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D H Lawson

Publications and source records attributed to D H Lawson.

At least 19 recordsLinked to original sources
PubMed1992

Cancer-related urinary proteinase inhibitor, EDC1: a new method for its isolation and evidence for multiple forms.

During the past several years, numerous laboratories have reported isolation and purification of proteinase inhibitors from human urine. Many of these molecules were incompletely characterized and some of them may have been artifacts in part because of harsh procedures used for their isolation. Consequently, there is disagreement and confusion regarding the biochemical characteristics of these inhibitors. We previously reported the isolation of a proteinase inhibitor, EDC1, from the urine of a leukemic patient. This molecule, M(r) 30 kDa, was antigenically related to plasma inter-alpha-trypsin inhibitor (IATI) and inhibited the growth of a virally transformed B cell line. Immunoreactive EDC1 was also the major component of low molecular weight proteinuria observed in cancer patients. We now report a new method for the isolation of EDC1 from urine of patients with adenocarcinomas of colon and lung and melanoma and compare its partial amino acid sequence with that of HI 30, a proteinase inhibitor previously isolated from pooled normal urine by Hochstrasser et al. [Hoppe-Seyler's Z Physiol Chem 357:153-162, 1976]. Our method involves i) a batchwise cation exchange, ii) gel filtration chromatography, iii) anion exchange chromatography on FPLC, and iv) reverse phase C18 chromatography on HPLC. This method is mild and results in an overall yield of 0.4 to 1.2 mg of EDC1/liter urine. On the basis of the partial N-terminal amino acid sequence of its N terminal (38 residues) and middle regions (29 residues), EDC1 appears to be identical with HI30. Surprisingly, during this isolation procedure, another proteinase inhibitor, M(r) 22 kDa, which cross-reacted with antisera to EDC1 and IATI, was also isolated. The 22 kDa molecule was a major component of the IATI related urinary molecules and was identical with the 30 kDa EDC1 in which first the 15 N terminal residues were clipped. The lower M(r) inhibitor was not an artifact formed during storage or isolation procedure because the Western blot analysis of fresh cancer and normal urine revealed the 30 and 22 kDa molecules. Thus, both the 30 kDa EDC1 (or HI30) and its clipped variant, the 22 kDa molecule, are physiologic components of IATI related urinary proteinase inhibitors and excretion of both forms may be increased in patients with advanced cancer.

Adenocarcinoma↗
PubMed1992

Postmarketing surveillance of captopril for hypertension.

1. A scheme for augmented spontaneous reporting of adverse drug events using advanced view data systems was developed and applied to study 67,698 consecutive patients prescribed captopril in general practice for the treatment of hypertension. 2. Captopril was an effective hypotensive agent in this population, as only 1.9% of patients were withdrawn because of apparent inefficacy. 3. Adverse effects of captopril resulted in withdrawal of treatment in 8.9% of recipients, and such effects were more frequent in elderly and female recipients. 4. Skin reactions--usually maculopapular rashes--tended to occur early during therapy whereas cough occurred much later and was reported more frequently in non-smokers. 5. Some 1.1% of recipients died during follow-up. There was no evidence of any unusual or unexpected causes of death which might be partially or totally captopril-related in the study cohort. 6. The study confirms the feasibility of large scale postmarketing surveillance studied in general practice and allowed risk benefit assessments to be made on the use of captopril for treating hypertension.

Aged↗
PubMed1992

Postmarketing surveillance of the safety of cimetidine: 10 year mortality report.

A total of 9928 cimetidine users were identified from prescriptions in four centres and followed for 10 years. The 'all-cause' mortality ratio fell from 1.9 in year 1 to 1.0 in years 8 to 10. Most of the early excess in mortality was attributable to cimetidine being given in the late stages of many diseases, often to counter adverse gastric effects of other drugs. Specific causes of mortality during years 5-10 of the study, were generally unremarkable. Significant increases in mortality ratios were apparent, however, for oesophageal cancer (years 5-7, 2.3; years 8-10, 1.9); lung cancer (years 5-7, 1.1; years 8-10, 1.7); diseases of the oesophagus, stomach, and duodenum (years 5-7, 3.3; years 8-10, 2.3); and chronic liver disease (years 5-7, 2.4; years 8-10, 3.3). None of these increases in mortality seems to be attributable to an adverse effect of cimetidine use. Data are also presented for mortality from diseases of the nervous system. Eight deaths (of which one was miscoded) were certified as being from motor neurone disease, representing a mortality ratio of 2.6 for years 2-10 of the study which is of borderline statistical significance. This study confirms that cimetidine is safe. Mortality from some diseases increased over the study period, but selection rather than any adverse effect of the drug is likely to be the explanation.

Cimetidine↗
PubMed1991

The yellow card: mark II.

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Drug-Related Side Effects and Adverse Reactions↗
PubMed1991

Randomized study of interleukin 2 (IL-2) alone vs IL-2 plus lymphokine-activated killer cells for treatment of melanoma and renal cell cancer.

The purpose of this study was to evaluate the efficacy and safety of a continuous-infusion interleukin 2 (IL-2) regimen for patients with metastatic melanoma and renal cell cancer. To investigate the contribution of adoptively transferred lymphokine-activated killer cells, patients were randomized to receive either IL-2 alone or IL-2 plus lymphokine-activated killer cells. Twenty-three patients with renal cell carcinoma and 20 with melanoma were entered into the protocol. There were no objective responses noted in the 38 assessable patients (20 with renal cell carcinoma, 18 with melanoma). Most patients demonstrated progressive disease following one 31-day cycle of weekly continuous-infusion IL-2. Grade I and II toxic reactions, including fever, rash, anorexia, and weight gain, were common and treated symptomatically. Significant in vivo stimulation of lymphokine-activated killer and natural killer cell activity was noted in most patients. This continuous-infusion IL-2 regimen with or without lymphokine-activated killer cells was ineffective in the treatment of melanoma and renal cell carcinoma.

Adult↗
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

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↗
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↗
PubMed1979

Adverse reactions to frusemide in hospital inpatients.

Out of 2580 medical inpatients included in a drug-surveillance programme, 585 (22.7%) were treated with frusemide. Of these, 123 (21.0%) had a total of 177 adverse reactions. The most common were hypovolaemia (85 cases), hyperuricaemia (54), and hypokalaemia (21). Most reactions were mild, and only three patients had potentially life-threatening effects. The incidence of adverse reactions increased significantly with daily dose, occurring in 47 patients (13.5%) given up to 40 mg, 42 (26.3%) given up to 80 mg, and 34 (43.6%) given over 80 mg (P less than 0.001). There was no clear association between side effects and a raised blood urea concentration on admission, confirming that treatment with frusemide is not more hazardous in patients with renal failure. Frusemide is a safe and highly effective diuretic. Nevertheless, in view of the potential seriousness of volume depletion, dosage should probably begin at 20 rather than 40 mg daily.

Aged↗