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Ipratropium bromide (IB), typically delivered by pressurized metered dose inhaler (pMDI), is used to treat patients with reversible airways obstruction. Use of the pMDI, unlike the Turbuhaler (TH), demands co-ordination of actuation with inspiration for efficient use. Two studies were carried out to compare the relative efficacy and potency of IB delivered by TH or pMDI. Both studies were of a randomized, double-blind and cross-over design. For the efficacy study, 15 patients received a cumulative dose of 160 microg IB via TH or pMDI as doses of 20, 20, 40 and 80 microg at 45 min intervals on two days. Forced expiratory volume in one second (FEV1) was measured prior to and 40 min after dosing. For the potency study, 33 patients received 10, 20 or 40 microg of IB via TH, 20 microg IB via pMDI, or placebo, on five days. FEV1 was recorded prior to and 15-360 min after dosing. For the efficacy study, there was no difference in FEV1 response to a cumulative dose of IB via pMDI and TH. More than 80% of the maximum effect was seen at the lowest dose (20 microg of IB). Regarding the potency study, the FEV1 response to 20 microg IB administered via pMDI was similar to that of 10 microg via TH; 20 microg via TH was significantly more effective than 20 microg via pMDI (p

The structure-activity relationships of some novel coronary dilator derivatives of palmitoyl carnitine in the rat isolated perfused heart are described. It has been shown previously that esterification of palmitoyl carnitine changes the activity of the compound from a coronary constrictor to a coronary dilator. In this study, it was found that the ester group is not a necessary requirement for coronary dilator activity, but only the absence of the negatively charged carboxylic acid group of palmitoyl carnitine, as compounds containing an ethyl group in place of the ester group were also active coronary dilators. Furthermore, substituting the methyl groups attached to the nitrogen atom of the molecule profoundly altered coronary dilator activity. A quaternary ammonium group was a necessary requirement for potent coronary dilator activity.

AIM: To investigate all patients referred to our center with non-responsive celiac disease (NRCD), to establish a cause for their continued symptoms. METHODS: We assessed all patients referred to our center with non-responsive celiac disease over an 18-mo period. These individuals were investigated to establish the eitiology of their continued symptoms. The patients were first seen in clinic where a thorough history and examination were performed with routine blood work including tissue transglutaminase antibody measurement. They were also referred to a specialist gastroenterology dietician to try to identift any lapses in the diet and sources of hidden gluten ingestion. A repeat small intestinal biopsy was also performed and compared to biopsies from the referring hospital where possible. Colonoscopy, lactulose hydrogen breath testing, pancreolauryl testing and computed tomography scan of the abdomen were undertaken if the symptoms persisted. Their clinical progress was followed over a minimum of 2 years. RESULTS: One hundred and twelve consecutive patients were referred with NRCD. Twelve were found not to have celiac disease (CD). Of the remaining 100 patients, 45% were not adequately adhering to a strict gluten-free diet, with 24 (53%) found to be inadvertently ingesting gluten, and 21 (47%) admitting non-compliance. Microscopic colitis was diagnosed in 12% and small bowel bacterial overgrowth in 9%. Refractory CD was diagnosed in 9%. Three of these were diagnosed with intestinal lymphoma. After 2 years, 78 patients remained well, eight had continuing symptoms, and four had died. CONCLUSION: In individuals with NRCD, a remediable cause can be found in 90%: with continued gluten ingestion as the leading cause. We propose an algorithm for investigation.

The 400 MHz 1H NMR spectrum of captopril in a variety of solvents is analysed and compared with those of epicaptopril and its disulphide analogue. A method for detecting isomeric and oxidative impurities by examination of a 1H NMR spectrum of captopril in DMSO-d6 is proposed. 13C NMR and MS data enable differentiation of captopril from its disulphide analogue but not from its diastereoisomer epicaptopril.

The vasodilator action of the isopropyl ester of palmitoyl carnitine (P1Pi) has been examined in perfused rat hearts and mesenteric vessels. The coronary vasodilator effect P1Pi was not significantly inhibited by flurbiprofen (10 microM), BW755C (10 microM), glibenclamide (10 microM) or the bradykinin B2 receptor antagonist D-Arg0[Hyp3,Thi5,8,D-Phe7]bradykinin (1 microM), indicating that the action of P1Pi is not mediated via arachidonic acid metabolites, ATP-dependent K+ channels or bradykinin B2 receptors. L-NG-Nitro arginine (100 microM) did not inhibit the vasodilator action of P1Pi whilst superoxide dismutase (20 and 50 U.ml-1) attenuated its vasodilator action. Methylene blue (10 microM) caused inhibition in three out of four hearts, while haemoglobin (1 microM) caused an irreversible inhibition of the action of P1Pi which was associated with a depression of myocardial contractility. In air-damaged mesenteric vascular beds the vasodilator action of P1Pi was not attenuated, whilst that of acetylcholine was abolished. In K(+)-depolarised mesenteric vascular beds the constrictor action of Ca2+ was attenuated by P1Pi. Therefore the vasodilator effect of P1Pi appears to be the result of a direct effect on smooth muscle.

Large prolactin-secreting pituitary adenomas with suprasellar extension are often complicated by visual field defects, for which surgical decompression is the accepted treatment. However, surgical management of large prolactinomas is often not curative. This report describes a group of six unselected male patients who presented with visual field defects and reduced visual acuity due to large pituitary tumours with suprasellar extension. All six patients also had loss of libido and/or impotence. A rapid serum prolactin estimation enabled the diagnosis of prolactinoma to be made, and CT revealed a large pituitary adenoma with suprasellar extension. The patients were treated with bromocriptine, in doses increasing from 2.5 to 20 mg daily, as the sole therapy. Symptoms were relieved and serum prolactin levels were restored to normal or near normal; visual field defects resolved and visual acuity recovered in all patients. A repeat CT showed evidence of tumour shrinkage especially of the suprasellar extension, in all the patients. A diagnosis of prolactinoma should always be considered in a patient with a large pituitary tumour. The clinical history and a rapid prolactin assay will confirm the diagnosis. Treatment with bromocriptine leads to rapid improvement in perimetry and visual acuity as well as tumour shrinkage, obviating the need for pituitary surgery.

Chiral cholinergic ligands with actions characteristic of nicotine rather than muscarine (e.g., effects blocked by hexamethonium but not by atropine) have already been encountered in preceding sections of Chapter 8. These include α-methylacetylcholine and muscarone, and a more general account of such agents is now presented. Interpretations of their stereostructure-activity relationships is made difficult by evidence that nicotinic agents often function indirectly by promoting the presynaptic release of ACh,(1–3) a feature of the action of certain muscarinic agents as well.(4) Thus nicotine itself has been classified as having indirect cholinergic action at guinea-pig ileum sites.(1) Tissue incubated with hemicholinium (which inhibits the synthesis of ACh(5) for 15 min) showed a 70–100% reduction in its response to the spasmogenic action of nicotine.

Dopamine (DA) 1 is an achiral molecule and thus presents a case akin to those of acetylcholine and histamine discussed in later chapters in which a pair of pharmacophores are separated by a bimethylene unit. Its receptors, nevertheless, display marked degrees of stereoselectivity toward chiral dopaminergic ligands of both agonist and antagonist character as reviewed by Cannon(1) and a Danish group,(2) respectively, and briefly by Baindur and Neumeyer.(3) The dopamine system has much in common with that of adrenergic agents, including features of in vivo synthesis, metabolism, uptake and release, and interaction with adenylate cyclase.

The preparation of some tropane analogues of pethidine and its reversed ester, chiefly with preferred 3α-m-hydroxyphenyl chair conformations, is described. The former were secured from tropan-3-one in a sequence of reactions involving cyanide attack, hydrolysis, Grignard attack and then rearrangements. The reversed ester was obtained by treating tropan-3-one with lithium phenyl, followed by acylation. Configurational and conformational assignments follow from NMR analysis. The antinociceptive potencies of these compounds in mice are reported, and discussed in relation to non-phenolic congeners and the 4-arylpiperidine moiety of morphine.

The phencyclidine analogues (±)-α-, (±)-β-, and (+)-α- and (–)-α-4-hydroxy-3-methyl-4-phenyl-l-(1-phenylcyclohexyl)piperidine, all with known relative and absolute stereochemistry, have been prepared, and their analgesic potencies related to corresponding prodines. In contrast to the prodines, the (±)-α-phencyclidine analogue was a more potent analgesic than its diastereoisomer, while in agreement with observations in the prodine series, the 3R, 4S-α-enantiomer displayed substantially greater potency than its mirror image form.

The synthesis of the isopropyl ester of carnitine and a series of fatty acid derivatives with fatty acid lengths C8-C30 is described. Bolus doses of these compounds (0·03–300 nmol) showed coronary vasodilator activity in the rat isolated heart. Increasing fatty acid chain length from C8 to C16 resulted in an increased vasodilator potency. Longer lasting vasodilation was observed with the C20 compound. Increasing fatty acid chain length to C30 was associated with a small dilator response preceded by vasoconstriction.

1. The effects of palmitoyl carnitine (PC) and novel derivatives were examined on the isolated Langendorff perfused heart of the rat. 2. Bolus injections of PC (1-300 nmol) produced coronary constriction accompanied by a cumulative irreversible depression of contractility. 3. Prior storage of PC in chloroform containing 2% ethanol in heat-sealed ampoules resulted in production of the ethyl ester of the compound (PCE). This compound was isolated and also synthesized (P1E). In contrast to PC, both PCE and P1E exhibited potent vasodilator activity. 4. Increasing the fatty acid chain length from palmitoyl to stearoyl resulted in a significant reduction in coronary dilator activity of the ester compound, whereas different ester groups did not affect the vasodilator action appreciably. Complete removal of the fatty acid chain abolished all vascular effects at the doses used. 5. The vasodilatation produced by these acyl carnitine esters was comparable to that produced by several known vasodilator drugs including verapamil, cromakalim, amyl nitrate and iloprost; however, the duration of the vasodilator response was more prolonged with the carnitate derivatives.

Atracurium besylate, 2,2′-(3,1 l-dioxo-4,10-dioxatridecylene}-bis-[6,7-dimethoxy-l-(3,4-dimethoxybenzyl)-2-methyl 1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonate is a potent non-depolarising (competitive) neuromuscular blocking agent in the cat, monkey, dog and anaesthetised man. In man, it caused complete paralysis of the tetanic response of the adductor pollicis muscles at doses of 0.2 mg/kg. Blockade was of medium duration with rapid spontaneous recovery, and was readily reversed by neostigmine. The electrocardiogram, heart rate, arterial blood pressure and central venous pressure were virtually unchanged following doses of 0.2-0.4 mg/kg. Intubation was readily accomplished in 1.5-2 min after administration of 0.25-0.3 mg/kg.

The synthesis and stereochemistry (configuration and preferred solute conformation) of some 4-alkyl (methyl, n-propyl, isobutyl)-4-(3-hydroxy-phenyl)-1-methylpiperidines and corresponding 3-methyl diastereoisomeric pairs are reported, together with their in vivo and in vitro activities as opioid ligands. All potent agonists exhibit a preference for axial 4-aryl chair conformations when protonated, and stereochemical analogies with rigid opioids of the benzomorphan class are discussed. Antagonist properties are found in compounds with preference for equatorial 4-aryl chairs, notably the cis 3,4-dimethyl derivative.

The preparation and stereochemical characterization of α- and β-isomers of 1,2-dimethyl-4–m-hydroxyphenyl-4-propiony-loxypiperidine are described. Both the α (axial 4-aryl/chair) and β (equatorial 4-aryl/chair) isomers were of low potency or inactive in mice antinociceptive tests. Shortcomings of the α-isomer as a model for the 4-arylpiperidine moiety of morphine are discussed.

The n.m.r. (1H, 13C) spectra of hydrochloride salts of pethidine, ketobemidone, 4-m-hydroxyphenyl-1,4-dimethylpiperidine, and the reversed ester of pethidine and its analogues are reported. Analysis of the data shows that, apart from the reversed esters, both N-protonated epimers are significantly populated when the salts are dissolved in D2O. The equatorial 4-aryl chair conformer is the major epimer of pethidine and ketobemidone, but the minor form in the case of the 1,4-dimethyl derivative. Little evidence for axial 4-aryl chair epimers has been found for solutes of the reversed esters of pethidine. The results corroborate previous computational studies, and are discussed in terms of differing binding modes of the two classes of 4-arylpiperidine ligand at opioid receptors.