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W Gillespie

Publications and source records attributed to W Gillespie.

At least 19 recordsLinked to original sources
PubMed2000

Clinical pharmacology studies in patients with renal impairment: past experience and regulatory perspectives.

The objective of this report is to provide a regulatory perspective on the quality of pharmacokinetic studies in renal impairment (RI) studies submitted in support of new drug applications (NDAs) or supplements to NDAs (sNDAs) submitted to the Food and Drug Administration (FDA). Fifty-one NDA and 20 sNDA submissions reviewed between 1996 and 1997 by the Office of Clinical Pharmacology and Biopharmaceutics were evaluated for the following: (1) whether an RI study was conducted; (2) contribution of the renal clearance to the overall clearance in subjects without renal impairment; (3) degree of plasma protein binding (%PB) in subjects without renal impairment; (4) dose proportionality of single and multiple doses; (5) study design, including dosing regimen; (6) definition of renal impairment; (7) stratification of renal functions; (8) number of subjects/group; (9) data analysis and interpretation; and (10) impact on labeling. Results of the analysis indicated that 67% of the NDAs and 30% of supplemental NDAs contained RI-studies (34/51 for NDAs and 6/20 for sNDAs). No obvious differences in the pharmacokinetic characteristics (e.g., percentage excreted unchanged in urine and %PB) were observed between drugs for which RI studies were conducted versus those not conducted. Most studies conducted were designed as single dose (70%). Seventy-five percent of the studies used doses within the therapeutic dosage range of the drug. The measured 24-hour creatinine clearance was most often used to assess the renal function. Stratification of renal function ranged from one to five groups, with 6 to 8 subjects enrolled per group. In most studies conducted (38/40), data were analyzed by point estimate using ANOVA. Results of RI studies were adequately reflected in the labeling. The survey reveals that RI study design can be improved for regulatory review purposes. In part based on this analysis, the FDA has prepared a guidance that provides recommendations on the design, analysis, and impact on dosing and labeling for RI studies to include recommendations on when RI studies do not need to be performed. The guidance proposes an equivalence approach with confidence intervals, as opposed to a point estimate approach, to assess the impact of RI on systemic exposure measures.

Attitude of Health Personnel↗
PubMed1999

Barriers to participation in randomised controlled trials: a systematic review.

METHOD: A systematic review of three bibliographic databases from 1986 to 1996 identified 78 papers reporting barriers to recruitment of clinicians and patients to randomised controlled trials. RESULTS: Clinician barriers included: time constraints, lack of staff and training, worry about the impact on the doctor-patient relationship, concern for patients, loss of professional autonomy, difficulty with the consent procedure, lack of rewards and recognition, and an insufficiently interesting question. Patient barriers included: additional demands of the trial, patient preferences, worry caused by uncertainty, and concerns about information and consent. CONCLUSIONS: To overcome barriers to clinician recruitment, the trial should address an important research question and the protocol and data collection should be as straightforward as possible. The demands on clinicians and patients should be kept to a minimum. Dedicated research staff may be required to support clinical staff and patients. The recruitment aspects of a randomised controlled trial should be carefully planned and piloted. Further work is needed to quantify the extent of problems associated with clinician and patient participation, and proper evaluation is required of strategies to overcome barriers.

Data Collection↗
PubMed1999

Fluoxetine and sertraline dosages in major depression.

In a retrospective study, we sought to determine medication dosages usually prescribed to obtain euthymia in 59 outpatients with a diagnosis of major depression treated with fluoxetine or sertraline. Charts of veterans admitted to the outpatient mental health clinic at the West Los Angeles Veterans Hospital with a diagnosis of major depression and treated with either fluoxetine or sertraline were reviewed. Progress notes were analyzed for a 6-month time period after the initiation of the medication treatment, and improvement was rated by a physician blind to the drug used for treatment. No significant differences were found in overall response rates between the fluoxetine (81% responders) and sertraline (76% responders) groups. Eighty-one percent of the fluoxetine responders compared to 32% of sertraline responders were at the manufacturer's recommended starting dose (MRSD) at the time of clinical response. One-third of patients receiving sertraline were started on or rapidly titrated to more than 50 mg/day. When only those patients receiving an adequate trial of sertraline at 50 mg were considered, 47% required a dose increase to achieve a remission. These data suggest that 50 mg of sertraline may be inadequate for some patients to achieve a resolution of symptoms of major depression and that many clinicians currently prescribe in a manner suggesting that they believe the MRSD is a suboptimal dosage.

Depressive Disorder↗
PubMed1993

Regulation of alpha 2,3-sialyltransferase expression correlates with conversion of peanut agglutinin (PNA)+ to PNA- phenotype in developing thymocytes.

Staining of thymus tissue with the plant lectin peanut agglutinin (PNA) is a classic technique for defining the cortical (PNA+) and medullary (PNA-) regions of this tissue. These two regions are primarily composed of immature and mature thymocytes, respectively. Conversion of the PNA+ to the PNA- phenotype has been attributed to masking of the cell surface carbohydrate receptors of PNA by sialic acid during the intrathymic maturation of these cells. We present evidence that the regulated expression of a single glycosyltransferase, a Gal beta 1,3GalNAc alpha 2,3-sialyltransferase, can account for this glycosylation change. This enzyme sialylates the preferred ligand of PNA, Gal beta 1,3GalNAc, forming the sequence NeuAc alpha 2,3Gal beta 1,3GalNAc, thus masking PNA binding sites. Expression of the enzyme is inversely proportional to expression of the PNA receptor, as evidenced by analysis of T-lymphoblastoid cell lines and by in situ hybridization experiments in human thymic tissue.

Arachis↗
PubMed1992

Cloning and expression of the Gal beta 1, 3GalNAc alpha 2,3-sialyltransferase.

Sequence information obtained by NH2-terminal sequence analysis of two molecular weight forms (45 and 48 kDa) of the porcine Gal beta 1,3GalNAc alpha 2,3-sialyltransferase was used to clone a full-length cDNA of the enzyme. The cDNA sequence revealed an open reading frame coding for 343 amino acids and a putative domain structure consisting of a short NH2-terminal cytoplasmic domain, a signal-anchor sequence, and a large COOH-terminal catalytic domain. This domain structure was confirmed by construction of a recombinant sialyltransferase in which the cytoplasmic domain and signal-anchor sequence of the enzyme was replaced with the cDNA of insulin signal sequence. Expression of the resulting construct in COS-1 cells produced an active sialyltransferase which was secreted into the medium in soluble form. Comparison of the cDNA sequence of the sialyltransferase with GenBank produced no significant homologies except with the previously described Gal beta 1,4GlcNAc alpha 2,6-sialyltransferase. Although the cDNA sequences of these two enzymes were largely nonhomologous, there was a 45-amino acid sequence which exhibited 65% identity. This observation suggests that the two sialyltransferases were derived, in part, from a common gene.

Amino Acid Sequence↗
PubMed1989

A transcriptional repressor of c-myc.

In murine plasmacytomas there is deregulated transcription of a translocated c-myc allele and undetectable transcription of the normal, unrearranged c-myc allele. Deregulated c-myc transcription probably contributes to the transformed phenotype of the tumour cells, whereas repression of the normal allele probably reflects the normal turn-off of c-myc in non-dividing plasma cells. We previously identified a plasmacytoma-specific protein which binds to the c-myc promoter region 290 base pairs 5' of the P1 transcription start site. This plasmacytoma repressor factor (myc-PRF; formerly myc-PCF) is not found in cell lines representing earlier B-cell stages during which c-myc is transcribed, so it could be a negative regulator of c-myc transcription in terminally differentiated B cells. Here we report that site-directed deletion of the binding site for this protein leads to a 30-fold increase in transcription of a stably transfected c-myc fusion construct in plasmacytoma cells but has no effect in L cells or 18-81 pre-B cells, which lack the protein. Myc-PRF interacts with another widely distributed protein, myc-CF1 (common factor 1), which binds nearby, and this association may be important in myc-PRF repression.

Animals↗