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Endogenous opiates, the enkephalins, have been identified in the brain and intestine. Their physiological role in the gut has yet to be determined, but since opiates have anti-diarrhoeal actions it was thought possible that they might be involved in the control of mucosal ion transport in addition to their known effects on motility. This possibility was studied using the lq'in vitro' technique of Ussing and Zerahn. Morphine (10^-6 to 10^-4M) induced a significant fall in potential difference (PD) and short-circuit current (I_sc) across stripped rabbit ileal mucosa, with no change in tissue resistance. A maximal electrical response was dependent on the presence of Na, Cl and HCO₃ in the bathing medium. A significant increase in Cl absorption due to a decrease in serosa to mucosa flux was provoked in response to morphine (2 x 10^-5M), accompanied by an increase in residual ion flux (J^R/_net), possibly due to HCO₃ secretion. Na transport was unaffected. Dextromoramide (10^-5M) mimicked the response to morphine, but the inactive isomer laevomoramide (10^-5M) had no effect. Naloxone (10^-6M) inhibited the response to morphine (2 x 10^-5M) and this inhibition was competitive in nature supporting the existence of mucosal opiate receptors. The enkephalin analogue Me-Tyr-D-Met-Gly-Phe-Pro-NH₂ also decreased the PD and I_sc and produced a similar increase in Cl absorption and J^R/_net. This analogue had a more rapid action and provoked a response at a lower dose (10^-8M) than morphine. Tetrodotoxin (10^-7M) inhibited the response to morphine (10^-4M) but blockade of cholinergic, α and β adrenergic and dopaminergic mechanisms had no effect. Morphine (10^-4M) inhibited the secretion produced by three secretagogues, prostaglandin E₂ (10^-5M), acetylcholine (10^-4M) and cholera toxin (1 μg/ml). Adenyl cyclase and cyclic AMP levels were unaffected by morphine, but the electrical response to morphine was increased by omitting Ca^+ + from the medium. Thus these studies provide evidence for the presence of mucosal opiate receptors which may have a physiological role, and demonstrate that opiates enhance Cl absorption and inhibit secretion provoked by three secretagogues. The mechanism of action may be related to an antagonism to intracellular calcium.

No description available.

This thesis describes the synthetic routes investigated in order to prepare amino estratrienes as potential small molecule mimics of endogenous opioid peptides. 3-Hydroxy-17 a-aminoestra-1,3,5(1 O)-triene was prepared from estra-1,3,5 (1 0)-trien-3,17p-diol by formation of the sulphonate ester 3-benzyloxy-1713- mesyloxyestra-1,3,5(1 O)-triene, displacement of the mesylate ester group with azide anion to give 3-benzyloxy-17a-azidoestra-1,3,5(10)-triene, followed by catalytic hydrogenation. As an altemative to hydrogenation, the Staudinger reaction was performed on the 17 a-azide but gave 3-benzyloxy-17 a( diethylphosphoramido )estra-1,3,5(1 O)-triene. A key compound, 3-Benzyloxy·6-azidomethyl-17p-acetoxyestra-1,3,5(1 0),6- tetraene was obtained from 3,17P-dihydroxyestra-1,3,5(10)-triene in seven steps. The synthesis involved benzylic oxidation of 3,17p-diacetoxyestra-1,3,5(1 O)-triene with chromium trioxide-3,5-dimethyl pyrazole complex to give the key intermediate, 3-benzyloxy-17 p-hydroxyestra-1,3,5(1 0)-trien-6-one. Sulphur ylid methylene insertion at the p-face of the 6-keto derivative gave 3-benzyloxy-6-spiro -epoxy- 17p-hydroxyestra-1 ,3,5(1 O)-triene. Base promoted isomerisation of the 6-spiro -epoxide gave 3-benzyloxy-6-hydroxymethyl-17p-hydroxyestra-1,3,5(10),6- tetraene. The allylic alcohol was acetylated and the key compound obtained from palladium(O)-catalysed allylic azidation. Other alternative approaches involved regioselective nucleophilic ring opening with azide anion of the 6-spiro -epoxide to give 3-benzyloxy-6-hydroxy-6- azidomethyl-17P-hydroxyestra-1,3,5(10)-triene. Manganese (IV) oxidation of the allylic alcohol gave the allylic aldehyde and its oxime, 3-benzyloxy-6-carbaldoxime- 17p-hydroxyestra-1,3,5(10),6-tetraene was obtained upon treatment with hydroxylamine hydrochloride. 3,17P-Bis(tert-butyldimethylsiloxy)estra-1,3,5(1 O)-triene gave [,,6-3,1713- bis(terl-butyldimethylsilyloxy)estra-1,3,5(1 O)-triene ]-tricarbonylchromium upon treatment with chromium hexacarbonyl. However, subsequent benzylic activation at position 6 and treatment with various electrophiles was unsuccessful.

High Performance Liquid Chromatography is currently used for the purpose of analytical evaluation of drugs. This is mainly because it allows the separation method both, a qualitative and a quantitative, analysis of high selectivity mixture evaluation and sensitivity. The diploma thesis deals with the issue of purity evaluation of pharmaceutical substance Nalbufin hydrochloride. The aim of the experimental part of the diploma thesis deals with the development and validation of the analytical method for assessing the purity of Nalbufin hydrochloride.An HPLC method was developed on a Nova-Pak C18 column. The mobile phase consisted of two components A and B. MF A composition was as follows: 0.97 g of sodium octane sulfonate was dissolved in 900 mL of water to which were added 100 mL of acetonitrile and 2 mL of triethylamine. Created solution was treated with phosphoric acid to pH 2.5. MF B had the following composition: 0.86g of sodium octanesulfonate was dissolved in 800 mL of water to which 200 mL was added acetonitrile of 2 mL of TEA. The resulting pH was adjusted to pH 2.5 with phosphoric acid. gradient MF had the following composition: From zero minutes from 100% A to 30 min. to 0% A. The 30-60min. 0% A, 60-61 min. with a linear change to 100% A, 61-70 min. equilibrium into the original conditions to 100% A at a flow rate of 1 mL/min. In the following section we evaluated the basic validation parameters: linear dynamic range 0.3 - 4.5 g/mL, we calculated the linear regression equation for Nalbuphine in R2 (0.9999), Oxycodone R2 (0.9999) and Noroxycodone R2 (0.9998). The method gave us detection limits for Nalbuphine 0.069 g/mL. Oxycodone had a detection limit of 0.053 g/mL and Noroxycodone 0.048mg / mL. The limist of quantification in these cases were 0.209 g / mL for Nalbuphine, 0.161 g/mL for Oxycodone and 0.147 g/mL for Noroxycodone. Repeatability for the limit of quantification was also set expressed by the relative standard deviation. For Nalbuphine - RSD = 0.40%, Oxycodone - RSD = 2.39% and Noroxycodone - RSD = 1.25% (RSD 7.0%). The following validation parameter was accuracy. The resulting RSD was 0.44% (RSD 5.0%). The last evaluated parameter was robustness. For pH 2.4, the change value was resolution of 1.5% and repeatability of RSD = 0.85%. The change of resolution value for pH 2.6 was 2.8% and repeatability RSD = 1.29% (max. 5% limit). The second factor observed for the robustness was the temperature change of the column. The arithmetic average was calculated from the individual peak areas and relative standard deviation RSD = 3.45% was evaluated with the change of resolution, which had a value of 3.34%. Thus, we can state that the developed chromatographic method has been verified in the givenvalidation parameters and is suitable for determining the purity of Nalbuphine hydrochloride.

No / Introduction: Harold Shipman, a general practitioner (GP) working near Manchester in England, is thought to have killed 250 of his patients by diamorphine overdose between 1975 and 1998. Opiates are recommended for relieving dyspnoea in end stage chronic obstructive pulmonary disease (COPD). Little is known about the effect of the Shipman case on clinician attitudes to prescribing of opiates in advanced COPD. Subjects and methods: Focus groups were held with a total of 39 health professionals in primary (n = 3) and secondary care settings (n = 2) in two sociodemographically contrasting areas of England. Results: Participants identified that the experience of dyspnoea in end-stage COPD was often distressing for patients, their families and their professional carers. Whilst opiates were recognised to be effective in relieving dyspnoea, the Shipman case, and associated fears of litigation, was identified as the key barrier to prescribing. Whilst this was seen as a particular problem within primary care settings leading, for example, GPs to admit patients to hospital rather than prescribe opiates, it was also considered an issue within acute hospital settings. Of particular concern to participants was recognising when an exacerbation was 'terminal' and hence opiate prescribing appropriate. Conclusions: There is evidence to show that opiates are effective in managing end-stage dyspnoea in COPD without hastening death. However, participants did not perceive this to be the case and expressed considerable anxiety about appropriate prescribing in this situation. Given the significant burden of dyspnoea on patients with advanced COPD, there is an urgent need for appropriate training to increase clinician confidence regarding opiate use in this patient group which is sensitive to the concerns raised by the Shipman murders.

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