ABSTRACT
Aim To investigate the antinociception, tolerance and withdrawal abstinence of δ/μ/κ opioid receptor triple agonist KUST201 ( DPI-125 ) in rats. Methods Male Sprague-Dawley rats were used to de-termine the time course of analgesic effects and ED50 effects of co-administration of naltrindole were assessed as well. In withdrawal experiments, KUST201 was ad-ministrated twice daily for 3 d with increasing doses each day. On the 4th day, the rats were given a single dose, challenged with naloxone 3 h later, and signs of abstinence were monitored. Results The ED50 values of KUST201 were 0. 34 mg·kg-1 in tail-pinch test and 0. 68 mg · kg-1 in hot-plate test. The antinociception actions of KUST201 started to decrease 1 h after ad-ministration, and disappeared after 2 h. In chronic tol-erance experiments, the antinociception actions started to decrease on d 3 , and completely disappeared on d 7 . Naltrindole could reduce the antinociceptive action of KUST201. In withdrawal experiments, abstinence scores increased significantly in the dose range between 2~8 times of tail-pinch ED50 . Conclusion Compared with previously reported δ/μ/κ triple agonist DPI-3290 , KUST201 exhibits similar antinociceptive effects in rats. The chronic tolerance to KUST201 actions de-velops less quickly, but the abstinence scores of KUST201 are slightly higher. The activation of δ-opi-oid receptor can synergistically enhance the antinoci-ception mediated by μ-receptor.
ABSTRACT
Alzheimer′s disease ( AD) is a type of neurodegener-ative disease. Recent studies indicate that neuronal degeneration and loss triggered by tau, APP and Aβare the probable risks for AD. Neurofibrillary tangles are formed after tau truncated by ac-tivated caspases and subsequently induced tau aggregates, which causes neuronal degeneration and loss. In addition, caspases are crucial components in the biological functioning in the apoptosis pathways. Apoptosis pathway involves activation of upstream ini-tiator caspase-8 and downstream executor caspase-3/-6/-7. After the actions of β- and γ-secretase, APP transforms into sAPPβand Aβ40/42 . Aggregated Aβ42 can activate apoptosis pathway through DR4/5 interaction. C-APP is truncated into C31 frag-ments by caspases and cell apoptosis is facilitated. N-APP, a product of sAPPβhydrolysis, can promote the abnormal develop-ment of neurons mediated by DR6. Caspase activates γ-secre-tase-activating protein to regulate activity ofγ-secretase, and the production of C31 and Aβ40/42 , which, then, causes the occur-rence of AD. This brief review summarizes the specific roles of caspases and the concerning apoptosis pathways on the mecha-nisms of neuronal degeneration and loss, and how they impact the occurrence of AD in the hope of uncovering additional poten-tial therapeutic targets that can be employed in drug development and clinical therapy for AD.
ABSTRACT
A GC method is described for measuring fentanyl in man plasma. Fentanyl was extracted at basic pH with cyclohexane-isobutyl alcohol (197:3) with Ro21-2212 added as internal standard and fentanyl derivative as earner. The drug was back-extracted in H2SO4, then the extract was made basic and recxtracted with ethyl ether-dichloromethane (9:1). The organic phase was evaporated at 40℃ under N2 and the residue was dissolved in ethanol. A. portion (2?l) was analyzed on a wide-bore capillary column (10 m ? 0.53 mm) of HP-1 (2.65 ?m), operated at 255℃ with N2 as carrier gas (8 ml/min) and N -P detector. The calibration graph was linear within the ranges of 0.25-100 ng/ml with a corelation coefficient of 0.9996 and the detected limit was 0.2 ng/ml. Mean recovery was 99.02% ? 6.81%. The coefficient of variation for the within- and between-run were all less than 8%. No interference was found from endogenous compounds, metabolites of parent drug or other commonly used drugs. The method was applied to therapeutic drug monitoring and pharmacokinetic studies.