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Biomedical subjects

K Hartley

Publications and source records attributed to K Hartley.

17 recordsLinked to original sources
PubMed1995

The preclinical toxicological evaluation of sumatriptan.

1 Sumatriptan is a potent and selective 5-HT1 receptor agonist marketed for the treatment of migraine by both oral and subcutaneous routes. An extensive toxicological programme employing high doses of sumatriptan was carried out in a range of animal species. The studies evaluated both the local and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential of sumatriptan. 2 The administration of relatively high single and repeated doses of sumatriptan was well tolerated by both rodents and dogs by the oral, subcutaneous and intravenous routes. Behavioural effects, suggestive of involvement of the central nervous system, were the most obvious result of such doses and were generally more pronounced in dogs than rodents. The reason for this may be related to the higher plasma concentrations of the drug achievable in dogs. Additional observations restricted to dogs, were transient, and included tachycardia, facial oedema and breaks in the continuity of secretion films on the corneal surface. A tendency for an increase in weight gain was seen for rats, while a slight decrease was usually seen for dogs. The only pathological changes related to treatment with high concentrations of sumatriptan consisted of local reactions at the site of subcutaneous administration. 3 Sumatriptan is an indole; the structures of this chemical class show varying propensities for nitrosation. However, appropriate testing with sumatriptan failed to identify any mutagenic nitroso compounds. 4 Sumatriptan was neither genotoxic nor oncogenic. 5 Reproductive studies demonstrated that sumatriptan was not teratogenic and had no effect on peri- and postnatal development. Some embryotoxicity was observed, but only at maternally toxic doses. A slight decrease in the success of insemination was also noted at high oral doses in rats. 6 Results of the toxicological programme performed in support of migraine therapy with sumatriptan provide good assurance of safety for subcutaneous and oral use.

Administration, Oral↗
PubMed1995

Quality of life in treated hypertension: a case-control community based study.

The aim of this case-control community study was to determine whether there was a difference in quality of life between hypertensive subjects and matched normotensive controls. Cases aged 40-79 years were randomly selected from a hypertensive register and matched with controls for age, sex, ethnicity and health centre. Cases had phase V diastolic blood pressure (DBP) > or = 100 mm Hg or systolic blood pressure (SBP) > or = 180 mm Hg, or were on anti-hypertensive medication. Controls had DBP < or = 90 mm Hg and no record of raised BP or anti-hypertensive treatment within the past year. Quality of life was measured by self-administered questionnaire. Data from 90 matched pairs, average age 62 years, with 47% men, were analysed; 80 hypertensive subjects were on anti-hypertensive medication. Hypertensive subjects showed an impairment in well-being compared with controls. They had a lower Health Status Index, had more sickness absence from work, greater symptomatic complaint and impaired psychological well-being. Relatives also reported a poorer quality of life in the hypertensive subjects. This impairment could be a result of the disease, adverse effects of drug treatment or to the effects of labelling.

Adult↗
PubMed1993

Cognitive function in hypertension: a community based study.

Cognitive function was investigated in a random sample of subjects on the general practitioners' registry of hypertensive patients in an inner city area and matched with normotensive controls. The response rate was 66% giving 90 matched pairs, average age 63 yrs, with 47% men. There was no difference in educational background or measures of reading ability between the two groups. Cognitive function tests showed a consistent trend of poorer performance in hypertensives, with significant differences in Verbal Learning (immediate recall and retention). Age was inversely related to cognitive function, but no additional deterioration with increasing age was shown in hypertensives.

Adult↗
PubMed1991

Risk of serious morbidity associated with hydralazine versus methyldopa treatment in hypertensive patients.

The medical records of patients presenting to the Hammersmith Hospital hypertension clinic between 1971 and 1981 were examined to determine presenting clinical data, treatment regimes, and both cardiovascular and non cardiovascular mortality and morbidity. When compared with 1004 patients receiving treatment other than hydralazine 310 patients on hydralazine had a significantly higher risk of developing renal disease (RR = 2.71) in men, and severe weight loss in women (RR = 3.06). Renal disease risk also tended to be high in women on hydralazine (RR = 1.95) compared with all other treatments, but this was not statistically significant and could be explained by poorer renal function and significantly higher untreated blood pressure in the hydralazine treated group at presentation. The 422 patients who were treated with methyldopa but not hydralazine had similar risk factors for cardiovascular disease compared with a group of 167 who received hydralazine but not methyldopa. Comparisons of event rates failed to find significant differences in morbidity or mortality between these two groups. The age adjusted male mortality was 14/1000 patient years on hydralazine and 12/1000 on methyldopa and 13/1000 and 6/1000 years for women respectively. There was no evidence of an increased risk of either renal disease (RR = 0.3 in men, RR = 0.3 in women) on hydralazine or weight loss (RR = 0.7 in men, RR = 1.6 in women), with similar presenting data. Systemic lupus erythematosus was a rare complication (2 of 314) of treatment with hydralazine.

Cardiovascular Diseases↗
PubMed1991

Myocardial infarction and stroke during treatment of hypertensive patients with different diuretic regimes.

A retrospective analysis of mortality and cardiovascular morbidity in patients being treated with a potassium losing diuretic alone or the combination of a potassium losing and sparing diuretic was performed in 1,935 patients attending a hypertension clinic between 1971 and 1981. In all, 713 patients were treated with a potassium losing diuretic and 472 patients were on a potassium sparing diuretic, usually in combination with a potassium loser. Presenting data on risk factors were similar between the two groups and age-adjusted cardiovascular morbidity and mortality was similar between the two groups. The relative risk (RR) for a myocardial infarction event on a potassium losing drug was 1.1 (95% CI 0.5-2.3) in men and 1.0 (0.4-2.5) in women. The corresponding risks for stroke were 0.8 and 0.7 respectively and total mortality was 1.3 and 1.1. However, following exclusion of patients with previous history of cardiovascular disease the risk of myocardial infarction in the potassium losing group was over three times that on a sparing diuretic, though the confidence intervals were wide. Total male mortality tended to be higher (RR = 2.4) but again failed to achieve statistical significance. An excess risk from potassium losing diuretics was found only in patients without cardiovascular disease and cannot be readily explained. This may be the result of treatment selection in different 'at risk' groups or chance in the performance of subgroup analyses.

Cardiovascular Diseases↗
PubMed1990

Detection of novel splicing patterns in a HPV16-containing keratinocyte cell line.

The W12 cell line was derived from a low grade cervical lesion, and is unique among HPV16-containing cell lines in carrying its HPV16 genome as a multicopy episome. As such it is thought to be more representative of a premalignant HPV16-induced tumor than the cervical cancers from which other cell lines have been derived. Using the polymerase chain reaction (PCR), we report here the identification and cloning of a number of novel cDNA species, which appear to be characteristic of the W12 cell line. Two species were identified with E6* coding capacity (E6*I and E6*III). The smaller of these (1009 bp) was predicted to encode a novel E6*III polypeptide containing C-terminal amino acids derived from an out of frame region of the E2/E4 ORFs. The larger species (1480 bp) contained, in addition to the E6*I ORF, an intact E7 ORF and probably represents the transcript for E7 expression, as the E7 protein was readily detectable in the W12 cell line. Both species appeared to be transcribed from the p97 promoter which has been shown to be active in other cell lines. A putative E2 repressor cDNA (891 bp), an E1/E4 message (883 bp), and two novel late cDNA species (1757 and 2031 bp) were also detected, allowing the identification of a splice acceptor immediately in front of the L1 open reading frame (nt 5637) and a splice donor at nt 3631. Although the 1757-base species has the capacity to encode a full-length L1 protein, both messages use a splice donor at nt 1301, and are thus not analogous to late species previously identified in HPV11. Of the six cDNAs cloned, only the 1480-bp E7 message has been observed in other HPV16-containing cell lines. The presence of L1 transcripts, and an E2 repressor mRNA, although unexpected, may reflect the different origins of the W12 cell line.

Amino Acid Sequence↗
PubMed1990

m-BACOD treatment for intermediate- and high-grade malignant lymphomas: a Southwest Oncology Group phase II trial.

One hundred six eligible patients with advanced intermediate- or high-grade malignant lymphoma were treated with methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) in a Southwest Oncology Group phase II trial. Patients were stratified by estimated bone marrow reserve, and impaired marrow reserve patients received reduced doses of cyclophosphamide and doxorubicin. The complete remission rate for normal marrow reserve patients was 65%, while the complete remission rate for impaired marrow reserve patients was 29%. With a median follow-up period of 41 months, 64% of complete responders in the normal marrow group are disease-free 3 years after their response. Three-year survival is 61% in the normal marrow reserve group and is 29% in the impaired marrow reserve group. Eighty-seven percent of treatment courses were given in accordance with protocol dosing and schedule. For doxorubicin, relative dose intensities were 0.75 and 0.61 (normal and impaired marrow reserve arms, respectively), for cyclophosphamide, 0.76 and 0.61, and for methotrexate, 0.55 and 0.45. Serum lactic dehydrogenase (LDH) level was the only pretreatment characteristic found to have a significant effect on overall survival. Severe or greater toxicity occurred in 97% and 89% of the normal and impaired marrow reserve groups, respectively, with granulocytopenia the principal toxicity. Treatment-related fatalities occurred in 8% of patients. m-BACOD is an effective but toxic treatment program for intermediate- and high-grade malignant lymphomas.

Adolescent↗
PubMed1989

Mortality in patients who have their antihypertensive therapy changed.

Medical records were examined for 1935 patients who presented sequentially to a hypertension clinic between 1971 and 1981. Patients were classified according to whether they were on a beta-blocker, methyldopa, a potassium-losing diuretic, or whether they had discontinued any of these treatments. Age-standardized mortality rates were calculated and the relative risks of stopping compared with non-stopping were computed. Those stopping a beta-blocker had a significantly higher mortality in the following year than those who continued, both in men [relative risk (RR) = 5.91, 95% confidence interval (Cl) 2.78-12.56] and women (RR = 5.67, 95% Cl 1.75-18.41). Moreover, women also had a significantly higher mortality when stopping methyldopa, compared with those who continued on the drug (RR = 4.91, 95% Cl 1.82-13.20). However, analysis of data from the years following withdrawal indicated that a high RR was not limited to the first year after the withdrawal of beta-blockers, but was still apparent in the fourth year after stopping. This indicates that the high mortality was not an early function of withdrawal. The high initial RR of mortality in women stopping methyldopa was followed by a substantial decrease in risk over the later years of follow-up. The high mortality in patients stopping particular antihypertensive drugs was not explained by known cardiovascular risk factors.

Adrenergic beta-Antagonists↗
PubMed1989

Alcohol, tobacco and public policy: the contribution of economics.

This article shows the contribution of economics to debates about prevention policy. The arguments used by various pressure groups favouring or opposing more effective prevention policies need to be subject to critical scrutiny and empirical testing. The market failure case for state intervention in alcohol and tobacco markets is assessed and an alternative public choice approach is outlined. The supply side of the market in the form of the alcohol and tobacco industries is analysed using a structure-performance framework. Consideration is given to how firms might respond to prevention policies through, say, lobbying or shifting higher taxes to suppliers or by diversifying into new markets.

Alcoholism↗
PubMed1987

The detection of fingerprints and other marks in body fluids by the use of agar gels.

Techniques are described whereby weak fingerprints in blood, semen and saliva on a variety of materials may be rapidly enhanced and photographed. The methods involve the use of flexible agar gels containing histochemical reagents for the development of prints made in these body fluids. The gels may be used on a variety of vertical, horizontal and irregular surfaces and in some cases could replace sprays and "fingerprint paints".

Agar↗
PubMed1986

Fifteen year survival of patients presenting with hypertension to a hospital clinic.

The survival has been determined for the 404 patients who presented to the Hammersmith Hospital Hypertension Clinic during the years 1962 to 1966 and in whom the untreated blood pressure was known. The fifteen year survival ranged from 72% for young men aged 30-49 at presentation to 27% for men aged 60-69. Sixty-eight percent of the deaths were cardiovascular or renal, 33% of all deaths were from ischaemic heart disease (IHD), 17% from stroke and 3% from renal causes. Death from any cause was predicted with statistical significance by age, the presence of accelerated or malignant hypertension, impaired renal function, smoking at presentation and systolic blood pressure. Death was not predicted by hypokalaemia, hyperuricaemia (after adjusting for renal function) and obesity.

Adult↗
PubMedDate not supplied

Fifteen-year survival of patients beginning treatment with methyldopa between 1962 and 1966.

The 15-year survival of a group of 205 patients who started treatment in the period 1962 through 1966 and who received methyldopa for two-thirds or more of the time has been investigated. At entry these patients had severe hypertension with an average pretreatment pressure of 216/126 mm Hg. Twenty-one percent had retinal hemorrhages, cotton-wool spots, or papilledema. Blood pressure showed a large fall in the first year, followed by a small, progressive, further fall up to the sixth year. After 5 years of treatment the blood pressure averaged 144/90 mm Hg in men and 151/91 mm Hg in women. The average daily dose of methyldopa was approximately 1500 mg and changed little over the 15-year period. Survival was analyzed by life tables. Approximately 81% of men and women aged 30 to 49.9 years at entry were still alive 10 years later. In the age group 60 to 69.9 years, 53.8% of men and 63.2% of women were still alive 10 years later. Seventy-nine of the patients died during the follow-up period, 89% from cardiovascular or renal disease. Ischemic heart disease (40%) was the major cause of death, followed by stroke (19%). No patients died from drug toxicity.

Adult↗