The Fundamental Study On Composition Of Morphine And Naloxone

Objective:To study stability of mixed liquor of naloxone hydrochloride and morphine hydrochloride,as well as the low-dose naloxone effects on morphine pharmacodynamics action and pharmacokinetic,and investigate the feasibility of preparing for composition of naloxone and morphie.Methods:(1).Naloxone hydrochloride and morphine hydrochloride were mixed according to different proportions,to observe there are color-change/sediment or not after a day,a week and a month,to measure PH and contents of naloxone and morphine. (2).Adult male Sprague-Dawley rats were randomly assigned into seven groups(6 rats for each group).Rats in group NS received normal saline,and in group M received 6mg/kg of morphine.When cumulative pain scores were observed,group M received 2mg/kg of morphine.When autonomic activities and arterial partial pressure of carbon dioxide were observed,group M received 15mg/kg of morphine.Different doses of naloxone(1μg/kg,100ng/kg,10ng/kg,1ng/kg and 0.1ng/kg)with 6mg/kg/2mg/kg /15mg/kg of morphine were given to the rats in group MN1,group MN2,group MN3, group MN4 and group MN5.Pain thresholds were determined at different time points before and after subcutaneous injection of normal saline or morphine or mixture of the drugs(morphine and naloxone).Specific markers of side effects(such as nausea, vomiting,sedation,pruritus,urinary retention,constipation,tolerance and dependence) induced by morphine were measured at different times.Blood was collected for measuring blood plasma motilin and histamine at time points of 30min,2h,4h and 24h after a subcutaneous administration as above.Urinary volume,excrement and Kaolin-intake were measured after administration.Acute pain was prodused by an in cision on the hind paw.Then they were given subcutaneous injection of the drugs in different doses as categorized above.Cumulative pain scores were observed within an hour.Open-field activity(crossing and rearing)in the rat was observed after administration within an hour.Sprague-Dawley rats were randomly assigned into three groups.Rats in group A received 15mg/kg of morphine.Different doses of naloxone (20μg/kg,1μg/kg)with 15mg/kg of morphine were given to the rats in group B,group C.After administration,arterial partial pressure of carbon dioxide(PaCO2)was determined within two hours.Pain thresholds were determined at time point of thirty minutes after injection,one time a day within eight days.Conditioned place preference was measured after twenty four hours in the last administration.(3).Three groups similar to the above grouping,morphine in plasm was determined at different time points after subcutaneous administration.Morphine parameter of pharmacokinetic was calculated by treatment sequence of pharmacokinetic(3P97).Results:(1)There was no sediment and color-change in mixture of morphine and naloxone after a month.There were no significant changes in value of PH and contents of morphine and nxloxone in mixture.(2)Low-dose of naloxone can enhance the analgesic effect of morphine,and the dose range 1ng/kg～100ng/kg may be acceptable, the pain thresholds increased and cumulative pain scores decreased significantly.Dose of 1μg/kg naloxone may antagonize the analgesic effect of morphine,while dose of 0.1ng/ kg naloxone,perhaps,is too low to show an effect.The dose range 10ng/kg～100ng/kg of naloxone restrainted increase of blood plasma motilin,histamine, kaolin-intake,and decrease of open-field activity,urinary volumeand excrement induced by morphine.Dose of 20μg/kg naloxone may antagonize the increase of PaCO2. The dose range 10ng/kg～100ng/kg of naloxone inhibited decrease of pain thresholds, and increase of conditioned place preference induced by morphine.(3)Process of morphine eliminate was inhibited by the dose range 10ng/kg～100ng/kg of naloxone. Apparent volume of distribution significantly decreased,and peak time and peak concentration significantly increased.Conclusion:(1)The chemical physical property of mixture of morphine and naloxone was stable on the condition of protecting from light.(2).The dose range 10ng/kg～100ng/kg of naloxone can enhance the analgesic effect of morphine,and inhibited the side-effects induced by morphine,such as nausea,vomiting,sedation, pruritus,urinary retention and constipation.The dose range 10ng/kg～100ng/kg of naloxone can restrain forming of tolerance and dependence induced by chronic administration morphine.(3).Process of morphine absorb and eliminate was inhibited by the dose range 10ng/kg～100ng/kg of naloxone,and peak time and peak concentration significantly increased.