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Biomedical subjects

D Cunningham

Publications and source records attributed to D Cunningham.

At least 271 records · Page 15Linked to original sources
PubMed1988

Basal lamina of rat myocardium. Its fate after death of cardiac myocytes.

As part of a study of the interactions between myocardial cells and extracellular matrix during healing of necrotic lesions, we have examined the fate of myocyte basal lamina (BL) after injury with ischemia, freeze-thawing, or isoproterenol. Using light and electron microscopy, and antibodies to three BL-associated antigens, we found that the BL of necrotic myocytes remained largely intact and continued to delineate the myocyte compartment from connective tissue space. Inflammatory cells entered the myocyte compartment through holes in the acellular BL and removed cell debris. The holes may have been produced by inflammatory cells and/or by the stretching force of the beating heart. After removal of debris, some BL sheaths of necrotic myocytes collapsed, resulting in spatial approximation of vessels. Interstitial cells deposited collagen and elastic fibers in the connective tissue space and within portions of the myocyte compartment. The acellular myocyte BL, collapsed or not, retained normal antigen staining for type IV collagen, laminin, and heparan sulfate for about 10 days, then showed diminished staining in patchy areas. These areas may correspond to BL disruption and degradation in conjunction with fibrosis, although a substantial amount of acellular BL remained in situ and became embedded in scar tissue. At least two types of granulo-vesicular bodies, measuring 25 to 60 and 60 to 160 nm respectively, were associated with the acellular BL; these were of unknown origin and function. The study shows that the fate of acellular BL in injured myocardium is similar to the fate of BL in other injured tissues; however, the appearance of holes in acellular BL, within hours after injury, is unusual and may enhance scar tissue formation. Whether the acellular BL contributes to regeneration of myocardium, as do acellular BLs in other injured tissues, remains to be determined.

Animals↗
PubMed1988

Myocyte reactions at the borders of injured and healing rat myocardium.

To better understand the apparent tendency of myocardium to heal by scarring rather than by restoration of normal structure, we have examined by light and electron microscopy the basic reactions of rat ventricular myocytes and their interactions with the extracellular matrix. Using three different types of necrotizing injuries, we found that necrotic myocytes separated from viable myocytes at intercalated discs leaving blunt-ended stumps at the edge of each lesion; the basal lamina of necrotic myocytes remained largely intact and spanned the gap between viable myocytes on opposite sides of each lesion. A small number of stumps were capped off by a new layer of basal lamina and showed no evidence of proliferative activity. The majority of the stumps developed cell processes that extended along the acellular myocyte basal lamina sheaths. These processes had one of two different fates. Some became apposed to similar processes, formed intercalated disc attachments, increased myofibrillar mass, and appeared to be associated with muscle reconstruction. Others developed elongate tapered ends, which terminated in myotendinous connections to scar tissue. The outcome of healing necrotic myocardium, like the healing of noncardiac necrotic tissue injuries, appears to be a function of cell growth and extracellular framework guidance; however, unlike healing of noncardiac tissues, healing of myocardium is uniquely complicated by continuing muscle contractions. We think the rhythmic pulling at the edges of necrotic lesions induces formation of myotendinous attachments, which anchor myocytes to scar tissue and probably prevent further growth.

Animals↗
PubMed1987

Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist.

15 patients receiving cytotoxic drugs (other than cisplatin) that had previously produced nausea and vomiting refractory to first-line antiemetics were given a selective 5-HT3 receptor antagonist (GR38032F), 4 mg intravenously and 4 mg orally, immediately before chemotherapy, the oral dose being repeated 5 and 10 h later. Nausea, vomiting, and side-effects were recorded for the ensuing 24 h. The 15 patients received a total of thirty-one courses of chemotherapy. Only 1 patient vomited. The only adverse events were dryness of the mouth in 1 patient, mild sedation in 1, and diarrhoea in 1, and these were not clearly drug related.

Antineoplastic Agents↗
PubMed1987

Evaluation of the prognostic factors in gastric cancer: the effect of chemotherapy on survival.

This is a retrospective review of 328 consecutive patients with histologically confirmed gastric adenocarcinoma diagnosed in one centre between 1974 and 1984. Of these patients, 128 (39 per cent) had a curative resection, 32 (9.8 per cent) had a palliative resection, 33 (10.0 per cent) had a gastro-enterostomy, 26 (7.9 per cent) had a Celestin tube inserted, 58 (17.7 per cent) had a laparotomy alone, and 51 (15.5 per cent) had no surgical procedure. The 5 year survival was 11 per cent but all long term survivors were patients who had a curative resection. Using multivariate analysis the best predictor of survival after curative resection was the presence or absence of serosal involvement (P = 0.0004). Patients with a long history of presenting symptoms (greater than 6 months) survived longer than those with a short history (P = 0.001). The impact of chemotherapy on the survival of 202 patients with advanced gastric cancer was analysed by multivariate analysis. The median survival of the 50 patients receiving combination chemotherapy was better than that of the 152 who did not (median survivals 160 versus 71 days; P less than 0.001). When deaths occurring within 14 days of diagnosis were excluded, the significance value dropped to P = 0.02. Comparison of the groups treated between 1974 and 1979, when 8 per cent of 92 patients received chemotherapy, with 1980-1984, when 45 per cent of 110 patients received chemotherapy, showed no significant difference in survival.

Adenocarcinoma↗
PubMed1987

Oral 4-hydroxyandrostenedione, a new endocrine treatment for disseminated breast cancer.

Thirty-one post-menopausal female patients, with locally advanced or disseminated breast cancer were treated with the aromatase inhibitor 4-hydroxyandrostenedione given orally at a dose of 500 mg daily. Twenty-nine patients had assessable disease. Eight patients (28%) had objective evidence of partial response and six remain in remission 7-10 months later. A further four patients (14%) had stabilisation of disease and 11 patients (37%) had progressive disease in spite of treatment. Plasma oestradiol levels were measured throughout therapy in 16 patients and were lowered to 53% +/- 8% of baseline levels within 7 days of commencing 4-hydroxyandrostenedione. With regard to toxicity, one patient developed a transient skin rash and another patient some facial swelling. A further patient developed a transient leucopaenia and treatment was therefore discontinued. Twenty-seven of the 30 evaluable patients (90%) experienced no side effects. These results indicate that oral administration of 4-hydroxyandrostenedione is an acceptable new treatment for post-menopausal women with disseminated breast cancer.

Administration, Oral↗
PubMed1987

Adenine nucleotide binding sites on beef heart F1 ATPase: photoaffinity labeling of beta-subunit Tyr-368 at a noncatalytic site and beta Tyr-345 at a catalytic site.

2-Azidoadenine [32P]nucleotide was bound specifically at catalytic or noncatalytic nucleotide binding sites on beef heart mitochondrial F1 ATPase. In both cases, photolysis resulted in nearly exclusive labeling of the beta subunit. The modified enzyme was digested with trypsin, and labeled peptides were purified by reversed-phase high-pressure liquid chromatography. Amino acid sequence analysis of the major 32P-labeled tryptic fragments showed beta-subunit Tyr-368 to be present at noncatalytic sites and beta Tyr-345 to be present at catalytic sites. From the relationship between the degree of inhibition and extent of modification, it is estimated that one-third of the catalytic sites or two-thirds of the noncatalytic sites must be modified to give near-complete inhibition of catalytic activity.

Adenine Nucleotides↗
PubMed1987

Diurnal variation in left ventricular function: a study of patients with myocardial ischaemia, syndrome X, and of normal controls.

Angina can occur in the early morning. The mechanism of this is unclear and both haemodynamic changes and coronary artery spasm may be important. The purpose of this study was to investigate the diurnal variation in pulmonary artery diastolic pressure (an indirect measure of left ventricular filling pressure) in six normal subjects, 18 patients with coronary artery disease, five with variant angina, and six with syndrome X. A transducer tipped catheter and a simple recording system were used to record ambulatory pulmonary artery diastolic pressure for 24 hours. Variation in pulmonary artery diastolic pressure was related to the timing of episodes of ST segment depression and elevation by simultaneously recording a frequency modulated electrocardiogram. Episodes of ST segment change occurred predominantly in the early morning (midnight to 6 am) in variant angina (eight out of 14 episodes) whereas in syndrome X all episodes were recorded during the day. In coronary artery disease both painful and painless episodes were distributed throughout the day, with 10 out of 67 episodes occurring between midnight and 6 am. A similar diurnal variation in pulmonary artery diastolic pressure was seen in the groups--that is, values were low during the day and higher at night, with the maximum values between midnight and 6 am. The 24 hour median pulmonary artery diastolic pressure was higher in patients with coronary artery disease than in the control group and those with syndrome X. The finding that pulmonary artery diastolic pressure, and therefore left ventricular end diastolic pressure, is greatest in the early morning may represent the background haemodynamic state in which other factors lead to myocardial ischaemia during these hours.

Adult↗
PubMed1987

Failure of conventional chemotherapy in aggressive lymphomas.

Between 1975 and 1982 in 2 centres in Glasgow, 53 previously untreated patients with aggressive non-Hodgkin's lymphomas received chemotherapy consisting of one of the following regimens-CVP, MOPP, CHOP or BACOP. Twenty nine patients (55%) entered complete remission (CR), 20 (38%) had partial remission (PR) and 4 (7%) had progressive disease (PD). Of the 29 patients in CR, 9 have relapsed and died, 5 died of infection, 4 died of non-malignant causes, and 11 (21%) remain alive and disease free. The median survival for the CR group is 40 months. All of the patients in the PR and PD group are dead, median survival 11 months. These chemotherapy regimens will cure only the minority of patients with aggressive lymphomas and the use of more intensive regimens is indicated.

Adult↗
PubMed1987

Oral gestrinone: a novel antiprogestin with no antitumor activity in endocrine-sensitive breast cancer.

We have treated 15 patients with locally advanced or metastatic breast cancer using the synthetic 19-norsteroid gestrinone (2.5 mg orally every 3 days). All patients had assessable disease and endocrine-sensitive tumors, as defined by a previous positive response to endocrine therapy. There were no objective responses. Six patients had disease stabilization and nine had progressive disease on treatment. Seven patients were given endocrine therapy after gestrinone and three have responded. Gestrinone has no significant antitumor activity in hormone-sensitive breast cancer. This, however, does not preclude its use in benign breast disease, particularly since other agents used for benign breast disease can mask occult primary carcinoma.

Administration, Oral↗
PubMed1986

Influence of polysorbate 80 (Tween 80) and etoposide (VP-16-213) on the pharmacokinetics and urinary excretion of adriamycin and its metabolites in cancer patients.

Polysorbate 80 (Tween 80) is present in the IV pharmaceutical preparation of VP-16-213 marketed as VePesid (Bristol-Myers) (etoposide 100 mg, benzylalcohol 150 mg, polyethylene glycol 300 3250 mg, citric acid 10 mg, Tween 80 400 mg and absolute alcohol to 5 ml per 100 mg ampule of VP16), to increase its miscibility with blood. We have examined the effects of 400 mg/m2 Tween 80 IV and 100 mg/m2 VP16 on the pharmacokinetics of Adriamycin (ADR, 30 or 40 mg/m2). ADR and metabolite concentrations were measured by HPLC. ADR plasma profiles were best fitted to a bi-exponential decay and a two-compartment open model. Tween 80 did not alter the values of the two ADR half-lives, nor did it affect metabolite kinetics of their urinary excretion. However, in a similar manner and consistently in all patients, both Tween 80 and VP16 increased the volume of distribution of the central compartment for ADR up to 3-fold, decreased the AUC of ADR up to 2-fold and increased its clearance by exactly the same amount. These effects were due to reduced plasma ADR concentrations during the early phase of its kinetics. Urinary excretion of ADR was also increased. In conclusion, VP16 is likely to affect the kinetics of drugs administered with it: early plasma concentrations will fall due to a general physiological effect of Tween 80 on the apparent volume of circulation.

Adult↗
PubMed1986

Small cell lung cancer: results of a phase II study of 1,2,4 triglycidylurazol.

Fourteen patients with small cell lung cancer (SCLC) received treatment with 1,2,4 triglycidylurazol (TGU) 600 mg/m2 or 800 mg/m2 as an IV bolus every 4 weeks. Twelve patients had received previous chemotherapy consisting of a five-drug regimen given for the short duration of only 9 weeks. All had measurable disease. Following TGU 11 patients had progressive disease and 3 patients had stable disease. The most frequent toxicity was nausea and vomiting, which occurred in all patients but was generally mild. Myelosuppression was common with a median white blood count nadir of 2.5 X 10(9)/l (range 0.9-7.4 X 10(9)/l) and median platelet count nadir of 76 X 10(9)/l (range 5-173 X 10(9)/l. Alopecia, thrombophlebitis, and hepatic or renal toxicity were not observed. In this study, TGU had no activity in SCLC, and the dose-limiting toxicity was myelosuppression.

Antineoplastic Agents↗
PubMed1986

Etoposide: a pharmacokinetic profile including an assessment of bioavailability.

The pharmacokinetics of intravenous etoposide (50-150 mg m-2) have been studied in 17 patients. Bioavailability studies on either the capsule or intravenous (i.v.) formulation were performed in 13 patients, 7 of whom received both oral formulations given in the dose range 50-250 mg m-2. After i.v. administration the mean +/- SD half-lives were t1/2 alpha 0.62 +/- 1.01 h and t1/2 beta 6.04 +/- 2.5 h. The bioavailability of etoposide was extremely variable: for the capsule it was 38 +/- 14% (range 10-55) and for the i.v. formulation it was 53 +/- 25% (range 31-88). The i.v. formulation was not significantly better than the capsule. The results confirm the low and variable bioavailability of oral etoposide.

Administration, Oral↗