Sustained-release naltrexone: novel treatment for opioid dependence

The devastating costs of opioid abuse and dependence underscore theneed for effective treatments for these disorders. At present, several different maintenance medications exist for treating opioid dependence, including methadone, buprenorphine and naltrexone. Of these, naltrexone is theonly one that possesses no opioid agonist effects. Instead, naltrexoneoccupies opioid receptors and prevents or reverses the effects produced by opioid agonists. Despite its clear pharmacologic effectiveness, its clinical effectiveness in treating opioid dependence has been disappointing, primarily due to non-compliance with taking the medication. However, the recent availability of sustained-release formulations of naltrexone has renewed interest in this medication. The present paper describes the development of sustained-release naltrexone formulations and discusses the clinical issues associated with their use in treating opioid dependence.     

Current understanding on pharmacokinetics,clinical efficacy and safety of progestins for treating pain associated to endometriosis

Introduction: Endometriosis is a chronic estrogen and progestogen responsive inflammatory disease associated with pain symptoms and infertility. The medical therapy of endometriosis aims to induce decidualization within the hormonally dependent ectopic endometrium, and it is often administered to ameliorate women’ pain symptoms or to prevent post-surgical disease recurrence. A variety of progestins have been used in monotherapy for the medical management of women with endometriosis.

Areas covered: This review aims to offer the reader a complete overview of pharmacokinetic (PK) and clinical efficacy of progestins for the treatment of endometriosis.

Expert opinion: Each progestin has a distinct PK parameters and pharmacodynamics affinity not only for progesterone receptor, but also for other steroid receptors, such as estrogen, androgen, and glucocorticoid. Moreover, progestins can also be delivered in different formulations. All these characteristics influence their final biological effect. Randomized, controlled, non-blinded studies support the use of oral progestin-only treatment for pelvic pain associated with endometriosis. Currently, the only two progestins approved by Food and Drug Administration (FDA) for the treatment of endometriosis are norethindrone acetate (NETA) and depot medroxyprogesterone acetate (DMPA).     

Evaluation of an injection depot formulation of buprenorphine: placebo comparison

AIMS: Buprenorphine is a mu-opioid partial agonist that is marketed in a sublingual formulation as a treatment for opioid dependence. A microcapsule depot sustained-release formulation has been developed which may offer effective treatment of opioid dependence while also minimizing risks of illicit diversion or patient non-compliance. The present study examined the efficacy of depot buprenorphine in suppressing the opioid withdrawal syndrome and in attenuating the effects of exogenous opioid challenge. DESIGN: A placebo-controlled, double-blind, randomized trial. SETTING: A closed residential research facility. PARTICIPANTS: A total of 15 opioid-dependent participants were enrolled into the 6-week study. INTERVENTION: Fifteen participants were randomized to receive a single subcutaneous depot injection containing buprenorphine (58 mg) or placebo. Two participants, both of whom received placebo, terminated participation after depot administration. Thirteen participants (six buprenorphine, seven placebo) completed the 6-week study and were assessed throughout the study for signs and symptoms of opioid withdrawal and for response to weekly subcutaneous challenges with 3 mg hydromorphone. MEASUREMENT: Subjective, physiological and observer-rated indices of opioid withdrawal and opioid agonist effects. FINDINGS: Depot buprenorphine provided more effective relief from opioid withdrawal than placebo, as evidenced by significantly fewer buprenorphine participants requiring supplemental medications for withdrawal suppression after depot administration compared to participants receiving placebo. In the weekly hydromorphone challenge sessions, depot buprenorphine significantly reduced opioid response on measures of subjective effects and pupillary diameter. CONCLUSIONS: Results from this double-blind, placebo-controlled study indicate that depot buprenorphine is effective in providing both withdrawal suppression and opioid blockade. Future studies examining additional doses and repeated dosing regimens with depot buprenorphine are warranted.     

Biodegradable donepezil lipospheres for depot injection: optimization and in-vivo evaluation

Objectives The purpose of this study was to develop an injectable depot liposphere delivery system with high loading capacity for controlled delivery of donepezil to decrease dosing frequency and increase patient compliance. Methods A 3² full factorial design was employed to study the effect of lipid type and drug‐to‐lipid ratio on the yield, encapsulation efficiency, mean diameter and the time required for 50% drug release (t_50%). The pharmacokinetic behaviour of the lipospheres in rabbits was studied using tandem mass spectrometry. Key findings The yields of preparations were in the range of 66.22–90.90%, with high encapsulation efficiencies (89.68–97.55%) and mean particle size of 20.68–35.94 µm . Both lipid type and drug‐to‐lipid ratio significantly affected t_50% (P < 0.0001), where the lipids can be arranged: glyceryl tripalmitate > compritol > cetyl alcohol, and the drug‐to‐lipid ratios can be arranged: 1 : 40 > 1 : 20 > 1 : 10. The flow time of lipospheres through 19‐gauge syringe needle was less than 6 s indicating good syringeability. The mean residence time of the subcutaneous and intramuscular lipospheres was significantly higher than the solution (almost 20 fold increase), with values of 11.04, 11.34 and 0.53 days, respectively (P < 0.01). Conclusion Subcutaneous and intramuscular delivery of donepezil glyceryl tripalmitate lipospheres achieves depot release, allowing less frequent dosing.     

Mechanism of adaptation of the vascular system to chronic changes in nitric oxide level in the organism

We studied the possibility of directed modulation of the efficiency of NO storage in rats due to adaptation to the chronic changes in plasma NO level. The efficiency of NO storage increased during long-term maintenance of high plasma level of NO and decreased in NO-deficient states. The compensatory changes in NO storage capacity of vessels depending on its organism content represent a new mechanism of adaptation of the cardiovascular system to chronic excess or deficit of NO, while directed modulation of this process can be important for the protection of the organism against both surplus or shortage of NO. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 12, pp. 626–630, December, 2006