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  • 1
    Electronic Resource
    Electronic Resource
    Impaired endothelium-dependent and independent vasodilation in patients with Type 2 (non-insulin-dependent) diabetes mellitus (1992)
    Springer
    Diabetologia 35 (1992), S. 771-776 
    Details
    ISSN: 1432-0428
    Keywords: Acetylcholine ; NG monomethyl-l-arginine ; endothelium derived relaxing factor ; glyceryl trinitrate ; venous occlusion plethysmography ; Type 2 (non-insulin-dependent) diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The endothelium plays a pivotal role in modulating the reactivity of vascular smooth muscle through the formation of several vasoactive substances. We examined the effects of endothelium-dependent and independent vasodilators on forearm blood flow in 29 patients with Type 2 (non-insulin-dependent) diabetes mellitus and in 21 control subjects, using venous occlusion plethysmography. Via a brachial artery cannula, increasing amounts of acetylcholine and glyceryl trinitrate were infused in doses of 60, 120, 180 and 240 mmol per min and 3, 6 and 9 nmol per min respectively. NG monomethyl-l-arginine, a stereospecific inhibitor of endothelium derived relaxing factor, was infused to inhibit basal and stimulated release of this dilator substance. Reactive hyperaemic forearm blood flow did not differ between groups. Forearm blood flow responses to each dose of acetylcholine were significantly greater in control than diabetic subjects (p〈0.01 for all doses). NG monomethyl-l-arginine attenuated forearm blood flow from maximal stimulated values when responses were compared with the natural decline to acetylcholine in forearm flow in both control and diabetic subjects (p〈0.05 for both groups), but had no effect on basal blood flow responses. Forearm blood flow responses to each dose of glyceryl trinitrate were significantly greater in control than diabetic subjects (p〈0.05 for all). These data provide evidence for endothelial and smooth muscle dysfunction in diabetes which may have important therapeutic implications.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00429099
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  • 2
    Electronic Resource
    Electronic Resource
    Dietary fish oil augments nitric oxide production or release in patients with Type 2 (non-insulin-dependent) diabetes mellitus (1993)
    Springer
    Diabetologia 36 (1993), S. 33-38 
    Details
    ISSN: 1432-0428
    Keywords: Acetylcholine ; NG monomethyl-l-arginine ; nitric oxide ; glyceryl trinitrate ; fish oils ; Type 2 (non-insulin-de-pendent) diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Decreased release of nitric oxide from damaged endothelium is responsible for the impaired endothelium-dependent vasodilator responses found in animal models of vascular disease. Dietary supplementation with fish oils has been shown to augment endothelium-dependent relaxations, principally by improving the release of nitric oxide from injured endothelium. Using forearm venous occlusion plethysmography we studied vascular responses to 60, 120, 180 and 240 nmol/min of acetylcholine (an endothelium-dependent vasodilator) and 3, 6 and 9 nmol/min of glyceryl trinitrate (an endothelium-independent vasodilator) infused into the brachial artery in 23 patients with Type 2 (non-insulin-dependent) diabetes mellitus. NG monomethyl-l-arginine was employed to inhibit stimulated and basal release of nitric oxide from the endothelium. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double-blind crossover fashion for 6 weeks followed by a 6-week washout period and a final 6-week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the active treatment periods at 6 and 18 weeks. Fish oil supplementation significantly improved forearm blood flow responses to each dose of acetylcholine when compared to the vasodilator responses recorded at baseline and after olive oil administration (p〈0.01). Neither fish oil nor olive oil supplementation produced any significant changes in forearm blood flow to the incremental infusions of glyceryl trinitrate when compared with responses recorded during the baseline studies. NG monomethyl-l-arginine significantly reduced forearm blood flow from maximal stimulated values to acetylcholine when compared to the uninhibited decline in flow to acetylcholine infusions at comparable time points (p〈0.01). Treatment with fish oils improved endothelium-dependent responses to acetylcholine without altering endothelium-independent responses to glyceryl trinitrate. By increasing stimulated nitric oxide release from the endothelium fish oils may afford protection against vasospasm and thrombosis in patients with diabetes mellitus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00399090
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  • 3
    Electronic Resource
    Electronic Resource
    Influence of the tissue distribution of ThioTEPA and its metabolite, TEPA, on the response of murine colon tumours (1987)
    Springer
    Cancer chemotherapy and pharmacology 20 (1987), S. 203-206 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Disposition studies in the same animals as those used for assessment of antitumour and toxic effects could increase understanding of the variation in response to cytotoxic drugs. Tissue and plasma levels of ThioTEPA and triethylenephosphoramide (TEPA) were measured to see if any correlation existed between them and the effects of the drug on a series of mouse colon tumours (MAC). The tumour panel included an ascitic form (MAC 15A), an anaplastic (MAC 13) and a well-differentiated (MAC 26) solid tumour, all grown subcutaneously. The maximum tolerated dose of ThioTEPA was 20 mg kg-1 in females bearing MAC 13 and 15 mg kg-1 in males having MAC 15A or 26. The diverse growth characteristics of the tumour cell lines necessitated the use of different methods for assessment of response. After administration of the maximum tolerated dose, the greatest response was observed in MAC 26, in which a growth delay of 15 days — twice the doubling time of the tumour volume — occurred. ThioTEPA produced 58% inhibition of MAC 13 tumour weight, but MAC 15A was unresponsive. One hour after intraperitoneal administration of ThioTEPA (20 mg kg-1), ratios of tissue to plasma concentration were 1.13, 0.87 and 1.17 in tumours and 0.80, 0.75 and 0.73 in spleens of mice bearing MAC 13, 15A and 26 respectively. These data show greater accumulation of drug in neoplastic than in normal tissues. The pattern of distribution of the metabolite was similar, but there was a lesser degree of tissue accumulation than by the drug. Concentrations of drug and metabolite in neoplastic tissues related to their protein content were 116.0, 126.3 and 183.3 μg ThioTEPA/g and 57.5, 83.1 and 78.6 μg TEPA/g in MAC 13, 15A and 26 respectively. Combination of these chemosensitivity and pharmacokinetic data indicates that differences in response of these tumours to ThioTEPA cannot be explained by the availability of the drug and metabolite. The therapeutic effects of ThioTEPA cannot be predicted purely from a knowledge of drug and metabolite disposition.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00570485
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  • 4
    Electronic Resource
    Electronic Resource
    Nonlinear pharmacokinetics for the elimination of 5-fluorouracil after intravenous administration in cancer patients (1982)
    Springer
    Cancer chemotherapy and pharmacology 9 (1982), S. 173-178 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Plasma concentrations of 5-fluorouracil (FU) and its primary catabolite, 5′, 6′-dihydro-5-fluorouracil (DHFU) were measured using gas-liquid chromatography after single-dose therapy with 7.2–14.4 mg/kg. Because of the limited sensitivity of the assay for drug levels in plasma, the urinary excretion of FU and metabolites was investigated using an ion-specific electrode after either a single bolus (7.0–9.6 mg/kg) or multiple-dose therapy (6.4–7.4 mg/kg/day). Half-life values for the elimination of FU from plasma (mean, 123.5 min) were greater in each patient than for the catabolite (mean, 109.2 min). Values of the area under the curve for FU profiles varied between patients (mean±SE, 12.7±1.9 μg·h/ml) by comparison with the relatively constant values for curves of DHFU concentrations (mean±SE, 2.8±0.15 μg·h/ml). In pharmacokinetic profiles of urinary excretion a transient phase of convex shape was apparent after 80%–98% of single doses of FU was excreted. Half-lives for the elimination of FU in urine were 2.6–5.9 h, which increased to 18–44 h on multiple dosing. The results demonstrate saturation in the elimination of FU after therapeutic doses, and are consistent with the proposal that reduction of FU to DHFU provides the rate-limiting step.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00257748
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