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Biomedical subjects

J E Arrowsmith

Publications and source records attributed to J E Arrowsmith.

30 records · Page 2Linked to original sources
PubMed1991

Measurement of the class III antidysrhythmic drug, UK-68,798, in plasma by radioimmunoassay.

A sensitive radioimmunoassay (RIA) for the specific determination of 1-(4-methanesulphonamidophenoxy)-2-[N-(4-methanesulphonamido -phenethyl)-N- methylamino]ethane (UK-68,798), a novel class III antidysrhythmic agent, in human plasma is described. Specific antisera were raised in sheep using desmesyl-UK-68,798-succinate-ovalbumin conjugate as the antigenic hapten carrier protein. The antisera produced exhibited high specificity for UK-68,798 compared with known metabolites from animals, other antidysrhythmic agents and co-administered drugs. Good correlation was found in a comparison of the RIA method with a high-performance liquid chromatography (HPLC) method (r = 0.997) and a 10-fold lower limit of determination was observed for the RIA method compared with the HPLC method (0.05 and 0.5 ng ml-1, respectively). The RIA method was applied to the analysis of UK-68,798 in plasma obtained from human volunteers receiving the compound.

Animals↗
PubMed1991

UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells.

UK-68,798 increased the duration and effective refractory period of cardiac action potentials recorded in vitro from canine ventricular muscle and Purkinje fibers in a concentration dependent manner from 5 nM to 1 microM. The resting membrane potential, amplitude and maximum upstroke velocity of action potentials were unaffected by UK-68,798, indicating the selective class III antiarrhythmic properties of this agent. UK-68,798 (5 nM-1 microM) increased the effective refractory period of isolated guinea pig papillary muscles at stimulation frequencies of 1 Hz and 5 Hz without influencing the conduction velocity, further confirming that UK-68,798 is devoid of class I antiarrhythmic activity including block of the sodium channel. Studies using single voltage clamped guinea pig ventricular myocytes indicated that UK-68,798 at concentrations of 50 nM and 2 microM blocks a time-dependent K+ current, with no appreciable effects on the time-independent K+ current or the inward calcium current. UK-68,798 is therefore a highly selective K+ channel blocking agent with class III antiarrhythmic properties, a profile that holds considerable promise for the therapy of life-threatening cardiac arrhythmias.

Action Potentials↗
PubMed1990

Selective class III antiarrhythmic agents. 1 Bis(arylalkyl)amines.

A series of bis(arylalkyl)amines is described and their effects on prolonging effective refractory period in isolated cardiac tissue listed. Most compounds prolonged the cardiac action potential without significantly altering the maximum rate of depolarization and may be defined as selective class III antiarrhythmic agents. It was found that a particularly advantageous structural feature was to have a methanesulfonamido moiety on both of the aryl rings. Thus, compound 16 [1-(4-methanesulfonamidophenoxy)2-[N-(4-methanesulfonamidophene thyl)-N- methylamine]ethane] was selected for further investigations. The compound is highly potent and selective class III agent which acts by blockade of cardiac potassium channels.

Action Potentials↗
PubMed1990

Local anaesthesia for fibreoptic bronchoscopy: transcricoid injection or the "spray as you go" technique?

Local anaesthesia for fibreoptic bronchoscopy should be given by a safe technique that is not unpleasant to the patient and should provide acceptable conditions for the bronchoscopist. Single injection transcricoid local anaesthesia was compared with the "spray as you go" technique in patients having day case fibreoptic bronchoscopy. Patients were randomised to receive either 100 mg lignocaine by a single cricothyroid puncture or 240 mg lignocaine instilled through the bronchoscope under direct vision. Further doses were given by the operator to both groups as required. The 30 patients receiving transcricoid lignocaine coughed less (3.56 (SD 3.1) coughs/min) than the 32 patients receiving lignocaine through the bronchoscope (5.89 (4.8)/min) despite receiving a lower total dose of lignocaine (322 (25.9) v 451 (20.9) mg). Cricothyroid puncture was not associated with any complications and was not unpleasant for the patients.

Administration, Topical↗
PubMed1989

Long acting dihydropyridine calcium antagonists. 2. 2-[2-Aminoheterocycloethoxy]methyl derivatives.

A series of [(2-aminoheterocycloethoxy)methyl]dihydropyridines were prepared as selective coronary vasodilators. Results showed that a wide variety of five- and six-membered heterocycles were acceptable at the 2-position of the dihydropyridine ring and in vitro potency and tissue selectivity was independent of the basicity of these heterocycles. The SAR indicated that activity was optimum when the largest ester group was placed at the 3 rather than 5 position. 2-[[2-[(3-Amino-1H-1,2,4-triazol-5-yl)amino]ethoxy]methyl]-4- (2,3-dichlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl- 1,4-dihydropyridine (3b) (UK-52,831) emerged as a potent (IC50 = 6.3 X 10(-9) M) and tissue-selective calcium channel blocker with a duration of action greater than 7 h in the anaesthetized dog.

Animals↗
PubMed1986

Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents.

A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting in effect. The two enantiomers have been prepared, and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen.

Amlodipine↗