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Biomedical subjects

S Weir

Publications and source records attributed to S Weir.

At least 19 recordsLinked to original sources
PubMed1998

The effect of food on the bioavailability of dolasetron mesylate tablets.

Anzemet (dolasetron mesylate) is being developed for the prevention of chemotherapy-induced emesis and postoperative nausea and vomiting. Twenty-four healthy male subjects were orally dosed with dolasetron mesylate, 200 mg, after either an overnight fast or a high-fat breakfast. The ratio of the mean area under the plasma concentration-time curve of the reduced active metabolite (MDL 74,156) to infinity (AUC(0-infinity)) values in fed compared to fasting subjects was 86.3% with a 90% confidence interval for the ratio within (80, 125)%, indicating bioequivalence. The ratio of the mean MDL 74,156 maximum plasma concentration (Cmax) values was 70.6% in fed versus fasted subjects. The time to Cmax was statistically significantly longer after the high-fat breakfast (mean values, 1.11 h fasting and 1.80 h fed), probably due to delayed gastric emptying. It may be concluded that, although the rate of absorption was somewhat delayed, the extent of absorption did not change significantly when dolasetron mesylate was given with food.

Adult↗
PubMed1998

Pharmacokinetics, pharmacodynamics, and tolerance of single- and multiple-dose fexofenadine hydrochloride in healthy male volunteers.

BACKGROUND: Fexofenadine is a selective, nonsedating H1-receptor antagonist that relieves symptoms of allergic conditions. METHODS: Two randomized, double-blind, parallel-group, placebo-controlled dose-escalation studies were performed in healthy men to determine the maximum tolerated oral dose, pharmacokinetics, pharmacodynamics, and safety of fexofenadine hydrochloride. In the first study, 87 subjects (6 in the active drug group and 2 in the placebo group) received single oral doses of fexofenadine hydrochloride ranging from 10 to 800 mg or placebo. In the second study, 32 subjects (3 in the active drug group and 1 in the placebo group) received multiple fexofenadine hydrochloride doses ranging from 20 to 690 mg or placebo twice daily for 28 1/2 days. Serial plasma and urine samples were collected. Fexofenadine concentrations were determined by HPLC and fluorescence. Wheal and flare response to intradermal histamine was used to evaluate antihistaminic activity. RESULTS: Fexofenadine hydrochloride was rapidly absorbed, reaching peak concentrations in 0.83 to 1.33 hours. Single-dose mean concentration ranged from 46 to 6383 ng/mL, and steady-state maximum plasma concentration ranged from 58 to 4677 ng/mL. Mean area under the plasma concentration-time curve was approximately proportional to dose. Oral clearance, renal clearance, and cumulative percent of drug excreted in urine were similar after single and multiple doses and were generally constant over the dose range studied. Inhibition of skin wheal and flare was shown for single doses of 40 mg and higher and for all multiple doses. No fexofenadine dose-related trends or apparent differences from placebo were found for any safety parameter. CONCLUSIONS: Fexofenadine hydrochloride was well tolerated at oral doses up to 11 times the recommended therapeutic dose. In addition, fexofenadine hydrochloride showed significant antihistaminic activity and dose-proportional pharmacokinetics over a wide dosing range.

Administration, Oral↗
PubMed1998

Replication of clinical innovations in multiple medical practices.

BACKGROUND: Many clinical innovations had been successfully developed and piloted in individual medical practice units of Kaiser Permanente in North Carolina during 1995 and 1996. Difficulty in replicating these clinical innovations consistently throughout all 21 medical practice units led to development of the interdisciplinary Clinical Innovation Implementation Team, which was formed by using existing resources from various departments across the region. REPLICATION MODEL: Based on a model of transfer of best practices, the implementation team developed a process and tools (master schedule and activity matrix) to quickly replicate successful pilot projects throughout all medical practice units. The process involved the following steps: identifying a practice and delineating its characteristics and measures (source identification); identifying a team to receive the (new) practice; piloting the practice; and standardizing, including the incorporation of learnings. The model includes the following components for each innovation: sending and receiving teams, an innovation coordinator role, an innovation expert role, a location expert role, a master schedule, and a project activity matrix. Communication depended on a partnership among the location experts (local knowledge and credibility), the innovation coordinator (process expertise), and the innovation experts (content expertise). RESULTS: Results after 12 months of working with the 21 medical practice units include integration of diabetes care team services into the practices, training of more than 120 providers in the use of personal computers and an icon-based clinical information system, and integration of a planwide self-care program into the medical practices--all with measurable improved outcomes. CONCLUSION: The model for sequential replication and the implementation team structure and function should be successful in other organizational settings.

Benchmarking↗
PubMed1998

Drug interactions at the renal level. Implications for drug development.

The kidney plays a major role in the elimination of drugs. The purpose of this paper is to: (i) review the mechanisms of renal elimination; (ii) identify potential mechanisms for renal drug interactions; (iii) review in vitro and in vivo animal models for studying renal elimination mechanisms and identifying potential drug-drug interactions; (iv) review experimental designs used in identifying drug-drug interactions in humans with an emphasis on gaining information regarding the mechanism of the interaction; and (v) make recommendations regarding the potential for renal drug interactions in drug development. It is concluded that clinically significant drug interactions resulting in toxicity because of some mechanism at the renal level appear to be relatively rare and that in vitro screening should not be done on all drugs during drug development. Five potential mechanisms exist for drug interactions at the renal level: (i) a displacement of bound drug resulting in an increase in drug excretion via an increase in glomerular filtration; (ii) competition at a tubular secretion site resulting in a decrease in drug excretion; (iii) competition at the tubular reabsorption site resulting in an increase in drug excretion; (iv) a change in urinary pH and/or flow that may increase or decrease drug excretion depending on the pKa of the drug; and (v) inhibition of renal drug metabolism. The most well known renal drug interaction is competitive inhibition of tubular secretion, ultimately leading to an increase in plasma drug concentration. Only when renal clearance is a major contributor to the total clearance (> 30%) and plasma concentrations are greater than the Michaelis-Menten transport constant does the potential exist for clinically significant renal drug-drug interactions because only then does nonlinear pharmacokinetics become evident. The potential for drug interactions is small when renal clearance is less than 20 to 30% of the total clearance and/or when plasma concentrations are less than the Michaelis-Menten transport constant, unless the drug has a narrow therapeutic window.

Animals↗
PubMed1997

Type-4 pili of Kingella denitrificans.

Kingella denitrificans possess type-4 pili, and the type strain, ATCC 33394, contains at least four complete copies of type-4 pilin-encoding genes. Previously reported hybridization patterns of K. denitrificans chromosomal DNA seen using a Neisseria gonorrhoeae pilin gene region probe, had been interpreted as representing possible partial, silent gene loci. This now appears to be due to cross-reaction to multiple copies of 18-bp inverted repeat structures. Data are presented on a variety of colony variants which have changed from a spreading-corroding (SC) phenotype to a nonspreading-noncorroding (N) phenotype. Interestingly, while the SC to N transition is most often associated with loss of piliation in other bacteria containing type-4 pili, many of the K. denitrificans N variants still produce pilin, and some still produce pili.

Bacterial Outer Membrane Proteins↗
PubMed1997

Infections with Roseomonas gilardii and review of characteristics used for biochemical identification and molecular typing.

Roseomonas is a recently described genus of gram-negative coccobacilli formerly designated as "pink-coccoid" groups I through IV by the Centers for Disease Control and Prevention (Atlanta, Ga) because of the organism's characteristic pink colonies. Since 1991 we have isolated Roseomonas from eight patients; in seven from blood cultures and in one from a skin lesion. The seven blood isolates were from patients with clinically significant underlying diseases who had central venous catheters in place; the majority were associated with polymicrobial catheter infections. Additional characteristics of their infections are described. The eight isolates had originally been identified by us as Centers for Disease Control (CDC) pink-coccoid group III. These organisms were re-identified using the criteria of Rihs et al, and all isolates fit most closely with Roseomonas gilardii. Antibiotic profiles were fairly homogeneous showing susceptibility to many antibiotics, but uniform resistance to cefoxitin, ceftazidime, and piperacillin. Attempts to determine whether the isolates were the same strain by pulsed-field gel electrophoresis suggested that 3 of the isolates were similar. Random amplified polymorphic DNA analysis, however, demonstrated that each of the eight isolates was a unique strain.

Adult↗
PubMed1996

Identification of four complete type 4 pilin genes in a single Kingella denitrificans genome.

We have cloned and sequenced four complete type 4 pilin genes from the type strain (ATCC 33394) of Kingella denitrificans. Two of these pilin genes, kdpB and kdpD, are in tandem, oriented in the same direction, and encode pilins of only 50% amino acid identity. The kdpA and kdpC loci are separately located from the kdpB-kdpD locus and from each other. At the DNA level kdpA and kdpC are nearly identical to kdpB and encode pilin proteins that are identical to KdpB. Bands of multiple hybridization previously hypothesized to be due to partial silent pilin gene loci are now shown to be due to the presence of 18-bp repeat sequences (IR18) associated with the pilin gene coding regions. These IR18 sequences exist most often as inverted repeats separated by 8 bp. IR18 sequences are structurally similar to the repetitive extragenic palindromic sequences of Escherichia coli, although they have different DNA sequences. The IR18 sequences also demonstrate homology to the DNA uptake sequences of Neisseria gonorrhoeae and may serve a similar function for K. denitrificans.

Amino Acid Sequence↗
PubMed1995

Pharmacokinetics of dolasetron following single- and multiple-dose intravenous administration to normal male subjects.

Dolasetron, Anzemet, a 5-hydroxytryptamine receptor antagonist, is under investigation as an antiemetic agent. The keto-reduced metabolite of dolasetron has been identified in human plasma and is probably responsible for the majority of the antiemetic activity. This study evaluated the pharmacokinetics of dolasetron and the reduced metabolite following single and multiple intravenous (IV) infusions of dolasetron mesylate in healthy male subjects. Four groups of subjects (six active/two placebo) received either dolasetron mesylate or placebo in single IV doses ranging from 0.30 to 0.60 mg kg-1 on day 1 and multiple IV doses ranging from 0.60 to 1.20 mg kg-1 d-1 on days 2-9. Dolasetron could be detected for less than 1 h, while the reduced metabolite appeared rapidly in the plasma, reaching a maximal plasma concentration in less than 1 h. Reduced metabolic maximal plasma concentration was proportional to the dose and the area under plasma concentration curve was linear based on regression analysis. The half-life of reduced metabolite ranged from 3.82 to 7.46 h. The mean renal clearance of reduced metabolite was 2.20-4.43 mL min-1 kg-1 and was dose independent. All of the evidence supports dose independent pharmacokinetics for the reduced metabolite. Upon multiple dosing, the reduced metabolite AUC can be predicted from the single-dose pharmacokinetics of this metabolite.

Adult↗
PubMed1995

Pharmacokinetics and pharmacodynamics of the monoamine oxidase B inhibitor mofegiline assessed during a phase I dose tolerance trial.

The safety, pharmacokinetics, and pharmacodynamics of single oral doses of up to 48 mg and daily (for 28 days) doses of up 24 mg mofegiline were investigated in healthy male volunteers. Plasma pharmacokinetics indicated rapid absorption and elimination: time to reach maximum concentration occurred at about 1 hour; half-life ranged from 1 to 3 hours. Maximal plasma concentration and area under the plasma concentration-time curve increased and oral clearance decreased disproportionately with dose. Mofegiline rapidly and markedly inhibited platelet monoamine oxidase B (MAOB) activity, which returned to baseline within 14 days. Urinary excretion of phenylethylamine increased proportionately with doses up to 24 mg. No changes in urinary elimination of catecholamines, blood pressure, heart rate, or ECG were observed. A classic maximum tolerated dose was not achieved in these studies. However, the 48 mg single dose and the 24 mg multiple daily dose far exceeded the dose (1 mg) that was associated with > 90% platelet MAOB inhibition.

Administration, Oral↗
PubMed1994

Evaluation of a targeted AIDS prevention intervention to increase condom use among prostitutes in Ghana.

OBJECTIVE: To assess the short- and long-term impact of a 6-month pilot intervention program on condom use among prostitutes in Accra, Ghana. DESIGN: The 4-year prospective study follows-up cohorts enrolled in the intervention in 1987 and 1988, comparing condom use in 1991 with that among a comparison group not enrolled in the intervention. SETTING: The community-based intervention was initiated in Accra, Ghana in 1987. PARTICIPANTS: Self-identified female prostitutes who volunteered participation. INTERVENTION: The educational intervention used local health workers to train and support selected prostitutes to be health educators and condom distributors to their peers. OUTCOME MEASURES: Self-reported condom use with clients. RESULTS: Reported condom use increased dramatically between 1987 and 1988 during the first 6 months of the intervention. In 1991, after 3 years of program relapse, 107 (43%) of the 248 women who had enrolled in 1987 or 1988 were still in prostitution and located for interview. Their level of condom use in 1991 was higher than pre-enrollment but similar to use among prostitutes never enrolled. Sixty-four per cent of those followed-up reported always using condoms with clients in 1991. These 'always users' were more likely to have maintained informal contact with project staff, know that HIV can be transmitted by healthy clients, and report that clients frequently initiate condom use. CONCLUSIONS: Findings support the development of long-range educational strategies that recognize the career longevity of prostitutes, available channels for informal program diffusion, individual changes in condom use over time, and the role of clients in condom negotiation.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Sequence divergence in two tandemly located pilin genes of Eikenella corrodens.

Eikenella corrodens normally inhabits the human respiratory and gastrointestinal tracts but is frequently the cause of abscesses at various sites. Using the N-terminal portion of the Moraxella nonliquefaciens pilin gene as a hybridization probe, we cloned two tandemly located pilin genes of E. corrodens 31745, ecpC and ecpD, and expressed the two pilin genes separately in Escherichia coli. A comparison of the predicted amino acid sequences of E. corrodens 31745 EcpC and EcpD revealed considerable divergence between the sequences of these two pilins and even less similarity to EcpA and EcpB of E. corrodens type strain ATCC 23834. EcpC from E. corrodens 31745 displayed high degrees of homology to the pilins of Neisseria gonorrhoeae and Pseudomonas aeruginosa. EcpD from E. corrodens 31745 showed the highest homologies with the pilin of one of the three P. aeruginosa classes, whereas EcpA and EcpB of strain ATCC 23834 most closely resemble Moraxella bovis pilins. These findings raise interesting questions about potential genetic transfer between different bacterial species, as opposed to convergent evolution.

Amino Acid Sequence↗
PubMed1992

Fundamental studies in reversed-phase liquid-solid extraction of basic drugs; III: Sample matrix effects.

Using a set of 13 basic solutes (including a quarternary ammonium compound) with controlled pKa, log P and plasma protein binding, the factors which influence the extraction of these compounds from plasma by reversed-phase liquid-solid extraction have been studied. Direct analysis of plasma, avoiding deproteination, etc., is possible providing the sample is applied to the cartridge under the appropriate conditions. These conditions are dictated by the degree of plasma protein binding and are controlled and predicted from the lipophilicity of the compound. Plasma samples containing lipophilic compounds (log D(pH 7.4) > 2.03) require acidification and samples containing more polar compounds (log D(pH 7.4) < 0.9) should be applied untreated. Failure to use the appropriate conditions can result in significant losses from the cartridge on application or washing. In the intermediate lipophilicity range the optimal application conditions cannot be predicted. The effect of various aqueous-organic wash solvents have been investigated, and it was found that the cationic but not the proteinaceous components of plasma also affect the extraction process. This phenomenon which is probably due to an attenuation of the secondary cation exchange mechanism, results in more facile elution than when compounds are applied in water.

Atenolol↗
PubMed1992

Identification of type 4 pili in Kingella denitrificans.

Kingella denitrificans is an occasionally pathogenic member of the family Neisseriaceae and is a member of the normal respiratory flora. Electron microscopy, colony morphology types, DNA transformation patterns, and immunoblots suggest that K. denitrificans and K. kingae have type 4 pili. This was confirmed by N-terminal amino acid sequencing for K. denitrificans.

Amino Acid Sequence↗
PubMed1991

The determinants of response to diltiazem in hypertension.

We examined factors (blood pressure, plasma renin activity, and age) influencing the antihypertensive response in essential hypertensive patients given 240 mg/day of slow-release diltiazem in an unblinded study after a placebo run-in period. Subjects provided a range of diastolic blood pressures (90 to 115 mm Hg), of age (31 to 70 years), and of plasma renin activity (0.1 to 2.7 ng angiotensin I/ml/hr) on a 70 to 150 mEq sodium diet. Blood pressure, plasma renin activity, and plasma diltiazem concentrations were measured after the first (n = 21) and final dose (n = 19) of 120 mg diltiazem, twice daily for 4 weeks. Multiple linear stepwise regression of change in blood pressure versus age, plasma renin activity, and baseline blood pressure showed baseline blood pressure was the only predictor of response (p = 0.0002). For each increase of 10 mm Hg in baseline pressure there was a 7 mm Hg greater decrease in diastolic blood pressure. We conclude that patient age and plasma renin activity are not clinically significant predictors of antihypertensive response to diltiazem in hypertension.

Adult↗
PubMed1990

Pili (fimbriae) of Branhamella species.

PURPOSE: Pili (fimbriae) have frequently been found to be involved in the attachment of bacteria to mucosal epithelial cells, an important initial step in the disease process. The purpose of this study was to determine if Branhamella catarrhalis expresses type 4 pili. MATERIALS AND METHODS: Piliated B. catarrhalis phenotypic characteristics of colony morphology, agar corrosion, twitching motility, competence for deoxyribonucleic acid (DNA) transformation, autoagglutination, and pellical formation were observed. DNA was isolated from Branhamella spp. and used in genomic Southern hybridizations with a Moraxella bovis pilin gene as a probe. Electron microscopy of negatively stained bacteria was carried out to visualize pili. RESULTS: B. catarrhalis has several (but not all) of the phenotypic characteristics that are related to the presence of type 4 (MePhe) pili in closely related Moraxella spp., including competence for DNA transformation, autoagglutination, pellicle formation, colony morphology, and pitting of agar. The one phenotype we have not found that is generally characteristic of type 4 piliated bacteria is twitching motility. Genomic Southern hybridization analysis using a cloned M. bovis Q pilin gene as a probe reveals DNA homologous to the Q pilin gene in B. catarrhalis, Branhamella ovis, Branhamella caviae, and Branhamella cuniculi. Examination of B. catarrhalis strain ATCC25240 by electron microscopy reveals two different kinds of pili. One kind appears similar to other type 4 pili, whereas a second class is short pili extending outward from all portions of the bacteria. CONCLUSION: Phenotypic, electron-microscopic, and hybridization data are all consistent with type 4 pili being present on some B. catarrhalis strains.

Fimbriae, Bacterial↗