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Biomedical subjects

Michael Williams

Publications and source records attributed to Michael Williams.

51 records · Page 3Linked to original sources
PubMed2002

N-[3-(1H-imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1),(1) a novel alpha(1)-adrenoceptor ligand with an enhanced in vitro and in vivo profile relative to phenylpropanolamine and midodrine.

N-[3-(1H-Imidazol-4-ylmethyl)phenyl]ethanesulfonamide (ABT-866, 1) is a novel alpha(1) agent having the unique profile of alpha(1A) (rabbit urethra, EC(50) = 0.60 microM) agonism with alpha(1B) (rat spleen, pA(2) = 5.4) and alpha(1D) (rat aorta, pA(2) = 6.2) antagonism. An in vivo dog model showed 1 to be more selective for the urethra over the vasculature than A-61603 (2), ST-1059 (3, the active metabolite of midodrine), and phenylpropanolamine (4).

Adrenergic alpha-Agonists↗
PubMed2002

ABT-866, a novel alpha(1A)-adrenoceptor agonist with antagonist properties at the alpha(1B)- and alpha(1D)-adrenoceptor subtypes.

N-[3-(1H-Imidazol-4-ylmethyl)phenyl]ethanesulfonamide, maleate (ABT-866) is a novel alpha(1)-adrenoceptor agent with mixed pharmacological properties in vitro. Compared to phenylephrine, ABT-866 demonstrates intrinsic activity at the alpha(1A)-adrenoceptor subtype present in the rabbit urethra (pD(2) = 6.22, with 80% of the phenylephrine response), reduced intrinsic activity at the alpha(1B)-adrenoceptor subtype in the rat spleen (pD(2)= 6.16, with 11% of the phenylephrine response), and no intrinsic activity at the rat aorta alpha(1D)-adrenoceptor subtype. ABT-866 also demonstrated antagonism at the rat spleen alpha(1B)-adrenoceptor (pA(2) = 5.39 +/- 0.08, slope = 1.20 +/- 0.12), and the rat aorta alpha(1D)-adrenoceptor (pA(2)= 6.18 +/- 0.09, slope = 0.96 +/- 0.13). This is in contrast to the weak non-selective activity seen with the alpha(1)-adrenoceptor agonist, phenylpropanolamine (2-amino-1-phenyl-1-propanol hydrochloride), and the alpha(1A/D)-adrenoceptor selective agonist 1-(2',5'-dimethoxyphenyl)-2-aminoethanol hydrochloride (ST-1059), the active metabolite of midodrine, that has been used clinically for the treatment of stress urinary incontinence. This study identifies a unique agent that may prove to be a valuable in vivo tool in testing the hypothesis that the alpha(1A)-adrenoceptor can be stimulated to contract the smooth muscle present in the urethra without evoking blood pressure elevations presumably caused by alpha(1B)- and alpha(1D)-adrenoceptor subtype involvements in the vasculature.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2002

Prospective use of molecular typing of Mycobacterium tuberculosis by use of restriction fragment-length polymorphism in a public tuberculosis-control program.

We performed a prospective, community-based evaluation of molecular typing of Mycobacterium tuberculosis isolates as a method for tuberculosis (TB) control. We performed restriction fragment-length polymorphism (RFLP) analysis of the insertion sequences IS6110 and pTBN12 for isolates recovered from 61 of 62 patients with culture-positive TB in St. Louis during 12 months. Twenty-four (39%) of the 61 patients were infected with an isolate with an RFLP pattern that was shared with >/=1 other isolate, and 11 (46%) also had epidemiologic links with patients in their cluster of cases. One case each of laboratory cross-contamination and occupational transmission were discovered. The patients in clusters were more likely to be younger, black, United States-born, to have substance abuse problems, and to live in poorer areas. A predictive algorithm for molecular identification of clusters had a sensitivity and a specificity of 75%. This study allowed the TB-control program in St. Louis to be redirected toward the affected subpopulations.

Adult↗
PubMed2002

Inter- and intrarater reliability of the Ashworth Scale and the Disability Assessment Scale in patients with upper-limb poststroke spasticity.

OBJECTIVE: To evaluate the reliability of the Ashworth Scale and the Disability Assessment Scale (DAS) in poststroke patients with upper-limb spasticity and functional disability. DESIGN: Single-center trial. SETTING: University medical center. PARTICIPANTS: Nine patients > or = 6 months poststroke with upper-limb spasticity and impairment in the areas of hygiene, dressing, limb posture, or pain were included in the analysis. INTERVENTIONS: Ten experienced medical professionals rated each patient in randomized order twice on the same day (results based on mean of evaluations at times 1 and 2). Elbow, wrist, finger, and thumb flexion tones were assessed by using the Ashworth score (range, 0-4), and functional disability was assessed using the DAS (range, 0-3). MAIN OUTCOME MEASURES: Intra- and interrater reliability of the Ashworth Scale and DAS. RESULTS: For the Ashworth parameters, 38 of 40 evaluations indicated excellent (weighted kappa > or = .75) or good (weighted kappa > or = .4) intrarater reliability. For DAS parameters, 31 of 40 evaluations indicated excellent or good intrarater reliability. The interrater reliability was also good for both the Ashworth Scale (Kendall W=.598-.792) and DAS (Kendall W=.494-.772) with statistically significant agreement found among raters (all P<.001). CONCLUSIONS: In patients with upper-limb spasticity after stroke, the Ashworth Scale and DAS had good intra- and interrater reliability when used by trained medical professions.

Adult↗
PubMed2002

(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637): a novel ATP-sensitive potassium channel opener efficacious in suppressing urinary bladder contractions. I. In vitro characterization.

Alterations in the myogenic activity of the bladder smooth muscle are thought to serve as a basis for the involuntary detrusor contractions associated with the overactive bladder. Activation of ATP-sensitive K(+) (K(ATP)) channels has been recognized as a potentially viable mechanism to modulate membrane excitability in bladder smooth muscle. In this study, we describe the preclinical pharmacology of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel 1,4-dihydropyridine K(ATP) channel opener (KCO) that demonstrates enhanced bladder selectivity for the suppression of unstable bladder contractions in vivo relative to other reference KCOs. A-278637 activated K(ATP) channels in bladder smooth muscle cells in a glyburide (glibenclamide)-sensitive manner as assessed by fluorescence membrane potential assays using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (EC(50) = 102 nM) and by whole cell patch clamp. Spontaneous (myogenic) phasic activity of pig bladder strips was suppressed (IC(50) = 23 nM) in a glyburide-sensitive manner by A-278637. A-278637 also inhibited carbachol- and electrical field-stimulated contractions of bladder strips, although the respective potencies were 8- and 13-fold lower compared with inhibition of spontaneous phasic activity. As shown in the accompanying article [Brune ME, Fey TA, Brioni JD, Sullivan JP, Williams M, Carroll WA, Coghlan MJ, and Gopalakrishnan M (2002) J Pharmacol Exp Ther 303:387-394], A-278637 suppressed myogenic contractions in vivo in a model of bladder instability with superior selectivity compared with other KCOs, WAY-133537 [(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)cyclobut-1-enylamino]-3-ethyl-benzonitrile] and ZD6169 [(S)-N-(4-benzoylphenyl)3,3,3-trifluro-2hydroxy-2-methyl-priopionamide]. A-278637 did not interact with other ion channels, including L-type calcium channels or other neurotransmitter receptor systems. The pharmacological profile of A-278637 represents an attractive basis for further investigations of selective K(ATP) channel openers for the treatment of overactive bladder via myogenic etiology.

ATP-Binding Cassette Transporters↗
PubMed2002

(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637): a novel ATP-sensitive potassium channel opener efficacious in suppressing urinary bladder contractions. II. in vivo characterization.

ATP-sensitive potassium (K(ATP)) channel openers (KCOs) have been shown to inhibit spontaneous myogenic contractile activity of the urinary bladder, a mechanism hypothesized to underlie detrusor instability and symptoms of overactive bladder. However, the therapeutic utility of KCOs has been limited by a lack of differentiation of bladder versus vascular effects. In this study, we evaluated the in vivo potency and bladder selectivity of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel dihydropyridine KCO, in a pig model of detrusor instability secondary to partial bladder outlet obstruction. For comparison, we profiled two KCOs, ((R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (WAY-133537) and (S)-N-(4-benzoylphenyl)-3,3,3-trifluro-2-hydroxy-2-methyl-propionamide (ZD6169), reported previously to have improved bladder selectivity in vivo and a calcium channel blocker, nifedipine. Effective doses of A-278637, WAY-133537, ZD6169, and nifedipine to inhibit unstable contraction area under the curve by 35% and to decrease mean arterial pressure by 10% were 4.2 and 12, 109 and 51, 661 and 371, and 136 and 30 nmol/kg i.v., yielding corresponding bladder selectivity ratios of 3, 0.5, 0.6, and 0.2. Therefore, A-278637 was approximately 5- to 6-fold more bladder-selective than the other KCOs and 15-fold more selective than nifedipine, the latter approximately 4.5-fold vascular-selective. The potency of KCOs to inhibit unstable contraction in vivo was accurately predicted by their potency to inhibit spontaneous contractile activity of pig detrusor strips in vitro. These results indicate that A-278637, with enhanced potency and bladder selectivity compared with the other compounds evaluated, could serve as a useful tool in the investigation of smooth muscle K(ATP) channel openers as novel therapeutic agents for the treatment of overactive bladder.

ATP-Binding Cassette Transporters↗
PubMed2002

Preclinical pharmacology of fiduxosin, a novel alpha(1)-adrenoceptor antagonist with uroselective properties.

Benign prostatic hyperplasia (BPH), common in aging males, is often treated with alpha(1)-adrenoceptor antagonists. To minimize hypotensive and other side effects, compounds with selective antagonist activity at alpha(1A)- and alpha(1D)- (compared with alpha(1B)-) adrenoceptors were evaluated that would block lower urinary tract alpha(1)-adrenoceptors in preference to cardiovascular alpha(1B)-adrenoceptors. Fiduxosin (3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-8-phenyl-pyrazino[2',3':4,5] thieno-[3,2-d]pyrimidine-2,4(1H,3H)-dione; ABT-980) was tested in radioligand binding assays, isolated tissue bioassays, intraurethral pressure (IUP) tests in isoflurane-anesthetized dogs, and blood pressure analyses in spontaneously hypertensive rats (SHR). Fiduxosin had higher affinity for cloned human alpha(1a)- (0.16 nM) and alpha(1d)-adrenoceptors (0.92 nM) in radioligand binding studies compared with alpha(1b)-adrenoceptors (25 nM) or in isolated tissue bioassays [pA(2) values of 8.5-9.6 for alpha(1A)-receptors in rat vas deferens or canine prostate strips, 8.9 at alpha(1D)-adrenoceptors (rat aorta), compared with 7.1 at alpha(1B)-adrenoceptors (rat spleen)]. Furthermore, the compound antagonized putative alpha(1L)-adrenoceptors in the rabbit urethra (pA(2) value of 7.58). Fiduxosin blocked epinephrine-induced increases in canine IUP (pseudo-pA(2) value of 8.12), eliciting only transient decreases in mean arterial blood pressure (MAP) in SHR. The area under the curve (AUC(0-->60) min) for the hypotensive response was dose related with a log index value for fiduxosin of 5.23, indicating a selectivity of 770-fold comparing IUP to MAP effects. Preferential antagonism of alpha(1A)- and alpha(1D)- versus alpha(1B)-adrenoceptors in vitro, blockade of putative alpha(1L)-sites in vitro, and selective effects on lower urinary tract function versus blood pressure in vivo by fiduxosin suggest the potential utility of this compound for the treatment of BPH.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2002

Effect of fiduxosin, an antagonist selective for alpha(1A)- and alpha(1D)-adrenoceptors, on intraurethral and arterial pressure responses in conscious dogs.

Fiduxosin is an alpha(1)-adrenoceptor antagonist with higher affinity for alpha(1A)-adrenoceptors and for alpha(1D)-adrenoceptors than for alpha(1B)-adrenoceptors. Our hypothesis is that such a compound with higher affinity for subtypes implicated in the control of lower urinary tract function and lower affinity for a subtype implicated in the control of arterial pressure could result in a superior clinical profile for the treatment of lower urinary tract symptoms suggestive of benign prostatic obstruction. The purpose of this study was to evaluate the potency and selectivity of fiduxosin for effects on prostatic intraurethral pressure (IUP) versus mean arterial pressure (MAP) relative to current clinical standards, terazosin and tamsulosin, in conscious dogs. Phenylephrine (PE)-induced increases in IUP and MAP were determined before and at various time points after an oral dose of each antagonist. Hypotensive potency was also determined. All three antagonists caused dose- and time-dependent blockade of the IUP and MAP pressor effects of PE. The IUP ED(50) values of fiduxosin, tamsulosin, and terazosin were 0.24, 0.004, and 0.23 mg/kg p.o., respectively. The corresponding MAP ED(50) values were 1.79, 0.006, and 0.09 mg/kg p.o. The rank order of IUP selectivity (ratio) was fiduxosin (7.5-fold), tamsulosin (1.5-fold), and terazosin (0.4 = 2.5-fold MAP-selective). Tamsulosin and terazosin caused dose-dependent hypotension, whereas no change in arterial pressure was seen after fiduxosin. These data, illustrating a superior selectivity profile of fiduxosin, are consistent with our hypothesis.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2002

A comparison of telepaediatric activity at two regional hospitals in Queensland.

We conducted a 15-month feasibility study of telepaediatrics. A novel service was offered to two hospitals in Queensland (Mackay and Hervey Bay). We used data from all other hospitals throughout the state as the control group. Although both intervention hospitals were provided with the same service, the telepaediatric activity generated and the effect on admissions and outpatient activity were markedly different. There was a significant decrease in the number of patient admissions to Brisbane from the Mackay region. In addition, there was an increase in the number of Mackay patients treated locally (as outpatients). In contrast, little change was observed in Hervey Bay. We assessed whether the observed differences between the two hospitals were due to various factors which influenced the use of the telepaediatric service. These factors included the method of screening patients before transfer to the tertiary centre and the physical distance between each facility and the tertiary centre. We believe that the screening method used for patient referrals was the most important determinant of the use of the telepaediatric service.

Journal Article↗
PubMed2002

A comparison of telepaediatric activity at two regional hospitals in Queensland.

We conducted a 15-month feasibility study of telepaediatrics. A novel service was offered to two hospitals in Queensland (Mackay and Hervey Bay). We used data from all other hospitals throughout the state as the control group. Although both intervention hospitals were provided with the same service, the telepaediatric activity generated and the effect on admissions and outpatient activity were markedly different. There was a significant decrease in the number of patient admissions to Brisbane from the Mackay region. In addition, there was an increase in the number of Mackay patients treated locally (as outpatients). In contrast, little change was observed in Hervey Bay. We assessed whether the observed differences between the two hospitals were due to various factors which influenced the use of the telepaediatric service. These factors included the method of screening patients before transfer to the tertiary centre and the physical distance between each facility and the tertiary centre. We believe that the screening method used for patient referrals was the most important determinant of the use of the telepaediatric service.

Child↗
PubMedDate not supplied

Prospective randomized trial of heated humidified versus cold dry carbon dioxide insufflation during laparoscopic gastric bypass.

BACKGROUND: The replacement of cold dry carbon dioxide with heated humidified gas for insufflation during complex laparoscopic procedures has been reported to decrease hypothermia and peritoneal cell desiccation, with a resultant decrease in postoperative pain and narcotic use and a shortened recovery, but may prevent the paralysis of the peritoneal polymorphonuclear cell cytokine cascade and add to the cost of the procedure. We report our outcomes comparing carbon dioxide insufflation with different characteristics during laparoscopic gastric bypass. METHODS: Fifty consecutive patients were randomized to undergo laparoscopic gastric bypass with either cold-dry or heated-humidified carbon dioxide insufflation. Statistical analysis of variance between groups was determined by Levine's t test with the Greenhouse-Geisser correction, at a significance level of P <.05. RESULTS: The two groups were similar for preoperative gender, age, weight, body mass index, and baseline C-reactive protein. The intraoperative room and patient core temperature, liters of insufflation used, lens cleanings, operating time, recovery room time, and narcotics used were not significantly different. The postoperative subjective analog shoulder pain score was significantly less (P = .025) for the heated-humidified group at 18 hours, but not at 6, 12, 24, or 48 hours. The abdominal pain scores and overall narcotic use, postoperative C-reactive protein, and length of stay were not significantly different between the two groups. CONCLUSION: Heated-humidified insufflation resulted in a transient reduction in subjective shoulder pain at 18 hours postoperatively, but no reduction in abdominal pain or narcotics used. We were unable to verify any clinically significant difference between the two groups comparing heated-humidified and cold-dry insufflation after laparoscopic gastric bypass.

Adult↗
PubMedDate not supplied

Psychosocial assessment of functional gastrointestinal disorders in clinical practice.

Functional gastrointestinal disorders are the most common conditions encountered in gastroenterology practice and are also commonly encountered in primary care. Psychosocial factors play an important role in these disorders (along with any chronic digestive disorder) by influencing healthcare seeking, illness behavior, symptom severity, quality of life, and digestive motility and sensation. Identification of relevant psychosocial factors in patients with chronic digestive disorders influences care and is a critical determinant of outcomes. This article provides a review of relevant psychosocial variables, assessment techniques, and therapeutic suggestions that can be of value in assessing patients with functional gastrointestinal disorders.

Adaptation, Psychological↗