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Biomedical subjects

A Campbell

Publications and source records attributed to A Campbell.

At least 181 records · Page 10Linked to original sources
PubMed1988

Decreasing sensitivity to neuroleptic agents in developing rats; evidence for a pharmacodynamic factor.

Developing rats are far more sensitive than adults to the behavioral effects of haloperidol. The present results support the hypothesis that this change may reflect age-related changes in brain responses such as alterations in drug-receptor or drug-effector mechanisms. Dose-response studies of catalepsy and ptosis were conducted in male Sprague-Dawley rats aged 30, 56, or 100 days. Resulting dose-effect curves were approximately parallel and showed rightward shifts with highly significant progressive increases of ED50. Similar developmental decreases in drug sensitivity (3-6x) were found following systemic (PO or IP) administration of haloperidol or the phenothiazine neuroleptic perphenazine, which differ markedly in structure, potency, distribution, and metabolism. Age-related decreases in drug sensitivity (3-4x) were also found using intracerebroventricular (ICV) administration of both agents in an attempt to bypass potential "pharmacokinetic" influences. Since the age-dependent decrease in sensitivity to both neuroleptics was found during the rising phase of drug action (1st hour) and ranked: PO greater than IP greater than ICV, some change in absorption and distribution of both drugs may occur in addition to the apparently important maturational decrease in target-organ sensitivity indicated by the responses to direct ICV injection and by the similarity of results obtained with dissimilar agents.

Administration, Oral↗
PubMed1988

Receptor affinity, neurochemistry and behavioral characteristics of the enantiomers of thioridazine: evidence for different stereoselectivities at D1 and D2 receptors in rat brain.

The binding characteristics of the enantiomers of thioridazine were assessed in the brain of the rat using competitive radioreceptor assays with tritiated ligands selective for dopamine D1 (SCH-23390), D2 (spiperone), norepinephrine alpha-1 (prazosin) and muscarinic (quinuclinidinyl benzilate) receptors. (+)-Thioridazine was shown to have 2.7 and 4.5 times higher affinity than (-)-thioridazine for D2 and alpha-1 receptors, respectively. In contrast, (-)-thioridazine had 10 times higher affinity for the D1 receptor. Both enantiomers showed similar affinities for the muscarinic receptor. In a second experiment, thioridazine, dopamine, norepinephrine, serotonin and their metabolites were assayed in the brain of the rat after acute administration of the enantiomers of thioridazine and the assessment of catalepsy. (+)-Thioridazine was 4.1 times as potent as (-)-thioridazine in elevating the turnover of dopamine in the striatum, but neither enantiomer affected the other monoamines. The concentration of thioridazine and its metabolites in the brain, for a given dose, was similar for both enantiomers. (-)-Thioridazine induced slightly more catalepsy than (+)-thioridazine and appeared to be more toxic at large doses. While racemic thioridazine had an intermediate effect between that of its two enantiomers in the binding and neurochemical assays, it appeared to induce more catalepsy than either enantiomer, suggesting a synergistic effect in this behavioral assay. It was concluded that (+)- and (-)-thioridazine act as partially selective D2 and D1 antagonists, respectively. Therefore, clinical administration of only one enantiomer of thioridazine, rather than the currently prescribed racemate, may result in an improved therapeutic profile and so be worthy of further investigation.

Animals↗
PubMed1988

Dose-catalepsy response to haloperidol in rat: effects of strain and sex.

Haloperidol induced catalepsy with a continuous dose-response between 0 or 0.03 and 10 mg/kg, IP in Brown Norway (BN), Fischer (FR). Long-Evans (LE), and Sprague-Dawley (SD) rats, with similar ED50 values for males (0.23-0.42 mg/kg), and generally greater but more varied drug sensitivity in females (ED50 = 0.13-0.45 mg/kg). Inconsistent findings regarding a biphasic dose-effect relationship in SD male and LE female rats led to testing both sexes and strains up to 200 mg/kg. Females showed a greater tendency than males of both strains to yield lower catalepsy scores at doses greater than 10 mg/kg, but in association with gross neurological toxicity. This paradigm evidently is not an adequate model for a proposed biphasic relationship between doses of high potency neuroleptic agents and acute dystonia in man.

Animals↗
PubMed1988

Synthesis and dopamine agonist and antagonist effects of (R)-(-)- and (S)-(+)-11-hydroxy-N-n-propylnoraporphine.

The R-(-) and S-(+) enantiomers of 11-hydroxy-N-n-propylnoraporphine, (R)-3 and (S)-3, were synthesized in six steps from 1-(3-methoxy-2-nitrobenzyl)isoquinoline. Neuropharmacological evaluation of the R and S isomers (by affinity to dopamine receptor sites in rat brain tissues, induction of stereotyped behavior, and interaction with motor arousal induced by (R)-apomorphine in the rat) indicated that, similar to the 10,11-dihydroxy congener 2, both enantiomers can bind to dopamine receptors but that only (R)-3 activates them, whereas (S)-3 shows activity as a dopaminergic antagonist.

Animals↗
PubMed1988

Intrapersonal and interpersonal discrepancy among delinquent and nondelinquent girls: a research note.

Delinquent and nondelinquent girls were compared to examine the relationship between delinquency and masculine self-concept. Ratings of self and ideal self were obtained to compute self-ideal discrepancy indices on (a) stereotypically sex-related traits and (b) traits which each subject selected as salient to making interpersonal judgements of women. Ratings were also made of best friend and mother to examine interpersonal as well as intra-personal discrepancy indices. For stereotypic sex-role traits, discrepancy indices for the three comparisons (self-ideal, self-mother, self-best friend) revealed no differences between delinquents and nondelinquents. For personally selected traits, significant differences did appear for self-mother and self-best friend discrepancies.

Adolescent↗
PubMed1988

Neuropharmacology and stereochemistry of dopamine receptor agonist and antagonist enantiomeric pairs.

Neuropharmacological evaluation of the R and S isomers of 11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) supports the impression that the 11-OH group in aporphines (analogous to the meta hydroxyl of dopamine, DA) is sufficient to confer high affinity and activity at DA receptors. As in the case of the catechol congeners, (R)-apomorphine (APO) and (R)-N-n-propylnorapomorphine (NPA), (R)-11-OH-NPa is a potent DA agonist while, like (S)-NPA, (S)-11-OH-NPa is a DA antagonist. Thus, (R) and (S)-11-OH-NPa are an additional pair of compounds in which one enantiomer is a DA agonist and the other an antagonist. Other analogous pairs are the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), and cis-1-methyl-5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-MDAT). All contain a meta hydroxyphenyl, an N-n-propyl, and a phenethylamine moiety which can be superimposed in a consistent way to discriminate the DA agonists from the antagonists, with the key feature in this discrimination being the direction of the ammonium hydrogen. An energy penalty must be incurred by 3-PPP to assume the required conformations and it may account for the relatively low potency of the 3-PPP enantiomers. This analysis supports the view that rigid analogs of flexible compounds when "frozen" in their biologically active conformation exhibit higher affinity interactions with the receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Mechanism of potentiation of antithrombin III [AT-III] inhibition by sulfated xylans.

Anticoagulant properties of three sulfated compounds prepared from xylans isolated from corn cobs, larchwood and oatspelts were compared with heparin and sodium pentosan polysulfate (SP-54) by studying their effects on activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) using pooled normal human plasma. These compounds were more effective than SP-54 in delaying coagulation by all the three procedures while oatspelts xylan sulfate was as effective as heparin in inhibiting APTT and PT and more effective than heparin in inhibiting TT on a molar basis. The sulfated xylans were more effective than heparin or SP-54 in potentiating the AT-III inhibition of amidolysis of H-D-Phe-Pip-Arg-pNa (S-2238) by thrombin (IIa) or amidolysis of Bz-Ile-Glu-Gly-Arg-pNa (S-2222) by Xa. Study of the high affinity binding of the xylan sulfates to AT-III-Sepharose column showed that the amount of the xylan sulfate recovered in the eluates from this peak was greatly increased with an increase in molecular weight (MW). A buffered mixture of IIa, AT-III and dansylarginine N-(3-ethyl-1,5-pentanediyl) amide (DAPA) was used to study the inactivation of IIa by AT-III. Larchwood xylan sulfate (2-10 micrograms) was found to accelerate this inactivation which was neutralized by human platelet factor 4 (PF4). The results also suggested an interaction between larchwood xylan sulfate and IIa which may potentiate an interaction between AT-III and IIa.

Anticoagulants↗
PubMed1987

Mechanism of anticoagulant action by protein inhibitors from bovine testes and salmon sperm.

A protein inhibitor was isolated from commercial preparations of salmon sperm and its physical and anticoagulant properties were compared with an inhibitor isolated earlier from commercial preparation of bovine testicular hyaluronidase. The inhibitor from bovine source was heat and acid labile and had a molecular weight of approximately equal to 35000 while the one from salmon sperm had a molecular weight of approximately equal to 5700 and was stable to heat and acid. To determine the mechanism of the inhibitory effect, a system of purified components consisting of isolated prothrombin, Factor Xa, Factor Va, Ca++, and vesicles of phosphatidylcholine (PCPS, 25% PS) was used. Included also was dansylarginine N- (3-ethyl-1,5-pentanedidyl) amide (DAPA) which binds newly formed thrombin and yields the time course of prothrombin conversion by virtue of enhanced fluorescence of the DAPA - thrombin complex. The inhibitor of bovine testes was effective only when PCPS was the limiting component suggesting that its action was directed against the phospholipid component of the prothrombinase complex. The inhibitor from salmon sperm was found to lower the rate of conversion of prothrombin to thrombin in an in vitro system where thrombin generation was measured by its action on the chromogenic substrate H-D-Phe-Pip-Arg-pNa (S-2238). It inhibited the conversion of Factor X to Xa and also the the amidolytic cleavage by Factor Xa of chromogenic substrate N-Benz-Ile-Glu-Gly-Arg-pNa (S-2222).

Animals↗
PubMed1987

S(+)methylenedioxy-N-n-propylnoraporphine: an orally active inhibitor of dopamine selective for rat limbic system.

The 10-11-methylenedioxy (MDO) derivative of S(+)N-n-propylnorapomorphine (NPA) was prepared and tested as a possible active prodrug to S(+)NPA, which we have recently found to exert in vivo activity suggestive of selective antagonism of dopamine receptors in the limbic forebrain but not the extrapyramidal basal ganglia. Like S(+)NPA, S(+)MDO-NPA inhibited the behavioral arousal induced by dopamine injected into nucleus accumbens of the rat, but not the head-turning response to dopamine injected into the corpus striatum. However, only MDO-NPA was orally active and it was somewhat longer-acting than NPA. The activity of S(+)MDO-NPA was prevented by pretreatment with the oxidase inhibitor SKF-525A. These properties are analogous to those of R(-)MDO-NPA, which we had previously reported as an orally active prodrug of the dopamine agonist R(-)NPA. Thus the methylenedioxy derivatives of the two entantiomers of NPA have properties desirable in a potentially clinically useful dopamine agonist and limbic dopamine antagonist, respectively.

Administration, Oral↗
PubMed1986

Behavioral effects of apomorphine isomers in the rat: selective locomotor-inhibitory effects of S(+)N-n-propylnorapomorphine.

The optical isomers of apomorphine (APO) and N-n-propylnorapomorphine (NPA) were evaluated behaviorally in the rat. Both R(-) isomers induced motor-excitatory effects and strong stereotyped sniffing, licking, and gnawing, as has been reported previously. The S(+) isomers selectively inhibited locomotor activity and did not induce stereotypy or catalepsy. These actions of the S(+) aporphines were selective against locomotor activity stimulated by low doses of R(-) isomers. (+)NPA (ID50 = 0.2 mg/kg) was 20 times more potent than (+)APO (ID50 = 4 mg/kg) in antagonizing the locomotor arousal-inducing effects of (-)APO (at ED50 = 0.3 mg/kg). (+)NPA also inhibited spontaneous locomotor activity much more potently (ID50 = 3.0 mg/kg) than did (+)APO (ID50 greater than 50 mg/kg). Neither S(+) aporphine had a significant effect against stereotypy induced by the R(-) isomers, even at high doses (up to 30 mg/kg). Inhibition of the effects of (-)APO by (+)NPA appeared not to be due to altered uptake of (-)APO into brain. These results suggest that S(+)NPA or its congeners and analogs may have selective antidopaminergic actions in limbic rather than striatal areas of mammalian brain.

Animals↗
PubMed1986

Diagnosis for interstitial lung disease in patients with acquired immunodeficiency syndrome (AIDS): a prospective comparison of bronchial washing, alveolar lavage, transbronchial lung biopsy, and open-lung biopsy.

This study was undertaken to compare prospectively the diagnostic yield of the various bronchoscopic techniques with that of open-lung biopsy for interstitial lung disease in patients with acquired immunodeficiency syndrome (AIDS). Under general anesthesia, 15 patients sequentially underwent bronchial washing, transbronchial lung biopsy, alveolar lavage, and open-lung biopsy in the same segment of lung. Of nine patients with Pneumocystis carinii, seven were diagnosed by means of the transbronchial lung biopsy, eight by the open-lung biopsy, and all nine by alveolar lavage. Of the six patients with cytomegalovirus, five were diagnosed by the open-lung biopsy, five by the transbronchial lung biopsy, and three by alveolar lavage. The sensitivities of the procedures for identifying infection were washings (15%), transbronchial lung biopsy (50%), alveolar lavage (73%), and open-lung biopsy (88%). Combined, transbronchial lung biopsy and alveolar lavage showed a diagnostic yield (85%) for infections comparable to that of open-lung biopsy (88%), thereby obviating the need for open-lung biopsy for such diagnoses. However, open-lung biopsy was the only procedure that diagnosed Kaposi's sarcoma in lung.

Acquired Immunodeficiency Syndrome↗
PubMed1986

A comparison of inpatient and outpatient Medicare allowable charges for continuous ambulatory peritoneal and center hemodialysis patients: a single-center study.

Medicare allowable charges were compared between 21 continuous ambulatory peritoneal dialysis (CAPD) and 25 center hemodialysis (CHD) patients for the 12-month period from Sept 1982 through Aug 1983 to determine if savings from CAPD therapy were offset by higher hospitalization charges. All adult patients on a single therapy for the 12-month period who were not dialyzed or hospitalized at other institutions were included. The CAPD and CHD patient groups did not differ significantly by age, sex, or incidence of systemic disease. However, the CHD group had significantly more black patients. The primary renal disease, the incidence of diabetes mellitus, and other systemic diseases did not differ between the groups. The number of hospital admissions was similar between the two groups. However, the CHD patients tended to have a higher number of hospital days than the CAPD group (17.5 v 12.4). Although the total hospital charges tended to be higher for CHD ($16,145) than CAPD patients ($9,872), this difference was not significant. Outpatient dialysis charges were significantly less expensive for CAPD ($16,470) than CHD ($28,233). Emergency department charges were also significantly less for the CAPD group. Charges for patients with and without systemic disease were analyzed separately. In both subgroups, all charges were less for CAPD therapy; however, this difference was significant only for outpatient dialysis charges. Total charges for the 12-month period were significantly less for the CAPD group ($26,453) than for CHD ($45,586). This demonstrates that hospitalization charges did not offset the savings of home dialysis in these patients.

Ambulatory Care Facilities↗