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Biomedical subjects

B Green

Publications and source records attributed to B Green.

At least 19 recordsLinked to original sources
PubMed2005

A pharmacokinetic-pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100.

BACKGROUND: AMD3100 is a small-molecule CXCR4 antagonist that has been shown to induce the mobilization of CD34 + hematopoietic progenitor cells from bone marrow to peripheral blood. AMD3100 has also been shown to augment the mobilization of CD34 + cells in cancer patients when administered in combination with granulocyte colony-stimulating factor (G-CSF) (filgrastim). The purpose of this study was to characterize the exposure-response relationship of AMD3100 in mobilizing CD34 + cells when administered as a single agent in healthy volunteers. METHODS: AMD3100 concentrations and CD34 + cell counts obtained from 29 healthy subjects in a single-dose, intensively sampled pharmacokinetic/pharmacodynamic (PK-PD) study were analyzed by use of nonlinear mixed effects regression with the software NONMEM. FOCE (first order conditional estimation) with interaction was the estimation method, and simultaneous PK-PD fitting was adopted. RESULTS: The pharmacokinetics of AMD3100 was described by a 2-compartment model with first-order absorption. The population estimates (+/-SE) for clearance and central volume of distribution were 5.17 +/- 0.49 L/h and 16.9 +/- 3.79 L, respectively. CD34 + cell mobilization was best described by an indirect effect model that stimulates the entry process of CD34 + from bone marrow to peripheral blood in the form of a sigmoid maximum effect model. The population estimates (+/-SE) of maximum effect, concentration causing 50% of maximum response, and equilibration time were 12.6 +/- 4.89, 53.6 +/- 11.9 mug/L, and 5.37 +/- 1.31 hours, respectively. CONCLUSIONS: This study characterizes the exposure-response relationship of AMD3100 in mobilizing CD34 + cells after subcutaneous administration. This PK-PD model will be useful in assessing relevant covariates and for optimizing the use of AMD3100 in various patient populations.

Adult↗
PubMed2005

Dosing strategy for enoxaparin in patients with renal impairment presenting with acute coronary syndromes.

BACKGROUND: Phase III clinical studies have confirmed that enoxaparin is superior to standard heparin in reducing the rate of recurrent ischaemic events in patients with non-ST elevation acute coronary syndromes. Patients with moderate to severe renal impairment were, however, excluded from these studies. Due to the hydrophilic disposition of enoxaparin, accumulation is likely in patients with renal dysfunction, thereby increasing the risk of haemorrhagic complications if standard weight adjusted treatment doses are used. Arbitrary dose reduction has been reported to increase the risk of ischaemic events, presumably due to inadequate enoxaparin concentrations. AIM: The aims of this study were to investigate the influence of glomerular filtration rate (GFR) on the pharmacokinetics of subcutaneously administered enoxaparin, and to develop a practical dosing algorithm in renal impairment that can easily be used at the bedside. METHODS: Thirty-eight patients, median age 78 years (range 44-87), mean GFR 32 ml min(-1) (range 16-117) and mean weight 69 kg (range 32-95), presenting with acute coronary syndrome were recruited into the study. Approximately 10 anti-Xa concentrations were taken per patient over their period of therapy. A population pharmacokinetic model was developed using non linear mixed effects modelling techniques, utilizing the software NONMEM. Stochastic simulations were performed to identify the most suitable dosing regimen. RESULTS: Three hundred and thirteen anti-Xa concentrations were collected. A two compartment, first order input model was identified as the best baseline model. Covariates found to improve model fitting were GFR as a linear function on clearance (CL) and weight as a linear function on the central volume compartment (Vc). The fraction of drug excreted unchanged (Fu) was estimated at 71%. CL and Vc from the final covariate model were estimated as; CL (l h(-1)) = 0.681 per 4.8 l hr(-1) (GFR) + 0.229 Vc (l) = 5.22 per 80 kg (total body weight) CONCLUSIONS: Clearance of enoxaparin was predictably related to GFR estimated using the Cockroft and Gault equation, with ideal body weight used as the size descriptor. According to our model no dosage adjustment from the standard 1.0 mg kg(-1) 12 hourly is required for the first 48 h of treatment. Maintenance doses thereafter can be calculated using standard proportional adjustments based on Fu equal to 0.71.

Administration, Cutaneous↗
PubMed2005

Factors predictive of intravenous fluid administration errors in Australian surgical care wards.

BACKGROUND: Intravenous (IV) fluid administration is an integral component of clinical care. Errors in administration can cause detrimental patient outcomes and increase healthcare costs, although little is known about medication administration errors associated with continuous IV infusions. OBJECTIVES: (1) To ascertain the prevalence of medication administration errors for continuous IV infusions and identify the variables that caused them. (2) To quantify the probability of errors by fitting a logistic regression model to the data. METHODS: A prospective study was conducted on three surgical wards at a teaching hospital in Australia. All study participants received continuous infusions of IV fluids. Parenteral nutrition and non-electrolyte containing intermittent drug infusions (such as antibiotics) were excluded. Medication administration errors and contributing variables were documented using a direct observational approach. RESULTS: Six hundred and eighty seven observations were made, with 124 (18.0%) having at least one medication administration error. The most common error observed was wrong administration rate. The median deviation from the prescribed rate was -47 ml/h (interquartile range -75 to +33.8 ml/h). Errors were more likely to occur if an IV infusion control device was not used and as the duration of the infusion increased. CONCLUSIONS: Administration errors involving continuous IV infusions occur frequently. They could be reduced by more common use of IV infusion control devices and regular checking of administration rates.

Fluid Therapy↗
PubMed2004

Do risk factors for lactic acidosis influence dosing of metformin?

BACKGROUND: Metformin is commonly prescribed to treat type 2 diabetes mellitus, however it is associated with the potentially lethal condition of lactic acidosis. Prescribing guidelines have been developed to minimize the risk of lactic acidosis development, although some suggest they are inappropriate and have created confusion amongst prescribers. The aim of this study was to investigate whether metformin dose was influenced by the presence of risk factors for lactic acidosis. METHODS: The study was prospective, and retrieved information from patients admitted to hospital who were prescribed metformin at their time of admission. RESULTS: Eighty-three patients were included in the study, 60 of whom had a least one risk factor for lactic acidosis. Of those 60 patients, 78.3% had a dose adjustment, with renal impairment, hepatic impairment, surgery and use of radiological contrast media--the risk factors most likely to result in a dose adjustment. When dose adjustments did occur, metformin was withheld on 88.7% of occasions. CONCLUSION: Metformin dose was influenced by the presence of risk factors for lactic acidosis, although it was dependent upon the number and particular risk factor/s present.

Acidosis, Lactic↗
PubMed2002

Carcinogen-DNA adducts in human breast epithelial cells.

Diet and environmental exposures are often regarded as significant etiologic factors in human breast cancer. Chemicals that may be involved in these exposures include heterocyclic amines, aromatic amines, and polycyclic aromatic hydrocarbons, which also serve as strong mammary carcinogens in different animal models. In this study, we chose to quantify the major DNA adducts derived from one member of each of these classes of carcinogens, that is, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 4-aminobiphenyl (ABP), and benzo[a]pyrene (B[a]P), respectively, in DNA isolated from exfoliated ductal epithelial cells in human breast milk. Milk was collected from healthy, nonsmoking mothers. The isolated DNA was digested to 3' nucleotides and subjected to (32)P-postlabeling. Adduct enrichment was achieved using Oasis Sep-Paks and the analyses were conducted by HPLC using radiometric detection. Critical to the analyses were the syntheses of bis(phosphate) standards for the C8-dG adducts of PhIP and ABP, and the N(2)-dG adduct of B[a]P, which were added to each reaction as UV markers. Of the 64 samples analyzed, adducts were found in 31 samples. Thirty samples contained detectable levels of PhIP adducts, with a mean value of 4.7 adducts/10(7) nucleotides; 18 were positive for ABP adducts with a mean value of 4.7 adducts/10(7) nucleotides; and 13 were found to contain B[a]P adducts with a mean level of 1.9 adducts/10(7) nucleotides. These data indicate that women are exposed to several classes of dietary and environmental carcinogens and that these carcinogens react with DNA in breast ductal epithelial cells, the cells from which most breast cancers arise.

Adult↗
PubMed2002

Myocardial infarction and type II diabetes--preferential treatment for high risk patients?

OBJECTIVES: To compare variability of blood glucose concentration in patients with type II diabetes with (cases) and without (controls) myocardial infarction. A secondary objective was identification of predictive factors for higher blood glucose on discharge from hospital. DESIGN: A retrospective matched case-control study. PARTICIPANTS: Medical notes of 101 type II diabetic patients admitted with a myocardial infarction (MI) and 101 type II diabetic patients (controls) matched on gender and age with no MI were reviewed. Blood glucose concentrations over two consecutive 48-h periods were collected. Demographic data and therapy on admission/discharge were also collected. RESULTS: Patient characteristics were comparable on recruitment excluding family history of cardiovascular disease (P=0.003), dyslipidaemia (P=0.004) and previous history of MI (P=0.007). Variability of blood glucose in cases was greater over the first 48 h compared with the second 48 h (P=0.03), and greater when compared with controls over the first 48 h (P=0.01). Cases with blood glucose on discharge >8.2 mmol / L (n=45) were less likely to have a history of previous MI (P=0.04), ischaemic heart disease (P=0.03) or hypertension (P=0.02). CONCLUSIONS: Type II diabetics with an MI have higher and more variable blood glucose concentrations during the first 48 h of admission. Only cardiovascular 'high risk' patients had target blood glucose set on discharge. The desirability of all MI patients with diabetes, having standardized-glucose infusions to reduce variability of blood glucose, should be evaluated in a randomized controlled trial.

Aged↗
PubMed2002

Osteoporosis prophylaxis during corticosteroid treatment: failure to prescribe.

AIMS: To investigate prescribing patterns to prevent steroid induced osteoporosis. To compare prophylactic prescribing with National Osteoporosis Society (NOS) guidelines. METHOD: All patients (n=92) taking oral corticosteroids admitted to general medical wards at a district general hospital were prospectively investigated over a nine month period. RESULTS: Variations from recommended management were revealed. Altogether 64.7% of all inpatients who qualified for prophylaxis for steroid induced osteoporosis were not provided with any suitable agent. It was also found that 21.6% of those who qualified for treatment received a bisphosphonate, the only treatment currently licensed for preventing steroid induced osteoporosis. Of those prescribed prophylactic treatment, a bisphosphonate was selected for 39.3%, hormone replacement therapy was given to 25.0%, and 35.7% received treatment that is not recommended in NOS guidelines. CONCLUSION: This study revealed substantial variations from NOS guidelines. It is suggested that osteoporosis prophylaxis during steroid treatment is promoted by local hospital guidelines, hospital and community pharmacists, audit, and general practitioners.

Adult↗
PubMed2001

Binding of correolide to the K(v)1.3 potassium channel: characterization of the binding domain by site-directed mutagenesis.

Correolide is a novel immunosuppressant that inhibits the voltage-gated potassium channel K(v)1.3 [Felix et al. (1999) Biochemistry 38, 4922-4930]. [(3)H]Dihydrocorreolide (diTC) binds with high affinity to membranes expressing homotetrameric K(v)1.3 channels, and high affinity diTC binding can be conferred to the diTC-insensitive channel, K(v)3.2, after substitution of three nonconserved residues in S(5) and S(6) with the corresponding amino acids present in K(v)1.3 [Hanner et al. (1999) J. Biol. Chem. 274, 25237-25244]. Site-directed mutagenesis along S(5) and S(6) of K(v)1.3 was employed to identify those residues that contribute to high affinity binding of diTC. Binding of monoiodotyrosine-HgTX(1)A19Y/Y37F ([(125)I]HgTX(1)A19Y/Y37F) in the external vestibule of the channel was used to characterize each mutant for both tetrameric channel formation and levels of channel expression. Substitutions at Leu(346) and Leu(353) in S(5), and Ala(413), Val(417), Ala(421), Pro(423), and Val(424) in S(6), cause the most dramatic effect on diTC binding to K(v)1.3. Some of the critical residues in S(6) appear to be present in a region of the protein that alters its conformation during channel gating. Molecular modeling of the S(5)-S(6) region of K(v)1.3 using the X-ray coordinates of the KcsA channel, and other experimental constraints, yield a template that can be used to dock diTC in the channel. DiTC appears to bind in the water-filled cavity below the selectivity filter to a hydrophobic pocket contributed by the side chains of specific residues. High affinity binding is predicted to be determined by the complementary shape between the bowl-shape of the cavity and the shape of the ligand. The conformational change that occurs in this region of the protein during channel gating may explain the state-dependent interaction of diTC with K(v)1.3.

Alanine↗
PubMed2001

Disordered eating behaviours in women with Type 2 diabetes mellitus.

The aim of the article is to investigate the relationship between disordered eating, particularly binge eating, and Type 2 diabetes in women. Subjects included 215 women with Type 2 diabetes (mean age: 58.9 years, mean body mass index (BMI)=33.5 kg/m(2)). Measurements included a structured clinical interview for disordered eating (Eating Disorder Examination, EDE), self-report measures of psychological functioning, glycosylated haemoglobin A1c, BMI. A total of 20.9% of women was binge eating regularly. Binge eating was associated with poorer well being, earlier age of diagnosis, poorer self-efficacy for diet and exercise self-management, and higher BMI. Binge eating frequency predicted blood glucose control after controlling for BMI and exercise level. A history of binge eating independently predicted age of diagnosis of diabetes. Binge eating is relatively common in women with Type 2 diabetes. The relationship between binge eating severity and diabetic control is not explained by overweight. Binge eating may be an independent risk factor for Type 2 diabetes.

Journal Article↗
PubMed2001

Elementary school-aged children's reports of their health: a cognitive interviewing study.

There are no standard methods for assessing the quality of young children's perceptions of their health and well-being and their ability to comprehend the tasks involved in reporting their health. This research involved three cross-sectional studies using cognitive interviews of 5-11-year-old children (N = 114) to determine their ability to respond to various presentations of pictorially illustrated questions about their health. The samples had a predominance of children in the 5-7-year-old range and families of lower and middle socio-economic status. The research questions in Study 1 involved children's ability to convert their health experiences into scaled responses and relate them to illustrated items (n = 35); Study 2 focused on the type of response format most effectively used by children (n = 19); and Study 3 involved testing children's understanding of health-related terms and use of a specific recall period (n = 60). The results of Study 1 showed that children identified with the cartoon drawing of a child depicted in the illustrated items, typically responding that the child was at or near their own age and of the same gender, with no differences related to race. Study 2 results indicated that children responded effectively to circles of graduated sizes to indicate their response and preferred them to same-size circles or a visual analogue scale. Tests of three-, four-, and five-point response formats demonstrated that children could use them all without confusion. In Study 3, expected age-related differences in understanding were obtained. In fact, the 5-year-old children were unable to understand a sufficient number of items to adequately describe their health. Virtually all children 8 years of age and older were able to fully understand the key terms and presentation of items, used the full five-point range of response options, and accurately used a 4-week recall period. Six- and seven-year-olds were more likely than older children to use only the extreme and middle responses on a five-point scale. No pattern of gender differences in understanding or in use of response options was found. We conclude that children as young as eight are able to report on all aspects of their health experiences and can use a five-point response format. Children aged 6-7 had difficulty with some health-related terms and tended to use extreme responses, but they understood the basic task requirements and were able to report on their health experiences. These results provide the guidance needed to develop and test a pediatric health status questionnaire for children 6-11 years old.

Analysis of Variance↗
PubMed2001

Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression.

The patterns of expression of glutathione S-transferases A1 and A2 in human liver (hGSTA1 and hGSTA2, respectively) are highly variable, notably in the ratio of hGSTA1/hGSTA2. We investigated if this variation had a genetic basis by sequencing the proximal promoters (-721 to -1 nucleotides) of hGSTA1 and hGSTA2, using 55 samples of human liver that exemplified the variability of hGSTA1 and hGSTA2 expression. Variants were found in the hGSTA1 gene: -631T or G, -567T, -69C, -52G, designated as hGSTA1*A; and -631G, -567G, -69T, -52A, designated as hGSTA1*B. Genotyping for the substitution -69C > T by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), showed that the polymorphism was widespread in Caucasians, African-Americans and Hispanics, and that it appeared to conform to allelic variation. Constructs consisting of the proximal promoters of hGSTA1*A, hGSTA1*B or hGSTA2, with luciferase as a reporter gene, showed differential expression when transfected into HepG2 cells: hGSTA1*A approximately hGSTA2 > hGSTA1*B. Similarly, mean levels of hGSTA1 protein expression in liver cytosols decreased significantly according to genotype: hGSTA1*A > hGSTA1-heterozygous > hGSTA1*B. Conversely, mean hGSTA2 expression increased according to the same order of hGSTA1 genotype. Consequently, the ratio of GSTA1/GSTA2 was highly hGSTA1 allele-specific. Because the polymorphism in hGSTA1 correlates with hGSTA1 and hGSTA2 expression in liver, and hGSTA1-1 and hGSTA2-2 exhibit differential catalysis of the detoxification of carcinogen metabolites and chemotherapeutics, the polymorphism is expected to be of significance for individual risk of cancer or individual response to chemotherapeutic agents.

Base Sequence↗
PubMed2001

Recent advances in the design and performance of research assistants.

Every laboratory needs personnel who work 24 hours a day 7 days a week, are efficient, obedient, capable of showing initiative, insightful and affable. Our experience of laboratory workers tells us that there is an immense way to go to achieve these goals. Having tired of the normal, Darwinian approach, a project has been initiated to achieve these ends through genetic technologies.

Humans↗
PubMed2001

Focus on clozapine.

Clozapine is a dibenzodiazepine derivative and a truly atypical anti-psychotic. Its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. Although it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia, its general use is limited because of the risk of agranulocytosis.

Agranulocytosis↗
PubMed2001

Systemic inflammatory response syndrome, organ failure, and outcome in critically ill obstetric patients treated in an ICU.

STUDY OBJECTIVES: To determine the incidence of systemic inflammatory response syndrome (SIRS) and organ failure and to describe the outcomes in critically ill obstetric patients who have been treated in medical ICUs. DESIGN: Retrospective review. SETTING: A multidisciplinary ICU at a tertiary-care institution. METHODS: We collected data on 74 obstetric patients who were admitted consecutively to the ICU from January 1991 through December 1998. Acute physiology and chronic health evaluation (APACHE) II scores were calculated. A p value < 0.05 was considered to be significant. MEASUREMENTS AND RESULTS: Fifty-eight percent of patients were admitted to the ICU postpartum. Their mean (+/- SD) age was 25.9 +/- 7.0 years, and 64% were African American and 34% were white. Fifty percent had preexisting medical conditions. Their mean APACHE II score was 14.0 +/- 5.9, and their predicted mortality rate was 17.6%. The most common reason for admission was respiratory insufficiency. Preeclampsia was present in 38% of patients, and hemolytic anemia, elevated liver enzymes, and low platelet count syndrome were present in 7% of patients. SIRS developed in 59% of patients. Patients with SIRS had longer ICU stays (p = 0.0008). Organ failure developed in 65% of patients, and ARDS developed in 15% of patients. Invasive mechanical ventilation was required in 45% of patients, and pulmonary artery catheterization was required in 35% of patients. The in-hospital mortality rate was 2.7%. There were five spontaneous abortions and eight perinatal deaths. CONCLUSIONS: The most common reason for admission to the ICU of critically ill obstetric patients was respiratory failure. Despite the severity of illness and the development of SIRS and organ failure in most patients, the mortality rate was low.

APACHE↗