The plasma pharmacokinetics of alpha-dihydroergocryptine (DHEC, CAS 14271-05-7) were investigated in 24 patients with Parkinson disease after the administration of repeated oral doses of 40 mg DHEC twice daily by means of a novel 40 mg DHEC tablet (Almirid 40 mg test T) and an established 20 mg DHEC tablet (Almirid 20 mg - reference R). The trial was conducted according to a randomised, controlled, open, within-subject cross-over design; steady-state was established by means of a stepwise up-titration from 5 to 40 mg b.i.d. from day D01 to D19; investigational treatments (40 mg DHEC b.i.d. by means of formulation R and T) were administered on day D20 and D21 according to a randomised, period-balanced within-subject cross-over; treatment with DHEC was down-titrated in stepwise fashion from day D22 to D34. Morning doses of 2 x 20 mg DHEC (reference) yielded a fast and relatively short lasting peak with a geometric mean Cmax of 2157 pg/mL (CV: 0.978) after a median tmax of 1.00 h. Cmin throughout the first 12 h was on average 189 pg/mL (CV: 0.908). There was a quite distinct diurnal effect: evening doses of 2 x 20 mg DHEC (treatment R), yielded a relatively lower exposure with geometric mean Cmax, Cav- and Cmin-values of 800 pg/mL (CV: 0.870), 389 pg/mL (0.813) and 177 pg/mL (CV: 0.942). In contrast, there was relatively little within-subject distinction between the two formulations: for the day profile after the morning dose, the estimated ratios of the true means (Pr:R) for Cmax Cmin and Cav were 1.18 (90% CI: 0.96 to 1.43 - CVm: 0.394), 0.96 (90% CI: 0.86 to 1.09 - CVm: 0.230) and 1.06 (90% CI: 0.93 to 1.21 - CVm: 0.254); for the night profile after the evening dose, the estimated ratio of the true means (muT:muR) for Cmax, Cmin and Cav were 1.11 (90% CI: 0.91 to 1.35 - CVm: 0.395), 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.232) and 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.220). In view of important medical-ethical constraints not to expose an unreasonably high number of subjects, these findings could be accepted as a sufficient demonstration of bioequivalence.

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ZusammenfassungZiel der Studie ist es, die distale, motorische Latenz (DML) und die residuale Latenz (RL) in frühen Stadien der diabetischen und alkoholischen PNP zu vergleichen. Es wurden 74 Patienten mit Diabetes, 40 mit Alkoholkrankheit und 70 gesunde Probanden untersucht. Die Patienten wurden in zwei Gruppen entspre− chend der konventionell gemessenen Nervenleitgeschwindigkeit eingeteilt. Gruppe 1: Patienten mit normaler Leitgeschwindig− keit (NLG); Gruppe 2: Patienten mit verlangsamter NLG im Ver− gleich zur Kontrollgruppe. Die Untersuchungen wurden am N. medianus und N. ulnaris durchgeführt. Die Muskelantworten wurden in üblicher Weise mit Oberflächenelektroden vom M. abductor pollicis brevis und M. abductor digiti minimi abgeleitet. Die DML für die Gesunden betrugen 2,91 0,24 ms für den N. ul− naris und 3,01 0,15 ms für den N. medianus. Die entsprechen− den Werte für die RL lagen bei 1.59 0,16 ms für den N. Ulnaris und 1,71 0,15 ms für den N. medianus. Es fand sich eine signifi− kante Verlängerung (p < 0,001) der DML und der RL bei den Neu− ropathien betreffend beide Nerven im Vergleich zur Kontroll− gruppe. Die Verzögerungen waren größer in Gruppe 2, wobei die Differenzen zwischen Gruppe 1 und Gruppe 2 nur für den N. medianus signifikant waren. Für den N. medianus war im Gegen− satz zum N. ulnaris der Mittelwert der RL signifikant größer als der der DML sowohl für Gruppe 1 als auch für Gruppe 2. Somit erscheint die RL als sensitiver als die DML und kann als wertvol− ler diagnostischer Parameter im frühen Nachweis der beschrie− benen Neuropathien gelten. AbstractThe aim of the present study was to compare the residual latency (RL) with the distal motor latency (DML) in the evaluation of ear− ly diabetic and alcoholic neuropathy. Patients with diabetes mel− litus (74), alcohol dependence (40) and healthy subjects (70) were included. Patients were divided into two groups based on conventional nerve conduction studies: Group 1: normal motor conduction velocity (MCV) and group 2: decreased MCV compar− ed with the control group. MCV of the median and ulnar nerve was examined. Compound muscle action potentials of the ab− ductor digiti minimi and abductor pollicis brevis muscles were recorded using standard surface techniques. The mean DML in healthy subjects was 2.91 0.24 and 3.01 0.15 ms for the ulnar and median nerve, respectively. The corresponding values for the RL were 1.59 0.16 and 1.71 0.15 ms. There was a significant prolongation (p < 0.001) of DML and RL in the neuropathy groups for both nerves compared with the control group. These prolon− gations were higher in group 2 for both neuropathies but the dif− ferences between mean values for group 1 and group 2 were sig− nificant only for the median nerve. The mean normalized in− crease of RL was significantly greater in the median nerve than in the ulnar nerve as compared with the increase of the DML.The residual latency appears to be more sensitive than the DML and can be a useful diagnostic parameter for early detection of distal neuropathies.