Sample records for naltrexone hydrochloride extended-release

  1. Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability.

    PubMed

    Johnson, Franklin; Setnik, Beatrice

    2011-01-01

    Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA, King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic, moderate-to-severe pain, contain pellets of extended-release morphine sulfate with a sequestered naltrexone core (MS-sNT). Taken as directed, morphine provides analgesia while naltrexone remains sequestered; if tampered with by crushing, naltrexone is released to mitigate morphine-induced euphoric effects. While it is necessary to establish that formulations intended to reduce attractiveness for abuse are successful in doing so, it is also necessary to demonstrate that product therapeutic integrity is maintained for patients. Data were reviewed from 3 studies to determine: 1) the quantity of naltrexone released when MS-sNT pellets are crushed (MS-sNTC) for at least 2 minutes with mortar and pestle); 2) the extent to which the naltrexone released upon crushing mitigated morphine-induced subjective effects; and 3) whether sequestered naltrexone precipitates opioid withdrawal when MS-sNT is taken as directed. The naltrexone bioavailability study compared naltrexone release from MS-sNTC with that from whole intact MS-sNT capsules (MS-sNTW) and an equal naltrexone solution (NS) dose. Equivalent bioavailability was established if 90% confidence intervals (CIs) for geometric mean ratios (maximum plasma naltrexone concentration [Cmax] and area under the concentration-time curve extrapolated to infinity [AUC∞]) fell between 80% and 125%. The oral pharmacodynamic study assessed drug liking and euphoria and pharmacokinetic properties of MS-sNTC and MS-sNTW compared with morphine sulfate solution (MSS) and placebo. The 12-month, open-label (OL) safety study evaluated safety of MS-sNT administered orally as directed in patients with chronic, moderate-to-severe pain. Safety assessments included withdrawal symptoms based on the Clinical Opiate Withdrawal Scale (COWS). Naltrexone from MS-sNTC met criteria for equivalent

  2. Effectiveness of Injectable Extended-Release Naltrexone vs Daily Buprenorphine-Naloxone for Opioid Dependence: A Randomized Clinical Noninferiority Trial.

    PubMed

    Tanum, Lars; Solli, Kristin Klemmetsby; Latif, Zill-E-Huma; Benth, Jurate Šaltyte; Opheim, Arild; Sharma-Haase, Kamni; Krajci, Peter; Kunøe, Nikolaj

    2017-12-01

    To date, extended-release naltrexone hydrochloride has not previously been compared directly with opioid medication treatment (OMT), currently the most commonly prescribed treatment for opioid dependence. To determine whether treatment with extended-release naltrexone will be as effective as daily buprenorphine hydrochloride with naloxone hydrochloride in maintaining abstinence from heroin and other illicit substances in newly detoxified individuals. A 12-week, multicenter, outpatient, open-label randomized clinical trial was conducted at 5 urban addiction clinics in Norway between November 1, 2012, and December 23, 2015; the last follow-up was performed on October 23, 2015. A total of 232 adult opioid-dependent (per DSM-IV criteria) individuals were recruited from outpatient addiction clinics and detoxification units and assessed for eligibility. Intention-to-treat analyses of efficacy end points were performed with all randomized participants. Randomization to either daily oral flexible dose buprenorphine-naloxone, 4 to 24 mg/d, or extended-release naltrexone hydrochloride, 380 mg, administered intramuscularly every fourth week for 12 weeks. Primary end points (protocol) were the randomized clinical trial completion rate, the proportion of opioid-negative urine drug tests, and number of days of use of heroin and other illicit opioids. Secondary end points included number of days of use of other illicit substances. Safety was assessed by adverse event reporting. Of 159 participants, mean (SD) age was 36 (8.6) years and 44 (27.7%) were women. Eighty individuals were randomized to extended-release naltrexone and 79 to buprenorphine-naloxone; 105 (66.0%) completed the trial. Retention in the extended-release naltrexone group was noninferior to the buprenorphine-naloxone group (difference, -0.1; with 95% CI, -0.2 to 0.1; P = .04), with mean (SD) time of 69.3 (25.9) and 63.7 (29.9) days, correspondingly (P = .33, log-rank test). Treatment with extended-release

  3. Gender differences in treatment and clinical characteristics among patients receiving extended release naltrexone.

    PubMed

    Herbeck, Diane M; Jeter, Kira E; Cousins, Sarah J; Abdelmaksoud, Reham; Crèvecoeur-MacPhail, Desirée

    2016-01-01

    Further research is needed to investigate real-world acceptability of extended-release naltrexone for alcohol and opioid use disorders, and potential gender differences. This study examines treatment and clinical characteristics among men and women receiving extended-release naltrexone in a large, publicly funded substance use disorder treatment system (N = 465; 52% female). Patient demographics, treatment characteristics, and the number of extended-release naltrexone doses received were collected from administrative data and treatment program staff. Additionally, patients provided information on experiences with extended-release naltrexone in an open-ended format at 1, 2, and 3 weeks following their first injection. For a subsample of patients (N = 220), alcohol/opioid cravings and specific adverse effects were also assessed. Compared to men, women reported experiencing a higher rate and mean number of adverse effects. Overall, craving scores showed substantial reductions over time. However, among patients taking extended-release naltrexone for alcohol use, women showed a significantly greater reduction in craving scores compared to men. No gender differences were observed in the number of extended-release naltrexone doses received. Although women may have a greater need for additional support in managing early adverse effects, extended-release naltrexone as an adjunct to psychosocial treatment may be an acceptable and promising treatment approach for both men and women, and particularly for women prescribed extended-release naltrexone for alcohol use. This study contributes further information on patients' experiences during the early course of extended-release naltrexone treatment in real-world settings. Understanding these experiences may assist policy makers and treatment providers in addressing challenges of implementing this treatment into wider practice.

  4. Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: a single-dose, randomized-sequence, open-label, three-way crossover trial in healthy volunteers.

    PubMed

    Johnson, Franklin K; Stark, Jeffrey G; Bieberdorf, Frederick A; Stauffer, Joe

    2010-06-01

    Morphine sulfate/sequestered naltrexone hydrochloride (HCl) (MS-sNT) extended-release fixed-dose combination capsules, approved by the US Food and Drug Administration (FDA) in August 2009 for chronic moderate to severe pain, contain extended-release morphine pellets with a sequestered core of the opioid antagonist naltrexone. MS-sNT was designed so that if the product is tampered with by crushing, the naltrexone becomes bioavailable to mitigate morphine-induced subjective effects, rendering the product less attractive for tampering. The primary aim of this study was to compare the oral bioavailability of naltrexone and its metabolite 6-beta-naltrexol, derived from crushed pellets from MS-sNT capsules, to naltrexone solution. This study also assessed the relative bioavailability of morphine from crushed pellets from MS-sNT capsules and that from the whole, intact product. This single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial was conducted in healthy volunteers. Adults admitted to the study center underwent a 10-hour overnight fast before study drug administration. Each subject received all 3 of the following treatments, 1 per session, separated by a 14-day washout: tampered pellets (crushed for >or=2 minutes with a mortar and pestle) from a 60-mg MS-sNT capsule (60 mg morphine/2.4 mg naltrexone); 60-mg whole, intact MS-sNT capsule; and oral naltrexone HCl (2.4 mg) solution. Plasma concentrations of naltrexone and 6-beta-naltrexol were measured 0 to 168 hours after administration. Morphine pharmaco-kinetics of crushed and whole pellets were determined 0 to 72 hours after administration. The analysis of relative bioavailability was based on conventional FDA criteria for assuming bioequivalence; that is, 90% CIs for ratios of geometric means (natural logarithm [In]-transformed C(max) and AUC) fell within the range of 80% to 125%. Subjects underwent physical examinations, clinical laboratory tests, and ECG at screening and study

  5. A multicenter, 12-month, open-label, single-arm safety study of oxycodone-hydrochloride/naltrexone-hydrochloride extended-release capsules (ALO-02) in patients with moderate-to-severe chronic noncancer pain.

    PubMed

    Arora, Samir; Setnik, Beatrice; Michael, Drass; Hudson, John D; Clemmer, Ray; Meisner, Paul; Pixton, Glenn C; Goli, Veeraindar; Sommerville, Kenneth W

    2014-01-01

    To evaluate the long-term safety of oxycodone-hydrochloride and sequestered naltrexone-hydrochloride (ALO-02) administered for up to 12 months. Open-label, single-arm safety study. Thirty-two US research centers (ClinicalTrials.gov identifier NCT01428583). Three hundred ninety-five adults (opioid experienced and opioid naïve) with moderate-to-severe chronic noncancer pain (CNCP). Open-label, oral ALO-02 capsules, daily dose ranging from 20 to 160 mg oxycodone for up to 12 months. Number and type of adverse events (AEs) and drugrelated AEs, including assessments of withdrawal (Clinical Opiate Withdrawal Scale; COWS), pharmacokinetics, efficacy, and aberrant behaviors (Current Opioid Misuse Measure). A total of 193 (48.9 percent) patients received ALO-02 for ≥181 days and 105 (26.6 percent) patients for ≥361 days. The most common treatment-emergent AEs were nausea (25.3 percent), constipation (21.3 percent), vomiting (13.9 percent), and headache (11.6 percent). The most common drug-related AEs were constipation (18.0 percent), nausea (14.9 percent), somnolence (8.4 percent), fatigue (6.8 percent), dizziness (5.6 percent), and vomiting (5.1 percent). A majority of patients (86.6 percent) had a maximum COWS total score below the level for mild withdrawal symptoms at every visit throughout the study. Pain severity scores as measured by the short Form of the Brief Pain Inventory (BPI-SF) decreased over time. Repeat dosing of ALO-02 for up to 12 months is safe and well tolerated in a CNCP population of both opioid-experienced and opioid-naïve patients. ALO-02 demonstrated a safety profile consistent with extended-release opioids and the expected analgesic efficacy. The addition of sequestered naltrexone had no significant clinical effect on patients when taken as directed.

  6. Extended-release naltrexone for pre-release prisoners: A randomized trial of medical mobile treatment

    PubMed Central

    Gordon, Michael S.; Vocci, Frank J.; Fitzgerald, Terrence T.; O'Grady, Kevin E.; O'Brien, Charles P.

    2017-01-01

    Background Extended-release naltrexone (XR-NTX), is an effective treatment for opioid use disorder but is rarely initiated in US prisons or with criminal justice populations. Mobile treatment for chronic diseases have been implemented in a variety of settings. Mobile treatment may provide an opportunity to expand outreach to parolees to surmount barriers to traditional clinic treatment. Methods Male and female prisoners (240) with pre-incarceration histories of opioid use disorder who are within one month of release from prison will be enrolled in this randomized clinical trial. Participants are randomized to one of two study arms: 1) [XR-NTX-OTx] One injection of long-acting naltrexone in prison, followed by 6 monthly injections post-release at a community opioid treatment program; or 2) [XR-NTX+ MMTx] One injection of long-acting naltrexone in prison followed by 6 monthly injections post-release at the patient's place of residence utilizing mobile medical treatment. The primary outcomes are: treatment adherence; opioid use; criminal activity; re-arrest; reincarceration; and HIV risk-behaviors. Results We describe the background and rationale for the study, its aims, hypotheses, and study design. Conclusions The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release prisoners. Finally, as many individuals in the criminal justice system drop out of treatment, this study will assess whether treatment at their place of residence will improve adherence and positively affect treatment outcomes. PMID:28011389

  7. Extended-release naltrexone for pre-release prisoners: A randomized trial of medical mobile treatment.

    PubMed

    Gordon, Michael S; Vocci, Frank J; Fitzgerald, Terrence T; O'Grady, Kevin E; O'Brien, Charles P

    2017-02-01

    Extended-release naltrexone (XR-NTX), is an effective treatment for opioid use disorder but is rarely initiated in US prisons or with criminal justice populations. Mobile treatment for chronic diseases has been implemented in a variety of settings. Mobile treatment may provide an opportunity to expand outreach to parolees to surmount barriers to traditional clinic treatment. Male and female prisoners (240) with pre-incarceration histories of opioid use disorder who are within one month of release from prison will be enrolled in this randomized clinical trial. Participants are randomized to one of two study arms: 1) [XR-NTX-OTx] One injection of long-acting naltrexone in prison, followed by 6 monthly injections post-release at a community opioid treatment program; or 2) [XR-NTX+ MMTx] One injection of long-acting naltrexone in prison followed by 6 monthly injections post-release at the patient's place of residence utilizing mobile medical treatment. The primary outcomes are: treatment adherence; opioid use; criminal activity; re-arrest; reincarceration; and HIV risk-behaviors. We describe the background and rationale for the study, its aims, hypotheses, and study design. The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release prisoners. Finally, as many individuals in the criminal justice system drop out of treatment, this study will assess whether treatment at their place of residence will improve adherence and positively affect treatment outcomes. ClinicalTrials.gov: NCT02867124. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Effect of food on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended release formulation of oxycodone with sequestered naltrexone.

    PubMed

    Gandelman, Kuan; Lamson, Michael; Salageanu, Joanne; Bramson, Candace; Matschke, Kyle; Malhotra, Bimal

    2015-09-01

    ALO-02 is being developed as an abuse-deterrent formulation of extended-release oxycodone hydrochloride with naltrexone hydrochloride sequestered in the core of pellets contained in capsules. The primary objective of this study was to assess the effects of administration of ALO-02 capsule whole under fed conditions or sprinkling the pellets from ALO-02 capsule on applesauce under fasting conditions on the pharmacokinetics (PK) of oxycodone, naltrexone and 6-ß-naltrexol compared with ALO-02 capsule administered whole under fasting conditions. The plasma naltrexone and 6-ß-naltrexol concentrations were used to assess the sequestration of naltrexone in the ALO-02 formulation. The secondary objective was to evaluate the safety and tolerability of single 40 mg doses of ALO-02 in healthy volunteers. This was an IRB-approved, open-label, single-dose, randomized, 3-period crossover study in 24 healthy adult volunteers, aged 18-55 years. Each subject was assigned to receive single 40 mg doses of ALO-02 administered whole (intact capsule) under fasting conditions, administered whole under fed conditions (high-fat breakfast ∼ 950 calories), or sprinkling the contents of the ALO-02 capsule (pellets) over applesauce and swallowing the dose without chewing under fasting conditions. Each treatment was separated by a 7-day washout interval. Plasma samples were analyzed just before dosing through 48 hours postdose for oxycodone, and through 120 hours postdose for naltrexone and its major metabolite, 6-ß-naltrexol. Pharmacokinetic parameters included maximum plasma concentration [Cmax ], area under the plasma concentration-time profile from time 0 to infinity [AUCinf ] and to the last quantifiable concentration [AUClast ], time to Cmax [Tmax ], and terminal half life [t1/2 ]. Adverse events, vital signs, and laboratory parameters were monitored for safety assessment. The t1/2 and Tmax values for oxycodone were similar for all 3 treatments. There was a lack of effect of

  9. 78 FR 16685 - Impax Laboratories, Inc.; Withdrawal of Approval of Bupropion Hydrochloride Extended-Release...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-18

    ...] Impax Laboratories, Inc.; Withdrawal of Approval of Bupropion Hydrochloride Extended-Release Tablets... Administration (FDA) is withdrawing approval of Bupropion Hydrochloride (HCl) Extended-Release Tablets, 300 Milligrams (mg) (Bupropion HCl Extended-Release Tablets 300 mg), under Abbreviated New Drug Application (ANDA...

  10. Naltrexone/bupropion for the treatment of obesity and obesity with Type 2 diabetes.

    PubMed

    Apovian, Caroline M

    2016-03-01

    Contrave(®) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity, and is used with lifestyle modification. Its safety and efficacy were assessed in four randomized, double-blind, placebo-controlled, 56-week Phase III clinical trials in 4536 adult subjects: COR-1, COR-II, COR-BMOD and COR-DM. All four studies demonstrated statistically significant and clinically meaningful weight loss following up to 52 weeks of treatment with naltrexone/bupropion compared with placebo. The average weight loss from baseline across the four studies was approximately 11-22 lbs (5-9 kg). Results show the efficacy of Contrave for weight loss, as well as significant improvements in cardiometabolic markers. This review focuses on the four studies, their outcomes and the mechanism of action of Contrave.

  11. Aversion to injection limits acceptability of extended-release naltrexone among homeless, alcohol-dependent patients.

    PubMed

    Friedmann, Peter D; Mello, Dawn; Lonergan, Sean; Bourgault, Claire; O'Toole, Thomas P

    2013-01-01

    Ending homelessness is a major priority of the Department of Veteran Affairs (VA), and alcohol use can be a barrier to stable housing. Clinical trials suggest that depot extended-release naltrexone (XR-NTX) is efficacious in reducing alcohol consumption among alcohol-dependent subjects. An open-label, randomized pilot study sought to examine the feasibility and effectiveness of XR-NTX versus oral naltrexone to improve alcohol consumption and housing stability among homeless, alcohol-dependent veterans at the Providence Veteran Affairs Medical Center. Of 215 potential candidates approached over a 16-month recruitment period, only 15 agreed to consider study entry and 7 were randomized. The primary reasons given for refusal were not wanting an injection; fear of needles; and not wanting to change drinking habits. Only 1 participant in the XR-NTX group returned after the first injection. Three participants in the oral naltrexone group attended all 7 visits and had good outcomes. Although XR-NTX has demonstrated efficacy in reducing heavy drinking, limited acceptance of the injection might reduce its effectiveness among homeless, alcohol-dependent patients.

  12. THE EFFECTS OF DRONABINOL DURING DETOXIFICATION AND THE INITIATION OF TREATMENT WITH EXTENDED RELEASE NALTREXONE

    PubMed Central

    Bisaga, Adam; Sullivan, Maria A.; Glass, Andrew; Mishlen, Kaitlyn; Pavlicova, Martina; Haney, Margaret; Raby, Wilfrid N.; Levin, Frances R.; Carpenter, Kenneth M.; Mariani, John J.; Nunes, Edward V.

    2015-01-01

    Background Evidence suggests that the cannabinoid system is involved in the maintenance of opioid dependence. We examined whether dronabinol, a cannabinoid receptor type 1 partial agonist, reduces opioid withdrawal and increases retention in treatment with extended release naltrexone (XR-naltrexone). Methods Opioid dependent participants were randomized to receive dronabinol 30 mg/d (n=40) or placebo (n=20), under double-blind conditions, while they underwent inpatient detoxification and naltrexone induction. Before discharge all participants received an injection of XR-naltrexone, with an additional dose given four weeks later. Dronabinol or placebo was given while inpatient and for 5 weeks afterwards. The primary outcomes were the severity of opioid withdrawal, measured with the Subjective Opioid Withdrawal Scale, and retention in treatment at the end of the inpatient phase and at the end of the 8-week trial. Results The severity of opioid withdrawal during inpatient phase was lower in the dronabinol group relative to placebo group (p=0.006). Rates of successful induction onto XR-naltrexone (dronabinol 66%, placebo 55%) and completion of treatment (dronabinol 35%, placebo 35%) were not significantly different. Post-hoc analysis showed that the 32% of participants who smoked marijuana regularly during the outpatient phase had significantly lower ratings of insomnia and anxiety and were more likely to complete the 8-week trial. Conclusion Dronabinol reduced the severity of opiate withdrawal during acute detoxification but had no effect on rates of XR-naltrexone treatment induction and retention. Participants who elected to smoke marijuana during the trial were more likely to complete treatment regardless of treatment group assignment. PMID:26187456

  13. Extended-release naltrexone opioid treatment at jail reentry (XOR)

    PubMed Central

    McDonald, Ryan D.; Tofighi, Babak; Laska, Eugene; Goldfeld, Keith; Bonilla, Wanda; Flannery, Mara; Santana-Correa, Nadina; Johnson, Christopher W.; Leibowitz, Neil; Rotrosen, John; Gourevitch, Marc N.; Lee, Joshua D.

    2017-01-01

    Background Extended-release naltrexone (XR-NTX) is an injectable monthly sustained-release mu opioid receptor antagonist, which blocks the typical effects of heroin and other opioid agonists. Use of XR-NTX among opioid dependent persons leaving jails and prisons is increasing despite scant high-quality evidence regarding XR-NTX’s effectiveness at re-entry. Methods This 24-week, open-label randomized controlled trial examines the effectiveness of XR-NTX as opioid relapse prevention at release from jail (N = 85) compared to enhanced treatment as usual (ETAU, N = 85). A third, non-randomized, quasi-experimental naturalistic arm of participants who have newly initiated a jail-to-community methadone treatment program (MTP, N = 85) allows for comparisons to a methadone standard-of-care. Results We describe the rationale, design, and primary and secondary outcomes of the study. The primary outcome is an opioid relapse event; the primary contrast is a time-to-relapse comparison of XR-NTX and ETAU over a 24-week treatment phase. Secondary outcomes are rates of: (a) post-release opioid treatment participation, (b) opioid, alcohol, and cocaine use, (c) injection drug use and HIV sexual risk behaviors, (d) overdose (fatal and non-fatal) and all-cause mortality, and, (e) re-incarceration. Conclusions XR-NTX is a potentially important, effective treatment and relapse prevention option for a large US population of persons with opioid use disorders leaving jails. This study will estimate XR-NTX’s effectiveness relative to existing standards of care, including counseling-only treatment-as-usual and methadone maintenance. PMID:27178765

  14. A randomized, double-blind study of hydromorphone hydrochloride extended-release tablets versus oxycodone hydrochloride extended-release tablets for cancer pain: efficacy and safety in Japanese cancer patients (EXHEAL: a Phase III study of EXtended-release HydromorphonE for cAncer pain reLief).

    PubMed

    Inoue, Satoshi; Saito, Yoji; Tsuneto, Satoru; Aruga, Etsuko; Ide, Azusa; Kakurai, Yasuyuki

    2017-01-01

    In Japan, there are limited options for switching opioid analgesics. Hydromorphone is an opioid analgesic that is routinely used instead of morphine for cancer pain; however, it is not yet available in Japan. The aim of this study was to assess the efficacy and safety of hydromorphone (DS-7113b) extended-release tablets in opioid-naïve patients with cancer pain not relieved by non-opioid analgesics. This was a multicenter, randomized, double-blind, parallel-group trial. A double-dummy method was used for blinding. Each randomized subject received either hydromorphone extended-release tablets plus placebo oxycodone hydrochloride extended-release tablets 4 mg/day (n=88) or placebo hydromorphone extended-release tablets plus oxycodone hydrochloride extended-release tablets 10 mg/day (n=93) orally for 7 days (once-daily dosing for hydromorphone and twice-daily dosing for oxycodone). The doses were adjusted as necessary. Efficacy was evaluated by change in visual analog scale (VAS) score from baseline to completion of treatment. The between-group difference in least squares mean changes in VAS score from baseline to completion or discontinuation of treatment was -0.4 mm (95% CI -5.9 to 5 mm) by analysis of covariance where the baseline VAS score was used as a covariate. The upper limit of the 95% CI was below 10 mm, which was predefined as the noninferiority limit. This verified the noninferiority of hydromorphone tablets relative to oxycodone tablets. The incidence of adverse events was 80.7% (71 of 88) in the hydromorphone group and 83.7% (77 of 93) in the oxycodone group. The most common adverse events were nausea, vomiting, somnolence, diarrhea, and constipation, most of which are commonly observed with opioid analgesics. The efficacy and safety of hydromorphone extended-release tablets were equivalent to those of the oxycodone extended-release formulation.

  15. Randomized Trial of Long-Acting Sustained-Release Naltrexone Implant vs Oral Naltrexone or Placebo for Preventing Relapse to Opioid Dependence

    PubMed Central

    Krupitsky, Evgeny; Zvartau, Edwin; Blokhina, Elena; Verbitskaya, Elena; Wahlgren, Valentina; Tsoy-Podosenin, Marina; Bushara, Natalia; Burakov, Andrey; Masalov, Dmitry; Romanova, Tatyana; Tyurina, Arina; Palatkin, Vladimir; Slavina, Tatyana; Pecoraro, Anna; Woody, George E.

    2013-01-01

    Context Sustained-release naltrexone implants may improve outcomes of nonagonist treatment of opioid addiction. Objective To compare outcomes of naltrexone implants, oral naltrexone hydrochloride, and nonmedication treatment. Design Six-month double-blind, double-dummy, randomized trial. Setting Addiction treatment programs in St Petersburg, Russia. Participants Three hundred six opioid-addicted patients recently undergoing detoxification. Interventions Biweekly counseling and 1 of the following 3 treatments for 24 weeks: (1) 1000-mg naltrexone implant and oral placebo (NI+OP group; 102 patients); (2) placebo implant and 50-mg oral naltrexone hydrochloride (PI+ON group; 102 patients); or (3) placebo implant and oral placebo (PI+OP group; 102 patients). Main Outcome Measure Percentage of patients retained in treatment without relapse. Results By month 6, 54 of 102 patients in the NI+OP group (52.9%) remained in treatment without relapse compared with 16 of 102 patients in the PI+ON group (15.7%) (survival analysis, log-rank test, P<.001) and 11 of 102 patients in the PI+OP group (10.8%) (P<.001). The PI+ON vs PI+OP comparison showed a nonsignificant trend favoring the PI+ON group (P=.07). Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P<.001, Fisher exact test, compared with the NI+OP group). Twelve wound infections occurred among 244 implantations (4.9%) in the NI+OP group, 2 among 181 (1.1%) in the PI+ON group, and 1 among 148 (0.7%) in the PI+OP group (P=.02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy. Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P=.12), and all resolved with antiallergy medication treatment. Other nonlocal-site adverse effects

  16. Effectiveness, safety and feasibility of extended-release naltrexone for opioid dependence: a 9-month follow-up to a 3-month randomized trial.

    PubMed

    Solli, Kristin Klemmetsby; Latif, Zill-E-Huma; Opheim, Arild; Krajci, Peter; Sharma-Haase, Kamni; Benth, Jūratė Šaltytė; Tanum, Lars; Kunoe, Nikolaj

    2018-05-28

    This is a follow-up study of a previously published randomized clinical trial conducted in Norway that compared extended-release naltrexone (XR-NTX) to buprenorphine-naloxone (BP-NLX) over 3 months. At the conclusion of the trial, participants were offered their choice of study medication for an additional 9 months. While BP-NLX was available at no cost through opioid maintenance treatment programmes, XR-NTX was available only through study participation, accounting for why almost all participants chose XR-NTX in the follow-up. The aim of this follow-up study was to compare differences in outcome between adults with opioid dependence continuing XR-NTX and those inducted on XR-NTX for a 9-month period, on measures of effectiveness, safety and feasibility. In this prospective cohort study, participants were either continuing XR-NTX, changed from BP-NLX to XR-NTX or re-included into the study and inducted on XR-NTX treatment. Five urban, out-patient addiction clinics in Norway. Opioid-dependent adults continuing (n = 54) or inducted on (n = 63) XR-NTX. XR-NTX administrated as intramuscular injections (380 mg) every fourth week. Data on retention, use of heroin and other illicit substances, opioid craving, treatment satisfaction, addiction-related problems and adverse events were reported every fourth week. Nine-month follow-up completion rates were 51.9% among participants continuing XR-NTX in the follow-up and 47.6% among those inducted on XR-NTX. Opioid abstinence rates were, respectively, 53.7 and 44.4%. No significant group differences were found in use of heroin and other opioids. Opioid-dependent individuals who elect to switch from buprenorphine-naltrexone treatment after 3 months to extended-release naltrexone treatment for 9 months appear to experience similar treatment completion and abstinence rates and similar adverse event profiles to individuals who had been on extended-release naltrexone from the start of treatment. © 2018 Society for the

  17. Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial.

    PubMed

    Mannelli, Paolo; Wu, Li-Tzy; Peindl, Kathleen S; Swartz, Marvin S; Woody, George E

    2014-05-01

    The approval of extended release injectable naltrexone (XR-NTX; Vivitrol(®)) has introduced a new option for treating opioid addiction, but studies are needed to identify its place within the spectrum of available therapies. The absence of physiological opioid dependence is a necessary and challenging first step for starting XR-NTX. Outpatient detoxification gives poor results and inpatient detoxification is either unavailable or too brief for the physiological effects of opioids to resolve. Here we present findings from an open label study that tested whether the transition from opioid addiction to XR-NTX can be safely and effectively performed in an outpatient setting using very low dose naltrexone and buprenorphine. Twenty treatment seeking opioid addicted individuals were given increasing doses of naltrexone starting at 0.25mg with decreasing doses of buprenorphine starting at 4 mg during a 7-day outpatient XR-NTX induction procedure. Withdrawal discomfort, craving, drug use, and adverse events were assessed daily until the XR-NTX injection, then weekly over the next month. Fourteen of the 20 participants received XR-NTX and 13 completed weekly assessments. Withdrawal, craving, and opioid or other drug use were significantly lower during induction and after XR-NTX administration compared with baseline, and no serious adverse events were recorded. Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with downward titration of low dose buprenorphine was safe, well tolerated, and completed by most participants. Further studies with larger numbers of subjects are needed to see if this approach is useful for naltrexone induction. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. 77 FR 9944 - Determination That REQUIP XL (Ropinerole Hydrochloride) Extended-Release Tablets, 3 Milligrams...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-21

    ... Parkinson's disease. REQUIP XL (ropinerole hydrochloride) extended-release tablets, 3 mg, are currently... amendments include what is now section 505(j)(7) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j... suspends approval of the drug's NDA or ANDA for reasons of safety or effectiveness or if FDA determines...

  19. Accelerated in vitro release testing method for naltrexone loaded PLGA microspheres.

    PubMed

    Andhariya, Janki V; Choi, Stephanie; Wang, Yan; Zou, Yuan; Burgess, Diane J; Shen, Jie

    2017-03-30

    The objective of the present study was to develop a discriminatory and reproducible accelerated release testing method for naltrexone loaded parenteral polymeric microspheres. The commercially available naltrexone microsphere product (Vivitrol ® ) was used as the testing formulation in the in vitro release method development, and both sample-and-separate and USP apparatus 4 methods were investigated. Following an in vitro drug stability study, frequent media replacement and addition of anti-oxidant in the release medium were used to prevent degradation of naltrexone during release testing at "real-time" (37°C) and "accelerated" (45°C), respectively. The USP apparatus 4 method was more reproducible than the sample-and-separate method. In addition, the accelerated release profile obtained using USP apparatus 4 had a shortened release duration (within seven days), and good correlation with the "real-time" release profile. Lastly, the discriminatory ability of the developed accelerated release method was assessed using compositionally equivalent naltrexone microspheres with different release characteristics. The developed accelerated USP apparatus 4 release method was able to detect differences in the release characteristics of the prepared naltrexone microspheres. Moreover, a linear correlation was observed between the "real-time" and accelerated release profiles of all the formulations investigated, suggesting that the release mechanism(s) may be similar under both conditions. These results indicate that the developed accelerated USP apparatus 4 method has the potential to be an appropriate fast quality control tool for long-acting naltrexone PLGA microspheres. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Naltrexone implants compared to methadone: outcomes six months after prison release.

    PubMed

    Lobmaier, Philipp P; Kunøe, Nikolaj; Gossop, Michael; Katevoll, Tormod; Waal, Helge

    2010-01-01

    After prison release, offenders with heroin use problems are at high risk of relapse and overdose death. There is a particular need for treatments that can be initiated in prison and continued after release into the community. Methadone maintenance treatment has been shown to reduce heroin use, criminality and mortality. Naltrexone implant treatment has not previously been evaluated in prison settings. This study compares the effects of naltrexone implants and methadone treatment on heroin and other illicit drug use, and criminality among heroin-dependent inmates after release from prison. Forty-six volunteers were randomly allocated to naltrexone implants or methadone before release. Intention-to-treat analyses showed reductions in both groups in frequency of use of heroin and benzodiazepines, as well as criminality, 6 months after prison release. Naltrexone implants may be a valuable treatment option in prison settings. 2010 S. Karger AG, Basel.

  1. Extended-Release Naltrexone: A Qualitative Analysis of Barriers to Routine Use.

    PubMed

    Alanis-Hirsch, Kelly; Croff, Raina; Ford, James H; Johnson, Kim; Chalk, Mady; Schmidt, Laura; McCarty, Dennis

    2016-03-01

    The Medication Research Partnership (a national health plan and nine addiction treatment centers contracted with the health plan) sought to facilitate the adoption of pharmacotherapy for alcohol and opioid use disorders. Qualitative analysis of interviews with treatment center change leaders, individuals working for the manufacturer and its technical assistance contractor, and health plan managers extracted details on the processes used to order, store, bill for, and administer extended-release naltrexone. Qualitative themes were categorized using domains from the Consolidated Framework for Implementation Research (intervention characteristics, outer setting, inner setting, and provider characteristics). Characteristics of XR-NTX that inhibited use included the complexity of ordering and using the medication; cost was also a barrier. Outer setting barriers reflected patient needs and external health plan policies on formulary coverage, benefit management, and reimbursement. Program structures, the lack of physician linkages, a culture resistant to the use of medication, and unease with change were inner setting elements that limited use of XR-NTX. Patient stereotypes and a lack of knowledge about XR-NTX affected practitioner willingness to treat patients and prescribe XR-NTX. The Consolidated Framework for Implementation Research provided a useful lens to understand and interpret the processes affecting access to XR-NTX. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Extended-release naltrexone (XR-NTX) attenuates brain responses to alcohol cues in alcohol-dependent volunteers: a bold FMRI study.

    PubMed

    Lukas, Scott E; Lowen, Steven B; Lindsey, Kimberly P; Conn, Nina; Tartarini, Wendy; Rodolico, John; Mallya, Gopi; Palmer, Christopher; Penetar, David M

    2013-09-01

    Oral naltrexone reduces heavy drinking, but is less consistent as an abstinence promoter, whereas once-monthly extended-release naltrexone (XR-NTX) also maintains abstinence. The present study sought to determine if alcohol cue reactivity is attenuated by XR-NTX. Twenty-eight detoxified alcohol-dependent adult male and female volunteers received a single i.m. injection of either XR-NTX or placebo under double-blind conditions. An fMRI/cue reactivity procedure was conducted immediately before and two weeks after injection. At baseline, alcohol-related visual and olfactory cues elicited significant increases in orbital and cingulate gyri, inferior frontal and middle frontal gyri. Subsequently, brain activation was significantly altered in XR-NTX-treated individuals. These affected brain regions are associated with the integration of emotion, cognition, reward, punishment, and learning/memory, suggesting that XR-NTX attenuates the salience of alcohol-related cues. Such an effect on brain function may interrupt the processes associated with "slips" and relapse, which may account for XR-NTX's ability to maintain abstinence. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial.

    PubMed

    DeFulio, Anthony; Everly, Jeffrey J; Leoutsakos, Jeannie-Marie S; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E; Silverman, Kenneth

    2012-01-01

    Naltrexone provides excellent opioid blockade, but its clinical utility is limited because opioid-dependent patients typically refuse it. An injectable suspension of naltrexone for extended release (XR-NTX) was recently approved by the FDA for treatment of opioid dependence. XR-NTX treatment may require concurrent behavioral intervention to maximize adherence and effectiveness, thus we sought to evaluate employment-based reinforcement as a method of improving adherence to XR-NTX in opiate dependent adults. Opioid-dependent adults (n=38) were detoxified and inducted onto oral naltrexone, then randomly assigned to contingency or prescription conditions. Participants received up to six doses of XR-NTX at four-week intervals. All participants could earn vouchers for attendance and performance at a therapeutic workplace. Contingency participants were required to accept XR-NTX injections to access the workplace and earn vouchers. Prescription participants could earn vouchers independent of their acceptance of XR-NTX injections. Contingency participants accepted significantly more naltrexone injections than prescription participants (87% versus 52%, p=.002), and were more likely to accept all injections (74% versus 26%, p=.004). Participants in the two conditions provided similar percentages of samples negative for opiates (72% versus 65%) and for cocaine (58% versus 54%). Opiate positivity was significantly more likely when samples were also cocaine positive, independent of naltrexone blockade (p=.002). Long-term adherence to XR-NTX in unemployed opiate dependent adults is low under usual care conditions. Employment-based reinforcement can maintain adherence to XR-NTX. Ongoing cocaine use appears to interfere with the clinical effectiveness of XR-NTX on opiate use. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  4. Opioid Challenge Evaluation of Blockade by Extended-Release Naltrexone in Opioid-Abusing Adults: Dose-Effects and Time-Course

    PubMed Central

    Bigelow, George E.; Preston, Kenzie L.; Schmittner, John; Dong, Qunming; Gastfriend, David R.

    2013-01-01

    Background Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans. Methods Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-hr intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) Visual Analog Scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade. Results Blockade of the VAS “any drug effect” response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150 and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing. Conclusions These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment. PMID:22079773

  5. Naltrexone modulates dopamine release following chronic, but not acute amphetamine administration: a translational study

    PubMed Central

    Jayaram-Lindström, N; Guterstam, J; Häggkvist, J; Ericson, M; Malmlöf, T; Schilström, B; Halldin, C; Cervenka, S; Saijo, T; Nordström, A-L; Franck, J

    2017-01-01

    The opioid antagonist naltrexone has been shown to attenuate the subjective effects of amphetamine. However, the mechanisms behind this modulatory effect are currently unknown. We hypothesized that naltrexone would diminish the striatal dopamine release induced by amphetamine, which is considered an important mechanism behind many of its stimulant properties. We used positron emission tomography and the dopamine D2-receptor radioligand [11C]raclopride in healthy subjects to study the dopaminergic effects of an amphetamine injection after pretreatment with naltrexone or placebo. In a rat model, we used microdialysis to study the modulatory effects of naltrexone on dopamine levels after acute and chronic amphetamine exposure. In healthy humans, naltrexone attenuated the subjective effects of amphetamine, confirming our previous results. Amphetamine produced a significant reduction in striatal radioligand binding, indicating increased levels of endogenous dopamine. However, there was no statistically significant effect of naltrexone on dopamine release. The same pattern was observed in rats, where an acute injection of amphetamine caused a significant rise in striatal dopamine levels, with no effect of naltrexone pretreatment. However, in a chronic model, naltrexone significantly attenuated the dopamine release caused by reinstatement of amphetamine. Collectively, these data suggest that the opioid system becomes engaged during the more chronic phase of drug use, evidenced by the modulatory effect of naltrexone on dopamine release following chronic amphetamine administration. The importance of opioid-dopamine interactions in the reinforcing and addictive effects of amphetamine is highlighted by the present findings and may help to facilitate medication development in the field of stimulant dependence. PMID:28440810

  6. Maternally Administered Sustained-Release Naltrexone in Rats Affects Offspring Neurochemistry and Behaviour in Adulthood

    PubMed Central

    Krstew, Elena V.; Tait, Robert J.; Hulse, Gary K.

    2012-01-01

    Naltrexone is not recommended during pregnancy. However, sustained-release naltrexone implant use in humans has resulted in cases of inadvertent foetal exposure. Here, we used clinically relevant dosing to examine the effects of maternally administered sustained-release naltrexone on the rat brain by examining offspring at birth and in adulthood. Maternal treatment (naltrexone or placebo implant) started before conception and ceased during gestation, birth or weaning. Morphometry was assessed in offspring at birth and adulthood. Adult offspring were evaluated for differences in locomotor behaviour (basal and morphine-induced, 10 mg/kg, s.c.) and opioid neurochemistry, propensity to self-administer morphine and cue-induced drug-seeking after abstinence. Blood analysis confirmed offspring exposure to naltrexone during gestation, birth and weaning. Naltrexone exposure increased litter size and reduced offspring birth-weight but did not alter brain morphometry. Compared to placebo, basal motor activity of naltrexone-exposed adult offspring was lower, yet they showed enhanced development of psychomotor sensitization to morphine. Developmental naltrexone exposure was associated with resistance to morphine-induced down-regulation of striatal preproenkephalin mRNA expression in adulthood. Adult offspring also exhibited greater operant responding for morphine and, in addition, cue-induced drug-seeking was enhanced. Collectively, these data show pronounced effects of developmental naltrexone exposure, some of which persist into adulthood, highlighting the need for follow up of humans that were exposed to naltrexone in utero. PMID:23300784

  7. A multicenter, primary-care-based, open-label study to assess the success of converting opioid-experienced patients with chronic moderate-to-severe pain to morphine sulfate and naltrexone hydrochloride extended-release capsules using a standardized conversion guide.

    PubMed

    Setnik, Beatrice; Roland, Carl L; Sommerville, Kenneth W; Pixton, Glenn C; Berke, Robert; Calkins, Anne; Goli, Veeraindar

    2015-01-01

    To evaluate the conversion of opioid-experienced patients with chronic moderate-to-severe pain to extended-release morphine sulfate with sequestered naltrexone hydrochloride (MSN) using a standardized conversion guide. This open-label, single-arm study was conducted in 157 primary care centers in the United States. A total of 684 opioid-experienced adults with chronic moderate-to-severe pain were converted to oral administration of MSN from transdermal fentanyl and oral formulations of hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and other morphine products using a standardized conversion guide. The primary endpoint was the percentage of patients achieving a stable MSN dose within a 6-week titration phase. Secondary endpoints included duration of time to stable dose, number of titration steps, safety and efficacy measures, and investigator assessment of conversion guide utility. Of the 684 patients, 51.3% were converted to a stable dose of MSN (95% confidence interval: 47.5%, 55.1%). The mean (standard deviation) number of days to stable dose was 20 (8.94), and number of titration steps to stable dose was 2.4 (1.37). The majority of adverse events were mild/moderate and consistent with opioid therapy. Mean pain scores at stable dose decreased from baseline. Investigators were generally satisfied with the conversion guide and, in 94% of cases, reported they would use it again. Conversion to MSN treatment using the standardized MSN conversion guide was an attainable goal in approximately half of the population of opioid-experienced patients with chronic moderate-to-severe pain. Investigators found the guide to be a useful tool to assist conversion of opioid-experienced patients to MSN.

  8. Neural correlates of adherence to extended-release naltrexone pharmacotherapy in heroin dependence

    PubMed Central

    Wang, A-L; Elman, I; Lowen, S B; Blady, S J; Lynch, K G; Hyatt, J M; O'Brien, C P; Langleben, D D

    2015-01-01

    Injectable extended-release naltrexone (XRNTX) presents an effective therapeutic strategy for opioid addiction, however its utility could be hampered by poor adherence. To gain a better insight into this phenomenon, we utilized blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) in conjunction with a validated cue-induced craving procedure to examine neural correlates of XRNTX adherence. We operationalized treatment adherence as the number of monthly XRNTX injections (range: 0–3) administered to a group of fully detoxified heroin-dependent subjects (n=32). Additional outcomes included urine toxicology screening and self-reported tobacco use. The presented heroin-related visual cues reliably elicited heroin craving in all tested subjects. Nine, five, three and 15 of the participants, respectively, received zero, one, two and three XRNTX injections, predicted by the individual baseline fMRI signal change in response to the cues in the medial prefrontal cortex, a brain region involved in inhibitory self-control and emotional appraisal. The incidence of opioid-positive urines during the XRNTX therapy was low and remained about half the pre-treatment rate after the XRNTX ended. During the treatment, cigarette smoking behaviors followed patterns of opioid use, while cocaine consumption was increased with reductions in opioid use. The present data support the hypothesis that medial prefrontal cortex functions are involved in adherence to opioid antagonist therapy. A potential role of concurrent non-opioid addictive substances consumption during the XRNTX pharmacotherapy warrants further investigation. Our findings set the stage for further bio-behavioral investigations of the mechanisms of relapse prevention in opioid dependence. PMID:25781230

  9. Naltrexone ER/Bupropion ER: A Review in Obesity Management.

    PubMed

    Greig, Sarah L; Keating, Gillian M

    2015-07-01

    Oral naltrexone extended-release/bupropion extended-release (naltrexone ER/bupropion ER; Contrave(®), Mysimba(™)) is available as an adjunct to a reduced-calorie diet and increased physical activity in adults with an initial body mass index (BMI) of ≥ 30 kg/m(2) (i.e. obese) or a BMI of ≥ 27 kg/m(2) (i.e. overweight) in the presence of at least one bodyweight-related comorbidity, such as type 2 diabetes mellitus, hypertension or dyslipidaemia. In 56-week phase III trials in these patient populations, oral naltrexone ER/bupropion ER 32/360 mg/day was significantly more effective than placebo with regard to percentage bodyweight reductions from baseline and the proportion of patients who achieved bodyweight reductions of ≥ 5 and ≥ 10%. Significantly greater improvements in several cardiometabolic risk factors were also observed with naltrexone ER/bupropion ER versus placebo, as well as greater improvements in glycated haemoglobin levels in obese or overweight adults with type 2 diabetes. Naltrexone ER/bupropion ER was generally well tolerated in phase III trials, with nausea being the most common adverse event. Thus, naltrexone ER/bupropion ER 32/360 mg/day as an adjunct to a reduced-calorie diet and increased physical activity, is an effective and well tolerated option for chronic bodyweight management in obese adults or overweight adults with at least one bodyweight-related comorbidity.

  10. Long-Acting Injectable Naltrexone Induction: A Randomized Trial of Outpatient Opioid Detoxification With Naltrexone Versus Buprenorphine.

    PubMed

    Sullivan, Maria; Bisaga, Adam; Pavlicova, Martina; Choi, C Jean; Mishlen, Kaitlyn; Carpenter, Kenneth M; Levin, Frances R; Dakwar, Elias; Mariani, John J; Nunes, Edward V

    2017-05-01

    At present there is no established optimal approach for transitioning opioid-dependent adults to extended-release injection naltrexone (XR-naltrexone) while preventing relapse. The authors conducted a trial examining the efficacy of two methods of outpatient opioid detoxification for induction to XR-naltrexone. Participants were 150 opioid-dependent adults randomly assigned 2:1 to one of two outpatient detoxification regimens, naltrexone-assisted detoxification or buprenorphine-assisted detoxification, followed by an injection of XR-naltrexone. Naltrexone-assisted detoxification lasted 7 days and included a single day of buprenorphine followed by ascending doses of oral naltrexone along with clonidine and other adjunctive medications. Buprenorphine-assisted detoxification included a 7-day buprenorphine taper followed by a week-long delay before administration of XR-naltrexone, consistent with official prescribing information for XR-naltrexone. Participants from both groups received behavioral therapy focused on medication adherence and a second dose of XR-naltrexone. Compared with participants in the buprenorphine-assisted detoxification condition, participants assigned to naltrexone-assisted detoxification were significantly more likely to be successfully inducted to XR-naltrexone (56.1% compared with 32.7%) and to receive the second injection at week 5 (50.0% compared with 26.9%). Both models adjusted for primary type of opioid use, route of opioid administration, and morphine equivalents at baseline. These results demonstrate the safety, efficacy, and tolerability of low-dose naltrexone, in conjunction with single-day buprenorphine dosing and adjunctive nonopioid medications, for initiating adults with opioid dependence to XR-naltrexone. This strategy offers a promising alternative to the high rates of attrition and relapse currently observed with agonist tapers in both inpatient and outpatient settings.

  11. Clonidine hydrochloride detoxification from methadone treatment--the value of naltrexone aftercare.

    PubMed

    Rawson, R A; Washton, A M; Resnick, R B; Tennant, F S

    1984-01-01

    Treatment outcomes were compared for 2 groups of subjects detoxified from methadone using clonidine. One group of 12 subjects was encouraged to continue in treatment with naltrexone, while the other 12 subjects did not have naltrexone treatment available. Results suggested that those subjects who had naltrexone available were more successful at completing the 10 day detoxification treatment and that the relapse rate at 30 days post-treatment was significantly reduced by naltrexone treatment.

  12. Extended-release intramuscular naltrexone (VIVITROL®): a review of its use in the prevention of relapse to opioid dependence in detoxified patients.

    PubMed

    Syed, Yahiya Y; Keating, Gillian M

    2013-10-01

    Naltrexone is a μ-opioid receptor antagonist that blocks the euphoric effects of heroin and prescription opioids. In order to improve treatment adherence, a once-monthly, intramuscular, extended-release formulation of naltrexone (XR-NTX) [VIVITROL(®)] has been developed, and approved in the USA and Russia for the prevention of relapse to opioid dependence, after opioid detoxification. The clinical efficacy of this formulation in patients with opioid dependence was demonstrated in a 24-week, randomized, double-blind, placebo-controlled, multicentre, phase III trial (ALK21-013; n = 250). In this trial, opioid-detoxified patients receiving XR-NTX 380 mg once every 4 weeks, in combination with psychosocial support, had a significantly higher median proportion of weeks of confirmed opioid abstinence during weeks 5-24, compared with those receiving placebo (primary endpoint). A significantly higher proportion of patients receiving XR-NTX achieved total confirmed abstinence during this period than those receiving placebo. XR-NTX was also associated with a significantly greater reduction in opioid craving and a significantly longer treatment retention period than placebo. XR-NTX was generally well tolerated in the phase III trial. The most common (incidence ≥5 %) treatment-emergent adverse events that also occurred more frequently with XR-NTX than with placebo were hepatic enzyme abnormalities, nasopharyngitis, insomnia, hypertension, influenza and injection-site pain. Thus, XR-NTX is a useful treatment option for the prevention of relapse to opioid dependence, following opioid detoxification.

  13. Neuropsychological functioning in buprenorphine maintained patients versus abstinent heroin abusers on naltrexone hydrochloride therapy.

    PubMed

    Messinis, Lambros; Lyros, Epameinondas; Andrian, Virginia; Katsakiori, Paraskevi; Panagis, George; Georgiou, Vasileios; Papathanasopoulos, Panagiotis

    2009-10-01

    Methadone and buprenorphine are among the most widely employed pharmacological treatments currently available for opioid addiction. Cognitive effects of buprenorphine in abstinent heroin abusers are nevertheless far from being understood. Neuropsychological performance of 18 buprenorphine-maintained patients (BMP) was evaluated relative to that of 32 currently abstinent heroin abusers on naltrexone hydrochloride therapy (FHAN), and 34 non-drug dependent controls. The three groups were demographically balanced. Clinical groups reported histories of similar patterns of drug use and had increased periods of abstinence from any illicit substance use including heroin. The BMP group performed poorer than controls on the RAVLT (encoding and delayed recall of verbal information), CTT (conceptual flexibility, executive functions) and the RBANS figure copy (visual perception) and delayed recall of visual information. There were no significant differences in any of the cognitive measures between the BMP and FHAN groups or between the FHAN group and controls. Furthermore, the non-differing percentage of abnormal cases between the two patient groups led us to infer that treatment with either BPM or FHAN is not accompanied by qualitative differences in the cognitive profiles of these patients. Overall, results suggest that treatment with naltrexone in abstinent heroin abusers may result in less impairment of cognitive functions compared to treatment with buprenorphine. These findings are relevant for improved prognosis and treatment strategies in opioid dependence.

  14. Cost-effectiveness of extended release naltrexone to prevent relapse among criminal justice-involved individuals with a history of opioid use disorder.

    PubMed

    Murphy, Sean M; Polsky, Daniel; Lee, Joshua D; Friedmann, Peter D; Kinlock, Timothy W; Nunes, Edward V; Bonnie, Richard J; Gordon, Michael; Chen, Donna T; Boney, Tamara Y; O'Brien, Charles P

    2017-08-01

    Criminal justice-involved individuals are highly susceptible to opioid relapse and overdose-related deaths. In a recent randomized trial, we demonstrated the effectiveness of extended-release naltrexone (XR-NTX; Vivitrol ® ) in preventing opioid relapse among criminal justice-involved US adults with a history of opioid use disorder. The cost of XR-NTX may be a significant barrier to adoption. Thus, it is important to account for improved quality of life and downstream cost-offsets. Our aims were to (1) estimate the incremental cost per quality-adjusted life-year (QALY) gained for XR-NTX versus treatment as usual (TAU) and evaluate it relative to generally accepted value thresholds; and (2) estimate the incremental cost per additional year of opioid abstinence. Economic evaluation of the aforementioned trial from the taxpayer perspective. Participants were randomized to 25 weeks of XR-NTX injections or TAU; follow-up occurred at 52 and 78 weeks. Five study sites in the US Northeast corridor. A total of 308 participants were randomized to XR-NTX (n = 153) or TAU (n = 155). Incremental costs relative to incremental economic and clinical effectiveness measures, QALYs and abstinent years, respectively. The 25-week cost per QALY and abstinent-year figures were $162 150 and $46 329, respectively. The 78-week figures were $76 400/QALY and $16 371/abstinent year. At 25 weeks, we can be 10% certain that XR-NTX is cost-effective at a value threshold of $100 000/QALY and 62% certain at $200 000/QALY. At 78 weeks, the cost-effectiveness probabilities are 59% at $100 000/QALY and 76% at $200 000/QALY. We can be 95% confident that the intervention would be considered 'good value' at $90 000/abstinent year at 25 weeks and $500/abstinent year at 78 weeks. While extended-release naltrexone appears to be effective in increasing both quality-adjusted life-years (QALYs) and abstinence, it does not appear to be cost-effective using generally accepted value

  15. Injectable and implantable sustained release naltrexone in the treatment of opioid addiction

    PubMed Central

    Kunøe, Nikolaj; Lobmaier, Philipp; Ngo, Hanh; Hulse, Gary

    2014-01-01

    Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid-addicted patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in intramuscular or implantable polymers that release naltrexone for 1–7 months have become available for clinical use and research. This qualitative review of the literature provides an overview of the technologies currently available for SRX and their effectiveness in reducing opioid use and other relevant outcomes. The majority of studies indicate that SRX is effective in reducing heroin use, and the most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on mortality and morbidity. In some studies, SRX also seems to affect other outcomes, such as concomitant substance use, vocational training attendance, needle use, and risk behaviour for blood-borne diseases such as hepatitis or human immunodeficiency virus. There is a general need for more controlled studies, in particular to compare SRX with agonist maintenance treatment, to study combinations of SRX with behavioural interventions, and to study at-risk groups such as prison inmates or opioid-addicted pregnant patients. The literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid addiction. PMID:23088328

  16. Injectable and implantable sustained release naltrexone in the treatment of opioid addiction.

    PubMed

    Kunøe, Nikolaj; Lobmaier, Philipp; Ngo, Hanh; Hulse, Gary

    2014-02-01

    Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid-addicted patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in intramuscular or implantable polymers that release naltrexone for 1-7 months have become available for clinical use and research. This qualitative review of the literature provides an overview of the technologies currently available for SRX and their effectiveness in reducing opioid use and other relevant outcomes. The majority of studies indicate that SRX is effective in reducing heroin use, and the most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on mortality and morbidity. In some studies, SRX also seems to affect other outcomes, such as concomitant substance use, vocational training attendance, needle use, and risk behaviour for blood-borne diseases such as hepatitis or human immunodeficiency virus. There is a general need for more controlled studies, in particular to compare SRX with agonist maintenance treatment, to study combinations of SRX with behavioural interventions, and to study at-risk groups such as prison inmates or opioid-addicted pregnant patients. The literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid addiction. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  17. 21 CFR 522.1465 - Naltrexone hydrochloride injection.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... this chapter. (c) Conditions of use in elk and moose—(1) Amount. 100 milligrams of naltrexone...) Indications for use. As an antagonist to carfentanil citrate immobilization in free-ranging or confined elk and moose (Cervidae). (3) Limitations. Available data are inadequate to recommend use in pregnant...

  18. Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine

    PubMed Central

    Marks, Katherine R.; Lile, Joshua A.; Stoops, William W.; Glaser, Paul E.A.; Hays, Lon R.; Rush, Craig R.

    2016-01-01

    Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric acid type A (GABAA) receptors (e.g., alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of d-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and “positive” subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone. Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6–7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected. Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like “positive” subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10 mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior. PMID:27043121

  19. Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine.

    PubMed

    Marks, Katherine R; Lile, Joshua A; Stoops, William W; Glaser, Paul E A; Hays, Lon R; Rush, Craig R

    2016-06-01

    Opioid antagonists (eg, naltrexone) and positive modulators of γ-aminobutyric acid type A receptors (eg, alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of D-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and "positive" subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone.Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6 to 7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected.Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like "positive" subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10-mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior.

  20. Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial

    PubMed Central

    Comer, Sandra D.; Sullivan, Maria A.; Yu, Elmer; Rothenberg, Jami L.; Kleber, Herbert D.; Kampman, Kyle; Dackis, Charles; O'Brien, Charles P.; Chiang, C. Nora; Hawks, Richard L.

    2013-01-01

    Context Naltrexone is a medication available in oral form that can completely block the effects produced by opioid agonists, such as heroin. However, poor medication compliance with naltrexone has been a major obstacle to the effective treatment of opioid dependence. Objective To evaluate the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence. Design, Setting, and Participants Randomized, double-blind, placebo-controlled, 8-week multi-center trial of male and female heroin-dependent patients who participated in the study between September 2000 and November 2003. Participants were stratified by years of heroin use (≥5, <4.9) and gender, and then randomized to receive one of three doses: placebo, 192 mg, or 384 mg depot naltrexone. Doses were administered at the beginning of Week 1 and then again four weeks later at the beginning of Week 5. All participants received twice-weekly relapse prevention therapy, provided observed urine samples, and completed other assessments at each visit. Main Outcome Measures Primary outcome measures were retention in treatment and percentage of opioid-negative urine samples. Results A total of 60 patients were randomized at two centers. Retention in treatment was dose related with 39%, 60%, and 68% of the patients in the placebo, naltrexone 192 mg, and naltrexone 384 mg groups, respectively, remaining in treatment at the end of the two-month treatment period. Analysis of the time to dropout revealed a significant main effect of dose with mean time to dropout of 27, 36, and 48 days, respectively, for the placebo, naltrexone 192 mg, and naltrexone 384 mg groups. The percentage of urine samples negative for opioids varied significantly as a function of dose, as did the percentage of urine samples negative for methadone, cocaine, benzodiazepines, and amphetamine. The percentage of urine samples negative for cannabinoids was not significantly different across groups. When the data were

  1. Development and in vitro evaluation of carboxymethyl chitosan based drug delivery system for the controlled release of propranolol hydrochloride

    NASA Astrophysics Data System (ADS)

    Hernawan; Nur Hayati, Septi; Nisa, Khoirun; Wheni Indrianingsih, Anastasia; Darsih, Cici; Kismurtono, Muhammad

    2017-12-01

    Propranolol hydrochloride is a nonselective β-adrenergic drug and has been used as angina pectoris, antihypertensive, and that of many other cardiovascular disorders. It has a relatively short plasma half-life and duration of action are considered too short in certain circumstances. Thus, it’s fascinating to elongate the action. The tablet formula was based on extended-release by a propranolol hydrochloride based carboxymethyl chitosan matrix. Here we used direct compression technique with internal wet granulation to prepare the tablets. The tablets were evaluated for physical properties (hardness, weight variation test, friability) and in vitro release studies. There was no interaction observed between propranolol hydrochloride and excipients. Dissolution profiles of each formulation were followed zero order model. In conclusion, these results strongly suggest that in appropriate proportions carboxymethyl chitosan with internal granulation is suitable for formulating propranolol hydrochloride controlled release.

  2. Sustained-release bupropion versus naltrexone in the treatment of pathological gambling: a preliminary blind-rater study.

    PubMed

    Dannon, Pinhas N; Lowengrub, Katherine; Musin, Ernest; Gonopolski, Yehudit; Kotler, Moshe

    2005-12-01

    Pathological gambling (PG) is a relatively common and highly disabling impulse control disorder. A range of psychotherapeutic agents, including selective serotonin reuptake inhibitors, mood stabilizers, and opioid antagonists, has been shown to be effective in the treatment of PG. The use of selective serotonin reuptake inhibitors and opioid antagonists for PG is consistent with the observation that PG shares features of both the obsessive-compulsive spectrum disorders and addictive disorders. The aim of the study is to compare the effectiveness of sustained-release bupropion versus naltrexone in the treatment of PG. Thirty-six male pathological gamblers were enrolled in our study. A comprehensive psychiatric diagnostic evaluation was performed at baseline on all patients, and patients were screened for symptoms of gambling, depression, and anxiety using the South Oaks Gambling Screen, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Clinical Global Impression-Severity Scale. In addition, the patients completed self-report questionnaires about their demographic status. Patients were randomized in 2 groups and received either naltrexone (n = 19) or sustained-release bupropion (n = 17) for 12 weeks in a parallel fashion. Treatment response was monitored using the Clinical Global Impression-Improvement Scale which was performed at weeks 2, 4, 8, and 12. Patients were also assessed for the presence of gambling behavior via an unstructured interview, which was also performed at weeks 2, 4, 6, 8, and 12. Raters were blind to the study treatment. The majority of patients responded well to the drug treatment. Twelve of 17 patients in the sustained-release bupropion group completed the 12-week study, and 13 of 19 naltrexone patients completed the study. Nine (75%) of the 12 completers were rated as full responders in the sustained-release bupropion group versus 10 (76%) of 12 in the naltrexone group. Three (25%) of 12 completers in the

  3. Baseline Characteristics of Patients Predicting Suitability for Rapid Naltrexone Induction

    PubMed Central

    Mogali, Shanthi; Khan, Nabil A.; Drill, Esther S.; Pavlicova, Martina; Sullivan, Maria A.; Nunes, Edward; Bisaga, Adam

    2015-01-01

    Background and Objectives Extended-release (XR) injection naltrexone has proved promising in the treatment of opioid dependence. Induction onto naltrexone is often accomplished with a procedure known as rapid naltrexone induction. The purpose of this study was to evaluate pre-treatment patient characteristics as predictors of successful completion of a rapid naltrexone induction procedure prior to XR naltrexone treatment. Methods A chart review of 150 consecutive research participants (N = 84 completers and N = 66 non-completers) undergoing a rapid naltrexone induction with the buprenorphone-clonidine procedure were compared on a number of baseline demographic, clinical and psychosocial factors. Logistic regression was used to identify client characteristics that may predict successful initiation of naltrexone after a rapid induction-detoxification. Results Patients who failed to successfully initiate naltrexone were younger (AOR: 1.040, CI: 1.006, 1.075), and using 10 or more bags of heroin (or equivalent) per day (AOR: 0.881, CI: 0.820, 0.946). Drug use other than opioids was also predictive of failure to initiate naltrexone in simple bivariate analyses, but was no longer significant when controlling for age and opioid use level. Conclusions Younger age, and indicators of greater substance dependence severity (more current opioid use, other substance use) predict difficulty completing a rapid naltrexone induction procedure. Such patients might require a longer period of stabilization and/or more gradual detoxification prior to initiating naltrexone. Scientific Significance Our study findings identify specific characteristics of patients who responded positively to rapid naltrexone induction. PMID:25907815

  4. Open-label pilot study of extended-release naltrexone to reduce drinking and driving among repeat offenders.

    PubMed

    Lapham, Sandra C; McMillan, Garnett P

    2011-09-01

    A high proportion of persons convicted of driving while impaired repeat the offense. Many continue drinking and driving, even when faced with long jail terms. Hence, they pose a serious public health threat. This preliminary study evaluated extended-release, injectable naltrexone suspension (XR-NTX) and supportive therapy in reducing (1) drinking and (2) attempts to drive after drinking among repeat driving while impaired offenders with an ignition interlock device installed in their vehicles. Treatment-seeking volunteers received medical management therapy and 3 monthly injections of XR-NTX. We compared data on alcohol consumption, alcohol biomarkers, and interlock information before, during, and after treatment using summary measures and Sign tests. Of 12 consented subjects, 10 received at least 1 injection, and 7 received all 3 injections. All subjects receiving medication reported a decrease in average drinks per day (P < 0.01) and abstinent days (P = 0.02) while on treatment versus pretreatment levels. Average daily drinks decreased by 77%, from 3.0 to 0.69 (P < 0.01), during treatment with XR-NTX. Average drinks per drinking day also declined by 39% during treatment, from 6.6 to 4.0 (P = 0.04). Percent days abstinent increased by 31%, from 56.8 to 81.96 (P = 0.02), which persisted after treatment completion. Biomarkers were consistent with reduced drinking. The percentage of vehicular failures to start due to elevated breath alcohol decreased from 3.1% of tests to 1.29% of tests. A randomized, controlled clinical trial is needed to demonstrate the efficacy of this promising treatment regimen for repeat offenders.

  5. Naltrexone/bupropion: Contrave(R); naltrexone SR/bupropion SR.

    PubMed

    2010-01-01

    In March 2010, Orexigen(R) Therapeutics submitted a new drug application (NDA) for approval of naltrexone sustained release (SR)/bupropion SR (Contrave(R)) for the treatment of obesity in the US. The tablet contains naltrexone SR 32 mg and bupropion SR 360 mg. The drug has been tested in four randomized, double-blind, placebo-controlled, phase III trials and the co-primary endpoints were met in each case. This review discusses the key development milestones and clinical trial program to date.

  6. A randomized double-blind, placebo-controlled efficacy and safety study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) for moderate-to-severe chronic low back pain treatment.

    PubMed

    Rauck, Richard L; Hale, Martin E; Bass, Almasa; Bramson, Candace; Pixton, Glenn; Wilson, Jacquelyn G; Setnik, Beatrice; Meisner, Paul; Sommerville, Kenneth W; Malhotra, Bimal K; Wolfram, Gernot

    2015-09-01

    The objective of this multicenter, double-blind, placebo-controlled, randomized withdrawal study was to evaluate the efficacy and safety of ALO-02, an abuse-deterrent formulation containing pellets of extended-release oxycodone hydrochloride (HCl) surrounding sequestered naltrexone HCl, compared with placebo in the treatment of moderate-to-severe chronic low back pain. An open-label titration period in which all patients received ALO-02 was followed by a double-blind treatment period where patients meeting treatment response criteria were randomized to either a fixed dose of ALO-02 or placebo. Daily average low back pain was assessed using an 11-point numeric rating scale (NRS)-Pain. Of the 663 patients screened, 410 received ALO-02 during the open-label conversion and titration period and 281 patients were randomized to the double-blind treatment period (n = 134, placebo; n = 147, ALO-02). Change in the mean NRS-Pain score from randomization baseline to the final 2 weeks of the treatment period was significantly different favoring ALO-02 compared with placebo (P = 0.0114). Forty-four percent of patients treated with placebo and 57.5% of patients treated with ALO-02 reported ≥30% improvement in weekly average NRS-Pain scores from screening to the final 2 weeks of the treatment period (P = 0.0248). In the double-blind treatment period, 56.8% of patients in the ALO-02 group and 56.0% of patients in the placebo group experienced a treatment-emergent adverse event (TEAE). The most common treatment-related TEAEs for ALO-02 during the treatment period were nausea, vomiting, and constipation, consistent with opioid therapy. ALO-02 has been demonstrated to provide significant reduction of pain in patients with chronic low back pain and has a safety profile similar to other opioids.

  7. Correlates of retention on extended-release naltrexone among persons living with HIV infection transitioning to the community from the criminal justice system.

    PubMed

    Springer, Sandra A; Brown, Shan-Estelle; Di Paola, Angela; Altice, Frederick L

    2015-12-01

    The acceptability of and retention on extended-release naltrexone (XR-NTX), an FDA-approved medication for the treatment of alcohol and opioid use disorders, among persons living with HIV disease (PLH) under criminal justice setting (CJS) supervision has not been evaluated to date. Two double-blind placebo-controlled randomized trials of XR-NTX for inmates with HIV disease transitioning to the community with (1) alcohol use disorders (AUDs) or (2) opioid use disorders, are underway. Reasons for not accepting XR-NTX and an evaluation of differences in demographic features between those who were retained on study drug and those who did not return for their second injection post-release are discussed. 70% of eligible persons consented to participate; almost 90% received their first injection; and almost 60% returned for their first injection after release. Variables found to be associated (p<0.10) with returning for the second injection included: not meeting criteria for hazardous drinking (p=0.035; OR 0.424 (CI 0.191-0.941)); being prescribed antiretroviral therapy (p=0.068; OR 2.170 (CI 0.943-4.992)); expressing experiencing serious depression 30 days prior to incarceration (p=0.068; OR 1.889 (CI 0.955-3.737)); not having a positive cocaine urine screen on the day of release (DOR) (p=0.011; OR 0.258 (CI 0.091-0.729)); and not meeting criteria for an AUD plus any substance use disorder (p=0.068; OR 0.521 (CI 0.259-1.048)). Only positive cocaine urine test on DOR was statistically significant after multivariate regression analyses (p=0.005; OR 0.207 (CI 0.068-0.623)). CJS based XR-NTX programs are highly acceptable among PLH, however retention on XR-NTX after release is negatively impacted by relapse to cocaine use. Published by Elsevier Ireland Ltd.

  8. Patient preferences and extended-release naltrexone: A new opportunity to treat opioid use disorders in Ukraine.

    PubMed

    Marcus, Ruthanne; Makarenko, Iuliia; Mazhnaya, Alyona; Zelenev, Alexei; Polonsky, Maxim; Madden, Lynn; Filippovych, Sergii; Dvoriak, Sergii; Springer, Sandra A; Altice, Frederick L

    2017-10-01

    Scaling up HIV prevention for people who inject drugs (PWID) using opioid agonist therapies (OAT) in Ukraine has been restricted by individual and structural factors. Extended-release naltrexone (XR-NTX), however, provides new opportunities for treating opioid use disorders (OUDs) in this region, where both HIV incidence and mortality continue to increase. Survey results from 1613 randomly selected PWID from 5 regions in Ukraine who were currently, previously or never on OAT were analyzed for their preference of pharmacological therapies for treating OUDs. For those preferring XR-NTX, independent correlates of their willingness to initiate XR-NTX were examined. Among the 1613 PWID, 449 (27.8%) were interested in initiating XR-NTX. Independent correlates associated with interest in XR-NTX included: being from Mykolaiv (AOR=3.7, 95% CI=2.3-6.1) or Dnipro (AOR=1.8, 95% CI=1.1-2.9); never having been on OAT (AOR=3.4, 95% CI=2.1-5.4); shorter-term injectors (AOR=0.9, 95% CI 0.9-0.98); and inversely for both positive (AOR=0.8, CI=0.8-0.9), and negative attitudes toward OAT (AOR=1.3, CI=1.2-1.4), respectively. In the context of Eastern Europe and Central Asia where HIV is concentrated in PWID and where HIV prevention with OAT is under-scaled, new options for treating OUDs are urgently needed. here suggest that XR-NTX could become an option for addiction treatment and HIV prevention especially for PWID who have shorter duration of injection and who harbor negative attitudes to OAT. Decision aids that inform patient preferences with accurate information about the various treatment options are likely to guide patients toward better, patient-centered treatments and improve treatment entry and retention. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Pseudoephedrine hydrochloride sustained-release pellets prepared by a combination of hot-melt subcoating and polymer coating.

    PubMed

    Yang, Zi Yi; Lu, Yan; Tang, Xing

    2008-12-01

    Pseudoephedrine hydrochloride is an active very highly water soluble substance. In order to control release of a drug with this property, we developed the application of a combination of hot-melt subcoating and polymer coating was developed. The main objective was to investigate the influence of this combination on the release of highly water soluble drug and how it works. Hot-melt subcoating was achieved by using a coating pan. Subsequently, the outer polymer coating was prepared by fluidized bed, and the drug release was determined by high-performance liquid chromatograph (HPLC) method. Hot-melt subcoating can form a barrier between the drug-loaded pellets and the polymer coating layer, which prevents migration of the drug during film application. Consequently, the level of polymer coating can be reduced significantly, and the effectiveness of the polymer coating increased. In this study, the release profile of pellets with a 10% hot-melt subcoating and 5% polymer coating weight gain met the dissolution requirement of USP29 for pseudoephedrine hydrochloride extended-release capsules. Compared with pellets only polymer coated (10% level), the polymer coating level of pellets prepared by this technology was reduced by half due to hot-melt subcoating. By means of this hot-melt subcoating and polymer coating, sustained-release pellets containing pseudoephedrine hydrochloride were successfully prepared.

  10. Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/bupropion extended release and phentermine-topiramate extended release.

    PubMed

    Halpern, Bruno; Mancini, Marcio C

    2017-01-01

    Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval. Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations. Expert opinion: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.

  11. An Evaluation of μ-Opioid Receptor (OPRM1) as a Predictor of Naltrexone Response in the Treatment of Alcohol Dependence

    PubMed Central

    Anton, Raymond F.; Oroszi, Gabor; O'Malley, Stephanie; Couper, David; Swift, Robert; Pettinati, Helen; Goldman, David

    2008-01-01

    Context: Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the μ-opioid receptor gene (OPRM1), might predict naltrexone response. Objective: To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone. Design: Pharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004. Setting: Eleven academic sites in the COMBINE Study. Participants: Recently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA. Interventions: Alcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI). Main Outcome Measures: Time trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome. Results: Alcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P=.07) and a decreased percentage of heavy drinking days (P=.04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P=.005). No gene

  12. Effects of injectable extended-release naltrexone (XR-NTX) for opioid dependence on residential rehabilitation outcomes and early follow-up.

    PubMed

    Leslie, Douglas L; Milchak, William; Gastfriend, David R; Herschman, Philip L; Bixler, Edward O; Velott, Diana L; Meyer, Roger E

    2015-04-01

    Little is known about the use of extended-release naltrexone (XR-NTX) during residential rehabilitation, and its effects on early outcomes and rates of follow-up treatment. This study examined patient characteristics and rates of treatment completion and engagement in post-residential care of opioid dependent patients who received XR-NTX during residential rehabilitation, compared with patients who did not receive this medication. Electronic records for opioid dependent patients from three Pennsylvania residential detoxification and treatment facilities (N = 7,687) were retrospectively analyzed. We determined the proportion of patients who received XR-NTX (INJ), and compared rates of treatment completion and engagement in follow-up care relative to a naturalistic control group of patients recommended for, but not administered, XR-NTX (Non-INJ). Data on whether the patient initiated follow-up care were available from one site (N = 3,724). Overall, 598 (7.8%) patients were recommended for XR-NTX and of these, 168 (28.1%) received injections. Compared to non-INJ patients, INJ patients were less likely to leave against medical advice (4.8% vs. 30.2%, p < .001) and more likely to initiate follow-up care (37.7% vs. 19.7%, p < .001). These differences remained significant after controlling for demographic covariates using regression analysis. XR-NTX was associated with higher rates of residential and early post-residential care engagement in patients with opioid dependence. XR-NTX may be an effective adjunct in the residential treatment and aftercare of patients with opioid dependence. © American Academy of Addiction Psychiatry.

  13. Healthcare utilization in adults with opioid dependence receiving extended release naltrexone compared to treatment as usual.

    PubMed

    Soares, William E; Wilson, Donna; Rathlev, Niels; Lee, Joshua D; Gordon, Michael; Nunes, Edward V; O'Brien, Charles P; Friedmann, Peter D

    2018-02-01

    Opioid use disorders have reached epidemic proportions, with overdose now the leading cause of accidental death in the United States. Extended release naltrexone (XR-NTX) has emerged as a medication treatment that reduces opioid use and craving. However, the effect of XR-NTX therapy on acute healthcare utilization, including emergency department visits and inpatient hospitalizations, remains uncertain. The objective of the current study is to evaluate hospital-based healthcare resource utilization in adults involved in the criminal justice system with a history of opioid use disorder randomized to XR-NTX therapy compared with treatment as usual (TAU) during a 6-month treatment phase and 12months post-treatment follow up. This retrospective exploratory analysis uses data collected in a published randomized trial. Comparisons of the number of emergency department visits and hospital admissions (for drug detox, psychiatric care and other medical reasons) were performed using chi square tests for any admission and negative binomial models for number of admissions. Of the 308 participants randomized, 96% had utilization data (76% complete 6months, 67% complete follow up). No significant differences were seen in overall healthcare utilization (IRR=0.88, 95%CI 0.63-1.23, p=0.45), or substance use-related drug detox hospitalizations (IRR=0.83, 95%CI 0.32-2.16, p=0.71). Despite having more participants report chronic medical problems at baseline (43% vs. 32%, p=0.05), those receiving XR-NTX generally experienced equivalent or lower rates of healthcare utilization compared to TAU. The XR-NTX group had significantly lower medical/surgical related hospital admissions (IRR=0.55, 95%CI 0.30-1.00, p=0.05) during the course of the entire study. XR-NTX did not significantly increase rates of healthcare utilization compared to TAU. Provider concerns regarding healthcare utilization should not preclude the consideration of XR-NTX as therapy for opioid use disorders. Copyright © 2018

  14. Clonidine Extended-Release Tablets for Pediatric Patients with Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Jain, Rakesh; Segal, Scott; Kollins, Scott H.; Khayrallah, Moise

    2011-01-01

    Objective: This study examined the efficacy and safety of clonidine hydrochloride extended-release tablets (CLON-XR) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Method: This 8-week, placebo-controlled, fixed-dose trial, including 3 weeks of dose escalation, of patients 6 to 17 years old with ADHD evaluated the…

  15. Efficacy of Tramadol Extended-Release for Opioid Withdrawal: A Randomized Clinical Trial.

    PubMed

    Dunn, Kelly E; Tompkins, D Andrew; Bigelow, George E; Strain, Eric C

    2017-09-01

    Opioid use disorder (OUD) is a significant public health problem. Supervised withdrawal (ie, detoxification) from opioids using clonidine or buprenorphine hydrochloride is a widely used treatment. To evaluate whether tramadol hydrochloride extended-release (ER), an approved analgesic with opioid and nonopioid mechanisms of action and low abuse potential, is effective for use in supervised withdrawal settings. A randomized clinical trial was conducted in a residential research setting with 103 participants with OUD. Participants' treatment was stabilized with morphine, 30 mg, administered subcutaneously 4 times daily. A 7-day taper using clonidine (n = 36), tramadol ER (n = 36), or buprenorphine (n = 31) was then instituted, and patients were crossed-over to double-blind placebo during a post-taper period. The study was conducted from October 25, 2010, to June 23, 2015. Retention, withdrawal symptom management, concomitant medication utilization, and naltrexone induction. Results were analyzed over time and using area under the curve for the intention-to-treat and completer groups. Of the 103 participants, 88 (85.4%) were men and 43 (41.7%) were white; mean (SD) age was 28.9 (10.4) years. Buprenorphine participants (28 [90.3%]) were significantly more likely to be retained at the end of the taper compared with clonidine participants (22 [61.1%]); tramadol ER retention was intermediate and did not differ significantly from that of the other groups (26 [72.2%]; χ2 = 8.5, P = .01). Time-course analyses of withdrawal revealed significant effects of phase (taper, post taper) for the Clinical Opiate Withdrawal Scale (COWS) score (taper mean, 5.19 [SE, .26]; post-taper mean, 3.97 [SE, .23]; F2,170 = 3.6, P = .03) and Subjective Opiate Withdrawal Scale (SOWS) score (taper mean,8.81 [SE, .40]; post-taper mean, 4.14 [SE, .30]; F2,170 = 15.7, P < .001), but no group effects or group × phase interactions. Analyses of area under the

  16. Modulation of venlafaxine hydrochloride release from press coated matrix tablet.

    PubMed

    Gohel, M C; Soni, C D; Nagori, S A; Sarvaiya, K G

    2008-01-01

    The aim of present study was to prepare novel modified release press coated tablets of venlafaxine hydrochloride. Hydroxypropylmethylcellulose K4M and hydroxypropylmethylcellulose K100M were used as release modifier in core and coat, respectively. A 3(2) full factorial design was adopted in the optimization study. The drug to polymer ratio in core and coat were chosen as independent variables. The drug release in the first hour and drug release rate between 1 and 12 h were chosen as dependent variables. The tablets were characterized for dimension analysis, crushing strength, friability and in vitro drug release. A check point batch, containing 1:2.6 and 1:5.4 drug to polymer in core and coat respectively, was prepared. The tablets of check point batch were subjected to in vitro drug release in dissolution media with pH 5, 7.2 and distilled water. The kinetics of drug release was best explained by Korsmeyer and Peppas model (anomalous non-Fickian diffusion). The systematic formulation approach enabled us to develop modified release venlafaxine hydrochloride tablets.

  17. Metformin extended release: metformin gastric retention, metformin GR, metformin XR.

    PubMed

    2005-01-01

    Metformin extended release [Glumetza, metformin hydrochloride, metformin gastric retention, metformin GR] is a proprietary once-a-day formulation of metformin hydrochloride under development with Depomed for the treatment of diabetes mellitus. In May 2002, Depomed licensed manufacturing and marketing rights for its proprietary formulation of metformin extended release (500mg dose) to Biovail Corporation for the US (including Puerto Rico) and Canada. Under the terms of the agreement, Biovail will pay DepoMed a 25 million dollars milestone fee upon approval of the 500mg dosage and also customary royalties on the net sales in the US and Canada. Biovail also agreed to acquire approximately 2.4 million of additionally issued Depomed shares for 12.3 million dollars. Biovail has subsequently developed a 1000mg dose of metformin extended release [metformin XR] using its proprietary Smartcoat delivery technology allowing a graduated release of the active drug from the tablet. In April 2004, Depomed and Biovail amended their original license agreement of May 2002. Under the terms of the amended agreement, Depomed will receive royalties on sales of Biovail's 1000mg tablet in the US and Canada. In turn, Biovail acquired access to Depomed's clinical data for the metformin 500mg tablet that will be used to accelerate regulatory filings for Biovail's 1000mg tablet and establish equivalence between the two dosages. Biovail is seeking marketing partners for metformin extended release (Glumetza) in the US. The company anticipates signing an agreement for the US during the second half of 2005. In Canada, Biovail Corporation will market Glumetzatrade mark through its Canadian division, Bioval Pharmaceuticals Canada. Depomed has an agreement with LG Life Sciences for the commercialisation and distribution of metformin extended release in Korea. Metformin GR is available for partnership in Europe and Asia. Biovail Corporation and Depomed announced in June 2005 that the US FDA has

  18. Employment-Based Reinforcement of Adherence to Depot Naltrexone in Unemployed Opioid-Dependent Adults: A Randomized Controlled Trial

    PubMed Central

    Everly, Jeffrey J.; DeFulio, Anthony; Koffarnus, Mikhail N.; Leoutsakos, Jeannie-Marie S.; Donlin, Wendy D.; Aklin, Will M.; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E.; Silverman, Kenneth

    2011-01-01

    Aims Naltrexone can be used to treat opioid dependence, but patients refuse to take it. Extended-release depot formulations may improve adherence, but long-term adherence rates to depot naltrexone are not known. This study determined long-term rates of adherence to depot naltrexone and whether employment-based reinforcement can improve adherence. Design Participants who were inducted onto oral naltrexone were randomly assigned to Contingency (n=18) or Prescription (n=17) groups. Participants were offered six depot naltrexone injections and invited to work at the therapeutic workplace weekdays for 26 weeks where they earned stipends for participating in job skills training. Contingency participants were required to accept naltrexone injections to maintain workplace access and to maintain maximum pay. Prescription participants could work independent of whether they accepted injections. Setting The therapeutic workplace, a model employment-based intervention for drug addiction and unemployment. Participants Opioid-dependent unemployed adults. Measurements Depot naltrexone injections accepted and opiate-negative urine samples. Findings Contingency participants accepted significantly more naltrexone injections than Prescription participants (81% versus 42%), and were more likely to accept all injections (66% versus 35%). At monthly assessments (with missing urine samples imputed as positive), the groups provided similar percentages of samples negative for opiates (74% versus 62%) and for cocaine (56% versus 54%). Opiate positive samples were more likely when samples were also positive for cocaine. Conclusions Employment-based reinforcement can maintain adherence to depot naltrexone. Future research should determine whether persistent cocaine use compromises naltrexone's effect on opiate use. Workplaces may be useful for promoting sustained adherence to depot naltrexone. PMID:21320227

  19. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Proguanil Hydrochloride.

    PubMed

    Plöger, Gerlinde F; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, Dirk W; Langguth, Peter; Mehta, Mehul U; Parr, Alan; Polli, James E; Shah, Vinod P; Tajiri, Tomokazu; Dressman, Jennifer B

    2018-07-01

    Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To elucidate the Biopharmaceutics Classification System (BCS) classification, experimental solubility and dissolution studies were also carried out. The antimalarial proguanil hydrochloride, effective via the parent compound proguanil and the metabolite cycloguanil, is not considered to be a narrow therapeutic index drug. Proguanil hydrochloride salt was shown to be highly soluble according to the U.S. Food and Drug Administration, World Health Organization, and European Medicines Agency guidelines, but data for permeability are inconclusive. Therefore, proguanil hydrochloride is conservatively classified as a BCS class 3 substance. In view of this information and the assessment of risks associated with a false positive decision, a BCS-based biowaiver approval procedure can be recommended for orally administered solid immediate release products containing proguanil hydrochloride, provided well-known excipients are used in usual amounts and provided the in vitro dissolution of the test and reference products is very rapid (85% or more are dissolved in 15 min at pH 1.2, 4.5, and 6.8) and is performed according to the current requirements for BCS-based biowaivers. Copyright © 2018 American Pharmacists Association®. All rights reserved.

  20. Development of in vitro-in vivo correlation of parenteral naltrexone loaded polymeric microspheres.

    PubMed

    Andhariya, Janki V; Shen, Jie; Choi, Stephanie; Wang, Yan; Zou, Yuan; Burgess, Diane J

    2017-06-10

    Establishment of in vitro-in vivo correlations (IVIVCs) for parenteral polymeric microspheres has been very challenging, due to their complex multiphase release characteristics (which is affected by the nature of the drug) as well as the lack of compendial in vitro release testing methods. Previously, a Level A correlation has been established and validated for polymeric microspheres containing risperidone (a practically water insoluble small molecule drug). The objectives of the present study were: 1) to investigate whether a Level A IVIVC can be established for polymeric microspheres containing another small molecule drug with different solubility profiles compared to risperidone; and 2) to determine whether release characteristic differences (bi-phasic vs tri-phasic) between microspheres can affect the development and predictability of IVIVCs. Naltrexone was chosen as the model drug. Three compositionally equivalent formulations of naltrexone microspheres with different release characteristics were prepared using different manufacturing processes. The critical physicochemical properties (such as drug loading, particle size, porosity, and morphology) as well as the in vitro release characteristics of the prepared naltrexone microspheres and the reference-listed drug (Vivitrol®) were determined. The pharmacokinetics of the naltrexone microspheres were investigated using a rabbit model. The obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method, and compared with the in vitro release profiles of the naltrexone microspheres obtained using USP apparatus 4. Level A IVIVCs were established and validated for predictability. The results demonstrated that the developed USP 4 method was capable of detecting manufacturing process related performance changes, and most importantly, predicting the in vivo performance of naltrexone microspheres in the investigated animal model. A critical difference between naltrexone and risperidone loaded

  1. Preparation and controlled release of mesoporous MCM-41/propranolol hydrochloride composite drug.

    PubMed

    Zhai, Qing-Zhou

    2013-01-01

    This article used MCM-41 as a carrier for the assembly of propranolol hydrochloride by the impregnation method. By means of chemical analysis, powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy and low-temperature N(2) adsorption-desorption at 77 K, the characterization was made for the prepared materials. The propranolol hydrochloride guest assembly capacity was 316.20 ± 0.31 mg/g (drug/MCM-41). Powder XRD test results indicated that during the process of incorporation, the frameworks of the MCM-41 were not destroyed and the crystalline degrees of the host-guest nanocomposite materials prepared still remained highly ordered. Characterization by SEM and TEM showed that the composite material presented spherical particle and the average particle size of composite material was 186 nm. FT-IR spectra showed that the MCM-41 framework existed well in the (MCM-41)-propranolol hydrochloride composite. Low-temperature nitrogen adsorption-desorption results at 77 K showed that the guest partially occupied the channels of the molecular sieves. Results of the release of the prepared composite drug in simulated body fluid indicated that the drug can release up to 32 h and its maximum released amount was 99.20 ± 0.11%. In the simulated gastric juice release pattern of drug, the maximum time for the drug release was discovered to be 6 h and the maximum cumulative released amount of propranolol hydrochloride was 45.13 ± 0.23%. The drug sustained-release time was 10 h in simulated intestinal fluid and the maximum cumulative released amount was 62.05 ± 0.13%. The prepared MCM-41 is a well-controlled drug delivery carrier.

  2. Low-Dose Naltrexone Treatment of Familial Benign Pemphigus (Hailey-Hailey Disease).

    PubMed

    Ibrahim, Omer; Hogan, Sara R; Vij, Alok; Fernandez, Anthony P

    2017-10-01

    Familial benign pemphigus, or Hailey-Hailey disease (HHD), is a rare and debilitating genetic dermatosis characterized by chronic, recurrent vesicles, erosions, and maceration in flexural areas. Despite the reported therapeutic modalities, such as topical and systemic corticosteroids, systemic immunomodulators, topical and systemic retinoids, and laser, HHD can still be markedly difficult to control. To assess low-dose naltrexone hydrochloride in the treatment of recalcitrant HHD. In this case series, 3 patients with biopsy-proven recalcitrant HHD were evaluated in the outpatient dermatology clinic at the Cleveland Clinic. Each patient was treated with low-dose naltrexone hydrochloride at a dosage of 1.5 to 3.0 mg per day. No laboratory monitoring was necessary. Clinical response (healing of erosions, improvement in erythema, and alleviation of pain), adverse effects, and subjective quality of life were monitored throughout the treatment. The study dates were January 2016 to January 2017. Objective clinical response as assessed by the treating dermatologist, subjective quality of life as reported by the patient, and recorded adverse effects were monitored throughout the treatment at intervals of 2 to 3 months. The 3 patients included a woman in her 40s and 2 men in their 60s. Each patient exhibited at least an 80% improvement in extent of disease, with one patient demonstrating 90% clearance. All 3 patients had substantial improvement in quality of life, with one patient reporting improvement in his depression. No adverse effects were recorded. Low-dose naltrexone may represent a low-cost and low-risk alternative or adjunct in the treatment of HHD.

  3. The Mixed Opioid Receptor Antagonist Naltrexone Mitigates Stimulant-Induced Euphoria: A Double-Blind, Placebo-Controlled Trial of Naltrexone.

    PubMed

    Spencer, Thomas J; Bhide, Pradeep; Zhu, Jinmin; Faraone, Stephen V; Fitzgerald, Maura; Yule, Amy M; Uchida, Mai; Spencer, Andrea E; Hall, Anna M; Koster, Ariana J; Feinberg, Leah; Kassabian, Sarah; Storch, Barbara; Biederman, Joseph

    Supratherapeutic doses of methylphenidate activate μ-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed μ-opioid antagonist, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential in subjects with attention-deficit/hyperactivity disorder (ADHD). We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate (January 2013 to June 2015). Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH) was administered twice daily, was titrated to ~1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with an oral test dose of 60 mg of immediate-release methylphenidate (IR-MPH). The primary outcome measure was Question 2 (Liking a Drug Effect) on the Drug Rating Questionnaire, Subject version, which was assessed after oral test doses of 60 mg of IR-MPH were administered after the third and sixth weeks of treatment with SODAS-MPH. Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS-MPH and randomized to naltrexone 50 mg/d or placebo. Thirty-one subjects completed through week 3, and 25 completed through week 6. Naltrexone significantly diminished the euphoric effect of IR-MPH during the heightened-risk titration phase (primary outcome; first 3 weeks) (χ² = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (χ² = 0.22, P = .64) of SODAS-MPH treatment. Preclinical findings are extended to humans showing that naltrexone may mitigate stimulant-associated euphoria. Our findings provide support for further studies combining opioid receptor antagonists with stimulants to reduce abuse potential. ClinicalTrials.gov identifier: NCT01673594.

  4. Naltrexone implant treatment for buprenorphine dependence--Mauritian case series.

    PubMed

    Jhugroo, Anil; Ellayah, Darmen; Norman, Amanda; Hulse, Gary

    2014-08-01

    Although substitution therapy with opiate agonist treatments such as methadone and buprenorphine has resulted in a reduction of illicit drug use related harm, such treatment has also resulted in severe problems in some countries where opioid-dependent individuals now inject illicitly sold buprenorphine or buprenorphine-naloxone instead of heroin. There is no approved treatment for buprenorphine dependence. Naltrexone is an opioid antagonist which has been used for the treatment of both alcohol and opioid dependencies. Although both buprenorphine and heroin resemble each other concerning their effects, buprenorphine has a higher affinity to opioid receptors than heroin. Therefore, it is not known if naltrexone can block the psychoactive effects of buprenorphine as it does for heroin. This paper presents observational case series data on the use of a sustained-release naltrexone implant for the treatment of buprenorphine dependence. To the authors' knowledge this is the first use of sustained-release naltrexone for this indication. © The Author(s) 2014.

  5. Development and validation of stability indicating method for the quantitative determination of venlafaxine hydrochloride in extended release formulation using high performance liquid chromatography

    PubMed Central

    Kaur, Jaspreet; Srinivasan, K. K.; Joseph, Alex; Gupta, Abhishek; Singh, Yogendra; Srinivas, Kona S.; Jain, Garima

    2010-01-01

    Objective: Venlafaxine,hydrochloride is a structurally novel phenethyl bicyclic antidepressant, and is usually categorized as a serotonin–norepinephrine reuptake inhibitor (SNRI) but it has been referred to as a serotonin–norepinephrine–dopamine reuptake inhibitor. It inhibits the reuptake of dopamine. Venlafaxine HCL is widely prescribed in the form of sustained release formulations. In the current article we are reporting the development and validation of a fast and simple stability indicating, isocratic high performance liquid chromatographic (HPLC) method for the determination of venlafaxine hydrochloride in sustained release formulations. Materials and Methods: The quantitative determination of venlafaxine hydrochloride was performed on a Kromasil C18 analytical column (250 × 4.6 mm i.d., 5 μm particle size) with 0.01 M phosphate buffer (pH 4.5): methanol (40: 60) as a mobile phase, at a flow rate of 1.0 ml/min. For HPLC methods, UV detection was made at 225 nm. Results: During method validation, parameters such as precision, linearity, accuracy, stability, limit of quantification and detection and specificity were evaluated, which remained within acceptable limits. Conclusions: The method has been successfully applied for the quantification and dissolution profiling of Venlafaxine HCL in sustained release formulation. The method presents a simple and reliable solution for the routine quantitative analysis of Venlafaxine HCL. PMID:21814426

  6. Employment-based reinforcement of adherence to depot naltrexone in unemployed opioid-dependent adults: a randomized controlled trial.

    PubMed

    Everly, Jeffrey J; DeFulio, Anthony; Koffarnus, Mikhail N; Leoutsakos, Jeannie-Marie S; Donlin, Wendy D; Aklin, Will M; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E; Silverman, Kenneth

    2011-07-01

    Naltrexone can be used to treat opioid dependence, but patients refuse to take it. Extended-release depot formulations may improve adherence, but long-term adherence rates to depot naltrexone are not known. This study determined long-term rates of adherence to depot naltrexone and whether employment-based reinforcement can improve adherence. Participants who were inducted onto oral naltrexone were assigned randomly to contingency (n = 18) or prescription (n = 17) groups. Participants were offered six depot naltrexone injections and invited to work at the therapeutic workplace on week days for 26 weeks, where they earned stipends for participating in job skills training. Contingency participants were required to accept naltrexone injections to maintain workplace access and to maintain maximum pay. Prescription participants could work independently of whether they accepted injections. The therapeutic workplace, a model employment-based intervention for drug addiction and unemployment. Opioid-dependent unemployed adults. Depot naltrexone injections accepted and opiate-negative urine samples. Contingency participants accepted significantly more naltrexone injections than prescription participants (81% versus 42%), and were more likely to accept all injections (66% versus 35%). At monthly assessments (with missing urine samples imputed as positive), the groups provided similar percentages of samples negative for opiates (74% versus 62%) and for cocaine (56% versus 54%). Opiate-positive samples were more likely when samples were also positive for cocaine. Employment-based reinforcement can maintain adherence to depot naltrexone. Future research should determine whether persistent cocaine use compromises naltrexone's effect on opiate use. Workplaces may be useful for promoting sustained adherence to depot naltrexone. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

  7. Effects of incentives for naltrexone adherence on opiate abstinence in heroin-dependent adults

    PubMed Central

    Jarvis, Brantley P.; Holtyn, August F.; DeFulio, Anthony; Dunn, Kelly E.; Everly, Jeffrey J.; Leoutsakos, Jeannie-Marie S.; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E.; Silverman, Kenneth

    2017-01-01

    Aim To test whether an incentive-based intervention that increased adherence to naltrexone also increased opiate abstinence. Design Post-hoc combined analysis of three earlier randomized controlled trials that individually showed that incentives for adherence to oral and to extended-release injection naltrexone dosing schedules increased naltrexone adherence but not opiate abstinence. Setting Outpatient therapeutic workplace in Baltimore, MD, USA. Participants 140 unemployed heroin-dependent adults participating from 2006–2010. Interventions Participants were hired in a model workplace for 26 weeks and randomized to a Contingency (n=72) or Prescription (n=68) group. Both groups were offered naltrexone. Contingency participants were required to take scheduled doses of naltrexone in order to work and earn wages. Prescription participants could earn wages independent of naltrexone adherence. Measures Thrice-weekly and monthly urine samples tested for opiates and cocaine and measures of naltrexone adherence (percentage of monthly urine samples positive for naltrexone or percentage of scheduled injections received). All analyses included prerandomization attendance, opiate use, and cocaine use as covariates. Additional analyses controlled for cocaine use and naltrexone adherence during the intervention. Findings Contingency participants had more opiate abstinence than Prescription participants (68.1% vs. 52.9% opiate-negative thrice-weekly urine samples, respectively; and 71.9% vs. 61.7% opiate-negative monthly urine samples, respectively) based on initial analyses (thrice-weekly samples, OR = 3.3, 95% CI = 1.7–6.5, p < .01; monthly samples, OR = 2.6, 95% CI = 1.0–7.1, p = .06) and on analyses that controlled for cocaine use (thrice-weekly samples, OR = 3.9, 95% CI = 3.3–4.5, p < .01; monthly samples, OR = 3.4, 95% CI = 1.1–11.1, p =.04), which was high and associated with opiate use. The difference in opiate abstinence rates between Contingency participants

  8. Enhancing acupuncture by low dose naltrexone.

    PubMed

    Hesselink, Jan M Keppel; Kopsky, David J

    2011-06-01

    To find appropriate and effective treatment options for chronic pain syndromes is a challenging task. Multimodal treatment approach has been gaining acceptance for chronic pain. However, combining treatments, such as acupuncture, with rational pharmacology is still in its infancy. Acupuncture influences the opioid and cannabinoid system through releasing endogenous receptor ligands. Low dose naltrexone also acts on both these systems, and upregulates the opioid and cannabinoid receptors. The authors hypothesise that low dose naltrexone could enhance the pain-relieving effect of acupuncture.

  9. Effect of naltrexone treatment on the treadmill exercise-induced hormone release in amenorrheic women.

    PubMed

    Botticelli, G; Bacchi Modena, A; Bresciani, D; Villa, P; Aguzzoli, L; Florio, P; Nappi, R E; Petraglia, F; Genazzani, A R

    1992-12-01

    The effect of an acute physical stress on hormone secretions before and after a 10-day naltrexone treatment in untrained healthy and amenorrheic women was investigated. Plasma levels of pituitary (LH, FSH, prolactin, GH, ACTH, beta-endorphin) and adrenal (cortisol, androstenedione, testosterone) hormones were measured at rest and in response to 60 min of physical exercise. The test was done both before and after a 10-day naltrexone (50 mg/day) treatment. Graded levels of treadmill exercise (50, 70 and 90% of maximal oxygen uptake (VO2) every 20 min) was used as physical stressor. While mean +/- SE plasma LH levels in control women were higher than in amenorrheic patients and increased following the naltrexone treatment (p < 0.01), no significant differences of basal plasma hormonal levels were observed between amenorrheic and eumenorrheic women, both before and after naltrexone treatment. Physical exercise at 90% VO2 induced a significant increase in plasma GH, ACTH, beta-endorphin, cortisol, androstenedione and testosterone levels in controls before naltrexone treatment (p < 0.01). The mean increase in plasma androstenedione and testosterone levels in control women was significantly higher after naltrexone treatment (p < 0.01). In amenorrheic patients before naltrexone, physical exercise induced an increase in plasma prolactin and GH levels, but not in plasma ACTH, beta-endorphin, cortisol, testosterone and androstenedione. After naltrexone treatment, the exercise induced a significant plasma ACTH, beta-endorphin and cortisol levels, while the increase of plasma prolactin levels was significantly higher than before treatment (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Adoption of Injectable Naltrexone in U.S. Substance Use Disorder Treatment Programs

    PubMed Central

    Aletraris, Lydia; Edmond, Mary Bond; Roman, Paul M

    2015-01-01

    Objective: Medication-assisted treatment for substance use disorders (SUDs) is not widely used in treatment programs. The aims of the current study were to document the prevalence of adoption and implementation of extended-release injectable naltrexone, the newest U.S. Food and Drug Administration–approved medication for alcohol use disorder (AUD), in U.S. treatment programs and to examine associations between organizational and patient characteristics and adoption. Method: The study used interview data from a nationally representative sample of 307 U.S. SUD treatment programs to examine adoption and implementation of injectable naltrexone. Results: Thirteen percent of programs used injectable naltrexone for AUD, and 3% of programs used it for opioid use disorder. Every treatment program that offered injectable naltrexone to its patients used it in conjunction with psychosocial treatment, particularly cognitive behavioral therapy. Multivariate logistic regression results indicated that adoption was positively associated with the provision of wraparound services, the percentage of privately insured patients, and the presence of inpatient detoxification services. For-profit status and offering inpatient services were negatively associated with adoption. Within adopting programs, an average of 4.1% of AUD patients and 7.1% of patients with opioid use disorder were currently receiving the medication, despite clinical directors’ reports of positive patient outcomes, particularly for relapsers and for those who had been noncompliant with other medications. Cost was a significant issue for the majority of adopting organizations. Conclusions: The rate of adoption of injectable naltrexone in U.S. treatment programs remains limited. Researchers should continue to examine patient, organizational, and external characteristics associated with the adoption and implementation of injectable naltrexone over time. PMID:25486403

  11. Sustained transdermal release of diltiazem hydrochloride through electron beam irradiated different PVA hydrogel membranes

    NASA Astrophysics Data System (ADS)

    Bhunia, Tridib; Goswami, Luna; Chattopadhyay, Dipankar; Bandyopadhyay, Abhijit

    2011-08-01

    Extremely fast release of diltiazem hydrochloride (water soluble, anti anginal drug used to treat chest pain) together with its faster erosion has been the primary problem in conventional oral therapy. It has been addressed in this paper by encapsulating the drug in electron beam irradiated various poly (vinyl alcohol) hydrogel membranes and delivering it through transdermal route. Results show excellent control over the release of diltiazem hydrochloride through these membranes subject to their physico-mechanicals.

  12. Effect of naltrexone and ondansetron on alcohol cue-induced activation of the ventral striatum in alcohol-dependent people.

    PubMed

    Myrick, Hugh; Anton, Raymond F; Li, Xingbao; Henderson, Scott; Randall, Patrick K; Voronin, Konstantin

    2008-04-01

    Medication for the treatment of alcoholism is currently not particularly robust. Neuroimaging techniques might predict which medications could be useful in the treatment of alcohol dependence. To explore the effect of naltrexone, ondansetron hydrochloride, or the combination of these medications on cue-induced craving and ventral striatum activation. Functional brain imaging was conducted during alcohol cue presentation. Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the magnetic resonance imaging suite of a major training hospital and medical research institute. Ninety non-treatment-seeking alcohol-dependent (by DSM-IV criteria) and 17 social drinking (< 14 drinks per week) paid volunteers recruited through advertisements at an academic center. A taste of alcohol and a series of alcohol-related pictures, neutral beverage pictures, and visual control images were provided to volunteers after 7 days of double-blind randomly assigned daily dosing with 50 mg of naltrexone (n = 23), 0.50 mg of ondansetron hydrochloride (n = 23), the combination of the 2 medications (n = 20), or matching placebos (n = 24). Difference in brain blood oxygen level-dependent magnetic resonance when viewing alcohol pictures vs neutral beverage pictures with a particular focus on ventral striatum activity comparison across medication groups. Self-ratings of alcohol craving. The combination treatment decreased craving for alcohol. Naltrexone with (P = .02) or without (P = .049) ondansetron decreased alcohol cue-induced activation of the ventral striatum. Ondansetron by itself was similar to naltrexone and the combination in the overall analysis but intermediate in a region-specific analysis. Consistent with animal data that suggest that both naltrexone and ondansetron reduce alcohol-stimulated dopamine output in the ventral striatum, the current study found evidence that these medications, alone or in combination

  13. Drug safety evaluation of naltrexone/bupropion for the treatment of obesity.

    PubMed

    Verpeut, Jessica L; Bello, Nicholas T

    2014-06-01

    Obesity is a known health risk for the development of several preventable diseases. Obesity-related metabolic alterations negatively impact different physiological mechanisms, which supports the rationale for the use of combined drug therapy. Naltrexone is an opioid antagonist for the treatment of opioid and alcohol dependency, whereas bupropion is a norepinephrine/dopamine reuptake inhibitor used to treat depression and smoking cessation. Although not effective as individual monotherapies for obesity, naltrexone and bupropion in combination produce weight loss and a metabolic profile beneficial for the potential treatment of obesity. This review examines the safety and antiobesity effects of naltrexone and bupropion alone and in combination. It reviews the results of four Phase III clinical trials of a novel fixed dose of sustained-released naltrexone/bupropion. Naltrexone/bupropion has a greater weight loss efficacy than two FDA-approved medications, orlistat and lorcaserin. Although the weight loss produced by phentermine/topiramate is superior to naltrexone/bupropion, the safety profile of naltrexone/bupropion has less severe adverse effects. In addition, naltrexone/bupropion is well tolerated, with nausea being the most reported adverse event. Unlike other centrally acting medications, lorcaserin and phentermine/topiramate, naltrexone/bupropion has no abuse potential.

  14. Silicone adhesive matrix of verapamil hydrochloride to provide pH-independent sustained release.

    PubMed

    Tolia, Gaurav; Li, S Kevin

    2014-02-01

    Providing pH-independent oral release of weakly basic drugs with conventional matrix tablets can be challenging because of the pH-dependent solubility characteristics of the drugs and the changing pH environment along the gastrointestinal tract. The aim of the present study was to use a hydrophobic polymer to overcome the issue of pH-dependent release of weakly basic model drug verapamil hydrochloride from matrix tablets without the use of organic buffers in the matrix formulations. Silicone pressure-sensitive adhesive (PSA) polymer was evaluated because of its unique properties of low surface energy, hydrophobicity, low glass transition temperature, high electrical resistance, and barrier to hydrogen ion diffusion. Drug release, hydrogen ion diffusion, tablet contact angle, and internal tablet microenvironment pH with matrix tablets prepared using PSA were compared with those using water-insoluble ethyl cellulose (EC). Silicone PSA films showed higher resistance to hydrogen ion diffusion compared with EC films. Verapamil hydrochloride tablets prepared using silicone PSA showed higher hydrophobicity and lower water uptake than EC tablets. Silicone PSA tablets also showed pH-independent release of verapamil and decreased in dimensions during drug dissolution. By contrast, verapamil hydrochloride tablets prepared using EC did not achieve pH-independent release.

  15. Ultra-low dose naltrexone enhances cannabinoid-induced antinociception.

    PubMed

    Paquette, Jay; Olmstead, Mary C; Olmstead, Mary

    2005-12-01

    Both opioids and cannabinoids have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to Gi/o-proteins. Surprisingly, the analgesic effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist, naltrexone. As opioid and cannabinoid systems interact, this study investigated whether ultra-low dose naltrexone also influences cannabinoid-induced antinociception. Separate groups of Long-Evans rats were tested for antinociception following an injection of vehicle, a sub-maximal dose of the cannabinoid agonist WIN 55 212-2, naltrexone (an ultra-low or a high dose) or a combination of WIN 55 212-2 and naltrexone doses. Tail-flick latencies were recorded for 3 h, at 10-min intervals for the first hour, and at 15-min intervals thereafter. Ultra-low dose naltrexone elevated WIN 55 212-2-induced tail flick thresholds without extending its duration of action. This enhancement was replicated in animals receiving intraperitoneal or intravenous injections. A high dose of naltrexone had no effect on WIN 55 212-2-induced tail flick latencies, but a high dose of the cannabinoid 1 receptor antagonist SR 141716 blocked the elevated tail-flick thresholds produced by WIN 55 212-2+ultra-low dose naltrexone. These data suggest a mechanism of cannabinoid-opioid interaction whereby activated opioid receptors that couple to Gs-proteins may attenuate cannabinoid-induced antinociception and/or motor functioning.

  16. Testing lyoequivalency for three commercially sustained-release tablets containing diltiazem hydrochloride.

    PubMed

    Maswadeh, Hamzah A; Al-Hanbali, Othman A; Kanaan, Reem A; Shakya, Ashok K; Maraqa, Anwar

    2010-01-01

    In vitro release kinetics of three commercially available sustained release tablets (SR) diltiazem hydrochloride were studied at pH 1.1 for 2 h and for another 6 h at pH 6.8 using the USP dissolution apparatus with the paddle assemble. The kinetics of the dissolution process was studied by analyzing the dissolution data using five kinetic equations: the zero-order equation, the first-order equation, the Higuchi square root equation, the Hixson-Crowell cube root law and the Peppas equation. Analyses of the dissolution kinetic data for diltiazem hydrochloride commercial SR tablets showed that both Dilzacard and Dilzem SR tablets released drug by Non-Fickian (Anomalous transport) release with release exponent (n) equal to 0.59 and 0.54, respectively, which indicate the summation of both diffusion and dissolution controlled drug release. Bi-Tildiem SR tablets released drug by super case II (n = 1.29) which indicate zero-order release due to the dissolution of polymeric matrix and relaxation of the polymer chain. This finding was also in agreement with results obtained from application of zero-order and Hixson-Crowell equations. A dissolution profile comparative study was done to test the lyoequivelancy of the three products by using the mean dissolution time (MDT), dissimilarity factor f1 and similarity factor f2. Results showed that the three products are different and not lyoequivalent.

  17. Does naltrexone affect craving in abstinent opioid-dependent patients?

    PubMed

    Dijkstra, Boukje A G; De Jong, Cor A J; Bluschke, Sarah M; Krabbe, Paul F M; van der Staak, Cees P F

    2007-06-01

    Naltrexone blocks the opioid receptors that modulate the release of dopamine in the brain reward system and therefore blocks the rewarding effects of heroin and alcohol. It is generally assumed that naltrexone leads to reduction of craving, but few studies have been performed to prove this. The purpose of the present study was to examine the effect of the administration of naltrexone on craving level after rapid opioid detoxification induced by naltrexone. A naturalistic study was carried out in which patients were followed during 10 months after rapid detoxification. Data about abstinence, relapse, and naltrexone use were collected by means of urine specimens. Craving was measured by the visual analogue scale craving, the Obsessive Compulsive Drug Use Scale, and the Desires for Drug Questionnaire. Results showed that patients who relapsed in opioid use experienced obviously more craving than abstinent people. Patients who took naltrexone did not experience significant less craving than those who did not. These results suggest that the use of opioids is associated with increased craving and that abstinence for opioids is associated with less craving, independent of the use of naltrexone. This is in contrast to the general opinion. Because of the naturalistic design of the study, no firm conclusions can be drawn, but the results grounded the needs of an experimental study.

  18. Development and evaluation of a novel modified-release pellet-based tablet system for the delivery of loratadine and pseudoephedrine hydrochloride as model drugs.

    PubMed

    Zeeshan, Farrukh; Bukhari, Nadeem Irfan

    2010-06-01

    Modified-release multiple-unit tablets of loratadine and pseudoephedrine hydrochloride with different release profiles were prepared from the immediate-release pellets comprising the above two drugs and prolonged-release pellets containing only pseudoephedrine hydrochloride. The immediate-release pellets containing pseudoephedrine hydrochloride alone or in combination with loratadine were prepared using extrusion-spheronization method. The pellets of pseudoephedrine hydrochloride were coated to prolong the drug release up to 12 h. Both immediate- and prolonged-release pellets were filled into hard gelatin capsule and also compressed into tablets using inert tabletting granules of microcrystalline cellulose Ceolus KG-801. The in vitro drug dissolution study conducted using high-performance liquid chromatography method showed that both multiple-unit capsules and multiple-unit tablets released loratadine completely within a time period of 2 h, whereas the immediate-release portion of pseudoephedrine hydrochloride was liberated completely within the first 10 min of dissolution study. On the other hand, the release of pseudoephedrine hydrochloride from the prolonged release coated pellets was prolonged up to 12 hr and followed zero-order release kinetic. The drug dissolution profiles of multiple-unit tablets and multiple-unit capsules were found to be closely similar, indicating that the integrity of pellets remained unaffected during the compression process. Moreover, the friability, hardness, and disintegration time of multiple-unit tablets were found to be within BP specifications. In conclusion, modified-release pellet-based tablet system for the delivery of loratadine and pseudoephedrine hydrochloride was successfully developed and evaluated.

  19. A Combination of Buprenorphine and Naltrexone Blocks Compulsive Cocaine Intake in Rodents Without Producing Dependence

    PubMed Central

    Wee, Sunmee; Vendruscolo, Leandro F.; Misra, Kaushik K.; Schlosburg, Joel E.; Koob, George F.

    2012-01-01

    Buprenorphine, a synthetic opioid that acts at both μ and κ opioid receptors, can decrease cocaine use in individuals with opioid addiction. However, the potent agonist action of buprenorphine at μ opioid receptors raises its potential for creating opioid dependence in non–opioid-dependent cocaine abusers. Here, we tested the hypothesis that a combination of buprenorphine and naltrexone (a potent μ opioid antagonist with weaker δ and κ antagonist properties) could block compulsive cocaine self-administration without producing opioid dependence. The effects of buprenorphine and various doses of naltrexone on cocaine self-administration were assessed in rats that self-administered cocaine under conditions of either short access (noncompulsive cocaine seeking) or extended access (compulsive cocaine seeking). Buprenorphine alone reproducibly decreased cocaine self-administration. Although this buprenorphine-alone effect was blocked in a dose-dependent manner by naltrexone in both the short-access and the extended-access groups, the combination of the lowest dose of naltrexone with buprenorphine blocked cocaine self-administration in the extended-access group but not in the short-access group. Rats given this low dose of naltrexone with buprenorphine did not exhibit the physical opioid withdrawal syndrome seen in rats treated with buprenorphine alone, and naltrexone at this dose did not block κ agonist–induced analgesia. The results suggest that the combination of buprenorphine and naltrexone at an appropriate dosage decreases compulsive cocaine self-administration with minimal liability to produce opioid dependence and may be useful as a treatment for cocaine addiction. PMID:22875830

  20. A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence.

    PubMed

    Wee, Sunmee; Vendruscolo, Leandro F; Misra, Kaushik K; Schlosburg, Joel E; Koob, George F

    2012-08-08

    Buprenorphine, a synthetic opioid that acts at both μ and κ opioid receptors, can decrease cocaine use in individuals with opioid addiction. However, the potent agonist action of buprenorphine at μ opioid receptors raises its potential for creating opioid dependence in non-opioid-dependent cocaine abusers. Here, we tested the hypothesis that a combination of buprenorphine and naltrexone (a potent μ opioid antagonist with weaker δ and κ antagonist properties) could block compulsive cocaine self-administration without producing opioid dependence. The effects of buprenorphine and various doses of naltrexone on cocaine self-administration were assessed in rats that self-administered cocaine under conditions of either short access (noncompulsive cocaine seeking) or extended access (compulsive cocaine seeking). Buprenorphine alone reproducibly decreased cocaine self-administration. Although this buprenorphine-alone effect was blocked in a dose-dependent manner by naltrexone in both the short-access and the extended-access groups, the combination of the lowest dose of naltrexone with buprenorphine blocked cocaine self-administration in the extended-access group but not in the short-access group. Rats given this low dose of naltrexone with buprenorphine did not exhibit the physical opioid withdrawal syndrome seen in rats treated with buprenorphine alone, and naltrexone at this dose did not block κ agonist-induced analgesia. The results suggest that the combination of buprenorphine and naltrexone at an appropriate dosage decreases compulsive cocaine self-administration with minimal liability to produce opioid dependence and may be useful as a treatment for cocaine addiction.

  1. Development of ligustrazine hydrochloride carboxymethyl chitosan and collagen microspheres: Formulation optimization, characterization, and vitro release

    PubMed Central

    Lin, Qiang; Huo, Qing; Qin, Yingzhe; Zhao, Zhuo; Tao, Fengyun

    2017-01-01

    ABSTRACT This study investigates the preparation of ligustrazine hydrochloride carboxymethyl chitosan and collagen microspheres. This experiment investigates effects of the ratio of carboxymethyl chitosan and collagen blend, water to oil ratio, stirring speed, and other factors on the microsphere properties. The experiment had the following conditions: a 1:2 proportion of carboxymethyl chitosan and collagen, a 1:2 proportion of drugs and materials, a 5:1 proportion of oil phase and water phase, 0.5% of span80, a 600r/min stirring speed, 3 ml of a cross-linking agent, 3 h of cross-linking curing, 1.25 ± 0.05 mm diameter LTH microcapsules, a 54.08% envelop rate, and a 14.16% carrier rate. The microspheres release rate reached 66% within 1 h, then steadily released within 5 h in vitro. The experimental results showed that the ligustrazine hydrochloride microsphere production process was stable and exhibited a good release effect compared with other ligustrazine hydrochloride tablets and pills. PMID:27689792

  2. Influence of Polymer Type on the Physical Properties and Release Profile of Papaverine Hydrochloride From Hard Gelatin Capsules.

    PubMed

    Polski, Andrzej; Iwaniak, Karol; Kasperek, Regina; Modrzewska, Joanna; Sobótka-Polska, Karolina; Sławińska, Karolina; Poleszak, Ewa

    2015-01-01

    The capsule is one of the most important solid dosage forms in the pharmaceutical industry. It is easier and faster to produce than a tablet, because it requires fewer excipients. Generally, capsules are easy to swallow and mask any unpleasant taste of the substances used while their release profiles can be easily modified. Papaverine hydrochloride was used as a model substance to show different release profiles using different excipients. The main aim of the study was to analyze the impact of using different polymers on the release profile of papaverine hydrochloride from hard gelatin capsules. Six series of hard gelatin capsules containing papaverine hydrochloride as a model drug and different excipients were made. Then, the angle of repose, flow rate, mass flow rate and volume flow rate of the powders used for capsule production were analyzed. The uniform weight and disintegration time of the capsules were studied. The dissolution study was performed in a basket apparatus, while the amount of papaverine hydrochloride released was determined spectrophotometrically at 251 nm. Only one formula of powder had satisfactory flow properties, while all formulas had good Hausner ratios. The best properties were from powder containing polyvinylpyrrolidone 10k. The disintegration time of capsules varied from 1:30 min to 2:00 min. As required by Polish Pharmacopoeia X, 80% of the active substance in all cases was released within 15 minutes. The capsules with polyvinylpyrrolidone 10k were characterized by the longest release. On the other hand, capsules containing microcrystalline cellulose had the fastest release profile. Using 10% of different polymers, without changing the other excipients, had a significant impact on the physical properties of the powders and papaverine hydrochloride release profile. The two most preferred capsule formulations contained either polyvinylpyrrolidone 10k or microcrystalline cellulose.

  3. 78 FR 38053 - Determination That OPANA ER (Oxymorphone Hydrochloride) Drug Products Covered by New Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-25

    ...] Determination That OPANA ER (Oxymorphone Hydrochloride) Drug Products Covered by New Drug Application 21-610... (oxymorphone hydrochloride (HCl)) Extended-Release Tablet products approved under new drug application (NDA) 21... refer to these drug products, and it will allow FDA to continue to approve ANDAs for oxymorphone HCl...

  4. [The use of natural and synthetic hydrophilic polymers in the formulation of metformin hydrochloride tablets with different profile release].

    PubMed

    Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

    2012-01-01

    Metformin hydrochloride after buformin and phenformin belongs to the group of biguanid derivatives used as oral anti-diabetic drugs. The object of the study is the technological analysis and the potential effect of biodegradable macromolecular polymers on the technological and therapeutic parameters of oral anti-diabetic medicinal products with metformin hydrochloride: Siofor, Formetic, Glucophage, Metformax in doses of 500mg and 1000mg and Glucophage XR in a dose of 500 mg of modified release. Market therapeutic products containing 500 and 1000 mg of metformin hydrochloride in a normal formulation and 500 mg of metformin hydrochloride in a formulation of modified release were analyzed. Following research methods were used: technological analysis of tablets, study of disintegration time of tablets, evaluation of pharmaceutical availability of metformin hydrochloride from tested therapeutic products, mathematical and kinetic analysis of release profiles of metformin hydrochloride, statistical analysis of mean differences of release coefficients. The percentage of excipients in the XR formulation is higher and constitutes 50.5% of a tablet mass. However, in standard formulations the percentage is lower, between 5.5% and 12.76%. On the basis of the results of disintegration time studies, the analysed therapeutic products can be divided into two groups, regardless the dose. The first one are preparations with faster (not fast!) disintegration: Glucophage i Metformax. The second group are preparations with slower disintegration, more balanced in the aspect of a high dose of the biologically active substance: Formetic and Siofor. Products with a lower content of excipients (Metformax, Glucophage) disintegrate in a faster way. The disintegration rate of the products with a higher content of excipients (Formetic, Siofor) is slower. The appearance of metformin hydrochloride concentration in the gastrointestinal contents, balanced in time, caused by a slower disintegration

  5. Improving clinical outcomes for naltrexone as a management of problem alcohol use

    PubMed Central

    Hulse, Gary K

    2013-01-01

    Despite being a relatively effective and safe treatment, the clinical management of alcohol abuse/dependence by oral naltrexone can be compromised due to the patient's non-compliance with daily use of this medication. Over the past decade an increasing body of research has suggested that the use of sustained release depot naltrexone preparations can overcome this issue and deliver improved clinical outcomes. However, at the same time, research findings from diverse areas of pharmacogenetics, neurobiology and behavioural psychology have also been converging to identify variables including genetic markers, patient psychosocial characteristics and drug use history differences, or clusters of these variables that play a major role in mediating the response of alcohol abuse/dependent persons to treatment by naltrexone. While this article does not attempt to review all available data pertaining to an individual alcohol dependent patient's response to treatment by naltrexone, it does identify relevant research areas and highlights the importance of data arising from them. The characterization of clinical markers, to identify those patients who are most likely to benefit from naltrexone and to tailor a more individual naltrexone treatment, will ultimately provide significant benefit to both patients and clinicians by optimizing treatment outcome. PMID:22946873

  6. [Influence of polymer type on the physical properties and the release study of papaverine hydrochloride from tablets].

    PubMed

    Kasperek, Regina; Polski, Andrzej; Sobótka-Polska, Karolina; Poleszak, Ewa

    2014-01-01

    Polymers are widely used in drug manufacturing. Researchers studied their impact on the bioavailability of active substances or on physical properties of tablets for many years. To study the influence of polymer excipients, such as microcrystalline cellulose (Avicel PH 101, Avicel PH 102), croscarmellose sodium, crospovidone or polyvinylpyrrolidone, on the release profile of papaverine hydrochloride from tablets and on the physical properties of tablets. Six series of uncoated tablets were prepared by indirect method, with previous wet granulation. Tablets contained papaverine hydrochloride and various excipients. The physical properties of the prepared granules, tablets and the release profile of papaverine hydrochloride from tablets were examined. The content of papaverine hydrochloride from the release study were determined spectrophotometrically. All tablets met the pharmacopoeia requirements during following tests: the disintegration time of tablets, uncoated tablets resistance to abrasion, the weight uniformity and dose formulations, their dimensions, the resistance to crushing of tablets and the drug substance content in the tablet. In four cases more than 80% of papaverine was released up to 2 min, in one formula it was up to 5 min, and in last one up to 10 min. Tablets containing crospovidone disintegrated faster than tablets with croscarmellose sodium. Adding gelatinized starch to the tablet composition increased the disintegration time, hardness and delayed the release of papaverine. During the wet granulation process, granules containing polyvinylpyrrolidone were characterized by a suitable flow properties and slightly prolonged disintegration time. Tablets containing Avicel PH 102 compared to tablets with Avicel PH 101 had less weight loss during the test of mechanical resistance, improved hardness and faster release profile of papaverine from tablets.

  7. Release of tetracycline hydrochloride from electrospun poly(ethylene-co-vinylacetate), poly(lactic acid), and a blend.

    PubMed

    Kenawy, El-Refaie; Bowlin, Gary L; Mansfield, Kevin; Layman, John; Simpson, David G; Sanders, Elliot H; Wnek, Gary E

    2002-05-17

    Electrospun fiber mats are explored as drug delivery vehicles using tetracycline hydrochloride as a model drug. The mats were made either from poly(lactic acid) (PLA), poly(ethylene-co-vinyl acetate) (PEVA), or from a 50:50 blend of the two. The fibers were electrospun from chloroform solutions containing a small amount of methanol to solubilize the drug. The release of the tetracycline hydrochloride from these new drug delivery systems was followed by UV-VIS spectroscopy. Release profiles from the electrospun mats were compared to a commercially available drug delivery system, Actisite (Alza Corporation, Palo Alto, CA), as well as to cast films of the various formulations.

  8. Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin.

    PubMed

    Ghosh, Priyanka; Lee, DoMin; Kim, Kyung Bo; Stinchcomb, Audra L

    2014-01-01

    The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone. Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship. The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement. The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery.

  9. Development and evaluation of natural gum-based extended release matrix tablets of two model drugs of different water solubilities by direct compression.

    PubMed

    Ofori-Kwakye, Kwabena; Mfoafo, Kwadwo Amanor; Kipo, Samuel Lugrie; Kuntworbe, Noble; Boakye-Gyasi, Mariam El

    2016-01-01

    The study was aimed at developing extended release matrix tablets of poorly water-soluble diclofenac sodium and highly water-soluble metformin hydrochloride by direct compression using cashew gum, xanthan gum and hydroxypropylmethylcellulose (HPMC) as release retardants. The suitability of light grade cashew gum as a direct compression excipient was studied using the SeDeM Diagram Expert System. Thirteen tablet formulations of diclofenac sodium (∼100 mg) and metformin hydrochloride (∼200 mg) were prepared with varying amounts of cashew gum, xanthan gum and HPMC by direct compression. The flow properties of blended powders and the uniformity of weight, crushing strength, friability, swelling index and drug content of compressed tablets were determined. In vitro drug release studies of the matrix tablets were conducted in phosphate buffer (diclofenac: pH 7.4; metformin: pH 6.8) and the kinetics of drug release was determined by fitting the release data to five kinetic models. Cashew gum was found to be suitable for direct compression, having a good compressibility index (ICG) value of 5.173. The diclofenac and metformin matrix tablets produced generally possessed fairly good physical properties. Tablet swelling and drug release in aqueous medium were dependent on the type and amount of release retarding polymer and the solubility of drug used. Extended release of diclofenac (∼24 h) and metformin (∼8-12 h) from the matrix tablets in aqueous medium was achieved using various blends of the polymers. Drug release from diclofenac tablets fitted zero order, first order or Higuchi model while release from metformin tablets followed Higuchi or Hixson-Crowell model. The mechanism of release of the two drugs was mostly through Fickian diffusion and anomalous non-Fickian diffusion. The study has demonstrated the potential of blended hydrophilic polymers in the design and optimization of extended release matrix tablets for soluble and poorly soluble drugs by direct

  10. Effects of Extended-Release Niacin and Extended-Release Niacin/Laropiprant on the Pharmacokinetics of Simvastatin in Healthy Subjects.

    PubMed

    Lauring, Brett; Dishy, Victor; De Kam, Pieter-Jan; Crumley, Tami; Wenning, Larissa; Liu, Fang; Sisk, Christine; Wagner, John; Lai, Eseng

    2015-01-01

    The use of multiple lipid-modifying agents with different mechanisms of action is often required to regulate lipid levels in patients with dyslipidemia. During combination therapy, alterations in the pharmacokinetics of any of the drugs used and their metabolites may occur. Three separate open-label, randomized, crossover studies evaluated the potential for pharmacokinetic interaction between extended-release niacin (with and without concomitant laropiprant) and simvastatin in healthy subjects. Study 1 used single doses of extended-release niacin and simvastatin; study 2 used multiple-dose coadministration of extended-release niacin/laropiprant and simvastatin in healthy subjects; and study 3 used single doses of both extended-release niacin and the coadministration of extended-release niacin/laropiprant and simvastatin in healthy Chinese subjects. During each treatment period, plasma samples were collected predose and at prespecified postdose time points for pharmacokinetic analyses. The safety and tolerability of simvastatin with and without coadministered extended-release niacin (or extended-release niacin/laropiprant) were assessed by clinical evaluation of adverse experiences. In 2 studies in healthy subjects, modest increases in exposure to simvastatin acid (by ∼60%) by extended-release niacin and extended-release niacin/laropiprant were observed. Based on the clinical experience with simvastatin, these effects are not believed to be clinically meaningful. In the third study on healthy Chinese subjects, no statistically meaningful increases in exposure to simvastatin by extended-release niacin and extended-release niacin/laropiprant were observed. In all populations examined in these studies, the coadministration of extended-release niacin and simvastatin was generally well tolerated.

  11. Perioperative Pain Management of a Patient Taking Naltrexone HCl/Bupropion HCl (Contrave): A Case Report.

    PubMed

    Ninh, Allen; Kim, Sang; Goldberg, Andrew

    2017-10-15

    A 42-year-old obese woman (body mass index = 30.2 kg/m) presented for urgent anterior cervical diskectomy and fusion. She had been taking oral naltrexone-bupropion extended-release (Contrave, Orexigen Therapeutics Inc, La Jolla, CA) for the past 6 months and continued using it until 12 hours preoperatively. Despite discontinuation of this medication, and employing an intraoperative and postoperative multimodal analgesia strategy, immediate pain control was inadequately achieved. Patients taking opioid antagonists who present for surgery pose unique challenges to the anesthesiologist and require extensive preoperative interdisciplinary discussions and planning for pain control throughout the perioperative period.

  12. Naltrexone sustained-release/bupropion sustained-release for the management of obesity: review of the data to date

    PubMed Central

    Caixàs, Assumpta; Albert, Lara; Capel, Ismael; Rigla, Mercedes

    2014-01-01

    Obesity is an emerging disease worldwide. Changes in living habits, especially with increased consumption of high-calorie foods and decreased levels of physical activity, lead to an energy imbalance that brings weight gain. Overweight and obesity are major risk factors for several chronic diseases (including cardiovascular diseases, diabetes, and cancer), reduce quality of life, and are associated with higher mortality. For all these reasons, it is of the utmost importance that the trend be reversed and obese people enabled to lose weight. It is known that eating a healthy diet and exercising regularly can help prevent obesity, but data show that in many cases these steps are not enough. This is the reason why, over the last few decades, several antiobesity drugs have been developed. However, the disappointing results demonstrated for the vast majority of them have not discouraged the pharmaceutical industry from continuing to look for an effective drug or combination of drugs. The systematic review presented here focuses on naltrexone sustained-release/bupropion sustained-release combination (Contrave®). We conclude from the current published reports that its effectiveness in the treatment of obesity can be estimated as a placebo-subtracted weight loss of around 4.5%. This weight reduction is moderate but similar to other antiobesity drugs. The safety profile of this combination is acceptable, despite additional data regarding cardiovascular disease being needed. PMID:25258511

  13. Naltrexone sustained-release/bupropion sustained-release for the management of obesity: review of the data to date.

    PubMed

    Caixàs, Assumpta; Albert, Lara; Capel, Ismael; Rigla, Mercedes

    2014-01-01

    Obesity is an emerging disease worldwide. Changes in living habits, especially with increased consumption of high-calorie foods and decreased levels of physical activity, lead to an energy imbalance that brings weight gain. Overweight and obesity are major risk factors for several chronic diseases (including cardiovascular diseases, diabetes, and cancer), reduce quality of life, and are associated with higher mortality. For all these reasons, it is of the utmost importance that the trend be reversed and obese people enabled to lose weight. It is known that eating a healthy diet and exercising regularly can help prevent obesity, but data show that in many cases these steps are not enough. This is the reason why, over the last few decades, several antiobesity drugs have been developed. However, the disappointing results demonstrated for the vast majority of them have not discouraged the pharmaceutical industry from continuing to look for an effective drug or combination of drugs. The systematic review presented here focuses on naltrexone sustained-release/bupropion sustained-release combination (Contrave(®)). We conclude from the current published reports that its effectiveness in the treatment of obesity can be estimated as a placebo-subtracted weight loss of around 4.5%. This weight reduction is moderate but similar to other antiobesity drugs. The safety profile of this combination is acceptable, despite additional data regarding cardiovascular disease being needed.

  14. Designing an extended release waxy matrix tablet containing nicardipine–hydroxy propyl β cyclodextrin complex

    PubMed Central

    Al-Zein, Hind; Sakeer, Khalil; Alanazi, Fars K.

    2011-01-01

    Aim The current study aimed to prepare a sustained release tablet for a drug which has poor solubility in alkaline medium using complexation with cyclodextrin. Nicardipine hydrochloride (NC) a weak basic drug was chosen as a model drug for this study. Method Firstly the most suitable binary system NC-HPβCD was selected in order to improve drug solubility in the intestinal media and then embedding the complexed drug into a plastic matrix, by fusion method, consists of glycerol monostearate (GMS) as an inert waxy substance and polyethylene glycol 4000 (PEG4000) as a channeling agent, after that the final solid dispersion [(NC:HPβCD):GMS:PEG4000] which was prepared at different ratios was mixed with other excipients, avicel PH101, lactose, and talc, to get a tablet owning dissolution profile complying with the FDA and USP requirements for the extended release solid dosage forms. Results Infrared spectroscopy (IR), differential scanning colorimetry (DSC), polarized microscopy and X-ray diffractometry proved that the coevaporation technique was effective in preparing amorphous cyclodextrin complexes with NC and trapping of NC within the HPβCD cavity by dissolving both in ethanol and evaporate the solvent using a rotavapor at 65 °C. Dissolution profile of NC enhanced significantly in pH 6.8 from NC:HPβCD inclusion complex prepared by the rotavapor (t-test Student p < 0.05). The release of NC from tablet containing [(NC:HPβCD):GMS:PEG4000] [(1):0.75:0.5] (w/w/w) solid dispersion (F8) was complying with the FDA dissolution requirements for extended release dosage forms, and studying the kinetics of the release showed that the diffusional contribution is the major factor controlling the drug release from that formula. Conclusion The prepared waxy matrix tablet containing NC complexes with CD shows promising results as extended release tablets. PMID:23960765

  15. Experience with an extended-release opioid formulation designed to reduce abuse liability in a community-based pain management clinic

    PubMed Central

    Rubino, Daniel

    2011-01-01

    Context With the growing public health concern over rising rates of opioid abuse, physicians have a responsibility to incorporate safeguards into their practice to minimize the potential for opioid misuse, abuse, and diversion. Patient-specific treatment regimens should include steps to monitor treatment success with regard to optimal pain management as well as inappropriate use of opioids and other substances. Opioid formulations designed to be less attractive for abuse are also being developed. While future studies are needed to determine the impact of such formulations in addressing the issue of opioid misuse in the community as a whole, the experience of practitioners who have utilized these formulations can highlight the practical steps to incorporate such formulations into the everyday patient-care setting. Purpose The purpose of this report is to describe experience in managing patients with chronic, moderate-to-severe pain using morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT) (EMBEDA®, King Pharmaceuticals® Inc, Bristol, TN, which was acquired by Pfizer Inc, New York, NY, in March 2011), a formulation designed with features to deter abuse/misuse, in a community-based pain management clinic. Case presentations Case reports demonstrating a clinical management plan for assessment, initial interview procedures, explanation/discussion of proposed therapies, patients’ treatment goals, conversion to MS-sNT, and titration and treatment outcomes are provided. Results The management approach yielded successful outcomes including pain relief, improved quality of life, treatment satisfaction, and patient acceptance of a formulation designed to deter abuse/misuse. Discussion The cases presented demonstrate that the communication accompanying complete pretreatment assessment, goal-setting and expectations, and attention to individual patient needs can enable optimization of pain-related outcomes, resulting in improved quality of life

  16. Naltrexone treatment reverses astrocyte atrophy and immune dysfunction in self-harming macaques

    PubMed Central

    Lee, Kim M.; Chiu, Kevin B.; Didier, Peter J.; Baker, Kate C.; MacLean, Andrew G.

    2015-01-01

    The role of glia in the development and treatment of behavioral abnormalities is understudied. Recent reports have observed glial activation in several disorders, including depression, autism spectrum disorders and self-injurious behaviors (SIB). In the current study, we examined SIB in the physiologically and anatomically relevant nonhuman primate (NHP) model. At the Tulane National Primate Research Center (TNPRC), approximately 5% of singly housed macaques develop symptoms of SIB. We have previously demonstrated that naltrexone hydrochloride can be effective in reducing SIB. We have also demonstrated that the astrocytes of animals with SIB are distinctly atrophic and display heightened innate immune activation compared with control animals. We have added a third group of animals (five macaques identified with SIB and treated with oral naltrexone at a dose of 3.2 mg/kg) to the previous cohort (six macaques with a history of SIB but not treated, and nine animals with no history of SIB) for this study. Gray and white matter astrocytes from frontal cortical tissue were examined following necropsy. Innate immune activation of astrocytes, which was increased in SIB animals, was markedly decreased in animals receiving naltrexone, as was atrophy of both grey and white matter astrocytes. This was concomitant with improved behavioral correlates. Preventing astrocyte activation in select areas of the brain to reduce injurious behavior is an innovative concept with implications for mental health studies. Differences in multiple areas of primate brain would help determine how self-injurious behavior develops. These studies suggest a stronger role for astrocytes in the cellular events associated with self-injurious behaviors. PMID:26191654

  17. Release kinetics of papaverine hydrochloride from tablets with different excipients.

    PubMed

    Kasperek, Regina; Polski, Andrzej; Zimmer, Łukasz; Poleszak, Ewa

    2014-01-01

    The influence of excipients on the disintegration times of tablets and the release of papaverine hydrochloride (PAP) from tablets were studied. Ten different formulations of tablets with PAP were prepared by direct powder compression. Different binders, disintegrants, fillers, and lubricants were used as excipients. The release of PAP was carried out in the paddle apparatus using 0.1 N HCl as a dissolution medium. The results of the disintegration times of tablets showed that six formulations can be classified as fast dissolving tablets (FDT). FDT formulations contained Avicel PH 101, Avicel PH 102, mannitol, (3-lactose, PVP K 10, gelatinized starch (CPharmGel), Prosolv Easy Tab, Prosolv SMCC 90, magnesium stearate, and the addition of disintegrants such as AcDiSol and Kollidon CL. Drug release kinetics were estimated by the zero- and first-order, Higuchi release rate, and Korsmeyer-Peppas models. Two formulations of the tablets containing PVP (K10) (10%), CPharmGel (10% and 25%), and Prosolv Easy Tab (44% and 60%) without the addition of a disintegrant were well-fitted to the kinetics models such as the Higuchi and zero-order, which are suitable for controlled- or sustained-release.

  18. Release Kinetics of Papaverine Hydrochloride from Tablets with Different Excipients

    PubMed Central

    Kasperek, Regina; Polski, Andrzej; Zimmer, Łukasz; Poleszak, Ewa

    2014-01-01

    Abstract The influence of excipients on the disintegration times of tablets and the release of papaverine hydrochloride (PAP) from tablets were studied. Ten different formulations of tablets with PAP were prepared by direct powder compression. Different binders, disintegrants, fillers, and lubricants were used as excipients. The release of PAP was carried out in the paddle apparatus using 0.1 N HCl as a dissolution medium. The results of the disintegration times of tablets showed that six formulations can be classified as fast dissolving tablets (FDT). FDT formulations contained Avicel PH 101, Avicel PH 102, mannitol, (3-lactose, PVP K 10, gelatinized starch (CPharmGel), Prosolv Easy Tab, Prosolv SMCC 90, magnesium stearate, and the addition of disintegrants such as AcDiSol and Kollidon CL. Drug release kinetics were estimated by the zero- and first-order, Higuchi release rate, and Korsmeyer-Peppas models. Two formulations of the tablets containing PVP (K10) (10%), CPharmGel (10% and 25%), and Prosolv Easy Tab (44% and 60%) without the addition of a disintegrant were well-fitted to the kinetics models such as the Higuchi and zero-order, which are suitable for controlled- or sustained-release. PMID:25853076

  19. Intranasal abuse potential of an abuse-deterrent oxycodone formulation compared to oxycodone immediate release and placebo in nondependent, recreational opioid users.

    PubMed

    Setnik, Beatrice; Schoedel, Kerri; Bartlett, Cindy; Dick, Chris; Hakim, Nasrat; Geoffroy, Pierre

    To assess the intranasal (IN) human abuse potential of ELI-200, a novel immediate-release (IR) oxycodone formulation containing sequestered naltrexone. Randomized, double-blind, double-dummy, active and placebo-controlled, five-way crossover study. Pharmacodynamics, safety, and pharmacokinetics (PKs) were evaluated for up to 36 hours postdose. Single site in Canada (INC Research Toronto). Healthy male and female nondependent recreational opioid users underwent a naloxone challenge and drug discrimination qualification test. Single IN dose of ground ELI-200 (30-mg oxycodone hydrochloride [HCl]/3-mg naltrexone HCl), crushed 30-mg oxycodone HCl IR (Roxicodone®), placebo, fixed placebo, and single oral dose of intact ELI-200 (30mg/3mg). Peak effect (E max ) for bipolar Drug Liking (0-100 point visual analog scale). Of the 44 randomized subjects, 37 completed all five treatment periods. All active treatments showed significantly higher (p<0.001) median Drug Liking E max relative to placebo. Significant reductions (p<0.001) in median Drug Liking [E max ] were observed for IN ELI-200 [56.0] compared to IN oxycodone IR [100.0]. Secondary positive or objective measures (High, Good Drug Effects, Overall Drug Liking, Take Drug Again, and maximum pupil constriction) showed significantly lower E max for IN ELI-200 (p<0.001) compared to IN oxycodone IR. IN administration of ELI-200 demonstrated significantly decreased effects on subjective and physiologic measures, and greater nasal irritation, compared to IN oxycodone IR. These findings, along with the PK profile of naltrexone, demonstrated that when ELI-200 capsules were ground and administered intranasally, the naltrexone component was rapidly released and conferred meaningful abuse-deterrent properties.

  20. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

    PubMed

    Greenway, Frank L; Fujioka, Ken; Plodkowski, Raymond A; Mudaliar, Sunder; Guttadauria, Maria; Erickson, Janelle; Kim, Dennis D; Dunayevich, Eduardo

    2010-08-21

    Despite increasing public health concerns regarding obesity, few safe and effective drug treatments are available. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m(2) and uncomplicated obesity or BMI 27-45 kg/m(2) with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web-based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward). This study is registered with ClinicalTrials.gov, number NCT00532779. 1742 participants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n

  1. Naltrexone

    MedlinePlus

    ... other information should I know? Brand names IMPORTANT WARNING: Naltrexone may cause liver damage when taken in ... these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately: confusion hallucinations (seeing ...

  2. Long-acting injectable versus oral naltrexone maintenance therapy with psychosocial intervention for heroin dependence: a quasi-experiment.

    PubMed

    Brooks, Adam C; Comer, Sandra D; Sullivan, Maria A; Bisaga, Adam; Carpenter, Kenneth M; Raby, Wilfrid M; Yu, Elmer; O'Brien, Charles P; Nunes, Edward V

    2010-10-01

    To conduct a quasi-experimental comparison of early clinical outcomes between injectable, sustained-release, depot naltrexone formulation versus oral naltrexone maintenance therapy in individuals with opiate dependence. Early retention in treatment and urine-confirmed opiate use in the first 8 weeks postdetoxification were compared between patients (diagnosed as opiate-dependent according to DSM-IV criteria) participating in 2 concurrently run randomized clinical trials of oral (n = 69; patients treated from September 1999 to May 2002) and long-acting injectable (n = 42; patients treated from November 2000 to June 2003) naltrexone maintenance therapy with psychosocial therapy. Long-acting injectable naltrexone produced significantly better outcome than oral naltrexone on days retained in treatment (F(1,106) = 6.49, P = .012) and for 1 measure of opiate use (F(1,106) = 5.26, P = .024); other measures were not significantly different, but differences were in the same direction. In subanalyses, there were interaction effects between baseline heroin use severity and type of treatment. In subanalyses, heroin users with more severe baseline use showed better retention with oral naltrexone maintenance therapy combined with intensive psychotherapy (behavioral naltrexone therapy) as compared to retention shown by severe heroin users treated with long-acting naltrexone injections combined with standard cognitive-behavioral therapy (χ²(1)= 9.31, P = .002); less severe heroin users evidenced better outcomes when treated with long-acting injectable naltrexone. This quasi-experimental analysis provides tentative indications of superior outcomes for heroin-dependent patients treated with long-acting injectable naltrexone compared to oral naltrexone. The finding that heroin users with more severe baseline use achieved better outcomes with oral naltrexone is most probably attributable to the intensive nature of the psychosocial treatments provided and points to the opportunity

  3. Naltrexone

    MedlinePlus

    ... Dependence When used as a treatment for alcohol dependency, naltrexone blocks the euphoric effects and feelings of ... dispense and prescribe medications for opioid and alcohol dependency. SAMHSA’s Division of Pharmacologic Therapies (DPT) provides opioid ...

  4. Naltrexone treatment reverses astrocyte atrophy and immune dysfunction in self-harming macaques.

    PubMed

    Lee, Kim M; Chiu, Kevin B; Didier, Peter J; Baker, Kate C; MacLean, Andrew G

    2015-11-01

    The role of glia in the development and treatment of behavioral abnormalities is understudied. Recent reports have observed glial activation in several disorders, including depression, autism spectrum disorders and self-injurious behaviors (SIB). In the current study, we examined SIB in the physiologically and anatomically relevant nonhuman primate (NHP) model. At the Tulane National Primate Research Center (TNPRC), approximately 5% of singly housed macaques develop symptoms of SIB. We have previously demonstrated that naltrexone hydrochloride can be effective in reducing SIB. We have also demonstrated that the astrocytes of animals with SIB are distinctly atrophic and display heightened innate immune activation compared with control animals. We have added a third group of animals (five macaques identified with SIB and treated with oral naltrexone at a dose of 3.2mg/kg) to the previous cohort (six macaques with a history of SIB but not treated, and nine animals with no history of SIB) for this study. Gray and white matter astrocytes from frontal cortical tissue were examined following necropsy. Innate immune activation of astrocytes, which was increased in SIB animals, was markedly decreased in animals receiving naltrexone, as was atrophy of both grey and white matter astrocytes. This was concomitant with improved behavioral correlates. Preventing astrocyte activation in select areas of the brain to reduce injurious behavior is an innovative concept with implications for mental health studies. Differences in multiple areas of primate brain would help determine how self-injurious behavior develops. These studies suggest a stronger role for astrocytes in the cellular events associated with self-injurious behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Opioid use and dropout in patients receiving oral naltrexone with or without single administration of injection naltrexone.

    PubMed

    Sullivan, Maria A; Bisaga, Adam; Glass, Andrew; Mishlen, Kaitlyn; Pavlicova, Martina; Carpenter, Kenneth M; Mariani, John J; Levin, Frances R; Nunes, Edward V

    2015-02-01

    Adherence to oral naltrexone has been poor and can be improved somewhat with behavioral therapy. We compared behavioral naltrexone therapy (BNT) to compliance enhancement (CE) and tested efficacy of single-dose injection naltrexone (XR-NTX; 384 mg) with behavioral therapies at further improving adherence to oral naltrexone. A 24-week, randomized, placebo-controlled trial (n=125) compared four treatment conditions following inpatient detoxification and oral naltrexone induction: (1) BNT+XR-NTX; (2) BNT+placebo injection; (3) CE+XR-NTX; and (4) CE+placebo injection. All participants were maintained on oral naltrexone throughout the trial. Primary outcome was retention in treatment. Of 89 randomized participants, 78.7% (70/89) completed 4 weeks, 58.2% (54/89) completed 8 weeks, 47.2% (42/89) completed 12 weeks, and 25.8% (23/89) completed 24 weeks. A Cox proportional hazards regression modeled time to dropout as a function of treatment condition, baseline opioid dependence severity (bags per day of heroin use), and their interaction. Interaction of conditions by baseline severity was significant (X3(2)=9.19, p=0.027). For low-severity patients (≤ 6 bags/day), retention was highest in the BNT-XR-NTX group (60% at 6 months), as hypothesized. For high-severity (>6 bags/day) patients, BNT-XR-NTX did not perform as well, due to high early attrition. For low-severity heroin users, single-dose XR-NTX improved long-term treatment retention when combined with behavioral therapy. In higher-severity opioid-dependent patients, XR-NTX was less helpful, perhaps because, combined with oral naltrexone, it produced higher blood levels and more withdrawal discomfort. When cost considerations recommend oral naltrexone following XR-NTX, the latter should be phased in slowly. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Opioid use and dropout in patients receiving oral naltrexone with or without single administration of injection naltrexone

    PubMed Central

    Sullivan, Maria A.; Bisaga, Adam; Glass, Andrew; Mishlen, Kaitlyn; Pavlicova, Martina; Carpenter, Kenneth M.; Mariani, John J; Levin, Frances R.; Nunes, Edward V.

    2015-01-01

    Background Adherence to oral naltrexone has been poor and can be improved somewhat with behavioral therapy. We compared Behavioral Naltrexone Therapy (BNT) to Compliance Enhancement (CE) and tested efficacy of single-dose injection naltrexone (XR-NTX; 384 mg) with behavioral therapies at further improving aherence to oral naltrexone. Methods A 24-week, randomized, placebo-controlled trial (N=125) compared four treatment conditions following inpatient detoxification and oral naltrexone induction: (1) BNT+XR-NTX; (2) BNT+ placebo injection; (3) CE+ XR-NTX; and (4) CE+placebo injection. All participants were maintained on oral naltrexone throughout the trial. Primary outcome was retention in treatment. Results Of 89 randomized participants, 78.7% (70/89) completed 4 weeks, 58.2% (54/89) completed 8 weeks, 47.2% (42/89) completed 12 weeks, and 25.8% (23/89) completed 24 weeks. A Cox proportional hazards regression modeled time to dropout as a function of treatment condition, baseline opioid dependence severity (bags per day of heroin use), and their interaction. Interaction of conditions by baseline severity was significant (X23 = 9.19, p = .027). For low-severity patients (<6 bags/day), retention was highest in the BNT-XRNTX group (60% at 6 months), as hypothesized. For high-severity (> 6 bags/day) patients, BNT-XR-NTX did not perform as well, due to high early attrition. Conclusion For low-severity heroin users, single-dose XR-NTX improved long-term treatment retention when combined with behavioral therapy. In higher-severity opioid-dependent patients, XR-NTX was less helpful, perhaps because, combined with oral naltrexone, it produced higher blood levels and more withdrawal discomfort. When cost considerations recommend oral naltrexone following XR-NTX, the latter should be phased in slowly. PMID:25555621

  7. Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules.

    PubMed

    Fukui, Atsuko; Fujii, Ryuta; Yonezawa, Yorinobu; Sunada, Hisakazu

    2002-11-01

    The release properties of phenylpropanolamine hydrochloride (PPA) from ethylcellulose (EC, ethylcellulose 10 cps (EC#10) and/or 100 cps (EC#100)) matrix granules prepared by the extrusion granulation method were examined. The release process could be divided into two parts, and was well analyzed by applying square-root time law and cube root law equations, respectively. The validity of the treatments was confirmed by the fitness of the simulation curve with the measured curve. At the initial stage, PPA was released from the gel layer of swollen EC in the matrix granules. At the second stage, the drug existing below the gel layer dissolved, and was released through the gel layer. Also, the time and release ratio at the connection point of the simulation curves was examined to determine the validity of the analysis. Comparing the release properties of PPA from the two types of EC matrix granules, EC#100 showed more effective sustained release than EC#10. On the other hand, changes in the release property of the EC#10 matrix granule were relatively more clear than that of the EC#100 matrix granule. Thus, it was supposed that EC#10 is more available for controlled and sustained release formulations than EC#100.

  8. The mesolimbic system participates in the naltrexone-induced reversal of sexual exhaustion: opposite effects of intra-VTA naltrexone administration on copulation of sexually experienced and sexually exhausted male rats.

    PubMed

    Garduño-Gutiérrez, René; León-Olea, Martha; Rodríguez-Manzo, Gabriela

    2013-11-01

    Male rats allowed to copulate until reaching sexual exhaustion exhibit a long-lasting sexual behavior inhibition (around 72 h) that can be reversed by systemic opioid receptor antagonist administration. Copulation activates the mesolimbic dopaminergic system (MLS) and promotes endogenous opioid release. In addition, endogenous opioids, acting at the ventral tegmental area (VTA), modulate the activity of the MLS. We hypothesized that endogenous opioids participate in the sexual exhaustion phenomenon by interacting with VTA opioid receptors and consequently, its reversal by opioid antagonists could be exerted at those receptors. In this study we determined the effects of intra-VTA infusion of different doses of the non-specific opioid receptor antagonist naltrexone (0.1-1.0 μg/rat) on the already established sexual behavior inhibition of sexually exhausted male rats. To elucidate the possible involvement of VTA δ-opioid receptors in the naltrexone-mediated reversal of sexual exhaustion, the effects of different doses of the selective δ-opioid receptor antagonist, naltrindole (0.03-1.0 μg/rat) were also tested. Results showed that intra-VTA injection of 0.3 μg naltrexone reversed the sexual inhibition of sexually exhausted rats, evidenced by an increased percentage of animals capable of showing two successive ejaculations. Intra-VTA infused naltrindole did not reverse sexual exhaustion at any dose. It is concluded that the MLS is involved in the reversal of sexual exhaustion induced by systemic naltrexone, and that μ-, but not δ-opioid receptors participate in this effect. Intra-VTA naltrexone infusion to sexually experienced male rats had an inhibitory effect on sexual activity. The opposite effects of intra-VTA naltrexone on male rat sexual behavior expression of sexually experienced and sexually exhausted rats is discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Pharmacokinetics of propafenone hydrochloride sustained-release capsules in male beagle dogs.

    PubMed

    Pan, Liping; Qian, Yafang; Cheng, Minlu; Gu, Pan; He, Yanna; Xu, Xiaowen; Ding, Li

    2015-01-01

    This paper describes the development and validation of a liquid chromatography-mass spectrometric assay for propafenone and its application to a pharmacokinetic study of propafenone administered as a new propafenone hydrochloride sustained-release capsule (SR-test), as an instant-release tablet (IR-reference) and as the market leader sustained-release capsule (Rythmol, SR-reference) in male beagle dogs (n=8). In Study A comparing SR-test with IR-reference in a crossover design T max and t 1/2 of propafenone for SR-test were significantly higher than those for IR-reference while C max and AUC were lower demonstrating the sustained release properties of the new formulation. In Study B comparing SR-test with SR-reference the observed C max and AUC of propafenone for SR-test (124.5±140.0 ng/mL and 612.0±699.2 ng·h/mL, respectively) were higher than for SR-reference (78.52±72.92 ng/mL and 423.6±431.6 ng·h/mL, respectively) although the differences were not significant. Overall, the new formulation has as good if not better sustained release characteristics to the market leader formulation.

  10. Accelerated in-vitro release testing methods for extended-release parenteral dosage forms.

    PubMed

    Shen, Jie; Burgess, Diane J

    2012-07-01

    This review highlights current methods and strategies for accelerated in-vitro drug release testing of extended-release parenteral dosage forms such as polymeric microparticulate systems, lipid microparticulate systems, in-situ depot-forming systems and implants. Extended-release parenteral dosage forms are typically designed to maintain the effective drug concentration over periods of weeks, months or even years. Consequently, 'real-time' in-vitro release tests for these dosage forms are often run over a long time period. Accelerated in-vitro release methods can provide rapid evaluation and therefore are desirable for quality control purposes. To this end, different accelerated in-vitro release methods using United States Pharmacopeia (USP) apparatus have been developed. Different mechanisms of accelerating drug release from extended-release parenteral dosage forms, along with the accelerated in-vitro release testing methods currently employed are discussed. Accelerated in-vitro release testing methods with good discriminatory ability are critical for quality control of extended-release parenteral products. Methods that can be used in the development of in-vitro-in-vivo correlation (IVIVC) are desirable; however, for complex parenteral products this may not always be achievable. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

  11. Accelerated in vitro release testing methods for extended release parenteral dosage forms

    PubMed Central

    Shen, Jie; Burgess, Diane J.

    2012-01-01

    Objectives This review highlights current methods and strategies for accelerated in vitro drug release testing of extended release parenteral dosage forms such as polymeric microparticulate systems, lipid microparticulate systems, in situ depot-forming systems, and implants. Key findings Extended release parenteral dosage forms are typically designed to maintain the effective drug concentration over periods of weeks, months or even years. Consequently, “real-time” in vitro release tests for these dosage forms are often run over a long time period. Accelerated in vitro release methods can provide rapid evaluation and therefore are desirable for quality control purposes. To this end, different accelerated in vitro release methods using United States Pharmacopoeia (USP) apparatus have been developed. Different mechanisms of accelerating drug release from extended release parenteral dosage forms, along with the accelerated in vitro release testing methods currently employed are discussed. Conclusions Accelerated in vitro release testing methods with good discriminatory ability are critical for quality control of extended release parenteral products. Methods that can be used in the development of in vitro-in vivo correlation (IVIVC) are desirable, however for complex parenteral products this may not always be achievable. PMID:22686344

  12. Naltrexone Injection

    MedlinePlus

    Naltrexone injection is used along with counseling and social support to help people who have stopped drinking ... injection is also used along with counseling and social support to help people who have stopped abusing ...

  13. Release behavior and kinetic evaluation of berberine hydrochloride from ethyl cellulose/chitosan microspheres

    NASA Astrophysics Data System (ADS)

    Zhou, Hui-Yun; Cao, Pei-Pei; Zhao, Jie; Wang, Zhi-Ying; Li, Jun-Bo; Zhang, Fa-Liang

    2014-12-01

    Novel ethyl cellulose/chitosan microspheres (ECCMs) were prepared by the method of w/o/w emulsion and solvent evaporation. The microspheres were spherical, adhesive, and aggregated loosely with a size not bigger than 5 μm. The drug loading efficiency of berberine hydrochloride (BH) loaded in microspheres were affected by chitosan (CS) concentration, EC concentration and the volume ratio of V(CS)/ V(EC). ECCMs prepared had sustained release efficiency on BH which was changed with different preparation parameters. In addition, the pH value of release media had obvious effect on the release character of ECCMs. The release rate of BH from sample B was only a little more than 30% in diluted hydrochloric acid (dHCl) and that was almost 90% in PBS during 24 h. Furthermore, the drug release data were fitted to different kinetic models to analyze the release kinetics and the mechanism from the microspheres. The released results of BH indicated that ECCMs exhibited non-Fickian diffusion mechanism in dHCl and diffusion-controlled drug release based on Fickian diffusion in PBS. So the ECCMs might be an ideal sustained release system especially in dHCl and the drug release was governed by both diffusion of the drug and dissolution of the polymeric network.

  14. 78 FR 23273 - Determination That the OXYCONTIN (Oxycodone Hydrochloride) Drug Products Covered by New Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-18

    ... Hydrochloride) Drug Products Covered by New Drug Application 20-553 Were Withdrawn From Sale for Reasons of... was often abused by manipulating the product to defeat its extended-release mechanism, causing the... example, by crushing the product to sprinkle it onto food or to administer it through a gastric tube. As...

  15. The cannabinoid anticonvulsant effect on pentylenetetrazole-induced seizure is potentiated by ultra-low dose naltrexone in mice.

    PubMed

    Bahremand, Arash; Shafaroodi, Hamed; Ghasemi, Mehdi; Nasrabady, Sara Ebrahimi; Gholizadeh, Shervin; Dehpour, Ahmad Reza

    2008-09-01

    Cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to G(i/o) proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoid-induced antinociception. Thus, concerning the seizure modulating properties of both classes of receptors this study investigated whether the ultra-low dose opioid antagonist naltrexone influences cannabinoid anticonvulsant effects. The clonic seizure threshold was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the opioid receptor antagonist naltrexone and a combination of ACEA and naltrexone doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic injection of ultra-low doses of naltrexone (1pg/kg to 1ng/kg, i.p.) significantly potentiated the anticonvulsant effect of ACEA (1mg/kg, i.p.). Moreover, the very low dose of naltrexone (500pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (10 and 100microg/kg). A similar potentiation by naltrexone (500pg/kg) of anticonvulsant effects of non-effective dose of ACEA (1mg/kg) was also observed in the generalized tonic-clonic model of seizure. The present data indicate that the interaction between opioid and cannabinoid systems extends to ultra-low dose levels and ultra-low doses of opioid receptor antagonist in conjunction with very low doses of cannabinoids may provide a potent strategy to modulate seizure susceptibility.

  16. Synthesis of Novel Basic Skeletons Derived from Naltrexone

    NASA Astrophysics Data System (ADS)

    Nagase, Hiroshi; Fujii, Hideaki

    We will describe eight interesting reactions using naltrexone derivatives. Almost all these reactions are characteristic of naltrexone derivatives, and can lead to the synthesis of many novel skeletons that provide new interesting pharmacological data. Some of the new reactions that were found with naltrexone derivatives were expanded into general reactions. For example, the reaction of 6α-hydroxyaldehyde derived from naltrexone led to the oxazoline dimer and the 1,3,5-trioxazatriquinane skeleton (triplet drug); this reaction was applied to general ketones which were converted to α-hydroxyaldehydes, followed by conversion to dimers and trimers, as described in Sect. 7.

  17. Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing

    PubMed Central

    Goodin, Burel; Kindler, Lindsay L.; Caudle, Robert M.; Edwards, Robert R.; Gravenstein, Nikolaus; Riley, Joseph L.; Fillingim, Roger B.

    2013-01-01

    The current study tested the hypothesis that conditioned pain modulation is mediated by the release of endogenous opioids with a placebo-controlled (sugar pill) study of naltrexone (50 mg) in 33 healthy volunteers over two counter-balanced sessions. Pain modulation consisted of rating of heat pain (palm) during concurrent cold water immersion (foot). Compared to baseline heat pain ratings, concurrent foot immersion lowered pain intensity ratings, which suggests an inhibitory effect, was reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. An exploratory analysis revealed that individual differences in catastrophizing moderated the effects of naltrexone; endogenous opioid blockade abolished modulation in subjects lower in catastrophizing while modulation was unaffected by naltrexone among high catastrophizers. The results suggest a role of endogenous opioids in endogenous analgesia, but hint that multiple systems might contribute to conditioned pain modulation, and that these systems might be differentially activated as a function of individual differences in responses to pain. PMID:22534819

  18. Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain.

    PubMed

    Van Bockstaele, Elisabeth J; Qian, Yaping; Sterling, Robert C; Page, Michelle E

    2008-05-15

    , animals were transcardially perfused and the brains were removed for verification of probe placement. Low dose naltrexone pre-treatment significantly attenuated withdrawal-induced increases of extracellular norepinephrine in the BNST, with a smaller effect in the FC. These findings suggest that alterations in norepinephrine release associated with withdrawal may be attenuated in forebrain targets of noradrenergic brainstem neurons that may underlie reduced behavioral signs of withdrawal following low dose naltrexone administration.

  19. Preparation, characterization and evaluation of ranitidine hydrochloride-loaded mucoadhesive microspheres.

    PubMed

    Dhankar, Vandana; Garg, Garima; Dhamija, Koushal; Awasthi, Rajendra

    2014-01-01

    Mucoadhesion enables localization of drugs to a defined region of the gastrointestinal tract through attractive interactions between polymers composing the drug delivery devices and the mucin layer of the intestinal epithelium. Thus, this approach can be used for enhancement of the oral bioavailability of the drug. The current communication deals with the development of ranitidine hydrochloride-loaded chitosan-based mucoadhesive microspheres. Microspheres were prepared by water-in-oil emulsion technique, using glutaraldehyde as a cross-linking agent. The effect of independent variables like stirring speed and polymer-to-drug ratio on dependent variables, i.e. percentage mucoadhesion, percentage drug loading, particle size and swelling index, was examined using a 3(2); factorial design. The microspheres were discrete, spherical, free-flowing and also showed high percentage drug entrapment efficiency (43-70%). An in vitro mucoadhesion test showed that the microspheres adhered strongly to the mucous layer for an extended period of time. The RC 4 batch exhibited a high percentage of drug encapsulation (70%) and mucoadhesion (75%). The drug release was sustained for more than 12 h. The drug release kinetics were found to follow Peppas' kinetics for all the formulations and the drug release was diffusion controlled. The preliminary results of this study suggest that the developed microspheres containing ranitidine hydrochloride could enhance drug entrapment efficiency, reduce the initial burst release and modulate the drug release.

  20. Treatment of Hailey-Hailey Disease With Low-Dose Naltrexone.

    PubMed

    Albers, Lauren N; Arbiser, Jack L; Feldman, Ron J

    2017-10-01

    Hailey-Hailey disease is a severe genetic blistering disease of intertriginous skin locations that can lead to poor quality of life and increased morbidities. Multiple therapies are available with inconsistent outcomes and potentially severe adverse effects. To determine whether low-dose naltrexone is an effective treatment for Hailey-Hailey disease. This study was a case series performed at a dermatology outpatient clinic of 3 patients with severe Hailey-Hailey disease recalcitrant to at least 4 therapies. Low-dose naltrexone, 3 mg nightly, titrated to 4.5 mg nightly in 2 patients. Reduction in size of lesions as well as subjective improvement of symptoms. All 3 patients noted significant healing of erosions and plaques starting from the peripheral aspect within 1 to 2 weeks of treatment, and clinical resolution of lesions within 2 months. Discontinuation of low-dose naltrexone resulted in flaring of symptoms, which cleared within 2 to 3 days on rechallenge with low-dose naltrexone. We present herein 3 cases of patients with severe Hailey-Hailey disease treated with low-dose naltrexone who achieved clinical resolution of symptoms. The success of these cases suggests low-dose naltrexone as a novel therapy for Hailey-Hailey disease. The possible mechanism may involve low-dose naltrexone influencing opioid or toll-like receptor signaling to improve calcium mobilization and improve keratinocyte differentiation and wound healing. Future studies are needed to clarify the mechanism and to define the role of low-dose naltrexone for treatment of Hailey-Hailey disease.

  1. Pharmacokinetics and effect of food after oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with Parkinson's disease.

    PubMed

    Hattori, N; Hasegawa, K; Sakamoto, T

    2012-10-01

    Ropinirole hydrochloride, a dopamine receptor agonist with a non-ergot alkaloid structure, is highly selective for the dopamine D(2) /D(3) receptors. This study was conducted to evaluate the steady-state pharmacokinetics, safety and efficacy after repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in the absence of L-dopa preparations in Japanese patients with Parkinson's disease (PD). This was a multicenter, open-label, uncontrolled study. The total duration of participation in the study ranged from 56 to 63 weeks. In the study, the plasma concentrations of ropinirole, its major metabolite SK&F104557 (N-depropyl ropinirole) and another metabolite SK&F89124 (ropinirole hydroxylated at the seventh position of the indole ring) were assessed. Safety based on adverse events, haematology, biochemistry, urinalysis and electrocardiography (ECG) (standard 12-lead ECG) were evaluated, and vital signs (blood pressure/pulse rate) were measured. Efficacy based on the Japanese version of Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (motor) and II [activities of daily living (ADL)] as well as tolerability was evaluated. After repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with PD, ropinirole, SK&F104557 and low levels of SK&F89124 were detected in plasma. The trough concentrations of ropinirole and the two metabolites increased in proportion to the dose when ropinirole hydrochloride prolonged-release tablets were administered at doses ranging from 2 to 16 mg/day. The plasma exposure to ropinirole and its two metabolites after intake of normal diet was comparable to that in the fasting state. The most common adverse events (10% or more) were somnolence, nausea, constipation, hallucination and nasopharyngitis. Most adverse events were mild or moderate in severity, and with no death. During the treatment period, serious adverse events were reported in five patients. Efficacy

  2. [Preparation of ondansetron hydrochloride osmotic pump tablets and their in vitro drug release].

    PubMed

    Zheng, Hang-sheng; Bi, Dian-zhou

    2005-12-01

    To prepare ondansetron hydrochloride osmotic pump tablets (OND-OPT) and investigate their in vitro drug release behavior. OND-OPT were prepared with a single punch press and pan coating technique. Osmotic active agents and plasticizer of coating film were chosen by drug release tests. The effects of the number, position and direction of drug release orifice on release behavior were investigated. The relation between drug release duration and thickness of coating film, PEG content of coating film and size of drug release orifice was established by uniform design experiment. The surface morphological change of coating film before and after drug release test was observed by scanning electron microscopy. The osmotic pumping release mechanism of OND-OPT was confirmed by drug release test with high osmotic pressure medium. Lactose-mannitol (1:2) was chosen as osmotic active agents and PEG400 as plasticizer of coating film. The direction of drug release orifice had great effect on the drug release of OND-OPT without HPMC, and had no effect on the drug release of OND-OPT with HPMC. The OND-OPT with one drug release orifice at the centre of the coating film on one surface of tablet released their drug with little fluctuation. The drug release duration of OND-OPT correlated with thickness of coating film and PEG content of coating film, and didn't correlate significantly with the size of drug release orifice. OND-OPT released their drug with osmotic pumping mechanism predominantly. OND-OPT are able to realize ideal controlled drug release.

  3. Pharmacokinetics of hydrocodone extended-release tablets formulated with different levels of coating to achieve abuse deterrence compared with a hydrocodone immediate-release/acetaminophen tablet in healthy subjects.

    PubMed

    Darwish, Mona; Bond, Mary; Tracewell, William; Robertson, Philmore; Yang, Ronghua

    2015-01-01

    A hydrocodone extended-release (ER) formulation employing the CIMA(®) Abuse-Deterrence Technology platform was developed to provide resistance against rapid release of hydrocodone when tablets are comminuted or taken with alcohol. This study evaluated the pharmacokinetics of three hydrocodone ER tablet prototypes with varying levels of polymer coating to identify the prototype expected to have the greatest abuse deterrence potential based on pharmacokinetic characteristics that maintain systemic exposure to hydrocodone comparable to that of a commercially available hydrocodone immediate-release (IR) product. In this four-period crossover study, healthy subjects aged 18-45 years were randomized to receive a single intact, oral 45-mg tablet of one of three hydrocodone ER prototypes (low-, intermediate-, or high-level coating) or an intact, oral tablet of hydrocodone IR/acetaminophen (APAP) 10/325 mg every 6 h until four tablets were administered, with each of the four treatments administered once over the four study periods. Dosing periods were separated by a minimum 5-day washout. Naltrexone 50 mg was administered to block opioid receptors. Blood samples for pharmacokinetic assessments were collected predose and through 72 h postdose. Parameters assessed included maximum observed plasma hydrocodone concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve from time 0 to infinity (AUC(0-∞)). Mean C(max) values were 49.2, 32.6, and 28.4 ng/mL for the low-, intermediate-, and high-level coating hydrocodone ER tablet prototypes, respectively, and 37.3 ng/mL for the hydrocodone IR/APAP tablet; respective median t(max) values were 5.9, 8.0, 8.0, and 1.0 h. Total systemic exposure to hydrocodone (AUC(0-∞)) was comparable between hydrocodone ER tablet prototypes (640, 600, and 578 ng·h/mL, respectively) and hydrocodone IR/APAP (581 ng·h/mL). No serious adverse events or deaths were reported. The most common adverse events included

  4. Favorable mortality profile of naltrexone implants for opiate addiction.

    PubMed

    Reece, Albert Stuart

    2010-01-01

    Several reports express concern at the mortality associated with the use of oral naltrexone for opiate dependency. Registry controlled follow-up of patients treated with naltrexone implant and buprenorphine was performed. In the study, 255 naltrexone implant patients were followed for a mean (+/- standard deviation) of 5.22 +/- 1.87 years and 2,518 buprenorphine patients were followed for a mean (+/- standard deviation) of 3.19 +/- 1.61 years, accruing 1,332.22 and 8,030.02 patient-years of follow-up, respectively. The crude mortality rates were 3.00 and 5.35 per 1,000 patient-years, respectively, and the age standardized mortality rate ratio for naltrexone compared to buprenorphine was 0.676 (95% confidence interval = 0.014 to 1.338). Most sex, treatment group, and age comparisons significantly favored the naltrexone implant group. Mortality rates were shown to be comparable to, and intermediate between, published mortality rates of an age-standardized methadone treated cohort and the Australian population. These data suggest that the mortality rate from naltrexone implant is comparable to that of buprenorphine, methadone, and the Australian population.

  5. A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of the extended-release tramadol hydrochloride/acetaminophen fixed-dose combination tablet for the treatment of chronic low back pain.

    PubMed

    Lee, Jae Hyup; Lee, Chong-Suh

    2013-11-01

    Chronic low back pain is a common condition that is often difficult to treat. The combination of tramadol hydrochloride and acetaminophen in an extended-release formulation has been shown to provide rapid and long-lasting analgesic effects resulting from the synergistic activity of these 2 active ingredients. The goal of this study was to evaluate the efficacy and safety of extended-release tramadol hydrochloride 75-mg/acetaminophen 650-mg fixed-dose combination tablets (TA-ER) for the treatment of chronic low back pain. This Phase III, double-blind, placebo-controlled, parallel-group study enrolled 245 patients with moderate to severe (≥4 cm on a 10-cm visual analog scale) chronic (≥3 months') low back pain insufficiently controlled by previous NSAIDs or cyclooxygenase-2-selective inhibitors and randomly assigned them to receive 4 weeks of either TA-ER or placebo. The primary efficacy end point was the percentage of patients with a pain intensity change rate ≥30% from baseline to final evaluation. Secondary end points included quality of life (Korean Short Form-36), functionality (Korean Oswestry Disability Index), and adverse events. The percentage of patients with a pain intensity change rate ≥30% was significantly higher (P < 0.05) in the TA-ER group than in the placebo group for both the full analysis set and the per-protocol population. Pain relief success rate from baseline was significantly higher with TA-ER versus placebo at days 8 and 15 but not at the final visit. Patients in the TA-ER group had significant improvements versus placebo in role-physical, general health, and reported health transition domains of the Korean Short Form-36 and significantly higher functional improvements in the personal care section of the Korean Oswestry Disability Index. Patient assessment of overall pain control as "very good" was also significantly higher with TA-ER than with placebo. Adverse events were reported more frequently with TA-ER than with placebo; the

  6. Comparison of Healthcare Utilization Among Patients Treated With Alcoholism Medications

    PubMed Central

    Mark, Tami L.; Montejano, Leslie B.; Kranzler, Henry R.; Chalk, Mady; Gastfriend, David R.

    2014-01-01

    Objectives To determine in a large claims database the healthcare utilization and costs associated with treatment of alcohol dependence with medications vs no medication and across 4 US Food and Drug Administration (FDA)–approved medications. Study Design Claims database analysis. Methods Eligible adults with alcohol dependence claims (n = 27,135) were identified in a commercial database (MarketScan; Thomson Reuters Inc, Chicago, Illinois). Following propensity score–based matching and inverse probability weighting on demographic, clinical, and healthcare utilization variables, patients who had used an FDA-approved medication for alcohol dependence (n = 2977) were compared with patients who had not (n = 2977). Patients treated with oral naltrexone hydrochloride (n = 2064), oral disulfiram (n = 2076), oral acamprosate calcium (n = 5068), or extended-release injectable naltrexone (naltrexone XR) (n = 295) were also compared for 6-month utilization rates of alcoholism medication, inpatient detoxification days, alcoholism-related inpatient days, and outpatient services, as well as inpatient charges. Results Patients who received alcoholism medications had fewer inpatient detoxification days (706 vs 1163 days per 1000 patients, P <.001), alcoholism-related inpatient days (650 vs 1086 days, P <.001), and alcoholism-related emergency department visits (127 vs 171, P = .005). Among 4 medications, the use of naltrexone XR was associated with fewer inpatient detoxification days (224 days per 1000 patients) than the use of oral naltrexone (552 days, P = .001), disulfiram (403 days, P = .049), or acamprosate (525 days, P <.001). The group receiving naltrexone XR also had fewer alcoholism-related inpatient days than the groups receiving disulfiram or acamprosate. More patients in the naltrexone XR group had an outpatient substance abuse visit compared with patients in the oral alcoholism medication groups. Conclusion Patients who received an alcoholism medication had lower

  7. The use of Hibiscus esculentus (Okra) gum in sustaining the release of propranolol hydrochloride in a solid oral dosage form.

    PubMed

    Zaharuddin, Nurul Dhania; Noordin, Mohamed Ibrahim; Kadivar, Ali

    2014-01-01

    The effectiveness of Okra gum in sustaining the release of propranolol hydrochloride in a tablet was studied. Okra gum was extracted from the pods of Hibiscus esculentus using acetone as a drying agent. Dried Okra gum was made into powder form and its physical and chemical characteristics such as solubility, pH, moisture content, viscosity, morphology study using SEM, infrared study using FTIR, crystallinity study using XRD, and thermal study using DSC and TGA were carried out. The powder was used in the preparation of tablet using granulation and compression methods. Propranolol hydrochloride was used as a model drug and the activity of Okra gum as a binder was compared by preparing tablets using a synthetic and a semisynthetic binder which are hydroxylmethylpropyl cellulose (HPMC) and sodium alginate, respectively. Evaluation of drug release kinetics that was attained from dissolution studies showed that Okra gum retarded the release up to 24 hours and exhibited the longest release as compared to HPMC and sodium alginate. The tensile and crushing strength of tablets was also evaluated by conducting hardness and friability tests. Okra gum was observed to produce tablets with the highest hardness value and lowest friability. Hence, Okra gum was testified as an effective adjuvant to produce favourable sustained release tablets with strong tensile and crushing strength.

  8. Naltrexone in the treatment of adolescent sexual offenders.

    PubMed

    Ryback, Ralph S

    2004-07-01

    Naltrexone is a long-acting opioid used clinically in alcoholism, drug abuse, bulimia nervosa, obsessive-compulsive disorder, and impulse-control disorders. This study investigated whether naltrexone can decrease sexual arousal in legally adjudicated adolescent sexual offenders. In an open-ended prospective study, naltrexone was given to 21 adolescents participating in an inpatient adolescent sexual offenders program who met any of the self-reported criteria of (1) masturbating 3 or more times per day, (2) feeling unable to control arousal, (3) spending more than 30% of awake time in sexual fantasies, or (4) having sexual fantasies or behavior that regularly intruded into and interfered with their functioning in the treatment program. After having been treated for more than 2 months, 13 patients had their naltrexone administratively stopped, thus providing a before, during, after, and resumption-of-treatment design. Behavioral changes were monitored daily with a fantasy-tracking log and a masturbation log. A positive result was recorded if there was more than a 30% decrease in any self-reported criterion that was applicable to each specific patient and this benefit lasted at least 4 months. Data were collected from July 2000 to December 2002. Leuprolide was given if naltrexone was not sufficiently helpful in controlling sexual impulses and arousal. Fifteen of 21 patients were considered to have a positive result and continued to respond for at least 4 months to an average dose of 160 mg per day with decreased sexual fantasies and masturbation. Dosages above 200 mg per day were not more helpful. Administrative discontinuation of naltrexone in a subset of 13 patients resulted in reoccurrence of symptoms that began when the dose taper reached 50 mg per day. There were no changes in clinical chemistries. Five of 6 patients who did not benefit from naltrexone responded favorably to leuprolide. Naltrexone at dosages of 100 to 200 mg per day provides a safe first step in

  9. [Limited role of naltrexone in the treatment of opiate addiction].

    PubMed

    van Brussel, G H

    2001-07-28

    Naltrexone has been used for many years as an opiate antagonist for maintenance treatment to prevent relapse in opiate addiction and, more recently, for rapid opiate detoxification with and without general anaesthesia. Naltrexone is useful for rapid detoxification without anaesthesia. However, the detoxification procedure under anaesthesia lacks a scientific basis. There is no clear evidence of the efficacy of naltrexone maintenance treatment. Poor compliance and possible receptor sensitisation means there may be a potentially increased risk of mortality through opiate overdose following cessation of naltrexone treatment and relapse into addiction.

  10. Overview of extended release tacrolimus in solid organ transplantation

    PubMed Central

    Patel, Neha; Cook, Abigail; Greenhalgh, Elizabeth; Rech, Megan A; Rusinak, Joshua; Heinrich, Lynley

    2016-01-01

    Tacrolimus (Prograf©, Astellas Pharma Europe Ltd, Staines, United Kingdom; referred to as tacrolimus-BID) is an immunosuppressive agent to prevent and treat allograft rejection in kidney transplant recipients in combination with mycophenolate mofetil, corticosteroids, with or without basiliximab induction. The drug has also been studied in liver, heart and lung transplant; however, these are currently off-label indications. An extended release tacrolimus formulation (Advagraf©, Astagraf XL©) allows for once-daily dosing, with the potential to improve adherence. Extended release tacrolimus has similar absorption, distribution, metabolism and excretion to tacrolimus-BID. Phase I pharmacokinetic trials comparing extended release tacrolimus and tacrolimus-BID have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration (tmax) with the extended release formulation; however, AUC0-24 was comparable between formulations. Overall extended release tacrolimus has a very similar safety and efficacy profile to tacrolimus-BID. It is not recommended in the use of liver transplant patient’s due to the increased risk of mortality in female recipients. There has been minimal data regarding the use of extended release tacrolimus in heart and lung transplant recipients. With the current data available for all organ groups the extended release tacrolimus should be dosed in a 1:1 fashion, the exception may be the cystic fibrosis population where their initial dose may need to be higher. PMID:27011912

  11. Overview of extended release tacrolimus in solid organ transplantation.

    PubMed

    Patel, Neha; Cook, Abigail; Greenhalgh, Elizabeth; Rech, Megan A; Rusinak, Joshua; Heinrich, Lynley

    2016-03-24

    Tacrolimus (Prograf(©), Astellas Pharma Europe Ltd, Staines, United Kingdom; referred to as tacrolimus-BID) is an immunosuppressive agent to prevent and treat allograft rejection in kidney transplant recipients in combination with mycophenolate mofetil, corticosteroids, with or without basiliximab induction. The drug has also been studied in liver, heart and lung transplant; however, these are currently off-label indications. An extended release tacrolimus formulation (Advagraf(©), Astagraf XL(©)) allows for once-daily dosing, with the potential to improve adherence. Extended release tacrolimus has similar absorption, distribution, metabolism and excretion to tacrolimus-BID. Phase I pharmacokinetic trials comparing extended release tacrolimus and tacrolimus-BID have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration (tmax) with the extended release formulation; however, AUC0-24 was comparable between formulations. Overall extended release tacrolimus has a very similar safety and efficacy profile to tacrolimus-BID. It is not recommended in the use of liver transplant patient's due to the increased risk of mortality in female recipients. There has been minimal data regarding the use of extended release tacrolimus in heart and lung transplant recipients. With the current data available for all organ groups the extended release tacrolimus should be dosed in a 1:1 fashion, the exception may be the cystic fibrosis population where their initial dose may need to be higher.

  12. New opioid receptor antagonist: Naltrexone-14-O-sulfate synthesis and pharmacology.

    PubMed

    Zádor, Ferenc; Király, Kornél; Váradi, András; Balogh, Mihály; Fehér, Ágnes; Kocsis, Dóra; Erdei, Anna I; Lackó, Erzsébet; Zádori, Zoltán S; Hosztafi, Sándor; Noszál, Béla; Riba, Pál; Benyhe, Sándor; Fürst, Susanna; Al-Khrasani, Mahmoud

    2017-08-15

    Opioid antagonists, naloxone and naltrexone have long been used in clinical practice and research. In addition to their low selectivity, they easily pass through the blood-brain barrier. Quaternization of the amine group in these molecules, (e.g. methylnaltrexone) results in negligible CNS penetration. In addition, zwitterionic compounds have been reported to have limited CNS access. The current study, for the first time gives report on the synthesis and the in vitro [competition binding, G-protein activation, isolated mouse vas deferens (MVD) and mouse colon assay] pharmacology of the zwitterionic compound, naltrexone-14-O-sulfate. Naltrexone, naloxone, and its 14-O-sulfate analogue were used as reference compounds. In competition binding assays, naltrexone-14-O-sulfate showed lower affinity for µ, δ or κ opioid receptor than the parent molecule, naltrexone. However, the μ/κ opioid receptor selectivity ratio significantly improved, indicating better selectivity. Similar tendency was observed for naloxone-14-O-sulfate when compared to naloxone. Naltrexone-14-O-sulfate failed to activate [ 35 S]GTPγS-binding but inhibit the activation evoked by opioid agonists (DAMGO, Ile 5,6 deltorphin II and U69593), similarly to the reference compounds. Schild plot constructed in MVD revealed that naltrexone-14-O-sulfate acts as a competitive antagonist. In mouse colon, naltrexone-14-O-sulfate antagonized the inhibitory effect of morphine with lower affinity compared to naltrexone and higher affinity when compared to naloxone or naloxone-14-O-sulfate. In vivo (mouse tail-flick test), subcutaneously injected naltrexone-14-O-sulfate antagonized morphine's antinociception in a dose-dependent manner, indicating it's CNS penetration, which was unexpected from such zwitter ionic structure. Future studies are needed to evaluate it's pharmacokinetic profile. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. The Use of Hibiscus esculentus (Okra) Gum in Sustaining the Release of Propranolol Hydrochloride in a Solid Oral Dosage Form

    PubMed Central

    Noordin, Mohamed Ibrahim; Kadivar, Ali

    2014-01-01

    The effectiveness of Okra gum in sustaining the release of propranolol hydrochloride in a tablet was studied. Okra gum was extracted from the pods of Hibiscus esculentus using acetone as a drying agent. Dried Okra gum was made into powder form and its physical and chemical characteristics such as solubility, pH, moisture content, viscosity, morphology study using SEM, infrared study using FTIR, crystallinity study using XRD, and thermal study using DSC and TGA were carried out. The powder was used in the preparation of tablet using granulation and compression methods. Propranolol hydrochloride was used as a model drug and the activity of Okra gum as a binder was compared by preparing tablets using a synthetic and a semisynthetic binder which are hydroxylmethylpropyl cellulose (HPMC) and sodium alginate, respectively. Evaluation of drug release kinetics that was attained from dissolution studies showed that Okra gum retarded the release up to 24 hours and exhibited the longest release as compared to HPMC and sodium alginate. The tensile and crushing strength of tablets was also evaluated by conducting hardness and friability tests. Okra gum was observed to produce tablets with the highest hardness value and lowest friability. Hence, Okra gum was testified as an effective adjuvant to produce favourable sustained release tablets with strong tensile and crushing strength. PMID:24678512

  14. Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules II. effects of the binder solution on the release process.

    PubMed

    Fukui, Atsuko; Fujii, Ryuta; Yonezawa, Yorinobu; Sunada, Hisakazu

    2004-03-01

    The release properties of phenylpropanolamine hydrochloride (PPA) from ethylcellulose (EC) matrix granules prepared by an extrusion granulation method were examined. The release process could be divided into two parts; the first and second stages were analyzed by applying square-root time law and cube-root law equations, respectively. The validity of the treatments was confirmed by the fitness of a simulation curve with the measured curve. In the first stage, PPA was released from the gel layer of swollen EC in the matrix granules. In the second stage, the drug existing below the gel layer dissolved and was released through the gel layer. The effect of the binder solution on the release from EC matrix granules was also examined. The binder solutions were prepared from various EC and ethanol (EtOH) concentrations. The media changed from a good solvent to a poor solvent with decreasing EtOH concentration. The matrix structure changed from loose to compact with increasing EC concentration. The preferable EtOH concentration region was observed when the release process was easily predictable. The time and release ratio at the connection point of the simulation curves were also examined to determine the validity of the analysis.

  15. Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules IV.(1)) Evaluation of the controlled release properties for in vivo and in vitro release systems.

    PubMed

    Fukui, Atsuko; Fujii, Ryuta; Yonezawa, Yorinobu; Sunada, Hisakazu

    2007-11-01

    In the pharmaceutical preparation of a controlled release drug, it is very important and necessary to understand the release properties. The dissolution test is a very important and useful method for understanding and predicting drug-release properties. It was readily confirmed in the previous paper that the release process could be assessed quantitatively by a combination of the square-root time law and cube-root law equations for ethylcellulose (EC) matrix granules of phenylpropanolamine hydrochloride (PPA). In this paper EC layered granules were used in addition to EC matrix. The relationship between release property and the concentration of PPA in plasma after administration using beagle dogs were examined. Then it was confirmed that the correlativity for EC layered granules and EC matrix were similar each other. Therefore, it was considered that the dissolution test is useful for prediction of changes in concentration of PPA in the blood with time. And it was suggested that EC layered granules were suitable as a controlled release system as well as EC matrix.

  16. Predictors for the efficacy of naltrexone treatment in alcohol dependence: sweet preference.

    PubMed

    Laaksonen, E; Lahti, J; Sinclair, J D; Heinälä, P; Alho, H

    2011-01-01

    To analyse the possible associations between sweet preference and the efficacy of naltrexone treatment of alcohol dependence. The preference for different concentrations of sucrose was evaluated in 78 participants diagnosed with alcohol dependence after treatment for 32 weeks with naltrexone or placebo without prior detoxification. A significant difference between naltrexone and placebo groups was found in the association between the preference for higher sucrose concentrations and relapses to heavy drinking. Higher sweet preference was significantly related to successful treatment measures in the naltrexone group but not in the placebo group. Sweet preference has a strong correlation to treatment outcomes with naltrexone, and sweet preference might be used as a predictor for better treatment results in alcoholics. Our study offers one possible new explanation of the clinical observation that naltrexone is not effective for every patient.

  17. Naltrexone for impulse control disorders in Parkinson disease

    PubMed Central

    Papay, Kimberly; Xie, Sharon X.; Stern, Matthew; Hurtig, Howard; Siderowf, Andrew; Duda, John E.; Minger, James

    2014-01-01

    Objective: Impulse control disorders (ICDs) in Parkinson disease (PD) are common and can be difficult to manage. The objective of this study was to determine the efficacy and tolerability of naltrexone, an opioid antagonist, for the treatment of ICDs in PD. Methods: Patients with PD (n = 50) and an ICD were enrolled in an 8-week, randomized (1:1), double-blind, placebo-controlled study of naltrexone 50–100 mg/d (flexible dosing). The primary outcome measure was response based on the Clinical Global Impression–Change score, and the secondary outcome measure was change in symptom severity using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease–Rating Scale (QUIP-RS) ICD score. Results: Forty-five patients (90%) completed the study. The Clinical Global Impression–Change response rate difference favoring naltrexone in completers was 19.8% (95% confidence interval [CI] −8.7% to 44.2%). While this difference was not significant (odds ratio = 1.6, 95% CI 0.5–5.2, Wald χ2 [df] = 0.5 [1], p = 0.5), naltrexone treatment led to a significantly greater decrease in QUIP-RS ICD score over time compared with placebo (regression coefficient for interaction term in linear mixed-effects model = −7.37, F[df] = 4.3 [1, 49], p = 0.04). The estimated changes in QUIP-RS ICD scores from baseline to week 8 were 14.9 points (95% CI 9.9–19.9) for naltrexone and 7.5 points (95% CI 2.5–12.6) for placebo. Conclusions: Naltrexone treatment was not efficacious for the treatment of ICDs in PD using a global assessment of response, but findings using a PD-specific ICD rating scale support further evaluation of opioid antagonists for the treatment of ICD symptoms in PD. Classification of evidence: This study provides Class I evidence that in patients with PD and an ICD, naltrexone does not significantly increase the probability of achieving response. However, the study lacked the precision to exclude an important difference in response rates. PMID

  18. Lyophilized sustained release mucoadhesive chitosan sponges for buccal buspirone hydrochloride delivery: formulation and in vitro evaluation.

    PubMed

    Kassem, Mohamed A A; ElMeshad, Aliaa N; Fares, Ahmed R

    2015-06-01

    This work aims to prepare sustained release buccal mucoadhesive lyophilized chitosan sponges of buspirone hydrochloride (BH) to improve its systemic bioavailability. Chitosan sponges were prepared using simple casting/freeze-drying technique according to 3(2) factorial design where chitosan grade was set at three levels (low, medium, and high molecular weight), and concentration of chitosan solution at three levels (0.5, 1, and 2%). Mucoadhesion force, ex vivo mucoadhesion time, percent BH released after 8 h (Q8h), and time for release of 50% BH (T50%) were chosen as dependent variables. Additional BH cup and core buccal chitosan sponge were prepared to achieve uni-directional BH release toward the buccal mucosa. Sponges were evaluated in terms of drug content, surface pH, scanning electron microscopy, swelling index, mucoadhesion strength, ex vivo mucoadhesion time, and in vitro drug release. Cup and core sponge (HCH 0.5E) were able to adhere to the buccal mucosa for 8 h. It showed Q8h of 68.89% and exhibited a uni-directional drug release profile following Higuchi diffusion model.

  19. Naltrexone for the treatment of comorbid tobacco and pornography addiction.

    PubMed

    Capurso, Noah A

    2017-03-01

    Co-occurring addictive disorders are common, however treatment strategies for this population have not been extensively studied. This is especially the case for behavioral addictions. We present a patient (N = 1) with tobacco use disorder and problematic pornography use treated with naltrexone. Naltrexone treatment resulted in a decrease in pornography viewing and cigarette smoking, however had the adverse effect of anhedonia. A lower dose modestly impacted pornography viewing but not smoking. Relevant literature regarding co-occurring addictions as well as use of naltrexone is reviewed. This report represents the first case of tobacco and pornography co-addiction in the literature and supports the assertion that treatment of one addictive disorder can benefit another in the dually addicted patient. The efficacy of naltrexone for smoking is notable as previous studies of naltrexone in smoking have been disappointing. This case suggests future treatment strategies for comorbid addictions. (Am J Addict 2017;26:115-117). © 2017 American Academy of Addiction Psychiatry.

  20. A randomized, double-blind, parallel-group, multicenter, placebo-controlled study of the safety and efficacy of extended-release guaifenesin/pseudoephedrine hydrochloride for symptom relief as an adjunctive therapy to antibiotic treatment of acute respiratory infections.

    PubMed

    LaForce, Craig; Gentile, Deborah A; Skoner, David P

    2008-07-01

    This study assessed the efficacy and safety of guaifenesin 600 mg and pseudoephedrine hydrochloride 60 mg extended-release bilayer tablets in providing relief of acute respiratory symptoms when used as an adjunct to antibiotics in patients with an acute respiratory infection (ARI). Adult patients experiencing symptoms of ARI and meeting the physician's usual diagnostic criteria for oral antibiotic treatment were prescribed an antibiotic and randomized to adjunctive guaifenesin/pseudoephedrine hydrochloride or matching placebo twice daily for 7 days. Patients completed symptom diaries and treatment assessments twice daily and attended office visits on Days 4 and 8. The safety/intent-to-treat (ITT) population analysis included 601 patients (guaifenesin/pseudoephedrine, n = 303; placebo, n = 298). Mean symptom scores were lower with guaifenesin/pseudoephedrine from Day 3 for every symptom assessed, with statistically significant improvements in total symptom score from Day 3 (P = 0.026). The greatest effects of treatment with guaifenesin/pseudoephedrine were observed for nasal congestion and sinus headache. Time to overall relief was shorter with guaifenesin/pseudoephedrine (P = 0.038). Significantly more patients reported "the medication was helping during the day" on Day 2 with guaifenesin/pseudoephedrine (P = 0.002). Patient assessments of symptom relief showed a significant preference for guaifenesin/pseudoephedrine versus placebo (P = 0.021). Treatment with guaifenesin/pseudoephedrine was well tolerated. Insomnia (2.6%), nausea (2.3%), and headache (1.3%) were the most common treatment-related adverse effects. As adjunctive therapy for symptom relief for patients taking antibiotics for ARIs, guaifenesin/pseudoephedrine shortened time to relief and improved bothersome respiratory symptoms better than placebo, with greatest effects seen for nasal congestion and sinus headache.

  1. Gemcitabine Hydrochloride-Loaded Functionalised Carbon Nanotubes as Potential Carriers for Tumour Targeting

    PubMed Central

    Das, Shilpee; Desai, Jagruti L.; Thakkar, Hetal P.

    2013-01-01

    The objective of the present work was to formulate gemcitabine hydrochloride loaded functionalised carbon nanotubes to achieve tumour targeted drug release and thereby reducing gemcitabine hydrochloride toxicity. Multiwalled carbon nanotubes were functionalised using 1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000. Optimised ratio 1:2 of carbon nanotubes:1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000 was taken for loading of gemcitabine hydrochloride. The formulation was evaluated for different parameters. The results showed that maximum drug loading efficiency achieved was 41.59% with an average particle size of 188.7 nm and zeta potential of −10−1 mV. Scanning electron microscopy and transmission electron microscopy images confirmed the tubular structure of the formulation. The carbon nanotubes were able to release gemcitabine hydrochloride faster in acidic pH than at neutral pH indicating its potential for tumour targeting. Gemcitabine hydrochloride release from carbon nanotubes was found to follow Korsmeyer-Peppas kinetic model with non-Fickian diffusion pattern. Cytotoxic activity of formulation on A549 cells was found to be higher in comparison to free gemcitabine hydrochloride. Stability studies indicated that lyophilised samples of the formulation were more stable for 3 months under refrigerated condition than at room temperature. Thus carbon nanotubes can be promising carrier for the anticancer drug gemcitabine hydrochloride. PMID:24591746

  2. Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-Naltrexone on incubation of heroin craving

    PubMed Central

    Theberge, Florence R.; Li, Xuan; Kambhampati, Sarita; Pickens, Charles L.; St. Laurent, Robyn; Bossert, Jennifer M.; Baumann, Michael H.; Hutchinson, Mark R.; Rice, Kenner C.; Watkins, Linda R.; Shaham, Yavin

    2013-01-01

    Background Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. Here we determined the effect of the TLR4 antagonist (+)-naltrexone (a μ-opioid receptor inactive isomer) on the time-dependent increases in cue-induced heroin seeking after withdrawal (incubation of heroin craving). Methods In an initial experiment, we trained rats for 9 h/day to self-administer heroin (0.1 mg/kg/infusion) for 9 days; lever presses were paired with a 5-sec tone-light cue. We then assessed cue-induced heroin seeking in 30-min extinction sessions on withdrawal day 1; immediately after testing, we surgically implanted rats with Alzet minipumps delivering (+)-naltrexone (0, 7.5, 15, 30 mg/kg/day, s.c.) for 14 days. We then tested the rats for incubated cue-induced heroin seeking in 3-h extinction tests on withdrawal day 13. Results We found that chronic delivery of (+)-naltrexone via minipumps during the withdrawal phase decreased incubated cue-induced heroin seeking. In follow-up experiments, we found that acute injections of (+)-naltrexone immediately before withdrawal day 13 extinction test had no effect on incubated cue-induced heroin seeking. Furthermore, chronic delivery of (+)-naltrexone (15 or 30 mg/kg/day) or acute systemic injections (15 or 30 mg/kg) had no effect on ongoing extended access heroin self-administration. Finally, in rats trained to self-administer methamphetamine (0.1 mg/kg/infusion, 9 h/d, 9 days), chronic delivery of (+)-naltrexone (30 mg/kg/day) during the withdrawal phase had no effect on incubated cue-induced methamphetamine seeking. Conclusions The present results suggest a critical role of TLR4 in the development of incubation of heroin, but not methamphetamine, craving. PMID:23384483

  3. Elucidation of release characteristics of highly soluble drug trimetazidine hydrochloride from chitosan-carrageenan matrix tablets.

    PubMed

    Li, Liang; Wang, Linlin; Shao, Yang; Tian, Ye; Li, Conghao; Li, Ying; Mao, Shirui

    2013-08-01

    The aim of this study was to better understand the underlying drug release characteristics from matrix tablets based on the combination of chitosan (CS) and different types of carrageenans [kappa (κ)-CG, iota (ι)-CG, and lambda (λ)-CG]. Highly soluble trimetazidine hydrochloride (TH) was used as a model drug. First, characteristics of drug release from different formulations were investigated, and then in situ complexation capacity of CG with TH and CS was studied by differential scanning calorimetry and Fourier transform infrared spectroscopy. Erosion and swelling of matrix were also characterized to better understand the drug-release mechanisms. Effects of pH and ionic strength on drug release were also studied. It was found that not only ι-CG and λ-CG could reduce the burst release of TH by the effect of TH-CG interaction, CS-ι-CG- and CS-λ-CG-based polyelectrolyte film could further modify the controlled-release behavior, but not CS-κ-CG. High pH and high ionic strength resulted in faster drug release from CS-κ-CG- and CS-ι-CG-based matrix, but drug release from CS-λ-CG-based matrix was less sensitive to pH and ionic strength. In conclusion, CS-λ-CG-based matrix tablets are quite promising as controlled-release drug carrier based on multiple mechanisms. Copyright © 2013 Wiley Periodicals, Inc.

  4. Aspirin and Extended-Release Dipyridamole

    MedlinePlus

    The combination of aspirin and extended-release dipyridamole is in a class of drugs called antiplatelet agents. It works by preventing excessive blood clotting. It is used to reduce the risk of stroke in patients who have had or ...

  5. Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illness

    DTIC Science & Technology

    2013-07-01

    AD_________________ Award Number: W81XWH-09-2-0065 TITLE: Trial of Naltrexone and Dextromethorphan ...AND SUBTITLE 5a. CONTRACT NUMBER Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illness 5b. GRANT NUMBER W81XWH-09-2-0065 5c...Sciences has demonstrated that Morphine-related analogs, including Naltrexone and Dextromethorphan , have great potency in anti-inflammation and

  6. Trial of Naltrexone and Dextromethorphan for Gulf War Veterans Illnesses

    DTIC Science & Technology

    2011-07-01

    W81XWH-09-2-0065 TITLE: Trial of Naltrexone and Dextromethorphan for Gulf War Veterans Illnesses PRINCIPAL INVESTIGATOR: William J. Meggs, MD...2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illness 5b. GRANT NUMBER W81XWH-09...that many with Gulf War Illness could enter either the naltrexone or dextromethorphan arm but not both. We are applying to allow subjects to enter

  7. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial

    PubMed Central

    Lee, Joshua D; Nunes, Edward V; Novo, Patricia; Bachrach, Ken; Bailey, Genie L; Bhatt, Snehal; Farkas, Sarah; Fishman, Marc; Gauthier, Phoebe; Hodgkins, Candace C; King, Jacquie; Lindblad, Robert; Liu, David; Matthews, Abigail G; May, Jeanine; Peavy, K Michelle; Ross, Stephen; Salazar, Dagmar; Schkolnik, Paul; Shmueli-Blumberg, Dikla; Stablein, Don; Subramaniam, Geetha; Rotrosen, John

    2018-01-01

    Summary Background Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX. Methods We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433. Findings Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10–1·68), most or all of this

  8. Diffusion of naltrexone across reconstituted human oral epithelium and histomorphological features.

    PubMed

    Giannola, Libero Italo; De Caro, Viviana; Giandalia, Giulia; Siragusa, Maria Gabriella; Campisi, Giuseppina; Florena, Ada Maria; Ciach, Tomasz

    2007-02-01

    In transbuccal absorption a major limitation could be the low permeability of the mucosa which implies low drug bioavailability. The ability of naltrexone hydrochloride (NLX) to penetrate a resembling histologically human buccal mucosa was assessed and the occurrence of any histomorphological changes observed. We used reconstituted human oral (RHO) non-keratinised epithelium as mucosal section and a Transwell diffusion cells system as bicompartmental model. Buccal permeation was expressed in terms of drug flux (J(s)) and permeability coefficients (K(p)). Data were collected using both artificial and natural human saliva. The main finding was that RHO does not restrain NLX permeation. Drug transport across the epithelium was observed also in presence of various concentrations of penetration enhancers, without any significant differences. On the contrary, the flux throughout the mucosa was extensively affected by iontophoresis. Histologically, no sign of flogosis was observed in any specimen under experiment without iontophoresis, whereas cytoarchitectural changes, up to nuclear pycnosis or cellular swelling, were determined as a consequence of the application of electric fields.

  9. Employment-based reinforcement of adherence to oral naltrexone treatment in unemployed injection drug users.

    PubMed

    Dunn, Kelly E; Defulio, Anthony; Everly, Jeffrey J; Donlin, Wendy D; Aklin, Will M; Nuzzo, Paul A; Leoutsakos, Jeannie-Marie S; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E; Silverman, Kenneth

    2013-02-01

    Oral naltrexone has high potential for use as a relapse prevention pharmacotherapy for opiate dependence yet suffers from notoriously poor adherence. This study evaluated whether entry to a therapeutic workplace could reinforce adherence with oral naltrexone. Opiate-dependent and cocaine-using injection drug users were detoxified, inducted onto oral naltrexone, and randomly assigned to a contingency (n = 35) or prescription (n = 32) group for a 26-week period. Contingency participants were required to ingest naltrexone under staff observation to gain access to the therapeutic workplace. Prescription participants received a take-home supply of naltrexone and could access the workplace independent of naltrexone ingestion. Primary outcome measures were percent of urine samples positive for naltrexone at 30-day assessments and negative for opiates and cocaine at 30-day assessments. Contingency participants provided significantly more urine samples that were positive for naltrexone compared with prescription participants (72% vs. 21%, p < .01); however, no effect of experimental group was observed on percent opiate-negative (71% vs. 60%, p = .19.) or cocaine-negative (56% vs. 53%, p = .82) samples in the contingency and prescription groups, respectively. Opiate-positive samples were significantly more likely to occur in conjunction with cocaine (p < .001) and when not protected by naltrexone (p < .02), independent of experimental group. Overall, these results show that contingent access to a therapeutic workplace significantly promoted adherence to oral naltrexone, and that the majority of opiate use occurred in conjunction with cocaine use, suggesting that untreated cocaine use may limit the effectiveness of oral naltrexone in promoting opiate abstinence. (c) 2013 APA, all rights reserved.

  10. Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illness

    DTIC Science & Technology

    2012-07-01

    AD_________________ Award Number: W81XWH-09-2-0065 TITLE: Trial of Naltrexone and Dextromethorphan ...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illness 5b. GRANT NUMBER W81XWH-09-2-0065...ABSTRACT Approval to separate the study into a separate dextromethorphan arm and naltrexone arm from the Department of Defense Institutional Review

  11. Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illness

    DTIC Science & Technology

    2010-07-01

    09-2-0065 TITLE: Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illness PRINCIPAL INVESTIGATOR: William Joel Meggs, MD, PhD...From - To) 1 JUL 2009 - 30 JUN 2010 4. TITLE AND SUBTITLE Trial of Naltrexone and Dextromethorphan for Gulf War Veteravns’ Illness 5a... dextromethorphan & naltrexone for gulf war illness. 15. SUBJECT TERMS Dextromethorphan , naltexone, gulf war illness 16. SECURITY CLASSIFICATION OF

  12. Novel Treatment Using Low-Dose Naltrexone for Lichen Planopilaris.

    PubMed

    Strazzulla, Lauren C; Avila, Lorena; Lo Sicco, Kristen; Shapiro, Jerry

    2017-11-01

    Lichen planopilaris (LPP) is a variant of lichen planus that affects the scalp causing scarring hair loss. Patients also frequently experience symptoms of scalp itch, pain, and burning. To date, there are no long-term remittive nor curative therapies available. Low-dose naltrexone has anti-inflammatory properties and has recently been described in the context of treating autoimmune conditions. This retrospective medical record review describes four LPP patients treated with low-dose (3 milligrams per day) naltrexone. This medication provided benefit in these four patients including reduction in symptoms of pruritus, clinical evidence of inflammation of the scalp, and disease progression. All patients tolerated naltrexone without adverse effects. This is the first case series demonstrating the beneficial effects of low-dose naltrexone for patients with LPP. This medication was well-tolerated by the patients and is cost-effective.

    J Drugs Dermatol. 2017;16(11):1140-1142.

    .

  13. Multimodal nanoporous silica nanoparticles functionalized with aminopropyl groups for improving loading and controlled release of doxorubicin hydrochloride.

    PubMed

    Wang, Xin; Li, Chang; Fan, Na; Li, Jing; He, Zhonggui; Sun, Jin

    2017-09-01

    The purpose of this study was to develop amino modified multimodal nanoporous silica nanoparticles (M-NSNs-NH 2 ) loaded with doxorubicin hydrochloride (DOX), intended to enhance the drug loading capacity and to achieve controlled release effect. M-NSNs were functionalized with aminopropyl groups through post-synthesis. The contribution of large pore sizes and surface chemical groups on DOX loading and release were systemically studied using transmission electron microscope (TEM), nitrogen adsorption/desorption measurement, Fourier transform infrared spectroscopy (FTIR), zeta potential analysis, X-ray photoelectron spectroscopy (XPS) and ultraviolet spectrophotometer (UV). The results demonstrated that the NSNs were functionalized with aminopropyl successfully and the DOX molecules were adsorbed inside the nanopores by the hydrogen bonding. The release performance indicated that DOX loaded M-NSNs significantly controlled DOX release, furthermore DOX loaded M-NSNs-NH 2 performed slower controlled release, which was mainly attributed to its stronger hydrogen bonding forces. As expected, we developed a novel carrier with high drug loading capacity and controlled release for DOX. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Design and in vitro/in vivo evaluation of sustained-release floating tablets of itopride hydrochloride.

    PubMed

    Ahmed, Sayed M; Ahmed Ali, Adel; Ali, Ahmed Ma; Hassan, Omiya A

    2016-01-01

    The aim of the present study was to improve the bioavailability of itopride (ITO) and sustain its action by formulating as a floating dosage form. Sustained-release floating tablets of ITO hydrochloride (HCl) were prepared by direct compression using different hydrocolloid polymers such as hydroxypropyl methylcellulose and ethylcellulose and/or methacrylic acid polymers Eudragit RSPM and Carbopol 934P. The floating property was achieved using an effervescent mixture of sodium bicarbonate and anhydrous citric acid (1:1 mol/mol). Hardness, friability, content uniformity, and dissolution rate of the prepared floating tablets were evaluated. The formulation F 10 composed of 28.5% Eudragit RSPM, 3% NaHCO 3 , and 7% citric acid provided sustained drug release. In vitro results showed sustained release of F 10 where the drug release percentage was 96.51%±1.75% after 24 hours ( P =0.031). The pharmacokinetic results indicated that the area under the curve (AUC 0-∞ ) of the prepared sustained-release floating tablets at infinity achieved 93.69 µg·h/mL compared to 49.89 µg·h/mL for the reference formulation (Ganaton ® ) and the relative bioavailability of the sustained-release formulation F 10 increased to 187.80% ( P =0.022). The prepared floating tablets of ITO HCl (F 10 ) could be a promising drug delivery system with sustained-release action and enhanced drug bioavailability.

  15. Employment-Based Reinforcement of Adherence to Oral Naltrexone Treatment in Unemployed Injection Drug Users

    PubMed Central

    Dunn, Kelly; Defulio, Anthony; Everly, Jeffrey J.; Donlin, Wendy D.; Aklin, Will M.; Nuzzo, Paul A.; Leoutsakos, Jeannie-Marie S.; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E.; Silverman, Kenneth

    2013-01-01

    Naltrexone has high potential for use as a relapse prevention pharmacotherapy for opiate dependence; however suffers from notoriously poor adherence when prescribed for oral self-administration. This study evaluated whether entry to a therapeutic workplace could be used to reinforce adherence with oral naltrexone. Opiate-dependent and cocaine-using injection drug users were detoxified, inducted onto oral naltrexone, and randomly assigned to a Contingency (n=35) or Prescription (n=32) group for a 26-week period. Contingency participants were required to ingest naltrexone under staff observation to gain access to the therapeutic workplace. Prescription participants received a take-home supply of naltrexone and could access the workplace independent of naltrexone ingestion. Primary outcome measures were percent of urine samples positive for naltrexone at 30-day assessments and negative for opiates and cocaine at 30-day assessments. Contingency participants provided significantly more urine samples that were positive for naltrexone compared to Prescription participants (72% vs. 21%, P<.01), however no effect of experimental group was observed on percent opiate-negative (71% vs. 60%, P=.19.) or cocaine-negative (56% vs. 53%, P=.82) samples in the Contingency and Prescription groups, respectively. Opiate-positive samples were significantly more likely to occur in conjunction with cocaine (P<.001), and when not protected by naltrexone (P<.02), independent of experimental group. Overall, these results show that contingent access to a therapeutic workplace significantly promoted adherence to oral naltrexone, and that the majority of opiate use occurred in conjunction with cocaine use, suggesting that untreated cocaine use may limit the effectiveness of oral naltrexone in promoting opiate abstinence. PMID:23205722

  16. Influence of dissolution media pH and USP1 basket speed on erosion and disintegration characteristics of immediate release metformin hydrochloride tablets.

    PubMed

    Desai, Divyakant; Wong, Benjamin; Huang, Yande; Tang, Dan; Hemenway, Jeffrey; Paruchuri, Srinivasa; Guo, Hang; Hsieh, Daniel; Timmins, Peter

    2015-01-01

    To investigate the influence of the pH of the dissolution medium on immediate release 850 mg metformin hydrochloride tablets. A traditional wet granulation method was used to manufacture metformin hydrochloride tablets with or without a disintegrant. Tablet dissolution was conducted using the USP apparatus I at 100 rpm. In spite of its pH-independent high solubility, metformin hydrochloride tablets dissolved significantly slower in 0.1 N HCl (pH 1.2) and 50 mM pH 4.5 acetate buffer compared with 50 mM pH 6.8 phosphate buffer, the dissolution medium in the USP. Metformin hydrochloride API compressed into a round 1200 mg disk showed a similar trend. When basket rotation speed was increased from 100 to 250 rpm, the dissolution of metformin hydrochloride tablets was similar in all three media. Incorporation of 2% w/w crospovidone in the tablet formulation improved the dissolution although the pH-dependent trend was still evident, but incorporation of 2% w/w croscarmellose sodium resulted in rapid pH-independent tablet dissolution. In absence of a disintegrant in the tablet formulation, the dissolution was governed by the erosion-diffusion process. Even for a highly soluble drug, a super-disintegrant was needed in the formulation to overcome the diffusion layer limitation and change the dissolution mechanism from erosion-diffusion to disintegration.

  17. Naltrexone Reverses Ethanol Preference and Protein Kinase C Activation in Drosophila melanogaster

    PubMed Central

    Koyyada, Rajeswari; Latchooman, Nilesh; Jonaitis, Julius; Ayoub, Samir S.; Corcoran, Olivia; Casalotti, Stefano O.

    2018-01-01

    Alcohol use disorder (AUD) is a major health, social and economic problem for which there are few effective treatments. The opiate antagonist naltrexone is currently prescribed clinically with mixed success. We have used naltrexone in an established behavioral assay (CAFE) in Drosophila melanogaster that measures the flies' preference for ethanol-containing food. We have confirmed that Drosophila exposed to ethanol develop a preference toward this drug and we demonstrate that naltrexone, in a dose dependant manner, reverses the ethanol-induced ethanol preference. This effect is not permanent, as preference for alcohol returns after discontinuing naltrexone. Additionally, naltrexone reduced the alcohol-induced increase in protein kinase C activity. These findings are of interest because they confirm that Drosophila is a useful model for studying human responses to addictive drugs. Additionally because of the lack of a closely conserved opiate system in insects, our results could either indicate that a functionally related system does exist in insects or that in insects, and potentially also in mammals, naltrexone binds to alternative sites. Identifying such sites could lead to improved treatment strategies for AUD. PMID:29593550

  18. Naltrexone in organic bulimia: a preliminary report.

    PubMed

    Childs, A

    1987-01-01

    Multiple lines of experimental evidence point to the involvement of endogenous opiates in appetite regulation. Post brain injury patients often exhibit driven eating behaviour. Since this problem fails to respond to behaviour modification, appetite suppressants, lithium, or any other usual approach, the use of the oral narcotic antagonist, Naltrexone, was given to three such patients. Naltrexone binds multiple opiate receptor sites in the hypothalamus, including the kappa receptors which have been implicated in appetite regulation, the use of this narcotic antagonist in hypothalamic hyperphagia appears to be a rational approach to this intractable problem. In this open trial, lasting from 4 1/2 to 9 months, the minimal effective dose appeared to be in the range of 100 mg per day. No side-effects (for example elevations in liver enzymes) were noted. All of the patients had an improved sense of well-being and their behaviours were less difficult to manage when on the Naltrexone. The significance of this preliminary trial is that narcotic antagonists may have a role in the treatment of brain-injured patients with bulimia. Also, Naltrexone may be useful in treating other maladaptive behavioural consequences of head trauma such as stealing, manipulation, demandingness, and depression. Likewise, the effects on the deranged endocrine system, such as the hypogonadism, are significant and deserve further exploration.

  19. Pharmacodynamic Profile of Tramadol in Humans: Influence of Naltrexone Pretreatment

    PubMed Central

    Stoops, William W.; Lofwall, Michelle R.; Nuzzo, Paul A.; Craig, Lori B.; Siegel, Anthony J.; Walsh, Sharon L.

    2012-01-01

    Rationale Tramadol is a prescription analgesic that activates mu opioid and monoamine receptor systems. Tramadol is thought to have limited abuse potential compared to mu opioid agonists, but laboratory data indicate that it shares some of their pharmacodynamic effects. Objectives This study evaluated the effect of mu opioid receptor blockade with naltrexone on the pharmacodynamic action of tramadol in humans. Methods This inpatient, double-blind, randomized, within-subject study examined the effects of oral placebo, tramadol (87.5, 175 and 350 mg) and hydromorphone (4 and 16 mg; positive control) after 1 hr pretreatment with oral naltrexone (0 and 50 mg). Ten recreational opioid users completed the study. Pharmacodynamic effects were measured before and for 7 hr after initial drug administration. Results Lower doses of tramadol and hydromorphone were generally placebo-like. Hydromorphone (16 mg) produced prototypic mu opioid agonist-like effects that were blocked by naltrexone. Tramadol (350 mg) produced miosis and increased ratings of “Good Effects” and “Liking ,” but also increased ratings of “Bad Effects.” Naltrexone reversed tramadol-induced physiological effects and mydriasis emerged, but unlike results with hydromorphone, naltrexone only partially attenuated tramadol’s positive subjective effects and actually enhanced several unpleasant subjective ratings. Conclusions Naltrexone can be used to disentangle the mixed neuropharmacological actions of tramadol. High dose tramadol produces a mixed profile of effects. These data suggest that both mu and non-mu opioid actions play a role in tramadol’s subjective profile of action. PMID:22623016

  20. Role of Bupropion Plus Naltrexone for the Management of Obesity

    PubMed Central

    Booth, Kemper; Clements, Jennifer N.

    2016-01-01

    Objective. The pharmacology, pharmacokinetics, efficacy, and safety of bupropion plus naltrexone for weight loss were reviewed. Data Sources. A MEDLINE search (1970 to November 2015) was conducted for English-language articles using specific MESH terms. Study Selection and Data Extraction. Published Phase 3 clinical trials with primary endpoints related to weight loss were included and critiqued in this review. Study Selection and Data Extraction. Five trials were retrieved and reviewed regarding the efficacy and safety of bupropion plus naltrexone among obese and overweight patients. Data Synthesis. Bupropion is a dopamine/norepinephrine reuptake inhibitor, and naltrexone is an opioid receptor antagonist. The combination of these agents has led to increased weight loss, compared to placebo, among overweight and obese patients with a body mass index (BMI) at or above 30 or BMI at or above 27 with a comorbid condition. The combination of bupropion and naltrexone can produce an average placebo-subtracted weight loss of 4.25% over 56 weeks. Gastrointestinal (ie, nausea, vomiting, constipation) and central nervous system adverse events (ie, headache, dizziness) were commonly reported, and there was a high dropout rate among participants. Conclusions. Bupropion plus naltrexone has demonstrated effective weight loss, in conjunction with lifestyle modifications, among overweight and obese patients with and without comorbidities. Bupropion plus naltrexone has not been studied among special patient populations, such as those with sleep apnea, osteoarthritis, or extreme BMIs. Additional clinical trials and postmarketing data will provide a better understanding of this medication for weight loss.

  1. The effect of excipients on the release kinetics of diclofenac sodium and papaverine hydrochloride from composed tablets.

    PubMed

    Kasperek, Regina; Trebacz, Hanna; Zimmer, Łukasz; Poleszak, Ewa

    2014-01-01

    For increased analgesic effect, new composed tablets containing diclofenac sodium (DIC) with an addition of papaverine hydrochloride (PAP) were prepared to investigate the mechanism of release of the active substances from tablets with different excipients in eight different formulations. To detect the possible interactions between active substances and excipients differential scanning calorimetry (DSC) was used. A shift of the melting point and enthalpy values of the physical mixtures of tablets components suggested a kind of interaction between components in certain formulations, however, the tabletting process was not disturbed in any of them. Kinetics of drug release from formulations was estimated by zero order, first order and Higuchi and Korsmeyer-Peppas models using results of dissolution of DIC and PAP from tablets. The study revealed that the mechanism of release of active substances was dependent on the excipients contained in tablets and the best fitted kinetics models were obtained for formulations with potentially prolonged release of DIC and PAP.

  2. Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illnesses

    DTIC Science & Technology

    2014-07-01

    09-2-0065 TITLE: Trial of Naltrexone and Dextromethorphan for Gulf War Veterans Illnesses PRINCIPAL INVESTIGATOR: William J. Meggs, MD, PhD... Dextromethorphan and Naltrexone for Gulf War Veterens’ Illness 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-09-2-0065 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR...neuron-inflammation, which can be down regulated, by Naltrexone and Dextromethorphan . This is untested but potentially ground breaking concept that

  3. PLGA Biodegradable Nanoparticles Containing Perphenazine or Chlorpromazine Hydrochloride: Effect of Formulation and Release

    PubMed Central

    Halayqa, Mohammed; Domańska, Urszula

    2014-01-01

    In our study, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles loaded with perphenazine (PPH) and chlorpromazine hydrochloride (CPZ-HCl) were formulated by emulsion solvent evaporation technique. The effect of various processing variables, including PLGA concentration, theoretical drug loading, poly(vinyl alcohol) (PVA) concentration and the power of sonication were assessed systematically to obtain higher encapsulation efficiency and to minimize the nanoparticles size. By the optimization formulation process, the nanoparticles were obtained in submicron size from 325.5 ± 32.4 to 374.3 ± 10.1 nm for nanoparticles loaded with PPH and CPZ-HCl, respectively. Nanoparticles observed by scanning electron microscopy (SEM) presented smooth surface and spherical shape. The encapsulation efficiency of nanoparticles loaded with PPH and CPZ-HCl were 83.9% and 71.0%, respectively. The drug loading were 51.1% and 39.4% for PPH and CPZ-HCl, respectively. Lyophilized nanoparticles with different PLGA concentration 0.8%, 1.3% and 1.6% (w/v) in formulation process were evaluated for in vitro release in phosphate buffered saline (pH = 7.4) by using dialysis bags. The release profile for both drugs have shown that the rate of PPH and CPZ-HCl release were dependent on a size and amount of drugs in the nanoparticles. PMID:25535080

  4. PLGA biodegradable nanoparticles containing perphenazine or chlorpromazine hydrochloride: effect of formulation and release.

    PubMed

    Halayqa, Mohammed; Domańska, Urszula

    2014-12-22

    In our study, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles loaded with perphenazine (PPH) and chlorpromazine hydrochloride (CPZ-HCl) were formulated by emulsion solvent evaporation technique. The effect of various processing variables, including PLGA concentration, theoretical drug loading, poly(vinyl alcohol) (PVA) concentration and the power of sonication were assessed systematically to obtain higher encapsulation efficiency and to minimize the nanoparticles size. By the optimization formulation process, the nanoparticles were obtained in submicron size from 325.5 ± 32.4 to 374.3 ± 10.1 nm for nanoparticles loaded with PPH and CPZ-HCl, respectively. Nanoparticles observed by scanning electron microscopy (SEM) presented smooth surface and spherical shape. The encapsulation efficiency of nanoparticles loaded with PPH and CPZ-HCl were 83.9% and 71.0%, respectively. The drug loading were 51.1% and 39.4% for PPH and CPZ-HCl, respectively. Lyophilized nanoparticles with different PLGA concentration 0.8%, 1.3% and 1.6% (w/v) in formulation process were evaluated for in vitro release in phosphate buffered saline (pH = 7.4) by using dialysis bags. The release profile for both drugs have shown that the rate of PPH and CPZ-HCl release were dependent on a size and amount of drugs in the nanoparticles.

  5. Formulation and Evaluation of Multilayered Tablets of Pioglitazone Hydrochloride and Metformin Hydrochloride

    PubMed Central

    Chowdary, Y. Ankamma; Raparla, Ramakrishna; Madhuri, Muramshetty

    2014-01-01

    In the treatment of type 2 diabetes mellitus a continuous therapy is required which is a more complex one. As in these patients there may be a defect in both insulin secretion and insulin action exists. Hence, the treatment depends on the pathophysiology and the disease state. In the present study, multilayered tablets of pioglitazone hydrochloride 15 mg and metformin hydrochloride 500 mg were prepared in an attempt for combination therapy for the treatment of type 2 diabetes mellitus. Pioglitazone HCl was formulated as immediate release layer to show immediate action by direct compression method using combination of superdisintegrants, namely, crospovidone and avicel PH 102. Crospovidone at 20% concentration showed good drug release profile at 2 hrs. Metformin HCl was formulated as controlled release layer to prolong the drug action by incorporating hydrophilic polymers such as HPMC K4M by direct compression method and guar gum by wet granulation method in order to sustain the drug release from the tablets and maintain its integrity so as to provide a suitable formulation. The multilayered tablets were prepared after carrying out the optimization of immediate release layer and were evaluated for various precompression and postcompression parameters. Formulation F13 showed 99.97% of pioglitazone release at 2 hrs in 0.1 N HCl and metformin showed 98.81% drug release at 10 hrs of dissolution in 6.8 pH phosphate buffer. The developed formulation is equivalent to innovator product in view of in vitro drug release profile. The results of all these evaluation tests are within the standards. The procedure followed for the formulation of these tablets was found to be reproducible and all the formulations were stable after accelerated stability studies. Hence, multilayered tablets of pioglitazone HCl and metformin HCl can be a better alternative way to conventional dosage forms. PMID:26556204

  6. Low Dose Naltrexone in the Treatment of Fibromyalgia.

    PubMed

    Metyas, Samy K; Yeter, Karen; Solyman, John; Arkfeld, Daniel

    2017-03-21

    Fibromyalgia is a chronic pain disorder characterized by diffuse musculoskeletal pain, fatigue, sleep disturbance and cognitive impairment. A significant number of fibromyalgia patients do not respond adequately to the current drugs (pregabalin, milnacipran, duloxetine) approved for fibromyalgia treatment by the Food and Drug Administration (FDA). Thus, there is still a need for adjunctive therapies. Naltrexone is an opioid receptor antagonist used to treat alcohol and opioid dependence. It is hypothesized that low dose naltrexone causes transient blockade of opioid receptors centrally resulting in a rebound of endorphin function which may attenuate pain in fibromyalgia. Treatment with low dose naltrexone may be an effective, highly tolerable and inexpensive treatment for fibromyalgia. Further controlled trials are needed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Impact of release characteristics of sinomenine hydrochloride dosage forms on its pharmacokinetics in beagle dogs

    PubMed Central

    Sun, Jin; Shi, Jie-Ming; Zhang, Tian-Hong; Gao, Kun; Mao, Jing-Jing; Li, Bing; Sun, Ying-Hua; He, Zhong-Gui

    2005-01-01

    AIM: To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride (SM•HCl) on its pharmacokinetics in beagle dogs. METHODS: The in vitro release behavior of two SM•HCl dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo SM•HCl pharmacokinetics was investigated and compared. RESULTS: The optimal SM•HCl sustained-release formulation was achieved by mixing slow- and rapid-release pellets (9:1, w/w). The SM•HCl release profiles of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs 68.7%. From a pharmacokinetic standpoint, the 24-h SM•HCl sustained-release pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67×0.52 h vs 9.83×0.98 h and the Cmax being 1 334.45±368.76 ng/mL vs 893.12±292.55 ng/mL, respectively. However, the AUC0-tn of two SM•HCl dosage forms was comparable and both preparations were statistically bioequivalent. Furthermore, the two preparations had good correlations between SM•HCl percentage absorption in vivo and the cumulative percentage release in vitro. CONCLUSION: The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves. PMID:16052686

  8. Naltrexone versus acamprosate: one year follow-up of alcohol dependence treatment.

    PubMed

    Rubio, G; Jiménez-Arriero, M A; Ponce, G; Palomo, T

    2001-01-01

    Naltrexone and acamprosate reduce relapse in alcohol dependence. They have not yet been compared in a published trial. The aim of this study was to compare the efficacy of these compounds in conditions similar to those in routine clinical practice. Random allocation to a year of treatment with naltrexone (50 mg/day) or acamprosate (1665-1998 mg/day) was made in 157 recently detoxified alcohol-dependent men with moderate dependence (evaluated using the Addictions Severity Index and Severity of Alcohol Dependence Scale). All were patients whom a member of the family would accompany regularly to appointments. Alcohol consumption, craving and adverse events were recorded weekly for the first 3 months, and then bi-weekly, by the treating psychiatrist who was not blinded. At 3-monthly intervals, investigators who were blinded to the treatment documented patients' alcohol consumption based on patients' accounts, information given by the psychiatrists when necessary, and reports from patients' families. Serum gamma-glutamyltransferase (GGT) was also measured. Efforts were made to sustain the blindness of the investigators. The same investigator did not assess the same patient twice. The integrity of the blindness was not checked. There was no difference between treatments in mean time to first drink (naltrexone 44 days, acamprosate 39 days) but the time to first relapse (five or more drinks in a day) was 63 days (naltrexone) versus 42 days (acamprosate) (P = 0.02). At the end of 1 year, 41% receiving naltrexone and 17% receiving acamprosate had not relapsed (P = 0.0009). The cumulative number of days of abstinence was significantly greater, and the number of drinks consumed at one time and severity of craving were significantly less, in the naltrexone group compared to the acamprosate group, as was the percentage of heavy drinking days (P = 0.038). More patients in the acamprosate than the naltrexone group were commenced on disulfiram during the study. Naltrexone patients

  9. Naltrexone for the treatment of alcoholism: clinical findings, mechanisms of action, and pharmacogenetics.

    PubMed

    Ray, Lara A; Chin, Pauline F; Miotto, Karen

    2010-03-01

    Naltrexone is an opioid receptor antagonist with established efficacy, albeit moderate, for the treatment of alcohol dependence. This manuscript provides a critical review of the literature on naltrexone as a pharmacotherapy for alcoholism by covering the following areas: (a) clinical findings from treatment studies; (b) pharmacokinetics and safety data; (c) medication compliance and persistence; and (d) neurobiological and biobehavioral mechanisms of action of naltrexone for the indication of alcohol dependence. This review will then focus on the emerging literature on naltrexone pharmacogenetics, which has the potential to identify responders on the basis of genetic variation and to use genetic tools to individualize the use of this medication. Limitations and future directions in the research and practice of naltrexone for alcoholism are also outlined.

  10. Naltrexone treatment for opioid dependence: Does its effectiveness depend on testing the blockade?

    PubMed Central

    Sullivan, Maria A.; Bisaga, Adam; Mariani, John J.; Glass, Andrew; Levin, Frances R.; Comer, Sandra D.; Nunes, Edward V.

    2013-01-01

    Background FDA approval of long-acting injectable naltrexone (Vivitrol) for opioid dependence highlights the relevance of understanding mechanisms of antagonist treatment. Principles of learning suggest an antagonist works through extinguishing drug-seeking behavior, as episodes of drug use (“testing the blockade”) fail to produce reinforcement. We hypothesized that opiate use would moderate the effect of naltrexone, specifically, that opiate-positive urines precede dropout in the placebo group, but not in the active-medication groups. Methods An 8-week, double-blind, placebo-controlled trial (N=57), compared the efficacy of low (192-mg) and high (384-mg) doses of a long-acting injectable naltrexone (Depotrex) with placebo (Comer et al., 2006). A Cox proportional hazard model was fit, modeling time-to-dropout as a function of treatment assignment and urine toxicology during treatment. Results Interaction of opiate urines with treatment group was significant. Opiate-positive urines predicted dropout on placebo and low-dose, but less so on high-dose naltrexone, where positive urines were more likely followed by sustained abstinence. Among patients with no opiate-positive urines, retention was higher in both low- and high-dose naltrexone conditions, compared to placebo. Conclusions Findings confirm that injection naltrexone produces extinction of drug-seeking behavior after episodes of opiate use. Adequate dosage appears important, as low-dose naltrexone resembled the placebo group; opiate positive urines were likely to be followed by dropout from treatment. The observation of high treatment retention among naltrexone-treated patients who do not test the blockade, suggests naltrexone may also exert direct effects on opiate-taking behavior that do not depend on extinction, perhaps by attenuating craving or normalizing dysregulated hedonic or neuroendocrine systems. PMID:23827259

  11. Efficacy of Naltrexone for the Treatment of Alcohol Dependence in Latino Populations.

    PubMed

    López, Cristina M; Barr, Simone C; Reid-Quiñones, Kathryn; de Arellano, Michael A

    2017-05-01

    Naltrexone has been identified as a promising psychopharmacological treatment for alcohol dependence. Previous studies have suggested that its efficacy may vary based on ethnic background. The current study examined the efficacy of naltrexone in the treatment of alcohol dependence in Latino adults, a previously unexplored population. This was a secondary analysis of the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. The overall COMBINE sample consisted of 1,383 adult participants who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for alcohol dependence, including 155 Latinos, who are the focus of this report. Consistent with the main trial, primary drinking outcomes, including percentage of days abstinent (PDA) and time to first heavy drinking day (TTHD), were examined. In addition, we examined the effects of naltrexone on a clinically relevant secondary outcome measure, global clinical outcome of alcohol consumption and alcohol-related problems. As seen with the subsample of African Americans from the COMBINE Study, results of the present analysis indicated that there were no significant effects of naltrexone on PDA and TTHD despite these significant effects in the original study. However, contrary to findings in the African American subsample, for Latino participants naltrexone was a significant predictor of a good global clinical outcome (i.e., abstinence or moderate drinking without problems). Naltrexone was not significantly associated with improvements in the primary drinking outcomes of PDA or TTHD at the end of treatment or at follow-up. However, Latinos appeared to benefit from naltrexone as demonstrated by improved ratings of global clinical outcome. These results indicate mixed findings for the efficacy of naltrexone among Latinos in the COMBINE Study.

  12. Synthesis and evaluation of chitosan-graft-poly (2-hydroxyethyl methacrylate-co-itaconic acid) as a drug carrier for controlled release of tramadol hydrochloride

    PubMed Central

    Subramanian, Kaliappa gounder; Vijayakumar, Vediappan

    2011-01-01

    Chitosan-graft-poly (2-hydroxyethyl methacrylate-co-itaconic acid) has been synthesized for different feed ratios of 2-hydroxyethyl methacrylate and itaconic acid and characterized by FT-IR, thermogravimetry and swelling in simulated biological fluids (SBF) and evaluated as a drug carrier with model drug, tramadol hydrochloride (TRM). Grafting decreased the thermal stability of chitosan. FT-IR spectra of tablet did not reveal any molecular level (i.e. at <10 nm scale) drug–polymer interaction. But differential scanning calorimetric studies indicated a probable drug–polymer interaction at a scale >100 nm level. The observed Korsmeyer–Peppas’s power law exponents (0.19–1.21) for the in vitro release profiles of TRM in SBF and other drugs such as 5-fluorouracil (FU), paracetamol (PCM) and vanlafaxine hydrochloride (VNF) with the copolymer carriers revealed an anomalous drug release mechanism. The decreased release rates for the grafted chitosan and the enhanced release rate for the grafts with increasing itaconic acid content in the feed were more likely attributed to the enhanced drug–matrix interaction and polymer–SBF interactions, respectively. The different release profiles of FU, PCM, TRM and VNF with the copolymer matrix are attributed to the different chemical structures of drugs. The above features suggest the graft copolymer’s candidature for use as a promising oral drug delivery system. PMID:23960799

  13. Naltrexone and Cognitive Behavioral Therapy for the Treatment of Alcohol Dependence

    PubMed Central

    Baros, AM; Latham, PK; Anton, RF

    2008-01-01

    Background Sex differences in regards to pharmacotherapy for alcoholism is a topic of concern following publications suggesting naltrexone, one of the longest approved treatments of alcoholism, is not as effective in women as in men. This study was conducted by combining two randomized placebo controlled clinical trials utilizing similar methodologies and personnel in which the data was amalgamated to evaluate sex effects in a reasonable sized sample. Methods 211 alcoholics (57 female; 154 male) were randomized to the naltrexone/CBT or placebo/CBT arm of the two clinical trials analyzed. Baseline variables were examined for differences between sex and treatment groups via analysis of variance (ANOVA) for continuous variable or chi-square test for categorical variables. All initial outcome analysis was conducted under an intent-to-treat analysis plan. Effect sizes for naltrexone over placebo were determined by Cohen’s D (d). Results The effect size of naltrexone over placebo for the following outcome variables was similar in men and women (%days abstinent (PDA) d=0.36, %heavy drinking days (PHDD) d=0.36 and total standard drinks (TSD) d=0.36). Only for men were the differences significant secondary to the larger sample size (PDA p=0.03; PHDD p=0.03; TSD p=0.04). There were a few variables (GGT at wk-12 change from baseline to week-12: men d=0.36, p=0.05; women d=0.20, p=0.45 and drinks per drinking day: men d=0.36, p=0.05; women d=0.28, p=0.34) where the naltrexone effect size for men was greater than women. In women, naltrexone tended to increase continuous abstinent days before a first drink (women d-0.46, p=0.09; men d=0.00, p=0.44). Conclusions The effect size of naltrexone over placebo appeared similar in women and men in our hands suggesting the findings of sex differences in naltrexone response might have to do with sample size and/or endpoint drinking variables rather than any inherent pharmacological or biological differences in response. PMID:18336635

  14. Niosomal encapsulation of ethambutol hydrochloride for increasing its efficacy and safety.

    PubMed

    El-Ridy, Mohammed Shafik; Yehia, Soad Aly; Kassem, Mahfouz Abd-El-Megeid; Mostafa, Dina Mahmoud; Nasr, Essam Amin; Asfour, Marwa Hasanin

    2015-01-01

    Tuberculosis (TB) is a worldwide health concern. In 2011, about 8.7 million new cases developed TB and 1.4 million people died from it. Enhancement of ethambutol hydrochloride activity and safety in treatment of TB through niosomal encapsulation. Niosomes were prepared by the thin-film hydration method. They were characterized, investigated for in vitro release, lung disposition and in vivo biological evaluation. Entrapment efficiency of ethambutol hydrochloride ranged from 12.20% to 25.81%. Zeta potential values inferred stability of neutral and negatively charged formulations. In vitro release was biphasic. Lung targeting was increased by niosomal encapsulation. Biological evaluation revealed superiority of niosomal ethambutol hydrochloride over the free drug. Neutral and negatively charged niosomal vesicles are dispersed homogenously unlike positively charged vesicles. Niosomal encapsulation results in controlled drug release. Niosomal formulations targeted more drugs to mice lungs for a prolonged period of time resulting in: decreased root-specific lung weight, bacterial counts in lung homogenates and optimizing pathological effect on guinea pigs lungs, livers and spleens. Encapsulation of ethambutol hydrochloride in niosomal formulations for the treatment of TB provides higher efficacy and safety compared with the free drug.

  15. Design and in vitro/in vivo evaluation of sustained-release floating tablets of itopride hydrochloride

    PubMed Central

    Ahmed, Sayed M; Ahmed Ali, Adel; Ali, Ahmed MA; Hassan, Omiya A

    2016-01-01

    Purpose The aim of the present study was to improve the bioavailability of itopride (ITO) and sustain its action by formulating as a floating dosage form. Materials and methods Sustained-release floating tablets of ITO hydrochloride (HCl) were prepared by direct compression using different hydrocolloid polymers such as hydroxypropyl methylcellulose and ethylcellulose and/or methacrylic acid polymers Eudragit RSPM and Carbopol 934P. The floating property was achieved using an effervescent mixture of sodium bicarbonate and anhydrous citric acid (1:1 mol/mol). Hardness, friability, content uniformity, and dissolution rate of the prepared floating tablets were evaluated. The formulation F10 composed of 28.5% Eudragit RSPM, 3% NaHCO3, and 7% citric acid provided sustained drug release. Results In vitro results showed sustained release of F10 where the drug release percentage was 96.51%±1.75% after 24 hours (P=0.031). The pharmacokinetic results indicated that the area under the curve (AUC0–∞) of the prepared sustained-release floating tablets at infinity achieved 93.69 µg·h/mL compared to 49.89 µg·h/mL for the reference formulation (Ganaton®) and the relative bioavailability of the sustained-release formulation F10 increased to 187.80% (P=0.022). Conclusion The prepared floating tablets of ITO HCl (F10) could be a promising drug delivery system with sustained-release action and enhanced drug bioavailability. PMID:28008229

  16. Immobilisation of impala (Aepyceros melampus) with a ketamine hydrochloride/medetomidine hydrochloride combination, and reversal with atipamezole hydrochloride.

    PubMed

    Bush, M; Raath, J P; Phillips, L G; Lance, W

    2004-03-01

    A combination of medetomidine hydrochloride (medetomidine) and ketamine hydrochloride (ketamine) was evaluated in 16 boma-confined and 19 free-ranging impalas (Aepyceros melampus) to develop a non-opiate immobilisation protocol. In free-ranging impala a dose of 220 +/- 34 microg/kg medetomidine and 4.4 +/- 0.7 mg/kg ketamine combined with 7500 IU of hyaluronidase induced recumbency within 4.5 +/- 1.5 min, with good muscle relaxation, a stable heart rate and blood pH. PaCO2 was maintained within acceptable ranges. The animals were hypoxic with reduced oxygen saturation and low PaO2 in the presence of an elevated respiration rate, therefore methods for respiratory support are indicated. The depth of sedation was adequate for minor manipulations but additional anaesthesia is indicated for painful manipulations. Immobilisation was reversed by 467 +/- 108 microg/kg atipamezole hydrochloride (atipamezole) intramuscularly, but re-sedation was observed several hours later, possibly due to a low atipamezole:medetomidine ratio of 2:1. Therefore, this immobilisation and reversal protocol would subject impalas to possible predation or conspecific aggression following reversal if they were released into the wild. If the protocol is used on free-ranging impala, an atipamezole:medetomidine ratio of 5:1 should probably be used to prevent re-sedation.

  17. The combination very low-dose naltrexone-clonidine in the management of opioid withdrawal.

    PubMed

    Mannelli, Paolo; Peindl, Kathleen; Wu, Li-Tzy; Patkar, Ashwin A; Gorelick, David A

    2012-05-01

    The management of withdrawal absorbs substantial clinical efforts in opioid dependence (OD). The real challenge lies in improving current pharmacotherapies. Although widely used, clonidine causes problematic adverse effects and does not alleviate important symptoms of opioid withdrawal, alone or in combination with the opioid antagonist naltrexone. Very low-dose naltrexone (VLNTX) has been shown to attenuate withdrawal intensity and noradrenaline release following opioid agonist taper, suggesting a combination with clonidine may result in improved safety and efficacy. We investigated the effects of a VLNTX-clonidine combination in a secondary analysis of data from a double-blind, randomized opioid detoxification trial. Withdrawal symptoms and treatment completion were compared following VLNTX (.125 or .25 mg/day) and clonidine (.1-.2 mg q6h) in 127 individuals with OD undergoing 6-day methadone inpatient taper at a community program. VLNTX was more effective than placebo or clonidine in reducing symptoms and signs of withdrawal. The use of VLNTX in combination with clonidine was associated with attenuated subjective withdrawal compared with each medication alone, favoring detoxification completion in comparison with clonidine or naltrexone placebo. VLNTX/clonidine was effective in reducing symptoms that are both undertreated and well controlled with clonidine treatment and was not associated with significant adverse events compared with other treatments. Preliminary results elucidate neurobiological mechanisms of OD and support the utility of controlled studies on a novel VLNTX + low-dose clonidine combination for the management of opioid withdrawal.

  18. Naltrexone treatment for opioid dependence: does its effectiveness depend on testing the blockade?

    PubMed

    Sullivan, Maria A; Bisaga, Adam; Mariani, John J; Glass, Andrew; Levin, Frances R; Comer, Sandra D; Nunes, Edward V

    2013-11-01

    FDA approval of long-acting injectable naltrexone (Vivitrol) for opioid dependence highlights the relevance of understanding mechanisms of antagonist treatment. Principles of learning suggest an antagonist works through extinguishing drug-seeking behavior, as episodes of drug use ("testing the blockade") fail to produce reinforcement. We hypothesized that opiate use would moderate the effect of naltrexone, specifically, that opiate-positive urines precede dropout in the placebo group, but not in the active-medication groups. An 8-week, double-blind, placebo-controlled trial (N=57), compared the efficacy of low (192 mg) and high (384 mg) doses of a long-acting injectable naltrexone (Depotrex) with placebo (Comer et al., 2006). A Cox proportional hazard model was fit, modeling time-to-dropout as a function of treatment assignment and urine toxicology during treatment. Interaction of opiate urines with treatment group was significant. Opiate-positive urines predicted dropout on placebo and low-dose, but less so on high-dose naltrexone, where positive urines were more likely followed by sustained abstinence. Among patients with no opiate-positive urines, retention was higher in both low- and high-dose naltrexone conditions, compared to placebo. Findings confirm that injection naltrexone produces extinction of drug-seeking behavior after episodes of opiate use. Adequate dosage appears important, as low-dose naltrexone resembled the placebo group; opiate positive urines were likely to be followed by dropout from treatment. The observation of high treatment retention among naltrexone-treated patients who do not test the blockade, suggests naltrexone may also exert direct effects on opiate-taking behavior that do not depend on extinction, perhaps by attenuating craving or normalizing dysregulated hedonic or neuroendocrine systems. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Employment-based Reinforcement of Adherence to Oral Naltrexone in Unemployed Injection Drug Users: 12-month Outcomes

    PubMed Central

    Dunn, Kelly; DeFulio, Anthony; Everly, Jeffrey J.; Donlin, Wendy D.; Aklin, Will M.; Nuzzo, Paul A.; Leoutsakos, Jeannie-Marie S.; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E.; Silverman, Kenneth

    2015-01-01

    Oral naltrexone could be a promising relapse prevention pharmacotherapy for recently detoxified opioid-dependent patients, however interventions are often needed to promote adherence with this treatment approach. We recently conducted a study to evaluate a 26-week employment-based reinforcement intervention of oral naltrexone in unemployed injection drug users (Dunn et al., 2013). Participants were randomly assigned into a Contingency (n=35) group required to ingest naltrexone under staff observation to gain entry into a therapeutic workplace, or a Prescription (n=32) group given a take-home supply of oral naltrexone and access to the workplace without observed ingestion. Monthly urine samples were collected and analyzed for evidence for naltrexone adherence, opioid use, and cocaine use. As previously reported, Contingency participants provided significantly more naltrexone-positive urine samples than Prescription participants during the 26-week intervention period. The goal of this current study is to report the 12-month outcomes, which occurred 6 months after the intervention ended. Results at the 12-month visit showed no between-group differences in naltrexone-positive, opioid-negative, or cocaine-negative urine samples, and no participant self-reported using naltrexone at the follow-up visit. These results show that even after a period of successfully reinforced oral naltrexone adherence longer-term naltrexone use is unlikely to be maintained after reinforcement contingencies are discontinued. PMID:25134047

  20. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study.

    PubMed

    Younger, Jarred; Mackey, Sean

    2009-01-01

    Fibromyalgia is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation. In this pilot clinical trial, we tested the effectiveness of low-dose naltrexone in treating the symptoms of fibromyalgia. Participants completed a single-blind, crossover trial with the following time line: baseline (2 weeks), placebo (2 weeks), drug (8 weeks), and washout (2 weeks). Ten women meeting criteria for fibromyalgia and not taking an opioid medication. Naltrexone, in addition to antagonizing opioid receptors on neurons, also inhibits microglia activity in the central nervous system. At low doses (4.5 mg), naltrexone may inhibit the activity of microglia and reverse central and peripheral inflammation. Participants completed reports of symptom severity everyday, using a handheld computer. In addition, participants visited the lab every 2 weeks for tests of mechanical, heat, and cold pain sensitivity. Low-dose naltrexone reduced fibromyalgia symptoms in the entire cohort, with a greater than 30% reduction of symptoms over placebo. In addition, laboratory visits showed that mechanical and heat pain thresholds were improved by the drug. Side effects (including insomnia and vivid dreams) were rare, and described as minor and transient. Baseline erythrocyte sedimentation rate predicted over 80% of the variance in drug response. Individuals with higher sedimentation rates (indicating general inflammatory processes) had the greatest reduction of symptoms in response to low-dose naltrexone. We conclude that low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia.

  1. [Low dose naltrexone in the treatment of dissociative symptoms].

    PubMed

    Pape, W; Wöller, W

    2015-03-01

    Following the hypothesis that blocking opioid receptors leads to a decline in opiate-modulated dissociative phenomena, experiences with naltrexone as medication for dissociative symptoms have been gained since 1999 (mainly in doses of 25-100 mg/day). In this study patients with severe trauma-related and dissociative disorders were treated with naltrexone in doses of 2-6 mg/day (0.06 mg/kg body weight). The low dose treatment with naltrexone proved to be effective whereby 11 out of 15 patients reported immediate positive effects and 7 described a lasting helpful effect. The majority of patients who felt positive effects reported a clearer perception of both their surroundings and their inner life. Assessment of reality and dealing with it improved as did the perception of their own body and affects as well as self-regulation. The treatment was very low in side effects. Treatment with low-dose naltrexone may be a helpful element in the treatment of patients with complex posttraumatic stress disorder. However, it has to be realized that the decrease of dissociation may lead patients to a not yet resolvable challenge, in as much as dissociation had previously been a necessary mechanism of self-protection.

  2. Naltrexone Maintenance Decreases Cannabis Self-Administration and Subjective Effects in Daily Cannabis Smokers.

    PubMed

    Haney, Margaret; Ramesh, Divya; Glass, Andrew; Pavlicova, Martina; Bedi, Gillinder; Cooper, Ziva D

    2015-10-01

    Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4-6 weeks, assessing cannabis' behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects ('good effect'). Participants in the placebo group had 7.6 times (95% CI: 1.1-51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of 'good effect' in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone's efficacy as a treatment for cannabis use disorder.

  3. High-dose naltrexone therapy for cocaine-alcohol dependence.

    PubMed

    Schmitz, Joy M; Lindsay, Jan A; Green, Charles E; Herin, David V; Stotts, Angela L; Moeller, F Gerard

    2009-01-01

    This randomized, double-blind, placebo-controlled study compared the effects of high-dose (100 mg/d) naltrexone versus placebo in a sample of 87 randomized subjects with both cocaine and alcohol dependence. Medication conditions were crossed with two behavioral therapy platforms that examined whether adding contingency management (CM) that targeted cocaine abstinence would enhance naltrexone effects compared to cognitive behavioral therapy (CBT) without CM. Primary outcome measures for cocaine (urine screens) and alcohol use (timeline followback) were collected thrice-weekly during 12 weeks of treatment. Retention in treatment and medication compliance rates were low. Rates of cocaine use and drinks per day did not differ between treatment groups; however naltrexone did reduce frequency of heavy drinking days, as did CBT without CM. Notably, adding CM to CBT did not enhance treatment outcomes. These weak findings suggest that pharmacological and behavioral interventions that have shown efficacy in the treatment of a single drug dependence disorder may not provide the coverage needed when targeting dual drug dependence.

  4. Epidemiologic and Molecular Pathophysiology of Chronic Opioid Dependence and the Place of Naltrexone Extended-Release Formulations in its Clinical Management

    PubMed Central

    Reece, Albert Stuart

    2012-01-01

    Naltrexone implants and depot injections (NI) are a novel form of treatment for opiate dependence (OD). Major questions relate to their absolute and relative efficacy and safety. Opportunely, six recent clinical trial data from several continents have uniformly provided dramatic evidence of the potent, dose-related and highly significant efficacy of NI, with minimal or manageable accompanying toxicity and safety concerns. The opiate-free lifestyle is attained significantly more often with NI adjusted O.R. = 6.00 (95% C.I. 3.86–9.50), P < 10−10. Other drug use and drug craving are also rapidly reduced. The optimum manner in which to commence NI remains to be established. Of particular relevance is the relative safety of NI compared to the chronic opiate agonists (COA) usually employed, as the long-term toxicity of COA is only just being elucidated. Large population-based studies have found elevated rates of cardiovascular disease, six cancers, liver and respiratory disease, and all-cause mortality in COA. Whilst opiates have been shown to trigger numerous molecular pathways, the most interesting is the demonstration that the opiate morphinan’s nucleus binds to the endotoxin groove of the TLR4-MD2 heterodimer. This has the effect of triggering a low grade endotoxaemic-like state, which over time may account for these protean clinical findings, an effect which is reversed by opiate antagonists. This emerging evidence suggests an exciting new treatment paradigm for OD and a corresponding increase in the role of NI in treatment. PMID:23055738

  5. Naltrexone + bupropion (Mysimba). Too risky for only modest weight loss.

    PubMed

    2015-10-01

    Weight loss and its long-term maintenance are mainly based on dietary measures and regular physical activity. There are currently no weight-loss medications with a favourable harm-benefit balance. Bupropion is chemically related to certain amphetamines, while naltrexone is an opioid receptor antagonist. A fixed-dose combination of these two drugs has received marketing authorisation in the European Union for obese patients and for over-weight patients with other cardiovascular risk factors. In five placebo-controlled, randomised, double-blind trials, the patients, weighing on average between 100 kg and 105 kg (average body mass index 36 kg/m2), the naltrexone + bupropion combination was associated with an average weight loss of a few additional kilograms compared with placebo, after 6 months or one year of treatment. There are no post-trial follow-up data to show whether or not the patients regained their lost weight after treatment discontinuation. One trial including more than 8900 patients examined the effect of the naltrexone + bupropion combination on the freauency of maior cardiovascular events, but poor handling of an interim analysis undermined the validity of the final results. The known adverse effects of bupropion consist of potentially severe neuropsychiatric disorders such as aggressiveness, depression and suicidal ideation, and also allergic reactions, including Stevens-Johnson syndrome. Misuse and excessive consumption have been reported. In trials in obese or overweight patients, the naltrexone + bupropion combination caused sometimes severe neuropsychiatric disorders, including seizures, cognitive impairment, dizziness, anxiety, sleep disorders and psychotic symptoms. In clinical trials, the combination led to an increase in blood pressure compared with placebo, and also an excess of cardiac arrhythmias. About half of patients who took naltrexone + bupropion experienced gastrointestinal disorders such as nausea, vomiting and constipation. The

  6. Naltrexone Maintenance Decreases Cannabis Self-Administration and Subjective Effects in Daily Cannabis Smokers

    PubMed Central

    Haney, Margaret; Ramesh, Divya; Glass, Andrew; Pavlicova, Martina; Bedi, Gillinder; Cooper, Ziva D

    2015-01-01

    Given that cannabis use is increasing in the United States, pharmacological treatment options to treat cannabis use disorder are needed. Opioid antagonists modulate cannabinoid effects and may offer a potential approach to reducing cannabis use. In this double-blind, placebo-controlled human laboratory study, we assessed the effects of naltrexone maintenance on the reinforcing, subjective, psychomotor, and cardiovascular effects of active and inactive cannabis. Nontreatment-seeking, daily cannabis smokers were randomized to receive naltrexone (50 mg: n=18 M and 5 F) or placebo (0 mg; n=26 M and 2 F) capsules for 16 days. Before, during, and after medication maintenance, participants completed 10 laboratory sessions over 4–6 weeks, assessing cannabis' behavioral and cardiovascular effects. Medication compliance was verified by observed capsule administration, plasma naltrexone, and urinary riboflavin. Relative to placebo, maintenance on naltrexone significantly reduced both active cannabis self-administration and its positive subjective effects (‘good effect'). Participants in the placebo group had 7.6 times (95% CI: 1.1–51.8) the odds of self-administering active cannabis compared with the naltrexone group. This attenuation of reinforcing and positive subjective effects also influenced cannabis use in the natural ecology. Naltrexone had intrinsic effects: decreasing ratings of friendliness, food intake, and systolic blood pressure, and increasing spontaneous reports of stomach upset and headache, yet dropout rates were comparable between groups. In summary, we show for the first time that maintenance on naltrexone decreased cannabis self-administration and ratings of ‘good effect' in nontreatment-seeking daily cannabis smokers. Clinical studies in patients motivated to reduce their cannabis use are warranted to evaluate naltrexone's efficacy as a treatment for cannabis use disorder. PMID:25881117

  7. Microparticulate drug delivery system containing tramadol hydrochloride for pain treatment.

    PubMed

    Ciurba, Adriana; Todoran, Nicoleta; Vari, C E; Lazăr, Luminita; Al Hussein, Stela; Hancu, G

    2014-01-01

    The current trend of replacing conventional pharmaceutical forms is justified because most substances administered in this form give fluctuations of therapeutic concentrations and often outside the therapeutic range. In addition, these formulations offer a reduction in the dose or the number of administrations, thus increasing patient compliance. In the experiment, we developed an appropriate technology for the preparation of gelatin microspheres containing tramadol hydrochloride by emulsification/cross-linking method. The formulated microspheres were characterized by product yield, size distribution, encapsulation efficiency and in vitro release of tramadol hydrochloride. Data obtained from in vitro release studies were fitted to various mathematical models to elucidate the transport mechanisms. The kinetic models used were zero-order, first-order, Higuchi Korsmeyer-Peppas and Hopfenberg. Spherical microspheres were obtained, with free-flowing properties. The entrapment efficiency of tramadol hydrochloride in microparticles was 79.91% and product yield -94.92%. As the microsphere size was increased, the entrapment efficiency increased. This was 67.56, 70.03, 79.91% for formulations MT80-250, MT8-500 and, MT250-500. High entrapment efficiency was observed for MT250-500 formulation. The gelatin microspheres had particle sizes ranging from 80 to 500 microm. The drug was released for a period of 12 hours with a maximum release of 96.02%. Of the three proposed formulations, MT250-500 presented desirable properties and optimal characteristics for the therapy of pain. Release of tramadol hydrochloridi was best fitted to Korsmeyer-Peppas equation because the Akaike Information Criterion had the lowest values for this kinetic model. These results suggest the opportunity to influence the therapeutic characteristics of gelatin microspheres to obtain a suitable drug delivery system for the oral administration of tramadol hydrochloride.

  8. Formulation and Evaluation of Tramadol hydrochloride Rectal Suppositories.

    PubMed

    Saleem, M A; Taher, M; Sanaullah, S; Najmuddin, M; Ali, Javed; Humaira, S; Roshan, S

    2008-09-01

    Rectal suppositories of tramadol hydrochloride were prepared using different bases and polymers like PEG, cocoa butter, agar and the effect of different additives on in vitro release of tramadol hydrochloride was studied. The agar-based suppositories were non-disintegrating/non-dissolving, whereas PEGs were disintegrating/dissolving and cocoa butter were melting suppositories. All the prepared suppositories were evaluated for various physical parameters like weight variation, drug content and hardness. The PEG and cocoa butter suppositories were evaluated for macromelting range, disintegration and liquefaction time. In vitro release study was performed by USP type I apparatus. The prepared suppositories were within the permissible range of all physical parameters. In vitro drug release was in the order of PEG>Agar>cocoa butter. Addition of PVP, HPMC in agar suppositories retards the release. The mechanism of drug release was diffusion controlled and follows first order kinetics. The results suggested that blends of PEG of low molecular weight (1000) with high molecular weight (4000 and 6000) in different percentage and agar in 10% w/w as base used to formulate rapid release suppositories. The sustained release suppositories can be prepared by addition of PVP, HPMC in agar-based suppositories and by use of cocoa butter as base.

  9. Single- and Multiple-dose Pharmacokinetics of a Lorcaserin Extended-release Tablet.

    PubMed

    Christopher, Ronald; Morgan, Mike; Ferry, Jim; Rege, Bhaskar; Tang, Yong; Kristensen, Allan; Shanahan, William

    2016-10-01

    Lorcaserin is a serotonin 2C receptor agonist indicated for chronic weight management as an adjunct to diet and exercise. The initial approved formulation is a 10-mg, immediate-release (IR) tablet for administration BID. These studies investigated the single- and multiple-dose pharmacokinetic properties of a new, recently US Food and Drug Administration-approved, extended-release, 20-mg once-daily formulation. We performed 2 separate 2-period, 2-sequence crossover studies in 36 healthy adults: a study comparing the IR formulation to the extended-release formulation under fasting conditions and a study comparing the extended-release formulation under fed and fasted conditions. Compared with lorcaserin IR, the T max after a single dose of lorcaserin extended-release was greater (median, 12 vs 3 hours), and the C max was 26% lower (38.8 vs 52.3 ng/mL). AUC data were bioequivalent for the 2 formulations in both single- and multiple-dose regimens, confirming no formulation effect on lorcaserin bioavailability. In fasted and fed conditions, T max after a single dose was identical (median, 12 hours), but C max was approximately 45% higher in the fed state (mean, 38.5 ng/mL fasted vs 56.1 ng/mL fed). However, at steady state, C max and AUC were determined to be bioequivalent between the fasted and fed states, indicating no clinically relevant food effect on the pharmacokinetic properties of lorcaserin extended-release. The safety profile was consistent between the 2 formulations. Overall, the results indicate that lorcaserin extended-release is a suitable once-daily alternative to the approved IR BID formulation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. [Determination of ephedrine hydrochloride, pseudoephedrine hydrochloride and methylephedrine hydrochloride in maxingshigan decoction by CE].

    PubMed

    Yu, Li-ping; Wang, Xiao-ke; Luo, Jia-bo

    2011-04-01

    To establish the method for determination of ephedrine hydrochloride, pseudoephedrine hydrochloride and methylephedrine hydrochloride in maxingshigan decoction by capillary electrophoresis. The separation was performed on a fused silica capillary of 60 cm x 55 microcrpm ID (52 cm of effective length). 60 mmol/L NaB4O7 + 10% (V/V) CH3OH (pH 9.0) was selected as the running buffer. The separation voltage was 12 kV. The samples was injected by gravity (10 s, 15 cm). The detection wavelength was 210 nm and berberine hydrochloride was the internal standard. The linear range of determination for ephedrine hydrochloride, pseudoephedrine hydrochloride and methylephedrine hydrochloride were 20.0-160.0 microg/mL (r = 0.9999), 7.5-60.0 microg/mL (r = 0.9991) and 2.0-10.0 microg/mL (r = 0.9993). The average recoveries were 98.0%, 97.0% and 97.8%, the precisions of the method were 2.31%, 2.21% and 2.00% (n=6), respectively. The method is convenient, rapid and accurate for the quality control of maxingshigan decoction.

  11. Opiate Antagonists Do Not Interfere With the Clinical Benefits of Stimulants in ADHD: A Double-Blind, Placebo-Controlled Trial of the Mixed Opioid Receptor Antagonist Naltrexone.

    PubMed

    Spencer, Thomas J; Bhide, Pradeep; Zhu, Jinmin; Faraone, Stephen V; Fitzgerald, Maura; Yule, Amy M; Uchida, Mai; Spencer, Andrea E; Hall, Anna M; Koster, Ariana J; Biederman, Joseph

    Methylphenidate activates μ-opioid receptors, which are linked to euphoria. μ-Opioid antagonists, such as naltrexone, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential. This study assessed whether the combination of naltrexone with methylphenidate is well-tolerated while preserving the clinical benefits of stimulants in subjects with attention-deficit/hyperactivity disorder (ADHD). We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate from January 2013 to July 2015. Spheroidal Oral Drug Absorption System (SODAS) methylphenidate was administered twice daily, was titrated to approximately 1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with a test dose of immediate-release methylphenidate. The primary outcome measure was the Adult ADHD Investigator Symptom Report Scale (AISRS). Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS methylphenidate and randomly assigned to naltrexone 50 mg or placebo. Thirty-one subjects completed the study through week 3, and 25 completed through week 6. Throughout 6 weeks of blinded naltrexone and open methylphenidate treatment, the coadministration of naltrexone with methylphenidate did not interfere with the clinical effectiveness of methylphenidate for ADHD symptoms. Additionally, the combination of naltrexone and methylphenidate did not produce an increase in adverse events compared with methylphenidate alone. Our findings provide support for the concept of combining opioid receptor antagonists with stimulants to provide an effective stimulant formulation with less abuse potential. ClinicalTrials.gov identifier: NCT01673594​.

  12. Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats.

    PubMed

    Mattioli, Theresa-Alexandra M; Milne, Brian; Cahill, Catherine M

    2010-04-16

    The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance. Spinal cord sections from rats administered chronic morphine showed significantly increased immuno-labelling of astrocytes and microglia compared to saline controls, consistent with activation. 3-D images of astrocytes from animals administered chronic morphine had significantly larger volumes compared to saline controls. Co-injection of ultra-low dose naltrexone attenuated this increase in volume, but the mean volume differed from saline-treated and naltrexone-treated controls. Astrocyte and microglial immuno-labelling was attenuated in rats co-administered ultra-low dose naltrexone compared to morphine-treated rats and did not differ from controls. Glial activation, as characterized by immunohistochemical labelling and cell size, was positively correlated with the extent of tolerance developed. Morphine-induced glial activation was not due to cell proliferation as there was no difference observed in the total number of glial cells following chronic morphine treatment compared to controls. Furthermore, using 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed following chronic morphine administration. Taken together, we demonstrate a positive correlation between the prevention of analgesic tolerance and the inhibition of spinal gliosis by treatment with ultra-low dose naltrexone

  13. Low dose Naltrexone for induction of remission in inflammatory bowel disease patients.

    PubMed

    Lie, Mitchell R K L; van der Giessen, Janine; Fuhler, Gwenny M; de Lima, Alison; Peppelenbosch, Maikel P; van der Ent, Cokkie; van der Woude, C Janneke

    2018-03-09

    Around 30% of patients with inflammatory bowel disease (IBD) are refractory to current IBD drugs or relapse over time. Novel treatments are called for, and low dose Naltrexone (LDN) may provide a safe, easily accessible alternative treatment option for these patients. We investigated the potential of LDN to induce clinical response in therapy refractory IBD patients, and investigated its direct effects on epithelial barrier function. Patients not in remission and not responding to conventional therapy were offered to initiate LDN as a concomitant treatment. In total 47 IBD patients prescribed LDN were followed prospectively for 12 weeks. Where available, endoscopic remission data, serum and biopsies were collected. Further the effect of Naltrexone on wound healing (scratch assay), cytokine production and endoplasmic reticulum (ER) stress (GRP78 and CHOP western blot analysis, immunohistochemistry) were investigated in HCT116 and CACO2 intestinal epithelial cells, human IBD intestinal organoids and patient samples. Low dose Naltrexone induced clinical improvement in 74.5%, and remission in 25.5% of patients. Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers. Inflamed mucosa from IBD patients showed high ER stress levels, which was reduced in patients treated with LDN. Cytokine levels in neither epithelial cells nor serum from IBD patients were affected. Naltrexone directly improves epithelial barrier function by improving wound healing and reducing mucosal ER stress levels. Low dose Naltrexone treatment is effective and safe, and could be considered for the treatment of therapy refractory IBD patients.

  14. Risk-Taking Propensity as a Predictor of Induction onto Naltrexone Treatment for Opioid Dependence

    PubMed Central

    Aklin, Will M.; Severtson, S. Geoffrey; Umbricht, Annie; Fingerhood, Michael; Bigelow, George E.; Lejuez, C. W.; Silverman, Kenneth

    2014-01-01

    Objective Heroin addiction is a chronic relapsing disorder that has devastating social, medical, and economic consequences. Naltrexone is an antagonist that blocks opioid effects and could be an effective medication for the treatment of opioid dependence. However, its clinical utility has been limited partly because of poor adherence and acceptability. Given the importance of compliance to naltrexone treatment for opioid dependence, the goal of the current study was to examine predictors involved in successful induction onto naltrexone treatment. Method Parametric and nonparametric statistical tests were performed on data from a sample of 64 individuals entering treatment who met DSM-IV criteria for opioid dependence. The relationship between naltrexone induction (i.e., inducted- vs. not-inducted onto naltrexone) and risk-taking propensity, as indexed by riskiness on the Balloon Analogue Risk Task (BART) was examined. Participants were recruited from local detoxification programs, inpatient drug treatment, and other Baltimore programs that provided services to opioid dependent adults (e.g., Baltimore Needle Exchange Program) during the period from August 2007 to September 2008. Results Positive association between risk-taking propensity and odds of naltrexone induction. Specifically, each five point increase in the total BART score was associated with a 25% decrease in odds of naltrexone induction (OR=0.76, 95% CI: 0.58–0.99, p = .041). This association remained statistically significant even after adjusting for potential confounds, including injection drug use and cocaine positive urine results (p = .05). After adjusting for the covariates, each five point increase in BART score was associated with 28% decrease in the odds of achieving the maintenance dose (AOR=0.73, 95% CI: 0.54–0.99, p = .046). Conclusions Risk taking propensity was predictive of induction onto naltrexone treatment, above and beyond injection drug use and cocaine-positive urine samples. PMID

  15. Naltrexone potentiates 4-aminopyridine seizures in the rat.

    PubMed

    Mihály, A; Bencsik, K; Solymosi, T

    1990-01-01

    The effects of a pharmacological blockade of the mu opiate receptors on the manifestation of tonic-clonic seizures were investigated in freely moving animals. 4-aminopyridine, a specific blocker of the neuronal K+ channels was used to produce generalized convulsions. After pretreatment of adult rats with 1 mg/kg naltrexone HCl, 3, 5, 7, 9, 14 mg/kg 4-aminopyridine was injected intraperitoneally, and the latencies of the symptoms generated by 4-aminopyridine were measured. Naltrexone HCl decreased these latencies and enhanced the seizures significantly. The experiments provided further evidence for the existence of a tonic anticonvulsant opioid system in the brain.

  16. Combined administration of buprenorphine and naltrexone produces antidepressant-like effects in mice

    PubMed Central

    Almatroudi, Abdulrahman; Husbands, Stephen M.; Bailey, Christopher P.; Bailey, Sarah J.

    2016-01-01

    Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focussed on the development of kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts as a partial μ-opioid receptor agonist and a κ-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of μ-opioid receptors would be reduced and the κ-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1mg/kg) with naltrexone (1mg/kg) functions as a short-acting κ-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1mg/kg) with naltrexone (1mg/kg) in CD-1 mice produced significant antidepressant-like responses in behaviours in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by treatment with buprenorphine alone, or in combination with naltrexone. We propose that the combination of buprenorphine with naltrexone represents a novel, and potentially a readily translatable approach, to the treatment of depression. PMID:26045511

  17. Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation.

    PubMed

    Webster, Lynn R

    2007-08-01

    Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.

  18. Bioequivalence of cyclobenzaprine hydrochloride extended-release capsule taken intact or sprinkled over applesauce
.

    PubMed

    Adar, Liat; Zarycranski, William; Conner, Jill B; Dragone, Jeffrey; Janka, Lindsay; Rabinovich-Guilatt, Laura

    2017-12-01

    Difficulty swallowing pills can compromise pain control in painful musculoskeletal disorders. This open-label, 2-period crossover study assessed pharmacokinetics and safety of cyclobenzaprine extended-release (CER) 30-mg capsule contents sprinkled over applesauce compared with intact capsules in healthy subjects. 32 subjects were randomized to treatment sequences AB or BA (A = single CER intact capsule; B = single CER capsule contents sprinkled over applesauce (15 mL)). Treatments were separated by a ≥ 14-day washout. Pharmacokinetic assessments included maximum observed plasma drug concentration (Cmax), time to Cmax (tmax), time to first quantifiable plasma drug concentration (tlag), and area under the plasma drug concentration-vs.-time curve from time 0 to the last measurable drug concentration (AUC0-t) and extrapolated to infinity (AUC0-∞). Bioequivalence was established if the 90% confidence intervals (CIs) of the geometric least squares (LS) means ratios of B:A of Cmax, AUC0-t, and AUC0-∞ were 80 - 125%. Safety was also assessed. Mean plasma drug concentration-vs.-time profiles were similar for CER intact and sprinkled over applesauce. The 90% CIs of LS means ratios indicated bioequivalence: Cmax 91.96 - 100.76%, AUC0-t 96.18 - 103.50%, and AUC0-∞ 95.70 - 103.07%. Median tmax was not significantly different (p > 0.05), and median tlag was the same (1 hour). All adverse effects were mild and resolved during the study. No clinically meaningful changes were noted for clinical laboratory values. CER capsules intact and sprinkled over applesauce are bioequivalent. Sprinkling CER capsule contents is not expected to affect efficacy or safety and can, therefore, be an option for patients with musculoskeletal pain and difficulty swallowing capsules.
.

  19. Opioids and social bonding: naltrexone reduces feelings of social connection

    PubMed Central

    Ray, Lara A.; Irwin, Michael R.; Way, Baldwin M.; Eisenberger, Naomi I.

    2016-01-01

    Close social bonds are critical to a happy and fulfilled life and yet little is known, in humans, about the neurochemical mechanisms that keep individuals feeling close and connected to one another. According to the brain opioid theory of social attachment, opioids may underlie the contented feelings associated with social connection and may be critical to continued bonding. However, the role of opioids in feelings of connection toward close others has only begun to be examined in humans. In a double-blind, placebo-controlled, crossover study of naltrexone (an opioid antagonist), 31 volunteers took naltrexone for 4 days and placebo for 4 days (separated by a 10-day washout period). Participants came to the laboratory once on the last day of taking each drug to complete a task designed to elicit feelings of social connection. Participants also completed daily reports of feelings of social connection while on naltrexone and placebo. In line with hypotheses, and for the first time in humans, results demonstrated that naltrexone (vs placebo) reduced feelings of connection both in the laboratory and in daily reports. These results highlight the importance of opioids for social bonding with close others, lending support to the brain opioid theory of social attachment. PMID:26796966

  20. Patient-reported health-related quality of life, work productivity, and activity impairment during treatment with ALO-02 (extended-release oxycodone and sequestered naltrexone) for moderate-to-severe chronic low back pain.

    PubMed

    Weil, Arnold J; Masters, Elizabeth T; Barsdorf, Alexandra I; Bass, Almasa; Pixton, Glenn; Wilson, Jacquelyn G; Wolfram, Gernot

    2017-10-17

    The efficacy of ALO-02, an abuse-deterrent formulation containing extended-release oxycodone and sequestered naltrexone, in the treatment of chronic low back pain (CLBP) was studied in a 12-week randomized controlled trial. Primary efficacy endpoint results have been published previously (Rauck et al., 2015). The current paper focuses on patient-reported outcomes for health-related quality of life (HRQL), work productivity, and activity impairment that were assessed during this study. This was a double-blind, placebo-controlled, randomized withdrawal study in patients with moderate-to-severe CLBP. After a screening period (≤2 weeks), patients entered an open-label titration period (4-6 weeks). Treatment responders were then randomized to a double-blind placebo-controlled treatment period (12 weeks). HRQL was assessed using changes in the Short Form-36 v2 Health Survey (SF-36v2) and the EuroQol-5 Dimensions Health Questionnaire 3-Level version (EQ-5D-3L). Work productivity and regular activities were evaluated using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). A total of 410 patients received ALO-02 during the open-label titration period, of which 280 (intent-to-treat (ITT) population) were treated during the double-blind placebo-controlled treatment period (placebo, n = 134; ALO-02, n = 146). Significant improvement was observed for all SF-36v2 subscales and component scores (p < 0.005) and the EQ-5D-3L summary index and visual analog scale (p < 0.0001) during the titration period. Improvement was also significant (p < 0.0001) for all WPAI:SHP outcomes except 'work time missed due to CLBP' for the titration period. Significant differences favoring ALO-02 compared with placebo were only observed for the SF-36v2 Bodily Pain subscale (p ≤ 0.0232; ITT population) during the double-blind treatment period and the overall study period (screening to the end of the double-blind treatment period). The percentage change

  1. Effects of Naltrexone on Smoking Cessation Outcomes and Weight Gain in Nicotine-Dependent Men and Women

    PubMed Central

    King, Andrea C.; Cao, Dingcai; O'Malley, Stephanie S.; Kranzler, Henry R.; Cai, Xiaochen; deWit, Harriet; Matthews, Alicia K.; Stachoviak, Ryan J.

    2015-01-01

    This study examined whether the opioid receptor antagonist naltrexone is efficacious in smoking cessation and whether sex moderates the response. We assessed smoking quit rates and weight gain in a double-blind randomized trial comparing oral naltrexone (n = 162) with placebo (n = 154) in nicotine-dependent participants who wanted to quit smoking. The medication was gradually titrated up to 50 mg during the week before the quit date and then maintained at this dose for 12 weeks. For the first 4 weeks after the quit date, all participants received a nicotine patch to mitigate tobacco withdrawal and attended weekly individual cognitive-behavioral smoking cessation counseling sessions. After this time, participants continued with naltrexone or placebo through 12 weeks. Follow-up assessments were conducted at 26 and 52 weeks. During treatment, naltrexone (vs placebo) increased quit rates, attenuated smoking urge, and reduced weight gain. At follow-up, after medication discontinuation, the effect of naltrexone on improving quit rates was no longer evident. Men and women experienced different benefits from naltrexone; men showed greater reductions in smoking, whereas women showed greater reductions in weight gain. In sum, naltrexone showed acute efficacy in treating nicotine dependence, but after the medication was discontinued, the effect on quit rate was not maintained. Further study of naltrexone in smoking cessation treatment and reduction of cessation-related weight gain, as well as preclinical investigation of mechanisms underlying sex differences, is warranted. PMID:22926596

  2. Extended-release mesalamine granules for ulcerative colitis.

    PubMed

    Love, Bryan L; Miller, April D

    2012-11-01

    To evaluate the efficacy and safety of extended-release mesalamine granules in the maintenance of remission in ulcerative colitis (UC). Literature was obtained through searches of MEDLINE (1990-June 2012) using the terms mesalamine granules, ulcerative colitis, Apriso, and Salofalk. Bibliographies from retrieved articles were searched for additional citations. All English-language articles reporting on use of extended-release mesalamine granules in humans identified through the search were evaluated and included. The preferred initial treatment for induction and maintenance of remission in mild to moderate UC is agents from the 5-aminosalicylate class (balsalazide, mesalamine, olsalazine, sulfasalazine). Mesalamine granules are available as an encapsulated product in the US and as a nonencapsulated formulation in Europe. Data evaluating encapsulated mesalamine granules for induction of remission are lacking; however, the European mesalamine granule formulation has been evaluated for induction of remission. Patients receiving mesalamine granules for induction achieved clinical and endoscopic remission more frequently than those receiving placebo. Two pivotal, randomized, double-blind, placebo-controlled, multicenter studies have evaluated encapsulated mesalamine granules for maintenance in 562 adults in remission from UC. In both studies, the proportion of patients who remained relapse-free at 6 months was higher for those receiving encapsulated mesalamine granules than placebo. Mesalamine granules are well tolerated, with headache, nausea, and upper respiratory infections being the most frequently reported adverse effects. Current evidence supports the use of extended-release mesalamine granules for maintenance of remission in mild to moderate UC. Further studies are necessary to examine the ideal dose and regimen of encapsulated mesalamine granules for induction of remission in UC.

  3. Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting.

    PubMed

    Latt, Noeline C; Jurd, Stephen; Houseman, Jennie; Wutzke, Sonia E

    2002-06-03

    To determine whether naltrexone is beneficial in the treatment of alcohol dependence in the absence of obligatory psychosocial intervention. Multicentre, randomised, double-blind, placebo-controlled trial. Hospital-based drug and alcohol clinics, 18 March 1998 - 22 October 1999. 107 patients (mean age, 45 years) fulfilling Diagnostic and statistical manual of mental disorders (4th edition) criteria for alcohol dependence. Patients with alcohol dependence were randomly allocated to naltrexone (50 mg/day) or placebo for 12 weeks. They were medically assessed, reviewed and advised by one physician, and encouraged to strive for abstinence and attend counselling and/or Alcoholics Anonymous, but this was not obligatory. Relapse rate; time to first relapse; side effects. On an intention-to-treat basis, the Kaplan-Meier survival curve showed a clear advantage in relapse rates for naltrexone over placebo (log-rank test, chi(2)(1) = 4.15; P = 0.042). This treatment effect was most marked in the first 6 weeks of the trial. The median time to relapse was 90 days for naltrexone, compared with 42 days for placebo. In absolute numbers, 19 of 56 patients (33.9%) taking naltrexone relapsed, compared with 27 of 51 patients (52.9%) taking placebo (P = 0.047). Naltrexone was well tolerated. Unlike previous studies, we have shown that naltrexone with adjunctive medical advice is effective in the treatment of alcohol dependence irrespective of whether it is accompanied by psychosocial interventions.

  4. Managing severe pain and abuse potential: the potential impact of a new abuse-deterrent formulation oxycodone/naltrexone extended-release product.

    PubMed

    Pergolizzi, Joseph V; Taylor, Robert; LeQuang, Jo Ann; Raffa, Robert B

    2018-01-01

    Proper management of severe pain represents one of the most challenging clinical dilemmas. Two equally important goals must be attained: the humanitarian/medical goal to relieve suffering and the societal/legal goal to not contribute to the drug abuse problem. This is an age-old problem, and the prevailing emphasis placed on one or the other goal has resulted in pendulum swings that have resulted in either undertreatment of pain or the current epidemic of misuse and abuse. In an effort to provide efficacious strong pain relievers (opioids) that are more difficult to abuse by the most dangerous routes of administration, pharmaceutical companies are developing products in which the opioid is manufactured in a formulation that is designed to be tamper resistant. Such a product is known as an abuse-deterrent formulation (ADF). ADF opioid products are designed to deter or resist abuse by making it difficult to tamper with the product and extracting the opioid for inhalation or injection. To date, less than a dozen opioid formulations have been approved by the US Food and Drug Administration to carry specific ADF labeling, but this number will likely increase in the coming years. Most of these products are extended-release formulations.

  5. Evaluation of the antibacterial effects of vancomycin hydrochloride released from agar-gelatin-bioactive glass composites.

    PubMed

    Rivadeneira, Josefina; Di Virgilio, Ana Laura; Audisio, M Carina; Boccaccini, Aldo R; Gorustovich, Alejandro A

    2015-01-13

    The aim of this work was to evaluate the perfomance of agar-gelatin (AG) composites and AG-containing 45S5 bioactive glass (BG) microparticles (AGBG) in relation to their water uptake capacity, sustained release of a drug over time, and antibacterial effects. The composites were fabricated by the gel-casting method. To impart the local drug release capacity, vancomycin hydrochloride (VC) was loaded in the composites in concentrations of 0.5 and 1 mg ml(-1). VC release was assessed in distilled water at 37 °C up to 72 h and quantified spectrophotometrically. The antibacterial activity of composites was evaluated by the inhibition zone test and the plate count method. The experiments were performed in vitro up to 48 h on three staphylococcus strains: Staphylococcus aureus ATCC29213, S. aureus ATCC6538 and Staphylococcus epidermidis ATCC12228. The results showed that the addition of BG to AG composites did not affect the degree of water uptake. The release of VC was significantly affected by the presence of BG. VC release was higher from AGBGVC films than from AGVC ones over prolonged incubation times. Bacterial inhibition zones were found around the composites. The halos were larger when the cells were put in contact with AGVC composites than when they were put in contact with AGBGVC ones. Nevertheless, the viable count method demonstrated that the composites inhibited Staphylococcus cell growth with no statistical differences. In conclusion, the addition of BG did not reflect an improvement in the parameters studied. On the other hand, composites loaded with VC would have a role in prophylaxis against bacterial infection.

  6. Stress-evoked opioid release inhibits pain in major depressive disorder.

    PubMed

    Frew, Ashley K; Drummond, Peter D

    2008-10-15

    To determine whether stress-evoked release of endogenous opioids might account for hypoalgesia in major depressive disorder (MDD), the mu-opioid antagonist naltrexone (50mg) or placebo was administered double-blind to 24 participants with MDD and to 31 non-depressed controls. Eighty minutes later participants completed a painful foot cold pressor test and, after a 5-min interval, began a 25-min arithmetic task interspersed with painful electric shocks. Ten minutes later participants completed a second cold pressor test. Negative affect was greater in participants with MDD than in non-depressed controls throughout the experiment, and increased significantly in both groups during mental arithmetic. Before the math task, naltrexone unmasked direct linear relationships between severity of depression, negative affect while resting quietly, and cold-induced pain in participants with MDD. In contrast, facilitatory effects of naltrexone on cold- and shock-induced pain were greatest in controls with the lowest depression scores. Naltrexone strengthened the relationship between negative affect and shock-induced pain during the math task, particularly in the depressed group, and heightened anxiety in both groups toward the end of the task. Thus, mu-opioid activity apparently masked a positive association between negative affect and pain in the most distressed participants. These findings suggest that psychological distress inhibits pain via stress-evoked release of opioid peptides in severe cases of MDD. In addition, tonic endogenous opioid neurotransmission could inhibit depressive symptoms and pain in people with low depression scores.

  7. Method‐of‐use study of naltrexone sustained release (SR)/bupropion SR on body weight in individuals with obesity

    PubMed Central

    Shan, Kevin; Walsh, Brandon; Gilder, Kye; Fujioka, Ken

    2016-01-01

    Objective This study assessed the effects of 32 mg naltrexone sustained release (SR)/360 mg bupropion SR (NB) on body weight in adults with obesity, with comprehensive lifestyle intervention (CLI), for 78 weeks. Methods In this phase 3b, randomized, open‐label, controlled study, subjects received NB + CLI or usual care (standard diet/exercise advice) for 26 weeks. NB subjects not achieving 5% weight loss at week 16 were discontinued, as indicated by product labeling. After week 26, usual care subjects began NB + CLI. Assessments continued through week 78. The primary end point was percent change in weight from baseline to week 26 in the per protocol population. Other end points included percentage of subjects achieving ≥5%, ≥10%, and ≥15% weight loss, percent change in weight at week 78, and adverse events (AEs) necessitating study medication discontinuation. Results NB + CLI subjects lost significantly more weight than usual care subjects at week 26 (8.52% difference; P < 0.0001). Weight loss persisted through 78 weeks. In total, 20.7% of subjects discontinued medication for AEs, including 7.0% for nausea. Conclusions Treatment with NB, used as indicated by prescribing information and with CLI, significantly improved weight loss over usual care alone. NB‐facilitated weight loss was sustained for 78 weeks and was deemed safe and well tolerated. PMID:28026920

  8. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: When are these medications most helpful?

    PubMed Central

    Maisel, Natalya C.; Blodgett, Janet C.; Wilbourne, Paula L.; Humphreys, Keith; Finney, John W.

    2014-01-01

    Aims Although debates over the efficacy of oral naltrexone and acamprosate in treating alcohol use disorders tend to focus on their global efficacy relative to placebo or their efficacy relative to each other, the underlying reality may be more nuanced. This meta-analysis examined when naltrexone and acamprosate are most helpful by testing: (1) the relative efficacy of each medication given its presumed mechanism of action (reducing heavy drinking versus fostering abstinence) and (2) whether different ways of implementing each medication (required abstinence before treatment, detoxification before treatment, goal of treatment, length of treatment, dosage) moderate its effects. Methods A systematic literature search identified 64 randomized, placebo-controlled, English-language clinical trials completed between 1970 and 2009 focused on acamprosate or naltrexone. Results Acamprosate had a significantly larger effect size than naltrexone on the maintenance of abstinence, and naltrexone had a larger effect size than acamprosate on the reduction of heavy drinking and craving. For naltrexone, requiring abstinence before the trial was associated with larger effect sizes for abstinence maintenance and reduced heavy drinking compared to placebo. For acamprosate, detoxification before medication administration was associated with better abstinence outcomes compared to placebo. Conclusions In treatment for alcohol use disorders, acamprosate has been found to be slightly more efficacious in promoting abstinence and naltrexone slightly more efficacious in reducing heavy drinking and craving. Detoxification before treatment or a longer period of required abstinence before treatment is associated with larger medication effects for acamprosate and naltrexone, respectively. PMID:23075288

  9. Effects of naltrexone are influenced by childhood adversity during negative emotional processing in addiction recovery.

    PubMed

    Savulich, G; Riccelli, R; Passamonti, L; Correia, M; Deakin, J F W; Elliott, R; Flechais, R S A; Lingford-Hughes, A R; McGonigle, J; Murphy, A; Nutt, D J; Orban, C; Paterson, L M; Reed, L J; Smith, D G; Suckling, J; Tait, R; Taylor, E M; Sahakian, B J; Robbins, T W; Ersche, K D

    2017-03-07

    Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone (n=18, alcohol) and in combination with cocaine and/or opioid dependence (n=21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence (n=21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone.

  10. Effects of naltrexone are influenced by childhood adversity during negative emotional processing in addiction recovery

    PubMed Central

    Savulich, G; Riccelli, R; Passamonti, L; Correia, M; Deakin, J F W; Elliott, R; Flechais, R S A; Lingford-Hughes, A R; McGonigle, J; Murphy, A; Nutt, D J; Orban, C; Paterson, L M; Reed, L J; Smith, D G; Suckling, J; Tait, R; Taylor, E M; Sahakian, B J; Robbins, T W; Ersche, K D

    2017-01-01

    Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone (n=18, alcohol) and in combination with cocaine and/or opioid dependence (n=21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence (n=21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone. PMID:28267152

  11. A Comparison of Sexual Side Effects of Antidepressants With and Without Naltrexone.

    PubMed

    Thapa, Mona; Petrakis, Ismene; Ralevski, Elizabeth

    2017-01-01

    The aim of the study was to compare the rate of sexual side effects of the selective serotonin reuptake inhibitor paroxetine versus the tricyclic antidepressant desipramine and to examine the effect of co-prescription of naltrexone on sexual side effects among participants in a randomized clinical trial. This was a secondary analysis (N = 88) of veterans who participated in a 12-week trial. All veterans were randomized into one of four treatment groups: (a) desipramine/naltrexone, (b) desipramine/placebo, (c) paroxetine/naltrexone, and (d) paroxetine/placebo. The main outcome measure was the frequency of sexual side effects consisting of "decreased sex drive" and/or "impotence" reported by veterans at each weekly visit. Approximately 61% of the veterans reported sexual side effects at least once during the trial, and 26.4% reported sexual side effects throughout the study. There were no significant differences in the frequency of sexual side effects among the four treatment groups. The results were similar when the comparison was made between the two antidepressant groups. There were no significant differences in the reporting of sexual side effects between those receiving desipramine and paroxetine. Also, the comparison between naltrexone and placebo did not alter the results. This is the first study to compare frequency of sexual side effect reporting between paroxetine and desipramine. We found no statistically significant differences in sexual side effect reporting between the two antidepressants. Also, the addition of naltrexone did not show any beneficial effect on the sexual side effect profile.

  12. Opioid Detoxification and Naltrexone Induction Strategies: Recommendations for Clinical Practice

    PubMed Central

    Sigmon, Stacey C.; Bisaga, Adam; Nunes, Edward V.; O'Connor, Patrick G.; Kosten, Thomas; Woody, George

    2015-01-01

    Background Opioid dependence is a significant public health problem associated with high risk for relapse if treatment is not ongoing. While maintenance on opioid agonists (i.e., methadone, buprenorphine) often produces favorable outcomes, detoxification followed by treatment with the μ-opioid receptor antagonist naltrexone may offer a potentially useful alternative to agonist maintenance for some patients. Method Treatment approaches for making this transition are described here based on a literature review and solicitation of opinions from several expert clinicians and scientists regarding patient selection, level of care, and detoxification strategies. Conclusion Among the current detoxification regimens, the available clinical and scientific data suggest that the best approach may be using an initial 2–4 mg dose of buprenorphine combined with clonidine, other ancillary medications, and progressively increasing doses of oral naltrexone over 3–5 days up to the target dose of naltrexone. However, more research is needed to empirically validate the best approach for making this transition. PMID:22404717

  13. Daily relations among affect, urge, targeted naltrexone, and alcohol use in young adults.

    PubMed

    Bold, Krysten W; Fucito, Lisa M; Corbin, William R; DeMartini, Kelly S; Leeman, Robert F; Kranzler, Henry R; O'Malley, Stephanie S

    2016-10-01

    Heavy drinking among young adults is a serious public health problem. Naltrexone, an opioid antagonist, has been shown to reduce drinking in young adults compared to placebo and can be taken on a targeted (i.e., as needed) basis. Understanding risk factors for drinking and naltrexone effects within-person in young adults may help to optimize the use of targeted naltrexone. The current study was a secondary analysis of daily diary data from 127 (n = 40 female) young adults (age 18-25) enrolled in a double-blind clinical trial of daily (25 mg) plus targeted (25 mg) naltrexone versus placebo. Hierarchical linear models were used to examine the effects of daily affect, urge, and taking targeted medication on same-day risk of drinking to intoxication (defined as estimated blood-alcohol-concentration, BAC ≥ .08 g%). Results indicated urge significantly mediated within-person positive affect-drinking relations on a daily level. Specifically, positive affect was associated with greater urge to drink, which in turn was associated with greater odds of BAC ≥ .08 g%. Furthermore, days of greater positive affect and urge were associated with taking a targeted dose of medication, which reduced the likelihood of intoxication by nearly 23% in the naltrexone group compared to placebo. Gender and family history of alcohol dependence were examined as moderators of these daily level effects. These results provide further evidence of naltrexone's ability to reduce alcohol consumption in young adults and identify potential within-person risk processes related to heavy drinking that could inform alcohol-related interventions for this population. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  14. Development of extended-release solid dispersion granules of tacrolimus: evaluation of release mechanism and human oral bioavailability.

    PubMed

    Tsunashima, Daisuke; Yamashita, Kazunari; Ogawara, Ken-Ichi; Sako, Kazuhiro; Hakomori, Tadashi; Higaki, Kazutaka

    2017-12-01

    We aimed to prepare a once-daily modified-release oral formulation of tacrolimus by utilizing an extended-release granules (ERG). Extended-release granules were prepared using ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC) and lactose via a solvent evaporation method with ethanol. Physicochemical and biopharmaceutical studies were performed to determine the formulation with optimum release profile of tacrolimus from ERG. Tacrolimus existed in an amorphous state in ERG. Tacrolimus release from ERG was attenuated by EC and facilitated by lactose, suggesting that drug release kinetics could adequately be regulated by these components. Those release profiles were consistent with Higuchi's equation, suggesting a diffusion-type release mechanism. Smooth surface of ERG changed to the structure with pores after the release test, likely derived from the dissolution of HPMC and lactose. But ERG structure formed by EC was still maintained after the release test, leading to the longer maintenance of diffusion-type release. Two ERG formulations selected by blood concentration simulation successfully provided long-term retention of tacrolimus in blood in a human absorption study. We successfully developed the formulation exhibiting a significant reduction in C max , the longer mean residence time and AUC close to that of an immediate-release tacrolimus formulation, being preferred from the viewpoint of safe and effective immunosuppressant pharmacotherapy. © 2017 Royal Pharmaceutical Society.

  15. Surveillance of Diversion and Nonmedical Use of Extended-Release Prescription Amphetamine and Oral Methylphenidate in the United States

    PubMed Central

    Sembower, Mark A.; Ertischek, Michelle D.; Buchholtz, Chloe; Dasgupta, Nabarun; Schnoll, Sidney H.

    2013-01-01

    This article examines rates of nonmedical use and diversion of extended-release amphetamine and extended-release oral methylphenidate in the United States. Prescription dispensing data were sourced from retail pharmacies. Nonmedical use data were collected from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Drug Diversion Program and Poison Center Program. Drug diversion trends nearly overlapped for extended-release amphetamine and extended-release oral methylphenidate. Calls to poison centers were generally similar; however, calls regarding extended-release amphetamine trended slightly lower than those for extended-release oral methylphenidate. Data suggest similar diversion and poison center call rates for extended-release amphetamine and extended-release oral methylphenidate. PMID:23480245

  16. Metformin extended release treatment of adolescent obesity: a 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up.

    PubMed

    Wilson, Darrell M; Abrams, Stephanie H; Aye, Tandy; Lee, Phillip D K; Lenders, Carine; Lustig, Robert H; Osganian, Stavroula V; Feldman, Henry A

    2010-02-01

    Metformin has been proffered as a therapy for adolescent obesity, although long-term controlled studies have not been reported. To test the hypothesis that 48 weeks of daily metformin hydrochloride extended release (XR) therapy will reduce body mass index (BMI) in obese adolescents, as compared with placebo. Multicenter, randomized, double-blind, placebo-controlled clinical trial. The 6 centers of the Glaser Pediatric Research Network from October 2003 to August 2007. Obese (BMI > or = 95th percentile) adolescents (aged 13-18 years) were randomly assigned to the intervention (n = 39) or placebo groups. Intervention Following a 1-month run-in period, subjects following a lifestyle intervention program were randomized 1:1 to 48 weeks' treatment with metformin hydrochloride XR, 2000 mg once daily, or an identical placebo. Subjects were monitored for an additional 48 weeks. Main Outcome Measure Change in BMI, adjusted for site, sex, race, ethnicity, and age and metformin vs placebo. After 48 weeks, mean (SE) adjusted BMI increased 0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in the metformin XR group (P = .03). This difference persisted for 12 to 24 weeks after cessation of treatment. No significant effects of metformin on body composition, abdominal fat, or insulin indices were observed. Metformin XR caused a small but statistically significant decrease in BMI when added to a lifestyle intervention program. clinicaltrials.gov Identifiers: NCT00209482 and NCT00120146.

  17. [Treatment of a serious autistic disorder in a child with Naltrexone in an oral suspension form].

    PubMed

    Desjardins, S; Doyen, C; Contejean, Y; Kaye, K; Paubel, P

    2009-04-01

    that sometimes includes the administration of psychotropic medication. One of these children presented with a severe autistic disorder according to the Childhood Autism Rating Scale (CARS). Considering ICD-10 criteria, he benefited from a multidisciplinary program, associating cognitive psychotherapy, psychomotor rehabilitation, speech therapy and educational intervention. However, persistent sleep disorder and motor instability led to successive prescriptions of several different psychotropic drugs. Initial treatment by thioridazine (10mg per day) followed by propericiazine (2.5mg per day) improved sleep, but was not efficient in reducing self-mutilating behaviour. A new treatment by risperidone (from 0.5mg to 1.5mg per day) was therefore chosen; however it lost its efficacy after five months. Finally, an anxiolytic (cyamemazine) and a thymoregulator (sodium valproate) were successively tried without yielding any clinical improvement. Owing to the persistence of communication difficulties, major instability, self-mutilating behaviour and heteroaggressiveness, treatment with naltrexone was subsequently chosen with parental consent. In France, naltrexone hydrochloride is only available in tablet form (Nalorex 50mg and Revia 50mg), which is not adapted to children at the efficient dose. Consequently, an oral suspension form marketed in Spain (Antaxone 50mg) was imported, having obtained the Afssaps' (the French drug administration) authorisation for its temporary use. The Connors and Nisonger scales were used as outcome measures of behavioural symptom change. The Conners scale is used to assess attention deficit and hyperactivity, whereas the Nisonger scale analyses social skills and behaviour disorders in children and adolescents with mental retardation. The onset of treatment, at a dose of 1mg/kg/day, led to a transitory increase in negative behaviour. However, a dose of 0.75mg/kg per day subsequently led to significant improvements, as shown by outcome measurements

  18. Outcome predictors for problem drinkers treated with combined cognitive behavioral therapy and naltrexone.

    PubMed

    Vuoristo-Myllys, Salla; Lipsanen, Jari; Lahti, Jari; Kalska, Hely; Alho, Hannu

    2014-03-01

    The opioid antagonist naltrexone, combined with cognitive behavioural therapy (CBT), has proven efficacious for patients with alcohol dependence, but studies examining how this treatment works in a naturalistic treatment setting are lacking. This study examined predictors of the outcome of targeted naltrexone and CBT in a real-life outpatient setting. Participants were 315 patients who attended a treatment program providing CBT combined with the targeted use of naltrexone. Mixture models for estimating developmental trajectories were used to examine change in patients' alcohol consumption and symptoms of alcohol craving from treatment entry until the end of the treatment (20 weeks) or dropout. Predictors of treatment outcome were examined with analyses of multinomial logistic regression. Minimal exclusion criteria were applied to enhance the generalizability of the findings. Regular drinking pattern, having no history of previous treatments, and high-risk alcohol consumption level before the treatment were associated with less change in alcohol use during the treatment. The patients with low-risk alcohol consumption level before the treatment had the most rapid reduction in alcohol craving. Patients who drank more alcohol during the treatment had lower adherence with naltrexone. Medication non-adherence is a major barrier to naltrexone's effectiveness in a real-life treatment setting. Patients with more severe alcohol problems may need more intensive treatment for achieving better treatment outcome in real-word treatment settings.

  19. Polyamidoamine (PAMAM) dendrimers as potential release modulators and oral bioavailability enhancers of vardenafil hydrochloride.

    PubMed

    Tawfik, Mai Ahmed; Tadros, Mina Ibrahim; Mohamed, Magdy Ibrahim

    2018-05-21

    Vardenafil hydrochloride (VAR) is an erectile dysfunction treating drug. VAR has a short elimination half-life (4-5 h) and suffers low oral bioavailability (15%). This work aimed to explore the dual potential of VAR-dendrimer complexes as drug release modulators and oral bioavailability enhancers. VAR-dendrimer complexes were prepared by solvent evaporation technique using four dendrimer generations (G4.5, G5, G5.5 and G6) at three concentrations (190 nM, 380 nM and 950 nM). The systems were evaluated for intermolecular interactions, particle size, zeta potential, drug entrapment efficiency percentages (EE%) and drug released percentages after 2 h (Q 2h ) and 24 h (Q 24h ). The results were statistically analyzed, and the system showing the highest desirability was selected for further pharmacokinetic studies in rabbits, in comparison to Levitra ® tablets. The highest desirability (0.82) was achieved with D10 system comprising VAR (10 mg) and G6 (190 nM). It possessed small particle size (113.85 nm), low PDI (0.19), positive zeta potential (+21.53), high EE% (75.24%), promising Q 2 h (41.45%) and Q 24 h (74.05%). Compared to Levitra ® tablets, the significantly (p < 0.01) delayed T max , prolonged MRT (0-∞) and higher relative bioavailability (3.7-fold) could clarify the dual potential of D10 as a sustained release system capable of enhancing VAR oral bioavailability.

  20. Cigarette Smoking Predicts Differential Benefit from Naltrexone for Alcohol Dependence

    PubMed Central

    Fucito, Lisa M.; Park, Aesoon; Gulliver, Suzy Bird; Mattson, Margaret E.; Gueorguieva, Ralitza V.; O’Malley, Stephanie S.

    2012-01-01

    Background Identifying factors that modify responsiveness to pharmacotherapies for alcohol dependence is important for treatment planning. Cigarette smoking predicts more severe alcohol dependence and poorer treatment response in general. Nevertheless, there is limited research on cigarette smoking as a potential predictor of differential response to pharmacological treatment of alcoholism. Methods We examined the association between cigarette smoking and drinking outcomes in the COMBINE study, a randomized, double-blind placebo-controlled 16-week trial comparing combinations of medications (i.e., acamprosate and naltrexone) and behavioral interventions (i.e., medical management (MM), combined behavioral therapy (CBI)) in 1383 alcohol dependent individuals. Results Smokers (i.e., more than half the sample) significantly differed from nonsmokers on several demographic and drinking-related variables at baseline and generally had poorer treatment outcomes than nonsmokers. However, smokers who received naltrexone had better drinking outcomes than smokers who received placebo, whereas alcohol use among nonsmokers did not vary by naltrexone assignment. This pattern of findings occurred independent of whether patients received CBI or MM and remained after controlling for alcoholism typology and baseline demographic differences. Approximately 9% of smokers quit smoking and an additional 10% reduced their cigarette intake during treatment. Reductions in smoking did not vary by treatment assignment. Conclusions These results suggest that naltrexone may be particularly beneficial for improving alcohol use outcomes in alcohol dependent smokers. Trial Registration The COMBINE Study, NCT000626, http://www.cscc.unc.edu/combine/. PMID:22541040

  1. Sensitivity of neuronal nicotinic acetylcholine receptors to the opiate antagonists naltrexone and naloxone: receptor blockade and up-regulation.

    PubMed

    Almeida, Luis E F; Pereira, Edna F R; Camara, Adriana L; Maelicke, Alfred; Albuquerque, Edson X

    2004-04-19

    In HEK293 cells stably expressing alpha4beta2 nAChRs, naltrexone, but not naloxone, blocked alpha4beta2 nAChRs via an open-channel blocking mechanism. In primary hippocampal cultures, naltrexone inhibited alpha7 nAChRs up-regulated by nicotine, and in organotypic hippocampal cultures naltrexone caused a time-dependent up-regulation of functional alpha7 nAChRs that was detected after removal of the drug. These results indicate that naltrexone could be used as a smoking cessation aid.

  2. In vitro-in vivo correlation for nevirapine extended release tablets.

    PubMed

    Macha, Sreeraj; Yong, Chan-Loi; Darrington, Todd; Davis, Mark S; MacGregor, Thomas R; Castles, Mark; Krill, Steven L

    2009-12-01

    An in vitro-in vivo correlation (IVIVC) for four nevirapine extended release tablets with varying polymer contents was developed. The pharmacokinetics of extended release formulations were assessed in a parallel group study with healthy volunteers and compared with corresponding in vitro dissolution data obtained using a USP apparatus type 1. In vitro samples were analysed using HPLC with UV detection and in vivo samples were analysed using a HPLC-MS/MS assay; the IVIVC analyses comparing the two results were performed using WinNonlin. A Double Weibull model optimally fits the in vitro data. A unit impulse response (UIR) was assessed using the fastest ER formulation as a reference. The deconvolution of the in vivo concentration time data was performed using the UIR to estimate an in vivo drug release profile. A linear model with a time-scaling factor clarified the relationship between in vitro and in vivo data. The predictability of the final model was consistent based on internal validation. Average percent prediction errors for pharmacokinetic parameters were <10% and individual values for all formulations were <15%. Therefore, a Level A IVIVC was developed and validated for nevirapine extended release formulations providing robust predictions of in vivo profiles based on in vitro dissolution profiles. Copyright 2009 John Wiley & Sons, Ltd.

  3. Effects of baclofen and naltrexone, alone and in combination, on the consumption of palatable food in male rats.

    PubMed

    Avena, Nicole M; Bocarsly, Miriam E; Murray, Susan; Gold, Mark S

    2014-10-01

    Excess consumption of palatable food has been shown to affect reward-related brain regions, and pharmaceutical treatments for drug addiction may also be effective in treating overeating of such foods. The GABA-B agonist baclofen and opioid antagonist naltrexone have both been used to treat addiction, and have been shown to suppress intake of certain foods. The combination of these drugs has shown to be more effective in reducing alcohol consumption than either drug alone. The present study assessed the effects of naltrexone and baclofen, alone and in combination, on intake of foods comprised of various macronutrients. Male Sprague-Dawley rats were given 12-hr daily access to chow and a fat emulsion, sugar-fat emulsion, or a sugar solution for 21 days. Rats were then administered (intraperitoneal) baclofen-naltrexone combinations (0.1 mg/kg naltrexone and 1.0 mg/kg baclofen, 1.0 mg/kg naltrexone and 1.8 mg/kg baclofen), and naltrexone (0.1, 1.0 mg/kg) and baclofen (1.0, 1.8 mg/kg) alone. The high dose of the baclofen-naltrexone combination reduced palatable food intake in both the fat and sugar-fat groups compared with vehicle, without affecting chow consumption in these groups. Naltrexone showed little significant effects on intake of either palatable food or chow. Baclofen also reduced palatable food intake in the fat and fat-sugar groups, but differences were only noted between the low and high dose. The combination of baclofen and naltrexone may be a useful tool in selectively targeting the consumption of high-fat and sugar- and fat-rich foods. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

  4. Cost-effectiveness of buprenorphine and naltrexone treatments for heroin dependence in Malaysia.

    PubMed

    Ruger, Jennifer Prah; Chawarski, Marek; Mazlan, Mahmud; Ng, Nora; Schottenfeld, Richard

    2012-01-01

    To aid public health policymaking, we studied the cost-effectiveness of buprenorphine, naltrexone, and placebo interventions for heroin dependence in Malaysia. We estimated the cost-effectiveness ratios of three treatments for heroin dependence. We used a microcosting methodology to determine fixed, variable, and societal costs of each intervention. Cost data were collected from investigators, staff, and project records on the number and type of resources used and unit costs; societal costs for participants' time were estimated using Malaysia's minimum wage. Costs were estimated from a provider and societal perspective and reported in 2004 US dollars. Muar, Malaysia. 126 patients enrolled in a randomized, double-blind, placebo-controlled clinical trial in Malaysia (2003-2005) receiving counseling and buprenorphine, naltrexone, or placebo for treatment of heroin dependence. Primary outcome measures included days in treatment, maximum consecutive days of heroin abstinence, days to first heroin use, and days to heroin relapse. Secondary outcome measures included treatment retention, injection drug use, illicit opiate use, AIDS Risk Inventory total score, and drug risk and sex risk subscores. Buprenorphine was more effective and more costly than naltrexone for all primary and most secondary outcomes. Incremental cost-effectiveness ratios were below $50 for primary outcomes, mostly below $350 for secondary outcomes. Naltrexone was dominated by placebo for all secondary outcomes at almost all endpoints. Incremental treatment costs were driven mainly by medication costs, especially the price of buprenorphine. Buprenorphine appears to be a cost-effective alternative to naltrexone that might enhance economic productivity and reduce drug use over a longer term.

  5. Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illness

    DTIC Science & Technology

    2015-07-01

    1 Award Number: W81XWH-09-2-0065 TITLE: Trial of Naltrexone and Dextromethorphan for Gulf War Veterans’ Illness PRINCIPAL INVESTIGATOR: William J... Dextromethorphan for Gulf War Veterans’ Illness 5a. CONTRACT NUMBER W81XWH-09-2-0065 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) William...is related to low grade neuron-inflammation, which can be down regulated, by Naltrexone and Dextromethorphan . This is untested but potentially

  6. Effects of crystallinity and surface modification of calcium phosphate nanoparticles on the loading and release of tetracycline hydro-chloride

    NASA Astrophysics Data System (ADS)

    Zhang, Huaizhi; Yan, Dong; Menike Korale Gedara, Sriyani; Dingiri Marakkalage, Sajith Sudeepa Fernando; Gamage Kasun Methlal, Jothirathna; Han, YingChao; Dai, HongLian

    2017-03-01

    The influences of crystallinity and surface modification of calcium phosphate nanoparticles (nCaP) on their drug loading capacity and drug release profile were studied in the present investigation. The CaP nanoparticles with different crystallinity were prepared by precipitation method under different temperatures. CaP nanoparticles with lower crystallinity exhibited higher drug loading capacity. The samples were characterized by XRD, FT-IR, SEM, TEM and BET surface area analyzer respectively. The drug loading capacity of nCaP was evaluated to tetracycline hydro-chloride (TCH). The internalization of TCH loaded nCaP in cancer cell was observed by florescence microscope. nCaP could be stabilized and dispersed in aqueous solution by poly(acrylic acid) surface modification agent, leading to enhanced drug loading capacity. The drug release was conducted in different pH environment and the experimental data proved that nCaP were pH sensitive drug carrier, suggesting that nCaP could achieve the controlled drug release in intracellular acidic environment. Furthermore, nCaP with higher crystallinity showed lower drug release rate than that of lower crystallinity, indicating that the drug release profile could be adjusted by crystallinity of nCaP. nCaP with adjustable drug loading and release properties are promising candidate as drug carrier for disease treatment.

  7. Sex differences in acute hormonal and subjective response to naltrexone: the impact of menstrual cycle phase

    PubMed Central

    Roche, Daniel J.O.; King, Andrea C.

    2015-01-01

    Women often exhibit larger hormonal and subjective responses to opioid receptor antagonists than men, but the biological mechanisms mediating this effect remain unclear. Among women, fluctuations in estradiol (E2) and progesterone (P4) across the menstrual cycle (MC) affect the endogenous opioid system. Therefore, the goal of the current study was to compare acute naltrexone response between women in the early follicular phase of the MC (low E2 and P4), women in the luteal phase of the MC (high E2 and P4), and men. Seventy healthy controls (n = 46 women) participated in two morning sessions in which they received 50 mg naltrexone or placebo in a randomized, counterbalanced order. Women were randomized to complete both sessions in either the early follicular (n = 23) or luteal phase of the MC. Serum cortisol, prolactin, and luteinizing hormone (LH), salivary cortisol, and subjective response were assessed upon arrival to the laboratory and at regular intervals after pill administration. In luteal and early follicular women but not men, naltrexone (vs. placebo) increased serum cortisol and prolactin levels from baseline; however, the naltrexone-induced increases in these hormones were significantly greater in luteal women than early follicular women. Additionally, only luteal women demonstrated an increase from baseline in salivary cortisol levels and the severity of adverse drug effects in response to naltrexone. In sum, the results indicate that luteal phase women are more sensitive to acute hormonal and subjective effects of naltrexone than early follicular women and men. These findings may have important implications for the use of naltrexone in women. PMID:25459893

  8. Oral heroin in opioid-dependent patients: pharmacokinetic comparison of immediate and extended release tablets

    PubMed Central

    Perger, Ludwig; Rentsch, Katharina M.; Kullak-Ublick, Gerd A.; Verotta, Davide; Fattinger, Karin

    2009-01-01

    In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (±SD) immediate and extended release doses were 719 ± 297 mg and 956 ± 404 mg, with high absolute morphine bioavailabilities of 56% to 61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10 to 15 min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only ~30% of maximal immediate release absorption being reached after 10 min and maintained for 3 to 4 h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially. PMID:19084595

  9. Design and in vitro and in vivo characterization of mucoadhesive matrix pellets of metformin hydrochloride for oral controlled release: a technical note.

    PubMed

    Ige, Pradum Pundlikrao; Gattani, Surendra Ganeshlal

    2012-03-01

    The aim of the current work was to design and develop matrix pellets of hydroxy propyl methyl cellulose K200M and microcrystalline cellulose in an admixture for a mucoadhesive gastroretentive drug delivery system. Pellets containing metformin hydrochloride (500 mg) were prepared by the pelletization technique using an extruder-spheronizer. Pellets were characterized by differential scanning calorimetry (DSC), x-ray diffraction (XRD), scanning electron microscopy (SEM), circularity, roundness, percent drug content, percent production yield, in vitro swelling, ex vivo mucoadhesion, in vitro drug release and in vivo x-ray imaging studies. Optimized pellets were sufficiently porous spheroids, free flowing, had smooth surfaces, had yields up to 75.45 ± 0.52% and had drug content up to 96.45 ± 0.19%. The average particle size of formulations MF2 and MF6 were 1.13 ± 0.41 mm and 1.22 ± 0.18 mm, respectively. Formulation MF6 exhibited strong adhesion, about 94.67%, to goat mucosal tissue, and the desired in vitro swelling, with a sustained drug release profile for 12 h and with retention in the upper small intestine of rabbits for 10 h. We conclude that hydroxy propyl methyl cellulose K200M and microcrystalline cellulose at a 2.80:1.00 w/w ratio could be an effective carrier for multiple unit controlled delivery of metformin hydrochloride.

  10. Acute Generalized Erythrodermic Pustular Psoriasis Associated with Bupropion/Naltrexone (Contrave®).

    PubMed

    Singh, Priyanka A; Cassel, Kerry P; Moscati, Ronald M; Eckersley, David

    2017-04-01

    We report a case of erythrodermic pustular psoriasis associated with initiation of bupropion/naltrexone (Contrave®; Orexigen Therapeutics, La Jolla, CA) in a patient with no history of psoriasis. A 55-year-old woman was transferred to our tertiary medical center from a community hospital for possible Stevens-Johnson syndrome 3 weeks after initiation of bupropion/naltrexone. The patient was admitted to the burn unit for wound treatment and hydration. She received intravenous cyclosporine during the admission that resulted in acute kidney injury and the therapy was discontinued. The skin biopsy ruled out Stevens-Johnson syndrome and was more consistent with generalized pustular psoriasis. After discharge, the patient followed up with her dermatologist. She was diagnosed with acute generalized and erythrodermic psoriasis and the patient was restarted on cyclosporine 100 mg twice a day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Few case reports of bupropion-induced generalized pustular psoriasis and erythrodermic psoriasis in patients with a history of psoriasis have been reported. To our knowledge, acute generalized erythrodermic pustular psoriasis associated with bupropion/naltrexone has not been reported in a patient without history of psoriasis. Due to increases in obesity and increases in prescribing of bupropion/naltrexone SR, health care providers should be aware of this possible severe adverse reaction. Published by Elsevier Inc.

  11. Statistical optimization of controlled release microspheres containing cetirizine hydrochloride as a model for water soluble drugs.

    PubMed

    El-Say, Khalid M; El-Helw, Abdel-Rahim M; Ahmed, Osama A A; Hosny, Khaled M; Ahmed, Tarek A; Kharshoum, Rasha M; Fahmy, Usama A; Alsawahli, Majed

    2015-01-01

    The purpose was to improve the encapsulation efficiency of cetirizine hydrochloride (CTZ) microspheres as a model for water soluble drugs and control its release by applying response surface methodology. A 3(3) Box-Behnken design was used to determine the effect of drug/polymer ratio (X1), surfactant concentration (X2) and stirring speed (X3), on the mean particle size (Y1), percentage encapsulation efficiency (Y2) and cumulative percent drug released for 12 h (Y3). Emulsion solvent evaporation (ESE) technique was applied utilizing Eudragit RS100 as coating polymer and span 80 as surfactant. All formulations were evaluated for micromeritic properties and morphologically characterized by scanning electron microscopy (SEM). The relative bioavailability of the optimized microspheres was compared with CTZ marketed product after oral administration on healthy human volunteers using a double blind, randomized, cross-over design. The results revealed that the mean particle sizes of the microspheres ranged from 62 to 348 µm and the efficiency of entrapment ranged from 36.3% to 70.1%. The optimized CTZ microspheres exhibited a slow and controlled release over 12 h. The pharmacokinetic data of optimized CTZ microspheres showed prolonged tmax, decreased Cmax and AUC0-∞ value of 3309 ± 211 ng h/ml indicating improved relative bioavailability by 169.4% compared with marketed tablets.

  12. Low-Dose Naltrexone: A New Therapy Option for Complex Regional Pain Syndrome Type I Patients.

    PubMed

    Sturn, Kayla M; Collin, Michael

    2016-01-01

    Naltrexone (an opioid antagonist) has long been used in patients overcoming alcohol and opioid dependency. However, at doses one-tenth of those commonly prescribed for the above conditions, an unexpected effect occurs that aids in alleviating pain. Although there are currently no randomized clinical trials supporting the use of low-dose naltrexone, we present a case study describing the impact of compounding low-dose naltrexone that has dramatically improved the patient's pain symptoms which were refractory to other treatments. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

  13. Single-Dose Pharmacokinetics of Methylphenidate Extended-Release Multiple Layer Beads Administered as Intact Capsule or Sprinkles Versus Methylphenidate Immediate-Release Tablets (Ritalin®) in Healthy Adult Volunteers

    PubMed Central

    Teuscher, Nathan S.; Kupper, Robert J.; Chang, Wei-Wei; Greenhill, Laurence; Newcorn, Jeffrey H.; Connor, Daniel F.; Wigal, Sharon

    2014-01-01

    Abstract Objectives: The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin®) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths. Methods: This was a single-center, randomized, open-label, three-period crossover study conducted in 26 fasted healthy adults (mean weight±standard deviation, 70.4±11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1×5 mg and 1×20 mg tablet) administered at 0, 4, and 8 hours. Results: MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3–112.4), 0.99 (95% CI, 95.3–102.8), and 0.99 (95% CI, 95.4–103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated

  14. Single-dose pharmacokinetics of methylphenidate extended-release multiple layer beads administered as intact capsule or sprinkles versus methylphenidate immediate-release tablets (Ritalin(®)) in healthy adult volunteers.

    PubMed

    Adjei, Akwete; Teuscher, Nathan S; Kupper, Robert J; Chang, Wei-Wei; Greenhill, Laurence; Newcorn, Jeffrey H; Connor, Daniel F; Wigal, Sharon

    2014-12-01

    The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin(®)) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths. This was a single-center, randomized, open-label, three-period crossover study conducted in 26 fasted healthy adults (mean weight±standard deviation, 70.4±11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1×5 mg and 1×20 mg tablet) administered at 0, 4, and 8 hours. MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3-112.4), 0.99 (95% CI, 95.3-102.8), and 0.99 (95% CI, 95.4-103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated absorption profiles of MPH. MPH-MLR 80

  15. Quality of life, binge eating and sexual function in participants treated for obesity with sustained release naltrexone/bupropion.

    PubMed

    Halseth, A; Shan, K; Gilder, K; Malone, M; Acevedo, L; Fujioka, K

    2018-04-01

    This multicenter, randomized, controlled, open-label trial examined weight-related quality of life, control over eating behaviour and sexual function after 26 weeks of treatment with either 32 mg naltrexone sustained release (SR)/360 mg bupropion SR plus a comprehensive lifestyle intervention program (NB + CLI, N = 153) or usual care (UC, N = 89), which included minimal lifestyle intervention. Impact of Weight on Quality of Life-Lite, Binge Eating Scale and Arizona Sexual Experiences Scale were assessed at baseline (BL) and weeks 16 and 26. NB + CLI and UC participants lost 9.46 and 0.94% respectively of initial body weight at week 26 (P < 0.0001). NB + CLI participants had greater improvements in Impact of Weight on Quality of Life-Lite total score than UC participants (P < 0.0001). In participants with moderate/severe Binge Eating Scale scores at BL, 91% of NB + CLI and 18% of UC participants experienced categorical improvements. In participants with Arizona Sexual Experiences Scale-defined sexual dysfunction at BL, 58% of NB + CLI and 19% of UC participants no longer met dysfunction criteria at week 26. The most frequent adverse events leading to discontinuation before week 26 in NB + CLI included nausea (10.5%); anxiety (3.3%); and headache, hypertension, insomnia and palpitations (1.3% each). Compared with UC, participants treated with NB + CLI experienced greater improvements in weight-related quality of life, control over eating behaviour, and sexual function.

  16. Cinacalcet hydrochloride (Amgen).

    PubMed

    Iqbal, Jameel; Zaidi, Mone; Schneider, Adina E

    2003-06-01

    Amgen Inc and Kirin Brewery Co Ltd, under license from NPS Pharmaceuticals Inc, are developing cinacalcet hydrochloride, the lead compound in a series of calcimimetics, for the potential treatment of primary and secondary hyperparathyroidism. Tecalcet hydrochloride was the first compound from this class to be extensively studied and most of the pharmacological data disclosed is for this compound. Cinacalcet hydrochloride was developed in an effort to improve on the poor pharmacokinetics and metabolism of tecalcet hydrochloride.

  17. Extended release of high molecular weight hydroxypropyl methylcellulose from molecularly imprinted, extended wear silicone hydrogel contact lenses.

    PubMed

    White, Charles J; McBride, Matthew K; Pate, Kayla M; Tieppo, Arianna; Byrne, Mark E

    2011-08-01

    Symptoms of contact lenses induced dry eye (CLIDE) are typically treated through application of macromolecular re-wetting agents via eye drops. Therapeutic soft contact lenses can be formulated to alleviate CLIDE symptoms by slowly releasing comfort agent from the lens. In this paper, we present an extended wear silicone hydrogel contact lens with extended, controllable release of 120 kDa hydroxypropyl methylcellulose (HPMC) using a molecular imprinting strategy. A commercial silicone hydrogel lens was tailored to release approximately 1000 μg of HPMC over a period of up to 60 days in a constant manner at a rate of 16 μg/day under physiological flowrates, releasing over the entire range of continuous wear. Release rates could be significantly varied by the imprinting effect and functional monomer to template ratio (M/T) with M/T values 0, 0.2, 2.8, 3.4 corresponding to HPMC release durations of 10, 13, 23, and 53 days, respectively. Lenses had high optical quality and adequate mechanical properties for contact lens use. This work highlights the potential of imprinting in the design and engineering of silicone hydrogel lenses to release macromolecules for the duration of wear, which may lead to decreased CLIDE symptoms and more comfortable contact lenses. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Cost-Effectiveness of Buprenorphine and Naltrexone Treatments for Heroin Dependence in Malaysia

    PubMed Central

    Ruger, Jennifer Prah; Chawarski, Marek; Mazlan, Mahmud; Ng, Nora; Schottenfeld, Richard

    2012-01-01

    Aims To aid public health policymaking, we studied the cost-effectiveness of buprenorphine, naltrexone, and placebo interventions for heroin dependence in Malaysia. Design We estimated the cost-effectiveness ratios of three treatments for heroin dependence. We used a microcosting methodology to determine fixed, variable, and societal costs of each intervention. Cost data were collected from investigators, staff, and project records on the number and type of resources used and unit costs; societal costs for participants’ time were estimated using Malaysia’s minimum wage. Costs were estimated from a provider and societal perspective and reported in 2004 US dollars. Setting Muar, Malaysia. Participants 126 patients enrolled in a randomized, double-blind, placebo-controlled clinical trial in Malaysia (2003–2005) receiving counseling and buprenorphine, naltrexone, or placebo for treatment of heroin dependence. Measurements Primary outcome measures included days in treatment, maximum consecutive days of heroin abstinence, days to first heroin use, and days to heroin relapse. Secondary outcome measures included treatment retention, injection drug use, illicit opiate use, AIDS Risk Inventory total score, and drug risk and sex risk subscores. Findings Buprenorphine was more effective and more costly than naltrexone for all primary and most secondary outcomes. Incremental cost-effectiveness ratios were below $50 for primary outcomes, mostly below $350 for secondary outcomes. Naltrexone was dominated by placebo for all secondary outcomes at almost all endpoints. Incremental treatment costs were driven mainly by medication costs, especially the price of buprenorphine. Conclusions Buprenorphine appears to be a cost-effective alternative to naltrexone that might enhance economic productivity and reduce drug use over a longer term. PMID:23226534

  19. Reduction of Alcohol Drinking in Young Adults by Naltrexone: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial of Efficacy and Safety

    PubMed Central

    O’Malley, Stephanie S.; Corbin, William R.; Leeman, Robert F.; DeMartini, Kelly S.; Fucito, Lisa M.; Ikomi, Jolomi; Romano, Denise M.; Wu, Ran; Toll, Benjamin A.; Sher, Kenneth J.; Gueorguieva, Ralitza; Kranzler, Henry R.

    2015-01-01

    Objective Naltrexone, an opioid antagonist, may facilitate reduction in drinking among young adults. We compared the efficacy and safety of naltrexone administered daily plus targeted dosing with placebo to reduce drinking in heavy drinking young adults. Methods Randomized, double-blind, placebo-controlled study, outpatient research center, March 2008-January 2012. Participants were ages 18-25, reporting ≥ 4 heavy drinking days in the prior 4 weeks. Interventions included naltrexone 25 mg daily plus 25 mg targeted (at most daily) in anticipation of drinking (n = 61) or daily/targeted placebo (n = 67). All received a personalized feedback session and brief counseling every other week. Primary outcomes were percent days heavy drinking (PHDD) and percent days abstinent (PDA) over the 8-week treatment period. Secondary outcomes included drinks/drinking day and percent days with estimated blood alcohol levels ≥0.08 g/dL. Results Of 140 randomized, 128 began treatment, comprising the evaluable sample. During treatment, PHDD (Naltrexone M=21.60, SD=16.05; Placebo M=22.90, SD=13.20) (p=0.58) and PDA (Naltrexone M=56.60, SD=22.52; Placebo M=62.50, SD=15.75) (p=0.39) did not differ by group. Naltrexone significantly reduced drinks per drinking day (Naltrexone M=4.90, SD=2.28; Placebo M=5.90, SD=2.51) (p=0.009) and percentage of drinking days with estimated BAC ≥0.08 g/dL (Naltrexone M=35.36, SD=28.40; Placebo M=45.74, SD=26.80) (p=0.042). There were no serious adverse events. Sleepiness was more common with naltrexone. Conclusions Naltrexone did not reduce frequency of drinking or heavy drinking days, but reduced secondary measures of drinking intensity. While effects were modest, the risk-benefit ratio favors offering naltrexone to help young adult heavy drinkers reduce their drinking. Registration clinicaltrials.gov NCT00568958 PMID:25742208

  20. Formulation of bi-layer matrix tablets of tramadol hydrochloride: Comparison of rate retarding ability of the incorporated hydrophilic polymers.

    PubMed

    Arif, Hasanul; Al-Masum, Abdullah; Sharmin, Florida; Reza, Selim; Sm Islam, Sm Ashraful

    2015-05-01

    Bi-layer tablets of tramadol hydrochloride were prepared by direct compression technique. Each tablet contains an instant release layer with a sustained release layer. The instant release layer was found to release the initial dose immediately within minutes. The instant release layer was combined with sustained release matrix made of varying quantity of Methocel K4M, Methocel K15MCR and Carbomer 974P. Bi-layer tablets were evaluated for various physical tests including weight variation, thickness and diameter, hardness and percent friability. Drug release from bi-layer tablet was studied in acidic medium and buffer medium for two and six hours respectively. Sustained release of tramadol hydrochloride was observed with a controlled fashion that was characteristic to the type and extent of polymer used. % Drug release from eight-hour dissolution study was fitted with several kinetic models. Mean dissolution time (MDT) and fractional dissolution values (T25%, T50% and T80%) were also calculated as well, to compare the retarding ability of the polymers. Methocel K15MCR was found to be the most effective in rate retardation of freely water-soluble tramadol hydrochloride compared to Methocel K4M and Capbomer 974P, when incorporated at equal ratio in the formulation.

  1. Daily relations among affect, urge, targeted naltrexone, and alcohol use in young adults

    PubMed Central

    Bold, Krysten W.; Fucito, Lisa M.; Corbin, William R.; DeMartini, Kelly S.; Leeman, Robert F.; Kranzler, Henry R.; O’Malley, Stephanie S.

    2016-01-01

    Heavy drinking among young adults is a serious public health problem. Naltrexone, an opioid antagonist, has been shown to reduce drinking in young adults compared to placebo and can be taken on a targeted (i.e., as needed) basis. Understanding risk factors for drinking and naltrexone effects within-person in young adults may help to optimize the use of targeted naltrexone. The current study was a secondary analysis of daily diary data from 127 (n=40 female) young adults (age 18-25) enrolled in a double-blind clinical trial of daily (25 mg) plus targeted (25 mg) naltrexone versus placebo. Hierarchical linear models were used to examine the effects of daily affect, urge, and taking targeted medication on same-day risk of drinking to intoxication (defined as estimated blood-alcohol-concentration, BAC≥.08g%). Results indicated urge significantly mediated within-person positive affect–drinking relations on a daily level. Specifically, positive affect was associated with greater urge to drink, which in turn was associated with greater odds of BAC≥.08g%. Furthermore, days of greater positive affect and urge were associated with taking a targeted dose of medication, which reduced the likelihood of intoxication by nearly 23% in the naltrexone group compared to placebo. Gender and family history of alcohol dependence were examined as moderators of these daily level effects. These results provide further evidence of naltrexone’s ability to reduce alcohol consumption in young adults and identify potential within-person risk processes related to heavy drinking that could inform alcohol-related interventions for this population. PMID:27690505

  2. Effects of naltrexone on alcohol drinking patterns and extinction of alcohol seeking in baboons

    PubMed Central

    Kaminski, Barbara J.; Duke, Angela N.; Weerts, Elise M.

    2012-01-01

    Rationale Understanding naltrexone’s effect on motivation to drink and pattern of drinking is important for better treatment outcomes and for comparison with novel medications. Objectives Naltrexone’s effects on number and pattern of seeking, self-administration, and extinction responses were evaluated in two groups of baboons trained under a 3 component chained schedule of reinforcement (CSR). Methods Alcohol (4% w/v; n=4; Alcohol Group) or a preferred non-alcoholic beverage (n=4; Control Group) was available for self-administration only in Component 3 of the CSR. Responses in Component 2 provided indices of motivation to drink (seeking). Naltrexone (0.32 – 3.2 mg/kg) and saline were administered before drinking and Component 2 extinction sessions. Results Acute doses of naltrexone significantly decreased total self-administration responses (p<0.01), intake volume (p<0.001) and g/kg of alcohol (p<0.01) in the Alcohol Group only. Pattern of drinking did not change, but number of drinks during the initial drinking bout was decreased significantly by naltrexone for both groups (P<0.05). During within-session extinction tests, acute naltrexone significantly decreased time to reach extinction (p<0.01) and number of seeking responses (p<0.05), particularly early in the extinction period in the Alcohol Group only. When administered chronically, naltrexone did not decrease progressive-ratio breaking points to gain access to alcohol, but dose-dependently reduced alcohol self-administration (p<0.05) by decreasing the magnitude of the initial drinking bout. Conclusions The results support clinical observations that naltrexone may be most effective at reducing self-administration in the context of ongoing alcohol availability and may reduce motivation to drink in the presence of alcohol-related cues. PMID:22451093

  3. Glucosamine Hydrochloride

    MedlinePlus

    ... sulfate. People take glucosamine hydrochloride by mouth for osteoarthritis, rheumatoid arthritis, glaucoma, a jaw disorder called temporomandibular ... with chondroitin sulfate, shark cartilage, and camphor for osteoarthritis. Glucosamine hydrochloride is used parenterally and short-term ...

  4. Yohimbine hydrochloride as an antagonist to xylazine hydrochloride-ketamine hydrochloride immobilization of white-tailed deer

    USGS Publications Warehouse

    Mech, L.D.; DelGiudice, G.D.; Karns, P.D.; Seal, U.S.

    1985-01-01

    Thirteen captive and one free-ranging white-tailed deer (Odocoileus virginianus) were immobilized one to six times each with ketamine hydrochloride and xylazine hydrochloride during winter and spring in northern Minnesota. Administration of 0.09 to 0.53 mg of yohimbine hydrochloride per kg IV after each trial reversed the immobilization. The deer raised their heads within a median time of 2.0 min, stood in 6.0 min and walked away in 9.5 min. No adverse side effects were observed for several weeks following the immobilization.

  5. Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn's disease: a pilot study.

    PubMed

    Smith, Jill P; Field, Douglas; Bingaman, Sandra I; Evans, Robert; Mauger, David T

    2013-04-01

    There is an unmet need for safe and effective medicines to treat children with Crohn's disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells. The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn's disease. A pilot clinical trial was conducted in children with moderate to severe Crohn's disease. Fourteen subjects with a mean age of 12.3 years (range, 8 to 17 y) were enrolled. Children were randomized to placebo or naltrexone (0.1 mg/kg) orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the Pediatric Crohn's Disease Activity Index (PCDAI) and Quality of life was monitored by the Impact III survey. Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn's disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an 8-week course of naltrexone therapy (21.7±3.9) (P=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score ≤10) and 67% had improved with mild disease activity (decrease in PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (P=0.035). Naltrexone therapy seems safe with limited toxicity when given to children with Crohn's disease and may reduce disease activity.

  6. The Properties of HPMC:PEO Extended Release Hydrophilic Matrices and their Response to Ionic Environments.

    PubMed

    Hu, Anran; Chen, Chen; Mantle, Michael D; Wolf, Bettina; Gladden, Lynn F; Rajabi-Siahboomi, Ali; Missaghi, Shahrzad; Mason, Laura; Melia, Colin D

    2017-05-01

    Investigate the extended release behaviour of compacts containing mixtures of hydrophilic HPMC and PEO in hydrating media of differing ionic strengths. The extended release behaviour of various HPMC:PEO compacts was investigated using dissolution testing, confocal microscopy and magnetic resonance imaging, with respect to polymer ratio and ionic strength of the hydrating media. Increasing HPMC content gave longer extended release times, but a greater sensitivity to high ionic dissolution environments. Increasing PEO content reduced this sensitivity. The addition of PEO to a predominantly HPMC matrix reduced release rate sensitivity to high ionic environments. Confocal microscopy of early gel layer development showed the two polymers appeared to contribute independently to gel layer structure whilst together forming a coherent and effective diffusion barrier. There was some evidence that poorly swollen HPMC particles added a tortuosity barrier to the gel layer in high ionic strength environments, resulting in prolonged extended release. MRI provides unique, non-invasive spatially resolved information from within the HPMC:PEO compacts that furthers our understanding of USP 1 and USP 4 dissolution data. Confocal microscopy and MRI data show that combinations of HPMC and PEO have advantageous extended release properties, in comparison with matrices containing a single polymer.

  7. Clinical Effects of Naltrexone on Autistic Behavior.

    ERIC Educational Resources Information Center

    Zingarelli, Gene; And Others

    1992-01-01

    Eight young adults (ages 19-39) with autism were given the opiate antagonist naltrexone to control self-injurious behavior and maladaptive idiosyncratic mannerisms. Although one subject appeared to have partial decreases in maladaptive behaviors, the drug did not clearly reduce the self-injurious and other maladaptive behaviors of the subjects.…

  8. The influence of Surelease and sodium alginate on the in-vitro release of tamsulosin hydrochloride in pellet dosage form.

    PubMed

    Kim, Min-Soo; Jun, Seoung Wook; Lee, Sibeum; Lee, Tae Wan; Park, Jeong-Sook; Hwang, Sung-Joo

    2005-06-01

    The objective of this study was to prepare controlled-release pellets containing 0.2 mg tamsulosin hydrochloride using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers with Surelease and sodium alginate. The release of tamsulosin HCl from pellets coated with the commercial aqueous ethylcellulose dispersion (Surelease) was investigated at different coating loads. In addition, the effect of sodium alginate on drug release was investigated by varying the ratio of sodium alginate to microcrystalline cellulose (MCC). Dissolution studies were first performed in 500 mL simulated gastric fluid (pH 1.2) containing 0.003% (w/w) polysorbate 80 and then in simulated intestinal fluids (pH 7.2). The morphology of pellet surfaces and cross sections were examined by scanning electron microscopy (SEM). Apparently, the spherical pellets were prepared using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers. The release profiles of tamsulosin HCl from Surelease-coated pellets were significantly affected by changing the content of Surelease, the pH of the dissolution medium and the ratio of sodium alginate to MCC. The drug release rates not only decreased with increase in the coating load, but also increased when the pH of the dissolution medium was increased from 1.2 to 7.2 regardless of the sodium alginate-to-MCC ratio. Moreover, the drug release rate at pH 7.2 was gradually increased by increasing the ratio of sodium alginate to MCC. SEM showed smooth surfaces of Surelease-coated pellets. These results suggest that Surelease and sodium alginate would be useful excipients in the preparation of controlled-release pellets with the desired release profiles.

  9. Quality of life, binge eating and sexual function in participants treated for obesity with sustained release naltrexone/bupropion

    PubMed Central

    Shan, K.; Gilder, K.; Malone, M.; Acevedo, L.; Fujioka, K.

    2018-01-01

    Summary Objective This multicenter, randomized, controlled, open‐label trial examined weight‐related quality of life, control over eating behaviour and sexual function after 26 weeks of treatment with either 32 mg naltrexone sustained release (SR)/360 mg bupropion SR plus a comprehensive lifestyle intervention program (NB + CLI, N = 153) or usual care (UC, N = 89), which included minimal lifestyle intervention. Methods Impact of Weight on Quality of Life‐Lite, Binge Eating Scale and Arizona Sexual Experiences Scale were assessed at baseline (BL) and weeks 16 and 26. Results NB + CLI and UC participants lost 9.46 and 0.94% respectively of initial body weight at week 26 (P < 0.0001). NB + CLI participants had greater improvements in Impact of Weight on Quality of Life‐Lite total score than UC participants (P < 0.0001). In participants with moderate/severe Binge Eating Scale scores at BL, 91% of NB + CLI and 18% of UC participants experienced categorical improvements. In participants with Arizona Sexual Experiences Scale‐defined sexual dysfunction at BL, 58% of NB + CLI and 19% of UC participants no longer met dysfunction criteria at week 26. The most frequent adverse events leading to discontinuation before week 26 in NB + CLI included nausea (10.5%); anxiety (3.3%); and headache, hypertension, insomnia and palpitations (1.3% each). Conclusion Compared with UC, participants treated with NB + CLI experienced greater improvements in weight‐related quality of life, control over eating behaviour, and sexual function. PMID:29670752

  10. Dosage form design and in vitro/in vivo evaluation of cevimeline extended-release tablet formulations.

    PubMed

    Tajiri, Shinichiro; Kanamaru, Taro; Kamada, Makoto; Makoto, Kamada; Konno, Tsutomu; Nakagami, Hiroaki

    2010-01-04

    The objective of the present work is to develop an extended-release dosage form of cevimeline. Two types of extended-release tablets (simple matrix tablets and press-coated tablets) were prepared and their potential as extended-release dosage forms were assessed. Simple matrix tablets have a large amount of hydroxypropylcellulose as a rate-controlling polymer and the matrix is homogeneous throughout the tablet. The press-coated tablets consisted of a matrix core tablet, which was completely surrounded by an outer shell containing a large amount of hydroxypropylcellulose. The simple matrix tablets could not sustain the release of cevimeline effectively. In contrast, the press-coated tablets showed a slower dissolution rate compared with simple matrix tablets and the release curve was nearly linear. The dissolution of cevimeline from the press-coated tablets was not markedly affected by the pH of the dissolution medium or by a paddle rotating speed over the range of 50-200 rpm. Furthermore, cevimeline was constantly released from the press-coated tablets in the gastrointestinal tract and the steady-state plasma drug levels were maintained in beagle dogs. These results suggested that the designed PC tablets have a potential for extended-release dosage forms.

  11. Real-time assessment of alcohol craving and naltrexone treatment responsiveness in a randomized clinical trial.

    PubMed

    Miranda, Robert; Treloar Padovano, Hayley; Gray, Joshua C; Wemm, Stephanie E; Blanchard, Alexander

    2018-08-01

    This secondary data analysis examined whether and how the dopamine receptor D 4 gene (DRD4) influenced naltrexone treatment responsiveness in a randomized clinical trial. We leveraged intensive experience sampling methods to test the hypothesis that craving recorded at drinking and non-drinking moments would mediate naltrexone effects on the likelihood of heavy drinking, but only among carriers of the DRD4 long (DRD4-L) allele. Participants (M age =29.8years, SD=12.1) were non-treatment seeking heavy drinkers (n=104, 54.8% female, 61.5% alcohol dependent) randomized to 3weeks of daily naltrexone (50mg) or placebo. During these 3weeks, participants used handheld electronic devices to complete real-time reports of alcohol use and craving multiple times per day in their natural environments. This approach afforded intensive repeated assessment of focal variables and provided in-the-moment data to test whether craving when not drinking or early in drinking episodes explained naltrexone effects on drinking. Moderated-mediation multilevel structural equation models showed that craving during non-drinking moments mediated the treatment effect of naltrexone on heavy drinking but only among carriers of the DRD4-L allele. The same pattern of associations was not shown when evaluating craving while participants were consuming alcoholic beverages. Findings provide the first in vivo evidence that, among carriers of the DRD4-L allele, naltrexone blunts craving in real-world settings, and this effect in turn reduces the likelihood of heavy drinking. This work highlights the utility of EMA methods for elucidating how treatments work and further demonstrates the importance of genetic factors for understanding individual differences in pharmacotherapy responsiveness. Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. 21 CFR 522.1222b - Ketamine hydrochloride with promazine hydrochloride and aminopentamide hydrogen sulfate injection.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... hydrochloride and aminopentamide hydrogen sulfate injection. 522.1222b Section 522.1222b Food and Drugs FOOD AND... hydrochloride with promazine hydrochloride and aminopentamide hydrogen sulfate injection. (a) Chemical name... hydrochloride, 10-[3-(dimethylamino) propyl] phenothiazine monohydrochloride, and aminopentamide hydrogen...

  13. 21 CFR 522.1222b - Ketamine hydrochloride with promazine hydrochloride and aminopentamide hydrogen sulfate injection.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... hydrochloride and aminopentamide hydrogen sulfate injection. 522.1222b Section 522.1222b Food and Drugs FOOD AND... hydrochloride with promazine hydrochloride and aminopentamide hydrogen sulfate injection. (a) Chemical name... hydrochloride, 10-[3-(dimethylamino) propyl] phenothiazine monohydrochloride, and aminopentamide hydrogen...

  14. 21 CFR 522.1222b - Ketamine hydrochloride with promazine hydrochloride and aminopentamide hydrogen sulfate injection.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... hydrochloride and aminopentamide hydrogen sulfate injection. 522.1222b Section 522.1222b Food and Drugs FOOD AND... hydrochloride with promazine hydrochloride and aminopentamide hydrogen sulfate injection. (a) Chemical name... hydrochloride, 10-[3-(dimethylamino) propyl] phenothiazine monohydrochloride, and aminopentamide hydrogen...

  15. 21 CFR 522.1222b - Ketamine hydrochloride with promazine hydrochloride and aminopentamide hydrogen sulfate injection.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... hydrochloride and aminopentamide hydrogen sulfate injection. 522.1222b Section 522.1222b Food and Drugs FOOD AND... hydrochloride with promazine hydrochloride and aminopentamide hydrogen sulfate injection. (a) Chemical name... hydrochloride, 10-[3-(dimethylamino) propyl] phenothiazine monohydrochloride, and aminopentamide hydrogen...

  16. EFFECT OF MAGNESIUM STEARATE CONCENTRATION ON DISSOLUTION PROPERTIES OF RANITIDINE HYDROCHLORIDE COATED TABLETS

    PubMed Central

    Uzunović, Alija; Vranić, Edina

    2007-01-01

    Most pharmaceutical formulations also include a certain amount of lubricant to improve their flowability and prevent their adhesion to the surfaces of processing equipment. Magnesium stearate is an additive that is most frequently used as a lubricant. Magnesium stearate is capable of forming films on other tablet excipients during prolonged mixing, leading to a prolonged drug liberation time, a decrease in hardness, and an increase in disintegration time. It is hydrophobic, and there are many reports in the literature concerning its adverse effect on dissolution rates. The objective of this study was to evaluate the effects of two different concentrations of magnesium stearate on dissolution properties of ranitidine hydrochloride coated tablet formulations labeled to contain 150 mg. The uniformity content was also checked. During the drug formulation development, several samples were designed for choice of the formulation. For this study, two formulations containing 0,77 and 1,1% of magnesium stearate added in the manufacture of cores were chosen. Fraction of ranitidine hydrochloride released in dissolution medium was calculated from calibration curves. The data were analyzed using pharmaco-peial test for similarity of dissolution profiles (f2 equation), previously proposed by Moore and Flanner. Application of f2 equation showed differences in time-course of ranitidine hydrochloride dissolution properties. The obtained values indicate differences in drug release from analyzed ranitidine hydrochloride formulations and could cause differences in therapeutic response. PMID:17848158

  17. What role does measuring medication compliance play in evaluating the efficacy of naltrexone?

    PubMed

    Baros, Alicia M; Latham, Patricia K; Moak, Darlene H; Voronin, Konstantin; Anton, Raymond F

    2007-04-01

    Compliance with medication in pharmacotherapy trials of alcoholism has been shown to be equal to, or more, important than in other areas of medicine. Research has suggested that naltrexone's effectiveness can be greatly influenced by the compliance of participants in clinical trials. Presently, we compare 2 compliance measurement methods [urine riboflavin and medication event monitoring system (MEMS)] used simultaneously to evaluate naltrexone's efficacy and the impact of compliance on the size of observable treatment effects. One hundred and thirty-seven of 160 randomized alcoholic patients completed 12-weeks (84 days) of naltrexone or placebo and cognitive behavioral therapy (CBT) or motivational enhancement therapy (MET). Urine riboflavin was determined during study weeks 2, 6, and 12. The MEMS provided a detailed computerized record of when a participant opened their medication bottle throughout the trial. Baseline predictors of MEMS (80% openings) and urine riboflavin (>or=1,500 ng/mL by fluorimetry) compliance were examined. The effects of the treatments in the compliant participants defined by one, the other, or both methods were compared and contrasted with a previously reported intent-to-treat analysis where compliance was not taken into account. Age was predictive of compliance. 105 participants were deemed compliant via urine riboflavin criteria, 87 via MEMS, and 77 when both criteria were met, with no significant differences between treatment groups. The most compliant participants showed a significant medication by therapy interaction. Those treated with naltrexone/CBT showed more abstinence days (p<0.03), less heavy drinking days (p<0.03) and less total drinks (p<0.03) than the other groups. The effect size of this interaction increased from about 0.2 in the intent-to-treat analysis, to about 0.4 to 0.5 in the compliant group analyses, with little difference between compliance measurement methods. Compliance measurement does appear to influence the

  18. SAFETY AND TOLERABILITY OF LOW DOSE NALTREXONE THERAPY IN CHILDREN WITH MODERATE TO SEVERE CROHN’S DISEASE: A PILOT STUDY

    PubMed Central

    Smith, Jill P.; Field, Douglas; Bingaman, Sandra; Evans, Robert; Mauger, David

    2012-01-01

    Background There is an unmet need for safe and effective medicines to treat children with Crohn’s disease. Recently, investigations have shown an association between endogenous opioid peptides and inflammatory cells. Aims The aims of this study were to evaluate the safety and tolerability of an opioid antagonist, naltrexone, in children with moderate to severe Crohn’s disease. Methods A pilot clinical trial was conducted in children with moderate to severe Crohn’s disease. Fourteen subjects with a mean age of 12.3 years (8–17, range) were enrolled. Children were randomized to placebo or naltrexone 0.1 mg/kg orally for 8 weeks followed by open-labeled treatment with 8 additional weeks of naltrexone. Safety and toxicity were monitored by physical examinations and blood chemistries. Clinical activity was assessed by the PCDAI (Pediatric Crohn’s Disease Activity Index) and Quality of life was monitored by the Impact III survey. Results Oral naltrexone was well tolerated without any serious adverse events in children with moderate to severe Crohn’s disease. PCDAI scores significantly decreased from pretreatment values (34.2±3.3) with an eight-week course of naltrexone therapy (21.7±3.9) (p=0.005). Twenty-five percent of those treated with naltrexone were considered in remission (score < 10) and 67% had improved with mild disease activity (decrease PCDAI score by at least 10 points) at the end of the study. Systemic and social quality of life improved with naltrexone treatment (p=0.035). Conclusions Naltrexone therapy appears safe with limited toxicity when given to children with Crohn’s disease and may reduce disease activity. PMID:23188075

  19. Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay.

    PubMed

    Dodou, Kalliopi; Armstrong, Andrew; Kelly, Ivan; Wilkinson, Simon; Carr, Kevin; Shattock, Paul; Whiteley, Paul

    2015-01-01

    Naltrexone (NTX) is a long-acting opiate antagonist. Low-dose naltrexone (LDN) therapy has shown promising results in the treatment of several autoimmune disorders. Our aim was to formulate NTX into a cream for the delivery of LDN and develop an analytical technique for the quantification of NTX and its active metabolite 6-β-naltrexol (NTXol) during transdermal diffusion cell permeation studies. A 1% w/w NTX cream was formulated and drug permeation was examined over 24 h using static Franz diffusion cells mounted with pig skin. A Liquid Chromatography Quadrupole-Time of Flight Mass Spectrometry (LC-MS Q-ToF) method was developed for the detection of NTX and NTXol in the receptor solution, skin membrane and residual cream on the donor chamber after completion of the diffusion studies. The cream formulation exhibited steady state release of NTX over 24 h after an initial lag time of 2.74 h. The bioconversion of NTX to NTXol in the skin membrane was 1.1%. It was concluded that the cream may be an effective formulation for the sustained transdermal delivery of LDN. The novel LC Q-ToF MS method allowed the accurate measurement of NTX and NTXol levels across the diffusion cell assemblies and the quantification of NTX metabolism in the skin.

  20. Self-association of analgesics in aqueous solution: micellar properties of dextropropoxyphene hydrochloride and methadone hydrochloride.

    PubMed

    Attwood, D; Tolley, J A

    1980-08-01

    The solution properties of several analgesics including dextropropoxyphene hydrochloride, methadone hydrochloride, dextromoramide acid tartrate and dipipanone hydrochloride have been examined using light scattering, conductivity, vapour pressure osmometry and surface tension techniques. A micellar pattern of association was established for dextropropoxyphene hydrochloride and methadone hydrochloride and critical micelle concentrations and aggregation numbers are reported. The hydrophobic contribution to the free energy of micellization of dextropropoxyphene was determined from measurement of the critical micelle concentration in the presence of added electrolyte.

  1. Low-dose naltrexone augmentation of nicotine replacement for smoking cessation with reduced weight gain: a randomized trial.

    PubMed

    Toll, Benjamin A; White, Marney; Wu, Ran; Meandzija, Boris; Jatlow, Peter; Makuch, Robert; O'Malley, Stephanie S

    2010-10-01

    Fear of weight gain is a significant obstacle to smoking cessation, preventing some smokers from attempting to quit. Several previous studies of naltrexone yielded promising results for minimization of post-quit weight gain. Given these encouraging findings, we endeavored to test whether minimization of weight gain might translate to better quit outcomes for a population that is particularly concerned about gaining weight upon quitting. Smokers (N=172) in this investigation were prospectively randomized to receive either 25 mg naltrexone or placebo for 27 weeks (1 week pre-, 26 weeks post-quit) for minimization of post-quit weight gain and smoking cessation. All participants received open label therapy with the nicotine patch for the first 8 weeks post-quit and behavioral counseling over the 27-week treatment. The 2 pre-specified primary outcomes were change in weight for continuously abstinent participants and biologically verified end-of-treatment 7-day point-prevalence abstinence at 26 weeks after the quit date. The difference in weight at 26 weeks post-quit between the naltrexone and placebo groups (naltrexone: 6.8 lbs ± 8.94 vs placebo: 9.7 lbs ± 9.19, p = 0.45) was not statistically different. Seven-day point-prevalence smoking abstinence rates at 26 weeks post-quit was not significantly different between the 2 groups (naltrexone: 22% vs placebo: 27%, p = 0.43). For smokers high in weight concern, the relatively small reduction in weight gain with low-dose naltrexone is not worth the potential for somewhat lower rates of smoking abstinence. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  2. Naltrexone Alone and With Sertraline for the Treatment of Alcohol Dependence in Alaska Natives and Non-Natives Residing in Rural Settings: A Randomized Controlled Trial

    PubMed Central

    O’Malley, Stephanie S.; Robin, Robert W.; Levenson, Aryeh L.; GreyWolf, Iva; Chance, Lawrence E.; Hodgkinson, Colin A.; Romano, Denise; Robinson, Jane; Meandzija, Boris; Stillner, Verner; Wu, Ran; Goldman, David

    2009-01-01

    Background Access to specialty alcoholism treatment in rural environments is limited and new treatment approaches are needed. The objective was to evaluate the efficacy of naltrexone alone and in combination with sertraline among Alaska Natives and other Alaskans living in rural settings. An exploratory aim examined whether the Asn40Asp polymorphism of the μ-opioid receptor gene (OPRMI) predicted response to naltrexone, as had been reported in Caucasians. Methods Randomized, controlled trial enrolling 101 Alaskans with alcohol dependence, including 68 American Indians/Alaska Natives. Participants received 16 weeks of either (1) placebo (placebo naltrexone + placebo sertraline), (2) naltrexone monotherapy (50 mg naltrexone + sertraline placebo) and (3) naltrexone + sertraline (100 mg) plus nine sessions of medical management and supportive advice. Primary outcomes included Time to First Heavy Drinking Day and Total Abstinence. Results Naltrexone monotherapy demonstrated significantly higher total abstinence (35%) compared with placebo (12%, p = 0027) and longer, but not statistically different, Time to First Heavy Drinking Day (p = 0.093). On secondary measures, naltrexone compared with placebo demonstrated significant improvements in percent days abstinent (p = 0.024) and drinking-related consequences (p = 0.02). Combined sertraline and naltrexone did not differ from naltrexone alone. The pattern of findings was generally similar for the American Indian/Alaska Native sub-sample. Naltrexone treatment response was significant within the group of 75 individuals who were homozygous for OPRM1 Asn40 allele. There was a small number of Asp40 carriers, precluding statistical testing of the effect of this allele on response. Conclusions Naltrexone can be used effectively to treat alcoholism in remote and rural communities, with evidence of benefit for American Indians and Alaska Natives. New models of care incorporating pharmacotherapy could reduce important health

  3. A comparison of the extended-release and standard-release formulations of tacrolimus in de novo kidney transplant recipients: a 12-month outcome study.

    PubMed

    Fanous, Helen; Zheng, Rebecca; Campbell, Carolyn; Huang, Michael; Nash, Michelle M; Rapi, Lindita; Zaltzman, Jeffrey S; Prasad, G V Ramesh

    2013-02-01

    BACKGROUND: Limited comparative data are available on the outcomes between extended-release and standard-release tacrolimus when used de novo in kidney transplant recipients (KTRs). METHODS: We identified KTRs transplanted at our institution during 2009-10 routinely prescribed extended-release tacrolimus and compared them with those transplanted during 2008-09 prescribed standard-release tacrolimus. Graft function (eGFR by MDRD-7 equation) at 12 months post-transplant (primary outcome); new-onset diabetes and other cardiovascular risk factors, BK viremia incidence, acute rejection, and graft survival to 12 months (secondary outcomes) were compared by intent-to-treat analysis. Time-to-steady-state concentration and number of dose adjustments required to attain steady state were recorded. RESULTS: There were no important demographic differences between the extended-release (N = 106) and standard-release (N = 95) cohorts. The estimated glomerular filtration rate (eGFR) at 12 months was similar (58.8 ± 17 versus 59.2 ± 18 mL/min/1.73 m(2), P = 0.307). There was no difference in new-onset diabetes (17 versus 20%, P = 0.581), BK viremia (10 versus 7%, P = 0.450), acute rejection (7 versus 16%, P = 0.067) or graft survival (97 versus 95%, P = 0.301). Time-to-steady state was similar (9.2 ± 1.1 versus 8.1 ± 4.7 days, P = 0.490) although extended-release patients required fewer adjustments to attain steady state (1.2 ± 1.7 [0-8] versus 1.7 ± 1.5 [0-7], P = 0.030) but a similar dose (7.2 ± 2.4 [2-17] versus 7 ± 2.7 [2-16] mg/day, P = 0.697). CONCLUSION: De novo KTRs prescribed extended-release or standard-release tacrolimus demonstrate similar 12-month outcomes.

  4. Organizational-Level Predictors of Adoption Across Time: Naltrexone in Private Substance-Use Disorders Treatment Centers*

    PubMed Central

    Oser, Carrie B.; Roman, Paul M.

    2014-01-01

    Objective Prominent on the nation's research agenda on substance-use disorders treatment is the dissemination of effective pharmacotherapies. Thus, the purpose of this article is to use a “diffusion of innovations” theoretical framework to examine the organizational-level predictors of the adoption of a pharmacotherapy, naltrexone (Revia), in private substance use-disorders treatment centers (N = 165). Method Data for these analyses were derived from the National Treatment Center Study, which contains four waves of data collected between 1994 and 2003. An event history model examined the impact of culture, leadership characteristics, internal structure, and external characteristics on the likelihood of adopting naltrexone between 1994 and 2003. Results The results suggest that organizations embracing a 12-step model and those employing more experienced administrators were significantly less likely to adopt naltrexone. Moreover, treatment centers that used prescription drugs, possessed an employee handbook, were accredited, and operated on a for-profit basis were significantly more likely to adopt naltrexone over time. Conclusions Structural characteristics do affect the innovation adoption behaviors of private substance-use disorders treatment centers. Organizational-level “research to practice” implications to further the adoption of innovative evidence-based treatments are discussed. PMID:17960303

  5. Depot naltrexone in lieu of incarceration: a behavioral analysis of coerced treatment for addicted offenders.

    PubMed

    Marlowe, Douglas B

    2006-09-01

    This article is part of a series of articles examining a proposal to offer depot naltrexone to certain nonviolent opiate-addicted criminal offenders in exchange for release from incarceration or diversion from prosecution. This "negative-reinforcement" behavioral paradigm could have a better chance of success than what has heretofore been attempted with drug-abusing offenders. Traditional correctional efforts have been largely unsuccessful due to the complexities of implementation and the side effects of punishment. Although positive reinforcement can be more efficacious, it has often been strenuously resisted on the ground that it is inequitable to reward antisocial individuals for doing what is minimally expected of most citizens. Negative reinforcement steers between these hurdles by avoiding the iatrogenic effects of punishment, while also being palatable to stakeholders. More research is needed to identify the effects, costs, and side effects of negative-reinforcement arrangements for drug offenders. The current proposal provides an excellent platform for conducting this research because the target intervention (depot naltrexone) is demonstrably efficacious, nonpsychoactive, and has few, if any, side effects. Therefore, use of this medication would be unlikely to invoke the same types of legal and ethical objections that have traditionally been levied against the use of psychoactive medications with vulnerable populations of institutionalized offenders. Specific recommendations are offered for questions that must be addressed in future research studies.

  6. Modeling the pharmacokinetics of extended release pharmaceutical systems

    NASA Astrophysics Data System (ADS)

    di Muria, Michela; Lamberti, Gaetano; Titomanlio, Giuseppe

    2009-03-01

    The pharmacokinetic (PK) models predict the hematic concentration of drugs after the administration. In compartment modeling, the body is described by a set of interconnected “vessels” or “compartments”; the modeling consisting of transient mass balances. Usually the orally administered drugs were considered as immediately available: this cannot describe the administration of extended-release systems. In this work we added to the traditional compartment models the ability to account for a delay in administration, relating this delay to in vitro data. Firstly, the method was validated, applying the model to the dosage of nicotine by chewing-gum; the model was tuned by in vitro/in vivo data of drugs (divalproex-sodium and diltiazem) with medium-rate release kinetics, then it was applied in describing in vivo evolutions due to the assumption of fast- and slow-release systems. The model reveals itself predictive, the same of a Level A in vitro/in vivo correlation, but being physically based, it is preferable to a purely statistical method.

  7. Genetic ancestry as an effect modifier of naltrexone in smoking cessation among African Americans: an analysis of a randomized controlled trial

    PubMed Central

    Bress, Adam; Kittles, Rick; Wing, Coady; Hooker, Stanley E; King, Andrea

    2015-01-01

    Objectives To determine if there were differential quit rates between AA and European Americans (EA) with the experimental treatment naltrexone, and examine the role of genetic ancestry on these outcomes among AAs. Methods Data from a previous randomized trial of 315 smokers to naltrexone vs. placebo were reanalyzed using West African (WA) genetic ancestry to define sub-populations. Logistic regression models were used to estimate treatment effects on early and end of treatment quit rates, by race and WA ancestry. Results Among EAs (n=136), naltrexone significantly increased quit rates at four weeks (62% vs. 43%, p=0.03) with directional, but not statistically significant effects at 12 weeks (30% vs. 18%, p=0.12). In contrast, among the AAs (n=95), quit rates did not differ between naltrexone and placebo groups at either interval (four weeks: 43% vs. 32%, p=0.27; 12 weeks: 22% vs. 18%, p=0.60). A median split was conducted in AAs for WA ancestry. Among AAs with low WA ancestry, quit rates were significantly higher with naltrexone compared with placebo (60% vs. 27%, p=0.03). There was no advantage in quit rates with naltrexone for the high WA ancestry group. Conclusions Naltrexone efficacy for smoking cessation varies across AA subjects with different levels of WA ancestry. These results suggest that genetic background may partially explain racial differences in drug response. PMID:25918964

  8. Desipramine hydrochloride overdose

    MedlinePlus

    ... overdose To use the sharing features on this page, please enable JavaScript. Desipramine hydrochloride is a type of medicine called a tricyclic antidepressant. It is taken to relieve symptoms of depression. Desipramine hydrochloride overdose ...

  9. Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN).

    PubMed

    Chopra, Pradeep; Cooper, Mark S

    2013-06-01

    Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome, which involves glial activation and central sensitization in the central nervous system. Here, we describe positive outcomes of two CRPS patients, after they were treated with low-dose naltrexone (a glial attenuator), in combination with other CRPS therapies. Prominent CRPS symptoms remitted in these two patients, including dystonic spasms and fixed dystonia (respectively), following treatment with low-dose naltrexone (LDN). LDN, which is known to antagonize the Toll-like Receptor 4 pathway and attenuate activated microglia, was utilized in these patients after conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms.

  10. Dissolution Studies of Papaverine Hydrochloride from Tablets in Three Pharmacopoeia Apparatuses.

    PubMed

    Polski, Andrzej; Kasperek, Regina; Rogowska, Magdalena; Iwaniak, Karol; Sobòtka-Polska, Karolina; Poleszak, Ewa

    2015-01-01

    In tablet production, the most important aspects are the physical properties of the tablets and their dissolution studies, which can be performed in four pharmacopoeial apparatuses. There are differences between them in construction and action, so differences in the results obtained are possible. The aim of the study was to compare the release of a model drug substance (papaverine hydrochloride) from tablets in three pharmacopoeial dissolution apparatus: a basket, a paddle (closed system) and flow-through cell (open system). The one series of tablets were produced by direct compression in a tablet press. The physical properties of the tablets (weight and size uniformity test, friability and hardness tests, disintegration time test), drug content and the release study of papaverine hydrochloride from tablets were studied in three dissolution apparatuses. The content of the active substance was studied spectrophotometrically. All tablets met the pharmacopoeic requirements. Over 80% of the model substance released from the tablets after 14 min in flow through the cell apparatus, while in the basket and paddle apparatuses after about 7 min 30 sec. After 20 min, the amount of the substance released in all apparatuses was over 90%. The release profiles of the drug substance in paddle and basket apparatuses were similar, while in the flow-through cell apparatus it was slightly slower. When the study conditions and composition of the tablets are the same, the release profile of the drug can be affected by the type of dissolution apparatus.

  11. Effects of amylin and bupropion/naltrexone on food intake and body weight are interactive in rodent models.

    PubMed

    Clapper, Jason R; Athanacio, Jennifer; Wittmer, Carrie; Griffin, Pete S; D'Souza, Lawrence; Parkes, David G; Roth, Jonathan D

    2013-01-05

    Antagonism of opioid systems (e.g., with naltrexone) has been explored as an anti-obesity strategy, and is particularly effective when co-administered with dual inhibitors of dopamine and norepinephrine reuptake (e.g., bupropion). Previously, we demonstrated that amylin enhances the food intake lowering and weight loss effects of neurohormonal (e.g., leptin, cholecystokinin, melanocortins) and small molecule (e.g., phentermine, sibutramine) agents. Here, we sought to characterize the interaction of amylin with naltrexone/bupropion on energy balance. Wild-type and amylin knockout mice were similarly responsive to the food intake lowering effects of either naltrexone (1mg/kg, subcutaneous) or bupropion (50mg/kg, subcutaneous) suggesting that they act independently of amylinergic systems and could interact additively when given in combination with amylin. To test this, diet-induced obese rats were treated (for 11 days) with vehicle, rat amylin (50 μg/kg/d, infused subcutaneously), naltrexone/bupropion (1 and 20mg/kg, respectively by twice daily subcutaneous injection) or their combination. We found that amylin+naltrexone/bupropion combination therapy exerted additive effects to reduce cumulative food intake, body weight and fat mass. In a separate study, the effects of amylin and naltrexone/bupropion administered at the same doses (for 14 days) were compared to a pair-fed group. Although the combination and pair-fed groups lost a similar amount of body weight, rats treated with the combination lost 68% more fat and better maintained their lean mass. These findings support the strategy of combined amylin agonism with opioid and catecholaminergic signaling systems for the treatment of obesity. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Pharmacokinetics of gabapentin in a novel gastric-retentive extended-release formulation: comparison with an immediate-release formulation and effect of dose escalation and food.

    PubMed

    Chen, Cuiping; Cowles, Verne E; Hou, Eddie

    2011-03-01

    The objectives of the 3 phase I studies described herein were (1) to compare the pharmacokinetics of gabapentin delivered from a novel gastric-retentive dosage form vs an immediate-release formulation, (2) to assess the dose proportionality of the gastric-retentive extended-release formulation, and (3) to determine the effect of food on the pharmacokinetics of gabapentin delivered from this formulation. The time to reach maximum plasma concentration (t(max)) was extended for gabapentin delivered from the gastric-retentive extended-release formulation compared with the immediate-release formulation. A dose-related increase in both the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) was observed as the gabapentin dose increased from 600 to 2400 mg. Fed status and increased fat content delayed t(max) and enhanced C(max) and AUC in proportion to the fat content. The pharmacokinetics of gabapentin delivered from this extended-release formulation allows a reduced dosing frequency while maintaining bioavailability and possibly diminishing the occurrence of adverse events attributable to a slower increase to the peak concentration compared with the immediate-release dosage form.

  13. Extended-Release Guaifenesin/Pseudoephedrine Hydrochloride for Symptom Relief in Support of a Wait-and-See Approach for the Treatment of Acute Upper Respiratory Tract Infections: A Randomized, Double-Blind, Placebo-Controlled Study.

    PubMed

    Septimus, Edward J; Albrecht, Helmut H; Solomon, Gail; Shea, Tim; Guenin, Eric P

    2017-01-01

    Despite the well-known fact that antibiotics (AB) are not effective against viruses, many patients ask for - and all too often doctors provide - AB for treating URTIs. Over-prescribing of AB is one of the key causes for the development of bacterial resistance, which the U.S. Centers for Disease Control and Prevention (CDC) calls "one of the world's most pressing public health problems". In addition to the CDC initiated "Get Smart About Antibiotics" campaign, focused on educating doctors the public about the importance of appropriate AB use, other programs tackling this problem include the development of new treatment paradigms. Data published at the Oregon Health & Science University demonstrated that a 'wait-and-see' approach, without an AB prescription for the treatment of acute childhood ear infections, was as quick, safe, and effective in resolving the infections as an AB prescription (Spiro DM, Tay KY, Arnold DH, Dziura JD, Baker MD, Shapiro ED. Wait-and-See Prescription for the Treatment of Acute Otitis Media. JAMA 2006; 296:1235-1241). To try and reduce inappropriate prescribing practices, a wait and see or delayed approach requires patients to return for a prescription if their symptoms persist or worsen. The aim of this study was to determine whether treatment with Mucinex D (Reckitt Benckiser LLC, Parsippany, New Jersey) lowers the use of antibiotics in the treatment of URTIs when compared with placebo. Patients aged 18 to 75 years with symptoms of acute URTIs were randomized to 1200 mg guaifenesin/120 mg pseudoephedrine hydrochloride extended-release, bilayer tablets or matching placebo for 7 consecutive days. Eligible patients met physician's criteria for antibiotic therapy but were considered suitable for a wait and see approach (withholding antibiotics for ≥48 hours). Patients recorded symptom ratings via an interactive voice response system. One thousand one hundred eighty-nine patients enrolled; data are presented for the modified intent

  14. Once daily, extended release ciprofloxacin for complicated urinary tract infections and acute uncomplicated pyelonephritis.

    PubMed

    Talan, David A; Klimberg, Ira W; Nicolle, Lindsay E; Song, James; Kowalsky, Steven F; Church, Deborah A

    2004-02-01

    We assessed the efficacy and safety of 1,000 mg extended release ciprofloxacin orally once daily vs conventional 500 mg ciprofloxacin orally twice daily, each for 7 to 14 days, in patients with a complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP). In this prospective, randomized, double-blind, North American multicenter clinical trial adults were stratified based on clinical presentation of cUTI or AUP and randomized to extended release ciprofloxacin or ciprofloxacin twice daily. Efficacy valid patients had positive pretherapy urine cultures (105 or greater cFU/ml) and pyuria within 48 hours of study entry. Bacteriological and clinical outcomes were assessed at the test of cure visit (5 to 11 days after therapy) and the late followup visit (28 to 42 days after therapy). The intent to treat population comprised 1,035 patients (extended release ciprofloxacin in 517 and twice daily in 518), of whom 435 were efficacy valid (cUTI in 343 and AUP in 92). For efficacy valid patients (cUTI and AUP combined) bacteriological eradication rates at test of cure were 89% (183 of 206) vs 85% (195 of 229) (95% CI -2.4%, 10.3%) and clinical cure rates were 97% (198 of 205) vs 94% (211 of 225) (95% CI -1.2%, 6.9%) for extended release vs twice daily ciprofloxacin. Late followup outcomes were consistent with test of cure findings. Eradication rates for Escherichia coli, which accounted for 58% of pathogens, were 97% or greater per group. Drug related adverse event rates were similar for extended release and twice daily ciprofloxacin (13% and 14%, respectively). Extended release ciprofloxacin at a dose of 1,000 mg once daily was as safe and effective as conventional treatment with 500 mg ciprofloxacin twice daily, each given orally for 7 to 14 days in adults with cUTI or AUP. It provides a convenient, once daily, empirical treatment option.

  15. Relative bioavailability of a newly developed 5-mg levomethadone hydrochloride IR tablet (L-Polamidon® 5 mg tablets) in comparison with the 5-mg levomethadone hydrochloride oral solution (L-Polamidon® solution for substitution) as reference product.

    PubMed

    Blume, Henning H; Wedemeyer, Ralf-Steven; Donath, Frank; Roscher, Katrin; Elvert, Gerd; Wagner, Daniel; Bley, Oliver; Vuia, Alexander; Todorova-Sanjari, Marina; Villalobos, Ramon; Schug, Barbara

    2015-04-01

    To establish the relative bioavailability (rBA) between two p.o. 5-mg levomethadone hydrochloride formulations, i.e., L-Polamidon® 5 mg tablets (test) vs. L-Polamidon® solution for substitution (reference). To assess the safety and tolerability of both formulations. A total of 33 healthy male subjects, aged 29 ± 6 years (BMI: 23.9 ± 2.5 kg/m2) completed this single center, open-label, randomized, 2-period cross-over study with single dose administrations under fasting conditions and coadministration with naltrexone for safety reasons. Administrations of both investigational products were separated by a washout period of at least 2 weeks, i.e., 13 treatmentfree days. The total dose for each subject was 2 x 5 mg resulting in 10 mg levomethadone hydrochloride. For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours postdose. A validated non-stereoselective liquid chromatography-tandem mass spectroscopy method (LC-MS/MS) was applied for the determination of levomethadone in plasma. The lower limit of quantitation was 0.100 ng/mL. Adverse events were descriptively analyzed in the study population. The geometric means of the parameters related with the extent of total exposure of levomethadone, i.e., AUC(0-tlast) and AUC(0-∞), were 244.422 ng x h/mL and 332.999 ng x h/mL for test and 246.837 ng x h/mL and 329.467 ng×h/mL for reference, respectively. The geometric means of the peak exposure for levomethadone, i.e., Cmax, were 8.923 ng/mL for test and 8.635 ng/mL for reference. The point estimates (PEs) of the Test/Reference (T/R) adjusted geometric mean ratios of AUC(0-last), AUC(0-∞), and C(max) were 99.20%, 101.42%, and 104.11%, respectively, and all of them showed 90%-confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment In total, 21 subjects experienced 55 AEs during the study, the most frequently reported AE, i.e., headache, accounted for 13 out of the total

  16. Investigation into the Effect of Ethylcellulose Viscosity Variation on the Drug Release of Metoprolol Tartrate and Acetaminophen Extended Release Multiparticulates-Part I.

    PubMed

    Mehta, R; Teckoe, J; Schoener, C; Workentine, S; Ferrizzi, D; Rajabi-Siahboomi, A

    2016-12-01

    Ethylcellulose is one of the most commonly used polymers to develop reservoir type extended release multiparticulate dosage forms. For multiparticulate extended release dosage forms, the drug release is typically governed by the properties of the barrier membrane coating. The ICH Pharmaceutical Development Guideline (ICH Q8) requires an understanding of the influence of critical material attributes and critical process parameters on the drug release of a pharmaceutical product. Using this understanding, it is possible to develop robust formulations with consistent drug release characteristics. Critical material attributes for ethylcellulose were evaluated, and polymer molecular weight variation (viscosity) was considered to be the most critical attribute that can impact drug release. To investigate the effect of viscosity variation within the manufacturer's specifications of ethylcellulose, extended release multiparticulate formulations of two model drugs, metoprolol tartrate and acetaminophen, were developed using ETHOCEL™ as the rate controlling polymer. Quality by Design (QbD) samples of ETHOCEL Std. 10, 20, and 100 Premium grades representing the low, medium, and high molecular weight (viscosity) material were organically coated onto drug layered multiparticulates to a 15% weight gain (WG). The drug release was found to be similar (f 2  > 50) for both metoprolol tartrate and acetaminophen multiparticulates at different coating weight gains of ethylcellulose, highlighting consistent and robust drug release performance. The use of ETHOCEL QbD samples also serves as a means to develop multiparticulate dosage formulations according to regulatory guidelines.

  17. Alterations of naltrexone-induced conditioned place avoidance by pre-exposure to high fructose corn syrup or heroin in Sprague-Dawley rats.

    PubMed

    Daniels, Stephen; Marshall, Paul; Leri, Francesco

    2016-02-01

    It has been suggested that withdrawal from sugar produces a set of symptoms that resemble those observed following withdrawal from opiate drugs. This study explored naltrexone-induced withdrawal in animals pre-exposed to acute, chronic, and intermittent high fructose corn syrup (HFCS) or acute and chronic heroin administration. Experiment 1 examined conditioned place avoidance (CPA) induced by different doses of naltrexone (0.01-1 mg/kg) in naïve male Sprague-Dawley rats. In experiment 2, rats received continuous or intermittent home cage HFCS access (0 or 50 %) prior to conditioning with 1 mg/kg naltrexone. In experiment 3, HFCS ingestion was increased by food restriction and rats were conditioned with 3 mg/kg naltrexone. In experiment 4, the timing and quantity of HFCS ingestion (0, 0.5, 1, 2 g/kg) was controlled by intragastric administration, and rats were conditioned with 1 mg/kg naltrexone. In experiment 5, rats received acute (2 mg/kg) or chronic heroin (3.5 mg/kg/day) prior to conditioning with 1 mg/kg naltrexone. Administration of naltrexone produced moderate conditioned place avoidance in naïve rats. Importantly, acute, continuous, and intermittent HFCS pre-exposure did not significantly amplify this effect, but acute and chronic heroin pre-exposure did. As assessed by CPA, these results in rats fail to support the hypothesis that an opioid antagonist can precipitate similar affective withdrawal states following pre-exposure to sugars and opiates.

  18. Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration of a single dose to American kestrels (Falco sparverius)

    USGS Publications Warehouse

    Guzman, David Sanchez-Migallon; KuKanich, Butch; Drazenovich, Tracy L.; Olsen, Glenn H.; Paul-Murphy, Joanne R.

    2014-01-01

    Results indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies regarding the effects of other doses, other administration routes, constantrate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels may be indicated.

  19. Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects.

    PubMed

    Hay, J L; La Vincente, S F; Somogyi, A A; Chapleo, C B; White, J M

    2011-03-01

    Previous reports have demonstrated greater antinociception following administration of a buprenorphine/naloxone combination compared to buprenorphine alone among healthy volunteers. The aim of the current investigation was to determine whether buprenorphine antinociception could be enhanced with the addition of ultra-low dose naltrexone, using a range of dose ratios. A repeated-measures, double-blind, cross-over trial was undertaken with 10 healthy participants. The effects of each buprenorphine:naltrexone ratio (100:1, 133:1, 166:1, and 200:1) on cold pressor tolerance time and respiration were compared to the effects of buprenorphine only. The 166:1 ratio was associated with significantly greater tolerance time to cold pressor pain than buprenorphine alone. Minimal respiratory depression and few adverse events were observed in all conditions. These findings suggest that, as previously described with naloxone, the addition of ultra-low dose naltrexone can enhance the antinociceptive effect of buprenorphine in humans. This potentiation is dose-ratio dependent and occurs without a concomitant increase in adverse effects. Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

  20. Concurrent Improvement in Both Binge Eating and Depressive Symptoms with Naltrexone/Bupropion Therapy in Overweight or Obese Subjects with Major Depressive Disorder in an Open-Label, Uncontrolled Study.

    PubMed

    Guerdjikova, Anna I; Walsh, Brandon; Shan, Kevin; Halseth, Amy E; Dunayevich, Eduardo; McElroy, Susan L

    2017-10-01

    Binge eating disorder (BED) is associated with obesity and major depressive disorder (MDD). Naltrexone extended-release (ER)/bupropion ER (NB) is approved as an adjunct to diet and physical activity for chronic weight management. In a prospectively designed 24-week open-label, single-arm, single-site trial of 25 women with MDD and overweight/obesity, NB reduced weight and depressive symptoms. This post hoc analysis investigated the relationship between change in self-reported binge eating behavior (evaluated with the Binge Eating Scale [BES]) and changes in weight, control of eating, and depressive symptoms. At baseline, 91% of subjects had moderate or severe BES scores, suggesting BED. BES scores were significantly improved from week 4, and by week 24, 83% reported "little or no problem." Improvement in BES scores correlated with improvement in depressive symptoms and control of eating. NB may be effective in reducing binge eating symptoms associated with MDD and overweight/obesity. Evaluation of NB in BED appears warranted. Orexigen Therapeutics, Inc.

  1. Maintaining remission in ulcerative colitis--role of once daily extended-release mesalamine.

    PubMed

    Oliveira, Lilliana; Cohen, Russell D

    2011-02-27

    The aminosalicylates (5-ASA; also referred to as mesalamine-based agents) are considered as first-line in the maintenance of remission of mild to moderate ulcerative colitis (UC). Traditionally these agents have required a large pill burden and multiple daily dosing regimens which may account for the low adherence rates, especially in patients in remission. Extended-release mesalamine is the first once daily mesalamine product approved by the Food and Drug Administration for the maintenance of UC remission. This review will examine the pharmacokinetics, dosing, efficacy, and safety data of extended-release mesalamine, and discuss the potential role of improving medication compliance and decreasing costs in UC maintenance.

  2. Opposing neural effects of naltrexone on food reward and aversion: implications for the treatment of obesity.

    PubMed

    Murray, Elizabeth; Brouwer, Sietske; McCutcheon, Rob; Harmer, Catherine J; Cowen, Philip J; McCabe, Ciara

    2014-11-01

    Opioid antagonism reduces the consumption of palatable foods in humans but the neural substrates implicated in these effects are less well understood. The aim of the present study was to examine the effects of the opioid antagonist, naltrexone, on neural response to rewarding and aversive sight and taste stimuli. We used functional magnetic resonance imaging (fMRI) to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 20 healthy volunteers who received a single oral dose of naltrexone (50 mg) and placebo in a double-blind, repeated-measures cross-over, design. Relative to placebo, naltrexone decreased reward activation to chocolate in the dorsal anterior cingulate cortex and caudate, and increased aversive-related activation to unpleasant strawberry in the amygdala and anterior insula. These findings suggest that modulation of key brain areas involved in reward processing, cognitive control and habit formation such as the dorsal anterior cingulate cortex (dACC) and caudate might underlie reduction in food intake with opioid antagonism. Furthermore we show for the first time that naltrexone can increase activations related to aversive food stimuli. These results support further investigation of opioid treatments in obesity.

  3. Acute behavioural effects of bupropion and naltrexone, alone and in combination, in non-deprived male rats presented with palatable mash.

    PubMed

    Wright, F L; Rodgers, R J

    2013-07-01

    In appetite research, drugs frequently progress to clinical trials on the basis of outcome (reduced food intake/body weight gain) with insufficient attention to process (behavioural analysis). Although bupropion and naltrexone (alone and in combination) reduce food consumption in rodents and humans, their effects on behaviour during feeding tests have not been thoroughly investigated. This study aimed to assess the behavioural specificity of anorectic responses to bupropion, naltrexone and their combination. Video analysis was employed to characterise the behavioural effects of acute systemic treatment with bupropion (10.0-40.0 mg/kg), naltrexone (0.1-3.0 mg/kg) and combined bupropion (20 mg/kg) plus naltrexone (0.1-1.0 mg/kg) in non-deprived male rats exposed for 1 h to palatable mash. Particular attention was paid to the behavioural satiety sequence (BSS). In experiment 1, the anorectic response to 40 mg/kg bupropion was associated with significant psychomotor stimulation and a complete disruption of the BSS. In experiment 2, the anorectic response to 3 mg/kg naltrexone was associated with an accelerated but otherwise normal BSS. In experiment 3, the co-administration of 20 mg/kg bupropion and naltrexone (0.1 and 1.0 mg/kg) not only produced an additive anorectic profile (including a reduced rate of eating), but the addition of the opioid receptor antagonist also concurrently attenuated the psychomotor stimulant response to the atypical antidepressant. Low-dose co-treatment with naltrexone and bupropion produces a stronger suppression of appetite than that seen with either agent alone and has the additional advantage of reducing some of the unwanted effects of bupropion.

  4. Ultra-Low Doses of Naltrexone Enhance the Antiallodynic Effect of Pregabalin or Gabapentin in Neuropathic Rats.

    PubMed

    Pineda-Farias, Jorge B; Caram-Salas, Nadia L; Salinas-Abarca, Ana B; Ocampo, Jorge; Granados-Soto, Vinicio

    2017-12-01

    Preclinical Research Treatment of neuropathic pain is an area of largely unmet medical need. Pregabalin and gabapentin are anticonvulsants widely used for the treatment of neuropathic pain. Unfortunately, these drugs are only effective in 50-60% of the treated patients. In addition, both drugs have substantial side effects. Several studies have reported that ultralow doses of opioid receptor antagonists can induce analgesia and enhance the analgesic effect of opioids in rodents and humans. The objective of the present study was to assess the antiallodynic synergistic interaction between gabapentinoids and naltrexone in rats. Oral administration of pregabalin (ED 50  = 2.79 ± 0.16 mg/kg) or gabapentin (ED 50  = 21.04 ± 2.87 mg/kg) as well as intrathecal naltrexone (ED 50  = 0.11 ± 0.02 ng) reduced in a dose-dependent manner tactile allodynia in rats. Maximal antiallodynic effects (∼100%) were reached with 30 mg/kg of pregabalin, 300 mg/kg of gabapentin or 0.5 ng of naltrexone. Co-administration of pregabalin or gabapentin and naltrexone in a fixed-dose ratio (1:1) remarkably reduced spinal nerve ligation-induced tactile allodynia showing a synergistic interaction. The data indicate that combinations of pregabalin or gabapentin and ultra-low doses of naltrexone are able to reduce tactile allodynia in neuropathic rats with lower doses that those used when drugs are given individually and with an improved side effects profile. Drug Dev Res 78 : 371-380, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  5. Stability of Clindamycin Hydrochloride in PCCA Base SuspendIt.

    PubMed

    Pramar, Yashoda V; Graves, Richard A; Ledet, Grace A; Phan, Kelly V; Bostanian, Levon A; Mandal, Tarun K

    2016-01-01

    Clindamycin is an effective antibiotic in the treatment of infections caused by certain gram-positive and gram-negative anaerobic microorganisms. While manufactured forms of the drug for pediatric use are available, there are instances when a compounded liquid dosage form is essential to meet unique patient needs. The purpose of this study was to determine the chemical stability of clindamycin hydrochloride in the PCCA base SuspendIt, a sugar-free, paraben- free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. It thickens upon standing to minimize settling of any insoluble drug particles and becomes fluid upon shaking to allow convenient pouring during administration to the patient. A robust stability-indicating high-performance liquid chromatographic assay for the determination of clindamycin hydrochloride in SuspendIt was developed and validated. This assay was used to determine the chemical stability of the drug in SuspendIt. Samples were prepared and stored under three different temperature conditions (5°C, 25°C, and 40°C), and assayed using the high-performance liquid chromatographic assay at pre-determined intervals over an extended period of time as follows: 7, 14, 30, 45, 60, 91, 120, and 182 days at each designated temperature. Physical data such as pH, viscosity, and appearance were also monitored. The study showed that drug concentration did not go below 90% of the label claim (initial drug concentration) at all three temperatures studied, barring isolated experimental errors. Viscosity and pH values also did not change significantly. Some variations in viscosity were attributed to the thixotropic nature of the vehicle. This study demonstrates that clindamycin hydrochloride is physically and chemically stable in SuspendIt for 182 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for clindamycin hydrochloride in a liquid dosage form, with an

  6. Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration of a single dose to American kestrels (Falco sparverius)

    USGS Publications Warehouse

    Sanchez-Migallon Guzman, David; KuKanich, Butch; Drazenovich, Tracy L.; Olsen, Glenn H.; Paul-Murphy, Joanne R.

    2014-01-01

    Conclusion and Clinical Relevance—Results indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies regarding the effects of other doses, other administration routes, constantrate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels may be indicated.

  7. Rates of opioid dispensing and overdose after introduction of abuse-deterrent extended-release oxycodone and withdrawal of propoxyphene.

    PubMed

    Larochelle, Marc R; Zhang, Fang; Ross-Degnan, Dennis; Wharam, J Frank

    2015-06-01

    In the second half of 2010, abuse-deterrent extended-release oxycodone hydrochloride (OxyContin; Purdue Pharma) was introduced and propoxyphene was withdrawn from the US market. The effect of these pharmaceutical market changes on opioid dispensing and overdose rates is unknown. To evaluate the association between 2 temporally proximate changes in the opioid market and opioid dispensing and overdose rates. Claims from a large national US health insurer were analyzed, using an interrupted time series study design. Participants included an open cohort of 31.3 million commercially insured members aged 18 to 64 years between January 1, 2003, and December 31, 2012, with median follow-up of 20 months (last follow-up, December 31, 2012). Introduction of abuse-deterrent OxyContin (resistant to crushing or dissolving) on August 9, 2010, and market withdrawal of propoxyphene on November 19, 2010. Standardized opioid dispensing rates and prescription opioid and heroin overdose rates were the primary outcomes. We used segmented regression to analyze changes in outcomes from 30 quarters before to 8 quarters after the 2 interventions. Two years after the opioid market changes, total opioid dispensing decreased by 19% from the expected rate (absolute change, -32.2 mg morphine-equivalent dose per member per quarter [95% CI, -38.1 to -26.3]). By opioid subtype, the absolute change in dispensing by milligrams of morphine-equivalent dose per member per quarter at 2 years was -11.3 (95% CI, -12.4 to -10.1) for extended-release oxycodone, 3.26 (95% CI, 1.40 to 5.12) for other long-acting opioids, -8.19 (95% CI, -9.30 to -7.08) for propoxyphene, and -16.2 (95% CI, -18.8 to -13.5) for other immediate-release opioids. Two years after the market changes, the estimated overdose rate attributed to prescription opioids decreased by 20% (absolute change, -1.10 per 100,000 members per quarter [95% CI, -1.47 to -0.74]), but heroin overdose increased by 23% (absolute change, 0.26 per 100

  8. Endogenous opioids, mu-opiate receptors and chloroquine-induced pruritus: a double-blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine-induced itching.

    PubMed

    Ajayi, A A; Kolawole, B A; Udoh, S J

    2004-12-01

    Chloroquine induces a severe generalized pruritus, in predisposed Black African patients, during treatment of malaria fever, and also in some Caucasian patients treated for rheumatological diseases. We have previously shown that chloroquine may release endogenous opioids and/or interact with micro-opiate receptors in rats, and that both histamine and malaria parasite blood density, contribute to the itching severity in malaria fever in humans. The aim of our present study was to assess and compare the antipruritic efficacy of the micro-opiate receptor antagonist, naltrexone, and the antihistamine, promethazine, in chloroquine treated patients with malaria fever. A double-blind, randomized, parallel group comparison of the chloroquine-induced pruritus intensity and time profile in patients with parasitologically proven malaria fever, who were pretreated with a single dose of either naltrexone 50 mg or promethazine 25 mg orally (six patients each). All patients had an established history of severe pruritus following chloroquine treatment of malaria fever. A self-assessed itching severity score was undertaken at 0, 6, 12, 24, 48 and 72 h after initial chloroquine dosing, and the areas under the pruritus-intensity time curve AUCP0-72 h was determined in each patient and correlated to the malaria parasite density in blood. Both naltrexone and promethazine subjectively reduced itching severity compared with prior historical experience. One patient on naltrexone and two on promethazine never experienced any itching. There was no statistically significant treatment effect, but a significant time effect (P = 0.001, F = 4.77 d.f. 5) by two-way repeated measures ANOVA. The AUCP for naltrexone was 82 +/- 25 units/h, and 57 +/- 34 units/h for promethazine [95% confidence interval for the difference being -73 to 123]. However, the malaria parasite density in the naltrexone group (740 +/- 178 microl(-1)) tended to be higher than in the promethazine group 314 +/- 69 microl(-1) (P

  9. 21 CFR 522.2470 - Tiletamine hydrochloride and zolazepam hydrochloride for injection.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Tiletamine hydrochloride and zolazepam hydrochloride for injection. 522.2470 Section 522.2470 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR...

  10. Preparation and in-vivo pharmacokinetic study of a novel extended release compression coated tablets of fenoterol hydrobromide.

    PubMed

    Elshafeey, Ahmed H; Sami, Elshaimaa I

    2008-01-01

    The aim of this study was to formulate extended release compression coated core tablets of fenoterol hydrobromide, a selective beta(2) adrenergic receptor agonist, in an attempt to prevent nocturnal asthma. Two hydrophilic polymers viz Kollidon SR, Polyox WSR 303 and a hydrophobic one (Precirol ATO5) were employed. Compression coated tablets were formulated by preparing a core tablet containing 7.5 mg drug and various amounts of polymer and Emcompress then compressed coated with the same polymeric materials. For comparison purpose different matrix tablets were also prepared employing the same polymers. In-vitro release studies were carried out at different pH (1.2 and 6.8). Pharmacokinetics of extended release tablets as well as commercially available immediate release tablets (Berotec) were studied after oral administration to beagle dogs using a new developed LC-MS/MS method with a lower limit of quantification of 1 ng/ml. Fenoterol release from compression coated tablets was significantly lower than matrix tablets. The mechanism of release was changed with the nature and content of polymer. The release pattern of drug from F16 containing 40 mg Kollidon SR divided in the core tablet (15 mg) and the rest in the compressed coat (25 mg) showed a typical zero order release kinetic that could extend drug release >10 h and reasonable time for 75% to be released (t(75)) (8.92 h). When compared to immediate release Berotec tablet the MRT was significantly extended from 7.03 +/- 0.76 to 10.93 +/- 1.25 h (P < 0.001) and HVD(t 50%Cmax) was also significantly extended from 2.71 +/- 0.68 to 6.81 +/- 0.67 h with expected prevention of nocturnal asthma.

  11. Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism.

    PubMed

    Krystal, John H; Madonick, Steven; Perry, Edward; Gueorguieva, Ralitza; Brush, Laura; Wray, Yola; Belger, Aysenil; D'Souza, Deepak Cyril

    2006-08-01

    The interplay of opiate and NMDA glutamate receptors may contribute to psychosis, cognitive function, alcoholism, and substance dependence. Ketamine and ethanol block the NMDA glutamate receptor. The purpose of this randomized double-blind, placebo-controlled human laboratory study was to evaluate whether the interactive effects of drugs acting at opiate and NMDA glutamate receptors might partially explain the efficacy of naltrexone for the treatment of alcoholism, that is, whether naltrexone 25 mg pretreatment would modulate ketamine effects in healthy human subjects. Two groups of healthy subjects were studied. An initial group (n=31) received a perception-altering subanesthetic dose of ketamine (bolus of 0.23 mg/kg over 1 min followed by a 60-min infusion of 0.58 mg/kg or saline bolus and infusion). A second group (n=24) completed the same testing procedures, but received a subperceptual ketamine dose (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg/kg/h). Ketamine produced positive symptoms, negative symptoms, emotional discomfort, and cognitive effects as measured by the Positive and Negative Syndrome Scale (PANSS) in a dose-related fashion. The lower ketamine dose produced subjective effects similar to two standard ethanol drinks, whereas the higher ketamine dose produced effects similar to five standard drinks. Although naltrexone produced no significant behavioral effects, it significantly magnified the increase in the total PANSS score produced by the lower subperceptual dose of ketamine, but not the higher perception-altering dose of ketamine. These data suggest that the interplay of opiate receptor antagonism and NMDA receptor antagonism may be relevant to the protective effects of naltrexone on alcohol consumption via potentiation of dysphoric effects associated with the NMDA receptor antagonist effects of ethanol. However, these data suggest that at levels of NMDA receptor antagonism associated with heavy drinking, this protective

  12. Benznidazole Extended-Release Tablets for Improved Treatment of Chagas Disease: Preclinical Pharmacokinetic Study

    PubMed Central

    Campos, Michel Leandro; Rosa, Talita Atanazio; Padilha, Elias Carvalho; Alzate, Alejandro Henao; Rolim, Larissa Araújo; Rolim-Neto, Pedro José

    2016-01-01

    Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediate-release tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentration in vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease. PMID:26883698

  13. THE PROCESS OF MASS TRANSFER ON THE SOLID-LIQUID BOUNDARY LAYER DURING THE RELEASE OF DICLOFENAC SODIUM AND PAPAVERINE HYDROCHLORIDE FROM TABLETS IN A PADDLE APPARATUS.

    PubMed

    Kasperek, Regina; Zimmer, Lukasz; Poleszak, Ewa

    2016-01-01

    The release study of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) from two formulations of the tablets in the paddle apparatus using different rotation speeds to characterize the process of mass transfer on the solid-liquid boundary layer was carried out. The dissolution process of active substances was described by values of mass transfer coefficients, the diffusion boundary layer thickness and dimensionless numbers (Sh and Re). The values of calculated parameters showed that the release of DIC and PAP from tablets comprising potato starch proceeded faster than from tablets containing HPMC and microcrystalline cellulose. They were obtained by direct dependencies between Sh and Re in the range from 75 rpm to 125 rpm for both substances from all tablets. The description of the dissolution process with the dimensionless numbers make it possible to plan the drug with the required release profile under given in vitro conditions.

  14. Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone.

    PubMed

    Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J

    2017-09-01

    Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental

  15. Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity.

    PubMed

    Padwal, Raj

    2009-10-01

    Contrave, under development by Orexigen Therapeutics Inc for the potential treatment of obesity, is an oral, sustained-release combination of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone. The proposed dual mechanism of action of the compound involves complementary stimulation of central melanocortin pathways, resulting in increased energy expenditure and reduced appetite. At the time of publication, Contrave was being assessed in phase III clinical trials. Preliminary data demonstrated placebo-subtracted weight losses of 3 to 7% and improvements in obesity-related comorbidities and cardiovascular risk factors. The primary adverse effect leading to discontinuation of treatment was nausea. Assuming that the results of the Contrave phase III clinical program reaffirm the efficacy and safety of the drug combination, this agent could be approved and launched to become a market leader in the anti-obesity therapeutic arena.

  16. Effects of naltrexone on electrocutaneous pain in patients with hypertension compared to normotensive individuals

    PubMed Central

    Ring, Christopher; France, Christopher R.; al'Absi, Mustafa; Edwards, Louisa; McIntyre, David; Carroll, Douglas; Martin, Una

    2008-01-01

    An opioid mechanism may help explain hypertensive hypoalgesia. A double-blind placebo-controlled design compared the effects of opioid blockade (naltrexone) and placebo on electrocutaneous pain threshold, pain tolerance, and retrospective McGill Pain Questionnaire ratings in 35 unmedicated patients with essential hypertension and 28 normotensive individuals. The hypertensives experienced less pain than normotensives during the assessment of their pain tolerance; however, this manifestation of hypertensive hypoalgesia was not moderated by naltrexone. These findings fail to support the hypothesis that essential hypertension is characterised by relative opioid insensitivity. PMID:18031920

  17. A Retrospective Cohort Study of Obstetric Outcomes in Opioid-Dependent Women Treated with Implant Naltrexone, Oral Methadone or Sublingual Buprenorphine, and Non-Dependent Controls.

    PubMed

    Kelty, Erin; Hulse, Gary

    2017-07-01

    Opioid pharmacotherapies play an important role in the treatment of opioid-dependent women; however, very little is known about the safety of naltrexone in pregnant patients. This study examined the obstetric health of opioid-dependent women who were treated with implant naltrexone during pregnancy, and compared them with women treated with methadone and/or buprenorphine and a cohort of non-opioid-dependent controls. Women treated with implant naltrexone, oral methadone or sublingual buprenorphine between 2001 and 2010, along with a cohort of age-matched controls, were linked with records from midwives, hospital and emergency departments (EDs) and the death registry to identify pregnancy and health events that occurred during pregnancy and in the post-partum period. Overall rates of pregnancy loss (requiring hospital or ED attendance) were significantly elevated in naltrexone-treated women compared with buprenorphine-treated women (p = 0.018) and controls (p < 0.001); however, they were not statistically different to methadone-treated women (p = 0.210). Birth rates in women on naltrexone implant treatment were significantly higher than in all three comparison groups (p < 0.001). Rates of hospital and ED attendance during pregnancy in the naltrexone-treated women were not statistically different to those of either the methadone or buprenorphine groups, and neither were overall complications during pregnancy and labour. Overall rates of complications during pregnancy were significantly higher in the naltrexone-treated women than in the controls. Opioid-dependent women treated with naltrexone implant had higher rates of birth than the other three groups (methadone- or buprenorphine-treated women, or age-matched controls). Overall rates of complications during pregnancy were elevated in naltrexone-treated women when compared with the control group, but were generally not significantly different to rates in methadone- or buprenorphine-treated women.

  18. Pediatric drug formulation of sodium benzoate extended-release granules.

    PubMed

    Combescot, E; Morat, G; de Lonlay, P; Boudy, V

    2016-01-01

    Urea cycle disorders are a group of inherited orphan diseases leading to hyperammonemia. Current therapeutic strategy includes high doses of sodium benzoate leading to three or four oral intakes per day. As this drug is currently available in capsules or in solution, children are either unable to swallow the capsule or reluctant to take the drug due to its strong bitter taste. The objective of the present study was to develop solid, multiparticulate formulations of sodium benzoate, which are suitable for pediatric patients (i.e. flavor-masked, easy to swallow and with a dosing system). Drug layering and coating in a fluidized bed were applied for preparing sustained-release granules. Two types of inert cores (GalenIQ® and Suglets®) and three different polymers (Kollicoat®, Aquacoat® and Eudragit®) were tested in order to select the most appropriate polymer and starter core for our purpose. Physical characteristics and drug release profiles of the pellets were evaluated. A Suglets® core associated with a Kollicoat® coating seems to be the best combination for an extended release of sodium benzoate. A curing period of 8 h was necessary to complete film formation and the resulting drug release pattern was found to be dependent of the acidity of the release medium.

  19. Advances in mechanistic understanding of release rate control mechanisms of extended-release hydrophilic matrix tablets.

    PubMed

    Timmins, Peter; Desai, Divyakant; Chen, Wei; Wray, Patrick; Brown, Jonathan; Hanley, Sarah

    2016-08-01

    Approaches to characterizing and developing understanding around the mechanisms that control the release of drugs from hydrophilic matrix tablets are reviewed. While historical context is provided and direct physical characterization methods are described, recent advances including the role of percolation thresholds, the application on magnetic resonance and other spectroscopic imaging techniques are considered. The influence of polymer and dosage form characteristics are reviewed. The utility of mathematical modeling is described. Finally, how all the information derived from applying the developed mechanistic understanding from all of these tools can be brought together to develop a robust and reliable hydrophilic matrix extended-release tablet formulation is proposed.

  20. Weight Loss With Naltrexone SR/Bupropion SR Combination Therapy as an adjunct to Behavior Modification: The COR-BMOD Trial

    PubMed Central

    Wadden, Thomas A.; Foreyt, John P.; Foster, Gary D.; Hill, James O.; Klein, Samuel; O’Neil, Patrick M.; Perri, Michael G.; Pi-Sunyer, F. Xavier; Rock, Cheryl L.; Erickson, Janelle S.; Maier, Holly N.; Kim, Dennis D.; Dunayevich, Eduardo

    2015-01-01

    This 56-week, randomized, placebo-controlled trial examined the efficacy and safety of naltrexone plus bupropion as an adjunct to intensive behavior modification (BMOD). A total of 793 participants (BMI = 36.5 ± 4.2 kg/m2) was randomly assigned in a 1:3 ratio to: (i) placebo + BMOD (N = 202); or (ii) naltrexone sustained-release (SR, 32 mg/day), combined with bupropion SR (360 mg/day) plus BMOD (i.e., NB32 + BMOD; N = 591). Both groups were prescribed an energy-reduced diet and 28 group BMOD sessions. Co-primary end points were percentage change in weight and the proportion of participants who lost ≥5% weight at week 56. Efficacy analyses were performed on a modified intent-to-treat population (ITT; i.e., participants with ≥1 postbaseline weight while taking study drug (placebo + BMOD, N = 193; NB32 + BMOD, N = 482)). Missing data were replaced with the last observation obtained on study drug. At week 56, weight loss was 5.1 ± 0.6% with placebo + BMOD vs. 9.3 ± 0.4% with NB32 + BMOD (P < 0.001). A completers analysis revealed weight losses of 7.3 ± 0.9% (N = 106) vs. 11.5 ± 0.6% (N = 301), respectively (P < 0.001). A third analysis, which included all randomized participants, yielded losses of 4.9 ± 0.6 vs. 7.8 ± 0.4%, respectively (P < 0.001). Significantly more NB32 + BMOD- vs. placebo + BMOD-treated participants lost ≥5 and ≥10% of initial weight, and the former had significantly greater improvements in markers of cardiometabolic disease risk. NB32 + BMOD was generally well tolerated, although associated with more reports of nausea than placebo + BMOD. The present findings support the efficacy of combined naltrexone/bupropion therapy as an adjunct to intensive BMOD for obesity. PMID:20559296

  1. Reward and relief dimensions of temptation to drink: construct validity and role in predicting differential benefit from acamprosate and naltrexone.

    PubMed

    Roos, Corey R; Mann, Karl; Witkiewitz, Katie

    2017-11-01

    Researchers have sought to distinguish between individuals whose alcohol use disorder (AUD) is maintained by drinking to relieve negative affect ('relief drinkers') and those whose AUD is maintained by the rewarding effects of alcohol ('reward drinkers'). As an opioid receptor antagonist, naltrexone may be particularly effective for reward drinkers. Acamprosate, which has been shown to down-regulate the glutamatergic system, may be particularly effective for relief drinkers. This study sought to replicate and extend prior work (PREDICT study; Glöckner-Rist et al. ) by examining dimensions of reward and relief temptation to drink and subtypes of individuals with distinct patterns of reward/relief temptation. We utilized data from two randomized clinical trials for AUD (Project MATCH, n = 1726 and COMBINE study, n = 1383). We also tested whether classes of reward/relief temptation would predict differential response to naltrexone and acamprosate in COMBINE. Results replicated prior work by identifying reward and relief temptation factors, which had excellent reliability and construct validity. Using factor mixture modeling, we identified five distinct classes of reward/relief temptation that replicated across studies. In COMBINE, we found a significant class-by-acamprosate interaction effect. Among those most likely classified in the high relief/moderate reward temptation class, individuals had better drinking outcomes if assigned to acamprosate versus placebo. We did not find a significant class-by-naltrexone interaction effect. Our study questions the orthogonal classification of drinkers into only two types (reward or relief drinkers) and adds to the body of research on moderators of acamprosate, which may inform clinical decision making in the treatment of AUD. © 2016 Society for the Study of Addiction.

  2. Controlled and extended drug release behavior of chitosan-based nanoparticle carrier.

    PubMed

    Yuan, Q; Shah, J; Hein, S; Misra, R D K

    2010-03-01

    Controlled drug release is presently gaining significant attention. In this regard, we describe here the synthesis (based on the understanding of chemical structure), structural morphology, swelling behavior and drug release response of chitosan intercalated in an expandable layered aluminosilicate. In contrast to pure chitosan, for which there is a continuous increase in drug release with time, the chitosan-aluminosilicate nanocomposite carrier was characterized by controlled and extended release. Drug release from the nanocomposite particle carrier occurred by degradation of the carrier to its individual components or nanostructures with a different composition. In both the layered aluminosilicate-based mineral and chitosan-aluminosilicate nanocomposite carriers the positively charged chemotherapeutic drug strongly bound to the negatively charged aluminosilicate and release of the drug was slow. Furthermore, the pattern of drug release from the chitosan-aluminosilicate nanocomposite carrier was affected by pH and the chitosan/aluminosilicate ratio. The study points to the potential application of this hybrid nanocomposite carrier in biomedical applications, including tissue engineering and controlled drug delivery. Copyright 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  3. Effects of naltrexone on post-abstinence alcohol drinking in C57BL/6NCRL and DBA/2J mice.

    PubMed

    Tomie, Arthur; Azogu, Idu; Yu, Lei

    2013-07-01

    The present experiment evaluated the effects of naltrexone, a non-selective opioid receptor antagonist, on post-abstinence alcohol drinking in C57BL/6NCRL and DBA/2J male mice. Home cage 2-bottle (alcohol vs. water) free-choice procedures were employed. During the pre-abstinence period, alcohol intake was much lower for the DBA/2J mice relative to the C57BL/6NCRL mice, and this strain difference was observed for groups receiving either 3% or 10% alcohol concentrations. The four-day abstinence period effectively reduced alcohol intakes (i.e., a negative alcohol deprivation effect, negative ADE) in both groups of DBA/2J mice, but had no effect on alcohol intakes in either group of C57BL/6NCRL mice. Both groups trained with 3% alcohol received the second four-day abstinence period, where the effects of acute administration of either naltrexone or saline on post-abstinence alcohol drinking were assessed. Naltrexone was more effective in reducing post-abstinence drinking of 3% alcohol in the DBA/2J mice than in the C57BL/6NCRL mice. In the DBA/2J mice, naltrexone further reduced, relative to saline-injected controls, the low levels of post-abstinence alcohol intake. Thus, the low baseline levels of alcohol drinking in DBA/2J mice were further diminished by the four-day abstinence period (negative ADE), and this suppressed post-abstinence level of alcohol drinking was still further reduced by acute administration of naltrexone. The results indicate that naltrexone is effective in reducing further the low levels of alcohol drinking induced by the negative ADE. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. 21 CFR 522.883 - Etorphine hydrochloride injection.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... milliliter of etorphine hydrochloride injection, veterinary, contains 1 mg of etorphine hydrochloride in... use the drug unless diprenorphine hydrochloride injection, veterinary, as provided for in § 522.723, is available for use in reversing the effects of etorphine hydrochloride injection, veterinary. (4...

  5. 21 CFR 522.883 - Etorphine hydrochloride injection.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... milliliter of etorphine hydrochloride injection, veterinary, contains 1 mg of etorphine hydrochloride in... use the drug unless diprenorphine hydrochloride injection, veterinary, as provided for in § 522.723, is available for use in reversing the effects of etorphine hydrochloride injection, veterinary. (4...

  6. Does adding low doses of oral naltrexone to morphine alter the subsequent opioid requirements and side effects in trauma patients?

    PubMed

    Farahmand, Shervin; Ahmadi, Omid; Dehpour, Ahmadreza; Khashayar, Patricia

    2012-01-01

    The present study aims to assess the influence of ultra-low doses of opioid antagonists on the analgesic properties of opioids and their side effects. In the present randomized, double-blind controlled trial, the influence of the combination of ultra-low-dose naltrexone and morphine on the total opioid requirement and the frequency of the subsequent side effects was compared with that of morphine alone (added with placebo) in patients with trauma in the upper or lower extremities. Although the morphine and naltrexone group required 0.04 mg more opioids during the study period, there was no significant difference between the opioid requirements of the 2 groups. Nausea was less frequently reported in patients receiving morphine and naltrexone. The combination of ultra-low-dose naltrexone and morphine in extremity trauma does not affect the opioid requirements; it, however, lowers the risk of nausea. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Formulation and evaluation of bilayer tablets of metoclopramide hydrochloride and diclofenac sodium.

    PubMed

    Gattani, Surendra G; Khabiya, Sohan S; Amrutkar, Jitendra R; Kushare, Sachin S

    2012-01-01

    The main objective of the present research work was to develop a bilayer tablet of metoclopramide hydrochloride (MTH) and diclofenac sodium (DS) in separate layers to avoid incompatibility and thus to maximize the efficacy of both drugs in combination for the effective treatment of migraine headaches. MTH and DS were formulated as immediate and sustained release layers respectively. In vitro dissolution kinetic studies of an optimized (D10) batch of DS in both sustained release layer and bilayer tablet forms show good linearity of regression coefficient 0.9773 (first order equation). The results reveal that an optimized immediate release layer (M5) of MTH and a sustained release layer (D10) of DS might be suitable for the treatment of migraine by sequential release of the two drugs in a bilayer tablet. Migraine is a type of recurring headache of moderate to severe intensity associated with gastrointestinal, neurological, and autonomic symptoms. In migraine, a combination of pretreatment with antiemetics is required for symptomatic treatment, when nausea and vomiting are severe. In our present research, we have selected the metoclopramide hydrochloride (MTH) active ingredient for study because it has an antiemetic effect and is a prokinetic agent. MTH is more effective to counteract gastric stasis associated with migraine, and it enhances the rate of absorption of non-steroidal anti-inflammatory drugs (NSAIDs). In the present investigation we combine MTH and a second active ingredient, diclofenac sodium, as a formulated bilayer tablet to prevent degradation of MTH.

  8. Naltrexone versus acamprosate in the treatment of alcohol dependence: A multi-centre, randomized, double-blind, placebo-controlled trial.

    PubMed

    Morley, Kirsten C; Teesson, Maree; Reid, Sophie C; Sannibale, Claudia; Thomson, Clare; Phung, Nghi; Weltman, Martin; Bell, James R; Richardson, Kylie; Haber, Paul S

    2006-10-01

    To compare the efficacy of acamprosate and naltrexone in the treatment of alcohol dependence. A double-blind, placebo-controlled trial. Three treatment centres in Australia. A total of 169 alcohol dependent subjects were given naltrexone (50 mg/day), acamprosate (1998 mg/day) or placebo for 12 weeks. All subjects were offered manualized compliance therapy, a brief intervention that targets problems that may affect treatment compliance such as ambivalence and misperceptions about medication. Time to the first drink, time to first relapse, drinks per drinking day and cumulative abstinence. In intention-to-treat analyses, there were no differences between groups on outcome measures of drinking, craving or biochemical markers. Similarly, analyses of the 94 subjects that completed the study in full and demonstrated 80% compliance, revealed no significant treatment effects. Differential treatment effects were identified after stratification according to scores on the Alcohol Dependence Scale (ADS) and Depression Anxiety and Stress Scale (DASS). A significant beneficial treatment effect on time to first relapse was revealed for subjects with 'no depression' allocated to naltrexone (n = 56; P < 0.01). In addition, a significant beneficial treatment effect was revealed in subjects with 'low dependence' allocated to naltrexone (n = 34; P < 0.05). The results of this study support the efficacy of naltrexone in the relapse prevention of alcoholism amongst those with low levels of clinical depression and alcohol dependence severity. No effect of acamprosate was found in our sample.

  9. Severe constipation associated with extended-release bupropion therapy.

    PubMed

    Lounsbery, Jody L; Medow, Mitchell A; Green, Christopher G

    2008-08-15

    A case of bupropion-induced constipation is reported. A 38-year-old man went to a clinic with a chief complaint of depression. He was prescribed extended-release bupropion 150 mg orally daily. Three weeks later, the patient returned to the clinic for a follow-up visit regarding his depression. He reported that his depression symptoms improved, but he complained of constipation and inflamed hemorrhoids from straining with defecation. He used docusate sodium, fiber supplements, and Preparation H(Wyeth) products with some relief. The bupropion was continued for his depression. Recommendations were given to the patient to increase fluids, maintain fiber intake, and add exercise. One week later, the patient complained of rectal pain and minimal bleeding. Prescriptions were given to the patient for hydrocortisone suppositories and 2.5% cream to be used twice daily. Three days later, the patient returned to the clinic complaining of increased pain and no relief from the hydrocortisone suppositories and cream. The rectal examination showed 3- and 5-cm hemorrhoids, one of which was thrombotic. The patient was instructed to continue hydrocortisone products, increase fluids, and continue docusate. Hemorrhoidectomy surgery was eventually performed, as well as a fissurectomy. The patient discontinued bupropion on his own due to the constipation approximately one week before the surgery. The constipation resolved after discontinuation of bupropion. Extended-release bupropion was the probable cause of severe constipation in a man with multiple medical problems.

  10. Maintaining remission in ulcerative colitis – role of once daily extended-release mesalamine

    PubMed Central

    Oliveira, Lilliana; Cohen, Russell D

    2011-01-01

    The aminosalicylates (5-ASA; also referred to as mesalamine-based agents) are considered as first-line in the maintenance of remission of mild to moderate ulcerative colitis (UC). Traditionally these agents have required a large pill burden and multiple daily dosing regimens which may account for the low adherence rates, especially in patients in remission. Extended-release mesalamine is the first once daily mesalamine product approved by the Food and Drug Administration for the maintenance of UC remission. This review will examine the pharmacokinetics, dosing, efficacy, and safety data of extended-release mesalamine, and discuss the potential role of improving medication compliance and decreasing costs in UC maintenance. PMID:21448448

  11. Steady-State Clinical Pharmacokinetics of Bupropion Extended-Release In Youths

    ERIC Educational Resources Information Center

    Daviss, W. Burleson; Perel, James M.; Birmaher, Boris; Rudolph, George R.; Melhem, Imad; Axelson, David A.; Brent, David A.

    2006-01-01

    Objective: To examine in children and adolescents the 24-hour, steady-state clinical pharmacokinetics of an extended-release (XL) formulation of bupropion (Wellbutrin XL). Method: Subjects were six male and four female patients (ages 11.5-16.2 years) prescribed bupropion XL in morning daily doses of either 150 mg (n = 5) or 300 mg (n = 5) for at…

  12. Delivery of prazosin hydrochloride from osmotic pump system prepared by coating the core tablet with an indentation.

    PubMed

    Liu, Longxiao; Wang, Jinchao; Zhu, Suyan

    2007-04-01

    The preparation of an osmotic pump tablet was simplified by elimination of laser drilling using prazosin hydrochloride as the model drug. The osmotic pump system was obtained by coating the indented core tablet compressed by the punch with a needle. A multiple regression equation was achieved with the experimental data of core tablet formulations, and then the formulation was optimized. The influences of the indentation size of the core tablet, environmental media, and agitation rate on drug release profile were investigated. The optimal osmotic pump tablet was found to deliver prazosin hydrochloride at an approximately constant rate up to 24 hr, and independent on both release media and agitation rate. Indentation size of core tablet hardly affected drug release in the range of 0.80-1.15 mm. The method that is simplified by elimination of laser drilling may be promising for preparation of an osmotic pump tablet.

  13. Formulation and dissolution kinetics study of hydrophilic matrix tablets with tramadol hydrochloride and different co-processed dry binders.

    PubMed

    Komersová, Alena; Lochař, Václav; Myslíková, Kateřina; Mužíková, Jitka; Bartoš, Martin

    2016-12-01

    The aim of this study is to present the possibility of using of co-processed dry binders for formulation of matrix tablets with drug controlled release. Hydrophilic matrix tablets with tramadol hydrochloride, hypromellose and different co-processed dry binders were prepared by direct compression method. Hypromelloses Methocel™ K4M Premium CR or Methocel™ K100M Premium CR were used as controlled release agents and Prosolv® SMCC 90 or Disintequik™ MCC 25 were used as co-processed dry binders. Homogeneity of the tablets was evaluated using scanning electron microscopy and energy dispersive X-ray microanalysis. The release of tramadol hydrochloride from prepared formulations was studied by dissolution test method. The dissolution profiles obtained were evaluated by non-linear regression analysis, release rate constants and other kinetic parameters were determined. It was found that matrix tablets based on Prosolv® SMCC 90 and Methocel™ Premium CR cannot control the tramadol release effectively for >12h and tablets containing Disintequik™ MCC 25 and Methocel™ Premium CR >8h. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Naltrexone for treatment of impaired awareness of hypoglycemia in type 1 diabetes: A randomized clinical trial

    PubMed Central

    Moheet, Amir; Mangia, Silvia; Kumar, Anjali; Tesfaye, Nolawit; Eberly, Lynn E; Bai, Yun; Kubisiak, Kristine; Seaquist, Elizabeth R

    2016-01-01

    Aims Impaired awareness of hypoglycemia (IAH) is a limiting factor in the treatment of type 1 diabetes (T1D) and is a challenging condition to reverse. The objective of this study was to test the hypothesis that naltrexone therapy in subjects with T1D and IAH will improve counterregulatory hormone response and recognition of hypoglycemia symptoms during hypoglycemia. Methods We performed a pilot randomized double blind trial of 4 weeks of naltrexone therapy (n=10) or placebo (n=12) given orally in subjects with T1D and IAH. Outcome measures included hypoglycemia symptom scores, counterregulatory hormone levels and thalamic activation as measured by cerebral blood flow using MRI during experimental hypoglycemia in all subjects before and after 4 weeks of intervention. Results After 4 weeks of therapy with naltrexone or placebo, no significant differences in response to hypoglycemia were seen in any outcomes of interest within each group. Conclusions In this small study, short-term treatment with naltrexone did not improve recognition of hypoglycemia symptoms or counterregulatory hormone response during experimental hypoglycemia in subjects with T1D and IAH. Whether this lack of effect is related to the small sample size or due to the dose, the advanced stage of study population or the drug itself should be the subject of future investigation. PMID:26345338

  15. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels.

    PubMed

    Younger, Jarred; Noor, Noorulain; McCue, Rebecca; Mackey, Sean

    2013-02-01

    To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue. Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain. When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported. The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication. Copyright © 2013 by the American College of Rheumatology.

  16. Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users.

    PubMed

    Marks, Katherine R; Lile, Joshua A; Stoops, William W; Rush, Craig R

    2014-07-01

    Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone. Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration.

  17. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain.

    PubMed

    Younger, Jarred; Parkitny, Luke; McLain, David

    2014-04-01

    Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

  18. The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders.

    PubMed

    Patten, Denise K; Schultz, Bob G; Berlau, Daniel J

    2018-03-01

    Chronic inflammatory diseases are complex to treat and have an impact on a large number of patients. Due to the difficulty of treating these diseases and the great impact on quality of life, patients often seek off-label, complimentary, or alternative medicines to gain relief from symptoms. Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia, and other diseases. Naltrexone is a mu-opioid receptor antagonist indicated by the U.S. Food and Drug Administration for opioid and alcohol dependence. It is hypothesized that lower than standard doses of naltrexone inhibit cellular proliferation of T and B cells and block Toll-like receptor 4, resulting in an analgesic and antiinflammatory effect. It is the purpose of this review to examine the evidence of the safety, tolerability, and efficacy of low-dose naltrexone for use in chronic pain and inflammatory conditions. Currently, evidence supports the safety and tolerability of low-dose naltrexone in multiple sclerosis, fibromyalgia, and Crohn's disease. Fewer studies support the efficacy of low-dose naltrexone, with most of these focusing on subjective measures such as quality of life or self-reported pain. These studies do demonstrate that low-dose naltrexone has subjective benefits over placebo, but evidence for more objective measures is limited. However, further randomized controlled trials are needed to determine the efficacy of low-dose naltrexone due to insufficient evidence supporting its use in these disease states. This review provides practitioners with the extent of low-dose naltrexone evidence so that they can be cognizant of situations where it may not be the most appropriate therapy. © 2018 Pharmacotherapy Publications, Inc.

  19. Naltrexone and Bupropion Combination Treatment for Smoking Cessation and Weight Loss in Patients With Schizophrenia.

    PubMed

    Lyu, Xuechan; Du, Jiang; Zhan, Guilai; Wu, Yujie; Su, Hang; Zhu, Youwei; Jarskog, Fredrik; Zhao, Min; Fan, Xiaoduo

    2018-01-01

    Objective: The rates of obesity and cigarette smoking are much higher in patients with schizophrenia compared to the general population. This study was to examine whether naltrexone and bupropion combination treatment can help weight loss and smoking cessation in patients with schizophrenia. Methods: Obese male schizophrenia patients with current cigarette smoking were randomized to receive adjunctive naltrexone (25 mg/day) and bupropion (300 mg/day) combination or placebo for 24 weeks. Twenty-two patients were enrolled in the study, and 21 patients completed the study (11 in the treatment group, and 10 in the placebo group). Body weight, body mass index (BMI), fasting lipids, smoking urge, expired carbon monoxide (CO) level and cigarettes smoked per week were measured at baseline and week 24. Results: There was no significant difference between two groups in changes in weight, BMI, fasting lipids, or cigarette smoking measures ( p 's > 0.05) Conclusion: Naltrexone and bupropion combination treatment didn't show weight loss or smoking cessation effect in patients with schizophrenia in this pilot study.Implications for future studies were discussed. ClinicalTrials.gov identifier: NCT02736474.

  20. Naltrexone and Bupropion Combination Treatment for Smoking Cessation and Weight Loss in Patients With Schizophrenia

    PubMed Central

    Lyu, Xuechan; Du, Jiang; Zhan, Guilai; Wu, Yujie; Su, Hang; Zhu, Youwei; Jarskog, Fredrik; Zhao, Min; Fan, Xiaoduo

    2018-01-01

    Objective: The rates of obesity and cigarette smoking are much higher in patients with schizophrenia compared to the general population. This study was to examine whether naltrexone and bupropion combination treatment can help weight loss and smoking cessation in patients with schizophrenia. Methods: Obese male schizophrenia patients with current cigarette smoking were randomized to receive adjunctive naltrexone (25 mg/day) and bupropion (300 mg/day) combination or placebo for 24 weeks. Twenty-two patients were enrolled in the study, and 21 patients completed the study (11 in the treatment group, and 10 in the placebo group). Body weight, body mass index (BMI), fasting lipids, smoking urge, expired carbon monoxide (CO) level and cigarettes smoked per week were measured at baseline and week 24. Results: There was no significant difference between two groups in changes in weight, BMI, fasting lipids, or cigarette smoking measures (p's > 0.05) Conclusion: Naltrexone and bupropion combination treatment didn't show weight loss or smoking cessation effect in patients with schizophrenia in this pilot study.Implications for future studies were discussed. ClinicalTrials.gov identifier: NCT02736474. PMID:29563871

  1. Maintenance on naltrexone+amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys.

    PubMed

    Moerke, Megan J; Banks, Matthew L; Cheng, Kejun; Rice, Kenner C; Negus, S Stevens

    2017-12-01

    Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0-0.1mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032-0.32mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Effects of Naltrexone Sustained- Release/Bupropion Sustained-Release Combination Therapy on Body Weight and Glycemic Parameters in Overweight and Obese Patients With Type 2 Diabetes

    PubMed Central

    Hollander, Priscilla; Gupta, Alok K.; Plodkowski, Raymond; Greenway, Frank; Bays, Harold; Burns, Colleen; Klassen, Preston; Fujioka, Ken

    2013-01-01

    OBJECTIVE To assess the efficacy and safety of 32 mg naltrexone sustained-release (SR)/360 mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetes drugs. RESEARCH DESIGN AND METHODS This was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardized lifestyle intervention and were randomized 2:1 to NB or placebo. Coprimary end points were percent weight change and achievement of ≥5% weight loss. Secondary end points included achievement of HbA1c <7% (53 mmol/mol), achievement of weight loss ≥10%, and change in HbA1c, waist circumference, fasting blood glucose, and lipids. RESULTS In the modified intent-to-treat population (54% female, 80% Caucasian, and mean age 54 years, weight 106 kg, BMI 37 kg/m2, and HbA1c 8.0% [64 mmol/mol]), NB resulted in significantly greater weight reduction (−5.0 vs. −1.8%; P < 0.001) and proportion of patients achieving ≥5% weight loss (44.5 vs. 18.9%, P < 0.001) compared with placebo. NB also resulted in significantly greater HbA1c reduction (−0.6 vs. −0.1% [6.6 vs. 1.1 mmol/mol]; P < 0.001), percent of patients achieving HbA1c <7% (53 mmol/mol) (44.1 vs. 26.3%; P < 0.001), and improvement in triglycerides and HDL cholesterol compared with placebo. NB was associated with higher incidence of nausea (42.3 vs. 7.1%), constipation (17.7 vs. 7.1%), and vomiting (18.3 vs. 3.6%). No difference was observed between groups in the incidence of depression, suicidal ideation, or hypoglycemia. CONCLUSIONS NB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes. PMID:24144653

  3. Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone.

    PubMed

    Roshanpour, Maryam; Ghasemi, Mehdi; Riazi, Kiarash; Rafiei-Tabatabaei, Neda; Ghahremani, Mohammad Hossein; Dehpour, Ahmad Reza

    2009-02-01

    The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a mouse model of clonic seizures induced by pentylenetetrazole, and whether ultra-low doses of the opioid receptor antagonist naltrexone which selectively block G(s) opioid receptors were capable of preventing the observed tolerance. The results showed that the morphine anticonvulsant effect could be subject to tolerance after repeated administration. Both the development and expression of tolerance were inhibited by ultra-low doses of naltrexone, suggesting the possible involvement of G(s)-coupled opioid receptors in the development of tolerance to the anticonvulsant effect of morphine.

  4. Functional modulation on macrophage by low dose naltrexone (LDN).

    PubMed

    Yi, Zhe; Guo, Shengnan; Hu, Xu; Wang, Xiaonan; Zhang, Xiaoqing; Griffin, Noreen; Shan, Fengping

    2016-10-01

    Previously it was confirmed that naltrexone, a non-peptide δ-opioid receptor selective antagonist is mainly used for alcoholic dependence and opioid addiction treatment. However, there is increasing data on immune regulation of low dose naltrexone (LDN). The aim of this work was to explore the effect of LDN on the phenotype and function of macrophage. The changes of macrophage after treatment with LDN were examined using flow cytometry (FCM); FITC-dextran phagocytosis and enzyme-linked immunosorbent assay (ELISA). We have found that LDN enhances function of macrophage as confirmed by up-regulating MHC II molecule and CD64 on macrophage while down-regulating CD206 expression. Furthermore the productions of TNF-α, IL-6, IL-1β, increased significantly. Macrophages in LDN treated group performed the enhanced phagocytosis. Therefore it is concluded that LDN could promote function of macrophage and this work has provided concrete data of impact on immune system by LDN. Especially the data would support interaction between CD4+T cell and macrophage in AIDS treatment with LDN in Africa (LDN has already been approved in Nigeria for the use in AIDS treatment). Copyright © 2016. Published by Elsevier B.V.

  5. Risk based In Vitro Performance Assessment of Extended Release Abuse Deterrent Formulations

    PubMed Central

    Xu, Xiaoming; Gupta, Abhay; Al-Ghabeish, Manar; Calderon, Silvia N.; Khan, Mansoor A.

    2016-01-01

    High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products. PMID:26784976

  6. Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users

    PubMed Central

    Marks, Katherine R.; Lile, Joshua A.; Stoops, William W.

    2014-01-01

    Rationale Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. Objectives The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone. Methods Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Results Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. Conclusions The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration. PMID:24464531

  7. [Low dose naltrexone for treatment of pain].

    PubMed

    Plesner, Karin Bruun; Vægter, Henrik Bjarke; Handberg, Gitte

    2015-10-09

    Recent years have seen an increasing interest in the use of low dose naltrexone (LDN) for off-label treatment of pain in diseases as fibromyalgia, multiple sclerosis and morbus Crohn. The evidence is poor, with only few randomized double-blind placebo-controlled studies. The studies currently available are reviewed in this paper. LDN could be a potentially useful drug in the future for the treatment of pain in fibromyalgia, but more studies are needed to verify that it is superior to placebo, and currently it cannot be recommended as first-line therapy.

  8. Sucrose and naltrexone prevent increased pain sensitivity and impaired long-term memory induced by repetitive neonatal noxious stimulation: Role of BDNF and β-endorphin.

    PubMed

    Nuseir, Khawla Q; Alzoubi, Karem H; Alhusban, Ahmed; Bawaane, Areej; Al-Azzani, Mohammed; Khabour, Omar F

    2017-10-01

    Pain in neonates is associated with short and long-term adverse outcomes. Data demonstrated that long-term consequences of untreated pain are linked to the plasticity of the neonate's brain. Sucrose is effective and safe for reducing painful procedures from single events. However, the mechanism of sucrose-induced analgesia is not fully understood. The role of the opioid system in this analgesia using the opioid receptor antagonist Naltrexone was investigated, plus the long-term effects on learning and memory formation during adulthood. Pain was induced in rat pups via needle pricks of the paws. Sucrose solution and/or naltrexone were administered before the pricks. All treatments started on day one of birth and continued for two weeks. At the end of 8weeks, behavioral studies were conducted to test spatial learning and memory using radial arm water maze (RAWM), and pain threshold via foot-withdrawal response to a hot plate. The hippocampus was dissected; levels of brain derived neurotrophic factor (BDNF) and endorphins were assessed using ELISA. Acute repetitive neonatal pain increased pain sensitivity later in life, while naltrexone with sucrose decreased pain sensitivity. Naltrexone and/or sucrose prevented neonatal pain induced impairment of long-term memory, while neonatal pain decreased levels of BDNF in the hippocampus; this decrease was averted by sucrose and naltrexone. Sucrose with naltrexone significantly increased β-endorphin levels in noxiously stimulated rats. In conclusion, naltrexone and sucrose can reverse increased pain sensitivity and impaired long-term memory induced by acute repetitive neonatal pain probably by normalizing BDNF expression and increasing β-endorphin levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Films based on soy protein-agar blends for wound dressing: Effect of different biopolymer proportions on the drug release rate and the physical and antibacterial properties of the films.

    PubMed

    Rivadeneira, Josefina; Audisio, M C; Gorustovich, Alejandro

    2018-04-01

    No single material can provide all requirements for wound dressings. Here, we evaluated the influence of different soy protein isolate and agar proportions (3:1, 1:1, and 1:3) in blend films on some of their physical-chemical and antibacterial properties to elucidate their potential as wound dressings. The films were synthesized by the gel casting method and ciprofloxacin hydrochloride was incorporated into the films. Films were characterized based on their surface morphology, water uptake ability, and weight loss profile. Also, the ciprofloxacin hydrochloride release kinetics was quantified spectrophotometrically. The antibacterial effect was evaluated against Staphylococcus aureus and Pseudomonas aeruginosa strains. The soy protein isolate-agar ratio affected the water uptake of the films and the release profile of ciprofloxacin hydrochloride but not the weight loss profile. The amount of drug released decreased near 80% because of the decrease in agar content in the films. The release kinetics of ciprofloxacin hydrochloride data best fitted to the Korsmeyer-Peppas model, suggesting that the mechanism of drug release was mainly of the diffusion type. All ciprofloxacin hydrochloride-releasing soy protein isolate-agar films strongly inhibited the cell viability of the bacterial strains studied. We concluded that water uptake and ciprofloxacin hydrochloride release can be controlled by changing the soy protein isolate-agar proportion. The proportions did not lead to changes in the antibacterial strength of the films.

  10. 21 CFR 522.536 - Detomidine hydrochloride injection.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Detomidine hydrochloride injection. 522.536... § 522.536 Detomidine hydrochloride injection. (a) Specification. Each milliliter of sterile aqueous solution contains 10 milligrams of detomidine hydrochloride. (b) Sponsor. See 052483 in § 510.600(c) of...

  11. Effects of extended-release niacin with laropiprant in high-risk patients.

    PubMed

    Landray, Martin J; Haynes, Richard; Hopewell, Jemma C; Parish, Sarah; Aung, Theingi; Tomson, Joseph; Wallendszus, Karl; Craig, Martin; Jiang, Lixin; Collins, Rory; Armitage, Jane

    2014-07-17

    Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain. After a prerandomization run-in phase to standardize the background statin-based LDL cholesterol-lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization). During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1

  12. 21 CFR 182.1047 - Glutamic acid hydrochloride.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Glutamic acid hydrochloride. 182.1047 Section 182.1047 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Food Substances § 182.1047 Glutamic acid hydrochloride. (a) Product. Glutamic acid hydrochloride. (b...

  13. 21 CFR 182.1047 - Glutamic acid hydrochloride.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Glutamic acid hydrochloride. 182.1047 Section 182.1047 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Food Substances § 182.1047 Glutamic acid hydrochloride. (a) Product. Glutamic acid hydrochloride. (b...

  14. Effectiveness of low-dose naltrexone in the post-detoxification treatment of opioid dependence.

    PubMed

    Mannelli, Paolo; Patkar, Ashwin A; Peindl, Kathleen; Murray, Heather W; Wu, Li-Tzy; Hubbard, Robert

    2007-10-01

    The clinical use of naltrexone (NTX) in the treatment of opioid dependence has been limited because of poor compliance and inconsistent outcomes. In particular, the therapeutic benefit of extended treatment with NTX after opioid detoxification is unclear. The present study evaluated whether the augmentation with low-dose NTX during the post-detoxification treatment of opioid dependence would improve outcomes. In an open-label naturalistic design, 435 opioid-dependent patients who had completed inpatient detoxification were offered the choice of entering 1 of the 2 outpatient treatment arms: clonidine extended treatment (CET) (clonidine + psychosocial treatment), or enhanced extended treatment (EET) (oral NTX [1-10 mg/d] + CET) for 21 days. The primary outcome measure was retention in treatment. Secondary outcomes included abstinence from opioids, dropouts, and adherence to postdischarge care. One hundred sixty-two patients (37.2%) accepted EET. Subjects receiving EET stayed longer in the program (F = 64.4; P = 0.000), were less likely to drop out, used less opioids, and followed through with referral to long-term outpatient treatment in a higher number, compared with patients in the CET arm (P = 0.000 in each case). The NTX + clonidine combination was safe and well tolerated. This preliminary study indicates the potential benefit of augmentation with low-dose NTX to improve outcomes after opioid detoxification for a preferred group of patients. Randomized controlled trials are necessary to further evaluate the role of low-dose NTX in the outpatient treatment of opioid dependence.

  15. Enhanced sensitivity to naltrexone-induced drinking suppression of fluid intake and sucrose consumption in maternally separated rats.

    PubMed

    Michaels, Clifford C; Holtzman, Stephen G

    2007-04-01

    Early-life stress has been identified as a risk factor in the development of a host of disorders, including substance abuse; however the link between early postnatal stress and changes in measures of reward has not been thoroughly researched. The current study had two main objectives: 1) to determine the impact of maternal separation (an animal model of early-life stress) on the consumption of 10% and 2.5% sucrose solutions by Long-Evans rat dams and male and female offspring, and 2) to determine the effect of the opioid antagonist naltrexone (0.1-3.0 mg/kg) on drinking by each of those groups. Dam-pup separations occurred for varying lengths of time during the first two postnatal weeks. In Experiment 1, a two-bottle choice test (sucrose solution vs. water) was administered across five days to both nonhandled (NH) and maternally-separated (MS) offspring as adults and to dams 2-4 weeks post-weaning. In Experiment 2, naltrexone was administered prior to two-bottle choice tests. MS males and the dams of MS litters exhibited increased intake of total fluid and sucrose solutions, whereas results from females were less consistent. Naltrexone elicited a greater decrease in fluid intake and sucrose intake in male MS offspring compared to male NH offspring. These results indicate that early postnatal stress alters both sucrose consumption, a non-drug measure of reward, and apparently the brain opioid systems that mediate naltrexone-induced drinking suppression.

  16. Baclofen novel gastroretentive extended release gellan gum superporous hydrogel hybrid system: in vitro and in vivo evaluation.

    PubMed

    El-Said, Ibrahim A; Aboelwafa, Ahmed A; Khalil, Rawia M; ElGazayerly, Omaima N

    2016-01-01

    Baclofen is a centrally acting skeletal muscle relaxant with a short elimination half-life, which results in frequent daily dosing and subsequent poor patient compliance. The narrow absorption window of baclofen in the upper gastrointestinal tract limits its formulation as extended release dosage forms. In this study, baclofen extended release superporous hydrogel (SPH) systems, including conventional SPH, SPH composite and SPH hybrid (SPHH), were prepared aiming to increase the residence of baclofen at its absorption window. The applicability of different polymers, namely, gellan gum, guar gum, polyvinyl alcohol and gelatin, was investigated in preparation of SPHH systems. The prepared SPH systems were evaluated regarding weight and volume swelling ratio, porosity, mechanical properties, incorporation efficiency, degree of erosion and drug release. In vivo assessment was performed in dogs to evaluate gastric residence time by X-ray studies. In addition, the oral bioavailability of baclofen relative to commercially available Lioresal® immediate release tablets was also investigated. The novel baclofen gellan SPHH cross linked with calcium chloride was characterized by optimum mechanical properties, acceptable swelling properties as well as extended drug release. It also exhibited a prolonged plasma profile when compared to twice daily administered Lioresal®.

  17. 75 FR 64313 - Endocrinologic and Metabolic Drugs Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-19

    ..., proposed tradename CONTRAVE (naltrexone HCl/bupropion HCl) extended-release tablets, manufactured by Orexigen Therapeutics, Inc., for the treatment of obesity and weight management, including weight loss and maintenance of weight loss in patients with an initial body mass index (BMI) of equal to or greater than 30...

  18. A non-rewarding, non-aversive buprenorphine/naltrexone combination attenuates drug-primed reinstatement to cocaine and morphine in rats in a conditioned place preference paradigm.

    PubMed

    Cordery, Sarah F; Taverner, Alistair; Ridzwan, Irna E; Guy, Richard H; Delgado-Charro, M Begoña; Husbands, Stephen M; Bailey, Christopher P

    2014-07-01

    Concurrent use of cocaine and heroin is a major public health issue with no effective relapse prevention treatment currently available. To this purpose, a combination of buprenorphine and naltrexone, a mixed very-low efficacy mu-opioid receptor agonist/kappa-opioid receptor antagonist/nociceptin receptor agonist, was investigated. The tail-withdrawal and the conditioned place preference (CPP) assays in adult Sprague Dawley rats were used to show that naltrexone dose-dependently blocked the mu-opioid receptor agonism of buprenorphine. Furthermore, in the CPP assay, a combination of 0.3 mg/kg buprenorphine and 3.0 mg/kg naltrexone was aversive. A combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone was neither rewarding nor aversive, but still possessed mu-opioid receptor antagonist properties. In the CPP extinction and reinstatement method, a combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone completely blocked drug-primed reinstatement in cocaine-conditioned rats (conditioned with 3 mg/kg cocaine, drug prime was 3 mg/kg cocaine) and attenuated drug-primed reinstatement in morphine-conditioned rats (conditioned with 5 mg/kg morphine, drug prime was 1.25 mg/kg morphine). These data add to the growing evidence that a buprenorphine/naltrexone combination may be protective against relapse in a polydrug abuse situation. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

  19. The efficacy of a low dose combination of topiramate and naltrexone on ethanol reinforcement and consumption in rat models.

    PubMed

    Moore, Catherine F; Protzuk, Omar A; Johnson, Bankole A; Lynch, Wendy J

    2014-01-01

    Combined medication approaches, by targeting multiple neurotransmitter systems involved in alcohol use disorders (AUDs), may be more efficacious than single-medication approaches. We examined, in animal models of consumption and reinforcement, the combined effects of naltrexone (an opioid antagonist) and topiramate (a GABA/glutamate modulator), two medications that have shown promise for treating AUDs, hypothesizing that their combination would be more efficacious than either alone. The effects of naltrexone and topiramate on ethanol consumption were examined in alcohol preferring (P) rats (N=10) and in rats from their background strain (Wistar, N=9) using conditions that induce high levels of consumption (24-h, 3-bottle, free-choice procedure). Low doses of each medication (1mg/kg, naltrexone; 10mg/kg, topiramate) were selected in an attempt to maximize their combined efficacy while minimizing potential side-effects. Their effects on ethanol reinforcement were assessed under a progressive-ratio schedule in additional groups of (N=22) P rats. A moderate dose of topiramate (20mg/kg) was also included to verify topiramate's efficacy on its own. In P rats, but not in Wistar rats, the combination effectively and persistently reduced consumption; whereas, neither dose alone was effective. The combination and naltrexone alone were equally effective at reducing ethanol reinforcement; however, with the combination, but not naltrexone alone, this effect was selective for ethanol. All treatments produced a similar decrease in home-cage food consumption. The 20mg/kg dose of topiramate also effectively reduced ethanol consumption and reinforcement. With greater efficacy and fewer side-effects, the combination shows promise as a treatment for AUDs. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. The efficacy of a low dose combination of topiramate and naltrexone on ethanol reinforcement and consumption in rat models

    PubMed Central

    Moore, Catherine F; Protzuk, Omar A; Johnson, Bankole A; Lynch, Wendy J

    2013-01-01

    Rationale Combined medication approaches, by targeting multiple neurotransmitter systems involved in alcohol use disorders (AUDs), may be more efficacious than single-medication approaches. Objectives We examined, in animals models of consumption and reinforcement, the combined effects of naltrexone (an opioid antagonist) and topiramate (a GABA/glutamate modulator), two medications that have shown promise for treating AUDs, hypothesizing that their combination would be more efficacious than either alone. Methods The effects of naltrexone and topiramate on ethanol consumption were examined in alcohol preferring (P) rats (N=10) and in rats from their background strain (Wistar, N=9) using conditions that induce high levels of consumption (24-hr, 3-bottle, free-choice procedure). Low doses of each medication (1 mg/kg, naltrexone; 10 mg/kg, topiramate) were selected in an attempt to maximize their combined efficacy while minimizing potential side-effects. Their effects on ethanol reinforcement were assessed under a progressive-ratio schedule in additional groups of (N=22) P rats. A moderate dose of topiramate (20 mg/kg) was also included to verify topiramate’s efficacy on its own. Results In P rats, but not Wistar rats, the combination effectively and persistently reduced consumption; whereas, neither dose alone was effective. The combination and naltrexone alone were equally effective at reducing ethanol reinforcement; however, with the combination, but not naltrexone alone, this effect was selective for ethanol. All treatments produced a similar decrease in home-cage food consumption. The 20 mg/kg dose of topiramate also effectively reduced ethanol consumption and reinforcement. Conclusions With greater efficacy and fewer side-effects, the combination shows promise as a treatment for AUDs. PMID:24252444

  1. Naltrexone moderates the relationship between cue-induced craving and subjective response to methamphetamine in individuals with methamphetamine use disorder.

    PubMed

    Roche, Daniel J O; Worley, Matthew J; Courtney, Kelly E; Bujarski, Spencer; London, Edythe D; Shoptaw, Steven; Ray, Lara A

    2017-07-01

    Reductions in cue-induced craving and subjective response to drugs of abuse are commonly used as initial outcome measures when testing novel medications for the treatment of addiction. Yet neither the relationship between these two measures at the individual level nor the moderating effects of pharmacotherapies on this relationship has been examined. This secondary data analysis sought to examine (1) the predictive relationship between cue-induced craving and subsequent acute subjective response to methamphetamine (MA) and (2) whether the opioid-receptor antagonist naltrexone moderated this association in a sample of non-treatment-seeking individuals who met DSM-IV criteria for MA use disorder (abuse or dependence). Participants (n = 30) completed two 4-day medication regimens (oral naltrexone 50 mg or placebo, in a randomized, counterbalanced, and double-blind fashion). On day 4 of each medication regimen, participants completed a cue-reactivity paradigm followed by intravenous MA administration. Methamphetamine craving was assessed after the cue-reactivity paradigm, and subjective response to MA was assessed during MA infusion. Cue-induced craving for MA was positively associated with post-infusion subjective MA effects, including positive (i.e., stimulation, good effects, feel drug, high), negative (i.e., anxious and depressed), and craving-related (i.e., want more, would like access to drug, crave) responses. Naltrexone, vs. placebo, significantly reduced the association between cue-induced craving and positive subjective response to MA. The findings indicate that naltrexone moderates the predictive relationship between cue-induced craving and positive subjective effects of MA, thereby suggesting a behavioral mechanism by which naltrexone may be efficacious in treating MA use disorder.

  2. Predictors of dropout in an outpatient treatment for problem drinkers including cognitive-behavioral therapy and the opioid antagonist naltrexone.

    PubMed

    Vuoristo-Myllys, Salla; Lahti, Jari; Alho, Hannu; Julkunen, Juhani

    2013-11-01

    This study investigated predictors of dropout in an outpatient treatment program for problem drinking that included individual cognitive-behavioral therapy combined with naltrexone. Specifically, we investigated whether sociodemographic factors, severity of alcohol dependence, history of problem drinking, or intensity of alcohol craving assessed at the beginning of the treatment predicted dropout from an outpatient program among a sample of 372 patients (65% male). We also investigated whether the effectiveness of the treatment (the change in alcohol consumption and symptoms of alcohol craving) or adherence to naltrexone was related to dropout. Predictors of dropout were investigated using an analysis of covariance with the number of attended treatment sessions as an independent variable. Our results demonstrated that the treatment entry factors predictive of dropout were younger age, lower severity of alcohol dependence, better ability to resist and control alcohol use, and lower obsession with alcohol. In addition, those who dropped out were more likely to begin the program by abstaining from alcohol and had lower adherence to naltrexone use than those who completed the program. The length of stay for treatment was not related to change in alcohol consumption. Patients with less severe alcohol-related problems may lack motivation for treatment, specifically cognitive-behavioral therapy and naltrexone. These patients may benefit more from less intensive treatments.

  3. Influence of limonene on the bioavailability of nicardipine hydrochloride from membrane-moderated transdermal therapeutic systems in human volunteers.

    PubMed

    Krishnaiah, Y S R; Satyanarayana, V; Bhaskar, P

    2002-10-24

    The aim of the present study was to develop a membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 4%w/w of limonene as a penetration enhancer. The permeability flux of nicardipine hydrochloride through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate (VA) content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED) on the permeability of nicardipine hydrochloride through EVA membrane 2825 (28% w/w VA) or membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE 4A MED/skin composite was higher than that coated with MA-31or MA-38. Thus a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED and 2%w/w HPC gel as reservoir containing 4%w/w of limonene as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady state plasma concentration of the drug with minimal fluctuations for 20 h with improved bioavailability in comparison with the immediate release capsule dosage form. Copyright 2002 Elsevier Science B.V.

  4. Simultaneous HPLC analysis of pseudophedrine hydrochloride, codeine phosphate, and triprolidine hydrochloride in liquid dosage forms.

    PubMed

    Manassra, Adnan; Khamis, Mustafa; El-Dakiky, Magdy; Abdel-Qader, Zuhair; Al-Rimawi, Fuad

    2010-03-11

    An HPLC method using UV detection is proposed for the simultaneous determination of pseudophedrine hydrochloride, codeine phosphate, and triprolidine hydrochloride in liquid formulation. C18 column (250mmx4.0mm) is used as the stationary phase with a mixture of methanol:acetate buffer:acetonitrile (85:5:10, v/v) as the mobile phase. The factors affecting column separation of the analytes were studied. The calibration graphs exhibited a linear concentration range of 0.06-1.0mg/ml for pseudophedrine hydrochloride, 0.02-1.0mg/ml for codeine phosphate, and 0.0025-1.0mg/ml for triprolidine hydrochloride for a sample size of 5microl with correlation coefficients of better than 0.999 for all active ingredients studied. The results demonstrate that this method is reliable, reproducible and suitable for routine use with analysis time of less than 4min. Copyright 2009 Elsevier B.V. All rights reserved.

  5. Extended-release niacin treatment of the atherogenic lipid profile and lipoprotein(a) in diabetes.

    PubMed

    Pan, Jianqiu; Van, Joanne T; Chan, Eve; Kesala, Renata L; Lin, Michael; Charles, M Arthur

    2002-09-01

    We tested the hypotheses that extended-release niacin is effective for the separate treatments of abnormalities in low-density liprotein (LDL) size, high-density lipoprotein (HDL)-2, and lipoprotein(a) [Lp(a)] without potential negative effects on glycated hemoglobin levels. The lipids that constitute the atherogenic lipid profile (ALP), such as triglycerides, small, dense LDL-cholesterol particle concentration, LDL particle size, total HDL-cholesterol (HDLc), HDL-2, and HDL-2 cholesterol concentration, as well as total LDL-cholesterol (LDLc) and Lp(a), were measured in 36 diabetic patients with primary abnormalities of LDL particle size (n = 25), HDL-2 (n = 23), and/or Lp(a) (n = 12) before and after extended-release niacin treatment. LDL particle size and HDL-2 were measured using polyacrylamide gradient gel electrophoreses and Lp(a) was measured by enzyme-linked immunosorbent assay (ELISA). After extended-release niacin, LDL peak particle diameter increased from 25.2 +/- 0.6 nm to 26.1 +/- 0.7 nm (P <.0001); small, dense LDLc concentration decreased from 30 +/- 17 mg/dL to 17 +/- 10 mg/dL (P <.0001); total HDLc increased from 42 +/- 9 mg/dL to 57 +/- 16 mg/dL (P <.0001); HDL-2 as the percent of total HDLc mass increased from 34% +/- 10% to 51% +/- 17% (P <.0001); and Lp(a) decreased from 37 +/- 10 mg/dL to 23 +/- 10 mg/dL (P <.001). Mean hemoglobin A(1c) level was improved during treatment from 7.5% +/- 1.6% to 6.5% +/- 0.9% (P <.0001). A subset of patients who had no change in hemoglobin A(1c) levels before and after treatment (6.8% +/- 1% v 6.7% +/- 1%; not significant) showed identical lipid changes. Twenty-two percent of patients were unable to tolerate extended-release niacin due to reversible side effects. These data indicate that in diabetic patients, extended-release niacin (1) is effective for separately treating diabetic dyslipidemias associated with abnormal LDL size, HDL-2, and Lp(a) independently of glycated hemoglobin levels; (2) must be used with

  6. 21 CFR 582.5875 - Thiamine hydrochloride.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5875 Thiamine hydrochloride. (a) Product. Thiamine hydrochloride. (b) Conditions of use...

  7. 21 CFR 582.5875 - Thiamine hydrochloride.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5875 Thiamine hydrochloride. (a) Product. Thiamine hydrochloride. (b) Conditions of use...

  8. 21 CFR 582.5875 - Thiamine hydrochloride.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5875 Thiamine hydrochloride. (a) Product. Thiamine hydrochloride. (b) Conditions of use...

  9. Physiologically Based Absorption Modeling to Design Extended-Release Clinical Products for an Ester Prodrug.

    PubMed

    Ding, Xuan; Day, Jeffrey S; Sperry, David C

    2016-11-01

    Absorption modeling has demonstrated its great value in modern drug product development due to its utility in understanding and predicting in vivo performance. In this case, we integrated physiologically based modeling in the development processes to effectively design extended-release (ER) clinical products for an ester prodrug LY545694. By simulating the trial results of immediate-release products, we delineated complex pharmacokinetics due to prodrug conversion and established an absorption model to describe the clinical observations. This model suggested the prodrug has optimal biopharmaceutical properties to warrant developing an ER product. Subsequently, we incorporated release profiles of prototype ER tablets into the absorption model to simulate the in vivo performance of these products observed in an exploratory trial. The models suggested that the absorption of these ER tablets was lower than the IR products because the extended release from the formulations prevented the drug from taking advantage of the optimal absorption window. Using these models, we formed a strategy to optimize the ER product to minimize the impact of the absorption window limitation. Accurate prediction of the performance of these optimized products by modeling was confirmed in a third clinical trial.

  10. Fatal and non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone.

    PubMed

    Kelty, Erin; Hulse, Gary

    2017-08-01

    Illicit opioid use is associated with high rates of fatal and non-fatal opioid overdose. This study aims to compare rates of fatal and serious but non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone, and to identify risk factors for fatal opioid overdose. Opioid dependent patients treated with methadone (n=3515), buprenorphine (n=3250) or implant naltrexone (n=1461) in Western Australia for the first time between 2001 and 2010, were matched against state mortality and hospital data. Rates of fatal and non-fatal serious opioid overdoses were calculated and compared for the three treatments. Risk factors associated with fatal opioid overdose were examined using multivariate cox proportional hazard models. No significant difference was observed between the three groups in terms of crude rates of fatal or non-fatal opioid overdoses. During the first 28days of treatment, rates of non-fatal opioid overdose were high in all three groups, as were fatal opioid overdoses in patients treated with methadone. However, no fatal opioid overdoses were observed in buprenorphine or naltrexone patients during this period. Following the first 28 days, buprenorphine was shown to be protective, particularly in terms of non-fatal opioid overdoses. After the cessation of treatment, rates of fatal and non-fatal opioid overdoses were similar between the groups, with the exception of lower rates of non-fatal opioid overdose in the naltrexone treated patients compared with the methadone treated patients. After the commencement of treatment, gender, and hospitalisations with a diagnosis of opioid poisoning, cardiovascular or mental health problems were significant predictors of subsequent fatal opioid overdose. Rates of fatal and non-fatal opioid overdose were not significantly different in patients treated with methadone, buprenorphine or implant naltrexone. Gender and prior cause-specific hospitalisations can be used to identify

  11. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis.

    PubMed

    Cree, Bruce A C; Kornyeyeva, Elena; Goodin, Douglas S

    2010-08-01

    To evaluate the efficacy of 4.5mg nightly naltrexone on the quality of life of multiple sclerosis (MS) patients. This single-center, double-masked, placebo-controlled, crossover study evaluated the efficacy of 8 weeks of treatment with 4.5mg nightly naltrexone (low-dose naltrexone, LDN) on self-reported quality of life of MS patients. Eighty subjects with clinically definite MS were enrolled, and 60 subjects completed the trial. Ten withdrew before completing the first trial period: 8 for personal reasons, 1 for a non-MS-related adverse event, and 1 for perceived benefit. Database management errors occurred in 4 other subjects, and quality of life surveys were incomplete in 6 subjects for unknown reasons. The high rate of subject dropout and data management errors substantially reduced the trial's statistical power. LDN was well tolerated, and serious adverse events did not occur. LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey (p = 0.04), a 6-point improvement on the Mental Health Inventory (p < 0.01), a 1.6-point improvement on the Pain Effects Scale (p =.04), and a 2.4-point improvement on the Perceived Deficits Questionnaire (p = 0.05). LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted.

  12. 76 FR 64945 - Teva Pharmaceutical Industries Ltd. and Cephalon, Inc.; Analysis of Agreement Containing Consent...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-19

    ... Pharmaceutical, Inc. (``Par'') all of Teva's rights and assets relating to its generic transmucosal fentanyl citrate lozenges (``fentanyl citrate'') and generic extended release cyclobenzaprine hydrochloride..., by lessening competition in the U.S. markets for fentanyl citrate, cyclobenzaprine hydrochloride, and...

  13. The Influence of Chitosan Cross-linking on the Properties of Alginate Microparticles with Metformin Hydrochloride-In Vitro and In Vivo Evaluation.

    PubMed

    Szekalska, Marta; Sosnowska, Katarzyna; Zakrzeska, Agnieszka; Kasacka, Irena; Lewandowska, Alicja; Winnicka, Katarzyna

    2017-01-22

    Sodium alginate is a polymer with unique ability to gel with different cross-linking agents in result of ionic and electrostatic interactions. Chitosan cross-linked alginate provides improvement of swelling and mucoadhesive properties and might be used to design sustained release dosage forms. Therefore, the aim of this research was to develop and evaluate possibility of preparing chitosan cross-linked alginate microparticles containing metformin hydrochloride by the spray-drying method. In addition, influence of cross-linking agent on the properties of microparticles was evaluated. Formulation of microparticles prepared by the spray drying of 2% alginate solution cross-linked by 0.1% chitosan was characterized by good mucoadhesive properties, high drug loading and prolonged metformin hydrochloride release. It was shown that designed microparticles reduced rat glucose blood level, delayed absorption of metformin hydrochloride and provided stable plasma drug concentration. Additionally, histopathological studies of pancreas, liver and kidneys indicated that all prepared microparticles improved degenerative changes in organs of diabetic rats. Moreover, no toxicity effect and no changes in rats behavior after oral administration of chitosan cross-linked alginate microparticles were noted.

  14. A Randomized, Phase 3 Trial of Naltrexone SR/Bupropion SR on Weight and Obesity-related Risk Factors (COR-II)

    PubMed Central

    Apovian, Caroline M; Aronne, Louis; Rubino, Domenica; Still, Christopher; Wyatt, Holly; Burns, Colleen; Kim, Dennis; Dunayevich, Eduardo

    2013-01-01

    Objective To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight-related risk factors in overweight and obese participants. Design and Methods CONTRAVE Obesity Research-II (COR-II) was a double-blind, placebo-controlled study of 1,496 obese (BMI 30-45 kg/m2) or overweight (27-45 kg/m2 with dyslipidemia and/or hypertension) participants randomized 2:1 to combined naltrexone sustained-release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) or placebo for up to 56 weeks. The co-primary endpoints were percent weight change and proportion achieving ≥5% weight loss at week 28. Results Significantly (P < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (−6.5% vs. −1.9%) and week 56 (−6.4% vs. −1.2%). More NB32-treated participants (P < 0.001) experienced ≥5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant-reported weight-related quality of life, and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. NB was not associated with increased events of depression or suicidality versus placebo. Conclusion NB represents a novel pharmacological approach to the treatment of obesity, and may become a valuable new therapeutic option. PMID:23408728

  15. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II).

    PubMed

    Apovian, Caroline M; Aronne, Louis; Rubino, Domenica; Still, Christopher; Wyatt, Holly; Burns, Colleen; Kim, Dennis; Dunayevich, Eduardo

    2013-05-01

    To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight-related risk factors in overweight and obese participants. CONTRAVE Obesity Research-II (COR-II) was a double-blind, placebo-controlled study of 1,496 obese (BMI 30-45 kg/m(2) ) or overweight (27-45 kg/m(2) with dyslipidemia and/or hypertension) participants randomized 2:1 to combined naltrexone sustained-release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) or placebo for up to 56 weeks. The co-primary endpoints were percent weight change and proportion achieving ≥ 5% weight loss at week 28. Significantly (P < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (-6.5% vs. -1.9%) and week 56 (-6.4% vs. -1.2%). More NB32-treated participants (P < 0.001) experienced ≥ 5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant-reported weight-related quality of life, and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. NB was not associated with increased events of depression or suicidality versus placebo. NB represents a novel pharmacological approach to the treatment of obesity, and may become a valuable new therapeutic option. Copyright © 2013 The Obesity Society.

  16. Spectrophotometric determination of meclizine hydrochloride and pyridoxine hydrochloride in laboratory prepared mixtures and in their pharmaceutical preparation

    NASA Astrophysics Data System (ADS)

    Ibrahim, Maha M.; Elzanfaly, Eman S.; El-Zeiny, Mohamed B.; Ramadan, Nesreen K.; Kelani, Khadiga M.

    2017-05-01

    In this paper, three rapid, simple, accurate and precise spectrophotometric methods were developed for the determination of meclizine hydrochloride in the presence of pyridoxine hydrochloride without previous separation. The methods under study are dual wavelength (DWL), ratio difference (RD) and continuous wavelet transform (CWT). On the other hand, pyridoxine hydrochloride (PYH) was determined directly at 291 nm. The methods obey Beer's law in the range of (5-50 μg/mL) for both compounds. All the methods were validated according to the ICH guidelines where the accuracy was found to be 98.29, 99.59, 100.42 and 100.62% for DWL, RD, CWT and PYH; respectively. Moreover the precision of the methods were calculated in terms of %RSD and it was found to be 0.545, 0.372, 1.287 and 0.759 for DWL, RD,CWT and PYH; respectively. The selectivity of the proposed methods was tested using laboratory prepared mixtures and assessed by applying the standard addition technique. So, they can be used for the routine analysis of pyridoxine hydrochloride and meclizine hydrochloride in quality-control laboratories.

  17. Evaluation of the counter-regulatory responses to hypoglycaemia in patients with type 1 diabetes during opiate receptor blockade with naltrexone.

    PubMed

    Naik, Sarita; Belfort-DeAguiar, Renata; Sejling, Anne-Sophie; Szepietowska, Barbara; Sherwin, Robert S

    2017-05-01

    Hypoglycaemia is the major limiting factor in achieving optimal glycaemic control in people with type 1 diabetes (T1DM), especially intensively treated patients with impaired glucose counter-regulation during hypoglycaemia. Naloxone, an opiate receptor blocker, has been reported to enhance the acute counter-regulatory response to hypoglycaemia when administered intravenously in humans. The current study was undertaken to investigate the oral formulation of the long-acting opiate antagonist, naltrexone, and determine if it could have a similar effect, and thus might be useful therapeutically in treatment of T1DM patients with a high risk of hypoglycaemia. We performed a randomized, placebo-controlled, double-blinded, cross-over study in which 9 intensively treated subjects with T1DM underwent a 2-step euglycaemic-hypoglycaemic-hyperinsulinaemic clamp on 2 separate occasions. At 12 hours and at 1 hour before the clamp study, participants received 100 mg of naltrexone or placebo orally. Counter-regulatory hormonal responses were assessed at baseline and during each step of the hyperinsulinaemic-clamp. Glucose and insulin levels did not differ significantly between the naltrexone and placebo visits; nor did the glucose infusion rates required to keep glucose levels at target. During hypoglycaemia, naltrexone, in comparison with the placebo group, induced an increase in epinephrine levels ( P  = .05). However, no statistically significant differences in glucagon, cortisol and growth hormone responses were observed. In contrast to the intravenous opiate receptor blocker naloxone, overnight administration of the oral long-acting opiate receptor blocker, naltrexone, at a clinically used dose, had a limited effect on the counter-regulatory response to hypoglycaemia in intensively treated subjects with T1DM. © 2016 John Wiley & Sons Ltd.

  18. Baclofen and naltrexone effects on alcohol self-administration: Comparison of treatment initiated during abstinence or ongoing alcohol access in baboons.

    PubMed

    Holtyn, August F; Kaminski, Barbara J; Weerts, Elise M

    2017-10-01

    Baclofen, a GABA B receptor agonist, is under investigation as a pharmacotherapy for alcohol use disorder. Treatment with a pharmacotherapeutic can be initiated during alcohol abstinence or active drinking, which may influence treatment outcomes. This study examined whether baclofen treatment initiated and maintained during alcohol abstinence would reduce alcohol seeking and self-administration upon return to alcohol access, and whether effects differed from treatment initiated and maintained during ongoing alcohol access. Naltrexone was tested under similar conditions for comparison. Five baboons self-administered alcohol under a three-component chained schedule of reinforcement that modeled periods of anticipation (Component 1), seeking (Component 2), and consumption (Component 3). Alcohol was only available in Component 3. In Experiment 1, baclofen (0.1-1.8mg/kg) or naltrexone (1.0-5.6mg/kg) was administered daily beginning on the first day of a 5-day abstinence period and treatment was continued for 5days of alcohol access. In Experiment 2, selected doses of both drugs were administered during ongoing alcohol access. When treatment was initiated during alcohol abstinence, baclofen and naltrexone did not significantly reduce total alcohol intake (g/kg) or alcohol seeking. In comparison, when treatment was initiated during ongoing alcohol access, both baclofen (1.8mg/kg) and naltrexone (3.2 and 5.6mg/kg) significantly reduced total alcohol intake (g/kg). Naltrexone (5.6mg/kg), but not baclofen, significantly reduced alcohol seeking. Initiation of baclofen treatment (or other alcohol use disorder treatments) during abstinence or active drinking may be an important factor in influencing efficacy and appropriate dose selection. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Putting the brakes on the "drive to eat": Pilot effects of naltrexone and reward based eating on food cravings among obese women

    PubMed Central

    Mason, Ashley E.; Laraia, Barbara; Daubenmier, Jennifer; Hecht, Frederick M.; Lustig, Robert H.; Puterman, Eli; Adler, Nancy; Dallman, Mary; Kiernan, Michaela; Gearhardt, Ashley N.; Epel, Elissa S.

    2015-01-01

    Purpose Obese individuals vary in their experience of food cravings and tendency to engage in reward-driven eating, both of which can be modulated by the neural reward system rather than physiological hunger. We examined two predictions in a sample of obese women: (1) whether opioidergic blockade reduced food-craving intensity, and (2) whether opioidergic blockade reduced an association between food-craving intensity and reward-driven eating, which is a trait-like index of three factors (lack of control over eating, lack of satiation, preoccupation with food). Methods Forty-four obese, pre-menopausal women completed the Reward-based Eating Drive (RED) scale at study start and daily food-craving intensity on 5 days on which they ingested either a pill-placebo (2 days), a 25mg naltrexone dose (1 day), or a standard 50mg naltrexone dose (2 days). Results Craving intensity was similar under naltrexone and placebo doses. The association between food-craving intensity and reward-driven eating significantly differed between placebo and 50mg naltrexone doses. Reward-driven eating and craving intensity were significantly positively associated under both placebo doses. As predicted, opioidergic blockade (for both doses 25mg and 50mg naltrexone) reduced this positive association between reward-driven eating and craving intensity to non-significance. Conclusions Opioidergic blockade did not reduce craving intensity; however, blockade reduced an association between trait-like reward-driven eating and daily food-craving intensity, and may help identify an important endophenotype within obesity. PMID:26164674

  20. Acute Myocardial Infarction following Naltrexone Consumption; a Case Report.

    PubMed

    Dadpour, Bita; Gholoobi, Arash; Tajoddini, Shahrad; Habibi, Amir

    2017-01-01

    Cardiovascular effects of opioid withdrawal have long been studied. It was reported that patients with underlying ischemic heart disease and atherosclerotic vessels may be complicated by a sudden physical and emotional stress due to withdrawal syndrome. But some other believes sudden increase in catecholamine level as a sympathetic overflow might effect on heart with and without underlying ischemia. In the current study, a patient on methadone maintenance therapy (MMT) who experienced myocardial infarction (MI) after taking naltrexone was described.

  1. Effects of alcoholism typology on response to naltrexone in the COMBINE study

    PubMed Central

    Bogenschutz, Michael P.; Tonigan, J. Scott; Pettinati, Helen M.

    2008-01-01

    Background This study investigated whether subgroups of alcohol dependent patients responded differently to naltrexone vs. placebo in the NIAAA COMBINE study. In particular, the A vs. B and the Early Onset vs. Late Onset typologies were examined. Relative to Type A alcoholics, Type Bs are characterized by greater severity, earlier onset, stronger family history, more childhood risk factors (e.g., conduct disorder), and greater frequency of comorbid psychiatric and substance use disorders. Methods COMBINE study participants were categorized as Type A or Type B using k-means cluster analysis and variables from 5 domains that have been shown to replicate the original Babor typology efficiently. Early Onset was defined as alcohol dependence beginning before age 25. For the planned analyses, the sample was reduced to the 618 participants receiving naltrexone alone or placebo, either with medical management (MM) alone or with MM plus the Combined Behavioral Intervention (CBI). The a priori primary outcome was percent heavy drinking days during treatment in the groups receiving MM without CBI. Results Among those receiving MM without CBI, Type A alcoholics had better drinking outcomes with naltrexone than placebo, whereas medication condition did not influence outcomes significantly in the Type Bs. Age of onset was not significantly related to outcome. For those receiving CBI, no significant effects were found for either typology. Conclusions In this sample, the beneficial effects of opioid antagonism were limited to Type A alcoholics receiving treatment in a medical management model. Future studies should investigate the relationship between clinically relevant genotypes, phenotypes such as typologies, and treatment response. More work is also needed to develop practical algorithms for phenotypic assignment. PMID:18828797

  2. Effects of alcoholism typology on response to naltrexone in the COMBINE study.

    PubMed

    Bogenschutz, Michael P; Scott Tonigan, J; Pettinati, Helen M

    2009-01-01

    This study investigated whether subgroups of alcohol-dependent patients responded differently to naltrexone versus placebo in the NIAAA COMBINE study. In particular, the A versus B and the Early Onset versus Late Onset typologies were examined. Relative to Type A alcoholics, Type B alcoholics are characterized by greater severity, earlier onset, stronger family history, more childhood risk factors (e.g., conduct disorder), and greater frequency of comorbid psychiatric and substance use disorders. COMBINE study participants were categorized as Type A or Type B using k-means cluster analysis and variables from 5 domains that have been shown to replicate the original Babor typology efficiently. Early Onset was defined as alcohol dependence beginning before age 25. For the planned analyses, the sample was reduced to the 618 participants receiving naltrexone alone or placebo, either with medical management (MM) alone or with MM plus the Combined Behavioral Intervention (CBI). The a priori primary outcome was percent heavy drinking days during treatment in the groups receiving MM without CBI. Among those receiving MM without CBI, Type A alcoholics had better drinking outcomes with naltrexone than placebo, whereas medication condition did not influence outcomes significantly in the Type Bs. Age of onset was not significantly related to outcome. For those receiving CBI, no significant effects were found for either typology. In this sample, the beneficial effects of opioid antagonism were limited to Type A alcoholics receiving treatment in a MM model. Future studies should investigate the relationship between clinically relevant genotypes, phenotypes such as typologies, and treatment response. More work is also needed to develop practical algorithms for phenotypic assignment.

  3. 21 CFR 520.1660b - Oxytetracycline hydrochloride capsules.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Oxytetracycline hydrochloride capsules. 520.1660b... Oxytetracycline hydrochloride capsules. (a) Specifications. The drug is in capsule form with each capsule containing 125 or 250 milligrams of oxytetracycline hydrochloride. Oxytetracycline is the antibiotic...

  4. Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats

    PubMed Central

    He, Shao-Qiu; Yang, Fei; Perez, Federico M.; Xu, Qian; Shechter, Ronen; Cheong, Yong-Kwan; Carteret, Alene F.; Dong, Xinzhong; Sweitzer, Sarah M.; Raja, Srinivasa N.; Guan, Yun

    2013-01-01

    Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5 mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75 to 6.0 mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150 µg/50 µL intraplantarly) and D-Ala2-MePhe4-Glyol5 enkephalin (300 µg/50 µL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5 mg/kg intraperitoneally) and MK-801 (0.2 mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3 mg/kg subcutaneously), but not loperamide (3 mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca2+]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3 µM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide’s inhibition of KCl-elicited [Ca2+]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug

  5. The Placebo Effect in Clinical Trials for Alcohol Dependence: An Exploratory Analysis of 51 Naltrexone and Acamprosate Studies

    PubMed Central

    Litten, Raye Z.; Castle, I-Jen P.; Falk, Daniel; Ryan, Megan; Fertig, Joanne; Chen, Chiung M.; Yi, Hsiao-ye

    2013-01-01

    Background The placebo effect often undermines efforts to determine treatment effectiveness in clinical trials. A significant placebo response occurs in alcohol trials, but it is not well understood. The purpose of this study was to characterize the placebo response across multiple naltrexone and acamprosate studies. Methods Fifty-one trials, 3 with a naltrexone and an acamprosate arm, 31 with at least 1 naltrexone arm, and 17 with at least 1 acamprosate arm, were identified from Cochrane reviews and PubMed search. To be included in this study, patients had to be at least 18 years old, abstinent from alcohol before randomization, and meet a diagnosis of alcohol dependence. Pearson correlation coefficients (rp) and simple linear regression were used to describe the strength of linear relationships between placebo response and treatment effect size. Spearman’s rank correlation coefficients (rs) were used to examine the strength of associations between study characteristics and placebo response. Results For the end-point measures of percent days abstinent and total abstinence, a negative relationship was evident between placebo response and treatment effect size in the naltrexone trials (rp = −0.55, p < 0.01 and rp = −0.20, p = 0.35, respectively) as well as in the acamprosate trials (rp = −0.45, p = 0.09 and rp = −0.56, p = 0.01, respectively). The placebo response for percent days abstinent was negatively correlated with mean age of participants (rs = −0.42, p = 0.05) across naltrexone trials and positively correlated with publication year (rs = 0.57, p = 0.03) across acamprosate trials. However, these two study characteristics were not significantly correlated with treatment effect size. Conclusion The placebo response varied considerably across trials and was negatively correlated with the treatment effect size. Additional studies are required to fully understand the complex nature of the placebo response and to evaluate approaches to minimize its

  6. Determination of naltrexone and 6beta-naltrexol in human blood: comparison of high-performance liquid chromatography with spectrophotometric and tandem-mass-spectrometric detection.

    PubMed

    Brünen, Sonja; Krüger, Ralf; Finger, Susann; Korf, Felix; Kiefer, Falk; Wiedemann, Klaus; Lackner, Karl J; Hiemke, Christoph

    2010-02-01

    We present data for a comparison of a liquid-chromatographic method coupled with tandem mass spectrometry (LC-MS/MS) and a high-performance liquid-chromatographic method with column switching and UV spectrophotometric detection. The two methods were developed for determination of naltrexone and 6beta-naltrexol in blood serum or plasma aiming to be used for therapeutic drug monitoring to guide the treatment of patients with naltrexone. For the high-performance liquid chromatography (HPLC)/UV detection, online sample cleanup was conducted on Perfect Bond C(18) material with 2% (vol/vol) acetonitrile in deionized water. Drugs were separated on a C(18) column using 11.5% (vol/vol) acetonitrile and 0.4% (vol/vol) N,N,N,N-tetramethylethylenediamine within 20 min. LC-MS/MS used naltrexone-d (3) and 6beta-naltrexol-d (4) as internal standards. After protein precipitation, the chromatographic separation was performed on a C(18) column by applying a methanol gradient (5-100%, vol/vol) with 0.1% formic acid over 9.5 min. The HPLC/UV method was found to be linear for concentrations ranging from 2 to 100 ng/ml, with a regression correlation coefficient of r (2) > 0.998 for naltrexone and 6beta-naltrexol. The limit of quantification was 2 ng/ml for naltrexone and 6beta-naltrexol. For the LC-MS/MS method the calibration curves were linear (r(2) > 0.999) from 0.5 to 200 ng/ml for both substances, and the limit of quantification was 0.5 ng/ml. The concentrations measured by the two methods correlated significantly for both substances (r(2) > 0.967; p < 0.001). Both methods could be used for therapeutic drug monitoring. The HPLC/UV method was advantageous regarding automatization and costs, whereas LC-MS/MS was superior with regard to sensitivity.

  7. Development of extended release dosage forms using non-uniform drug distribution techniques.

    PubMed

    Huang, Kuo-Kuang; Wang, Da-Peng; Meng, Chung-Ling

    2002-05-01

    Development of an extended release oral dosage form for nifedipine using the non-uniform drug distribution matrix method was conducted. The process conducted in a fluid bed processing unit was optimized by controlling the concentration gradient of nifedipine in the coating solution and the spray rate applied to the non-pareil beads. The concentration of nifedipine in the coating was controlled by instantaneous dilutions of coating solution with polymer dispersion transported from another reservoir into the coating solution at a controlled rate. The USP dissolution method equipped with paddles at 100 rpm in 0.1 N hydrochloric acid solution maintained at 37 degrees C was used for the evaluation of release rate characteristics. Results indicated that (1) an increase in the ethyl cellulose content in the coated beads decreased the nifedipine release rate, (2) incorporation of water-soluble sucrose into the formulation increased the release rate of nifedipine, and (3) adjustment of the spray coating solution and the transport rate of polymer dispersion could achieve a dosage form with a zero-order release rate. Since zero-order release rate and constant plasma concentration were achieved in this study using the non-uniform drug distribution technique, further studies to determine in vivo/in vitro correlation with various non-uniform drug distribution dosage forms will be conducted.

  8. Optimization of Melatonin Dissolution from Extended Release Matrices Using Artificial Neural Networking.

    PubMed

    Martarelli, D; Casettari, L; Shalaby, K S; Soliman, M E; Cespi, M; Bonacucina, G; Fagioli, L; Perinelli, D R; Lam, J K W; Palmieri, G F

    2016-01-01

    Efficacy of melatonin in treating sleep disorders has been demonstrated in numerous studies. Being with short half-life, melatonin needs to be formulated in extended-release tablets to prevent the fast drop of its plasma concentration. However, an attempt to mimic melatonin natural plasma levels during night time is challenging. In this work, Artificial Neural Networks (ANNs) were used to optimize melatonin release from hydrophilic polymer matrices. Twenty-seven different tablet formulations with different amounts of hydroxypropyl methylcellulose, xanthan gum and Carbopol®974P NF were prepared and subjected to drug release studies. Using dissolution test data as inputs for ANN designed by Visual Basic programming language, the ideal number of neurons in the hidden layer was determined trial and error methodology to guarantee the best performance of constructed ANN. Results showed that the ANN with nine neurons in the hidden layer had the best results. ANN was examined to check its predictability and then used to determine the best formula that can mimic the release of melatonin from a marketed brand using similarity fit factor. This work shows the possibility of using ANN to optimize the composition of prolonged-release melatonin tablets having dissolution profile desired.

  9. Bupropion-SR plus naltrexone-SR for the treatment of mild-to-moderate obesity.

    PubMed

    Ali, Khawla F; Shukla, Alpana P; Aronne, Louis J

    2016-01-01

    Naltrexone-bupropion is a recently approved drug combination for chronic weight management. In this article, we discuss the rationale for its use as a combination followed by a comprehensive review of safety and efficacy data from major preclinical, phase II and III clinical trials.

  10. Formulation and in vivo evaluation of membrane-moderated transdermal therapeutic systems of nicardipine hydrochloride using carvone as a penetration enhancer.

    PubMed

    Krishnaiah, Y S R; Satyanarayana, V; Bhaskar, P

    2003-01-01

    A membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride was developed using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 8%w/w of carvone as a penetration enhancer. The permeability flux of nicardipine hydrochloride through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38, or TACKWHITE A 4MED) on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28%w/w vinyl acetate) or EVA 2825 membrane/skin composite also was studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED and 2%w/w HPC gel as reservoir containing 8%w/w of carvone as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 23 hr with improved bioavailability in comparison with the immediate-release capsule dosage form.

  11. Drug Release and Skin Permeation from Lipid Liquid Crystalline Phases

    NASA Astrophysics Data System (ADS)

    Costa-Balogh, F. O.; Sparr, E.; Sousa, J. J. S.; Pais, A. A. C. C.

    We have studied drug release and skin permeation from several different liquid crystalline lipid formulations that may be used to control the respective release rates. We have studied the release and permeation through human skin of a water-soluble and amphiphilic drug, propranolol hydrochloride, from several formulations prepared with monoolein and phytantriol as permeation enhancers and controlled release excipients. Diolein and cineol were added to selected formulations. We observed that viscosity decreases with drug load, wich is compatible with the occurrence of phase changes. Diolein stabilizes the bicontinuous cubic phases leading to an increase in viscosity and sustained release of the drug. The slowest release was found for the cubic phases with higher viscosity. Studies on skin permeation showed that these latter formulations also presented lower permeability than the less viscous monoolein lamellar phases. Formulations containing cineol originated higher permeability with higher enhancement ratios. Thus, the various formulations are adapted to different circumstances and delivery routes. While a slow release is usually desired for drug sustained delivery, the transdermal route may require a faster release. Lamellar phases, which are less viscous, are more adapted to transdermal applications. Thus, systems involving lamellar phases of monoolein and cineol are good candidates to be used as skin permeation enhancers for propranolol hydrochloride.

  12. An extended-release formulation of oxybutynin chloride for the treatment of overactive urinary bladder.

    PubMed

    Goldenberg, M M

    1999-04-01

    Detrusor instability, or urinary incontinence, is common in elderly patients, particularly elderly women. The clinical symptoms of overactive, or unstable, urinary bladder include urge urinary incontinence, urgency, and frequency. Mixed urinary incontinence, which comprises urge urinary incontinence and stress incontinence, is manifested by increased intraabdominal pressure on coughing or sneezing. The detrusor muscle of the bladder is under the control of the parasympathetic, or muscarinic, nervous system. The drug of choice in this condition is oxybutynin chloride, which has the ability to block acetylcholine released from parasympathetic nerves in the urinary bladder, preventing contractions of the muscle and exerting a direct spasmolytic effect on the bladder. A new extended-release oral tablet formulation, OROS oxybutynin, uses osmotic pressure to deliver the drug at a controlled rate over approximately 24 hours. It resembles a conventional tablet but has a two-part core consisting of a drug layer and below it, a "push" layer containing osmotically active components, the whole surrounded by a semipermeable membrane with a laser-drilled opening in the drug side. Water in the gastrointestinal tract enters the tablet and mixes with the drug to form a suspension. The "push" layer expands and pushes the suspended drug out of the orifice and into the gastrointestinal tract for eventual absorption. Pharmacokinetic studies have indicated a slow rise in mean plasma concentration of the isomer R-oxybutynin for 4 to 6 hours after a single dose of OROS oxybutynin, followed by maintenance of steady concentrations for up to 24 hours, minimizing the fluctuations between peak and trough associated with TID dosing of 5-mg immediate-release oxybutynin tablets. Efficacy and safety studies comparing the extended-release with the immediate-release formulation of oxybutynin demonstrated equivalent efficacy in patients with overactive urinary bladder. The adverse-event profile of

  13. Behavioural profile of exendin-4/naltrexone dose combinations in male rats during tests of palatable food consumption.

    PubMed

    Wright, F L; Rodgers, R J

    2014-09-01

    The glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 potently suppresses food intake in animals and humans. However, little is known about the behavioural specificity of this effect either when administered alone or when co-administered with another anorectic agent. The present study characterises the effects of exendin-4, both alone and in combination with naltrexone, on behaviours displayed by male rats during tests with palatable mash. Experiment 1 examined the dose-response effects of exendin-4 (0.025-2.5 μg/kg, IP), while experiment 2 profiled the effects of low-dose combinations of the peptide (0.025 and 0.25 μg/kg) and naltrexone (0.1 mg/kg). In experiment 1, exendin-4 dose dependently suppressed food intake as well as the frequency and rate of eating. However, these effects were accompanied by dose-dependent reductions in all active behaviours and, at 2.5 μg/kg, a large increase in resting and disruption of the behavioural satiety sequence (BSS). In experiment 2, while exendin-4 (0.25 μg/kg) and naltrexone each produced a significant reduction in intake and feeding behaviour (plus an acceleration in the BSS), co-treatment failed to produce stronger effects than those seen in response to either compound alone. Similarities between the behavioural signature of exendin-4 and that previously reported for the emetic agent lithium chloride would suggest that exendin-4 anorexia is related to the aversive effects of the peptide. Furthermore, as low-dose combinations of the peptide with naltrexone failed to produce an additive/synergistic anorectic effect, this particular co-treatment strategy would not appear to have therapeutic significance.

  14. 21 CFR 522.883 - Etorphine hydrochloride injection.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... § 522.883 Etorphine hydrochloride injection. (a) Chemical name. 6,7,8,14 - tetrahydro - alpha - methyl - alpha - propyl - 6,14 - endo-ethenooripavine-alpha-methanol hydrochloride. (b) Specifications. Each...

  15. 21 CFR 522.883 - Etorphine hydrochloride injection.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... § 522.883 Etorphine hydrochloride injection. (a) Chemical name. 6,7,8,14 - tetrahydro - alpha - methyl - alpha - propyl - 6,14 - endo-ethenooripavine-alpha-methanol hydrochloride. (b) Specifications. Each...

  16. Developing dissolution testing methodologies for extended-release oral dosage forms with supersaturating properties. Case example: Solid dispersion matrix of indomethacin.

    PubMed

    Tajiri, Tomokazu; Morita, Shigeaki; Sakamoto, Ryosaku; Mimura, Hisahi; Ozaki, Yukihiro; Reppas, Christos; Kitamura, Satoshi

    2015-07-25

    The objective of this study was to develop an in vitro dissolution test method with discrimination ability for an extended-release solid dispersion matrix of a lipophilic drug using the United States Pharmacopeia (USP) Apparatus 4, flow-through cell apparatus. In the open-loop configuration, the sink condition was maintained by manipulating the flow rate of the dissolution medium. To evaluate the testing conditions, the drug release mechanism from an extended-release solid dispersion matrix containing hydrophobic and hydrophilic polymers was investigated. As the hydroxypropyl methylcellulose (HPMC) maintained concentrations of indomethacin higher than the solubility in a dissolution medium, the release of HPMC into the dissolution medium was also quantified using size-exclusion chromatography. We concluded that the USP Apparatus 4 is suitable for application to an in vitro dissolution method for orally administered extended-release solid dispersion matrix formulations containing poorly water-soluble drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Update on tolterodine extended-release for treatment of overactive bladder

    PubMed Central

    Omotosho, Tola; Chen, Chi Chiung Grace

    2010-01-01

    Overactive bladder is a prevalent condition which negatively impacts quality of life and puts a significant economical burden on society. First-line therapy often includes pharmacotherapy with antimuscarinic medications, and numerous research studies have demonstrated that tolterodine extended-release (ER) is an efficacious and tolerable formulation of this class of medication. This review provides an update on the clinical use of tolterodine ER, detailing the current literature on its efficacy, tolerability, adverse effects, and comparability with other commonly prescribed medications for the treatment of overactive bladder. PMID:24198627

  18. Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis.

    PubMed

    Ludwig, Michael D; Turel, Anthony P; Zagon, Ian S; McLaughlin, Patricia J

    2016-01-01

    A retrospective study was conducted on patients at Penn State Hershey Medical Center diagnosed with relapsing-remitting multiple sclerosis between 2006 and 2015. Laboratory and clinical data collected over this 10-year period were reviewed. Two cohorts of patients were established based on their relapsing-remitting multiple sclerosis therapy at the time of their first visit to Penn State. One group of patients ( n  = 23) was initially prescribed low dose naltrexone at the time first seen at Hershey. This group was offered low dose naltrexone because of symptoms of fatigue or refusal to take an available disease-modifying therapy. The second group of patients ( n  = 31) was treated with the glatiramer acetate (Copaxone) and offered low dose naltrexone as an adjunct therapy to their disease-modifying therapy. Patient data from visits after 1-50 months post-diagnosis were evaluated in a retrospective manner. Data obtained from patient charts included clinical laboratory values from standard blood tests, timed 25-foot walking trials, and changes in magnetic resonance imaging reports. Statistical analyses between the groups and for each patient over time indicated no significant differences in clinical laboratory values, timed walking, or changes in magnetic resonance imaging. These data suggest that the apparently non-toxic, inexpensive, biotherapeutic is safe and if taken alone did not result in an exacerbation of disease symptoms.

  19. Evaluating the Impact of Naltrexone on the Rat Gambling Task to Test Its Predictive Validity for Gambling Disorder.

    PubMed

    Di Ciano, Patricia; Le Foll, Bernard

    2016-01-01

    Gambling Disorder has serious consequences and no medications are currently approved for the treatment of this disorder. One factor that may make medication development difficult is the lack of animal models of gambling that would allow for the pre-clinical screening of efficacy. Despite this, there is evidence from clinical trials that opiate antagonists, in particular naltrexone, may be useful in treating gambling disorder. To-date, the effects of naltrexone on pre-clinical models of gambling have not been evaluated. The purpose of the present study was to evaluate the effects of naltrexone in an animal model of gambling, the rat gambling task (rGT), to determine whether this model has some predictive validity. The rGT is a model in which rats are given a choice of making either a response that produces a large reward or a small reward. The larger the reward, the greater the punishment, and thus this task requires that the animal inhibit the 'tempting' choice, as the smaller reward option produces overall the most number of rewards per session. People with gambling disorder chose the tempting option more, thus the rGT may provide a model of problem gambling. It was found that naltrexone improved performance on this task in a subset of animals that chose the 'tempting', disadvantageous choice, more at baseline. Thus, the results of this study suggest that the rGT should be further investigated as a pre-clinical model of gambling disorder and that further investigation into whether opioid antagonists are effective in treating Gambling Disorder may be warranted.

  20. Pinosylvin-Based Polymers: Biodegradable Poly(Anhydride-Esters) for Extended Release of Antibacterial Pinosylvin.

    PubMed

    Bien-Aime, Stephan; Yu, Weiling; Uhrich, Kathryn E

    2016-07-01

    Pinosylvin is a natural stilbenoid known to exhibit antibacterial bioactivity against foodborne bacteria. In this work, pinosylvin is chemically incorporated into a poly(anhydride-ester) (PAE) backbone via melt-condensation polymerization, and characterized with respect to its physicochemical and thermal properties. In vitro release studies demonstrate that pinosylvin-based PAEs hydrolytically degrade over 40 d to release pinosylvin. Pseudo-first order kinetic experiments on model compounds, butyric anhydride and 3-butylstilbene ester, indicate that the anhydride linkages hydrolyze first, followed by the ester bonds to ultimately release pinosylvin. An antibacterial assay shows that the released pinosylvin exhibit bioactivity, while in vitro cytocompatibility studies demonstrate that the polymer is noncytotoxic toward fibroblasts. These preliminary findings suggest that the pinosylvin-based PAEs can serve as food preservatives in food packaging materials by safely providing antibacterial bioactivity over extended time periods. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Lipids bearing extruded-spheronized pellets for extended release of poorly soluble antiemetic agent-Meclizine HCl.

    PubMed

    Qazi, Faaiza; Shoaib, Muhammad Harris; Yousuf, Rabia Ismail; Nasiri, Muhammad Iqbal; Ahmed, Kamran; Ahmad, Mansoor

    2017-04-12

    Antiemetic agent Meclizine HCl, widely prescribed in vertigo, is available only in immediate release dosage forms. The approved therapeutic dose and shorter elimination half-life make Meclizine HCl a potential candidate to be formulated in extended release dosage form. This study was aimed to develop extended release Meclizine HCl pellets by extrusion spheronization using natural and synthetic lipids. Influence of lipid type, drug/lipid ratio and combinations of different lipids on drug release and sphericity of pellets were evaluated. Thirty two formulations were prepared with four different lipids, Glyceryl monostearate (Geleol ® ), Glyceryl palmitostearate (Precirol ® ), Glyceryl behenate (Compritol ® ) and Carnauba wax, utilized either alone or in combinations of drug/lipid ratio of 1:0.5-1:3. Dissolution studies were performed at variable pH and release kinetics were analyzed. Fourier transform infrared spectroscopy was conducted and no drug lipid interaction was found. Sphericity indicated by shape factor (e R ) varied with type and concentration of lipids: Geleol ® (e R  = 0.891-0.997), Precirol ® (e R  = 0.611-0.743), Compritol ® (e R  = 0.665-0.729) and Carnauba wax (e R  = 0.499-0.551). Highly spherical pellets were obtained with Geleol ® (Aspect ratio = 1.005-1.052) whereas irregularly shaped pellets were formed using Carnauba wax (Aspect ratio = 1.153-1.309). Drug release was effectively controlled by three different combinations of lipids: (i) Geleol ® and Compritol ® , (ii) Geleol ® and Carnauba wax and (iii) Geleol ® , Compritol ® and Carnauba wax. Scanning electron microscopy of Compritol ® pellets showed smooth surface with pores, whereas, irregular rough surface with hollow depressions was observed in Carnauba wax pellets. Energy dispersive spectroscopy indicated elemental composition of lipid matrix pellets. Kinetics of (i) Geleol ® and Compritol ® pellets, explained by Korsmeyer-Peppas (R 2  = 0.978-0.993) indicated

  2. Enhanced drug encapsulation and extended release profiles of calcium-alginate nanoparticles by using tannic acid as a bridging cross-linking agent.

    PubMed

    Abulateefeh, Samer R; Taha, Mutasem O

    2015-01-01

    Calcium alginate nanoparticles (NPs) suffer from sub-optimal stability in bio-relevant media leading to low drug encapsulation efficiency and uncontrolled release profiles. To sort out these drawbacks, a novel approach is proposed herein based on introducing tannic acid into these NPs to act as a bridging cross-linking aid agent. Calcium-alginate NPs were prepared by the ionotropic gelation method and loaded with diltiazem hydrochloride as a model drug. These NPs were characterized in terms of particle size, zeta potential, and morphology, and results were explained in accordance with Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). The incorporation of tannic acid led to more than four folds increase in drug encapsulation efficiency (i.e. from 15.3% to 69.5%) and reduced burst drug release from 44% to around 10% within the first 30 min. These findings suggest the possibility of improving the properties of Ca-alginate NPs by incorporating cross-linking aid agents under mild conditions.

  3. A Pilot Study of Naltrexone and BASICS for Heavy Drinking Young Adults

    PubMed Central

    Leeman, Robert F.; Palmer, Rebekka S.; Corbin, William R.; Romano, Denise M.; Meandzija, Boris; O’Malley, Stephanie S.

    2008-01-01

    Heavy drinking young adults often have limited motivation to change their drinking behavior. Adding pharmacotherapy to brief counseling is a novel approach to treating this population. A small open-label pilot study was conducted to assess the feasibility of offering eight weeks of daily and targeted (i.e., taken as needed in anticipation of drinking) naltrexone with BASICS (brief motivational) counseling to heavy drinking young adults; to assess the tolerability of the medication in this population and to obtain preliminary efficacy data. The sample (N = 14) showed strong adherence to study appointments and medication taking, supporting the feasibility of this approach. Overall, the medication was well-tolerated. Significant reductions from baseline were observed in drinks per drinking day and in percent heavy drinking days and these gains were maintained one month after treatment ended. A significant decrease in alcohol-related consequences was also observed. Findings from this small pilot study suggest that naltrexone in combination with BASICS represents a promising strategy to reduce heavy drinking among young adults. PMID:18502591

  4. Maintenance Medication for Opiate Addiction: The Foundation of Recovery

    PubMed Central

    Bart, Gavin

    2012-01-01

    Illicit use of opiates is the fastest growing substance use problem in the United States and the main reason for seeking addiction treatment services for illicit drug use throughout the world. It is associated with significant morbidity and mortality related to HIV, hepatitis C, and overdose. Treatment for opiate addiction requires long-term management. Behavioral interventions alone have extremely poor outcomes, with more than 80% of patients returning to drug use. Similarly poor results are seen with medication assisted detoxification. This article provides a topical review of the three medications approved by the FDA for long-term treatment of opiate dependence: the opioid agonist methadone, the opioid partial agonist buprenorphine, and the opioid antagonist naltrexone. Basic mechanisms of action and treatment outcomes are described for each medication. Results indicate that maintenance medication provides the best opportunity for patients to achieve recovery from opiate addiction. Extensive literature and systematic reviews show that maintenance treatment with either methadone or buprenorphine is associated with retention in treatment, reduction in illicit opiate use, decreased craving, and improved social function. Oral naltrexone is ineffective in treating opiate addiction but recent studies using extended release naltrexone injections have shown promise. While no direct comparisons between extended release naltrexone injections and either methadone or buprenorphine exist, indirect comparison of retention shows inferior outcome compared to methadone and buprenorphine. Further work is needed to compare directly each medication and determine individual factors that can assist in medication selection. Until such time, selection of medication should be based on informed choice following a discussion of outcomes, risks, and benefits of each medication. PMID:22873183

  5. Cessation of Long-Term Naltrexone Therapy and Self-Injury: A Case Study.

    ERIC Educational Resources Information Center

    Crews, W. David, Jr.; And Others

    1993-01-01

    This case study of a woman with profound mental retardation and a history of severe self-injurious behavior (SIB) found that the dramatic decrease in SIB following Naltrexone administration was maintained through placebo and no drug phases and at six-month follow-up. Findings are discussed in terms of endogenous opioid system theories of SIB. (DB)

  6. On the behavioural specificity of hypophagia induced in male rats by mCPP, naltrexone, and their combination.

    PubMed

    Wright, F L; Rodgers, R J

    2014-02-01

    Serotonergic (5-hydroxytryptamine, 5-HT) and opioidergic mechanisms are intimately involved in appetite regulation. In view of recent evidence of positive anorectic interactions between opioid and various non-opioid substrates, our aim was to assess the behavioural specificity of anorectic responses to the opioid receptor antagonist naltrexone, the 5-HT2C/1B receptor agonist mCPP and their combination. Behavioural profiling techniques, including the behavioural satiety sequence (BSS), were used to examine acute drug effects in non-deprived male rats tested with palatable mash. Experiment 1 characterised the dose-response profile of mCPP (0.1-3.0 mg/kg), while experiment 2 assessed the effects of combined treatment with a sub-anorectic dose of mCPP (0.1 mg/kg) and one of two low doses of naltrexone (0.1 and 1.0 mg/kg). Experiment 1 confirmed the dose-dependent anorectic efficacy of mCPP, with robust effects on intake and feeding-related measures observed at 3.0 mg/kg. However, that dose was also associated with other behavioural alterations including increased grooming, reductions in locomotion and sniffing, and disruption of the BSS. In experiment 2, naltrexone dose-dependently reduced food intake and time spent feeding, effects accompanied by a behaviourally selective acceleration in the BSS. However, the addition of 0.1 mg/kg mCPP did not significantly alter the behavioural changes observed in response to either dose of naltrexone given alone. In contrast to recently reported positive anorectic interactions involving low-dose combinations of opioid receptor antagonists or mCPP with cannabinoid CB1 receptor antagonists, present results would not appear to provide any support for potentially clinically relevant anorectic interactions between opioid and 5-HT2C/1B receptor mechanisms.

  7. Gestational naltrexone ameliorates fetal ethanol exposures enhancing effect on the postnatal behavioral and neural response to ethanol

    PubMed Central

    Youngentob, Steven L; Kent, Paul F; Youngentob, Lisa M

    2012-01-01

    The association between gestational exposure to ethanol and adolescent ethanol abuse is well established. Recent animal studies support the role of fetal ethanol experience-induced chemosensory plasticity as contributing to this observation. Previously, we established that fetal ethanol exposure, delivered through a dam’s diet throughout gestation, tuned the neural response of the peripheral olfactory system of early postnatal rats to the odor of ethanol. This occurred in conjunction with a loss of responsiveness to other odorants. The instinctive behavioral response to the odor of ethanol was also enhanced. Importantly, there was a significant contributory link between the altered response to the odor of ethanol and increased ethanol avidity when assessed in the same animals. Here, we tested whether the neural and behavioral olfactory plasticity, and their relationship to enhanced ethanol intake, is a result of the mere exposure to ethanol or whether it requires the animal to associate ethanol’s reinforcing properties with its odor attributes. In this later respect, the opioid system is important in the mediation (or modulation) of the reinforcing aspects of ethanol. To block endogenous opiates during prenatal life, pregnant rats received daily intraperitoneal administration of the opiate antagonist naltrexone from gestational day 6–21 jointly with ethanol delivered via diet. Relative to control progeny, we found that gestational exposure to naltrexone ameliorated the enhanced postnatal behavioral response to the odor of ethanol and postnatal drug avidity. Our findings support the proposition that in utero ethanol-induced olfactory plasticity (and its relationship to postnatal intake) requires, at least in part, the associative pairing between ethanol’s odor quality and its reinforcing aspects. We also found suggestive evidence that fetal naltrexone ameliorated the untoward effects of gestational ethanol exposure on the neural response to non

  8. 21 CFR 520.1660c - Oxytetracycline hydrochloride tablets/boluses.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Oxytetracycline hydrochloride tablets/boluses. 520....1660c Oxytetracycline hydrochloride tablets/boluses. (a) Specifications. Each tablet or bolus contains 250, 500, or 1,000 milligrams of oxytetracycline hydrochloride. (b) Sponsors. For sponsors in § 510...

  9. 78 FR 66009 - Determination That INVEGA (Paliperidone) Extended-Release Tablet, 12 Milligrams, Was Not...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-04

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-P-0775... Reasons of Safety or Effectiveness AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) has determined that INVEGA (paliperidone) extended-release tablet...

  10. Preparation of a Sustained-Release Nebulized Aerosol of R-terbutaline Hydrochloride Liposome and Evaluation of Its Anti-asthmatic Effects via Pulmonary Delivery in Guinea Pigs.

    PubMed

    Li, Qingrui; Zhan, Shuyao; Liu, Qing; Su, Hao; Dai, Xi; Wang, Hai; Beng, Huimin; Tan, Wen

    2018-01-01

    An aerosolized liposome formulation for the pulmonary delivery of an anti-asthmatic medication was developed. Asthma treatment usually requires frequent administration of medication for a sustained bronchodilator response. Liposomes are known for their sustained drug release capability and thus would be a suitable delivery system for prolonging the therapeutic effect of anti-asthmatic medication. Liposomes prepared by thin film hydration were loaded with a model drug, R-terbutaline hydrochloride(R-TBH), using an ammonium sulfate-induced transmembrane electrochemical gradient. This technique provided an encapsulation efficiency of up to 71.35% and yielded R-TBH liposomes with a particle size of approximately 145 ± 20 nm. According to stability studies, these R-TBH liposomes should be stored at 4°C before usage. Compared to R-TBH solution, which showed 90.84% release within 8 h, liposomal R-TBH had a cumulative release of 73.53% at 37°C over 192 h. A next generation impactor (NGI) was used to analyze the particle size distribution in the lungs of R-TBH liposome aerosol in vitro at 5°C. The therapeutic efficacy of the nebulized aerosol of the R-TBH liposomes was assessed via pulmonary delivery in guinea pigs. The results showed that, compared to the R-TBH solution group, the R-TBH liposome group had a prolonged anti-asthma effect.

  11. Development of a level A in vitro-in vivo correlation for extended release dosage forms of quetiapine fumarate.

    PubMed

    Gonçalves de Lima, L; Rossi de Campos, D

    2016-05-01

    Quetiapine is an atypical antipsychotic recommended as first-line treatment for acute bipolar depression. The extended-release quetiapine formulation is intended to be administered as an once-daily dosing. The development of an in vitro-in vivo correlation (IVIVC) and the use of in vitro data to predict in vivo bioavailability parameters has been of great interest for the rational development and evaluation process for extended release dosage forms. The aim of this study was to develop an IVIVC for quetiapine extended release formulation. In vitro dissolution rate data were obtained using USP apparatus 2 at 50 rpm, in 3 bio-relevant dissolution media with different pH values (1.2, 4.5 and 6.8). The drug release profiles of the 2 extended release dosage forms were compared using the similarity factor (f 2). The relative bioavailability of quetiapine was evaluated by a single-dose, randomized-sequence, open-label, 2 period cross over study with 16 healthy volunteers. A linear level A IVIVC model was established using percentage of absorbed and dissolved data obtained at pH 1.2. The developed IVIVC model was employed to predict quetiapine concentration-time profiles, as well as the bioequivalence parameters for test formulation. Percent prediction errors were estimated for Cmax and AUC to evaluate the validity of the correlation. The values did not exceed 15%, proving the predictability of the correlation model. In conclusion, the established level A IVIVC model proved to be an excellent tool for predicting the rate and extent of quetiapine absorption as characterized by Cmax and AUC for test formulation. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Long-Term Effectiveness and Safety of Dexmethylphenidate Extended-Release Capsules in Adult ADHD

    ERIC Educational Resources Information Center

    Adler, Lenard A.; Spencer, Thomas; McGough, James J.; Jiang, Hai; Muniz, Rafael

    2009-01-01

    Objective: This study evaluates dexmethylphenidate extended release (d-MPH-ER) in adults with ADHD. Method: Following a 5-week, randomized, controlled, fixed-dose study of d-MPH-ER 20 to 40 mg/d, 170 adults entered a 6-month open-label extension (OLE) to assess long-term safety, with flexible dosing of 20 to 40 mg/d. Exploratory effectiveness…

  13. Structure-based analysis reveals hydration changes induced by arginine hydrochloride.

    PubMed

    Nakakido, Makoto; Tanaka, Yoshikazu; Mitsuhori, Mariko; Kudou, Motonori; Ejima, Daisuke; Arakawa, Tsutomu; Tsumoto, Kouhei

    2008-10-01

    Arginine hydrochloride has been used to suppress protein aggregation during refolding and in various other applications. We investigated the structure of hen egg-white lysozyme (HEL) and solvent molecules in arginine hydrochloride solution by X-ray crystallography. Neither the backbone nor side-chain structure of HEL was altered by the presence of arginine hydrochloride. In addition, no stably bound arginine molecules were observed. The number of hydration water molecules, however, changed with the arginine hydrochloride concentration. We suggest that arginine hydrochloride suppresses protein aggregation by altering the hydration structure and the transient binding of arginine molecules that could not be observed.

  14. Predictable pulsatile release of tramadol hydrochloride for chronotherapeutics of arthritis.

    PubMed

    Dabhi, Chandu; Randale, Shivsagar; Belgamwar, Veena; Gattani, Surendra; Tekade, Avinash

    2010-07-01

    The present investigation deals with the development of a pH and time-dependent press-coated pulsatile drug delivery system for delivering drugs into the colon. The system consists of a drug containing core, coated by a combination of natural polymer Delonix regia gum (DRG) and hydroxypropyl methylcellulose (HPMC K4M) in various proportions, which controls the onset of release. The whole system was coated with methacrylic acid copolymers, which not only prevents the drug release in the stomach, but also prolongs the lag time. Tramadol HCl was used as a model drug and varying combinations of DRG and HPMC K4M were used to achieve the desired lag time before rapid and complete release of the drug in the colon. It was observed that the lag time depends on the coating ratio of DRG to HPMC and also on press coating weight. Drug release was found to be increased by 15-30% in the presence of colonic microbial flora. The results showed the capability of the system in achieving pulsatile release for a programmable period of time and pH-dependent release to attain colon-targeted delivery.

  15. Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing.

    PubMed

    Skowyra, Justyna; Pietrzak, Katarzyna; Alhnan, Mohamed A

    2015-02-20

    Rapid and reliable tailoring of the dose of controlled release tablets to suit an individual patient is a major challenge for personalized medicine. The aim of this work was to investigate the feasibility of using a fused deposition modelling (FDM) based 3D printer to fabricate extended release tablet using prednisolone loaded poly(vinyl alcohol) (PVA) filaments and to control its dose. Prednisolone was loaded into a PVA-based (1.75 mm) filament at approximately 1.9% w/w via incubation in a saturated methanolic solution of prednisolone. The physical form of the drug was assessed using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Dose accuracy and in vitro drug release patterns were assessed using HPLC and pH change flow-through dissolution test. Prednisolone loaded PVA filament demonstrated an ability to be fabricated into regular ellipse-shaped solid tablets using the FDM-based 3D printer. It was possible to control the mass of printed tablet through manipulating the volume of the design (R(2) = 0.9983). On printing tablets with target drug contents of 2, 3, 4, 5, 7.5 and 10mg, a good correlation between target and achieved dose was obtained (R(2) = 0.9904) with a dose accuracy range of 88.7-107%. Thermal analysis and XRPD indicated that the majority of prednisolone existed in amorphous form within the tablets. In vitro drug release from 3D printed tablets was extended up to 24h. FDM based 3D printing is a promising method to produce and control the dose of extended release tablets, providing a highly adjustable, affordable, minimally sized, digitally controlled platform for producing patient-tailored medicines. Copyright © 2015. Published by Elsevier B.V.

  16. Low-dose naltrexone (LDN): A promising treatment in immune-related diseases and cancer therapy.

    PubMed

    Li, Zijian; You, Yue; Griffin, Noreen; Feng, Juan; Shan, Fengping

    2018-06-06

    Naltrexone, a non-selective antagonist of opioid receptors, is mainly used as rehabilitation therapy for discharged opiate addicts to eliminate addiction in order to maintain a normal life and prevent or reduce relapse. In recent years, there have been some novel and significant findings on the off-label usage of naltrexone. Within a specific dosage window, LDN can act as an immunomodulator in multiple autoimmune diseases and malignant tumors as well as alleviate the symptoms of some mental disorders. The results of increasing studies indicate that LDN exerts its immunoregulatory activity by binding to opioid receptors in or on immune cells and tumor cells. These new discoveries indicate that LDN may become a promising immunomodulatory agent in the therapy for cancer and many immune-related diseases. In this article, we review the pharmacological functions and mechanisms of LDN as well as its clinical therapeutic potential as revealed by our team and other researchers. Copyright © 2018. Published by Elsevier B.V.

  17. 21 CFR 522.1465 - Naltrexone hydrochloride injection.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) Indications for use. As an antagonist to carfentanil citrate immobilization in free-ranging or confined elk... free-ranging animals for 45 days before or during hunting season. Federal law restricts this drug to...

  18. 21 CFR 522.1465 - Naltrexone hydrochloride injection.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) Indications for use. As an antagonist to carfentanil citrate immobilization in free-ranging or confined elk... free-ranging animals for 45 days before or during hunting season. Federal law restricts this drug to...

  19. 21 CFR 522.1465 - Naltrexone hydrochloride injection.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) Indications for use. As an antagonist to carfentanil citrate immobilization in free-ranging or confined elk... free-ranging animals for 45 days before or during hunting season. Federal law restricts this drug to...

  20. Supramolecular assembly in the epiisopiloturine hydrochloride salt

    NASA Astrophysics Data System (ADS)

    Mafud, Ana Carolina; Reinheimer, Eric W.; Lima, Filipe Camargo Dalmatti Alves; Batista, Larissa Fernandes; de Paula, Karina; Véras, Leiz Maria Costa; de Souza de Almeida Leite, José Roberto; Venancio, Tiago; Mascarenhas, Yvonne Primerano

    2017-05-01

    Epiisopiloturine hydrochloride (Epi-HCl) salt was synthetized from epiisopiloturine, an in vivo anthelmintic compound against Schistosoma mansoni worms. Despite there being no acute toxicity in mammalian cells, the compound's water insolubility makes its administration difficult. In this communication, we report the characterization of Epi-HCl its features by spectroscopy, thermal analysis, and PXRD. The single crystals suitable to X-ray diffraction were grown by slow evaporation technique. To better understand the nature of Epi-HCl' solid state, SS-NMR was also used. The salt's intramolecular structure was maintained via cation-pi intramolecular interactions, which in conjunction with hydrogen bonding, gives rise to an extended supramolecular assembly. The interatomic distances within the cations and environment around the chloride anion vary as function of temperature, suggesting a packing relaxation.

  1. Degree of corneal anaesthesia after topical application of 0.4% oxybuprocaine hydrochloride and 0.5% proparacaine hydrochloride ophthalmic solution in clinically normal cattle.

    PubMed

    Little, W B; Jean, G St; Sithole, F; Little, E; Jean, K Yvorchuk-St

    2016-06-01

    The use of corneal anaesthesia is necessary for a range of clinical purposes. Therefore, we assessed and compared the efficacy of corneal anaesthesia after application of 0.4% oxybuprocaine hydrochloride and 0.5% proparacaine hydrochloride ophthalmic solution in clinically normal cattle. The 24 clinically normal cows were allocated into two groups. Cows in group 1 (n = 12) received 0.2 mL of 0.4% oxybuprocaine hydrochloride with fluorescein ophthalmic solution in one eye and 0.2 mL of sterile saline (0.9% NaCl) with fluorescein in the contralateral eye (control). Group 2 (n = 12) received 0.2 mL of 0.4% oxybuprocaine hydrochloride with fluorescein ophthalmic solution in one eye and 0.2 mL of 0.5% proparacaine hydrochloride with fluorescein in the contralateral eye (control). In each group, corneal touch threshold was determined by Cochet-Bonnet aesthesiometer for both eyes immediately prior to topical administration of solutions, at 1 min and 5 min after administration of topical solutions and every 5 min thereafter for a total of 75 min. Significant corneal anaesthesia was noted immediately following topical application of both oxybuprocaine and proparacaine as compared with controls, with maximal corneal anaesthesia noted 1 min after administration. Both oxybuprocaine and proparacaine produced significant corneal anaesthesia for the duration of the 75-min study. Neither oxybuprocaine hydrochloride nor proparacaine hydrochloride treatment resulted in visible adverse effects. There are limited data available demonstrating the efficacy and duration of corneal anaesthetic agents in cattle. Both oxybuprocaine hydrochloride and proparacaine hydrochloride should be considered practical options for providing corneal anaesthesia in cattle in a clinical setting. © 2016 Australian Veterinary Association.

  2. Sustaining pattern of phenformin hydrochloride using various polymers and waxes.

    PubMed

    Pandey, V P; Kannappan, N; Manavalan, R; Subburaj, T

    2002-01-01

    The present study was carried out to formulate matrix tablets of phenformin hydrochloride. Granules of phenformin HCl were prepared by using ethyl cellulose, eudragit RS 100, gum acacia, carnauba wax, stearyl alcohol, glyceryl monostearate and triethanol amine. Thus the granules were compressed and fourteen tablets formulations were prepared. All the physical parameters of granules and matrix tablets were studied including compatibility study. One commercial timed disintegration capsule was also included for study and comparison. The results of in vitro studies showed that sustained release matrix tablet might be prepared using carnauba wax, stearyl alcohol, triethanol amine and magnesium stearate.

  3. Co-relationship between sexual dysfunction and high-risk sexual behavior in patients receiving buprenorphine and naltrexone maintenance therapy for opioid dependence.

    PubMed

    Ramdurg, Santosh; Ambekar, Atul; Lal, Rakesh

    2015-01-01

    People suffering from substance dependence suffer from various sexual dysfunctions and are at risk for indulging in various high-risk sexual behaviors and thus are vulnerable to acquire various infections such as HIV/AIDS and other sexually transmitted infections. The aim of the study was to evaluate the correlation between sexual dysfunction and high-risk sexual behavior in opioid-dependent men receiving buprenorphine and naltrexone maintenance therapy. Semi-structured questionnaire, brief male sexual functioning inventory and HIV-risk taking behavior scale was administered to a sample of 60 sexually active men, receiving buprenorphine (n = 30) and naltrexone (n = 30) maintenance therapy for opioid dependence. The main outcomes are correlation between severity of sexual dysfunction and HIV-risk taking behavior. The study results showed 83% of the men on buprenorphine and 90% on naltrexone reported at least one of the sexual dysfunction symptoms. There was a negative correlation between sexual dysfunction and HIV-risk taking behavior that suggest severe the dysfunction, higher the risk taking behavior. Significant correlation was present with overall sexual dysfunction and HIV-risk taking behavior (P = 0.028 and in naltrexone receiving group premature ejaculation versus HIV-risk taking behavior however, (P = 0.022, P < 0.05) there were no significant differences among both the groups except above findings. Conclusion was treatment is associated with sexual dysfunctions and HIV-risk taking behavior, which has clinical implication. Future research should explore this further using biochemical analyses.

  4. Co-relationship between sexual dysfunction and high-risk sexual behavior in patients receiving buprenorphine and naltrexone maintenance therapy for opioid dependence

    PubMed Central

    Ramdurg, Santosh; Ambekar, Atul; Lal, Rakesh

    2015-01-01

    Introduction: People suffering from substance dependence suffer from various sexual dysfunctions and are at risk for indulging in various high-risk sexual behaviors and thus are vulnerable to acquire various infections such as HIV/AIDS and other sexually transmitted infections. AIM: The aim of the study was to evaluate the correlation between sexual dysfunction and high-risk sexual behavior in opioid-dependent men receiving buprenorphine and naltrexone maintenance therapy. Materials and Methods: Semi-structured questionnaire, brief male sexual functioning inventory and HIV-risk taking behavior scale was administered to a sample of 60 sexually active men, receiving buprenorphine (n = 30) and naltrexone (n = 30) maintenance therapy for opioid dependence. Results: The main outcomes are correlation between severity of sexual dysfunction and HIV-risk taking behavior. The study results showed 83% of the men on buprenorphine and 90% on naltrexone reported at least one of the sexual dysfunction symptoms. There was a negative correlation between sexual dysfunction and HIV-risk taking behavior that suggest severe the dysfunction, higher the risk taking behavior. Significant correlation was present with overall sexual dysfunction and HIV-risk taking behavior (P = 0.028 and in naltrexone receiving group premature ejaculation versus HIV-risk taking behavior however, (P = 0.022, P < 0.05) there were no significant differences among both the groups except above findings. Conclusion: Conclusion was treatment is associated with sexual dysfunctions and HIV-risk taking behavior, which has clinical implication. Future research should explore this further using biochemical analyses. PMID:26257480

  5. 21 CFR 520.863 - Ethylisobutrazine hydrochloride tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Ethylisobutrazine hydrochloride tablets. 520.863 Section 520.863 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Ethylisobutrazine hydrochloride tablets. (a) Specifications. Each tablet contains either 10 milligrams or 50...

  6. 21 CFR 520.2582 - Triflupromazine hydrochloride tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Triflupromazine hydrochloride tablets. 520.2582 Section 520.2582 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Triflupromazine hydrochloride tablets. (a) Specifications. Each tablet contains either 10 milligrams or 25...

  7. 21 CFR 524.1662a - Oxytetracycline hydrochloride and hydrocortisone spray.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Oxytetracycline hydrochloride and hydrocortisone... NEW ANIMAL DRUGS § 524.1662a Oxytetracycline hydrochloride and hydrocortisone spray. (a) Specifications. Each 3-ounce unit of oxytetracycline hydrochloride and hydrocortisone spray contains 300...

  8. 21 CFR 524.1662a - Oxytetracycline hydrochloride and hydrocortisone spray.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Oxytetracycline hydrochloride and hydrocortisone... NEW ANIMAL DRUGS § 524.1662a Oxytetracycline hydrochloride and hydrocortisone spray. (a) Specifications. Each 3-ounce unit of oxytetracycline hydrochloride and hydrocortisone spray contains 300...

  9. 21 CFR 524.1662a - Oxytetracycline hydrochloride and hydrocortisone spray.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Oxytetracycline hydrochloride and hydrocortisone... NEW ANIMAL DRUGS § 524.1662a Oxytetracycline hydrochloride and hydrocortisone spray. (a) Specifications. Each 3-ounce unit of oxytetracycline hydrochloride and hydrocortisone spray contains 300...

  10. 21 CFR 524.1662a - Oxytetracycline hydrochloride and hydrocortisone spray.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Oxytetracycline hydrochloride and hydrocortisone... NEW ANIMAL DRUGS § 524.1662a Oxytetracycline hydrochloride and hydrocortisone spray. (a) Specifications. Each 3-ounce unit of oxytetracycline hydrochloride and hydrocortisone spray contains 300...

  11. Tamarind seed gum-hydrolyzed polymethacrylamide-g-gellan beads for extended release of diclofenac sodium using 32 full factorial design.

    PubMed

    Nandi, Gouranga; Nandi, Amit Kumar; Khan, Najim Sarif; Pal, Souvik; Dey, Sibasish

    2018-07-15

    Development of tamarind seed gum (TSG)-hydrolyzed polymethacrylamide-g-gellan (h-Pmaa-g-GG) composite beads for extended release of diclofenac sodium using 3 2 full factorial design is the main purpose of this study. The ratio of h-Pmaa-g-GG and TSG and concentration of cross-linker CaCl 2 were taken as independent factors with three different levels of each. Effects of polymer ratio and CaCl 2 on drug entrapment efficiency (DEE), drug release, bead size and swelling were investigated. Responses such as DEE and different drug release parameters were statistically analyzed by 3 2 full factorial design using Design-Expert software and finally the formulation factors were optimized to obtain USP-reference release profile. Drug release rate was found to decrease with decrease in the ratio of h-Pmaa-g-GG:TSG and increase in the concentration of Ca 2+ ions in cross-linking medium. The optimized formulation showed DEE of 93.25% and an extended drug release profile over a period of 10h with f 2 =80.13. Kinetic modeling unveiled case-I-Fickian diffusion based drug release mechanism. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Amantadine Ameliorates Dopamine-Releasing Deficits and Behavioral Deficits in Rats after Fluid Percussion Injury

    PubMed Central

    Huang, Eagle Yi-Kung; Tsui, Pi-Fen; Kuo, Tung-Tai; Tsai, Jing-Jr.; Chou, Yu-Ching; Ma, Hsin-I; Chiang, Yung-Hsiao; Chen, Yuan-Hao

    2014-01-01

    Aims To investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery. Materials and Methods In this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.6mg/kg/hour for 8 weeks. The dopamine-releasing conditions and metabolism were analyzed sequentially by fast scan cyclic voltammetry (FSCV) and high-pressure liquid chromatography (HPLC). Novel object recognition (NOR) and fixed-speed rotarod (FSRR) behavioral tests were used to determine treatment effects on cognitive and motor deficits after injury. Results Sequential dopamine-release deficits were revealed in 6-Pa-fluid-percussion cerebral cortical injured animals. The reuptake rate (tau value) of dopamine in injured animals was prolonged, but the tau value became close to the value for the control group after amantadine therapy. Cognitive and motor learning impairments were shown evidenced by the NOR and FSRR behavioral tests after injury. Chronic amantadine therapy reversed dopamine-release deficits, and behavioral impairment after fluid percussion injuries were ameliorated in the rats treated by using amantadine-pumping infusion. Conclusion Chronic treatment with amantadine hydrochloride can ameliorate dopamine-release deficits as well as cognitive and motor deficits caused by cerebral fluid-percussion injury. PMID:24497943

  13. 'Miracle cure' or 'liquid handcuffs': reporting on naltrexone and methadone in the Australian print media.

    PubMed

    Matthew-Simmons, Francis; Ritter, Alison

    2014-09-01

    The news media is an important source of information regarding new developments in medicine and public health interventions. Previous research has indicated that in many cases, reporting on new treatments can be inaccurate or sensationalist. This paper presents analysis of Australian print media reporting on two treatment options for heroin dependence (naltrexone and methadone). The aim of this study was to quantitatively compare the volume and content of Australian print media reporting on these two treatments, one of which had a long history of use in Australia, and the other which was comparatively newer. The study constituted a quantitative content analysis of a sample of 859 Australian newspaper articles, published over a 10-year period (1997-2007). Each article paragraph was coded for positive outcomes/benefits of treatment, as well as negative outcomes associated with treatment. The analysis revealed that during this period, the Australian print media was significantly more likely to report the potential positive outcomes of naltrexone treatment, compared with the negative outcomes. In contrast, reporting on methadone focused more on the negative outcomes and side effects. The relative frequency by which the benefits of naltrexone were mentioned in this sample of news content is somewhat at odds with the extant efficacy and effectiveness research evidence. The findings suggest that reporting on these treatments in the Australian print media has not been balanced. This type of reporting has potential implications for public attitudes, as well as policy decisions. © 2014 Australasian Professional Society on Alcohol and other Drugs.

  14. Accelerometric comparison of the locomotor pattern of horses sedated with xylazine hydrochloride, detomidine hydrochloride, or romifidine hydrochloride.

    PubMed

    López-Sanromán, F Javier; Holmbak-Petersen, Ronald; Varela, Marta; del Alamo, Ana M; Santiago, Isabel

    2013-06-01

    To evaluate the duration of effects on movement patterns of horses after sedation with equipotent doses of xylazine hydrochloride, detomidine hydrochloride, or romifidine hydrochloride and determine whether accelerometry can be used to quantify differences among drug treatments. 6 healthy horses. Each horse was injected IV with saline (0.9% NaCl) solution (10 mL), xylazine diluted in saline solution (0.5 mg/kg), detomidine diluted in saline solution (0.01 mg/kg), or romifidine diluted in saline solution (0.04 mg/kg) in random order. A triaxial accelerometric device was used for gait assessment 15 minutes before and 5, 15, 30, 45, 60, 75, 90, 105, and 120 minutes after each treatment. Eight variables were calculated, including speed, stride frequency, stride length, regularity, dorsoventral power, propulsive power, mediolateral power, and total power; the force of acceleration and 3 components of power were then calculated. Significant differences were evident in stride frequency and regularity between treatments with saline solution and each α2-adrenoceptor agonist drug; in speed, dorsoventral power, propulsive power, total power, and force values between treatments with saline solution and detomidine or romifidine; and in mediolateral power between treatments with saline solution and detomidine. Stride length did not differ among treatments. Accelerometric evaluation of horses administered α2-adrenoceptor agonist drugs revealed more prolonged sedative effects of romifidine, compared with effects of xylazine or detomidine. Accelerometry could be useful in assessing the effects of other sedatives and analgesics. Accelerometric data may be helpful in drug selection for situations in which a horse's balance and coordination are important.

  15. 21 CFR 522.1662b - Oxytetracycline hydrochloride with lidocaine injection.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Oxytetracycline hydrochloride with lidocaine... FORM NEW ANIMAL DRUGS § 522.1662b Oxytetracycline hydrochloride with lidocaine injection. (a) Specifications. The drug contains 50 or 100 milligrams of oxytetracycline hydrochloride and 2 percent lidocaine...

  16. A Controlled Trial of Extended-Release Guanfacine and Psychostimulants for Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Wilens, Timothy E.; Bukstein, Oscar; Brams, Matthew; Cutler, Andrew J.; Childress, Ann; Rugino, Thomas; Lyne, Andrew; Grannis, Kara; Youcha, Sharon

    2012-01-01

    Objective: To examine efficacy, tolerability, and safety of guanfacine extended release (GXR; less than or equal to 4 mg/d) adjunctive to a long-acting psychostimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years of age with suboptimal, but partial, response to psychostimulant…

  17. Insomnia: Zolpidem Extended-Release for the Treatment of Sleep Induction and Sleep Maintenance Symptoms

    PubMed Central

    Doghramji, Paul P.

    2007-01-01

    Insomnia impairs daytime functioning or causes clinically significant daytime distress. The consequences of insomnia, if left untreated, may contribute to the risks of developing additional serious conditions, such as psychiatric illness, cardiovascular disease, or metabolic issues. Furthermore, some comorbidities associated with insomnia may be bidirectional in their causality because psychiatric and other medical problems can increase the risk for insomnia. Regardless of the serious consequences of inadequately treated insomnia, clinicians often do not inquire into their patients' sleep habits, and patients, in turn, are not forthcoming with details of their sleep difficulties. The continuing education of physicians and patients with regard to insomnia and currently available therapies for the treatment of insomnia is, therefore, essential. Insomnia may present as either a difficulty falling asleep, difficulty maintaining sleep, or waking too early without being able to return to sleep. Furthermore, these symptoms often change over time in an unpredictable manner. Therefore, when considering a sleep medication, one with efficacy for the treatment of multiple insomnia symptoms is recommended. A modified-release formulation of zolpidem, zolpidem extended-release, has been approved for the treatment of insomnia characterized by both difficulty in falling asleep and maintaining sleep. Here, we review studies supporting the use of zolpidem extended-release in the treatment of sleep-onset and sleep maintenance difficulties. PMID:17435620

  18. Compatibility of cholecalciferol, haloperidol, imipramine hydrochloride, levodopa/carbidopa, lorazepam, minocycline hydrochloride, tacrolimus monohydrate, terbinafine, tramadol hydrochloride and valsartan in SyrSpend SF PH4 oral suspensions.

    PubMed

    Polonini, H C; Silva, S L; Cunha, C N; Brandão, M A F; Ferreira, A O

    2016-04-01

    A challenge with compounding oral liquid formulations is the limited availability of data to support the physical, chemical and microbiological stability of the formulation. This poses a patient safety concern and a risk for medication errors. The objective of this study was to evaluate the compatibility of the following active pharmaceutical ingredients (APIs) in 10 oral suspensions, using SyrSpend SF PH4 (liquid) as the suspending vehicle: cholecalciferol 50,000 IU/mL, haloperidol 0.5 mg/mL, imipramine hydrochloride 5.0 mg/mL, levodopa/carbidopa 5.0/1.25 mg/mL, lorazepam 1.0 mg/mL, minocycline hydrochloride 10.0 mg/mL, tacrolimus monohydrate 1.0 mg/mL, terbinafine 25.0 mg/mL, tramadol hydrochloride 10.0 mg/mL and valsartan 4.0 mg/mL. The suspensions were stored both refrigerated (2 - 8 degrees C) and at controlled room temperature (20 - 25 degrees C). This is the first stability study for these APIs in SyrSpend SF PH4 (liquid). Further, the stability of haloperidol,ilmipramine hydrochloride, minocycline, and valsartan in oral suspension has not been previously reported in the literature. Compatibility was assessed by measuring percent recovery at varying time points throughout a 90 days period. Quantification of the APIs was performed by high performance liquid chromatography (HPLC-UV). Given the percentage of recovery of the APIs within the suspensions, the beyond-use date of the final preparations was found to be at least 90 days for most suspensions both refrigerated and at room temperature. Exceptions were: Minocycline hydrochloride at both storage temperatures (60 days), levodopa/carbidopa at room temperature (30 days), and lorazepam at room temperature (60 days). This suggests that compounded suspensions of APIs from different pharmacological classes in SyrSpend SF PH4 (liquid) are stable.

  19. Assessment of extended-release opioid analgesics for the treatment of chronic pain.

    PubMed

    Gudin, Jeffrey A

    2013-03-01

    Approximately 3.8 million patients annually receive extended-release (ER) or long-acting opioid prescriptions in the outpatient setting, around half of which are written by primary care physicians. Compared with short-acting, immediate-release (IR) formulations, ER and oral long-acting opioid analgesics are associated with clinical advantages, such as extended periods of time during which drug plasma levels are within the therapeutic range, decreased peak-to-trough fluctuations, and prolonged analgesia over the dosing period. Additionally, ER opioids offer a more convenient, less frequent dosing regimen to chronic pain patients who are often taking several concomitant medications. The increased utilization of ER opioids has been accompanied by a rise in the misuse and abuse of these formulations. Certain pharmacokinetic parameters (e.g., longer time to maximum drug plasma concentration, lower maximum drug plasma concentration) may decrease the abuse potential of intact ER opioids by limiting the positive subjective and reinforcing effects relative to IR formulations. Putative abuse-deterrent formulations have also recently been introduced to impede physical manipulation of these formulations, or reduce the harm resulting from such behavior. Such formulations may represent an incremental advance to reduce non-oral forms of abuse. This article reviews the pharmacokinetic profiles and abuse-deterrent features of newer ER opioid analgesics for the treatment of moderate to severe chronic pain.

  20. Influence of menthol and pressure-sensitive adhesives on the in vivo performance of membrane-moderated transdermal therapeutic system of nicardipine hydrochloride in human volunteers.

    PubMed

    Krishnaiah, Y S R; Satyanarayana, V; Bhaskar, P

    2003-05-01

    A membrane-moderated transdermal therapeutic system of nicardipine hydrochloride was developed using 2% w/w hydroxypropylcellulose (HPC) gel as a reservoir system containing 5% w/w of menthol as a penetration enhancer. The permeability flux of nicardipine hydrochloride through the ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28% w/w vinyl acetate) or EVA 2825 membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new transdermal therapeutic system for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED, and 2% w/w HPC gel as reservoir containing 5% w/w of menthol as a penetration enhancer. In vivo studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 26h with improved bioavailability in comparison with the immediate release capsule dosage form.

  1. Electrospinning of PLGA/gum tragacanth nanofibers containing tetracycline hydrochloride for periodontal regeneration.

    PubMed

    Ranjbar-Mohammadi, Marziyeh; Zamani, M; Prabhakaran, M P; Bahrami, S Hajir; Ramakrishna, S

    2016-01-01

    Controlled drug release is a process in which a predetermined amount of drug is released for longer period of time, ranging from days to months, in a controlled manner. In this study, novel drug delivery devices were fabricated via blend electrospinning and coaxial electrospinning using poly lactic glycolic acid (PLGA), gum tragacanth (GT) and tetracycline hydrochloride (TCH) as a hydrophilic model drug in different compositions and their performance as a drug carrier scaffold was evaluated. Scanning electron microscopy (SEM) results showed that fabricated PLGA, blend PLGA/GT and core shell PLGA/GT nanofibers had a smooth and bead-less morphology with the diameter ranging from 180 to 460 nm. Drug release studies showed that both the fraction of GT within blend nanofibers and the core-shell structure can effectively control TCH release rate from the nanofibrous membranes. By incorporation of TCH into core-shell nanofibers, drug release was sustained for 75 days with only 19% of burst release within the first 2h. The prolonged drug release, together with proven biocompatibility, antibacterial and mechanical properties of drug loaded core shell nanofibers make them a promising candidate to be used as drug delivery system for periodontal diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Efficacy and Safety of Dexmethylphenidate Extended-Release Capsules in Children with Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Greenhill, Laurence L.; Muniz, Rafael; Ball, Roberta R.; Levine, Alan; Pestreich, Linda; Jiang, Hai

    2006-01-01

    Objective: The efficacy and safety of dexmethylphenidate extended release (d-MPH-ER) was compared to placebo in pediatric patients with attention-deficit/hyperactivity disorder (ADHD). Method: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, two-phase study included 97 patients (ages 6-17 years) with…

  3. Controlled release of optimized electroporation enhances the transdermal efficiency of sinomenine hydrochloride for treating arthritis in vitro and in clinic

    PubMed Central

    Feng, Shun; Zhu, Lijun; Huang, Zhisheng; Wang, Haojia; Li, Hong; Zhou, Hua; Lu, Linlin; Wang, Ying; Liu, Zhongqiu; Liu, Liang

    2017-01-01

    Sinomenine hydrochloride (SH) is an ideal drug for the treatment of rheumatoid arthritis and osteoarthritis. However, high plasma concentration of systemically administered SH can release histamine, which can cause rash and gastrointestinal side effects. Topical delivery can increase SH concentration in the synovial fluid without high plasma level, thus minimizing systemic side effects. However, passive diffusion of SH was found to be inefficient because of the presence of the stratum corneum layer. Therefore, an effective method is required to compensate for the low efficiency of SH passive diffusion. In this study, transdermal experiments in vitro and clinical tests were utilized to explore the optimized parameters for electroporation of topical delivery for SH. Fluorescence experiment and hematoxylin and eosin staining analysis were performed to reveal the mechanism by which electroporation promoted permeation. In vitro, optimized electroporation parameters were 3 KHz, exponential waveform, and intensity 10. Using these parameters, transdermal permeation of SH was increased by 1.9–10.1 fold in mice skin and by 1.6–47.1 fold in miniature pig skin compared with passive diffusion. After the electroporation stimulation, the intercellular intervals and epidermal cracks in the skin increased. In clinical tests, SH concentration in synovial fluid was 20.84 ng/mL after treatment with electroporation. Therefore, electroporation with optimized parameters could significantly enhance transdermal permeation of SH. The mechanism by which electroporation promoted permeation was that the electronic pulses made the skin structure looser. To summarize, electroporation may be an effective complementary method for transdermal permeation of SH. The controlled release of electroporation may be a promising clinical method for transdermal drug administration. PMID:28670109

  4. Problem drinking and low-dose naltrexone-assisted opioid detoxification.

    PubMed

    Mannelli, Paolo; Peindl, Kathleen; Patkar, Ashwin A; Wu, Li-Tzy; Tharwani, Haresh M; Gorelick, David A

    2011-05-01

    The influence of alcohol use on opioid dependence is a major problem that warrants a search for more effective treatment strategies. The addition of very-low-dose naltrexone (VLNTX) to methadone taper was recently associated with reduced withdrawal intensity during detoxification. In a secondary analysis of these data, we sought to determine whether problem drinking affects detoxification outcomes and whether symptoms are influenced by VLNTX use. Opioid-dependent patients (N = 174) received naltrexone (0.125 or 0.250 mg/day) or placebo in a double-blind, randomized design during methadone-based, 6-day inpatient detoxification. Alcohol consumption was assessed at admission using the Addiction Severity Index and selfreport. Outcome measures were opioid withdrawal intensity, craving, and retention in treatment. Problem drinking-opioid dependent patients (n = 79) showed episodic heavy alcohol use and reported increased subjective opioid withdrawal intensity (p = .001), craving (p = .001), and significantly lower rate of retention in treatment (p = .02). Individuals with problem drinking and opioid dependence who were treated with VLNTX (n = 55) showed reduced withdrawal (p = .05) and a lower rate of treatment discontinuation (p = .03), resuming alcohol intake in smaller numbers the day following discharge (p = .03). Treatment effects were more pronounced on anxiety, perspiration, shakiness, nausea, stomach cramps, and craving. There were no group differences in use of adjuvant medications and no treatment-related adverse events. Heavy drinking is associated with worse opioid detoxification outcomes. The addition of VLNTX is safe and is associated with reduced withdrawal symptoms and better completion rate in these patients. Further studies should explore the use of VLNTX in detoxification and long-term treatment of combined alcohol-opioid dependence and alcohol dependence alone.

  5. Validation of the IntelliCap® system as a tool to evaluate extended release profiles in human GI tract using metoprolol as model drug.

    PubMed

    Söderlind, Erik; Abrahamsson, Bertil; Erlandsson, Fredrik; Wanke, Christoph; Iordanov, Ventzeslav; von Corswant, Christian

    2015-11-10

    A clinical study was conducted to validate the in vivo drug release performance of IntelliCap® CR capsules. 12 healthy, male volunteers were administered IntelliCap® CR capsules, filled with metoprolol as a BCS 1 model drug, and programmed to release the drug with 3 different release profiles (2 linear profiles extending over 6h and 14h, respectively, and a pulsed profile with two equal pulses separated by 5h) using a cross-over design. An oral metoprolol solution was included as a reference. Standard bioavailability variables were determined. In vivo drug release-time profiles for the IntelliCap® CR capsules were calculated from the plasma drug concentrations by deconvolution, and they were subsequently compared with the in vitro drug release profiles including assessment of level A in vitro/in vivo correlation (IVIVC). The relative bioavailability for the linear, extended release profiles was about 85% which is similar to other extended release administrations of metoprolol. There was an excellent agreement between the predetermined release profiles and the in vivo release for these two administrations. For IntelliCap® CR capsules programmed to deliver 2 distinct and equal drug pulses, the first pulse was delivered as expected whereas only about half of the second dose was released. Thus, it is concluded that the IntelliCap® system is well suited for the fast and reliable generation of in vivo pharmacokinetic data for extended release drug profiles, e.g. in context of regional drug absorption investigations. For immediate release pulses delivered in the distal GI tract this version of the device appears however less suitable. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis.

    PubMed

    Rahn, Kristen A; McLaughlin, Patricia J; Zagon, Ian S

    2011-03-24

    Endogenous opioids inhibit the onset and progression of experimental autoimmune encephalomyelitis (EAE) with 30days of treatment. This study examined the long term effects of the opioid growth factor (OGF, [Met(5)]-enkephalin) and a low dose of the opioid antagonist naltrexone (LDN) on expression of myelin oligodendrocyte glycoprotein (MOG)-induced EAE. C57BL/6 mice began receiving daily injections of 10mg/kg OGF (MOG+OGF), 0.1mg/kg naltrexone (MOG+LDN), or saline (MOG+Vehicle) at the time of EAE induction and continuing for 60days. In contrast to 100% of the MOG+Vehicle group with behavioral symptoms of EAE, 63% and 68% of the MOG+OGF and MOG+LDN mice expressed disease. Both severity and disease indices of EAE in OGF- and LDN-treated mice were notably decreased from MOG+Vehicle cohorts. By day 60, 6- and 3-fold more animals in the MOG+OGF and MOG+LDN groups, respectively, had a remission compared to MOG+Vehicle mice. Neuropathological studies revealed i) astrocyte activation and neuronal damage as early as day 10 (prior to behavioral symptoms) in all MOG-injected groups, ii) a significant reduction of activated astrocytes in MOG+OGF and MOG+LDN groups compared to MOG+Vehicle mice at day 30, and iii) no demyelination on day 60 in mice treated with OGF or LDN and not displaying disease symptoms. These results indicate that treatment with OGF or LDN had no deleterious long-term repercussions and did not exacerbate EAE, but i) halted progression of disease, ii) reversed neurological deficits, and iii) prevented the onset of neurological dysfunction across a considerable span of time. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Naltrexone-sensitive analgesia following exposure of mice to 2450-MHz radiofrequency radiation (RFR)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Maillefer, R.H.; Quock, R.M.

    1991-03-11

    This study was conducted to determine whether exposure to RFR might induce sufficient thermal stress to activate endogenous opioid mechanisms and induce analgesia. Male Swiss Webster mice, 20-25 g, were exposed to 10, 15 or 20 mV/cm{sup 2} RFR in a 2,450-MHz waveguide system for 10 min, then tested in the abdominal constriction paradigm. Specific absorption rates (SAR) were 23.7 W/kg at 10 mW/cm{sup 2}, 34.6 W/kg at 15 mW/cm{sup 2} and 45.5 W/kg at 20 mW/cm{sup 2}. Confinement in the exposure chamber alone did not appreciably alter body temperature but did appear to induce a stress-associated analgesia that wasmore » insensitive to the opioid receptor blocker naltrexone. Exposure of confined mice to RFR elevated body temperature and further increased analgesia in SAR-dependent manner. The high-SAR RFR-induced analgesia, but not the hyperthermia, was reduced by naltrexone. These findings suggest that (1) RFR produces SAR-dependent hyperthermia and analgesia and (2) RFR-induced analgesia is mediated by opioid mechanisms while confinement-induced analgesia involves non-opioid mechanisms.« less

  8. [Cetyltrimethylammonium bromide for fluorescence enhancement of anhydrotetracycline hydrochloride and iso-tetracycline].

    PubMed

    Zha, Jian-peng; Lin, Ying; Yang, Xing-hui; Hou, Hai-ni; Wei, Tie-jun; Chen, Xing-li

    2002-06-01

    Fluorescence enhancement of anhydrotetracycline hydrochloride and iso-tetracycline has been described. The fluorescence intensities of anhydrotetracycline hydrochloride and iso-tetracycline with cetyltrimethylammonium bromide (CTMAB) enhanced by micellar solution have been examined. It is found that fluorescence enhancement of anhydrotetracycline hydrochloride and iso-tetracycline depends on the concentration of CTMAB and pH of the solution. It can be used to develop sensitive methods for the determination of tetracycline hydrochloride and its decomposition product.

  9. pH-controlled drug release for dental applications

    NASA Astrophysics Data System (ADS)

    Wironen, John Francis

    A large proportion of the dental fillings replaced at present are revised because of the perceived presence of a recurrent caries under or adjacent to the restoration. Many of these perceived caries may not exist, while others may go undetected. This work describes the preparation of drug loaded polymer microspheres that sense the presence of the bacteria that cause caries by the associated presence of acid by-products of digestion. These microspheres are designed to swell and release their antimicrobial drugs once the pH drops to a level that would normally cause caries. The preparation of the microspheres as well as their loading with potassium fluoride, chlorhexidine digluconate, chlorhexidine dihydrochloride, chlorhexidine diacetate, and tetracycline hydrochloride are described. A detailed study of the controlled release behavior of fluoride as a function of polymer composition and pH is presented first. A study of the release kinetics of potassium fluoride, chlorhexidine digluconate, diacetate, dihydrochloride, and tetracycline hydrochloride as a function of pH in the same polymer system is then presented. Additional studies of the swelling kinetics of chlorhexidine-loaded microspheres in various pH buffers are discussed with special reference to correlations with the controlled-release data. Finally, an experiment in which the microspheres are tested in an in vitro bacteria model that includes Streptococcus mutans is presented and discussed in detail.

  10. Evaluation of therapeutic effect of low dose naltrexone in experimentally-induced Crohn's disease in rats.

    PubMed

    Tawfik, Dina Ibrahim; Osman, Afaf Sayed; Tolba, Hedayat Mahmoud; Khattab, Aida; Abdel-Salam, Lubna O; Kamel, Mahmoud M

    2016-10-01

    Crohn's disease is a relapsing inflammatory condition afflicting the digestive tract. Drugs used for treatment of Crohn's disease may be associated with serious side effects. Endogenous opioid peptides modulate inflammatory cytokine production. Opioid antagonists have been shown to play a role in healing and repair of tissues. This work was designed to detect the possible beneficial effects of opioid antagonist naltrexone in indomethacin-induced Crohn's disease in rats. Enteritis was induced in male albino rats by two subcutaneous injection of indomethacin in a dose of 7.5mg/kg 24h apart started on day one. Salfasalazine, naltrexone and their combination were administered orally from day one of induction of enteritis to day 10. Disease activity index, serum levels of C-reactive protein and tumor necrosis factor-α, macroscopic and microscopic pathological scores and in vitro motility studies were evaluated. Induction of enteritis resulted in significant increase of disease activity index, significant elevation of serum levels of C-reactive protein and tumor necrosis factor-α, significant deterioration of pathological scores and significant increase in the mean contractility response of the isolated ileal segments compared with normal untreated rats. Treatment with sulfasalazine, low dose of natrexone or their combination resulted in significant improvement of all measured parameters compared with enteritis group. The current finding could provide new interesting opportunity for developing new therapeutic approaches for treatment of Crohn's disease. Use of naltrexone, especially in small dose, has little side effects making it of interest for treatment of Crohn's disease. Also, it provides the possibility of reduced doses of other drugs if it is used as combined therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. An experimental and theoretical investigation of loperamide hydrochloride-glutaric acid cocrystals.

    PubMed

    Bruni, Giovanna; Maietta, Mariarosa; Maggi, Lauretta; Mustarelli, Piercarlo; Ferrara, Chiara; Berbenni, Vittorio; Freccero, Mauro; Scotti, Federico; Milanese, Chiara; Girella, Alessandro; Marini, Amedeo

    2013-07-11

    Cocrystallization is a powerful method to improve the physicochemical properties of drugs. Loperamide hydrochloride is a topical analgesic for the gastrointestinal tract showing low and pH-dependent solubility; for this reason, an enhancement of its solubility or dissolution rate, particularly at the pH of the intestinal tract, could improve its local efficacy. Here we prepared cocrystals of this active principle with glutaric acid and so obtained a new crystalline solid representing a viable alternative to improve the physicochemical properties and thus the pharmaceutical behavior of the drug. Differential scanning calorimetry, X-ray powder diffraction, Fourier infrared spectroscopy, solid-state NMR, and scanning electron microscopy coupled to the energy-dispersive X-ray spectrometry were used to investigate the new solid-phase formation. DFT calculations at B3LYP/6-31G(d) level of theory, in the gas phase, including frequencies computation, provided a rationale for the interaction between loperamide hydrochloride and glutaric acid. The cocrystals showed improved water solubility in comparison with loperamide HCl, and the pharmaceutical formulation proposed was able to release the drug more rapidly in comparison with three reference commercial products when tested at neutral pH values.

  12. Elevated mu-opioid receptor expression in the nucleus of the solitary tract accompanies attenuated withdrawal signs after chronic low dose naltrexone in opiate-dependent rats.

    PubMed

    Van Bockstaele, E J; Rudoy, C; Mannelli, P; Oropeza, V; Qian, Y

    2006-02-15

    We previously described a decrease in withdrawal behaviors in opiate-dependent rats that were chronically treated with very low doses of naltrexone in their drinking water. Attenuated expression of withdrawal behaviors correlated with decreased c-Fos expression and intracellular signal transduction elements [protein kinase A regulatory subunit II (PKA) and phosphorylated cAMP response element binding protein (pCREB)] in brainstem noradrenergic nuclei. In this study, to determine whether similar cellular changes occurred in forebrain nuclei associated with drug reward, expressions of PKA and pCREB were analyzed in the ventral tegmental area, frontal cortex, striatum, and amygdala of opiate-treated rats that received low doses of naltrexone in their drinking water. No significant difference in PKA or pCREB was detected in these regions following drug treatment. To examine further the cellular mechanisms in noradrenergic nuclei that could underlie attenuated withdrawal behaviors following low dose naltrexone administration, the nucleus of the solitary tract (NTS) and locus coeruleus (LC) were examined for opioid receptor (OR) protein expression. Results showed a significant increase in muOR expression in the NTS of morphine-dependent rats that received low doses of naltrexone in their drinking water, and increases in muOR expression were also found to be dose dependent. Protein expression of muOR in the LC and deltaOR in either brain region remained unchanged. In conclusion, our previously reported decreases in c-Fos and PKA expression in the NTS following pretreatment with low doses of naltrexone may be partially explained by a greater inhibition of NTS neurons resulting from increased muOR expression in this region.

  13. Low-dose prazosin alone and in combination with propranolol or naltrexone: effects on ethanol and sucrose seeking and self-administration in the P rat.

    PubMed

    Verplaetse, Terril L; Czachowski, Cristine L

    2015-08-01

    Evidence suggests that the noradrenergic system mediates ethanol reinforcement. However, preclinical studies suggest that noradrenergic antagonists block other oral reinforcers indicating possible unwanted secondary medication effects. This study examined combinations of low-dose prazosin with propranolol or naltrexone using a behavioral paradigm that separately assesses reinforcer seeking and self-administration. Male alcohol-preferring (P) rats (n = 20/experiment) were trained to complete a response requirement (RR) resulting in access to 1 % sucrose (n = 10) or 10 % ethanol (n = 10) for 20 min. Rats received vehicle, prazosin alone (0.125, 0.25, 0.5, and 1.0 mg/kg, intraperitoneally (IP)), or prazosin in combination with propranolol (5 mg/kg (IP); Exp. 1) or in combination with naltrexone (0.03 mg/kg, subcutaneously (SC); Exp. 2). For Exp. 1, prazosin alone effectively decreased sucrose seeking more than ethanol seeking, but decreased ethanol self-administration only. Propranolol alone effectively decreased ethanol seeking more than sucrose seeking and decreased ethanol intake only. At some dose combinations, there was a greater attenuation of ethanol and sucrose intake relative to either drug alone. For Exp. 2, prazosin alone and naltrexone alone were effective in decreasing ethanol seeking and intake only. Combination treatment was more effective than either drug alone at decreasing ethanol seeking and consumption and sucrose intake, but not sucrose seeking. Propranolol and naltrexone alone were specific to ethanol indicating that low doses of either medication may be beneficial in treating alcohol use disorders. Prazosin in combination with propranolol or naltrexone was more effective than either drug alone and also reduced sucrose-reinforced behaviors. These data suggest that the noradrenergic system is a viable target for developing treatment approaches for problem drinkers.

  14. Low-Dose Prazosin Alone and in Combination with Propranolol or Naltrexone: Effects on Ethanol- and Sucrose-Seeking and Self-Administration in the P Rat

    PubMed Central

    Verplaetse, Terril L.; Czachowski, Cristine L.

    2015-01-01

    Rationale Evidence suggests that the noradrenergic system mediates ethanol-reinforcement. However, preclinical studies suggest that noradrenergic antagonists block other oral reinforcers indicating possible unwanted secondary medication effects. Methods This study examined combinations of low-dose prazosin with propranolol or naltrexone using a behavioral paradigm that separately assesses reinforcer-seeking and self-administration. Male alcohol-preferring (P) rats (n=20/experiment) were trained to complete a response requirement (RR) resulting in access to 1% sucrose (n=10) or 10% ethanol (n=10) for 20min. Rats received vehicle, prazosin alone (0.125, 0.25, 0.5, 1.0 mg/kg; intraperitoneally (IP)) or prazosin in combination with propranolol (5 mg/kg (IP); Exp1) or in combination with naltrexone (0.03 mg/kg (subcutaneously (SC); Exp2). Results For Exp1, prazosin alone effectively decreased sucrose-seeking more than ethanol-seeking, but decreased ethanol self-administration only. Propranolol alone effectively decreased ethanol-seeking more than sucrose-seeking and decreased ethanol intake only. At some dose combinations, there was a greater attenuation of ethanol and sucrose intake relative to either drug alone. For Exp2, prazosin alone and naltrexone alone were effective in decreasing ethanol-seeking and intake only. Combination treatment was more effective than either drug alone at decreasing ethanol-seeking and consumption and sucrose intake, but not sucrose-seeking. Conclusions Propranolol and naltrexone alone were specific to ethanol indicating that low doses of either medication may be beneficial in treating alcohol use disorders. Prazosin in combination with propranolol or naltrexone was more effective than either drug alone, but also reduced sucrose-reinforced behaviors. These data suggest that the noradrenergic system is a viable target for developing treatment approaches for problem drinkers. PMID:25743758

  15. Development and evaluation of a sublingual film of the antiemetic granisetron hydrochloride.

    PubMed

    Kalia, Vani; Garg, Tarun; Rath, Gautam; Goyal, Amit Kumar

    2016-05-01

    The objective of this study was to develop an oral transmucosal formulation of an antiemetic drug that can not only serve in the active form but also provide a controlled release profile. In this study, sublingual films based on the biodegradable and water-soluble polymers, that is HPMCK-4M and PVPK-30, were developed by the solvent casting method, and were loaded with the antiemetic drug granisetron hydrochloride (granisetron HCl). The entrapment efficiency of the developed formulation was found to be 86%. The in vitro profile showed an instant release of the drug from the sublingual film, in a pattern following the first order kinetics array. The in vivo studies showed that granisetron HCl was delivered in its active state and showed effective results, as compared to its activity in the marketed formulation.

  16. Investigation of structure, vibrational and NMR spectra of oxycodone and naltrexone: A combined experimental and theoretical study

    NASA Astrophysics Data System (ADS)

    Tavakol, Hossein; Esfandyari, Maryam; Taheri, Salman; Heydari, Akbar

    2011-08-01

    In this work, two important opioid antagonists, naltrexone and oxycodone, were prepared from thebaine and were characterized by IR, 1H NMR and 13C NMR spectroscopy. Moreover, computational NMR and IR parameters were obtained using density functional theory (DFT) at B3LYP/6-311++G** level of theory. Complete NMR and vibrational assignment were carried out using the observed and calculated spectra. The IR frequencies and NMR chemical shifts, determined experimentally, were compared with those obtained theoretically from DFT calculations, showed good agreements. The RMS errors observed between experimental and calculated data for the IR absorptions are 85 and 105 cm -1, for the 1H NMR peaks are 0.87 and 0.17 ppm and for those of 13C NMR are 5.6 and 5.3 ppm, respectively for naltrexone and oxycodone.

  17. Netupitant and Palonosetron Hydrochloride

    Cancer.gov

    This page contains brief information about netupitant and palonosetron hydrochloride and a collection of links to more information about the use of this combination drug, research results, and ongoing clinical trials.

  18. Trifluridine and Tipiracil Hydrochloride

    Cancer.gov

    This page contains brief information about trifluridine and tipiracil hydrochloride and a collection of links to more information about the use of this combination drug, research results, and ongoing clinical trials.

  19. Preparation and evaluation of sustained release microballoons of propranolol.

    PubMed

    Porwal, A; Swami, G; Saraf, Sa

    2011-01-01

    The purpose of the present investigation was to characterize, optimize and evaluate microballoons of Propranolol hydrochloride and to increase its boioavailability by increasing the retention time of the drug in the gastrointestinal tract. Propranolol hydrochloride-loaded microballoons were prepared by the non-aqueous O/O emulsion solvent diffusion evaporation method using Eudragit RSPO as polymer. It was found that preparation temperature determined the formation of cavity inside the microballoon and this in turn determined the buoyancy. Microballoons were subjected to particle size determination, micromeritic properties, buoyancy, entrapment efficiency, drug loading, in vitro drug release and IR study. The correlation between the buoyancy, bulk density and porosity of microballoons were elucidated. The release rate was determined in simulated gastric fluid (SGF) of pH 1.2 at 37±0.5°C. The microballoons presented spherical and smooth morphologies (SEM) and were porous due to presence of hollow cavity. Microballoons remained buoyant for >12 hrs for the optimized formulation. The formulation demonstrated favorable in vitro floating and release characteristics. The encapsulation efficiency was high. In vitro dissolution kinetics followed the Higuchi model. The drug release from microballoons was mainly controlled by diffusion and showed a biphasic pattern with an initial burst release, followed by sustained release for 12 hrs. The amount of the drug which released up to 12 hrs was 82.05±0.64%. Statistical analysis (ANOVA) showed significant difference (p<0.05) in the cumulative amount of drug released after 30 min, and up to 12 hrs from optimized formulations. The designed system for propanolol would possibly be advantageous in terms of increased bioavailability and patient compliance.

  20. Development of an Extended-Release Formulation for Apremilast and a Level A in Vitro-in Vivo Correlation Study in Beagle Dogs.

    PubMed

    Tang, Meiqiong; Hu, Ping; Huang, Shigui; Zheng, Qiang; Yu, Hao; He, Yun

    2016-11-01

    The primary objective of the present study was to develop extended-release matrix formulations of apremilast for the oral delivery and to study their in vitro and in vivo correlation. Five extended-release formulations containing hydroxypropylmethylcellulose (HPMC) as the retarding excipient with different release rate of apremilast were prepared. Dissolution tests of all the formulated tablets were performed in water, pH 4.0 and 6.8 buffer solutions. The in vitro release kinetics was studied and supported by Korsmeyer-Peppas's equation as it presented highest values of correlation coefficients (r 2 up to 0.966). Among all formulated tablets, F2 (HPMC 25%) and F4 (HPMC 35%) were selected to perform an in vivo study in beagle dogs to obtain various pharmacokinetic parameters, i.e., peak plasma concentration (C max ), time to peak plasma concentration (t max ), area under the plasma-concentration vs. time curve (AUC). Higher t max and t 1/2 , lower C max and elimination coefficient (K e ) were observed for both extended formulations compared to marketed immediate-release products (Otezla ® ). Level A in vitro-in vivo correlations were created with the help of Wagner-Nelson and numeric deconvolution methods. Both formulations showed good in vitro-in vivo correlations whose accuracies were further verified by an internal validation.

  1. Development and evaluation of buccoadhesive tablet for selegiline hydrochloride based on thiolated polycarbophil.

    PubMed

    Wasnik, Mangesh N; Godse, Rutika D; Nair, Hema A

    2014-05-01

    Selegiline hydrochloride (SHCl), a monoamine oxidase B inhibitor, is used as an adjunct in the therapy of Parkinson's disease. This study is concerned with the preparation and evaluation of mucoadhesive buccal tablet for controlled systemic delivery of SHCl. Buccal absorption of selegiline can bypass its first-pass metabolism and improve bioavailability accompanied by greatly reduced metabolite formation, which is potentially of enhanced therapeutic value in patients with Parkinson's disease. Polycarbophil-cysteine (PCP-cys) conjugate, which is a thiolated derivative of the mucoadhesive polymer polycarbophil, was synthesized by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-mediated amide bond coupling. Tablets of SHCl based on native and thiolated polycarbophil were prepared. The prepared tablets were evaluated for drug content, swelling behavior, mucoadhesive strength, in vitro drug release, ex vivo permeation and in vitro cytotoxicity. PCP-cys tablets showed enhanced mucoadhesion and retarded drug release compared to polycarbophil tablets. Permeation data of SHCl from matrices prepared using the PCP-cys polymer revealed a significantly higher value of apparent permeability in comparison to polycarbophil, which supported the information in literature that thiolation imparts permeation enhancing properties to mucoadhesive polymers. In vitro cytotoxicity studies on PCP-cys using L-929 mouse fibroblast cell line indicated that conjugation with cysteine does not impart any apparent toxicity to polycarbophil. The results from the study indicate that the buccal delivery of SHCl using thiolated polycarbophil tablet could provide a way for improved therapy of Parkinson's disease.

  2. Chemical Immobilization of Sloth Bears (Melursus ursinus) with Ketamine Hydrochloride and Xylazine Hydrochloride: Hematology and Serum Biochemical Values

    PubMed Central

    Veeraselvam, M.; Sridhar, R.; Perumal, P.; Jayathangaraj, M. G.

    2014-01-01

    The present study was conducted to define the physiological responses of captive sloth bears immobilized with ketamine hydrochloride and xylazine hydrochloride and to determine and compare the values of hematology and serum biochemical parameters between sexes. A total of 15 sloth bears were immobilized using combination of ketamine hydrochloride and xylazine hydrochloride drugs at the dose rate of 5.0 milligram (mg) per kg body weight and 2.0 mg per kg body weight, respectively. The use of combination of these drugs was found satisfactory for the chemical immobilization of captive sloth bears. There were no significant differences observed in induction time and recovery time and physiological parameters such as heart rate, respiratory rate, and rectal temperature between sexes. Health related parameters comprising hematological values like packed cell volume (PCV), hemoglobin (Hb), red blood cell count (RBC), erythrocyte indices, and so forth and biochemical values like total protein, blood urea nitrogen (BUN), creatinine, alkaline amino-transferase (ALT), aspartate amino-transferase (AST), and so forth were estimated in 11 (5 males and 6 females) apparently healthy bears. Comparison between sexes revealed significant difference in PCV (P < 0.05) and mean corpuscular hemoglobin concentration (MCHC) (P < 0.05). The study might help to evaluate health profiles of sloth bears for appropriate line treatment. PMID:24876990

  3. Production of extended release mini-tablets using directly compressible grades of HPMC.

    PubMed

    Mohamed, Faiezah A A; Roberts, Matthew; Seton, Linda; Ford, James L; Levina, Marina; Rajabi-Siahboomi, Ali R

    2013-11-01

    Hypromellose (HPMC) has been previously used to control drug release from mini-tablets. However, owing to poor flow, production of mini-tablets containing high HPMC levels is challenging. Directly compressible (DC) HPMC grades have been developed by Dow Chemical Company. To compare the properties of HPMC DC (METHOCEL™ K4M and K100M) with regular (REG) HPMC grades. Particle size distribution and flowability of HPMC REG and DC were evaluated. 3 mm mini-tablets, containing hydrocortisone or theophylline as model drugs and 40% w/w HPMC DC or REG were produced. Mini-tablets containing HPMC DC grades were manufactured using a rotary press simulator at forces between 2-4 kN and speeds of 5, 10, 15 or 20 rpm. Mini-tablets containing HPMC REG were produced manually. The improved flowability of HPMC DC grades, which have a narrower particle size distribution and larger particle sizes, meant that simulated large scale production of mini-tablets with good weight uniformity (CV 1.79-4.65%) was feasible. It was not possible to automatically manufacture mini-tablets containing HPMC REG due to the poor flowability of the formulations. Drug release from mini-tablets comprising HPMC DC and REG were comparable. Mini-tablets containing HPMC DC illustrated a higher tensile strength compared to mini-tablets made with HPMC REG. Mini-tablets produced with HPMC DC at different compression speeds had similar drug release profiles. Production of extended release mini-tablets was successfully achieved when HPMC DC was used. Drug release rate was not influenced by the different HPMC DC grades (K4M or K100M) or production speed.

  4. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke.

    PubMed

    Sacco, Ralph L; Diener, Hans-Christoph; Yusuf, Salim; Cotton, Daniel; Ounpuu, Stephanie; Lawton, William A; Palesch, Yuko; Martin, Reneé H; Albers, Gregory W; Bath, Philip; Bornstein, Natan; Chan, Bernard P L; Chen, Sien-Tsong; Cunha, Luis; Dahlöf, Björn; De Keyser, Jacques; Donnan, Geoffrey A; Estol, Conrado; Gorelick, Philip; Gu, Vivian; Hermansson, Karin; Hilbrich, Lutz; Kaste, Markku; Lu, Chuanzhen; Machnig, Thomas; Pais, Prem; Roberts, Robin; Skvortsova, Veronika; Teal, Philip; Toni, Danilo; Vandermaelen, Cam; Voigt, Thor; Weber, Michael; Yoon, Byung-Woo

    2008-09-18

    Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.) 2008 Massachusetts Medical Society

  5. Comparative treatment and mortality correlates and adverse event profile of implant naltrexone and sublingual buprenorphine.

    PubMed

    Reece, Albert Stuart

    2009-10-01

    There is increasing interest in the use of implantable naltrexone as a new treatment for opiate dependence. This center has been one of the leaders in this form of treatment in Australia and has recently completed a registry-controlled review of our mortality data. As part of the study of the safety profile of this therapy, we were interested to review both the treatment correlates of previously presented mortality data and of adverse events. A total of 255 naltrexone implant therapy (NIT) and 2,518 buprenorphine (BUP) patients were followed for 1,322.22 and 8,030.02 patient-years, respectively. NIT patients had significantly longer days in treatment per episode (mean +/- standard deviation, 238.32 +/- 110.11 vs. 46.96 +/- 109.79), total treatment duration (371.21 +/- 284.64 vs. 162.50 +/- 245.76), and mean treatment times but fewer treatment episodes than BUP (all p < .0001). Serious local tissue reaction or infection each occurred in 1% of 200 NIT episodes. These data show that NIT economizes treatment resources without compromising safety concerns.

  6. Intranasal naltrexone and atipamezole for reversal of white-tailed deer immobilized with carfentanil and medetomidine

    PubMed Central

    Shury, Todd K.; Caulkett, Nigel A.; Woodbury, Murray R.

    2010-01-01

    Carfentanil and medetomidine were used to immobilize 8 captive female white-tailed deer (Odocoileus virginianus) using mean dosages [± standard deviation (s)] of 14.2 ± 1.11 μg/kg carfentanil and 17.8 ± 2.03 μg/kg of medetomidine. Deer were reversed by intranasally or intramuscularly administered naltrexone and atipamezole. Dosages of carfentanil and medetomidine proved reliable for immobilization of most, but not all deer, with a mean induction time of 13.3 ± 3.13 min. Effective and reliable immobilization will require higher dosages of carfentanil and possibly medetomidine than were used in this study. No significant differences in recovery times were observed for deer given reversal agents intranasally (9.45 ± 5.37 min) versus intramuscularly (7.60 ± 4.42 min). Naltrexone and atipamezole can be administered intranasally at 1.5 mg/kg and 0.1 mg/kg, respectively to safely and quickly reverse the effects of carfentanil and medetomidine in immobilized white-tailed deer. This route could potentially be useful for other reversal agents. PMID:20676292

  7. Continuous manufacturing of extended release tablets via powder mixing and direct compression.

    PubMed

    Ervasti, Tuomas; Simonaho, Simo-Pekka; Ketolainen, Jarkko; Forsberg, Peter; Fransson, Magnus; Wikström, Håkan; Folestad, Staffan; Lakio, Satu; Tajarobi, Pirjo; Abrahmsén-Alami, Susanna

    2015-11-10

    The aim of the current work was to explore continuous dry powder mixing and direct compression for manufacturing of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compositions with varying particle size and a relatively low amount of the matrix former hydroxypropyl methylcellulose (HPMC). Standard grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufactured via integrated continuous mixing and direct compression. The most robust tablet quality (weight, assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compositions containing DC2 compared with those containing CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufacturing systems. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Simulated Driving Changes in Young Adults with ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine

    ERIC Educational Resources Information Center

    Kay, Gary G.; Michaels, M. Alex; Pakull, Barton

    2009-01-01

    Background: Psychostimulant treatment may improve simulated driving performance in young adults with attention-deficit/hyperactivity disorder (ADHD). Method: This was a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with mixed amphetamine salts--extended release (MAS XR) 50 mg/day (Cohort 1) and…

  9. Developmental rates of immatures of three Chrysomya species (Diptera: Calliphoridae) under the effect of methylphenidate hydrochloride, phenobarbital, and methylphenidate hydrochloride associated with phenobarbital.

    PubMed

    Rezende, Fábio; Alonso, Marcela A; Souza, Carina M; Thyssen, Patrícia J; Linhares, Arício X

    2014-05-01

    Entomotoxicology is focused on obtaining data on necrophagous entomofauna, for criminal investigations purposes. This study aimed to evaluate the effect of different concentrations of methylphenidate hydrochloride, phenobarbital, and their association on the developmental rate, larval and pupal survivorship, and the interval of emergence of adults of Chrysomya albiceps (Wiedemann), Chrysomya megacephala (Fabricius), and Chrysomya putoria (Wiedemann) (Diptera: Calliphoridae). Considering the therapeutic dose (TD) of methylphenidate hydrochloride (0.29 mg/Kg), the concentrations tested were 10× TD, 50× TD, and 100× TD. For phenobarbital, the concentrations used were 1× TD (=150 mg/Kg), 3.3× TD, and 6.7× TD. For the association of the drugs, the combinations used were 10× TD-methylphenidate hydrochloride plus 1× TD-phenobarbital, 50× TD-methylphenidate hydrochloride plus 3.3× TD-phenobarbital, and 100× TD-methylphenidate hydrochloride plus 6.7× TD-phenobarbital. The control group, without addition of drug, was maintained under the same conditions of temperature (25 ± 1 °C), humidity (70 ± 10%), and photoperiod (12 h). Specimens of each group were weighed every 12 h until pupariation. The developmental rate of the three Chrysomya species immatures was monitored. For C. albiceps the developmental time was delayed in 24 h for methylphenidate hydrochloride group and in 12 h for the phenobarbital and the drugs association groups. The effect was observed only at specific ages for C. megacephala, without altering the developmental time. For C. putoria, the developmental time was delayed in 12 h for methylphenidate hydrochloride group and in 24 h for the phenobarbital and the drugs association groups. The emergence interval was similar among all experimental groups, but larval and pupal viabilities were affected in different ways.

  10. Evaluation of Gum of Moringa oleifera as a Binder and Release Retardant in Tablet Formulation

    PubMed Central

    Panda, D. S.; Choudhury, N. S. K.; Yedukondalu, M.; Si, S.; Gupta, R.

    2008-01-01

    The present study was undertaken to find out the potential of gum from Moringa oleifera to act as a binder and release retardant in tablet formulations. The effect of calcium sulphate dihydrate (water insoluble) and lactose (water soluble) diluent on the release of propranolol hydrochloride was studied. The DSC thermograms of drug, gum and mixture of gum/drug indicated no chemical interaction. Tablets (F1, F2, F3, and F4) were prepared containing calcium sulphate dihydrate as diluent, propranolol hydrochloride as model drug using 10%, 8%, 6% and 4% w/v of gum solution as binder. Magnesium stearate was used as lubricant. Physical and technological properties of granules and tablets like flow rate, Carr index, Hausner ratio, angle of repose, hardness, friability and disintegration time were determined and found to be satisfactory. Tablets were prepared by wet granulation method containing calcium sulphate dihydrate as excipient, propranolol hydrochloride as model drug using 10%, 20% and 30% of gum as release retardant, magnesium stearate was used as lubricant. Similarly tablets were prepared replacing lactose with calcium sulphate dihydrate. Despite of the widely varying physico-chemical characteristics of the excipients, the drug release profiles were found to be similar. The drug release increased with increasing proportions of the excipient and decreased proportion of the gum irrespective of the solubility characteristics of the excipient. The values of release exponent ‘n’ are between 0.37 and 0.54. This implies that the release mechanism is Fickian. There is no evidence that the dissolution or erosion of the excipient has got any effect on the release of the drug. The t50% values for tablets containing calcium sulphate dihydrate were on an average 10%-15% longer than the tablets containing lactose as excipient. These relatively small differences in t50% values suggest that the nature of excipient used appeared to play a minor role in regulating the release

  11. Single dose pharmacokinetics of fenspiride hydrochloride: phase I clinical trial.

    PubMed

    Montes, B; Catalan, M; Roces, A; Jeanniot, J P; Honorato, J M

    1993-01-01

    The absolute bioavailability of fenspiride has been studied in twelve healthy volunteers. It was administered IV and orally in single doses of 80 mg fenspiride hydrochloride according to a randomised crossover pattern. Following IV administration, the plasma clearance of fenspiride was about 184 ml.min-1, and its apparent volume of distribution was moderately large (215 l). When given orally as a tablet, fenspiride exhibited fairly slow ab- sorption; the maximum plasma concentration (206 ng.ml-1) was achieved 6 h after administration. The absolute bioavailability was almost complete (90%). The tablet had slow release characteristics. The elimination half-life obtained from the plasma data was 14 to 16 h independent of the route of administration.

  12. Temperature-dependent THz vibrational spectra of clenbuterol hydrochloride

    NASA Astrophysics Data System (ADS)

    Yang, YuPing; Lei, XiangYun; Yue, Ai; Zhang, Zhenwei

    2013-04-01

    Using the high-resolution Terahertz Time-domain spectroscopy (THz-TDS) and the standard sample pellet technique, the far-infrared vibrational spectra of clenbuterol hydrochloride (CH), a β 2-adrenergic agonist for decreasing fat deposition and enhancing protein accretion, were measured in temperature range of 77-295 K. Between 0.2 and 3.6 THz (6.6-120.0 cm-1), seven highly resolved spectral features, strong line-narrowing and a frequency blue-shift were observed with cooling. However, ractopamine hydrochloride, with some structural and pharmacological similarities to clenbuterol hydrochloride, showed no spectral features, indicating high sensitivity and strong specificity of THz-TDS. These results could be used for the rapid and nondestructive CH residual detection in food safety control.

  13. Naltrexone-loaded poly[La-(Glc-Leu)] polymeric microspheres for the treatment of alcohol dependence: in vitro characterization and in vivo biocompatibility assessment.

    PubMed

    Pagar, Kunal P; Vavia, Pradeep R

    2014-06-01

    The poly[La-(Glc-Leu)] copolymer was applied in the present investigation as polymeric carrier to fabricate naltrexone (NTX)-loaded poly[La-(Glc-Leu)] microspheres in the single emulsion solvent evaporation technique for the long-term treatment of alcohol dependence. Newly synthesized poly[La-(Glc-Leu)] copolymer exhibited diminished crystallanity, good biocompatibility and favorable biodegradability to be explored for drug delivery application. Scanning Electron Microscopy study revealed smooth and spherical-shaped NTX-loaded polymeric microspheres with a mean size of 10-90 µm. Influence of various decisive formulation variables such as amount of polymer, stabilizer concentration, homogenization speed, homogenization time, drug loading and organic-to-aqueous phase ratio on particle size, and entrapment efficiency was studied. Differential scanning calorimeter and X-ray diffractometry study confirmed the drug entrapment within polymer matrix into the microsphere environment. In vitro drug release showed the sustained drug release of formulation for the period of 28 d giving biphasic release pattern. Histological examination of NTX-loaded poly[La-(Glc-Leu)] microspheres injected intramuscularly into the thigh muscle of Wistar rats showed minimal inflammatory reaction, demonstrating that NTX-loaded microspheres were biocompatible. Insignificant increase in the serum creatine phosphokinase level (p < 0.05) as compared with the normal value revealed good muscle compatibility of the poly[La-(Glc-Leu)] microsphere system. Biocompatible nature and sustained drug-release action of poly[La-(Glc-Leu)] microspheres may have potential application in depot therapy.

  14. Plasma concentrations of remoxipride and the gastrointestinal transit of 111In-marked extended-release coated spheres

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Graffner, C.; Wagner, Z.; Nilsson, M.I.

    1990-01-01

    To explore the oral absorption of remoxipride, spheres of remoxipride were labeled with indium-111 colloid before coating with a release-controlling ethylcellulose membrane. Since the labeling remained inside the coating, it was suitable as a marker. Eight healthy volunteers were given a single dose of 100 mg remoxipride in 111In-marked spheres as a multiple-unit capsule. The radioactivity and the position of the spheres (microcapsules) were followed externally for 30 hr by gamma scintigraphy. Parallel to this, plasma concentrations were drawn for 48 hr to confirm the extended dissolution and absorption of remoxipride. The hard gelatin, multiple-unit capsule released the microcapsules withinmore » the stomach. These were then rapidly emptied into the small intestine, within 0.5-1 hr. There was then an immediate distribution in the upper small intestine before collection in the lower portion, within 2-5 hr. After passing into the large intestine, there was again extended distribution of the microcapsules. A mean Cmax of 2.7 microM remoxipride was achieved 4 hr after drug administration and a mean AUC of 26.1 mumol.L-1.hr was achieved. Judging from the absorption versus time profile, calculated according to the Wagner-Nelson method, and the scintigraphic images, it is concluded that the main absorption occurs from the small intestine. Data from four volunteers, however, indicated a comparatively good absorption also from the large intestine. Due to the good absorption properties, it is reasonable to expect a low variation in the extent of bioavailability of remoxipride after administration in an extended-release, multiple-unit capsule formulation.« less

  15. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone

    PubMed Central

    Hutchinson, Mark R.; Zhang, Yingning; Brown, Kimberley; Coats, Benjamen D.; Shridhar, Mitesh; Sholar, Paige W.; Patel, Sonica J.; Crysdale, Nicole Y.; Harrison, Jacqueline A.; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R.

    2008-01-01

    Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)-naltrexone, (+)-naloxone, and (-))-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by (+)-naloxone and (-))-naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)-naloxone and (-))-naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-))-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-))-opioid agonists suppress pain. PMID:18662331

  16. Effects of the Opioid Receptor Antagonist Naltrexone on Smoking and Related Behaviors in Smokers Preparing to Quit: A Randomized Controlled Trial

    PubMed Central

    King, Andrea; Cao, Dingcai; Zhang, Lingjiao; Rueger, Sandra Yu

    2013-01-01

    Aims To determine if naltrexone affects smoking behaviours in smokers preparing to quit, and whether such pre-quit responses predict post-quit date outcomes. Design Double-blind, placebo-controlled, randomized study. Current study focused on smoking-related outcomes in the pre-quit phase, which was one week prior to the quit date, and these findings were linked with reductions in same outcomes demonstrated in the post-quit phase previously published for this RCT in mediation analyses. Setting Community sample of adult smokers desiring to quit in Chicago, Illinois USA. Participants Participants were 315 smokers randomized to naltrexone (n=161; mean age=42.6 years; 60% white) or placebo (n=154; mean age=41.3 years; 55% white). Measurements Difference from baseline in the number of cigarettes smoked during pre-quit phase interval was the primary outcome. Secondary pre-quit outcomes were assessed using Likert scales of subjective responses and consumption of cigarettes, alcohol, and food. Number of cigarettes smoked, alcoholic drinks consumed, and the Brief Questionnaire of Smoking Urges were assessed in the post-quit phase. Findings Relative to placebo, naltrexone decreased the number of cigarettes smoked (−4.21 vs. −2.93, p<.05), smoking urge (p=.02), and number of alcoholic drinks consumed (p=.04). Exploratory mediation analyses linking outcomes of the pre quit and post quit phases found that naltrexone’s effects on reducing smoking urge, cigarettes smoked and alcoholic drinks consumed in the pre-quit phase demonstrated full mediation of their respective effects during the post-quit phase. Conclusions Naltrexone taken in the week before a quit attempt appears to reduce cigarette consumption, urges to smoke and alcohol consumption relative to placebo. The size of the effect statistically mediates the size of similar effects after the quit date. PMID:23714324

  17. Brain targeted oral delivery of doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles against ketamine induced psychosis: behavioral, biochemical, neurochemical and histological alterations in mice.

    PubMed

    Yadav, Monu; Parle, Milind; Sharma, Nidhi; Dhingra, Sameer; Raina, Neha; Jindal, Deepak Kumar

    2017-11-01

    To develop statistically optimized brain targeted Tween 80 coated chitosan nanoparticulate formulation for oral delivery of doxycycline hydrochloride for the treatment of psychosis and to evaluate its protective effect on ketamine induced behavioral, biochemical, neurochemical and histological alterations in mice. 3 2 full factorial design was used to optimize the nanoparticulate formulation to minimize particle size and maximize entrapment efficiency, while independent variables chosen were concentration of chitosan and Tween 80. The optimized formulation was characterized by particle size, drug entrapment efficiency, Fourier transform infrared, Transmission electron microscopy analysis and drug release behavior. Pure doxycycline hydrochloride (25 and 50 mg/kg, p.o.) and optimized doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles (DCNP opt ) (equivalent to 25 mg/kg doxycycline hydrochloride, p.o.) were explored against ketamine induced psychosis in mice. The experimental studies for DCNP opt , with mean particle size 237 nm and entrapment efficiency 78.16%, elucidated that the formulation successfully passed through blood brain barrier and exhibited significant antipsychotic activity. The underlying mechanism of action was further confirmed by behavioral, biochemical, neurochemical estimations and histopathological study. Significantly enhanced GABA and GSH level and diminished MDA, TNF-α and dopamine levels were observed after administration of DCNP opt at just half the dose of pure doxycycline hydrochloride, showing better penetration of doxycyline hydrochloride in the form of Tween 80 coated nanoparticles through blood brain barrier. This study demonstrates the hydrophilic drug doxycycline hydrochloride, loaded in Tween 80 coated chitosan nanoparticles, can be effectively brain targeted through oral delivery and therefore represents a suitable approach for the treatment of psychotic symptoms.

  18. Preparation and evaluation of sustained release microballoons of propranolol

    PubMed Central

    Porwal, A; Swami, G; Saraf, SA

    2011-01-01

    Background and the purpose of the study The purpose of the present investigation was to characterize, optimize and evaluate microballoons of Propranolol hydrochloride and to increase its boioavailability by increasing the retention time of the drug in the gastrointestinal tract. Methods Propranolol hydrochloride-loaded microballoons were prepared by the non-aqueous O/O emulsion solvent diffusion evaporation method using Eudragit RSPO as polymer. It was found that preparation temperature determined the formation of cavity inside the microballoon and this in turn determined the buoyancy. Microballoons were subjected to particle size determination, micromeritic properties, buoyancy, entrapment efficiency, drug loading, in vitro drug release and IR study. The correlation between the buoyancy, bulk density and porosity of microballoons were elucidated. The release rate was determined in simulated gastric fluid (SGF) of pH 1.2 at 37±0.5°C. Results The microballoons presented spherical and smooth morphologies (SEM) and were porous due to presence of hollow cavity. Microballoons remained buoyant for >12 hrs for the optimized formulation. The formulation demonstrated favorable in vitro floating and release characteristics. The encapsulation efficiency was high. In vitro dissolution kinetics followed the Higuchi model. The drug release from microballoons was mainly controlled by diffusion and showed a biphasic pattern with an initial burst release, followed by sustained release for 12 hrs. The amount of the drug which released up to 12 hrs was 82.05±0.64%. Statistical analysis (ANOVA) showed significant difference (p<0.05) in the cumulative amount of drug released after 30 min, and up to 12 hrs from optimized formulations. Conclusion The designed system for propanolol would possibly be advantageous in terms of increased bioavailability and patient compliance. PMID:22615657

  19. Tramadol extended-release in the management of chronic pain

    PubMed Central

    McCarberg, Bill

    2007-01-01

    Chronic, noncancer pain such as that associated with osteoarthritis of the hip and knee is typically managed according to American College of Rheumatology guidelines. Patients unresponsive to first-line treatment with acetaminophen receive nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors. However, many patients may have chronic pain that is refractory to these agents, or they may be at risk for the gastrointestinal, renal, and cardiovascular complications associated with their use. Tramadol, a mild opioid agonist and norepinephrine and serotonin reuptake inhibitor, is recommended by current guidelines for the treatment of moderate to moderately severe pain in patients who have not responded to previous oral therapy, or in patients who have contraindications to COX-2 inhibitors and nonselective NSAIDs. An extended-release (ER) formulation of tramadol was approved by the US Food and Drug Administration in September 2005. In contrast with immediate-release (IR) tramadol, this ER formulation allows once-daily dosing, providing around-the-clock analgesia. In clinical studies, tramadol ER has demonstrated a lower incidence of adverse events than that reported for IR tramadol. Unlike nonselective NSAIDs and COX-2 inhibitors, tramadol ER is not associated with gastrointestinal, renal, or cardiovascular complications. Although tramadol is an opioid agonist, significant abuse has not been demonstrated after long-term therapy. It is concluded that tramadol ER has an efficacy and safety profile that warrants its early use for the management of chronic pain, either alone or in conjunction with nonselective NSAIDs and COX-2 inhibitors. PMID:18488071

  20. Venlafaxine extended-release for depression following spinal cord injury: a randomized clinical trial.

    PubMed

    Fann, Jesse R; Bombardier, Charles H; Richards, J Scott; Wilson, Catherine S; Heinemann, Allen W; Warren, Ann Marie; Brooks, Larry; McCullumsmith, Cheryl B; Temkin, Nancy R; Warms, Catherine; Tate, Denise G

    2015-03-01

    Depression is prevalent and associated with negative outcomes in individuals with spinal cord injury (SCI). Antidepressants are used routinely to treat depression, yet no placebo-controlled trials have been published in this population to our knowledge. To determine the efficacy and tolerability of venlafaxine hydrochloride extended-release (XR) for major depressive disorder (MDD) or dysthymic disorder in persons with chronic SCI. Multisite, randomized (1:1), double-blind, placebo-controlled Project to Improve Symptoms and Mood After SCI (PRISMS) trial. All research staff conducting screening, intervention, and outcome procedures were blinded to randomization status. We screened 2536 patients from outpatient clinics at 6 SCI treatment centers in the United States and randomized 133 participants into the trial. Participants were 18 to 64 years old and at least 1 month after SCI, with MDD or dysthymic disorder. Seventy-four percent of participants were male, and participants were on average 40 years old and 11 years after SCI. Forty-seven percent had cervical injuries, 53.4% had American Spinal Injury Association injury severity A (complete injury) SCI, 24.1% had at least 2 prior MDD episodes, and 99.2% had current MDD. Common comorbidities included chronic pain (93.9%), significant anxiety (57.1%), and history of substance dependence (44.4%). Twelve-week trial of venlafaxine XR vs placebo using a flexible-dose algorithm. The Hamilton Depression Rating Scale (HAM-D 17-item version and Maier subscale, which focuses on core depression symptoms and excludes somatic symptoms) over 12 weeks. Mixed-effects models revealed a significant difference between the venlafaxine XR and placebo groups in improvement on the Maier subscale from baseline to 12 weeks (treatment effect, 1.6; 95% CI, 0.3-2.9; P = .02) but not on the HAM-D 17-item version (treatment effect, 1.0; 95% CI, -1.4 to 3.4; P = .42). Participants receiving venlafaxine XR reported significantly less SCI

  1. 21 CFR 522.1222 - Ketamine hydrochloride injectable dosage forms.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Ketamine hydrochloride injectable dosage forms. 522.1222 Section 522.1222 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... ANIMAL DRUGS § 522.1222 Ketamine hydrochloride injectable dosage forms. ...

  2. 21 CFR 522.1222 - Ketamine hydrochloride injectable dosage forms.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Ketamine hydrochloride injectable dosage forms. 522.1222 Section 522.1222 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... ANIMAL DRUGS § 522.1222 Ketamine hydrochloride injectable dosage forms. ...

  3. 21 CFR 522.1222 - Ketamine hydrochloride injectable dosage forms.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Ketamine hydrochloride injectable dosage forms. 522.1222 Section 522.1222 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... ANIMAL DRUGS § 522.1222 Ketamine hydrochloride injectable dosage forms. ...

  4. 21 CFR 522.1222 - Ketamine hydrochloride injectable dosage forms.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Ketamine hydrochloride injectable dosage forms. 522.1222 Section 522.1222 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... ANIMAL DRUGS § 522.1222 Ketamine hydrochloride injectable dosage forms. ...

  5. 76 FR 68766 - Draft Blueprint for Prescriber Education for Long-Acting/Extended-Release Opioid Class-Wide Risk...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-07

    ...] Draft Blueprint for Prescriber Education for Long-Acting/ Extended-Release Opioid Class-Wide Risk... announcing the availability of a draft document entitled ``Blueprint for Prescriber Education for the Long... intended for use by continuing education (CE) providers to develop educational materials to train...

  6. Development and statistical optimization of nefopam hydrochloride loaded nanospheres for neuropathic pain using Box-Behnken design.

    PubMed

    Sukhbir, S; Yashpal, S; Sandeep, A

    2016-09-01

    Nefopam hydrochloride (NFH) is a non-opioid centrally acting analgesic drug used to treat chronic condition such as neuropathic pain. In current research, sustained release nefopam hydrochloride loaded nanospheres (NFH-NS) were auspiciously synthesized using binary mixture of eudragit RL 100 and RS 100 with sorbitan monooleate as surfactant by quasi solvent diffusion technique and optimized by 3 5 Box-Behnken designs to evaluate the effects of process and formulation variables. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetric (DSC) and X-ray diffraction (XRD) affirmed absence of drug-polymer incompatibility and confirmed formation of nanospheres. Desirability function scrutinized by design-expert software for optimized formulation was 0.920. Optimized batch of NFH-NS had mean particle size 328.36 nm ± 2.23, % entrapment efficiency (% EE) 84.97 ± 1.23, % process yield 83.60 ± 1.31 and % drug loading (% DL) 21.41 ± 0.89. Dynamic light scattering (DLS), zeta potential analysis and scanning electron microscopy (SEM) validated size, charge and shape of nanospheres, respectively. In-vitro drug release study revealed biphasic release pattern from optimized nanospheres. Korsmeyer Peppas found excellent kinetics model with release exponent less than 0.45. Chronic constricted injury (CCI) model of optimized NFH-NS in Wistar rats produced significant difference in neuropathic pain behavior ( p  < 0.05) as compared to free NFH over 10 h indicating sustained action. Long term and accelerated stability testing of optimized NFH-NS revealed degradation rate constant 1.695 × 10 -4 and shelf-life 621 days at 25 ± 2 °C/60% ± 5% RH.

  7. Investigating the safety and efficacy of naltrexone for anti-psychotic induced weight gain in severe mental illness: study protocol of a double-blind, randomized, placebo-controlled trial.

    PubMed

    Tek, Cenk; Guloksuz, Sinan; Srihari, Vinod H; Reutenauer, Erin L

    2013-06-27

    Obesity is a growing health problem leading to high rates of mortality and morbidity in patients with severe mental illness (SMI). The increased rate of obesity is largely attributed to antipsychotic use. The effect of antipsychotic medications on H1 and 5HT2 receptors has been associated with weight gain, but there is also a substantial amount of evidence showing that D2 receptor blockade may be responsible for weight gain by interacting with the dopamine-opioid system. Unfortunately, current available medications for weight loss have limited efficacy in this population. Naltrexone, an opioid receptor antagonist, may be a promising agent to reduce antipsychotic induced weight gain by decreasing food cravings. We aim to investigate the safety and efficacy of two doses of naltrexone (25 mg & 50 mg) versus placebo for weight and health risk reduction in overweight and obese individuals (BMI ≥ 28) with SMI, who gained weight while being treated with antipsychotics. One hundred and forty four patients will be recruited throughout the greater New Haven area. The participants will be randomized to naltrexone 25 mg/day, naltrexone 50 mg/day, or placebo in a 1:1:1 ratio. Participants will be on the study medication for 52 weeks, and assessed weekly for the first 4 weeks and bi-weekly thereafter. The primary outcome measurements are weight reduction and percentage achieving clinically significant weight loss (5% of total body weight). Waist circumference, body mass index, serum lipid profile, fasting glucose, and glycosylated hemoglobin are the secondary outcome measures. The effect of naltrexone on other outcome measurements such as schizophrenia symptoms, depression, dietary consumption, quality of life, cognitive functioning, physical activity, metabolism/inflammation markers, serum leptin, ghrelin, peptide YY, adinopectin, high sensitivity CRP, interleukin 6, interleukin-1B, interleukin-18, and tumor necrosis factor alpha (TNF-α) will be evaluated. The data will be

  8. Development of metoprolol tartrate extended-release matrix tablet formulations for regulatory policy consideration.

    PubMed

    Nellore, R V; Rekhi, G S; Hussain, A S; Tillman, L G; Augsburger, L L

    1998-01-02

    This research study was designed to develop model extended-release (ER) matrix tablet formulations for metoprolol tartrate (100 mg) sufficiently sensitive to manufacturing variable and to serve as the scientific basis for regulatory policy development on scale-up and post approval changes for modified-release dosage forms (SUPAC-MR). Several grades and levels of hydroxypropyl methylcellulose (Methocel K4M, K15M, K100M and K100LV), fillers and binders and studied. Three granulation processes were evaluated; direct compression, fluid-bed or high-shear granulation. Lubrication was performed in a V-blender and tablets were compressed on an instrumented rotary tablet press. Direct compression formulations exhibited poor flow, picking and sticking problems during tableting. High-shear granulation resulted in the formation of hard granules that were difficult to mill but yielded good tablets. Fluid-bed granulations were made using various binders and appeared to be satisfactory in terms of flow and tableting performance. In vitro drug release testing was performed in pH 6.8 phosphate buffer using USP apparatus 2 (paddle) at 50 rpm. At a fixed polymer level, drug release from the higher viscosity grades (K100M) was slower as compared to the lower viscosity grades (K100LV). In addition, release from K100LV was found to be more sensitive to polymer level changes. Increased in polymer level from 10 to 40% and/or filler change from lactose to dicalcium phosphate resulted in about 25-30% decrease in the amount of metoprolol release after 12 h. The results of this study led to the choice of Methocel K100LV as the hydrophilic matrix polymer and fluid-bed granulation as the process of choice for further evaluation of critical and non-critical formulation and processing variables.

  9. Nefopam hydrochloride loaded microspheres for post-operative pain management: synthesis, physicochemical characterization and in-vivo evaluation.

    PubMed

    Sharma, Neelam; Arora, Sandeep; Madan, Jitender

    2018-02-01

    Once-daily oral dosage of nefopam hydrochloride loaded sustained release microspheres (NPH-MS) was investigated as novel therapeutic strategy for post-operative pain management. Microspheres were synthesized using poly-3-hydroxybutyrate and poly-(ɛ-caprolactone) by double emulsion solvent evaporation technique. NPH-MS were characterized through FTIR, PXRD and SEM. In-vitro drug release study revealed sustained behavior till 24 h. Haemolysis was <5% which signified haemocompatibility of formulation. ED50 in rat tail-flick anti-nociceptive test was found ∼18.12 mg/kg. In post-operative pain model, reversal of mechanical allodynia and thermal hyperalgesia by NPH-MS was statistically significant (p < .001) as compared with NPH till 24 h post-dose.

  10. Fundamentals of ionic conductivity relaxation gained from study of procaine hydrochloride and procainamide hydrochloride at ambient and elevated pressure.

    PubMed

    Wojnarowska, Z; Swiety-Pospiech, A; Grzybowska, K; Hawelek, L; Paluch, M; Ngai, K L

    2012-04-28

    The pharmaceuticals, procaine hydrochloride and procainamide hydrochloride, are glass-forming as well as ionically conducting materials. We have made dielectric measurements at ambient and elevated pressures to characterize the dynamics of the ion conductivity relaxation in these pharmaceuticals, and calorimetric measurements for the structural relaxation. Perhaps due to their special chemical and physical structures, novel features are found in the ionic conductivity relaxation of these pharmaceuticals. Data of conductivity relaxation in most ionic conductors when represented by the electric loss modulus usually show a single resolved peak in the electric modulus loss M(")(f) spectra. However, in procaine hydrochloride and procainamide hydrochloride we find in addition another resolved loss peak at higher frequencies over a temperature range spanning across T(g). The situation is analogous to many non-ionic glass-formers showing the presence of the structural α-relaxation together with the Johari-Goldstein (JG) β-relaxation. Naturally the analogy leads us to name the slower and faster processes resolved in procaine hydrochloride and procainamide hydrochloride as the primary α-conductivity relaxation and the secondary β-conductivity relaxation, respectively. The analogy of the β-conductivity relaxation in procaine HCl and procainamide HCl with JG β-relaxation in non-ionic glass-formers goes further by the finding that the β-conductivity is strongly related to the α-conductivity relaxation at temperatures above and below T(g). At elevated pressure but compensated by raising temperature to maintain α-conductivity relaxation time constant, the data show invariance of the ratio between the β- and the α-conductivity relaxation times to changes of thermodynamic condition. This property indicates that the β-conductivity relaxation has fundamental importance and is indispensable as the precursor of the α-conductivity relaxation, analogous to the relation found

  11. Formulation and evaluation of buccal film of Ivabradine hydrochloride for the treatment of stable angina pectoris

    PubMed Central

    Lodhi, Mohasin; Dubey, Akhilesh; Narayan, Reema; Prabhu, Prabhakara; Priya, Sneh

    2013-01-01

    Background: Ivabradine hydrochloride is an anti-anginal drug with a biological half-life of about 2 h, and repeated daily administration is needed to maintain effective plasma level. Present investigation of buccal films of Ivabradine hydrochloride is an attempt to avoid the repeated administration and release of drug in more controlled fashion, thereby, to improve the bioavailability. Materials and Methods: Buccal patches were fabricated by solvent casting technique and were evaluated for its physical properties like physical appearance, weight uniformity, thickness, swelling index, surface pH, mucoadhesive time, and folding endurance, in vitro and ex vivo release studies. Results: A combination of hydroxypropyl methyl cellulose (HPMC) K15M and K100M with carbopol 940, PEG 6000 gave promising results. Further, the drug content of all the formulations was determined and was found to be uniform. All the formulations were subjected to in vitro release study using phosphate buffer pH 6.6. Patches exhibited drug release in the range of 90.36% ± 0.854 to 98.37% ± 0.589 at the end of six hrs. The best formulations (F2 and F5) containing the composition of HPMC K15-37.50 mg, carbopol-0.42 mg, PEG6000-16.87 mg, Aspertane-0.28 mg, Tween-0.0023 mg and HPMC K100-37.50 mg, carbopol-0.42 mg, PEG6000-16.87 mg, Aspertane-0.28 mg, Tween-0.0023 mg respectively exhibited in vitro drug release of 97.61% ± 0.589 and 98.37% ± 0.114 respectively. The results of ex vivo diffusion using goat cheek pouch revealed that the drug release rate was retarded up to seven hrs. Films prepared with permeation enhancer (Tween 80) showed faster drug release. Finally, stability studies were carried out by using human saliva for the optimized formulation (F2-F5). Conclusion: The present study indicated enormous potential of mucoadhesive buccal patches containing Ivabradine for systemic delivery with an added advantage of circumventing hepatic first pass metabolism. Further work is recommended to

  12. Gastroretentive extended-release floating granules prepared using a novel fluidized hot melt granulation (FHMG) technique.

    PubMed

    Zhai, H; Jones, D S; McCoy, C P; Madi, A M; Tian, Y; Andrews, G P

    2014-10-06

    The objective of this work was to investigate the feasibility of using a novel granulation technique, namely, fluidized hot melt granulation (FHMG), to prepare gastroretentive extended-release floating granules. In this study we have utilized FHMG, a solvent free process in which granulation is achieved with the aid of low melting point materials, using Compritol 888 ATO and Gelucire 50/13 as meltable binders, in place of conventional liquid binders. The physicochemical properties, morphology, floating properties, and drug release of the manufactured granules were investigated. Granules prepared by this method were spherical in shape and showed good flowability. The floating granules exhibited sustained release exceeding 10 h. Granule buoyancy (floating time and strength) and drug release properties were significantly influenced by formulation variables such as excipient type and concentration, and the physical characteristics (particle size, hydrophilicity) of the excipients. Drug release rate was increased by increasing the concentration of hydroxypropyl cellulose (HPC) and Gelucire 50/13, or by decreasing the particle size of HPC. Floating strength was improved through the incorporation of sodium bicarbonate and citric acid. Furthermore, floating strength was influenced by the concentration of HPC within the formulation. Granules prepared in this way show good physical characteristics, floating ability, and drug release properties when placed in simulated gastric fluid. Moreover, the drug release and floating properties can be controlled by modification of the ratio or physical characteristics of the excipients used in the formulation.

  13. Randomized controlled trial of a mobile phone intervention for improving adherence to naltrexone for alcohol use disorders.

    PubMed

    Stoner, Susan A; Arenella, Pamela B; Hendershot, Christian S

    2015-01-01

    Naltrexone is a front-line treatment for alcohol use disorders, but its efficacy is limited by poor medication adherence. This randomized controlled trial evaluated whether a mobile health intervention could improve naltrexone adherence. Treatment-seeking participants with an alcohol use disorder (N = 76) were randomized to intervention and control conditions. All participants received naltrexone (50 mg/day) with a medication event monitoring system (MEMS) and a prepaid smartphone, and received a daily text message querying medication side effects, alcohol use, and craving. Those in the intervention arm received additional medication reminders and adherence assessment via text message. The primary outcome, proportion of participants with adequate adherence (defined as ≥80% of prescribed doses taken through Week 8), did not differ between groups in intent-to-treat analyses (p = .34). Mean adherence at study midpoint (Week 4) was 83% in the intervention condition and 77% in the control condition (p = .35). Survival analysis found that the intervention group sustained adequate adherence significantly longer (M = 19 days [95% CI = 0.0-44.0]) than those in the control group (M = 3 days [95% CI = 0.0-8.1]) during the first month of treatment (p = .04). Medication adherence did not predict drinking outcomes. These results suggest that in the context of daily monitoring and assessment via cell phone, additional text message reminders do not further improve medication adherence. Although this initial trial does not provide support for the efficacy of text messaging to improve adherence to pharmacotherapy for alcohol use disorders, additional trials with larger samples and alternate designs are warranted. ClinicalTrials.gov: NCT01349985.

  14. Daunorubicin Hydrochloride and Cytarabine Liposome

    Cancer.gov

    This page contains brief information about daunorubicin hydrochloride and cytarabine liposome and a collection of links to more information about the use of this drug, research results, and ongoing clinical trials.

  15. Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial.

    PubMed

    Koren, Gideon; Clark, Shannon; Hankins, Gary D V; Caritis, Steve N; Umans, Jason G; Miodovnik, Menachem; Mattison, Donald R; Matok, Ilan

    2015-03-18

    Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo. We randomized women suffering from NVP to receive Diclegis® (n = 131) or placebo (n = 125) for 14 days at doses ranging from 2-4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing. Doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement. Doxylamine succinate-pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy. Clinical Trial Registration No: NCT00614445 .

  16. Guanfacine Extended Release in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Placebo-Controlled Trial

    ERIC Educational Resources Information Center

    Sallee, Floyd R.; McGough, James; Wigal, Tim; Donahue, Jessica; Lyne, Andrew; Biederman, Joseph

    2009-01-01

    A double-blind, 9-week, randomized trial was done to compare the efficacy of guanfacine extended release (GXR) with a placebo in treating children and adolescents with attention-deficit/hyperactivity disorders (ADHD). Results find a significant reduction in ADHD from baseline to endpoint for all daily doses of GXR which were measured at 1-, 2-,…

  17. A pharmaceutical industry perspective on the economics of treatments for alcohol and opioid use disorders

    PubMed Central

    Gastfriend, David R

    2014-01-01

    Individuals with alcohol and/or drug use disorders often fail to receive care, or evidence-based care, yet the literature shows health economic benefits. Comparative effectiveness research is emerging that examines approved approaches in terms of real, total healthcare cost/utilization. Comprehensive retrospective insurance claims analyses are few but tend to be nationally distributed and large. The emerging pattern is that, while treatment in general is cost effective, specific therapeutics can yield different health economic outcomes. Cost/utilization data consistently show greater savings with pharmacotherapies (despite their costs) versus psychosocial treatment alone. All FDA-approved addiction pharmacotherapies (oral naltrexone, extended-release naltrexone, acamprosate, disulfiram, buprenorphine, buprenorphine/naloxone, and methadone) are intended for use in conjunction with psychosocial management, not as stand-alone therapeutics; hence, pharmacotherapy costs must offer benefits in addition to abstinence alone or psychological therapy. Patient persistence is problematic, and (despite its cost) extended-release pharmacotherapy may be associated with lower or no greater total healthcare cost, mostly due to reduced hospitalization. The reviewed studies use rigorous case-mix adjustment to balance treatment cohorts but lack the randomization that clinical trials use to protect against confounding. Unlike trials, however, these studies can offer generalizability to diverse populations, providers, and payment models—and are of particular salience to payers. PMID:25236185

  18. Drug treatment of obesity: current status and future prospects.

    PubMed

    Kakkar, Ashish Kumar; Dahiya, Neha

    2015-03-01

    Obesity is a growing epidemic and a major contributor to the global burden of disease. Obesity strains the healthcare systems and has profound economic and psychosocial consequences. Historically, pharmacotherapy for obesity has witnessed the rise and fall of several promising drug candidates that had to be eventually withdrawn due to unacceptable safety concerns. Currently four drugs are approved for chronic weight management in obese adults: orlistat, lorcaserin, phentermine/topiramate extended release and naltrexone/bupropion extended release. While lorcaserin and phentermine/topiramate were approved by US Food and Drug Administration (FDA) in 2012, after a gap of 13 years following the licensing of orlistat, naltrexone/bupropion has been recently approved in 2014. This review provides a brief overview of these current therapeutic interventions available for management of obesity along with the evidence of their safety and efficacy. Additionally, several novel monotherapies as well as combination products are undergoing evaluation in various stages of clinical development. These therapies if proven successful will strengthen the existing armamentarium of antiobesity drugs and will be critical to combat the global public health crisis of obesity and its associated co-morbidities. Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  19. Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations.

    PubMed

    Lionberger, Robert A; Raw, Andre S; Kim, Stephanie H; Zhang, Xinyuan; Yu, Lawrence X

    2012-04-01

    FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times. Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem. Models were validated using in-house data submitted to the FDA. Using dissolution profiles expressed by the Weibull model as input for the CAT model, dissolution spaces were derived for simulated test formulations. The AUC(0-1.5) parameter was indicative of IR characteristics of early exposure and effectively distinguished among formulations that produced different pharmacodynamic effects. The AUC(1.5-t) parameter ensured equivalence with respect to the sustained release phase of Ambien CR. The variability of AUC(0-1.5) is higher than other PK parameters, but is reasonable for use in an equivalence test. In addition to the traditional PK parameters of AUCinf and Cmax, AUC(0-1.5) and AUC(1.5-t) are recommended to provide bioequivalence measures with respect to label indications for Ambien CR: onset of sleep and sleep maintenance.

  20. Low-dose naltrexone for disease prevention and quality of life.

    PubMed

    Brown, Norman; Panksepp, Jaak

    2009-03-01

    The use of low-dose naltrexone (LDN) for the treatment and prophylaxis of various bodily disorders is discussed. Accumulating evidence suggests that LDN can promote health supporting immune-modulation which may reduce various oncogenic and inflammatory autoimmune processes. Since LDN can upregulate endogenous opioid activity, it may also have a role in promoting stress resilience, exercise, social bonding, and emotional well-being, as well as amelioration of psychiatric problems such a autism and depression. It is proposed that LDN can be used effectively as a buffer for a large variety of bodily and mental ailments through its ability to beneficially modulate both the immune system and the brain neurochemistries that regulate positive affect.

  1. Acute kidney injury is common with intravenous abuse of extended-release oral oxymorphone and delayed renal recovery rates are associated with increased KDIGO staging.

    PubMed

    Bonnecaze, Alex K; Wilson, Matthew Whitaker; Dharod, Ajay; Fletcher, Alison; Miller, P J

    2017-08-12

    Prescription opioid abuse poses a serious problem in the United States, representing 615 per 100,000 deaths annually. Extended-release oxymorphone (Opana-ER) is an oral opioid pain medication that has recently been found to cause thrombotic microangiopathy when intravenously abused. In this retrospective study, prevalence and outcomes of AKI among patients intravenously abusing extended-release oral oxymorphone were analyzed. A query of electronic medical records for "drug abuse" at an academic medical center during January 2012 to December 2015 was performed and yielded 2350 patients. Patients were further identified by documented intravenous abuse of extended-release oxymorphone. Patients were stratified based on multiple renal indices and outcomes. Potential confounders were also identified. 165 patients were found to have a documented history of intravenous abuse of extended-release oral oxymorphone. Prevalence of AKI in this population was a 47.8%. KDIGO stage-I patients consisted of 17.8% of patients with AKI, 40.5% were classified as KDIGO stage-II AKI, and 41.8% were classified as KDIGO stage-III AKI. Among patients with AKI, average age was found to be 37.5 years, 59.4% experienced renal recovery, 56.9% required intensive care unit admission, 13.9% progressed to end-stage renal disease (ESRD), and 7.6% expired during admission. Clinicians should be educated to help recognize intravenous abuse of extended-release oral oxymorphone and its associated effects. Our data suggests AKI is common in these patients; higher KDIGO staging appears to be associated with slower rates of renal recovery, increased comorbidities and progression to both CKD and ESRD. This article is protected by copyright. All rights reserved.

  2. Development and Characterization of Novel Floating-Mucoadhesive Tablets Bearing Venlafaxine Hydrochloride.

    PubMed

    Misra, Raghvendra; Bhardwaj, Peeyush

    2016-01-01

    The present investigation is concerned about the development of floating bioadhesive drug delivery system of venlafaxine hydrochloride which after oral administration exhibits a unique combination of floating and bioadhesion to prolong gastric residence time and increase drug bioavailability within the stomach. The floating bioadhesive tablets were prepared by the wet granulation method using different ratios of hydroxypropyl methyl cellulose (HPMC K4MCR) and Carbopol 934PNF as polymers. Sodium bicarbonate (NaHCO3) and citric acid were used as gas (CO2) generating agents. Tablets were characterized for floating properties, in vitro drug release, detachment force, and swelling index. The concentration of hydroxypropyl methyl cellulose and Carbopol 934PNF significantly affects the in vitro drug release, floating properties, detachment force, and swelling properties of the tablets. The optimized formulation showed the floating lag time 72 ± 2.49 seconds and duration of floating 24.50 ± 0.74 hr. The in vitro release studies and floating behavior were studied in simulated gastric fluid (SGF) at pH 1.2. Different drug release kinetics models were also applied. The in vitro drug release from tablets was sufficiently sustained (more than 18 hr) and the Fickian transports of the drug from the tablets were confirmed. The radiological evidence suggests that the tablets remained buoyant and altered position in the stomach of albino rabbit and mean gastric residence time was prolonged (more than > 6 hr).

  3. Effects of Extended-Release Guanfacine on ADHD Symptoms and Sedation-Related Adverse Events in Children with ADHD

    ERIC Educational Resources Information Center

    Faraone, Stephen V.; Glatt, Stephen J.

    2010-01-01

    Objective: Guanfacine extended release (GXR) is a selective alpha[subscript 2A]-adrenoceptor agonist that is shown to be an effective nonstimulant treatment for the symptoms of attention-deficit/hyperactivity disorder. This report documents the time course and predictors of symptom efficacy and sedation-related adverse events (AEs) that emerge…

  4. Effects of Varenicline Alone and in Combination With Low-dose Naltrexone on Alcohol-primed Smoking in Heavy-drinking Tobacco Users: A Preliminary Laboratory Study.

    PubMed

    Roberts, Walter; Shi, Julia M; Tetrault, Jeanette M; McKee, Sherry A

    Heavy-drinking tobacco users are less likely to successfully quit smoking than their moderate-drinking counterparts, even when they are prescribed smoking cessation medication. One strategy for improving treatment outcomes in this subgroup of tobacco users may be to combine medication therapies to target both alcohol and tobacco use simultaneously. Adding naltrexone to frontline smoking cessation treatments may improve treatment outcomes in this group. This double-blind, placebo-controlled human laboratory study examined the effects of varenicline (2 mg/d) and varenicline (2 mg/d), combined with a low dose of naltrexone (25 mg/d) on alcohol-primed smoking behavior in a laboratory model of smoking relapse in heavy-drinking tobacco users (n = 30). Participants attended a laboratory session and received an alcohol challenge (target breath alcohol concentration = 0.030 g/dL). They completed a smoking delay task that assessed their ability to resist smoking followed by an ad libitum smoking phase (primary outcomes). They also provided ratings of subjective drug effects and craving, and carbon monoxide levels were measured after smoking (secondary outcomes). Participants receiving varenicline monotherapy delayed smoking longer and smoked fewer cigarettes than those on placebo. Participants receiving varenicline + low-dose naltrexone did not delay smoking longer than those receiving varenicline alone. Participants in both active medication arms smoked fewer cigarettes ad libitum than those receiving placebo. Varenicline can improve smoking outcomes even after an alcohol prime, supporting its use in heavy drinkers who wish to quit smoking. Findings did not support increased efficacy of combined varenicline + low-dose naltrexone relative to varenicline monotherapy.

  5. Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety.

    PubMed

    Dedic, Nina; Kühne, Claudia; Jakovcevski, Mira; Hartmann, Jakob; Genewsky, Andreas J; Gomes, Karina S; Anderzhanova, Elmira; Pöhlmann, Max L; Chang, Simon; Kolarz, Adam; Vogl, Annette M; Dine, Julien; Metzger, Michael W; Schmid, Bianca; Almada, Rafael C; Ressler, Kerry J; Wotjak, Carsten T; Grinevich, Valery; Chen, Alon; Schmidt, Mathias V; Wurst, Wolfgang; Refojo, Damian; Deussing, Jan M

    2018-06-01

    The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.

  6. Pharmacokinetic drug evaluation of extended release lorcaserin for the treatment of obesity.

    PubMed

    Hurren, Kathryn M; Dunham, Marissa W

    2017-08-01

    Lorcaserin is a serotonin 2C receptor antagonist that was FDA approved in 2012. Lorcaserin is recently available as an extended-release (ER) formulation for the treatment of obesity as an adjunct to lifestyle modification. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of lorcaserin ER will be reviewed. Expert opinion: Lorcaserin ER 20mg daily provides drug exposure bioequivalent to lorcaserin immediate release (IR) 10mg twice daily. Lorcaserin IR is associated with 3.3 and 3.0% placebo-subtracted weight loss in patients without and with diabetes, respectively. A1C was reduced by 0.9% in patients with diabetes. Common side effects include headache, dry mouth, constipation, dizziness, fatigue, and nausea. Lorcaserin provides potential advantages over other antiobesity medications in regards to tolerability and simplicity of medication initiation, but may not be as effective as other options. Lorcaserin ER offers improved ease of administration and anticipated adherence compared to the IR formulation. The place in therapy for lorcaserin ER and other antiobesity medications will be further clarified by results of pending clinical trials addressing cardiovascular outcomes as well as the role pharmacogenomics and comorbid disease states may play in choosing patient-specific therapy.

  7. Presynaptic Modulation of the Hippocampal Mossy Fiber Synapse.

    DTIC Science & Technology

    1992-09-14

    naltrexone . Quadazocine also reversed U-62,066E inhibition of the potassium-evoked release of L-glutamate, but not dynorphin B-like immunoreactivity. These...facilitation of Glu release by muscarine was dose -dependent and was antagonized by the prior application of atropine. The effects of a variety of...and naltrexone . Quadazocine also reversed U-62,066E inhibition of the potassium-evoked release of L-glutamate, but not dynorphin B-like immunoreac

  8. Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

    PubMed

    Tompkins, David Andrew; Lanier, Ryan K; Harrison, Joseph A; Strain, Eric C; Bigelow, George E

    2010-07-01

    Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed. Preclinical and clinical studies have shown that opioids combined with ultra-low-dose naltrexone (NTX) may have increased analgesic potency and have suggested reduced abuse or dependence liability. This study addressed whether addition of ultra-low-dose naltrexone might decrease the abuse liability of oxycodone (OXY) in humans. This double-blind, placebo-controlled study systematically examined the subjective and physiological effects of combining oral OXY and ultra-low NTX doses in 14 experienced opioid abusers. Seven acute drug conditions given at least 5 days apart were compared in a within-subject crossover design: placebo, OXY 20 mg, OXY 40 mg, plus each of the active OXY doses combined with 0.0001 and 0.001 mg NTX. The methods were sensitive to detecting opioid effects on abuse liability indices, with significant differences between all OXY conditions and placebo as well as between 20 and 40 mg OXY doses on positive subjective ratings (e.g., "I feel a good drug effect" or "I like the drug"), on observer- and participant-rated opioid agonist effects, and on a drug-versus-money value rating. There were no significant differences or evident trends associated with the addition of either NTX dose on any abuse liability indices. The addition of ultra-low-dose NTX to OXY did not decrease abuse liability of acutely administered OXY in experienced opioid abusers.

  9. Low dose naltrexone (LDN) enhances maturation of bone marrow dendritic cells (BMDCs).

    PubMed

    Meng, Jingjuan; Meng, Yiming; Plotnikoff, Nicholas P; Youkilis, Gene; Griffin, Noreen; Shan, Fengping

    2013-12-01

    It has been demonstrated previously that immune cell activation and proliferation were sensitive to the effects of naltrexone, a non-peptidic δ-opioid receptor selective antagonist and opioid receptors on BMDCs have been detected [1]. However, there is little prior data published on naltrexone and DCs. Therefore, we hypothesized that LDN could exert modulating effect on BMDCs. In present study, we studied influence of LDN on both phenotypic and functional maturation of BMDCs. Changes of BMDC post-treatment with LDN were evaluated using conventional light microscope and transmission electron microscopy (TEM); flow cytometry(FCM); cytochemistry; acid phosphatase activity(ACP) test; FITC-dextran bio-assay; mixed lymphocytes and enzyme-linked immunosorbent assay (ELISA). We have found that LDN enhances maturation of BMDCs as evidenced by 1) up-regulating the expression of MHC II, CD40, CD83, CD80 and CD86 molecules on BMDCs; 2) down-regulating the rates of pinocytosis and phagocytosis accompanied by the results of decreased ACP, and FITC-dextran bio-assay; 3) mounting potential of BMDCs to drive T cell; and 4) inducing secretion of higher levels of IL-12 and TNF-α. It is therefore concluded that LDN can efficiently promote the maturation of BMDCs via precise modulation inside and outside BMDCs. Our study has provided meaningful mode of action on the role of LDN in immunoregulation, and rationale on future application of LDN for enhancing host immunity in cancer therapy and potent use in the design of DC-based vaccines for a number of diseases.

  10. 21 CFR 520.1242c - Levamisole hydrochloride and piperazine dihydrochloride.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... an aqueous solution which contains in each fluid ounce 0.36 gram of levamisole hydrochloride and piperazine dihydrochloride equivalent to 3.98 grams of piperazine base. (2) The drug is a soluble powder which when reconstituted with water contains in each fluid ounce 0.45 gram of levamisole hydrochloride...

  11. 21 CFR 520.1242c - Levamisole hydrochloride and piperazine dihydrochloride.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... an aqueous solution which contains in each fluid ounce 0.36 gram of levamisole hydrochloride and piperazine dihydrochloride equivalent to 3.98 grams of piperazine base. (2) The drug is a soluble powder which when reconstituted with water contains in each fluid ounce 0.45 gram of levamisole hydrochloride...

  12. 21 CFR 520.1242c - Levamisole hydrochloride and piperazine dihydrochloride.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... an aqueous solution which contains in each fluid ounce 0.36 gram of levamisole hydrochloride and piperazine dihydrochloride equivalent to 3.98 grams of piperazine base. (2) The drug is a soluble powder which when reconstituted with water contains in each fluid ounce 0.45 gram of levamisole hydrochloride...

  13. Protopine hydrochloride.

    PubMed

    Dostál, J; Zák, Z; Necas, M; Slavík, J; Potácek, M

    2001-05-01

    Protopine hydrochloride (5,6,14,14a-tetrahydro-14a-hydroxy-7-methyl-8H-bis[1,3]benzodioxolo[5,6-a:4,5-g]quinolizinium chloride, C20H20NO5(+)-Cl(-)) is the salt of the isoquinoline alkaloid protopine. It is formed by the action of dilute hydrochloric acid on the protopine free base. The N-methyl and hydroxyl groups are in a trans configuration in the quinolizine ring and the central quinolizine N-C bond is unusually long [1.579 (2) A]. The crystal is a racemate.

  14. Extended release amoxicillin/clavulanate: optimizing a product for respiratory infections based on pharmacodynamic principles.

    PubMed

    Jacobs, Michael R

    2005-06-01

    Acute bacterial respiratory tract infections cause a great deal of human morbidity and mortality. Treatment guidelines for these infections include macrolides, doxycycline, beta-lactams and beta-lactam/beta-lactamase inhibitor combinations such as amoxicillin/clavulanic acid to provide coverage for the common respiratory pathogens, including penicillin and macrolide nonsusceptible Streptococcus pneumoniae, as well as beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis. In response to recent guidelines recommending higher dose amoxicillin to extend coverage to a higher percentage of S. pneumoniae, a new formulation of amoxicillin/clavulanic acid was developed. This formulation includes a higher amoxicillin dose, with part of the amoxicillin dose being in an extended release formulation, without increasing the clavulanate dose, for twice-daily oral treatment of these infections. Clinical studies of community-acquired pneumonia and acute rhinosinusitis have shown that the new formulation is well tolerated and highly efficacious, with clinical outcomes equivalent to comparators.

  15. In-Silico Analysis of Amotosalen Hydrochloride Binding to CD-61 of Platelets.

    PubMed

    Chaudhary, Hammad Tufail

    2016-11-01

    To determine the docking of Amotosalen hydrochloride (AH) at CD-61 of platelets, and to suggest the cause of bleeding in AH treated platelets transfusion. Descriptive study. Medical College, Taif University, Taif, Saudi Arabia, from October 2014 to May 2015. The study was carried out in-silico. PDB (protein data bank) code of Tirofiban bound to CD-61 was 2vdm. CD-61 was docked with Tirofiban using online docking tools, i.e. Patchdock and Firedock. Then, Amotosalen hydrochloride and CD-61 were also docked. Best docking poses to active sites of 2vdm were found. Ligplot of interactions of ligands and CD-61 were obtained. Then comparison of hydrogen bonds, hydrogen bond lengths, and hydrophobic bonds of 2vdm molecule and best poses of docking results were done. Patchdock and Firedock results of best poses were also analysed using SPSS version 16. More amino acids were involved in hydrogen and hydrophobic bonds in Patchdock and Firedock docking of Amotosalen hydrochloride with CD-61 than Patchdock and Firedock docking of CD-61 with Tirofiban. The binding energy was more in latter than former. Amotosalen hydrochloride binds to the active site of CD-61 with weaker binding force. Haemorrhage seen in Amotosalen hydrochloride-treated platelets might be due to binding of Amotosalen hydrochloride to CD-61.

  16. Presynaptic control of dopamine release by BETA-phenylethylamine

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zharikova, A.D.; Godukhin, O.V.

    The authors study the effect of extracellular ions (Ca/sup 2 +/, Na/sup 2 +/) on the beta-phenylethylamine (beta-PEA) releasing effect, dependence of this effect on the membrane potential of dopaminergic endings, and the participation of dopamine presynaptic autoreceptors in the realization of the effects of beta-PEA on dopamine (DA) release. Experi ments were carried out on noninbred male albino rats. By means of a microsyringe, (/sup 3/H)-DA hydrochloride was injected. The significance of the difference in levels of (/sup 3/H)-DA release during analogous periods of perfusion in the groups of animals compared was estimated by Student's test. These experiments inmore » vivo thus demonstrated the ability of beta-PEA to regulate DA release in different directions depending on the functional state of the dopaminergic neuron.« less

  17. Study on the syhthesis process of tetracaine hydrochloride

    NASA Astrophysics Data System (ADS)

    Li, Wenli; Zhao, Jie; Cui, Yujie

    2017-05-01

    Tetrachloride hydrochloride is a local anesthetic with long-acting ester, and it is usually present in the form of a hydrochloride salt. Firsleb first synthesized the tetracaine by experiment in 1928, which is one of the recognized clinical potent anesthetics. This medicine has the advantages of stable physical and chemical properties, the rapid role and long maintenance. Tetracaine is also used for ophthalmic surface anesthesia as one of the main local anesthetic just like conduction block anesthesia, mucosal surface anesthesia and epidural anesthesia. So far, the research mainly engaged in its clinical application research, and the research strength is relatively small in the field of synthetic technology. The general cost of the existing production process is high, and the yield is low. In addition, the reaction time is long and the reaction conditions are harsh. In this paper, a new synthetic method was proposed for the synthesis of tetracaine hydrochloride. The reaction route has the advantages of few steps, high yield, short reaction time and mild reaction conditions. The cheap p-nitrobenzoic acid was selected as raw material. By esterification with ethanol and reaction with n-butyraldehyde (the reaction process includes nitro reduction, aldol condensation and hydrogenation reduction), the intermediate was transesterified with dimethylaminoethanol under basic conditions. Finally, the PH value was adjusted in the ethanol solvent. After experiencing 4 steps reaction, the crude tetracaine hydrochloride was obtained.

  18. Varenicline, low dose naltrexone, and their combination for heavy-drinking smokers: human laboratory findings.

    PubMed

    Ray, Lara A; Courtney, Kelly E; Ghahremani, Dara G; Miotto, Karen; Brody, Arthur; London, Edythe D

    2014-10-01

    Heavy-drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available. The present study used a double-blind, randomized, 2 × 2 medication design, testing varenicline alone (VAR; 1 mg twice daily), low dose naltrexone alone (L-NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on cigarette craving and subjective response to alcohol and cigarettes in a sample (n = 130) of heavy-drinking daily smokers (≥10 cigarettes/day). All participants were tested after a 9-day titration period designed to reach a steady state on the target medication. Testing was completed at 12 h of nicotine abstinence, after consuming a standard dose of alcohol (target breath alcohol concentration = 0.06 g/dl) and after smoking the first cigarette of the day. The combination of VAR + L-NTX was superior to placebo, and at times superior to monotherapy, in attenuating cigarette craving, cigarette and alcohol "high," and in reducing ad-lib consumption of both cigarettes and alcohol during the 9-day medication titration period. These preliminary findings indicate that clinical studies of the combination of VAR + L-NTX for heavy drinkers trying to quit smoking are warranted and may ultimately improve clinical care for this sizeable and treatment-resistant subgroup of smokers.

  19. Effect of food on early drug exposure from extended-release stimulants: results from the Concerta, Adderall XR Food Evaluation (CAFE) Study.

    PubMed

    Auiler, J F; Liu, K; Lynch, J M; Gelotte, C K

    2002-01-01

    Stimulant therapy is the mainstay of treatment for children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). Once-daily, extended-release oral formulations offer long acting control of symptoms by modifying drug delivery and absorption. In particular, consistency in early drug exposure is important for symptom control during school or work hours. Because these once-daily formulations are usually taken in the morning, the timing of the doses with breakfast is important. This study compared the effect of a high-fat breakfast on early drug exposure from a morning dose of two extended-release stimulant formulations: the osmotic-controlled OROS tablet of methylphenidate HCI (CONCERTA) and the capsule containing extended-release beads of mixed amphetamine salts (ADDERALL XR). The study had a single-dose, open-label, randomised, four-treatment, crossover design in which healthy subjects received either 36 mg CONCERTA or 20 mg ADDERALL XR in the morning after an overnight fast or a high-fat breakfast. Serial blood samples were collected over 28h to determine plasma concentrations of methylphenidate and amphetamine. The food effect on early drug exposure and the pharmacokinetic profiles up to 8 h after dosing of the two extended-release stimulants were directly compared using partial area (AUC(p4h), AUC(p6h) and AUC(p8h)) fed/fasted ratios. Amphetamine concentrations were markedly lower when the subjects had eaten breakfast, resulting in lower early drug exposures (p < 0.0001). By contrast, methylphenidate concentrations over the same 8 h were unaffected by breakfast, providing consistent levels of early drug exposure. Therefore, as a child's or adult's eating pattern varies, methylphenidate exposure over the first 8 h would be expected to have less day-to-day variation compared with amphetamine exposure. The osmotic-controlled OROS tablet provides a reliable and consistent delivery of methylphenidate HCI, independent of food, for patients with

  20. Postpartum immobilization of adult female moose using xylazine, ketamine and yohimbine hydrochlorides.

    PubMed

    Garner, D L; Addison, E M

    1994-01-01

    Twenty-two free-ranging adult female moose (Alces alces) were immobilized with a 1:4 mixture of xylazine hydrochloride (XH) and ketamine hydrochloride (KH). Mean (SD) dosages/animal for XH and KH were 419 (148) and 1565 (433) mg, respectively. Mean (SD) induction time was 18.4 (9.7) minutes. Reversal with yohimbine hydrochloride using a mean dosage of 83 mg/animal resulted in a mean (SD) recovery time of 22.8 (28.5) minutes.