S-nitrosocaptopril: acute in-vivo pulmonary vasodepressor effects in pulmonary hypertensive rats

The effects of S-nitrosocaptopril (SNOcap), administered either intravenously or by oral gavage, on pulmonary artery pressure (PAP) were examined in anaesthetised normotensive rats and rats with hypoxic pulmonary hypertension (10% oxygen for 1 week). Mean PAP (MPAP) values in hypoxic and normoxic rats were (mmHg) 26 +/- 1.7 and 15 +/- 1.1, respectively. When given intravenously, 1 mg kg(-1) SNOcap reduced MPAP by 28 and 32% in hypoxic and normoxic rats, respectively. The effects of 2 mg kg(-1) were no greater than those of 1 mg kg(-1). Pulmonary vasoclepressor responses reached equilibrium in 1.7 +/- 0.18 min following intravenous administration. When given orally 30 min before the measurement of PAP, 30 mg kg(-1), but not 10 mg kg(-1), significantly reduced MPAP in hypoxic rats to 17 +/- 1.5 mmHg. These in-vivo data are consistent with previous in-vitro data showing that SNOcap has direct pulmonary vasorelaxant properties in both large and small pulmonary arteries and also show that SNOcap causes pulmonary vasodepression in the setting of pulmonary hypertension. Since SNOcap also inhibits pulmonary vascular angiotensin converting enzyme (ACE) in pulmonary blood vessels (previous study), it would be an interesting drug with which to assess the benefits of direct pulmonary vasodilatation combined with ACE inhibition (which attentuates pulmonary vascular remodelling) in a long-term study in pulmonary hypertension.

Clinicians' attitudes to clinical practice guidelines

To the Editor: In their systematic review of clinicians' attitudes to clinical practice guidelines, Farquhar et al1 found that, although healthcare providers reported high satisfaction with guidelines, a significant number also expressed concerns about their practicality, their role in cost-cutting and their potential for increasing litigation. The review, however, did not address other potentially significant concerns of clinicians regarding the perceived validity of guidelines and the influence of external agencies (such as the pharmaceutical industry) on treatment recommendations.

Effect of vehicle pretreatment on the flux, retention, and diffusion of topically applied penetrants in vitro

Purpose. The flux of a topically applied drug depends on the activity in the skin and the interaction between the vehicle and skin. Permeation of vehicle into the skin can alter the activity of drug and the properties of the skin barrier. The aim of this in vitro study was to separate and quantify these effects. Methods. The flux of four radiolabeled permeants (water, phenol, diflunisal, and diazepam) with log K-oct/water values from 1.4 to 4.3 was measured over 4 h through heat-separated human epidermis pretreated for 30 min with vehicles having Hildebrand solubility parameters from 7.9 to 23.4 (cal/cm(3))(1/2). Results. Enhancement was greatest after pretreatment with the more lipophilic vehicles. A synergistic enhancement was observed using binary mixtures. The flux of diazepam was not enhanced to the same extent as the other permeants, possibly because its partitioning into the epidermis is close to optimal (log K-oct 2.96). Conclusion. An analysis of the permeant remaining in the epidermis revealed that the enhancement can be the result of either increased partitioning of permeant into the epidermis or an increasing diffusivity of permeants through the epidermis.

Evaluation of cyclooxygenase 2 inhibitor use in patients admitted to a large teaching hospital

Background: The heavy usage of coxibs in Australia far outstrips the predicted usage that was based on the treatment of patients with risk factors for upper gastro-intestinal adverse events from conventional anti--inflammatory agents. This raises questions regarding the appropriateness of prescribing. Aims: To determine: (i) the relationship between prescriptions for cyclooxygenase 2 (COX-2) inhibitors and objective evidence of inflammatory arthritis, (ii) prior experience with paracetamol and/or conventional non-steroidal anti-inflammatory drugs (NSAIDs), and (iii) contraindications to the use of NSAIDs. Methods: Drug utilization evaluation and rheumato-logical assessment was conducted on 70 consecutive patients admitted on COX-2 inhibitors to a 480-bed metropolitan hospital. The main outcome measures were: the indication for COX-2 inhibitor; objective -evidence of inflammatory arthritis; previous trial of -paracetamol or conventional NSAIDs; and patient -satisfaction. Results: Only 11 patients (16%) had symptoms or signs of an inflammatory arthropathy, and met Pharmaceut-ical Benefits Schedule criteria for prescribing a COX-2 inhibitor. Fifty-nine patients (84%) had chronic osteo-arthritis, degenerative spinal disease, injury or malignancy, without overt active inflammation. Fourteen patients (20%) had trialled regular paracetamol prior to using any NSAID treatment. Conventional NSAIDs had been previously used by 51 patients (73%). Eleven patients (16%) reported previous adverse gastrointestinal effects from conventional NSAIDs. On the basis of significant renal impairment (creatinine clearance 5/10). Conclusions: Drug utilization data indicate that COX-2 inhibitors are frequently used first line for degenerative osteoarthritis in the absence of overt inflammation, without prior adequate trial of paracetamol and with disregard for the cautions and contraindications of these agents. These findings may explain the unprecedented Pharmaceutical Benefits Schedule expenditure on COX-2 inhibitors in Australia.

Transdermal penetration of vasoconstrictors - Present understanding and assessment of the human epidermal flux and retention of free bases and ion-pairs

Purpose. As reductions in dermal clearance increase the residence time of solutes in the skin and underlying tissues we compared the topical penetration of potentially useful vasoconstrictors (VCs) through human epidermis as both free bases and ion-pairs with salicylic acid (SA). Methods. We determined the in vitro epidermal flux of ephedrine, naphazoline, oxymetazoline, phenylephrine, and xylometazoline applied as saturated solutions in propylene glycol: water (1: 1) and of ephedrine, naphazoline and tetrahydrozoline as 10% solutions of 1: 1 molar ratio ion-pairs with SA in liquid paraffin. Results. As free bases, ephedrine had the highest maximal flux, Jmax = 77.4 +/- 11.7 mug/cm(2)/h, being 4-fold higher than tetrahydrozoline and xylometazoline, 6-fold higher than phenylephrine, 10-fold higher than naphazoline and 100-fold higher than oxymetazoline. Stepwise regression of solute physicochemical properties identified melting point as the most significant predictor of flux. As ion-pairs with SA, ephedrine and naphazoline had similar fluxes (11.5 +/- 2.3 and 12.0 +/- 1.6 mug/cm(2)/h respectively), whereas tetrahydrozoline was approximately 3-fold slower. Corresponding fluxes of SA from the ion-pairs were 18.6 +/- 0.6, 7.8 +/- 0.8 and 1.1 +/- 0.1 respectively. Transdermal transport of VC's is discussed. Conclusions. Epidermal retention of VCs and SA did not correspond to their molar ratio on application and confirmed that following partitioning into the stratum corneum, ion-pairs separate and further penetration is governed by individual solute characteristics.

Unexpected clobetasol propionate profile in human stratum corneum after topical application in vitro

Purpose. The validity of using drug amount-depth profiles in stratum corneum to predict uptake of clobetasol propionate into stratum corneum and its transport into deeper skin layers was investigated. Methods. In vitro diffusion experiments through human epidermis were carried out using Franz-type glass diffusion cells. A saturated solution of clobetasol propionate in 20% (V/V) aqueous propylene glycol was topically applied for 48 h. Steady state flux was calculated from the cumulative amount of drug permeated vs. time profile. Epidermal partitioning was conducted by applying a saturated drug solution to both sides of the epidermis and allowing time to equilibrate. The tape stripping technique was used to define drug concentration-depth profiles in stratum corneum for both the diffusion and equilibrium experiments. Results. The concentration-depth profile of clobetasol propionate in stratum corneum for the diffusion experiment is biphasic. A logarithmic decline of the drug concentration over the first four to five tape strips flattens to a relatively constant low concentration level in deeper layers. The drug concentration-depth profile for the equilibrium studies displays a similar shape. Conclusions. The shape of the concentration-depth profile of clobetasol propionate is mainly because of the variable partitioning coefficient in different stratum corneum layers.