Effects of Adenosine Agonists on Intraocular Pressure and Aqueous Humor Dynamics in Cynomolgus Monkeys

The effects of single or multiple topical doses of the relatively selective A₁adenosine receptor agonists (R)-phenylisopropyladenosine (R-PIA) and N⁶-cyclohexyladenosine (CHA) on intraocular pressure (IOP), aqueous humor flow (AHF) and outflow facility were investigated in ocular normotensive cynomolgus monkeys. IOP and AHF were determined, under ketamine anesthesia, by Goldmann applanation tonometry and fluorophotometry, respectively. Total outflow facility was determined by anterior chamber perfusion under pentobarbital anesthesia. A single unilateral topical application of R-PIA (20–250 μg) or CHA (20–500 μg) produced ocular hypertension (maximum rise=4.9 or 3.5 mmHg) within 30 min, followed by ocular hypotension (maximum fall=2.1 or 3.6 mmHg) from 2–6 hr. The relatively selective adenosine A₂antagonist 3,7-dimethyl-1-propargylxanthine (DMPX, 320 μg) inhibited the early hypertension, without influencing the hypotension. Neither 100 μg R-PIA nor 500 μg CHA clearly altered AHF. Total outflow facility was increased by 71% 3 hr after 100 μg R-PIA. In conclusion, the early ocular hypertension produced by topical adenosine agonists in cynomolgus monkeys is associated with the activation of adenosine A₂receptors, while the subsequent hypotension appears to be mediated by adenosine A₁receptors and results primarily from increased outflow facility.     

Neurophysiological correlates of mental arithmetic

Thirteen subjects were extensively trained on nine multiplication problems varying in difficulty. Practice was associated with a reaction time speed up and an attenuation of the problem size effect. The introduction of previously unpracticed problems led to a performance rebound to pretraining levels, indicating practice specificity. The event-related potentials were characterized by a late positive complex, followed by a positive slow wave. Offset latency of positive slow wave and preresponse amplitude at parietal electrodes showed practice specificity effects that systematically changed with practice and problem size, indicating an association with the load imposed on working memory. The peak of the late positive complex probably reflects task learning or adaptation effects because it was attenuated by practice predominantly at frontal electrodes, showed no practice specificity, and was not affected by problem size.     

Isolation,identification, and characterization of a palladium complex in the catalytic deprotection of a protected peptide

The final catalytic deprotection in the large scale synthesis of thymopentin (Arg-Lys-Asp-Val-Tyr) produced an impurity which had not previously been observed. Isolation by preparative HPLC and spectroscopic characterization led to a postulated structure of the impurity as the 1: 1 thymopentin-palladium complex. A complex corresponding to the proposed structure was independently synthesized and shown to have identical chromatographic and spectroscopic properties with the isolated material. Proton and carbon (13) NMR were used to determine the coordination sites of the peptide with palladium. The susceptibility of the complex to hydrogenation indicated a possible source for its formation.     

Crack and cocaine use in South London drug addicts: 1987–1989

There has been great concern in recent years about the abuse of cocaine, particularly in its smokable form ‘crack’. This paper presents data drawn from 441 patients seen by a South London Community Drug Team between 1987 and 1989. Only four (1%) cited cocaine abuse as the main drug problem. Heroin was the most common main drug. Detailed information was available on 355 of these subjects. During the study period 63 patients reported using cocaine and the proportion of subjects using cocaine increased from 13% to 29%. Within the sub-group of cocaine users, there was a marked increase in the use of smokable forms of cocaine from 15% in 1987 to 75% in 1989. In view of the increased dependence risk associated with smoking cocaine, this is seen as an ominous development.     

Flecainide Induced Atrial Tachycardia with 1:1 Ventricular Conduction During Exercise Testing

Wide complex tachycardias may represent a rare proarrhythmic effect of some antiarrhythmic agents. The authors describe a patient who developed a wide complex tachycardia developing during stress testing while on therapy with flecainide, and the difficulty in interpreting the electrocardiogram. This article reviews potential proarrhythmic effects of flecainide in the treatment of atrial dysrhythmias and the difficulty in differentiating associated wide complex tachycardias.     

Methylation in positions 1 and 7 of angiotensin II A structure-activity relationship study

Six analogues of angiotensin II (Ang) were synthesized with modifications in positions 1 and 7. The study was undertaken in order to learn more about the influence of alkylations in positions 1 and 7 and their interdependence. Previous studies have shown that x,x-dimethylation of Gly (aminoisobutyric acid, Aib) in position 1 produces quite potent analogues, as does N-methylation of Gly (sarcosine). Combination of both C^x- and N^x-methylations to N-Me-Aib¹, however, did not produce an affinity increase. Decyclisation of the Pro⁷-residue produced moderately active analogues with position 7 N-methylation and inactive analogues if the N-alkylation was suppressed. In order to investigate a possible stereochemical interdependence of positions 1 and 7, a group of peptides with combinations of position 1 and 7 alkylations were investigated. The following analogues were prepared: [Sar¹, Aib⁷]Ang, [Sar¹,Aib⁷,Leu⁸]Ang, [Aib^1,7]Ang, [Aib^1,7, Leu⁸]Ang, [N-Me-Aib¹,Aib⁷]Ang, [N-Me-Aib¹,Aib⁷,Leu⁸]Ang. They were synthesized by classical solid phase synthesis using the BOC-TFA-HF scheme. The biological properties of these peptides were assessed on the rabbit aorta preparation and their binding potencies were measured on bovine adrenal membranes. Both on agonistic and antagonistic [Leu⁸]Ang analogues single Aib substitutions in position 1 or 7 induced affinity reduction in both bioassays. Simultaneous Aib modifications in positions 1 and 7 induced more important affinity loss in a synergic manner in both bioassays and as well for agonists and antagonists. The N-Me-Aib¹ modifications induce similar affinity loss with or without concomitant Aib⁷ modification. Agonistic (Phe⁸) analogues containing Aib in position 7 all have reduced intrinsic activity, indicating for the first time an influence of this position on the activation mechanism of the Ang receptor of the Type AT₁. © Munksgaard 1994.     

Quantification of CMV viraemia in a case of transfusion-related graft-versus-host disease associated with purine analogue treatment

We report a patient who developed transfusion-associated graft-versus-host-disease (GvHD) and concurrent cytomegalovirus (CMV) infection, both complications thought to be related to severe T lymphocyte depletion induced by treatment with a purine analogue drug, fludarabine. CMV viraemia was detected by qualitative PCR and the viral load in positive samples was measured using a fully quantitative PCR assay. This quantitative assay enabled the evaluation of the efficacy of antiviral interventions based on the qualitative PCR result. The case illustrates the risks associated with the use of purine analogue drugs, as well as the value of quantitative CMV PCR assays for monitoring CMV infection in immunocompromised patients.