Skin tolerability associated with transdermal drug delivery systems: an overview

As transdermal patches become more widely prescribed, it is important that clinicians understand: (a) the common causes of skin reactions with these medications; (b) how to minimize these reactions; and (c) how to manage the signs and symptoms. Here we review published data for skin reactions with patch medications approved within the past decade. Overall, the most common application site signs and symptoms appear to be localized redness (erythema) or itching, sometimes accompanied by swelling (edema). Typically, these are mild to moderate in severity, transient in nature, and occur in 20% to 50% of patients. Most are localized to the area of application, and resolve spontaneously within several days following patch removal. Discontinuations due to these types of event are infrequent, ranging from 1.7% to 6.8% in the 6-month trials reviewed here. Based on expert opinion, the majority of these skin reactions would be a form of irritant contact dermatitis, with infrequent cases of allergic contact dermatitis. These types of reactions usually cause minimal pain or discomfort to the patient, and are unlikely to be of medical concern. Signs and symptoms of irritant contact dermatitis may be minimized by rotation of the application site, careful removal of the patch, and appropriate use of moisturizers and topical corticosteroids. In conclusion, the potential advantages of transdermal patches usually outweigh any additional skin issues; however, further research into treatment and management strategies is required.     

Prevalence of intracranial large artery stenosis and occlusion in patients with acute ischaemic stroke or TIA

Intracranial large artery stenosis and occlusion disease has been considered to be the cause of 8–10 % of ischaemic strokes in North America, and 30–50 % of strokes and more than 50 % of transient ischaemic attacks in Chinese population. So far we do not know the real prevalence of intracranial disease (ID) and the distribution of its risk factors in European population. We aimed to determine the prevalence and risk factors of ID in a European stroke population with computed tomography angiography (CTA). A retrospective study of consecutive ischaemic patients at the Stroke Unit of Utrecht, The Netherlands, from September 2006 to August 2008 was conducted. We assessed the presence of occlusion and/or stenosis of intracranial Internal Carotid Artery (ICA) and Middle Cerebral Artery on post-contrast 30-mm reconstruction axial CTA images. We analyzed the proportion of patients with ID, and the association of ID with risk factors and stroke subtype. In 220 patients (187 with stroke, 33 with TIA; mean age was 65 years, 57.3 % were male), intracranial stenosis was found in 6.4 % (95 % CI 3.9–10.4), intracranial occlusion in 34.5 % (95 % CI 28.6–41.0), and both occlusion and stenosis in 2.3 % (95 % CI 1.0–5.2). Multivariate analysis showed that the variables independently associated with ID were: extracranial ICA atherosclerosis (OR, 24.64; 95 % CI 6.30–96.38) and stroke subtypes TACS–PACS (OR, 7.61; 95 % CI 3.31–17.49). In conclusion, prevalence of intracranial stenosis in our study may well be consistent with previous observations in European and non-European population. ID may have been an underestimated condition in ischaemic Caucasian population.     

Enhanced contractility of small blood vessels in JNK knockout mice

The c-Jun N-terminal kinases (JNKs) form a subfamily of the mitogen-activated protein kinases (MAPK). These signalling pathways regulate various processes such as mitosis, cellular differentiation, stress response or apoptosis in multicellular organisms. There is rising evidence about the role of JNKs activities in neurodegenerative and metabolic diseases as well as in immunological disorders. The physiological functions of JNKs, however, remain to be elucidated. Recent data have demonstrated an essential role of JNKs in the cardiovascular system and the regulation of carbon hydrate and glucose metabolism. Therefore, we have investigated the contractility of blood vessels in mice with genetically deleted JNK1, JNK2, JNK3 and JNK2+3 isoforms and their respective wildtypes. The contractility of the isolated segments from A. carotis communis was measured by small blood vessel wire myograph. Contraction induced by 80 mM KCl was significantly increased in arteries from JNK2+3 double knockout compared to controls and single knockouts. The maximal contraction generated by the -agonists phenylephrine or noradrenaline (10 μM) was significantly enhanced in JNK2+3 knockout arteries compared with arteries from the remaining strains. Inhibition of NOS by Nw-nitro-l-arginine did not change the pattern of vasoconstriction, but vasoconstriction by noradrenaline following NOS inhibition was significantly enhanced in the arteries from JNK2+3 double knockout mice.

In conclusion, genetic deletion of JNK2+3 in mice results in altered contractility of carotid arteries and this might depend on the function of the smooth muscles rather than on the endothelium. These findings have implications for the long-term treatment with pharmacological JNK inhibitors for neurodegenerative or metabolic diseases such as stroke or diabetes.     

Effects of ondansetron on portal hemodynamics in liver cirrhosis

OBJECTIVE: The double-blind randomized pilot study was undertaken to compare the effects of a 10-day course of ondansetron 8 mg/day and propranolol 80 mg/day perorally in treating portal hypertension. SUBIECTS AND METHODS: 16 patients with liver disease were enrolled in the study. Measurements of portal vein diameter, portal blood flow velocity and portal blood flow volume were done at days 1, 5 and 10 of treatment using duplex Doppler sonography. RESULTS: The propranolol group demonstrated a decrease in portal venous diameter, while patients treated with ondansetron exhibited reduced portal blood flow velocity values. A decreased portal blood flow volume was found in both groups after 10 days of therapy. CONCLUSION: No statistically significant differences were found between the groups with the exception of portal venous diameter which is significantly lower at the end of the treatment in the case of propranolol.     

Decreased cortisol secretion by adrenal glands perfused with the P-glycoprotein inhibitor valspodar and mitotane or doxorubicin

The aim of this study was to investigate the role of P-glycoprotein (P-gp) in the adrenal gland. It has been presumed that P-gp, rather than being involved in physiological cortisol secretion, plays a role in protecting the adrenacortical cells from xenobiotics. To explore this a study was performed on perfused bovine adrenal glands. Individual experimental groups were perfused with either a selective P-gp blocker (valspodar) alone, with a xenobiotic (mitotane or doxorubicin) alone or with both valspodar and a xenobiotic. The cumulative amounts of cortisol secreted in each individual group were calculated and the two-sample t-test was used to compare the mean values of cumulative amounts. The mean value of cortisol secreted from the group of adrenals perfused with the P-gp blocker was not significantly different from that of the control group. Treatment with either mitotane or doxorubicin decreased the amount of cortisol secreted but not significantly when compared to the amount of cortisol secreted in basal conditions. However, treatment with the P-gp blocker valspodar in addition to either mitotane or doxorubicin significantly decreased cortisol secreted compared to the amount of cortisol secreted by the glands treated with either mitotane (p=0.009) or doxorubicin (p=0.017) alone. The regressive changes discovered in all experimental groups were most prominent when valspodar was used with either mitotane or doxorubicin. We found that P-gp blockade increases by xenobiotic (mitotane and doxorubicin)-induced damage of adrenocortical cells, which points to a role of P-gp in the protection of adrenal gland from xenobiotics.