Soft [beta]-adrenoceptor agonists for topical use in psoriasis

Psoriasis is characterised by epidermal proliferation and inflammation resulting in the appearance of elevated erythematous plaques. The ratio of c~AMP/c~GMP is decreased in psoriatic skin and when the epidermal cell surface receptors are stimulated by β-adrenergic agonists, intracellular ATP is transformed into c-AMP, thus restoring the c~AMP/c~GMP levels. This thesis describes a series of β-adrenoceptor agonists for topical delivery based upon the soft-drug approach. Soft drugs are defined as biologically active, therapeutically useful chemical compounds (drugs) characterised by a predictable and controllable In vivo destruction (metabolism) to non-toxic moieties. after they achieve their therapeutic role, The N-substituent can accommodate a broad range of structures and here the alkoxycarbonylethyl group has been used to provide metabolic susceptability. The increased polarity of the dihydroxy acid, expected after metabolic conversion of the soft~drug, ethyl N-[2'-(3',4'-dihydroxyphenyl)-2'-hydroxyethyl]-3- aminopropionate, should eliminate agonist activity. Further. to prevent oxidation and enhance topical delivery, the catechol hydroxyl groups have been esterified to produce a pro-soft-drug which generates the soft-drug in enzymic systems. The chemical hydrolysis of the pro-soft-drug proceeded via the formation of the dlpivaloyloxy acid and it failed to generate the active dihydroxy ester soft-drug. In contrast, in the presence of porcine liver carboxyesterase, the hydrolysis of the pro-soft drug proceeded via the formation of the required active soft-drug. This compound, thus, has the appropnate kinetic features to enable it to be evaluated further as a drug for the treatment of psoriasis. The pH rate-profile for the hydrolysis of soft-drug indicated a maximum stability at pH ∼ 4.0. The individual rate constants for the degradation and the pKa were analysed by nonlinear regression. The pKa of 7.40 is in excellent agreement with that determined by direct titration (7.43) and indicates that satisfactory convergence was achieved. The soft-drug was poorly transported across a silicone membrane; it was also air-sensitive due to oxidation of the catechol group. The transport of the pro-soft-drug was more efficient and, over the donor pH range 3-8, increased with pH. At lower values, the largely protonated species was not transported. However, above pH 7. chemical degradation was rapid so that a donor pH of 5-6 was optimum. The β-adrenergic agonist activity of these compounds was tested in vitro by measuring chronotropic and inotropic responses in the guinea pig atria and relaxation of guinea pig trachea precontracted with acetylcholine (10-3 M). The soft~drug was a full agonist on the tracheal preparation but was less potent than isoprenaline. Responses of the soft~drug were competitively antagonised by propranolol (10-6 M). The soft~drug produced an increase in force and rate of the isolated atrial preparatIon. The propyl analogue was equally potent with ED50 of 6.52 x 10-7 M. In contrast, at equivalent doses, the dihydroxy acid showed no activity; only a marginal effect was observed on the tracheal preparation. For the pro~soft-drug, responses were of slow onset, in both preparations, with a slowly developing relaxatlon of the tracheal preparatlon at high concentrations (10-5 M). This is consistent with in vitro results where the dipivaloyl groups are hydrolysed more readily than the ethyl ester to gIve the active soft-drug. These results confirm the validity tif the pro-soft-drug approach to the deUvery of β-adrenoceptor agonists.

The experiences of con sultations on oral anticoagula-tion for AF:the importance of qualitative research incardiovascular sciences

Objectives: Multiple-perspective qualitative designs can aid researchersto develop a more multifaceted account of a phenomenon and as aform of triangulation of data. Two interlinking studies aimed toexplore patients’ and physicians’ experiences of atrial fibrillation (AF)and warfarin.Methods: Audio-recorded semistructured individual interviews wereused. Study 1: Three AF patient subgroups were interviewed (n = 11);accepted, refused, or discontinued warfarin. Study 2: Four physiciansubgroups (n = 16): consultant cardiologists, consultant general physi-cians, general practitioners, and cardiology registrars. Data was ana-lyzed using interpretative phenomenological analysis, a qualitativemethodology.Results: Study 1: Three overarching themes comprised patients’ experi-ences: the initial consultation, life after the consultation, and patients’reflections. Patients commented on the reassurance experienced duringthe consultation, but they perceived the decision-making processmostly led by the physician. Lack of education and take-home materi-als during the initial consultation were highlighted. Patients’ uptake ofinformation was influenced by past experiences and knowledge ofstroke and/or bleeding. Study 2: Two overarching themes covered phy-sicians’ experiences: communicating information and challenges withwarfarin prescription for AF. Physicians’ approach to the consultationstyle shifted through a continuum of compliance-adherence-concor-dance during the consultation. Time and the perceived patient trust inthem as the expert led to physicians to adopt a paternalistic approach.Guideline adherence and the need to adopt a multidisciplinaryapproach were pointed out as current challenges.Conclusion: There is a need to target patients’ and physicians’ abilityto communicate with each other in a comprehensible way. This projecthas illustrated the benefit of using a qualitative approach to under-stand the lived experience of the physician–patient consultation.Disclosure of Interest: None declare