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Biomedical subjects

M A Graham

Publications and source records attributed to M A Graham.

69 records · Page 4Linked to original sources
PubMed1987

The effect of the anthrapyrazole antitumour agent CI941 on rat liver microsome and cytochrome P-450 reductase mediated free radical processes. Inhibition of doxorubicin activation in vitro.

The anthrapyrazole CI941 is one of a new series of DNA complexing drugs which displays high level broad spectrum antitumour activity in mice. In view of the proposed role of drug free radical formation, superoxide generation and lipid peroxidation in anthracycline and anthraquinone induced toxicities, the redox biochemistry of CI941 has been investigated. Studies have been performed in vitro using rat liver microsomes and purified cytochrome P-450 reductase. In addition, the ability of CI941 to undergo chemical reduction has been examined. Pulse radiolysis of CI941 demonstrated that the drug can undergo chemical reduction with a one electron reduction potential of E1(7) = -538 +/- 10 mV. However, electron spin resonance (ESR) spectroscopy studies using either NADPH fortified microsomes or cytochrome P-450 reductase, failed to detect a drug free radical signal. Unlike doxorubicin, CI941 (150 microM) inhibited basal rate microsomal NADPH consumption by 45%. Furthermore, CI941 (50-200 microM) antagonised doxorubicin stimulated (1.8-fold) NADPH oxidation by over 50%. CI941 also antagonised the formation of a doxorubicin free radical ESR signal in a concentration dependent manner. CI941 induced minimal superoxide generation in the presence of either microsomes or cytochrome P-450 reductase and inhibited doxorubicin induced (50 microM) superoxide formation by up to 80% (50-200 microM CI941). Importantly, CI941 inhibits both basal rate and doxorubicin (100 microM) stimulated lipid peroxidation (52% inhibition at 5 microM CI941). These data suggest that CI941 is unlikely to induce free radical mediated tissue damage in vivo. On the contrary, CI941 may have a protective role if used in combination with doxorubicin.

Animals↗
PubMed1987

Factors affecting psychological adjustment to a fetal death.

The loss of a child in utero can be a tragic experience. The purpose of the present study was to examine some patient characteristics that may predict which women are likely to have problems in adjusting to the loss and to examine the effectiveness of interventions by care providers in facilitating emotional recovery. Twenty-eight women who were no more than 4 weeks post partum from a fetal death were interviewed while waiting to see their physicians at the fetal demise clinic at Los Angeles County Women's Hospital. It was found that women were less depressed after the loss if they already had children, if they did not blame themselves for the death, and if they received a picture of the infant or were allowed to see the infant. Women benefited from sympathy from the medical personnel and being kept informed of problems as they developed.

Adaptation, Psychological↗
PubMed1986

Low central nervous system penetration of N2,N4,N6,-trihydroxymethyl-N2,N4,N6,-trimethylmelamine (Trimelamol): a cytotoxic s-triazine with reduced neurotoxicity.

Trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine) is an analogue of pentamethylmelamine (PMM). In early clinical trials PMM failed to show significant anti-tumour activity in man which was attributed to poor metabolic activation. Trimelamol does not require activation and is therefore expected to be more active in man. PMM caused dose-limiting emesis and sedation whereas Trimelamol is much less neurotoxic in rodents. The relative penetration of PMM and Trimelamol into mouse brain has therefore been examined. Mice receiving PMM at 90 mg kg-1 i.p. were found to have high concentrations of the drug in the CNS compared to plasma (mean brain/plasma ratio 1.04) whereas animals receiving Trimelamol had consistently low CNS concentrations (mean brain/plasma ratio 0.08). This difference did not correlate with plasma protein binding which is greater for PMM (68.2%) than for Trimelamol (17.5%). However, it does appear to be related to lipophilicity. In Phase I clinical trial Trimelamol has proved much less emetic than PMM and causes no acute sedation. It is likely that this reduction in toxicity may be explained by the relatively poor ability of Trimelamol to enter the CNS.

Altretamine↗
PubMed1985

Sudden death in hemodialysis patients.

Hemodialysis patients may die suddenly and unexpectedly from a number of causes. These may be divided into those deaths due directly to and occurring during hemodialysis, those deaths occurring while the patient is not undergoing dialysis, and those deaths that may occur at any time. The first group includes brain herniation, air embolism, acute hemorrhage as a result of machine malfunction or fistula rupture, electrocution, cardiac arrhythmia caused by hypokalemia, complications of subclavian intravenous catheter insertion, third-degree heart block as a result of triglyceride emulsion, and disseminated intravascular coagulation (DIC) or hyperkalemia caused by overheated dialysate. The second group includes deaths due to pericardial tamponade because of effusion and suicidal causes of death (exsanguination, electrolyte imbalance as a result of excessive intake of salt, fluid, or potassium) as well as more conventional methods of suicide. The last category includes people dying of arteriosclerotic cardiovascular disease, hypertensive cardiovascular disease, and internal hemorrhage. Investigation of these deaths, including pertinent historical, laboratory, and autopsy data and investigation of dialysis equipment, is discussed.

Aged↗
PubMed1982

Incidental carcinoma of the prostate at the time of transurethral resection: importance of evaluating every chip.

Incidental adenocarcinoma of the prostate has been divided into stage A1--less than 3 foci of well differentiated adenocarcinoma present and stage A2--3 or more foci of poorly differentiated tumor present. The clinical significance of these 2 stages has been well documented, with stage A1 lesions causing no increased mortality, while up to 30 per cent of patients with clinical stage A2 disease will have positive pelvic lymph nodes at exploration and, thus, will have surgical stage D1 tumor. Most pathology laboratories submit only a fraction of the transurethral resection chips for permanent blocks. In an effort to evaluate the over-all incidence and distribution of stages A1 and A2 lesions were began a prospective study in 1978 whereby all prostatic chips were submitted for permanent sections. A review of 500 consecutive cases of transurethral resection for clinically benign prostates before 1978 revealed 43 cases of adenocarcinoma: 10 (23 per cent) stage A1 and 33 (77 per cent) stage A2. A review of a similar series of 500 consecutive patients since 1978 revealed 71 cases of adenocarcinoma: 17 (24 per cent) clinical stage A1 and 54 (76 per cent) clinical stage A2. Thus, we found that since 178 incidental adenocarcinoma of the prostate has increased by 65 per cent and the distribution of stages A1 and A2 lesions has remained unchanged, 76 per cent of these lesions being clinical stage A2 with its much greater clinical significance. Evaluation of every chip does make a clinically significant difference in the subsequent management of patients with incidental adenocarcinoma of the prostate.

Adenocarcinoma↗
PubMedDate not supplied

Pharmacokinetics of high dose methylprednisolone and use in hematological malignancies.

The pharmacokinetics of oral and intravenous high dose methylprednisolone (Solu-medrone, Upjohn) were compared in patients with hematological malignancies. The aim of the study was to determine the oral bioavailability of high dose methylprednisolone and to establish whether this is a feasible and more convenient route of administration. The plasma pharmacokinetics were described by a one-compartment open model with peak plasma levels of 6.9 +/- 2.5 micrograms/ml. Total area under the plasma concentration versus time curve was similar by either route. Mean relative oral bioavailability was generally high (91 +/- 27 per cent). Retrospective analysis of 34 patients with chronic lymphocytic leukemia (CLL), non-Hodgkin's and Hodgkin's lymphoma treated with high dose methylprednisolone showed 11 responses including two complete remissions among nine patients with CLL. There was significant improvement in platelet counts in thrombocytopenic patients and treatment was well tolerated and toxicity was relatively low. High dose methylprednisolone may therefore be a useful palliative treatment for hematological malignancies, particularly where marrow suppression is a problem.

Administration, Oral↗
PubMedDate not supplied

Vascular rejection in heart transplant recipients.

Antibody medicated (vascular) rejection has recently been described in heart transplantation. We report our experience with vascular rejection in a series of 62 patients who did not receive perioperative lymphocyte antibody therapy. Sixty-five rejections were reported, of which 58 (89%) were pure cellular; five (8%) had both cellular and vascular components, and two (3%) had only vascular rejection. Vascular rejection was very common in patients in whom hemodynamic compromise developed, and hemodynamic compromise was significantly more common in vascular than cellular rejection. Treatment for vascular rejection included plasmapheresis, intravenous methylprednisolone, and cyclophosphamide. Only one death occurred in this series, and that occurred in a patient with vascular rejection where the diagnosis and initiation of therapy were delayed. The role of vascular rejection in patients with hemodynamic compromise is discussed.

Antibody Formation↗