Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne's muscular dystrophy, with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment. (Funded by Prosensa Therapeutics; Netherlands National Trial Register number, NTR1241.).

Mirtazapine is the first noradrenergic and specific serotonergic antidepressant ('NaSSA'). It is rapidly and well absorbed from the gastrointestinal tract after single and multiple oral administration, and peak plasma concentrations are reached within 2 hours. Mirtazapine binds to plasma proteins (85%) in a nonspecific and reversible way. The absolute bioavailability is approximately 50%, mainly because of gut wall and hepatic first-pass metabolism. Mirtazapine shows linear pharmacokinetics over a dose range of 15 to 80mg. The presence of food has a minor effect on the rate, but does not affect the extent, of absorption. The pharmacokinetics of mirtazapine are dependent on gender and age: females and the elderly show higher plasma concentrations than males and young adults. The elimination half-life of mirtazapine ranges from 20 to 40 hours, which is in agreement with the time to reach steady state (4 to 6 days). Total body clearance as determined from intravenous administration to young males amounts to 31 L/h. Liver and moderate renal impairment cause an approximately 30% decrease in oral mirtazapine clearance; severe renal impairment causes a 50% decrease in clearance. There were no clinically or statistically significant differences between poor (PM) and extensive (EM) metabolisers of debrisoquine [a cytochrome P450 (CYP) 2D6 substrate] with regard to the pharmacokinetics of the racemate. The pharmacokinetics of mirtazapine appears to be enantioselective, resulting in higher plasma concentrations and longer half-life of the (R)-(-)-enantiomer (18.0 +/-2.5h) compared with that of the (S)-(+)-enantiomer (9.9+/-3. lh). Genetic CYP2D6 polymorphism has different effects on the enantiomers. For the (R)-(-)-enantiomer there are no differences between EM and PM for any of the kinetic parameters; for (S)-(+)-mirtazapine the area under the concentration-time curve (AUC) is 79% larger in PM than in EM, and a corresponding longer half-life was found. Approximately 100% of the orally administered dose is excreted via urine and faeces within 4 days. Biotransformation is mainly mediated by the CYP2D6 and CYP3A4 isoenzymes. Inhibitors of these isoenzymes, such as paroxetine and fluoxetine, cause modestly increased mirtazapine plasma concentrations (17 and 32%, respectively) without leading to clinically relevant consequences. Enzyme induction by carbamazepine causes a considerable decrease (60%) in mirtazapine plasma concentrations. Mirtazapine has little inhibitory effects on CYP isoenzymes and, therefore, the pharmacokinetics of coadministered drugs are hardly affected by mirtazapine. Although no concentration-effect relationship could be established, it was found that with therapeutic dosages of mirtazapine (15 to 45 mg/day), plasma concentrations range on average from 5 to 100 microg/L.

GENETICALLY hypertensive rats appear to be less responsive to noxious stimuli than their normotensive controls. 1 A similar finding has been reported in rats with renal hypertension 1 ' 2 and in humans with essential hypertension.3 Therefore a relationship between the central regulatory mechanisms involved in pain sensitivity and blood pressure may exist.Other data also indicate a possible relationship between these regulatory mechanisms. The hypotensive drug clonidine appears to cause analgesia in rats 4 ' 5 and a decrease in blood pressure in spontaneously hypertensive rats (SHR), which can be prevented by the opiate antagonist naloxone.6 Furthermore, clonidine alleviates opiate withdrawal symptoms in morphinetreated animals; 5 in this respect it is also important that opioid peptides are involved in both pain perception and analgesia and central cardiovascular control.7 "" We have studied the response to thermal and threshold electric stimuli of SHR, Wistar-Kyoto (WKY) controls, renal (two-kidney, one clip Goldblatt), and DOCA-salt hypertensive Wistar rats, together with the appropriate sham-operated control animals. These responses were assessed repeatedly during the development of hypertension and on one occasion only in animals with developed hypertension. Methods and MaterialsMale SHR, WKY rats, and regular normotensive Wistar (Wu/Cpb) rats were obtained from Central Breeding Laboratories TNO (Zeist, the Netherlands). Production of Hypertension Renal HypertensionUnder ether anesthesia, renal hypertension was induced by the application of a solid silver clip (0.20 mm, i. d.) to the left renal artery of rats weighing 120 to 130 g.12 Control animals were subjected to the same operative procedure, but no clip was applied. DOCA-Salt HypertensionDOCA-salt hypertension was produced by the subcutaneous implantation of deoxycorticosterone (two pellets containing 20 mg each) under pentobarbitone

Pain sensitivity in Spontaneously Hypertensive Rats (SHR) and normotensive Wistar-Kyoto controls (WKY) as well as in experimentally hypertensive Wistar rats has been studied. Results indicate a diminished responsiveness to noxious stimuli in SHR when compared with WKY. This hypoalgesia is altered neither by chronic treatment with the antihypertensive drugs hydralazine and captopril nor by the peripherally acting opiate antagonist N-methylnaloxone. Induction of renal and DOCA-salt hypertension in Wistar rats and Wistar-Kyoto rats did not affect nociceptive responsiveness. It is concluded that opiate receptors within the central nervous system are involved in the hypoalgesia in SHR and that pain perception appears to be dissociated from blood pressure regulation in the rat strains used.

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