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D H Lawson

Publications and source records attributed to D H Lawson.

At least 37 records · Page 2Linked to original sources
PubMed1991

Post-cimetidine surveillance for up to ten years: incidence of carcinoma of the stomach and oesophagus.

The long-term effects of cimetidine on the occurrence of gastric and oesophageal cancer were assessed in a prospective cohort study of 9928 patients who had been prescribed cimetidine. They were first identified between 1978 and 1980, and cancer registrations and deaths were identified among them over a period of up to 10 years. One hundred and eleven cancers were identified after the start of cimetidine treatment: 71 were adenocarcinomas of the stomach, 27 were carcinomas of the cardia and/or oesophagus (22 adenocarcinomas, five unknown histology) and the remaining 13 tumours were squamous cell cancers of the oesophagus. Only six patients presented with early gastric cancers. Over a period of eight years the ratio of observed to expected (O/E) gastric cancer deaths has fallen from 10.7 (p < 0.001) to 1.2 (NS). The O/E ratio of oesophageal cancer deaths also fell over the first six years of study, from 5.4 (p < 0.01) to 1.4 (NS) but it has risen slightly in years 7 and 8 to 3.7 (p < 0.05). These findings do not suggest that there is an increased risk of developing oesophageal or gastric cancer from cimetidine treatment, and are generally consistent with cimetidine being used inadvertently to treat the early symptoms of gastric and oesophageal cancer. The slight rise in oesophageal cancer deaths in years 7 and 8 was unexpected and will be the subject of further observation.

Adenocarcinoma↗
PubMed1990

Plasma inter-alpha-trypsin inhibitor-related urinary glycoprotein EDC1 inhibits the growth of a Burkitt's lymphoma cell line.

A homogeneous preparation of a urinary glycoprotein has been isolated from urine of patients with malignant melanoma and advanced adenocarcinomas of colon and lung. This molecule, Mr 30 kDa, is homologous to EDC1, a proteinase inhibitor antigenically related to plasma inter-alpha-trypsin inhibitor (IATI) originally isolated from the urine of a leukemic patient, E.D. The newly isolated EDC1 inhibits cellular proliferation of a Burkitt's lymphoma cell line, Raji, growing in serum-free medium supplemented with insulin, transferrin, selenium, and linoleic acid. This concentration-dependent inhibitory effect was monitored in terms of change in cell number and 3H-thymidine incorporation. The growth of cells treated with approximately 3.3 pmol EDC1/ml was 50% that of the control group by both assays. EDC1 was not cytotoxic to the cells because the EDC1-treated cells excluded trypan blue and resumed normal growth after removal of EDC1. In addition, EDC1 treatment of Raji cells prelabeled with 3H-labeled DNA did not release more radioactivity into the conditioned medium than the untreated labeled cells. EDC1 did not affect the growth of Hs2B2, a B-lymphoblast cell line, and Hs294T, a human malignant melanoma cell line. Equimolar and larger quantities of other proteinase inhibitors with inhibitory profiles similar to that of EDC1 (alpha-1 proteinase inhibitor, soybean trypsin inhibitor, lima bean trypsin inhibitor, and turkey ovomucoid) did not affect the growth of Raji cells. Raji cells have an absolute requirement of transferrin as a nutrient and require insulin to modulate the expression of transferrin receptors. The cells also synthesize interleukin-1 as an autocrine growth stimulator. EDC1 did not form a detectable complex with transferrin, insulin, or any autocrine factor synthesized by the cells.

Alpha-Globulins↗
PubMed1990

Risk factors for adverse drug reactions--epidemiological approaches.

Age by itself is not an important risk factor for ADRs. Age-related changes are the consequence of a number of individual factors, for example morbidity associated with polypharmacy, decline in renal or liver function in the elderly, hypoalbuminaemia, reduced body weight, etc. The relationship between gastrointestinal bleeding and non-steroidal anti-inflammatory drugs can be assessed globally in large cohort studies with access to computerized data, but complete accuracy requires access to the original patient records. The increase in the risk of GI bleeding in users of NSAIDs and aspirin was 50% above that in non-users. About a quarter of ADRs in hospitalized patients seem not to arise from purely pharmacological mechanisms. They are mainly due to allergic, anaphylactoid, or idiosyncratic reactions and to intolerance. In such non-pharmacological reactions, the time of exposure, reaction time, and even dosage may be important factors in identification of the causal drug. The use of benzodiazepines can be optimized by taking into account potency, time of action and the different syndromes encountered after withdrawal. Following long-term use problems of relapse and rebound are being increasingly recognized, in addition to organic withdrawal symptoms. In psychiatric patients extrapyramidal disorders due to neuroleptics are common. The rates of these ADRs differ markedly between various drugs, even after dosages and co-medications are taken into account. Epidemiological screening for potentially carcinogenic drugs can only be done in large cohorts of patients with pre-recorded full information sets as may be found in an HMO (Health Maintenance Organization). The findings of several such studies have been published in specialist cancer journals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Atracurium--a post-marketing surveillance study: methods and U.S. experience.

Two companion post-marketing studies have evaluated the frequency of adverse events amongst patients receiving atracurium. In this first report, we describe the study methods used in both centres and the findings of the study conducted at the Group Health Co-operative of Puget Sound, U.S.A. In this study, the frequency of adverse events in 1013 patients receiving atracurium was substantially the same as that in 851 patients receiving other neuromuscular blocking agents. In both groups there were no instances of cardiac arrest, anaphylaxis or death, no adverse effects associated with failure to antagonize neuromuscular block, and no instances of previously unreported types of adverse effects. We conclude that the safety profile of atracurium is similar to that of other neuromuscular blocking agents and that this type of observational study of anaesthetic agents may prove a useful tool for surveillance of new drugs used primarily in hospitals.

Anesthesia Recovery Period↗
PubMed1989

Atracurium--a post-marketing surveillance study: U.K. study and discussion.

Two companion post-marketing studies have evaluated the frequency of adverse events amongst patients receiving atracurium. In this second report, we describe the Scottish study and discuss findings in both centres. In this study we compare the frequency of adverse events in 477 patients receiving atracurium with those in 484 patients who received vecuronium. The frequency of reported serious adverse events was low during surgery and in the recovery room. Although the overall incidence of adverse experiences was slightly lower after atracurium, there were no significant difference between the groups in frequency of major adverse events. This type of study is believed to be of value in the future surveillance of new drugs for hospital use.

Anesthesia Recovery Period↗
PubMed1987

Serum alpha-1 proteinase inhibitor in advanced cancer: mass variants and functionally inert forms.

In 1984, we reported that while immunoreactive levels of serum alpha-1 proteinase inhibitor (API) increased significantly in nine patients with advanced solid tumors, the functional activity of the inhibitor, as measured by the serum trypsin inhibitory capacity, did not increase proportionately. This suggested that a portion of the circulating API was functionally inert. We have now assayed immunoreactive titers and trypsin inhibitory capacity of serum API of 49 patients with advanced carcinomas and 27 healthy controls. Immunoreactive levels of API (expressed as percentage of normal pooled serum which was taken as 100%) in cancer subjects were significantly elevated as compared to normals (mean +/- SE: 233 +/- 9.0% versus 102 +/- 2.0%, P less than 0.05). Although the trypsin inhibitory capacity of the cancer group (16.0 +/- 0.9 units/ml) was significantly elevated (P less than 0.05) as compared to normals (9.9 +/- 0.1 units/ml), this increase was less than that in the immunoreactive titer of API, suggesting the existence of functionally inert API in serum. The fraction of API which was functionally active in this group of cancer patients was 71.0 +/- 3.0% which was significantly less than the normal 98.0 +/- 2.0% (P less than 0.05). In 12 patients followed serially, both immunoreactive levels of API and the trypsin inhibitory capacity increased significantly at the time of clinical progression of disease. There was a significant correlation between increasing absolute granulocyte count and increasing trypsin inhibitory capacity (correlation coefficient 0.66; P less than 0.001). Neither disease progression nor increasing granulocyte count, however, was associated with increasing proportion of functionally inactive API. The inactive form of API had the same molecular weight as the native molecule as shown by gel permeation chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis/Western blot analysis of cancer sera. Therefore, the inactive form was not due to a complex between API and a tumor-derived protease or to proteolytic fragmentation of the native API. Elastase inhibitory capacity of cancer sera with subactive API was essentially identical with trypsin inhibitory capacity indicating that the active site methionine was not oxidized in the inert API. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis/Western blot analysis showed that both normal and cancer serum API existed as two mass variants, at Mr 58,000 and 56,000. Both variants formed complexes with elastase and were functionally active.

Blood Proteins↗
PubMed1987

Preparation of a monoclonal antibody to a melanoma growth-stimulatory activity released into serum-free culture medium by Hs0294 malignant melanoma cells.

Autostimulatory growth factors may contribute to the ability of malignant cells to escape normal growth controls. We have previously shown that Hs0294 human malignant melanoma cells release into culture medium an acid-soluble, heat-stable, trypsin-sensitive, autostimulatory monolayer mitogen which can be purified from acetic acid extracts of conditioned medium by gel filtration, reverse-phase high-performance liquid chromatography, and preparative electrophoresis. The majority of this melanoma growth-stimulatory activity (MGSA) resides in a 16-Kd moiety, though bioactivity is also associated with 24-26 and less than 14-Kd forms of MGSA (Richmond and Thomas: J Cell Physiol 129:375, 1986). In order to further characterize this growth factor, monoclonal antibodies were prepared against a partially purified preparation of the autostimulatory melanoma mitogen. Monoclonal antibody clones were selected based on supernate inhibition of 3H-thymidine incorporation in serum-free Hs0294 melanoma cultures. One of these, termed FB2AH7, slows, but does not completely block, the growth of Hs0294 cells in serum-free medium in a dose-dependent manner. This antibody does not slow the growth of normal rat kidney fibroblasts, which neither produce nor require this mitogen, in either serum-free medium or medium containing 0.8% calf serum. This monoclonal antibody also blocks the mitogenic effects of partially purified preparations of this melanoma growth stimulatory activity (MGSA) on both Hs0294 cells and normal rat kidney fibroblasts. The FB2AH7 antibody has been demonstrated to bind MGSA by Western blot and by immunoprecipitation procedures. Western blot analysis of reverse-phase high-performance liquid chromatography purified growth factor demonstrated that FB2AH7 antibody binds to the 16-Kd and approximately 13-14-Kd forms of MGSA. FB2AH7 antibody can be used in immunoprecipitation experiments to bind the approximately 13-16-Kd forms of MGSA. The specificity of the binding of FB2AH7 antibody for MGSA but not other growth factors has been demonstrated in a modified dot blot assay. These data thus support the hypothesis that MGSA is an autostimulatory melanoma mitogen distinct from other growth factors.

Animals↗
PubMed1987

Review: post-marketing surveillance of the safety of cimetidine--the problems of data interpretation.

Experience obtained during post-marketing surveillance of the safety of cimetidine emphasizes the difficulties in interpretation posed by the high background frequency of disease of all types in drug takers. The multiple sources of confounding factors, and their high prevalence, make it impossible to detect adverse events which mimic ordinary disease, particularly when a consistent relationship between adverse event and drug exposure is not observed. The inclusion of controls emphasizes the difficulties but does not ease interpretation.

Adult↗
PubMed1987

Post marketing surveillance of captopril (for hypertension): a preliminary report.

1 The methodology and interim results of a post marketing surveillance of captopril, the first orally active angiotensin converting enzyme inhibitor are presented. 2 Utilising viewdata technology, details of hypertensive patients were entered directly into a mainframe computer. This allowed day to day monitoring of events; a facility not available with paper-based methods. 3 The design of the study allowed analysis of results including some details of efficacy, concomitant therapy, any disease symptoms and reasons for withdrawal. These factors could be categorised according to sex and age. 4 This preliminary report is based on the first 13,295 patients entered from July 1983 with follow-up until January 1985. The results of the study confirm the safety of captopril in the patients studied.

Aged↗
PubMed1986

Growth factor and cytogenetic abnormalities in cultured nevi and malignant melanomas.

It has been proposed that benign nevi that fail to differentiate normally may undergo stepwise growth and morphologic changes resulting in progression toward dysplastic nevi, which in some cases progress into malignant melanoma. In this study, we sought to determine the relationship between production of endogenous growth factors and the appearance of chromosomal abnormalities in cultured nevi and melanomas. Newly established cultures from 8 nevi with benign histology and 6 malignant melanomas, and 2 malignant melanoma cell lines were studied. Assays for mitogenic growth factors were based on stimulation of [3H]thymidine incorporation into DNA in Hs0294 malignant melanoma cells, produced by serum-free conditioned medium from nevus or melanoma cultures. Karyotypes were examined in cultures of an equivalent passage. Three of the 8 nevus cultures were mitogen-negative and displayed normal karyotypes; one nevus culture was mitogen-positive and had a normal karyotype, although the biopsied tissue demonstrated histologic evidence of benign melanocytic proliferation; one was mitogen-negative initially, but had an extra chromosome 8 in 2 of 50 cells; 3 were mitogen-positive and chromosomally abnormal. Each of the cultures in this latter group exhibited reciprocal translocation (rcpt) as the only identifiable abnormality [rcpt(6;15), rcpt(10;15), rcpt(15;20)], or a constitutional rcpt(4;5). Thus, there was direct correlation between growth factor production and chromosome abnormality in 6 of 8 benign nevus cultures. In the newly established melanoma cultures there was also concordance between growth factor and chromosomal status; conditioned media from 4 of 6 were mitogen-positive by at least one assay, and all 4 of the mitogen-positive cultures had chromosomally abnormal cell populations. Of the 2 melanoma cultures negative for growth factors, one was also negative for chromosome abnormality; the other had chromosomal change consisting of increased polyploidy. Both melanoma cell lines had abnormal karyotypes and were mitogen-positive. Though numerous chromosome changes were noted in the karyotypically abnormal melanoma cells, 6 of the 8 cultures exhibited abnormalities in chromosomes 1, 6, and/or 7. These data suggest that steps in the progression from benign nevi toward dysplastic nevi or malignant melanoma include: proliferation resulting from altered production of endogenous mitogenic growth factors; and development of specific chromosomal abnormalities.

Cells, Cultured↗
PubMed1986

Record linkage study of hypokalaemia in hospitalized patients.

Retrospective analysis of biochemical data from 58,167 hospital inpatients revealed that 21% developed hypokalaemia during hospitalization-in 5.2% the serum potassium was less than 3.0 mmol/l. Subsequent evaluation showed a positive correlation between hypokalaemia and both female sex and hospital mortality. Patients with leukaemia and lymphoid tumours, especially when receiving antibiotic or cytotoxic therapy, and patients with gastro-intestinal malignancy were amongst those most frequently experiencing hypokalaemia. There was no significant association with cardiovascular disease. Drug and intravenous fluid administration accounted for the hypokalaemia in 56% of patients. While drug-related hypokalaemia was most commonly seen with diuretics, it was also apparent following use of steroids, insulin and haematinics.

Aged↗
PubMed1986

Trends in psychotropic prescribing in general practice and general medical patients.

Psychotropic drug prescribing in 1280 medical inpatients between 1973-75 was compared with that in 1200 similar patients during 1982-83. Three benzodiazepines accounted for 64% of prescriptions in 1973-75 and nine benzodiazepines for 82% of prescriptions in 1982-83. Over the decade, use of psychotropic drugs fell from 56% to 38% (P less than 0.001), primarily due to a reduction in patients treated only in hospital (34% vs 16%, P less than 0.001). Before admission, the proportions of patients receiving these drugs were similar (17% vs 18%). During admission, concomitant administration of similar drugs declined from 22% of patients in 1973-75 to 11% in 1982-83 (P less than 0.001), while concurrent prescribing before admission increased from 13 to 19%. The marked fall in psychotropic drug use and in inappropriate concomitant therapy indicates an encouraging trend towards more rational drug use at least in hospital. This was achieved without fiscal control and further rationalization of prescribing habits may be achieved by self-audit within the profession without legislative action.

Adolescent↗
PubMed1986

Diabetes mellitus and primary hepatocellular carcinoma.

In view of the increasing incidence of primary hepatocellular carcinoma in western Europe and concern that this may in part be related to long-term use of drugs which cause hepatic microsomal enzyme induction, we undertook a comparison of long-term drug use in 105 patients with hepatocellular carcinoma and equal numbers of age and sex-matched patients with colorectal tumours and with fractures of femur. We found no patients with hepatocellular carcinoma who were long-term anticonvulsant users and only one who used oral contraceptives. However, we observed a four-fold excess of diabetic patients among the group with hepatocellular carcinoma. This association did not appear to be due to pre-existing haemochromatosis, alcoholic cirrhosis or viral hepatitis. The association was strongest in patients receiving drug treatment for diabetes, but the data, although suggestive, were insufficient to determine whether any specific anti-diabetic agent could be responsible. Further studies are required to elucidate the nature of this unexpected association. An association of this magnitude with diabetes mellitus could account at least in part for the increasing incidence of hepatocellular carcinoma in western Europe.

Adult↗