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H Matthews

Publications and source records attributed to H Matthews.

36 records · Page 2Linked to original sources
PubMed1993

Monitoring of clinical trials and interim analyses from a drug sponsor's point of view.

This paper illustrates aspects of data monitoring of clinical trials in the pharmaceutical industry. Formal interim analyses are performed at least in part to address the question of whether the trial should proceed or whether there should be an early termination of the trial. For formal interim analyses, frequently independent data and safety monitoring committees are utilized for monitoring clinical trials, and adjustments to nominal significance levels for test statistics are required. Various statistical methods developed during the last fifteen years are utilized. Administrative interim analyses are those analyses that are performed without any intention to stop the trial as a consequence of those analyses. For administrative interim analyses, adjustments to significance levels may not be required, but results must still be carefully interpreted. Regardless of the interim analyses performed, it is critical that the plans for interim analyses be identified in the study protocol, and the dissemination of interim results be carefully restricted. The following clinical trials sponsored by Merck Sharp and Dohme Research Laboratories (MSDRL) will illustrate these points: CONSENSUS; CONSENSUS II; 4S; Haemophilus influenza type b efficacy trial; famotidine in upper gastrointestinal haemorrhage, and a phase II analgesic study. It is anticipated that data monitoring and interim analysis activities will increase for future clinical trials due to the availability of appropriate statistical methods and improved data management systems.

Clinical Trials as Topic↗
PubMed1993

Anti-PRP antibody levels after a primary series of PRP-OMPC and persistence of antibody titres following primary and booster doses.

The Haemophilus influenzae capsular polysaccharide-outer membrane protein conjugate, PRP-OMPC (PedvaxHIB) elicits very good antibody responses in infants > or = 2 months of age after the first dose. Increasing age at time of first vaccination correlates with higher antibody responses. Anti-PRP responses are consistently high with the first injection among all population groups studied. Booster doses stimulate anamnestic antibody responses after one year of age. Among US children (excluding Navajo and Apache children) given a primary injection at 14-18 months of age, the geometric mean titre (GMT) after 2 to 3 years was > 1 micrograms/ml. US children (excluding Navajo and Apache children) given a primary series at 2 and 4 months of age and a booster at 18 months of age also had an anti-PRP GMT > 1 micrograms/ml 2.5 years later. Navajo and Apache children given a primary series at 2 and 4 months of age and a booster at 12-15 months had antibody levels of 1.50 micrograms/ml one year later. Antibody persistence data suggest there will be long-term protection against Haemophilus influenzae b disease following immunization with PRP-OMPC.

Antibodies, Bacterial↗
PubMed1993

Deaths and necropsies in a thoracic unit.

BACKGROUND: There is concern about the decrease in the number of requests for necropsies, so a study was undertaken to assess current clinical practice. METHOD: A prospective study was made of all deaths occurring under the care of five chest physicians and three thoracic surgeons at East Birmingham Hospital from 1 April to 30 June 1989. RESULTS: A necropsy was sought in 34 of 58 deaths (59%) and was performed in 22 instances (38%). Major unexpected findings which would have affected clinical management were noted in three patients (14%). The mean delay in reporting results of histological examinations was 146 days (range 41-260 days). As the result of an increase in pathology technical staff levels and alteration in the practice of processing histological data, there was a substantial improvement during the corresponding period in 1990 (mean reduction 58 days, 95% confidence limits 39-77 days). Apart from patients with histologically proved carcinoma, there was no consistent pattern for requests for necropsies. CONCLUSIONS: Necropsies continue to reveal diagnoses which were not suspected while the patient was alive. Although the number of requests made by clinical staff for necropsies is reasonable, the reasons for the requests are not consistent. Guidelines are suggested to improve the number of successful requests and to maximise the information obtained from them.

Autopsy↗
PubMed1991

Oka/Merck varicella vaccine in healthy children: final report of a 2-year efficacy study and 7-year follow-up studies.

A large double-blind, randomized, placebo-controlled trial of live attenuated Oka/Merck varicella vaccine was conducted among healthy children, 1-14 years of age. During the first varicella season, the efficacy of the vaccine among susceptible children was 100%1. During the second varicella season, 22 children were diagnosed with varicella; 21 cases in placebo recipients and one in a vaccine recipient. The overall efficacy of the vaccine through two varicella seasons was 98%. After the code for the study was broken, the original group of vaccine recipients continued to be followed for development of varicella. The estimated proportion of vaccine recipients who remained varicella-free at the end of 7 years was 95%. The 23 cases of varicella that occurred in vaccine recipients over the 7-year period were considerably milder than natural varicella. The average number of lesions was 53, 50% of the children had non-vesicular rashes, and 14% of the children had a temperature greater than or equal to 38.9 degrees C (102 degrees F), oral. The persistence of antibody in a subset of vaccine recipients followed for 6 years was 100%.

Adolescent↗
PubMed1991

Interstitial deletion of the long arm of chromosome 18, del(18)(q12.2q21.1): a report of three cases of an autosomal deletion with a mild phenotype.

We describe three unrelated patients with apparently identical interstitial deletions of the segment (18) (q12.2q21.1). They were a short and markedly mentally retarded 5 year old girl, a macrocephalic and obese 2 1/2 year old boy with moderate mental retardation, and a macrocephalic, severely mentally retarded 5 year old boy. Findings common to all five liveborn patients so far identified as carrying this deletion include a pattern of minor dysmorphic features (prominent forehead, ptosis of the upper eyelids, full periorbital tissue, epicanthic folds, strabismus), muscular hypotonia, seizures, behavioural disorders, and lack of major malformations.

Abnormalities, Multiple↗
PubMed1991

Varicella vaccine (VARIVAX) in healthy children and adolescents: results from clinical trials, 1987 to 1989.

A total of 3303 healthy children and adolescents, aged 12 months to 17 years, were vaccinated with one of five production lots of a live attenuated varicella vaccine (VARIVAX) containing 1000 to 1625 plaque-forming units per dose. The vaccine was generally well tolerated. Ninety-six percent (2381/2475) of vaccinees responded to vaccination by producing antibody as measured by a glycoprotein-based enzyme-linked immunosorbent assay; 99% (569/576) of those tested maintained antibody at 1 year following vaccination. The incidence of varicella following household exposure in vaccinees was approximately 12%; household contact historically results in 87% infection. Nearly all of the vaccinees who had varicella after vaccination had a clinically modified disease.

Adolescent↗
PubMed1990

Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) (PedvaxHIB): clinical evaluation.

Although systemic infections caused by Haemophilus influenzae type b occur worldwide, detailed epidemiologic data are available in but a few countries. The public health impact of morbidity, mortality, and serious sequelae from disease caused by H influenzae type b has stimulated the search for control strategies. In the United States now, active immunoprophylaxis is largely favored over treatment of prophylaxis with antibiotics. This preference stems from three major observations: that high mortality and morbidity persist despite the availability of potent antimicrobial agents, that antibiotic-resistant strains of H influenzae type b have emerged, and that implementation of antimicrobial prophylaxis on a large scale has been unsatisfactory. Moreover, universal vaccination has been projected as offering a higher economic benefit than other control strategies. A matter of more proximate importance, however, is the search for H influenzae type b vaccines that will confer protection to all age groups, including infants younger than 18 months of age and subpopulations specifically at risk for invasive disease caused by H influenzae type b. Haemophilus b conjugate vaccine (meningococcal protein conjugate), PedvaxHIB (PRP-OMPC), is a conjugate H influenzae type b vaccine developed at Merck Sharp & Dohme Research Laboratories that now is undergoing extensive clinical evaluation to assess its prospects for disease control when first administered in early infancy. This is an interim report of results obtained in studies conducted in diverse locations throughout the United States.

Antibodies, Bacterial↗
PubMed1989

A selective inhibitor of N8-acetylspermidine deacetylation in mice and HeLa cells without effects on histone deacetylation.

The inhibitory effects of 7-[N-(3-aminopropyl)amino]heptan-2-one (APAH) on N8-acetylspermidine deacetylation were studied. In in vitro studies, APAH produced inhibition (apparent Ki of 0.18 microM) of N8-acetylspermidine deacetylation by the 100,000g supernatant fraction of rat liver. This apparent Ki was 60-fold less than the apparent Km (11 microM) for deacetylation of the substrate, N8-acetylspermidine, suggesting that APAH could be a potent, effective inhibitor in vivo. APAH was administered to mice by intraperitoneal injection at a dose of 200 mg/kg, and polyamine and acetylpolyamine levels in liver and spleen were measured. In tissues of control mice, N8-acetylspermidine was not detectable but increased to detectable levels 30-360 min after APAH treatment. These data are consistent with inhibition of the deacetylase by APAH. Increases in putrescine and N1-acetylspermidine levels occurred in liver after APAH treatment with increases in N1-acetylspermidine levels observed in spleen. In HeLa cells, a significant increase in N8-acetylspermidine was observed following 24 h exposure to 10 microM APAH while no change occurred in the acetylation level of HeLa cell histones. In contrast, 24 h exposure to 10 mM sodium butyrate produced no change in N8-acetylspermidine levels and an increase in the acetylation level of histones H4 and H2B. These results suggest that APAH has a relatively selective inhibitory effect on N8-acetylspermidine but not histone deacetylation. This is the first report of significant levels of N8-acetylspermidine in animal tissues and of the effects of in vivo inhibition of N8-acetylspermidine deacetylase.

Acetylation↗
PubMed1987

Biotyping, serotyping and phage typing of Streptococcus faecalis isolated from dental plaque in the human mouth.

Thirty Streptococcus faecalis isolates from mixed dental plaque samples were classified into four groups on the basis of biotype, tetracycline susceptibility, phage type and serotype combinations. The organisms were from patients on haemodialysis, from staff of the dialysis unit, and from controls. Three biotypes were distinguished by seven biochemical tests: production of acid from inositol, sucrose and xylose; rapid or delayed production of acid from sorbitol; gelatin liquefaction; and production of alkaline phosphatase and beta-galactosidase. With a set of eight typing antisera for S. faecalis, 15 strains were non-typable, 12 were serotype 1 and three were serotype 19. With a set of 17 bacteriophages specific for S. faecalis, all of the oral isolates were typable; 40% were lysotype I1 and the remainder lysotype V6b. On the basis of biotype-serotype-phage-type combinations, indications of possible spread of strains between haemodialysis patients and dialysis unit staff were obtained. Biotyping and serotyping of 13 German isolates of S. faecalis of phage type I1 from four clinical sources and tripartite typing of three control strains provided additional evidence for the potential of biotyping in distinguishing between strains of identical serotype and phage type. One oral isolate of S. faecium was of phage type XX. None of the oral isolates of S. faecalis, of which 14 exhibited delayed sorbitol fermentation, reacted with group-G streptococcal grouping reagents or antiserum. Slow sorbitol fermentation does not appear to be a definitive phenotypic marker for S. faecalis strains possessing antigens that react with both group-D and group-G grouping reagents.

Adolescent↗
PubMed1987

Analysis of the effect of a sunscreen agent on the suppression of natural killer cell activity induced in human subjects by radiation from solarium lamps.

Previous studies in rodents have shown that ultraviolet radiation (UVR) may have direct effects on the immune system in the skin and at higher doses may induce systemic suppression of immune responses. We have previously shown that UVR from sun or solarium beds may induce systemic effects in human subjects. The purpose of the present study was to examine whether these systemic effects in human subjects could be prevented by use of commercially available sunscreen agents. Groups of 12 normal subjects were exposed to radiation from solarium lamps after application of a sunscreen agent or the base used in its preparation. Twelve half-hourly exposures induced a depression of natural killer (NK) cell activity against a melanoma and the K562 target cell which was not prevented by use of the sunscreen agent. Changes in functional activity were accompanied by a reduction in NK cell numbers assessed by Leu-11 monoclonal antibodies against the labile Fc receptor. Application of the sunscreen agent also did not protect against effects of solarium exposure on recall antigen skin tests and immunoglobulin production in vitro in pokeweed mitogen-stimulated cultures of B and T cells. These results suggest that further evaluation of the wave-length spectrum of UVR and the effectiveness of sunscreen agents in prevention of UVR-induced effects on the immune system is needed.

B-Lymphocytes↗
PubMed1985

Antigenic determinants of human thyroglobulin differentiated using antigen fragments.

Human thyroglobulin (Tg) was digested with V8 protease and the fragments separated by high performance liquid chromatography (HPLC). The antigenic relationship of the fragments was investigated using mouse monoclonal antibodies to human Tg. The binding of Hashimoto's disease autoantibodies to the fragments was measured by radioimmunoassay. This demonstrated that a minority of the patients recognize an epitope on Tg which others do not. The epitopes identified by the autoantibodies were substantially destroyed in the smaller fragments tested, but these smaller fragments were more efficient stimulators of Tg-specific T-cell lines than the larger fragments which carry the antibody binding determinants. This suggests that the parts of the Tg molecule which stimulate autoimmune B cells differ from those which stimulate T cells.

Animals↗
PubMed1985

Simple procedure for removal of AMP from NADP preparation.

A simple and reliable procedure for removal of AMP from NADP preparation is described. In this procedure, a mixture of AMP and NADP solution is first incubated with 5'-nucleotidase to hydrolyze AMP to adenosine and inorganic phosphate (Pi). The reaction mixture is then applied to a Dowex 1 (formate) column. Adenosine and 5'-nucleotidase are removed by washing the column with 20 mM HCOOH. NADP is finally eluted with 3.5 M HCOOH followed by precipitation and washing with acetone. The yield of salt-free NADP is about 80%. Although Pi is coeluted with NADP in the acid form (H3PO4), it is removed during the precipitation and repeated washing with acetone. A slight modification of this procedure for simultaneous removal of AMP, ADP, and ATP from NADP preparation has also been discussed.

Adenosine Monophosphate↗
PubMedDate not supplied

Immunogenicity and safety of Haemophilus influenzae type b polysaccharide-Neisseria meningitidis conjugate vaccine in 7.5 micrograms liquid formulation: a comparison of three lots with the 15.0 micrograms lyophilized formulation. Study Group for 7.5 micrograms Liquid PedvaxHIB.

We conducted a multicenter, single-blind, randomized comparisons of the immunogenicity and safety of three manufacturing-scale lots of 7.5 micrograms liquid Haemophilus influenzae type b polysaccharide- Neisseria meningitidis conjugate vaccine (PRP-OMPC) and a single lot of 15.0 micrograms lyophilized PRP OMPC. A total of 908 infants were entered into the study. Each infant received two primary injections intramuscularly 2 months apart beginning at age 2-6 months and a booster injection at 12-15 months. Blood samples for serology were obtained before each injection and 1 month after the second and the booster dose. Immune responses were measured by radioimmunoassay. Approximately 80% of the infants achieved a titer > 1.0 micrograms ml-1 after the second primary dose of all four lots tested: the geometric mean titer (GMT) was ca 3 micrograms ml-1 for each vaccine group. After the booster dose, more than 90% of infants from each vaccine group had a titer > 1.0 microgram ml-1;GMTs ranged from 8 to 10 micrograms ml-1. No serious vaccine-associated adverse reactions were reported. Thus the 7.5 liquid PRP OMPC vaccine was at least as immunogenic and well tolerated as the 15.0 micrograms lyophilized vaccine.

Bacterial Outer Membrane Proteins↗
PubMedDate not supplied

Smoking cessation: a consensus statement with special reference to primary care.

Nicotine addiction is a serious medical condition that needs to be treated like any other chronic disease. Primary care must play a key role in smoking cessation and offering help should be a routine part of primary care practice. As the most frequent opportunity for intervention lies within primary care, GPs should ensure that they raise the issue of stopping smoking at least annually with their smoking patients. When the smoker is ready to stop, the initial personal involvement of the GP is likely to increase the chance of a successful quit attempt. Follow-up may be with another healthcare professional. The support of healthcare professionals for the smoker who is motivated to quit, combined with appropriate pharmacotherapy, can substantially increase the chances of a successful quit attempt. Secondary care staff should also make every effort to help people to stop smoking and should communicate effectively with primary care--opportunities during hospitalisation are frequently missed. Specialist smoking cessation clinics have an essential role in providing more intensive specialist treatment and the expertise to partner and support the primary care effort. Smoking cessation is one of the most cost-effective healthcare interventions that can be made.

Family Practice↗