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Biomedical subjects

D E Clarke

Publications and source records attributed to D E Clarke.

At least 19 recordsLinked to original sources
PubMed2001

Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, double-blind crossover study.

The aim of the study was to evaluate the potential role for a selective alpha1-adrenoceptor agonist in the treatment of urinary stress incontinence. A randomised, double-blind, placebo-controlled, crossover study design was employed. Half log incremental doses of intravenous methoxamine or placebo (saline) were administered to a group of women with genuine stress incontinence while measuring maximum urethral pressure (MUP), blood pressure, heart rate, and symptomatic side effects. Methoxamine evoked non-significant increases in MUP and diastolic blood pressure but caused a significant rise in systolic blood pressure and significant fall in heart rate at maximum dosage. Systemic side effects including piloerection, headache, and cold extremities were experienced in all subjects. The results indicate that the clinical usefulness of direct, peripherally acting sub-type-selective alpha1-adrenoceptor agonists in the medical treatment of stress incontinence may be limited by associated piloerection and cardiovascular side effects.

Adrenergic alpha-Agonists↗
PubMed2000

Perspectives of women living with schizophrenia.

OBJECTIVE: The study investigated the perceptions of women with schizophrenia or schizoaffective disorder about their illness in the context of their life stages and corresponding health needs. This paper reports narratively and through direct quotations what the women's daily lives are like. METHODS: Five focus groups totaling 28 women who identified themselves as having schizophrenia or schizoaffective disorder and who were living in the community met to discuss their health-related needs, ranging from parenting and reproductive health to relationships and getting older. Verbatim transcripts were analyzed inductively, and data were coded and organized around key themes. RESULTS: This group of women led marginalized, deprived lives in the face of multiple losses, social stigma, limited interpersonal contacts, and poverty. Perceived rejection and criticism were commonplace. The women felt that the health care system focused on their illness and that they had become invisible as women. Nevertheless, they conveyed a persistent sense of wanting life to improve and hoping that it could. CONCLUSIONS: The quality of a woman's life can be seriously impaired by illness or its treatment. Health care providers can help improve the lives of women with severe mental illness by focusing on how options and alternatives are presented, by exploring the impact of illness and treatment on a woman's day-to-day life, and by determining the appropriate structure of the therapeutic relationship.

Adult↗
PubMed2000

Evaluation of a networked self-testing program.

The use of a computerized, multiple-choice test bank to present practice and assessment tests on a network was evaluated with 46 men and 119 women from a first-year class in psychology. A correlation of .65 (p < .001) between scores on a traditional paper-and-pencil test and scores on a computerized test provided some validity for the computerized assessment. Regression analysis showed that ability (previous academic performance) and motivation (number of practice tests taken) accounted for 73% of the explained variance in computerized test scores. Sex differences did not enter the regression equation significantly.

Adolescent↗
PubMed1999

Human cloned alpha1A-adrenoceptor isoforms display alpha1L-adrenoceptor pharmacology in functional studies.

The recombinant alpha1A-adrenoceptor displays a distinct pharmacological profile ('classical alpha1A-adrenoceptor') in homogenate binding assays, but displays the properties of the so-called alpha1L-adrenoceptor in functional studies in whole cells at 37 degrees C. As three splice variants of the human alpha1A-adrenoceptor have been described previously (alpha1A-1, alpha1A-2 and alpha1A-3), we have compared their functional pharmacological profiles, when expressed stably in Chinese hamster ovary (CHO-K1) cells (antagonist inhibition of noradrenaline-stimulated [3H]inositol phosphates accumulation). A fourth, novel isoform (alpha1A-4) has also been studied: alpha1A-4 mRNA predominates in several human tissues including prostate, liver, heart and bladder. In homogenate binding studies, all four isoforms displayed essentially identical affinity profiles, with prazosin (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl)piperazine), tamsulosin (5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2-methoxybenzen esulfonamide), RS-17053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alphad imethyl-1H-indole-3-ethanamine hydrochloride), WB 4101 ((2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride) and 5-Me-urapidil (5-methyl-6[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]amino]-1,3-d imethyuracil) all displaying subnanomolar affinities. In functional studies, noradrenaline accelerated [3H]inositol phosphates production with potencies (p[A]50) of between 5.8 and 6.6. The affinities of prazosin, RS-17053, WB 4101 and 5-Me-urapidil, at antagonizing responses to noradrenaline, were reduced by approximately 10-fold (cf. binding data), while those for tamsulosin and indoramin (N-[1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]benzamide) remained constant or increased, consistent with the previously described alpha1L-adrenoceptor. Thus, all four human recombinant alpha1A-adrenoceptor isoforms display the pharmacology of the alpha1L-adrenoceptor when studied in functional assays, consistent with the hypothesis that the putative alpha1L-adrenoceptor represents a functional phenotype of the alpha1A-adrenoceptor.

Adrenergic alpha-Agonists↗
PubMed1999

In vitro alpha1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor selective antagonists.

It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the alpha1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. The present study describes the alpha1-adrenoceptor (alpha1-AR) subtype selectivities of two novel alpha1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned alpha1A-, alpha1B- and alpha1D-AR showed nanomolar affinity and significant alpha1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the alpha1B- and alpha1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing alpha1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). The alpha1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a 'uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1999

The crystalline components of dental calculus in the domestic cat.

Feline dental calculus was found to consist of carbonate-containing hydroxyapatite, Ca10(PO4)3(CO3)3(OH)2. Other forms of calcium phosphates consistently present in human calculus, and calcium carbonates found in horse, dog, and miniature pig calculus were not present. Calculus composition was performed using wet chemical method, x-ray diffraction, spectrographic analysis, and infrared spectrophotometric analysis. All samples showed traces of amorphous material, including magnesium and ammonium, but were negative for uric acid, cysteine, and oxalate.

Animals↗
PubMed1998

Molecular cloning, genomic characterization and expression of novel human alpha1A-adrenoceptor isoforms.

We have isolated and characterized from human prostate novel splice variants of the human alpha1A-adrenoceptor, several of which generate truncated products and one isoform, alpha(1A-4), which has the identical splice site as the three previously described isoforms. Long-PCR on human genomic DNA showed that the alpha(1A-4) exon is located between those encoding the alpha(1A-1) and alpha(1A-3) variants. CHO-K1 cells stably expressing alpha(1A-4) showed ligand binding properties similar to those of the other functional isoforms as well as agonist-stimulated inositol phosphate accumulation. Quantitative PCR analyses revealed that alpha(1A-4) is the most abundant isoform expressed in the prostate with high levels also detected in liver and heart.

Adrenergic alpha-Antagonists↗
PubMed1998

Alpha1L-adrenoceptor mediation of smooth muscle contraction in rabbit bladder neck: a model for lower urinary tract tissues of man.

1. The alpha1-adrenoceptor population mediating contractile responses to noradrenaline (NA) in smooth muscles of the bladder neck from rabbit (RBN) has been characterized by use of quantitative receptor pharmacology. 2. Experiments with several 'key' alpha1-adrenoceptor antagonists of varying subtype selectivities (RS-17053, BMY 7378, indoramin, 5-methylurapidil, prazosin, REC 15/2739, SNAP 5089, terazosin, WB 4101, tamsulosin, (+)-cyclazosin and RS-100329) were conducted. Schild regression analyses yielded affinity (mean pKb) estimates of 7.1, 6.2, 8.6, 8.6, 8.4, 9.3, 7.0, 7.4, 8.9, 10.0, 7.1 and 9.3, respectively, although deviations from unit Schild regression slope question the robustness of data for RS-17053 and SNAP 5089. 3. The nature of antagonism by these agents and the profile of affinity determinations generated together suggest that a single alpha1-adrenoceptor subtype mediates contractile responses of RBN to NA. Additional studies with phenylephrine indicated also an agonist-independence of this profile. Pharmacologically, this profile was reminiscent of that described as 'alpha1L'-adrenoceptor, which has been shown to mediate contractions of several tissues including lower urinary tract (LUT) tissues of man. Furthermore, a similarity was noticed between the 'alpha1L'-adrenoceptor described here in RBN and the rabbit and human cloned alpha1a-adrenoceptor (based on data from both whole cell radioligand binding at 37 degrees C and [3H]-inositol phosphates accumulation assays), characterizations of which have been published elsewhere. 4. In conclusion, the RBN appears to provide a predictive pharmacological assay for the study of NA-induced smooth muscle contraction in LUT tissues of man.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1998

Relationship between diet, dental calculus and periodontal disease in domestic and feral cats in Australia.

OBJECTIVE: To compare the dental calculus scores and prevalence of periodontal disease in domestic cats eating commercially available canned and dry foods with those in feral cats consuming a diet consisting of small mammals, birds, reptiles and insects. ANIMALS: Twenty-nine feral cats and 20 domestic cats were included in the study. PROCEDURE: A dental chart and dental calculus scores were recorded using the maxillary canine, maxillary third and fourth premolar, mandibular canine, mandibular fourth premolar and first molar teeth on both sides. Periodontal disease was recorded using gingival recession, increased periodontal pocket formation, radiographic alveolar bone loss, osteomyelitis, furcation and root exposure, and the presence of calculus as indicators. RESULTS: Dental calculus scores were significantly higher in domestic cats than in feral cats. There was no statistical difference in the prevalence of periodontal disease between the two groups. CONCLUSIONS: It can be inferred that diet may play a role in the accumulation of calculus, but a diet based on live prey does not protect cats against periodontal disease.

Animal Feed↗
PubMed1998

Inpatient group psychotherapy: the role of the staff nurse.

Inpatient groups are inherently different from outpatient groups and require modification in approach. Patients' needs, staff interests and expertise, and the needs of the health care system are major driving forces in the development of inpatient groups. A co-therapy model helps to achieve a balance between skills and abilities of the therapist.

Hospitalization↗
PubMed1997

N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.

Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.

Adolescent↗
PubMed1997

Drug discovery: some directional pointers.

Everybody in the pharmaceutical industry has a view on management and drug discovery. In this article, David Clarke expresses his personal views. Emphasis is placed on the role of the scientist, and the influence of the manager in programmatic scientific decision making is de-emphasized. An operational scheme for reorganization is proposed.

Career Choice↗
PubMed1997

Tetrodotoxin inhibits neuropathic ectopic activity in neuromas, dorsal root ganglia and dorsal horn neurons.

Neuropathic pain or persistent dysesthesias may be initiated by mechanical, chemical, or ischemic damage to peripheral sensory nerves. In animal models of neuropathic pain, transection or constrictive injury to peripheral nerves produces ectopic discharges originating at both injury sites and related dorsal root ganglia (DRG), and, consequently, hyperexcitability in associated dorsal horn (DH) neurons of the spinal cord. Since ectopic discharges are inhibited by agents that block voltage-sensitive Na+ channels, it has been postulated that accumulation of Na+ channels in the membrane at nerve injury sites may contribute to, or be responsible for, the development of ectopic neuronal activity (ENA). The present study therefore, tested the sensitivity of ENA to intravenously administered tetrodotoxin (TTX), an extremely potent and selective Na+ channel blocker. Comparative effects of TTX on cardiac parameters such as heart rate (HR) and diastolic blood pressure (DBP) were also studied. Experiments were performed on adult male Sprague-Dawley rats in which the common sciatic nerve had been transected 4-10 days earlier. Neuromal activity was measured in fine bundles of microfilaments teased from sciatic nerves, and extracellular microelectrode recordings were made from DRG and DH neurons. Cardiovascular parameters were recorded simultaneously. Intravenously administered TTX induced dose-dependent inhibition of ENA, with that originating from neuromas being the most sensitive; ED50 values (expressed as microg/kg, with 95% confidence limits) for neuromal, DRG and DH neuron activity were: 0.8 (0.6-1.2), 4.3 (2.2-8.4) and 36.2 (16.1-81.3), respectively. Inhibition of ENA in neuromas and DRG did not recover within 10 min after 100 or 300 microg/kg TTX. By comparison, the ED50 value for the initial decrease of HR was 17.9 (15.0-21.5) microg/kg, and partial recovery occurred within approximately 3 min. These data support the hypothesis that Na+ channel accumulation contributes to the generation of ectopic discharges in neuromas and DRG, and suggest that TTX-sensitive Na+ channels located at the nerve injury site and DRG play an important role in the genesis of neuropathic pain.

Action Potentials↗
PubMed1997

Pharmacological characterization of an alpha 1A-adrenoceptor mediating contractile responses to noradrenaline in isolated caudal artery of rat.

1. The alpha 1-adrenoceptor population mediating contraction of caudal artery of rat has been characterized by using quantitative receptor pharmacology. 2. Cumulative concentration-effect (E/[A]) curves to noradrenaline (NA) yielded a p[A]50 of 5.56 +/- 0.05 (n = 16). Prazosin caused concentration-dependent, parallel, dextral shifts of E/[A] curves to NA yielding a pKb of 8.9 (Schild regression slope = 1.0). RS-17053 (N-[2-(2-cyclopropyl methoxy phenoxy) ethyl]-5-chloro-alpha, alpha-dimethyl-1H-indole- 3-ethanamine hydrochloride; 10-100 nM), a selective alpha 1 A-adrenoceptor antagonist, produced non-parallel, biphasic, dextral shifts of E/[A] curves to NA, suggesting the involvement of more than one alpha 1-adrenoceptor subtype. Analysis of the high affinity component yielded an apparent pA2 value of 9.2 +/- 0.3. 3. A-61603, a selective agonist at alpha 1A adrenoceptors behaved as a full agonist relative to NA and yielded monophasic E/[A] curves with a p[A50] of 7.59 +/- 0.04 (n = 15). Pretreatment of tissues with chloroethylclonidine (CEC; 100 microM for 20 min, followed by 40 min washout), which preferentially alkylates alpha 1B- and alpha 1D-adrenoceptors, did not alter E/[A] curves to A-61603. Prazosin (3-300 nM) caused concentration-dependent, parallel, dextral shifts of E/[A] curves to A-61603 yielding a pA2 estimate of 9.2 +/- 0.2. 4. Experiments with alpha 1-adrenoceptor antagonists of varying subtype selectivities (RS-17053, SNAP 5089, tamsulosin, 5-methylurapidil, BMY 7378, HV 723 and REC 15/2739) revealed parallel dextral shifts of E/[A] curves to A-61603. Schild regression analyses yielded pA2 estimates of 9.2, 9.3, 11.2, 9.0, 6.3, 8.7 and 10.0 for RS-17053, SNAP 5089, tamsulosin, 5-methylurapidil, BMY 7378, HV 723 and REC 15/2739, respectively, although deviations from unit slope (possibly reflecting a secondary involvement of another alpha 1-adrenoceptor) hindered estimations of pKb for some antagonists. The antagonist affinity profile obtained reflects best that described for the alpha 1A-adrenoceptor. 5. In conclusion, caudal artery of rat contracts in response to NA via activation of at least two alpha 1-adrenoceptor subtypes. One of these subtypes displays the pharmacology of the alpha 1A-adrenoceptor, while the other remains to be defined. Use of the novel selective agonist, A-61603, allows for limited pharmacological isolation of the alpha 1A-adrenoceptor permitting characterization of the properties of selective antagonists.

Adrenergic alpha-Agonists↗
PubMed1997

Pharmacological pleiotropism of the human recombinant alpha1A-adrenoceptor: implications for alpha1-adrenoceptor classification.

1. Three fully-defined alpha1-adrenoceptors (alpha1A, alpha1B and alpha1D) have been established in pharmacological and molecular studies. A fourth alpha1-adrenoceptor, the putative alpha1L-adrenoceptor, has been defined in functional but not molecular studies, and has been proposed to mediate contraction of human lower urinary tract tissues; its relationship to the three fully characterized alpha1-adrenoceptors is not known. 2. In the present study, binding affinities were estimated by displacement of [3H]-prazosin in membrane homogenates of Chinese hamster ovary (CHO-K1) cells stably expressing the human alpha1A-, alpha1B- and alpha1D-adrenoceptors and were compared with affinity estimates obtained functionally in identical cells by measuring inhibition of noradrenaline (NA)-stimulated accumulation of [3H]-inositol phosphates. 3. For the alpha1A-adrenoceptor, binding studies revealed a pharmacological profile typical for the classically defined alpha1A-adrenoceptor, such that prazosin, RS-17053, WB 4101, 5-methylurapidil, Rec 15/2739 and S-niguldipine all displayed subnanomolar affinity. A different profile of affinity estimates was obtained in inositol phosphates accumulation studies: prazosin, WB 4101, 5-methylurapidil, RS-17053 and S-niguldipine showed 10 to 40 fold lower affinity than in membrane binding. However, affinity estimates were not 'frameshifted', as tamsulosin, indoramin and Rec 15/2739 yielded similar, high affinity estimates in binding and functional assays. 4. In contrast, results from human alpha1B- and alpha1D-adrenoceptors expressed in CHO-K1 cells gave antagonist affinity profiles in binding and functional assays that were essentially identical. 5. A concordance of affinity estimates from the functional (inositol phosphates accumulation) studies of the alpha1A-adrenoceptor in CHO-K1 cells was found with estimates published recently from contractile studies in human lower urinary tract tissues (putative alpha1L-adrenoceptor). These data show that upon functional pharmacological analysis, the cloned alpha1A-adrenoceptor displays pharmacological recognition properties consistent with those of the putative alpha1L-adrenoceptor. Why this profile differs from that obtained in membrane binding, and whether it explains the alpha1L-adrenoceptor pharmacology observed in many native tissues, requires further investigation.

Adrenergic Agents↗