 30 or 40 microg/kg/d with more CD34+ cells/kg/apheresis harvested after the three highest dose levels. 35 additional patients were randomized to receive 10 or 30 microg/ kg. The median number of CD34+ cells collected after 10 microg/ kg (n = 31) was 0.7 x 10(6)/kg/apheresis (range 0.1-4.4) as compared to 1.2 (range 0.1-6.8) after 30 microg/kg (n = 32) (P = 0.04). Among patients randomized to 10 v 30 microg/kg, more (50%) achieved > or = 5.0 x 10(6) CD34+ cells/kg and less aphereses were required to achieve > or = 2.5 x 10(6) CD34+ cells/kg after the higher dose (P = 0.04). In multivariate analyses, patients receiving 10 microg/kg (n = 31) had lower yields of CD34+ cells (P = 0.026) and had a 3.3-fold increase in the probability of not achieving > or = 5.0 x 10(6) CD34+ cells/kg as compared to patients receiving 20-40 microg/kg (n = 59). Patients who had received radiation had a 2.9-fold probability of not achieving > or = 2.5 x 10(6) CD34+ cells/kg. These data suggest that, in patients with good marrow reserves, doses of filgrastim > 10 microg/kg/d mobilized more CD34+ cells and may be useful when high numbers of CD34+ cells are desired.

Antigens, CD34↗
PubMed1998

Microbiological profile of anterior chamber aspirates following uncomplicated cataract surgery.

Anterior chamber aspirate cultures were done for 66 patients who underwent either an uncomplicated intracapsular cataract extraction, extracapsular cataract extraction with posterior-chamber intraocular lens implantation, or phacoemulsification with posterior-chamber intraocular lens implantation. The aspirate was obtained at the time of wound closure. The aspirates were immediately transferred to the microbiology laboratory where one drop of the aspirate was placed on a glass slide for gram stain, and the remainder was unequally divided and inoculated into blood agar, chocolate agar and thioglycolate broth. The cultures were incubated at 37 degrees C with 5% CO2 and held for 5 days. Of 66 patients 4 (6%), had smear-positive anterior chamber aspirates. None of the aspirates showed any growth on any of the 3 culture media used. None of the eyes in the study developed endophthalmitis. This study concludes that there is no contamination of the anterior chamber by viable bacteria after cataract surgery, irrespective of the mode of intervention.

Aged↗
PubMed1997

Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter.

A series of N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues has been prepared that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a significantly higher affinity for the dopamine transporter than the parent compound, N-methyl-3 alpha- (diphenylmethoxy)tropane (benztropine, Cogentin). Yet like the parent compound, it retained high affinity for muscarinic receptors. A series of N-substituted compounds were prepared from nor-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane via acylation followed by hydride reduction of the amide or by direct alkylation. All compounds containing a basic tropane nitrogen displaced [3H]WIN 35,428 at the dopamine transporter (Ki range = 8.5-634 nM) and blocked dopamine uptake (IC50 range = 10-371 nM) in rat caudate putamen, whereas ligands with a nonbasic nitrogen were virtually inactive. None of the compounds demonstrated high binding affinity at norepinephrine or serotonin transporters. Importantly, a separation of binding affinities for the dopamine transporter versus muscarinic m1 receptors was achieved by substitution of the N-methyl group with other N-alkyl or arylalkyl substituents (eg. n-butyl, allyl, benzyl, 3-phenylpropyl, etc.). Additionally, the most potent and selective analogue in this series at the dopamine transporter, N-(4"-phenyl-n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogue failed to substitute for cocaine in rats trained to discriminate cocaine from saline. Potentially, new leads toward the development of a pharmacotherapeutic for cocaine abuse and other disorders affecting the dopamine transporter may be discovered.

Animals↗
PubMed1997

Tyrosinium-D-tetrahydroisoquinoline-3-carboxylate 1.5-hydrate and tyrosyl-D-tetrahydroisoquinoline-3-carboxamide hydrate.

Crystals of the two dipeptide title compounds, Tyr-D-Tic, C19H20N2O4.1.5H2O, and Tyr-D-Tic-NH2, C19H21N3O3.H2O, were prepared by the sitting-drop method. Tyr-D-Tic is orthorhombic (P2(1)2(1)2(1)) and crystallizes as a zwitterion. The asymmetric unit contains two peptide molecules and three molecules of water. Tyr-D-Tic-NH2 crystals are monoclinic (P2(1)), the asymmetric unit containing one peptide molecule and one molecule of water. Despite some differences in packing, the conformation of the two dipeptides is almost identical (r.m.s. deviation for non-H atoms is approximately 0.18 A).

Crystallography, X-Ray↗
PubMed1997

2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters.

Cocaine is a potent stimulant of the mammalian central nervous system. Its reinforcing and stimulant properties have been associated with its propensity to bind to monoamine transporter systems. It has generally been assumed that the amino function on monoamines is a requirement for binding to monoamine transporters. In particular, the 8-amino function on the tropane skeleton of cocaine and cocaine analogs has been assumed to provide an ionic bond to the aspartic acid residue on the dopamine transporter (DAT). We have prepared the first 8-oxa analogs of the 3-aryltropanes (WIN compounds) and have found that the 3 beta-(3,4-dichlorophenyl) (6g) and 3 alpha-(3,4-dichlorophenyl) (7g) analogs are particularly potent (IC50 = 3.27 and 2.34 nM, respectively) inhibitors of the dopamine transporter. We now describe the synthesis and biology of the family of 2-carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes and demonstrate that an amino nitrogen is not required for binding to the DAT.

Animals↗
PubMed1997

Retinoblastoma in a dog.

OBJECTIVE: To describe and classify a retinal tumor found in a dog that histologically resembles human retinoblastoma and to discuss the molecular mechanisms of retinal oncogenesis. METHODS: A dog eye with a retinal tumor was examined histologically. Studies including immunocytochemical analysis for retinal S-antigen and glial fibrillary acidic protein, enzyme histochemical analysis for carbonic anhydrase, and nick-end DNA labeling were used to characterize the tumor. Normal retina from another dog and other tumors from dogs, including 2 ciliary body medulloepitheliomas and a brain medulloepithelioma, were examined as controls. RESULTS: The retinal tumor disclosed characteristics typical of human retinoblastoma, including Flexner-Wintersteiner rosettes. It showed strong immunoreactivity with S-antigen and glial fibrillary acidic protein. Carbonic anhydrase activity also could be shown in the tumor. Apoptosis was found to be the predominant method of cell death as shown by nick-end DNA labeling. In contrast to the other tumors examined, this tumor contained areas with retinal photoreceptor and glial differentiation. CONCLUSIONS: The histopathologic findings and differential staining characteristics in this retinal tumor are compatible with retinoblastoma, making this, to our knowledge, the first documented case of spontaneous retinoblastoma in an animal.

Animals↗