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Biomedical subjects

R C Young

Publications and source records attributed to R C Young.

At least 145 records · Page 8Linked to original sources
PubMed1990

Total synthesis of the four stereoisomers of dihexadecanoyl phosphatidylinositol and the substrate stereospecificity of human erythrocyte membrane phosphatidylinositol 4-kinase.

A new and convenient method for the preparation of the four stereoisomers of dihexadecanoyl phosphatidylinositol has been developed. An enantiomeric pair of acid-labile, pentaprotected myo-inositol building blocks was synthesized in high yield and coupled with chiral phenyl dihexadecanoylglyceryl phosphates to give the fully protected phosphatidylinositols. These were subsequently deprotected by hydrogenolysis and self-hydrolysis in aqueous ethanol to give the desired pure products. Comparison of these compounds as potential substrates for a partially purified phosphatidylinositol 4-kinase (EC 2.7.1.67) derived from human erythrocyte membranes revealed that the chirality of the inositol ring is crucial for efficient phosphorylation, whereas the chirality of the glycerol moiety is relatively unimportant. Moreover, the similarity in phosphorylation rates of the naturally occurring mammalian phospholipid, I, and its synthetic stereochemical counterpart, compound 10a, suggests that the enzyme is relatively tolerant to changes in fatty acid composition.

1-Phosphatidylinositol 4-Kinase↗
PubMed1990

Purine derivatives as competitive inhibitors of human erythrocyte membrane phosphatidylinositol 4-kinase.

The possibility of deriving a potent, cell-penetrating inhibitor of human erythrocyte PI 4-kinase, competitive with respect to ATP, has been investigated in a series of purine derivatives and analogues. The purine nucleus is not essential for binding to the ATP site but offers the advantage of synthetic accessibility to its derivatives. The optimum substitution pattern in purine was found to be an electron-releasing substituent in the 6-position (e.g. amino, as in adenine, 1) and a compact, lipophilic group in either the 8-position or, preferably, the 9-position, suggesting the importance of the N-1 lone pair and hydrophobic contributions of the 8- and 9-substituents to binding. The most potent inhibitor synthesized was 9-cyclohexyladenine (54), which has an apparent Ki value of 3.7 microM.

1-Phosphatidylinositol 4-Kinase↗
PubMed1990

Inositol phospholipid-dependent cellular signalling: opportunities for drug discovery.

In this review, phosphoinositide metabolism is discussed and potential sites for therapeutic intervention are identified. The rapid recent progress in several branches of inositol chemistry has greatly improved our knowledge of the structural requirements for recognition by a variety of key enzymes involved in the pathways, and by the physiological receptor for D-myo-inositol 1,4,5-trisphosphate. Based on existing leads, drug opportunities arise in reducing polarity, in the utilisation of apolar pro-drugs, and in the development of innovative intracellular delivery systems. The identification of novel pharmacophores for future exploration is likely.

Animals↗
PubMed1990

Late complications of Hodgkin's disease management.

In the past several decades, Hodgkin's disease has been transformed from a uniformly fatal illness to one that can be treated with the expectation of long-term remission or cure in the majority of patients. Because patients now survive for long periods after curative intervention, various complications have been identified. The spectrum of complications following curative therapy is quite diverse and includes immunologic, cardiovascular, pulmonary, thyroid, and gonadal dysfunction. In addition, second malignant neoplasms in the form of acute leukemia as well as secondary solid tumors have now been documented to occur with increased frequency in patients cured of Hodgkin's disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Effect of glutathione on DNA repair in cisplatin-resistant human ovarian cancer cell lines.

We have studied the effect of glutathione reduction by buthionine sulfoximine (BSO), a specific inhibitor of gamma -glutamyl cysteine synthetase, on DNA repair after cisplatin damage in an ovarian cancer cell line with in vitro induced resistance to cisplatin. In addition, we have examined the effect of aphidicolin, a specific inhibitor of DNA polymerase alpha, in combination with BSO on cisplatin-associated DNA repair. BSO treatment was found to partially inhibit DNA repair, and the addition of aphidicolin caused nearly a 100% inhibition in DNA repair activity. Treatment of cells with glutathione ester after BSO resulted in complete recovery of DNA repair activity or partial recovery if aphidicolin was present. The significance of these results to the chemosensitizing effects of BSO medicated glutathione reduction is discussed.

Aphidicolin↗
PubMed1989

Chronicity and relapse in geriatric depression.

Recent advances in the methodology of longitudinal investigations have permitted the identification of predictors of chronicity and relapse of depression. However, findings from mixed-age populations may not be directly applicable to geriatric depression. The effects of medical illness, cognitive dysfunction, and neuroradiological abnormalities on the outcome of geriatric depression merit further evaluation. Late-onset depression requires special attention, since medical and neurological disorders may be particularly important factors in these cases.

Aged↗
PubMed1989

Clonidine challenge of cortisol secretion in dementia and geriatric depression.

The effect of oral clonidine challenge on cortisol secretion was evaluated in seven patients with primary degenerative dementia and in seven patients with major depression. Postclonidine cortisol levels were decreased in all depressed patients and in demented patients with hypercortisolemia at baseline. Demented patients with normal cortisol levels at baseline developed increased post-clonidine cortisol levels. These preliminary findings suggest differences in noradrenergic regulation of cortisol secretion among patients with primary degenerative dementia.

Aged↗
PubMed1989

Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting.

The Ann Arbor classification for describing the stage of Hodgkin's disease at initial presentation has formed the basis upon which treatment is selected and has allowed comparison of results achieved by different investigators for almost two decades. A meeting was convened to review the classification and modify it in the light of experience gained in its use and new techniques for evaluating disease. It was concluded that the structure of the classification be maintained. It was particularly recommended: (1) that computed tomography (CT) be included as a technique for evaluating intrathoracic and infradiaphragmatic lymph nodes; (2) that the criteria for clinical involvement of the spleen and liver be modified to include evidence of focal defects with two imaging techniques and that abnormalities of liver function be ignored; (3) that the suffix 'X' to designate bulky disease (greater than 10 cm maximum dimension) be introduced; and (4) that a new category of response to therapy, unconfirmed/uncertain complete remission (CR[u]), be introduced to accommodate the difficulty of persistent radiological abnormalities of uncertain significance.

Hodgkin Disease↗
PubMed1989

Treatment of localized aggressive lymphomas with combination chemotherapy followed by involved-field radiation therapy.

Localized lymphomas of diffuse and aggressive histology sometimes undergo early hematogenous dissemination such that local therapies (surgery alone or followed by radiation therapy) are not curative in 100% of cases. We have treated 47 clinical stage I or IE patients with aggressive lymphoma histologies (diffuse large-cell, diffuse mixed, diffuse immunoblastic, follicular large-cell, diffuse small-non-cleaved cell) with four monthly cycles of an eight-drug combination chemotherapy program consisting of cyclophosphamide, etoposide, doxorubicin, nitrogen mustard (mechlorethamine), procarbazine, high-dose methotrexate with leucovorin rescue, and prednisone (Pro-MACE-MOPP) administered systemically followed by 40 Gy involved-field radiation therapy. Forty-five (96%) patients achieved a complete remission and no patient has relapsed with a median follow-up time of 42 months (range, 8 to 90). Both patients failing to achieve a complete remission died of lymphoma, and one patient died free of lymphoma 45 months after diagnosis during coronary artery bypass surgery unrelated to lymphoma or its treatment. Hospital admissions were necessary to manage complications on nine of 188 (5%) cycles of treatment. There were no treatment-related deaths. ProMACE-MOPP plus involved-field radiation therapy is safe and effective treatment for localized aggressive lymphoma.

Adult↗
PubMed1989

A role for histamine and H2-receptors in opioid antinociception.

To investigate the role of brain H2-receptors in opioid antinociceptive mechanisms, the effects of several antagonists of histamine H2-receptors were determined on morphine (MOR)-induced antinociception, opioid-mediated footshock-induced antinociception (FSIA) and on other opiate effects in rats. Zolantidine dimaleate (ZOL), the first brain-penetrating H2 antagonist (0.03-1.6 mumol/kg s.c.) caused a dose-related inhibition of MOR antinociception in both the tail-flick and hot-plate tests, with no effect on base-line responding. ZOL also inhibited opioid FISA with a similar potency. MOR-induced locomotor activity was also reduced by ZOL, but no effect was seen on MOR-induced hyperthermia, catalepsy or lethality. ZOL (10(-5) M) was inactive at mu, delta or kappa opioid receptors and showed at least 35-fold higher affinity at the H2-receptor than at receptors for serotonin, dopamine, norepinephrine or acetylcholine in brain. To clarify further the role of H2-receptors in ZOL's antiopiate activity, the potencies of seven structural congeners of ZOL were determined on the H2-receptor and on MOR antinociception. Over 3 orders of magnitude, the rank order of potencies of the compounds for inhibiting MOR antinociception was highly correlated with their potencies as H2 antagonists. Cimetidine, unlike other H2 antagonists, potentiated MOR antinociception, potentiated opioid FSIA and increased brain MOR levels, actions that are not likely to be due to blockade of H2-receptors. These findings strongly suggest that stimulation of opioid receptors leads to antinociception by mechanisms that include activation of brain H2-receptors.

Analgesia↗