Daily Average Consumption of 2 Long-Acting Opioids: An Interrupted Time Series Analysis

PubMed Central

Puenpatom, R. Amy; Szeinbach, Sheryl L.; Ma, Larry; Ben-Joseph, Rami H.; Summers, Kent H.

2012-01-01

Background Oxycodone controlled release (CR) and oxymorphone extended release (ER) are frequently prescribed long-acting opioids, which are approved for twice-daily dosing. The US Food and Drug Administration approved a reformulated crush-resistant version of oxycodone CR in April 2010. Objective To compare the daily average consumption (DACON) for oxycodone CR and for oxymorphone ER before and after the introduction of the reformulated, crush-resistant version of oxycodone CR. Methods This was a retrospective claims database analysis using pharmacy claims from the MarketScan database for the period from January 2010 through March 2011. The interrupted time series analysis was used to evaluate the impact of the introduction of reformulated oxycodone CR on the DACON of the 2 drugs—oxycodone CR and oxymorphone ER. The source of the databases included private-sector health data from more than 150 medium and large employers. All prescription claims containing oxycodone CR and oxymorphone ER dispensed to members from January 1, 2010, to March 31, 2011, were included in the analysis. Prescription claims containing duplicate National Drug Codes, missing member identification, invalid quantities or inaccurate days supply of either drug, and DACON values of <1 and >500 were removed. Results The database yielded 483,063 prescription claims for oxycodone CR and oxymorphone ER from January 1, 2010, to March 31, 2011. The final sample consisted of 411,404 oxycodone CR prescriptions (traditional and reformulated) dispensed to 85,150 members and 62,656 oxymorphone ER prescriptions dispensed to 11,931 members. Before the introduction of reformulated oxycodone CR, DACON values for the highest strength available for each of the 2 drugs were 0.51 tablets higher for oxycodone CR than for oxymorphone ER, with mean DACON values of 3.5 for oxycodone CR and 3.0 for oxymorphone ER (P <.001). The differences of mean DACON between the 2 drugs for all lower strengths were 0.46 tablets, with mean DACON values of 2.7 for oxycodone CR and 2.3 for oxymorphone ER (P <.001). After the introduction of the new formulation, the difference in mean DACON between the 2 drugs was slightly lower: 0.45 tablets for the highest-strength and 0.40 tablets for the lower-strength pairs. Regression analyses showed that the immediate and overall impact of the reformulation of oxycodone CR on the DACON of oxycodone CR was minimal, whereas no changes were seen in the DACON of oxymorphone ER. The estimated DACON for oxycodone CR decreased by 0.1 tablets, or 3.7% (P <.001), 6 months after the new formulation was introduced. Conclusion The mean DACON was 0.4 tablets per day higher for oxycodone CR compared with oxymorphone ER for all dosage strengths for the entire study period. After the introduction of the reformulated oxycodone CR, the DACON for this drug was slightly mitigated; however, there was a minimal impact on the mean differences between oxycodone CR and oxymorphone ER. PMID:24991311

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.

Prescription histories and dose strengths associated with overdose deaths.

PubMed

Hirsch, Anne; Proescholdbell, Scott K; Bronson, William; Dasgupta, Nabarun

2014-07-01

Misuse, abuse, and diversion of prescription drugs are large and growing public health problems that have resulted in an overdose epidemic. We investigated whether short-acting or extended-release opioids were more frequently prescribed to those who died of an overdose and whether there was a linear relationship between dose strength and associated overdose deaths. The study population was North Carolina residents in 2010. We conducted a retrospective, population-based, descriptive study of medication histories of overdose decedents using data from vital statistics, medical examiner records, and a prescription drug monitoring program. Unintentional or undetermined drug overdoses were responsible for 892 deaths. Out of 191 deaths involving methadone, only two were patients in opioid treatment programs. Immediate-release oxycodone was involved in the greatest number of opioid-related deaths. Out of 221 oxycodone deaths, 134 (61%) of the decedents filled a prescription for oxycodone in the 60 days prior to death. The most common strength dispensed within 60 days to a decedent who died of an oxycodone overdose was 10 mg for immediate-release (72 prescriptions). Immediate-release oxycodone products (rho = 1.00, P < 0.01) and extended-release fentanyl products (rho = 1.00, P < 0.01) showed strong increasing linear trends between dose strength and proportion of prescriptions dispensed to decedents. A significant proportion of overdose decedents had been prescribed the same type of drugs that contributed to their death, especially for decedents who died from overdoses involving oxycodone, hydrocodone, and alprazolam. Higher dose strengths for certain opioids had higher associated mortality, and certain immediate-release opioids may be considered for public health prevention efforts.

[Conversion ratio between intravenous oxycodone/hydrocotarnine and sustained-release oral oxycodone in patients with cancer pain].

PubMed

Kokubun, Hideya; Nakamura, Kazuyo; Fukawa, Misako; Matoba, Motohiro; Hoka, Sumio; Yago, Kazuo

2007-12-01

The demand for oxycodone increases in the treatment of patients with cancer pain, but there is no injection formulation containing oxycodone as a single ingredient in Japan. Instead, we have an oxycodone/hydrocotarnine compound product. Long ago, hydrocotarnine was added to enhance the analgesic effect of oxycodone. However, the mechanism of hydrocotarnine is unclear, and few studies have mentioned the conversion ratio between intravenous and oral oxycodone. In the present study, in order to define the conversion ratio between them, we investigated 18 patients treated by intravenous or oral oxycodone and changed to another administration route during their treatment. We surveyed the change in pain level and adverse effects before and after changing the administration route. The conversion ratio from oral oxycodone to intravenous oxycodone/hydrocotarnine was 0.71+/-0.12 (mean+/-S. D.), and no obvious change in adverse effect was observed.

Oxycodone for cancer-related pain.

PubMed

Schmidt-Hansen, Mia; Bennett, Michael I; Arnold, Stephanie; Bromham, Nathan; Hilgart, Jennifer S

2015-02-27

Many patients with cancer experience moderate to severe pain that requires treatment with strong opioids, of which oxycodone and morphine are examples. Strong opioids are, however, not effective for pain in all patients, nor are they well-tolerated by all patients. The aim of this review was to assess whether oxycodone is associated with better pain relief and tolerability than other analgesic options for patients with cancer pain. To assess the effectiveness and tolerability of oxycodone for pain in adults with cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE and MEDLINE In-Process (Ovid), EMBASE (Ovid), Science Citation Index, Conference Proceedings Citation Index - Science (ISI Web of Science), BIOSIS (ISI), PsycINFO (Ovid) and PubMed to March 2014. We also searched Clinicaltrials.gov, metaRegister of Controlled Trials (mRCT), EU Clinical Trials Register and World Health Organization International Clinical Trials Registry Platform (ICTRP). We checked the bibliographic references of relevant identified studies and contacted the authors of the included studies to find additional trials not identified by the electronic searches. No language, date or publication status restrictions were applied to the search. We included randomised controlled trials (parallel-group or cross-over) comparing oxycodone (any formulation or route of administration) with placebo or an active drug (including oxycodone) for cancer background pain in adults. Two authors independently extracted study data (study design, participant details, interventions and outcomes) and independently assessed the quality of the included studies according to standard Cochrane methodology. Where possible, we meta-analysed the pain intensity data using the generic inverse variance method, otherwise these data were summarised narratively along with the adverse event and patient preference data. The overall quality of the evidence for each outcome was assessed according to the GRADE approach. We included 17 studies which enrolled/randomised 1390 patients with 1110 of these analysed for efficacy and 1170 for safety. The studies examined a number of different drug comparisons. Four studies compared controlled release (CR) oxycodone to immediate release (IR) oxycodone and pooled analysis of three of these studies showed that the effects of CR and IR oxycodone on pain intensity after treatment were similar (standardised mean difference (SMD) 0.1, 95% confidence interval (CI) -0.06 to 0.26; low quality evidence). This was in line with the finding that none of the included studies reported differences in pain intensity between the treatment groups. Three of the four studies also found similar results for treatment acceptability and adverse events in the IR and CR groups; but one study reported that, compared to IR oxycodone, CR oxycodone was associated with significantly fewer adverse events.Six studies compared CR oxycodone to CR morphine and pooled analysis of five of these studies indicated that pain intensity did not differ significantly between the treatments (SMD 0.14, 95% CI -0.04 to 0.32; low quality evidence). There were no marked differences in adverse event rates, treatment acceptability or quality of life ratings.The remaining seven studies either compared oxycodone in various formulations or compared oxycodone to different alternative opioids. None of them found any clear superiority or inferiority of oxycodone for cancer pain, neither as an analgesic agent nor in terms of adverse event rates and treatment acceptability.The quality of this evidence base was limited by the risk of bias of the studies and by small sample sizes for many outcomes. Random sequence generation and allocation concealment were under-reported, and the results were substantially compromised by attrition with data missing from more than 20% of the enrolled/randomised patients for efficacy and from more than 15% for safety. Overall, the data included within this review suggest that oxycodone offers similar levels of pain relief and adverse events to other strong opioids including morphine, which is commonly considered the gold standard strong opioid. Our conclusions are consistent with other recent reviews and suggest that while the reliability of the evidence base is low, given the absence of important differences within this analysis it seems unlikely that larger head to head studies of oxycodone versus morphine will be justified. This means that for clinical purposes oxycodone or morphine can be used as first line oral opioids for relief of cancer pain.

Prolonged-Release Oxycodone/Naloxone Improves Anal Sphincter Relaxation Compared to Oxycodone Plus Macrogol 3350.

PubMed

Poulsen, Jakob Lykke; Brock, Christina; Grønlund, Debbie; Liao, Donghua; Gregersen, Hans; Krogh, Klaus; Drewes, Asbjørn Mohr

2017-11-01

Opioid analgesics inhibit anal sphincter function and contribute to opioid-induced bowel dysfunction (OIBD). However, it is unknown whether the inhibition can be reduced by opioid antagonism with prolonged-release (PR) naloxone and how this compares to laxative treatment. To compare the effects of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350 on anal sphincter function and gastrointestinal symptoms. A randomized, double-blind, crossover trial was conducted in 20 healthy men. Participants were treated for 5 days with combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Resting anal pressure, anal canal distensibility, and relaxation of the internal sphincter to rectal distension were evaluated before treatment (baseline) and on day 5. The Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire, stool frequency, and stool consistency were assessed daily. Both PR oxycodone/naloxone and PR oxycodone plus macrogol treatment decreased sphincter relaxation compared to baseline (- 27.5%; P < 0.001 and - 14.7%; P = 0.01). However, sphincter relaxation was increased after PR naloxone/oxycodone treatment compared to macrogol (difference = + 17.6%; P < 0.001). Resting anal pressure and anal canal distensibility did not differ between treatments. PAC-SYM abdominal symptoms score was lower during PR naloxone compared to macrogol (0.2 vs. 3.2; P = 0.002). The number of bowel movements was lower during PR naloxone versus macrogol (4.2 vs. 5.4; P = 0.035). Relaxation of the internal anal sphincter was significantly better after PR oxycodone/naloxone treatment compared to PR oxycodone plus macrogol 3350. These findings highlight that OIBD may require specific therapy against the complex, pan-intestinal effects of opioids.

77 FR 41415 - Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-13

... INFORMATION CONTACT: Astrid Lopez-Goldberg, Center for Drug Evaluation and Research, Food and Drug... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0563] Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration and...

Reformulation of controlled-release oxycodone and pharmacy dispensing patterns near the US-Canada border.

PubMed

Gomes, Tara; Paterson, J Michael; Juurlink, David N; Dhalla, Irfan A; Mamdani, Muhammad M

2012-01-01

In August 2010, a tamper-resistant formulation of controlled-release oxycodone (OxyContin-OP) was introduced in the United States but not in Canada. Our objective was to determine whether introduction of OxyContin-OP in the United States influenced prescription volumes for the original controlled-release oxycodone formulation (OxyContin) at Canadian pharmacies near the international border. We conducted a population-based, serial, cross-sectional study of prescriptions dispensed from pharmacies in the 3 cities with the highest volume of US-Canada border crossings in Ontario: Niagara Falls, Windsor and Sarnia. We analyzed data on all outpatient prescriptions for OxyContin dispensed by Canadian pharmacies near each border crossing between 2010 Apr. 1 and 2012 Feb. 29. We calculated and compared monthly prescription rates, adjusted per 1000 population and stratified by tablet strength. The number of tablets dispensed near 4 border crossings in the 3 Canadian cities remained stable over the study period. However, the rate of dispensing at pharmacies near the Detroit-Windsor Tunnel increased roughly 4-fold between August 2010 and February 2011, from 505 to 1969 tablets per 1000 population. By April 2011, following warnings to prescribers and pharmacies regarding drug-seeking behaviour, the dispensing rate declined to 1683 tablets per 1000 population in this area. By November 2011, the rate had returned to levels observed in early 2010. Our analyses suggest that 242 075 excess OxyContin tablets were dispensed near the Detroit-Windsor Tunnel between August 2010 and October 2011. Prescribing of the original formulation of controlled-release oxycodone rose substantially near a major international border crossing following the introduction of a tamper-resistant formulation in the United States. It is possible that the restriction of this finding to the area surrounding the Detroit-Windsor Tunnel reflects specific characteristics of this border crossing, including its high traffic volume, direct access to the downtown core and drug-trafficking patterns in the Detroit area. Our findings highlight the potential impact of cross-border differences in medication availability on drug-seeking behaviour.

Synthetic Geopolymers for Controlled Delivery of Oxycodone: Adjustable and Nanostructured Porosity Enables Tunable and Sustained Drug Release

PubMed Central

Forsgren, Johan; Pedersen, Christian; Strømme, Maria; Engqvist, Håkan

2011-01-01

In this article we for the first time present a fully synthetic mesoporous geopolymer drug carrier for controlled release of opioids. Nanoparticulate precursor powders with different Al/Si-ratios were synthesized by a sol-gel route and used in the preparation of different geopolymers, which could be structurally tailored by adjusting the Al/Si-ratio and the curing temperatures. In particular, it was shown that the pore sizes of the geopolymers decreased with increasing Al/Si ratio and that completely mesoporous geopolymers could be produced from precursor particles with the Al/Si ratio 2∶1. The mesoporosity was shown to be associated with a sustained and linear in vitro release profile of the opioid oxycodone. A clinically relevant release period of about 12 h was obtained by adjusting the size of the pellets. The easily fabricated and tunable geopolymers presented in this study constitute a novel approach in the development of controlled release formulations, not only for opioids, but whenever the clinical indication is best treated with a constant supply of drugs and when the mechanical stability of the delivery vehicle is crucial. PMID:21423616

Cost-effectiveness analysis of oxycodone with naloxone versus oxycodone alone for the management of moderate-to-severe pain in patients with opioid-induced constipation in Canada.

PubMed

Goeree, Ron; Goeree, Jeff

2016-01-01

Approximately 20-30% of Canadians suffer from chronic pain. Guidelines for the management of chronic pain support the use of controlled-release (CR) opioids to treat chronic pain. Although effective in managing chronic pain, oxycodone is associated with high rates of opioid-induced constipation (OIC). The cost-effectiveness of a combination of oxycodone for the management of pain and naloxone for the relief of OIC has not previously been evaluated for Canada. A decision analytic model was developed to estimate the cost-utility of combination oxycodone/naloxone compared to oxycodone alone in four populations. Drug costs for managing pain and healthcare costs related to managing OIC were included in the analysis and the primary measure of effectiveness was quality adjusted life years (QALYs) derived from OIC rates observed in clinical trials. The analysis was conducted from a healthcare system perspective, used a 1-year time horizon, and results were expressed in 2015 Canadian dollars. In all four patient populations, there was a trade-off between slightly higher total expected costs for Targin treated patients compared to oxycodone treated patients, but also improved clinical benefits in terms of reduced OIC, which resulted in higher QALYs for patients. Although analgesic costs were found to be slightly higher for Targin treated patients, Targin also resulted in cost offsets to the healthcare system in terms of less rescue laxative drug use and other resources required for the management of OIC. The resulting 1-year cost-utility of Targin compared to oxycodone ranged from $2178-$7732 per QALY gained in the base case analysis, and it was found that these cost-utility results remained robust and at low values throughout a series of one-way deterministic analyses of uncertainty. The clinical effectiveness of oxycodone/naloxone in managing pain and OIC compared to CR oxycodone alone resulted in low cost-utility estimates.

An abuse-deterrent, microsphere-in-capsule formulation of extended-release oxycodone: alternative modes of administration to facilitate pain management in patients with dysphagia.

PubMed

McCarberg, Bill H; Kopecky, Ernest A; O'Connor, Melinda; Marseilles, Ann; Varanasi, Ravi K; Thompson, Christy; Fleming, Alison B

2016-12-01

Patients with chronic pain may experience difficulty swallowing, in part due to worsening disease, comorbid conditions, iatrogenic etiology, or age. Patients or caregivers may manipulate extended-release (ER) opioid formulations to facilitate oral dosing due to a lack of therapeutic options that allow for sprinkle or enteral feeding tube administration. If crushed or broken, current oral ER opioids can be associated with adverse sequelae, including risk of potentially fatal overdose. To review the safety, in vitro dissolution data, and in vivo pharmacokinetic data that support alternative modes of administration of oxycodone DETERx (Xtampza ER) via sprinkling onto soft foods for oral ingestion or via enteral feeding tubes. A review of oxycodone DETERx data from in vitro and in vivo studies was conducted to demonstrate support for alternative routes and modes of administration. There was no difference in the dissolution profile when administered with various soft foods or when mixed with various liquid vehicles and administered via nasogastric (NG) or gastrostomy (G) tubes, based on in vitro studies. When sprinkled onto applesauce and administered orally, the microspheres were bioequivalent to the intact oxycodone capsules. When crushed or chewed, the formulation maintained its pharmacokinetic profile; no bolus dose of opioid was released. The sprinkle-dose study was limited by the single-dose study design, as well as the small sample size. Oxycodone DETERx is the first ER oxycodone formulation that can be administered either intact, sprinkled onto soft foods, or via NG/G tubes, thereby providing options for treating pain in patients who have difficulty swallowing.

The effects of analgesics on central processing of tonic pain: A cross-over placebo controlled study.

PubMed

Lelic, Dina; Hansen, Tine M; Mark, Esben B; Olesen, Anne E; Drewes, Asbjørn M

2017-09-01

Opioids and antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) are recognized as analgesics to treat moderate to severe pain, but the central mechanisms underlying their analgesia remain unclear. This study investigated how brain activity at rest and exposed to tonic pain is modified by oxycodone (opioid) and venlafaxine (SNRI). Twenty healthy males were included in this randomized, cross-over, double-blinded study. 61-channel electroencephalogram (EEG) was recorded before and after five days of treatment with placebo, oxycodone (10 mg extended release b.i.d) or venlafaxine (37.5 mg extended release b.i.d) at rest and during tonic pain (hand immersed in 2 °C water for 80 s). Subjective pain and unpleasantness scores of tonic pain were recorded. Spectral analysis and sLORETA source localization were done in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta1 (12-18 Hz) and beta2 (18-32 Hz) frequency bands. Oxycodone decreased pain and unpleasantness scores (P < 0.05), whereas venlafaxine decreased the pain scores (P < 0.05). None of the treatments changed the spectral indices or brain sources underlying resting EEG. Venlafaxine decreased spectral indices in alpha band of the EEG to tonic pain, whereas oxycodone decreased the spectral indices and brain source activity in delta and theta frequency bands (all P < 0.05). The brain source activity predominantly decreased in the insula and inferior frontal gyrus. The decrease of activity within insula and inferior frontal gyrus is likely involved in pain inhibition due to oxycodone treatment, whereas the decrease in alpha activity is likely involved in pain inhibition due to venlafaxine treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Randomized, Double-Blind, Double-Dummy Study to Evaluate the Intranasal Human Abuse Potential and Pharmacokinetics of a Novel Extended-Release Abuse-Deterrent Formulation of Oxycodone

PubMed Central

Kopecky, Ernest A.; Smith, Michael D.; Fleming, Alison B.

2016-01-01

Objective. Evaluate the human abuse potential (HAP) of an experimental, microsphere-in-capsule formulation of extended-release oxycodone (oxycodone DETERx®) (herein “DETERx”). Design. Randomized, double-blind, double-dummy, positive- and placebo-controlled, single-dose, four-phase, four-treatment, crossover study. Setting. Clinical research site. Subjects. There were 39 qualifying subjects (72% male, 85% white, mean age of 27 years) with 36 completing all four Double-blind Treatment Periods. Methods. The four phases encompassed: 1) Screening; 2) Drug Discrimination; 3) Double-blind Treatment; and 4) Follow-up. Drug Discrimination tests ensured that subjects could distinguish placebo from opioid. The four Double-blind Treatments compared DETERx—administered as either a crushed intranasal (IN) or an intact oral (PO) preparation—with immediate-release oxycodone IN (OXY-IR IN) and with an intact IN and PO placebo DETERx control. Results. For primary pharmacokinetic (PK) assessments, abuse quotient (Cmax/Tmax) was lower with DETERx IN than DETERx PO; both treatments were substantially lower than OXY-IR IN (6.24, 8.60, and 69.6 ng/mL/h, respectively). For drug liking, the primary subjective pharmacodynamic (PD) endpoint, both DETERx IN and DETERx PO produced significantly lower scores than OXY-IR IN (P ≤ 0.0001 for each); DETERx IN was less liked than DETERx PO (P ≤ 0.05), mirroring the PK relationships. Objectively assessed pupillometry corroborated the more rapid and significantly greater effect of OXY-IR IN than either DETERx IN or DETERx PO (P ≤ 0.007 for each). Overall safety profiles of DETERx and OXY-IR were comparable and both were well tolerated. Conclusions. Pharmacokinetic and pharmacodynamic outcomes suggest that DETERx IN has relatively low HAP; continued research in larger populations is suggested. PMID:26814256

Person-level changes in oxycodone use after the introduction of a tamper-resistant formulation in Australia

PubMed Central

Buckley, Nicholas A.; Degenhardt, Louisa; Larance, Briony; Cairns, Rose; Dobbins, Timothy A.; Pearson, Sallie-Anne

2018-01-01

BACKGROUND: Australia introduced tamper-resistant controlled-release (CR) oxycodone in April 2014. We quantified the impact of the reformulation on dispensing, switching and poisonings. METHODS: We performed interrupted time-series analyses using population-representative national dispensing data from 2012 to 2016. We measured dispensing of oxycodone CR (≥ 10 mg), discontinuation of use of strong opioids and switching to other strong opioids after the reformulation compared with a historical control period. Similarly, we compared calls about intentional opioid poisoning using data from a regional poisons information centre. RESULTS: After the reformulation, dispensing decreased for 10–30 mg (total level shift −11.1%, 95% confidence interval [CI], −17.2% to −4.6%) and 40–80 mg oxycodone CR (total level shift −31.5%, 95% CI −37.5% to −24.9%) in participants less than 65 years of age but was unchanged in people 65 years of age or older. Compared with the previous year, discontinuation of use of strong opioids did not increase (adjusted hazard ratio [HR] 0.95, 95% CI 0.91 to 1.00), but switching to oxycodone/naloxone did increase (adjusted HR 1.54, 95% CI 1.32 to 1.79). Switching to morphine varied by age (p < 0.001), and the greatest increase was in participants less than 45 years of age (adjusted HR 4.33, 95% CI 2.13 to 8.80). Participants switching after the reformulation were more likely to be dispensed a tablet strength of 40 mg or more (adjusted odds ratio [OR] 1.40, 95% CI 1.09 to 1.79). Calls for intentional poisoning that involved oxycodone taken orally increased immediately after the reformulation (incidence rate ratio (IRR) 1.31, 95% CI 1.05–1.64), but there was no change for injected oxycodone. INTERPRETATION: The reformulation had a greater impact on opioid access patterns of people less than 65 years of age who were using higher strengths of oxycodone CR. This group has been identified as having an increased risk of problematic opioid use and warrants closer monitoring in clinical practice. PMID:29581162

Person-level changes in oxycodone use after the introduction of a tamper-resistant formulation in Australia.

PubMed

Schaffer, Andrea L; Buckley, Nicholas A; Degenhardt, Louisa; Larance, Briony; Cairns, Rose; Dobbins, Timothy A; Pearson, Sallie-Anne

2018-03-26

Australia introduced tamper-resistant controlled-release (CR) oxycodone in April 2014. We quantified the impact of the reformulation on dispensing, switching and poisonings. We performed interrupted time-series analyses using population-representative national dispensing data from 2012 to 2016. We measured dispensing of oxycodone CR (≥ 10 mg), discontinuation of use of strong opioids and switching to other strong opioids after the reformulation compared with a historical control period. Similarly, we compared calls about intentional opioid poisoning using data from a regional poisons information centre. After the reformulation, dispensing decreased for 10-30 mg (total level shift -11.1%, 95% confidence interval [CI], -17.2% to -4.6%) and 40-80 mg oxycodone CR (total level shift -31.5%, 95% CI -37.5% to -24.9%) in participants less than 65 years of age but was unchanged in people 65 years of age or older. Compared with the previous year, discontinuation of use of strong opioids did not increase (adjusted hazard ratio [HR] 0.95, 95% CI 0.91 to 1.00), but switching to oxycodone/naloxone did increase (adjusted HR 1.54, 95% CI 1.32 to 1.79). Switching to morphine varied by age ( p < 0.001), and the greatest increase was in participants less than 45 years of age (adjusted HR 4.33, 95% CI 2.13 to 8.80). Participants switching after the reformulation were more likely to be dispensed a tablet strength of 40 mg or more (adjusted odds ratio [OR] 1.40, 95% CI 1.09 to 1.79). Calls for intentional poisoning that involved oxycodone taken orally increased immediately after the reformulation (incidence rate ratio (IRR) 1.31, 95% CI 1.05-1.64), but there was no change for injected oxycodone. The reformulation had a greater impact on opioid access patterns of people less than 65 years of age who were using higher strengths of oxycodone CR. This group has been identified as having an increased risk of problematic opioid use and warrants closer monitoring in clinical practice. © 2018 Joule Inc. or its licensors.

Effects of dextromethorphan and oxycodone on treatment of neuropathic pain in mice.

PubMed

Yang, Pao-Pao; Yeh, Geng-Chang; Huang, Eagle Yi-Kung; Law, Ping-Yee; Loh, Horace H; Tao, Pao-Luh

2015-09-22

Neuropathic pain is a very troublesome and difficult pain to treat. Although opioids are the best analgesics for cancer and surgical pain in clinic, only oxycodone among opioids shows better efficacy to alleviate neuropathic pain. However, many side effects associated with the use of oxycodone render the continued use of it in neuropathic pain treatment undesirable. Hence, we explored whether dextromethorphan (DM, a known N-methyl-D-aspartate receptor antagonist with neuroprotective properties) could potentiate the anti-allodynic effect of oxycodone and underlying mechanisms regarding to glial cells (astrocytes and microglia) activation and proinflammatory cytokines release in a spinal nerve injury (SNL) mice model. Oxycodone produced a dose-dependent anti-allodynic effect. Co-administration of DM at a dose of 10 mg/kg (i.p.) (DM10) which had no anti-allodynic effect by itself enhanced the acute oxycodone (1 mg/kg, s.c.) effect. When the chronic anti-allodynic effects were examined, co-administration of DM10 also significantly enhanced the oxycodone effect at 3 mg/kg. Furthermore, oxycodone decreased SNL-induced activation of glial cells (astrocytes and microglia) and plasma levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α). Co-administration of DM10 potentiated these effects of oxycodone. The combined use of DM with oxycodone may have therapeutic potential for decreasing the effective dose of oxycodone on the treatment of neuropathic pain. Attenuation of the glial activation and proinflammatory cytokines in the spinal cord may be important mechanisms for these effects of DM.

[Solutions for the clinical problems of analgesics for cancer pain treatment in Japan].

PubMed

Kokubun, Hideya; Matoba, Motohiro; Yamada, Yasuhiko; Yago, Kazuo

2011-01-01

The pain experienced by cancer patients can be managed in 70-90% of cases by the World Health Organisation protocol for cancer pain. However, cancer pain treatment in Japan is not sufficiently effective. To use medicine safely and effectively, various problems must be solved. Therefore, in this study, appropriate usage of cancer pain treatment was examined. We were able to use acetaminophen suppositories (800 mg each) in cancer pain patients. It was suggested that high serum concentrations of oxycodone and hydrocotarnine might be observed in geriatric patients or in the state of decreased hepatic blood flow, making dose adjustment is necessary for such patients. We also clarified that the conversion ratio from oral oxycodone to intravenous ocycodone/hydrocotarnine was 0.71±0.12. In addition, we clarified the pharmacokinetics of controlled-release oxycodone in patients with cancer pain. Moreover, the findings of our study indicate that in the steady state, the serum concentrations of fentanyl are not maintained at a constant level for 3 days following the use of transdermal fentanyl. We established a method of appropriately passing a nasal duct for sustained release of fine granules of morphine sulfate. Resolution of the clinical problems associated with cancer pain treatments is anticipated to allow the proper use of cancer pain treatments in Japan.

Comparison of opioid doctor shopping for tapentadol and oxycodone: a cohort study.

PubMed

Cepeda, M Soledad; Fife, Daniel; Vo, Lien; Mastrogiovanni, Gregory; Yuan, Yingli

2013-02-01

Obtaining opioids from multiple prescribers, known as doctor shopping, is 1 example of opioid abuse and diversion. The dual mechanism of action of tapentadol could make tapentadol less likely to be abused than other opioids. The aim of this retrospective cohort study was to compare the risk of shopping behavior between tapentadol immediate release (IR) and oxycodone IR. Subjects exposed to tapentadol or oxycodone with no recent opioid use were included and followed for 1 year. The primary outcome was the proportion of subjects who developed shopping behavior defined as subjects who had opioid prescriptions written by >1 prescriber with ≥1 day of overlap filled at ≥3 pharmacies. The opioids involved in the shopping episodes were assessed. A total of 112,821 subjects were exposed to oxycodone and 42,940 to tapentadol. Shopping behavior was seen in .8% of the subjects in the oxycodone group and in .2% of the subjects in the tapentadol group, for an adjusted odds ratio of 3.5 (95% confidence interval, 2.8 to 4.4). In the oxycodone group, 28.0% of the shopping events involved exclusively oxycodone, whereas in the tapentadol group, .6% of the shopping events involved exclusively tapentadol. Results suggest that the risk of shopping behavior is substantially lower with tapentadol than with oxycodone. The risk of opioid doctor shopping, ie, obtaining opioid prescriptions from multiple prescribers, is lower with tapentadol than with oxycodone. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Opioid Concentrations in Oral Fluid and Plasma in Cancer Patients With Pain.

PubMed

Heiskanen, Tarja; Langel, Kaarina; Gunnar, Teemu; Lillsunde, Pirjo; Kalso, Eija A

2015-10-01

Measuring opioid concentrations in pain treatment is warranted in situations where optimal opioid analgesia is difficult to reach. To assess the usefulness of oral fluid (OFL) as an alternative to plasma in opioid concentration monitoring in cancer patients on chronic opioid therapy. We collected OFL and plasma samples from 64 cancer patients on controlled-release (CR) oral morphine, CR oral oxycodone, or transdermal (TD) fentanyl for pain. Samples were obtained on up to five separate days. A total of 213 OFL and plasma samples were evaluable. All patients had detectable amounts of the CR or TD opioid in both plasma and OFL samples. The plasma concentrations of oxycodone and fentanyl (determination coefficient R(2) = 0.628 and 0.700, respectively), but not morphine (R(2) = 0.292), were moderately well correlated to the daily opioid doses. In contrast to morphine and fentanyl (mean OFL/plasma ratio 2.0 and 3.0, respectively), the OFL oxycodone concentrations were significantly higher than the respective plasma concentrations (mean OFL/plasma ratio 14.9). An active transporter could explain the much higher OFL vs. plasma concentrations of oxycodone compared with morphine and fentanyl. OFL analysis is well suited for detecting the studied opioids. For morphine and fentanyl, an approximation of the plasma opioid concentrations is obtainable, whereas for oxycodone, the OFL/plasma concentration relationship is too variable for reliable approximation results. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet
.

PubMed

Scheidel, Bernhard; Maritz, Martina A; Gschwind, Yves J; Steigerwald, Kerstin; Guth, Volker; Kovacs, Peter; Rey, Helene

2017-11-01

To evaluate and to compare the bioavailability, the influence of food intake on the bioavailability, and the safety and tolerability of a newly-developed oxycodone once-daily (OOD) prolonged-release tablet with an established oxycodone twice-daily (OTD) prolonged-release tablet after single-dose administration under fasting or fed conditions as well as after multiple-dose administration. Three single-center, open-label, randomized, balanced, two-treatment, two-period, two-sequence crossover studies were conducted. In each study, 36 healthy volunteers were randomized to receive 10 mg oxycodone daily as OOD (oxycodone HCL 10-mg PR tablets XL (Develco Pharma Schweiz AG, Pratteln, Switzerland); administration of 1 tablet in the morning) or as OTD (reference formulation: oxygesic 5-mg tablets (Mundipharma GmbH, Limburg an der Lahn, Germany); administration of 1 tablet in the morning and 1 tablet in the evening). Tablets were administered once daily or twice daily under fasting conditions (study 1) or under fed conditions (study 2) as well as after multiple-dose administration (study 3). A sufficient number of blood samples were taken for describing plasma profiles and for calculation of pharmacokinetic parameters. Plasma concentrations of oxycodone were determined by LC-MS/MS. Safety and tolerability were monitored and assessed in all three studies. Plasma profiles of OOD reveal sustained concentrations of oxycodone over the complete dosing interval of 24 hours. In comparison to the OTD reference formulation, the OOD test formulation showed a slightly slower increase of concentrations within the absorption phase and similar plasma concentrations at the maximum and at the end of the dosing interval (24 hours). Extent of bioavailability (AUC), maximum plasma concentrations (C_max), and plasma concentrations at the end of the dosing interval (C_τ,ss,24h) of OOD could be classified as comparable to OTD considering 90% confidence intervals (CIs) and acceptance limits of 80.00 - 125.00%. Bioavailability of OOD was not influenced by concomitant food intake. OOD and OTD were generally well tolerated, a difference between the two products could not be observed. The new 10-mg OOD formulation provides sustained oxycodone plasma concentrations over the dosing interval of 24 hours and is suitable for once-daily administration. Bioavailability of OOD could be classified as comparable to the twice-daily administration of the OTD reference formulation. The new formulation widens and optimizes the range of strong opioid drug products in patient-centered therapy of chronic pain with simplified dosing and better compliance.
.

Comparison of the risks of shopping behavior and opioid abuse between tapentadol and oxycodone and association of shopping behavior and opioid abuse.

PubMed

Cepeda, M Soledad; Fife, Daniel; Kihm, Mary A; Mastrogiovanni, Greg; Yuan, Yingli

2014-12-01

This study compared the risks of opioid shopping behavior and opioid abuse between tapentadol immediate release and oxycodone immediate release and, to validate the definition of shopping, examined the association between opioid shopping and opioid abuse further. This retrospective cohort study using linked dispensing and diagnosis databases followed opioid-naive patients for development of shopping behavior and/or opioid abuse during 1 year after initial exposure to tapentadol or oxycodone. Shopping was defined by having overlapping opioid prescriptions from >1 prescriber filled at ≥3 pharmacies; abuse by having International Classification of Diseases, 9th revision diagnoses reflecting opioid abuse, addiction, or dependence. To determine their association, we cross-tabulated shopping and opioid abuse and calculated odds ratios. Risks of developing each outcome were estimated using logistic regression. Among 277,401 participants initiating opioid use with tapentadol (39,524) or oxycodone (237,877), 0.6% developed shopping behavior, 0.75% developed abuse. Higher proportions of patients in the oxycodone group developed shopping behavior and abuse than in the tapentadol group (shopping: adjusted odds ratio [95% confidence interval], 0.45 [0.36-0.55]; abuse: 0.44 [0.37-0.54]). Shopping behavior and abuse were associated; of those with shopping behavior, 6.5% had abuse. Age (18 to 64 y), sex (male), prior benzodiazepine use, paying cash, and history (mood disorders, abuse of nonopioid medications, and back pain) were risk factors for developing either outcome. Shopping behavior and abuse measure complementary, but associated, constructs, which further validates the current definition of shopping. The risk of developing either is lower among patients who initiate opioid use with tapentadol than those who initiate opioid use with oxycodone.

Comparison of the Risks of Shopping Behavior and Opioid Abuse Between Tapentadol and Oxycodone and Association of Shopping Behavior and Opioid Abuse

PubMed Central

Fife, Daniel; Kihm, Mary A.; Mastrogiovanni, Greg; Yuan, Yingli

2014-01-01

Objectives: This study compared the risks of opioid shopping behavior and opioid abuse between tapentadol immediate release and oxycodone immediate release and, to validate the definition of shopping, examined the association between opioid shopping and opioid abuse further. Materials and Methods: This retrospective cohort study using linked dispensing and diagnosis databases followed opioid-naive patients for development of shopping behavior and/or opioid abuse during 1 year after initial exposure to tapentadol or oxycodone. Shopping was defined by having overlapping opioid prescriptions from >1 prescriber filled at ≥3 pharmacies; abuse by having International Classification of Diseases, 9th revision diagnoses reflecting opioid abuse, addiction, or dependence. To determine their association, we cross-tabulated shopping and opioid abuse and calculated odds ratios. Risks of developing each outcome were estimated using logistic regression. Results: Among 277,401 participants initiating opioid use with tapentadol (39,524) or oxycodone (237,877), 0.6% developed shopping behavior, 0.75% developed abuse. Higher proportions of patients in the oxycodone group developed shopping behavior and abuse than in the tapentadol group (shopping: adjusted odds ratio [95% confidence interval], 0.45 [0.36-0.55]; abuse: 0.44 [0.37-0.54]). Shopping behavior and abuse were associated; of those with shopping behavior, 6.5% had abuse. Age (18 to 64 y), sex (male), prior benzodiazepine use, paying cash, and history (mood disorders, abuse of nonopioid medications, and back pain) were risk factors for developing either outcome. Discussion: Shopping behavior and abuse measure complementary, but associated, constructs, which further validates the current definition of shopping. The risk of developing either is lower among patients who initiate opioid use with tapentadol than those who initiate opioid use with oxycodone. PMID:24370606

Decreased diversion by doctor-shopping for a reformulated extended release oxycodone product (OxyContin).

PubMed

Chilcoat, Howard D; Coplan, Paul M; Harikrishnan, Venkatesh; Alexander, Louis

2016-08-01

Doctor-shopping (obtaining prescriptions from multiple prescribers/pharmacies) for opioid analgesics produces a supply for diversion and abuse, and represents a major public health issue. An open cohort study assessed changes in doctor-shopping in the U.S. for a brand extended release (ER) oxycodone product (OxyContin) and comparator opioids before (July, 2009 to June, 2010) versus after (January, 2011 to June, 2013) introduction of reformulated brand ER oxycodone with abuse-deterrent properties, using IMS LRx longitudinal data covering >150 million patients and 65% of retail U.S. prescriptions. After its reformulation, the rate of doctor-shopping decreased 50% (for 2+ prescribers/3+ pharmacies) for brand ER oxycodone, but not for comparators. The largest decreases in rates occurred among young adults (73%), those paying with cash (61%) and those receiving the highest available dose (62%), with a 90% decrease when stratifying by all three characteristics. The magnitude of doctor-shopping reductions increased with increasing number of prescribers/pharmacies (e.g., 75% reduction for ≥2 prescribers/≥4 pharmacies). The rate of doctor-shopping for brand ER oxycodone decreased substantially after its reformulation, which did not occur for other prescription opioids. The largest reductions in doctor-shopping occurred with characteristics associated with higher abuse risk such as youth, cash payment and high dose, and with more specific thresholds of doctor-shopping. A higher prescriber and/or pharmacy threshold also increased the magnitude of the decrease, suggesting that it better captured the effect of the reformulation on actual doctor-shoppers. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Safety and efficacy of an oxycodone vaccine: Addressing some of the unique considerations posed by opioid abuse

PubMed Central

Peterson, S. J.; Laudenbach, M.; Baruffaldi, F.; Carroll, F. I.; Comer, S. D.; Navarro, H. A.; Langston, T. L.; Runyon, S. P.; Winston, S.; Pravetoni, M.; Pentel, P. R.

2017-01-01

Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naïve controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose. PMID:29194445

Comparison of oral oxycodone and naproxen in soft tissue injury pain control: a double-blind randomized clinical trial.

PubMed

Fathi, Marzieh; Zare, Mohammad Amin; Bahmani, Hamid Reza; Zehtabchi, Shahriar

2015-09-01

This randomized clinical trial compares the efficacy and safety of oral oxycodone (an oral opioid) with naproxen (a nonsteroidal anti-inflammatory drug) in acute pain control in patients with soft tissue injury. It also evaluates the need for additional doses of analgesics in the first 24 hours of discharge from emergency department (ED). Adult (>18 years old) patients with soft tissue injuries were enrolled in a teaching urban ED. Subjects were randomly allocated to receive a single dose of oral oxycodone (5 mg) or oral naproxen (250 mg). Pain scores and drugs' adverse effects were assessed before, 30 minutes, and 60 minutes after medication. efficacy in pain control (reduction in pain scale >2 points) and safety (rate of side effects). The need for additional pain medication after discharge was assessed by follow-up phone call 24 hours after discharge. A total of 150 patients were enrolled. Pain scores were similar in oxycodone vs naproxen groups before (6.21 ± 0.9 in vs 6.0 ± 1.0), 30 minutes (4.5 ± 1.4 vs 4.4 ± 1.2), and 60 minutes (2.5 ± 1.3 in vs 2.6 ± 1.3) after medication, respectively. Twelve (16.0%) patients in oral oxycodone group and 5 (6.6%) patients in naproxen group needed more analgesics in first 24 hours after ED discharge. Adverse effects were more common in oxycodone group (statistically significant difference). The most common adverse effects in oxycodone group were nausea, (13.3%); vomiting, (8.0%); dizziness, (5.3%); drowsiness, 3 (4.0%); and pruritis, (2.7%). Oral oxycodone is as effective as naproxen in soft tissue injury pain control but has a less favorable safety profile. Copyright © 2015 Elsevier Inc. All rights reserved.

Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability.

PubMed

Cooper, Ziva D; Bedi, Gillinder; Ramesh, Divya; Balter, Rebecca; Comer, Sandra D; Haney, Margaret

2018-02-05

Cannabinoids combined with opioids produce synergistic antinociceptive effects, decreasing the lowest effective antinociceptive opioid dose (i.e., opioid-sparing effects) in laboratory animals. Although pain patients report greater analgesia when cannabis is used with opioids, no placebo-controlled studies have assessed the direct effects of opioids combined with cannabis in humans or the impact of the combination on abuse liability. This double-blind, placebo-controlled, within-subject study determined if cannabis enhances the analgesic effects of low dose oxycodone using a validated experimental model of pain and its effects on abuse liability. Healthy cannabis smokers (N = 18) were administered oxycodone (0, 2.5, and 5.0 mg, PO) with smoked cannabis (0.0, 5.6% Δ 9 tetrahydrocannabinol [THC]) and analgesia was assessed using the Cold-Pressor Test (CPT). Participants immersed their hand in cold water (4 °C); times to report pain (pain threshold) and withdraw the hand from the water (pain tolerance) were recorded. Abuse-related effects were measured and effects of oxycodone on cannabis self-administration were determined. Alone, 5.0 mg oxycodone increased pain threshold and tolerance (p ≤ 0.05). Although active cannabis and 2.5 mg oxycodone alone failed to elicit analgesia, combined they increased pain threshold and tolerance (p ≤ 0.05). Oxycodone did not increase subjective ratings associated with cannabis abuse, nor did it increase cannabis self-administration. However, the combination of 2.5 mg oxycodone and active cannabis produced small, yet significant, increases in oxycodone abuse liability (p ≤ 0.05). Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy, without increases in cannabis's abuse liability. These findings support future research into the therapeutic use of opioid-cannabinoid combinations for pain.

Attenuation of morphine-induced delirium in palliative care by substitution with infusion of oxycodone.

PubMed

Maddocks, I; Somogyi, A; Abbott, F; Hayball, P; Parker, D

1996-09-01

We have observed among patients of the Southern Community Hospice Programme that up to 25% experience acute delirium when treated with morphine and improve when the opioid is changed to oxycodone or fentanyl. This study aimed to confirm by a prospective trial that oxycodone produces less delirium than morphine in such patients. Oxycodone was administered by a continuous subcutaneous infusion, as this allowed more flexible and reliable dosing, and patients were monitored for any adverse reactions to the drug. Thirteen patients completed the study. Statistically significant improvements in mental state and nausea and vomiting occurred following a change from morphine to oxycodone. Pain scores improved but did not reach a level of statistical significance. The phenotype status of the patients was tested to establish their capacity to metabolize oxycodone. One patient who did not achieve adequate pain control proved to be a poor metabolizer. These results show that oxycodone administered by the subcutaneous route can provide effective analgesia without significant side effects in patients with morphine-induced delirium. This treatment allows patients to remain more comfortable and lucid in their final days. A small proportion of patients who do not metabolize oxycodone effectively may not receive this benefit.

Opioid use following the introduction of an extended-release oxycodone formulation with tamper-resistant properties: Prospective historical chart review in methadone-maintained patients.

PubMed

Sankey, Christopher; Setnik, Beatrice; Harsanyi, Zoltan; Michalko, Ken; Yang, Zejiang; Geoffroy, Pierre

2016-01-01

Emerging data are demonstrating that tamper-resistant opioids may play an important role in changing prescription opioid abuse behaviors. This study was a chart review to examine if the reformulation of OxyContin® into a version with tamper-resistant properties (OxyNEO®) had an impact on oxycodone-positive urine drug screens (UDSs) in opioid-dependent patients receiving methadone maintenance therapy (MMT). The historical element of this study examined 250 eligible charts from patients on MMT who had data during the time periods when only OxyContin was available (baseline period), during the transition to OxyNEO, and when only OxyNEO was available. The prospective element included an exploratory questionnaire regarding retrospective opioid use. The study was conducted at three methadone clinics, in Oshawa, Peterborough, and Scarborough in Ontario, Canada. Male and female patients were eligible if they had a diagnosis of opioid dependency, received MMT, and had at least one oxycodone-positive UDS during the baseline period. This was a noninterventional study. The main outcome was the number of oxycodonepositive UDSs. The results demonstrated a marked reduction in oxycodone-positive UDSs that showed stepwise, statistically significant decreases during the transition and post-OxyContin periods relative to baseline. While the oxycodone-positive UDS results were decreasing, morphine-related-positive UDSs remained relatively stable during the same periods. There were no significant gender differences noted. The introduction of OxyNEO was associated with a statistically significant reduction in oxycodone exposure in a population of methadone-maintained patients.

Internet-based survey of nonmedical prescription opioid use in the United States.

PubMed

Katz, Nathaniel; Fernandez, Kathrine; Chang, Alan; Benoit, Christine; Butler, Stephen F

2008-01-01

Prescription opioid misuse is a growing problem in the United States. There are limited data to illuminate the nature of this issue. The Internet seems to be a novel approach in surveying populations of opioid users. An Internet-based survey of nonmedical opioid users visiting informational drug websites was used to measure rates of nonmedical use and characterize users. The prescription opioid module of the Addiction Severity Index Multimedia Version Connect was adapted to include variables such as favorite opioid. Links to the survey were posted on an informational drug website. Nonmedical use rates for KADIAN (morphine sulfate extended-release tablets), OxyContin (oxycodone HCl controlled-release tablets), Vicodin (hydrocodone bitartrate and acetaminophen tablets), and product-classes (morphine ER, oxycodone ER, and hydrocodone) were calculated. Descriptive statistics were calculated for remaining questions. During a 1-month recruitment period, 896 valid individuals completed the survey. Majority were white (78.3%) and male (72.4%). Participants were less likely to have used KADIAN in the past 30 days compared with OxyContin (P<0.0001) and Vicodin (P=0.0021). Additionally, participants were less likely to have used morphine ER in the previous 30 days than either oxycodone ER (P<0.0001) or hydrocodone (P<0.0001). Among OxyContin, Vicodin, and KADIAN users, OxyContin (43.8%), Dilaudid (15.6%), and fentanyl (9.4%) were the top 3 favorite opioids. This project demonstrates the feasibility of conducting product-specific, online surveys with rapid recruitment of participants from websites. This approach differentiates rates of nonmedical use of specific prescription opioids and provides other insights into individuals who nonmedically use opioids.

Pharmacokinetics and variation in the clearance of oxycodone and hydrocotarnine in patients with cancer pain.

PubMed

Kokubun, Hideya; Fukawa, Misako; Matoba, Motohiro; Hoka, Sumio; Yamada, Yasuhiko; Yago, Kazuo

2007-11-01

Compound injections of oxycodone and hydrocotarnine are currently used as one of the treatment options for some cases with cancer pain. However, there have been no reports examining the factors that influence oxycodone and hydrocotarnine clearance, so detailed examination is necessary. As for hydrocotarnine, there have been no reports examining the pharmacokinetics. Therefore in this study, we determined the pharmacokinetics of oxycodone and hydrocotarnine in patients with cancer pain. The study was conducted on 19 patients, in whom pain control was attempted by using the compound injections of oxycodone and hydrocotarnine. We used HPLC-electrochemical detector (ECD) to determine oxycodone and hydrocotarnine serum concentrations, and used the nonlinear least-squares method (MULTI) for calculation of the pharmacokinetic parameters. Furthermore, we examined the factors that influence the clearance of oxycodone and hydrocotarnine by multiple regression analysis (step wise method). The pharmacokinetic parameters were as follows: Oxycodone; V(d)=226.7+/-105.5 l (mean+/-S.D.), CL=37.9+/-25.1 l/h, t(1/2)=4.1+/-1.9 h. Hydrocotarnine; V(d)=276.8+/-237.2 l, CL=95.1+/-64.3 l/h, t(1/2)=2.0+/-0.7 h. The clearance of oxycodone represented by a regression formula was significantly correlated to the age, the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance of hydrocotarnine represented by a regression formula was significantly correlated to the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance also indicated that oxycodone concentration in the blood was likely to be higher in patients having these factors. Oxycodone/hydrocotarnine compound injections should be used with caution and dose reduction may be necessary in such populations.

Economic study on the impact of side effects in patients taking oxycodone controlled-release for noncancer pain.

PubMed

Anastassopoulos, Kathryn P; Chow, Wing; Tapia, Crisanta I; Baik, Rebecca; Ackerman, Stacey J; Biondi, David; Kim, Myoung S

2012-10-01

Chronic pain is a prevalent condition in the United States. Musculoskeletal pain, including joint and back pain, is the most common type of chronic pain, and many patients with back pain have a neuropathic component. Pain has direct economic consequences. While oxycodone controlled-release (CR) is one of the most widely used oral long-acting opioids for pain, including pain with a neuropathic component, it is often associated with bothersome side effects, resulting in additional medical resource use (MRU) and costs. To examine the impact on MRU and costs to payers of side effects in patients taking oxycodone CR alone or in combination with other pain medications for noncancer pain (including those with neuropathic pain symptoms). A nationwide convenience sample of adults in the United States, who participated in a survey research panel and reported current use of oxycodone CR for noncancer pain, completed an online survey between November 2, 2010, and December 13, 2010. Respondents were excluded if they reported current use of other extended-release or long-acting opioid prescription medications. The survey consisted of questions on demographics, clinical characteristics, pain characteristics, experience with pain medication, and MRU associated with side effects. Payer costs were calculated based on the MRU reported by the respondents multiplied by Medicare reimbursement rates for hospitalizations and outpatient visits and average wholesale price (AWP) minus 20% for medications. A subgroup of patients who reported neuropathic pain symptoms also was examined. After applying the exclusion criteria, 432 respondents completed the survey. Approximately half of the respondents (n = 219; 50.7%) reported neuropathic pain symptoms. The majority of respondents were Caucasian (88.4%) and female (63.7%) with an average age of 41.8 years (14.89). Respondents most frequently reported low back pain (41.2%), followed by osteoarthritis/rheumatoid arthritis (20.4%), neuropathic pain (10.6%), and fibromyalgia (9.0%). Respondents reported having their pain condition for an average of 5.4 (7.42) years. On days when taken, respondents reported a mean oxycodone CR daily dose of 83.3 mg (126.93) taken in an average of 2 doses. Most respondents (82.4%) reported experiencing at least 1 side effect with 77.5% being bothered by at least 1 side effect. The most frequently reported side effects ( greater than 25%) were drowsiness (41.4%), constipation (37.0%), fatigue or daytime sleepiness (36.6%), and dizziness (27.1%). Among respondents who reported being bothered by one or more side effects in the previous month, MRU associated with side effects was reported by 39.1% of respondents and significantly increased as the level of side-effect bother increased from 19.8% among those "A little bit bothered" to 38.4% among those "Bothered" to 61.0% among those "Extremely bothered" (P less than 0.001). Additionally, total average payer costs (in 2010 dollars) per respondent in the previous month associated with side effects were $238 ($1,159) and also significantly increased as the level of side-effect bother increased from $61 ($512) among those "A little bit bothered" to $238 ($1,160) among those "Bothered" to $425 ($1,561) among those "Extremely bothered" (P less than 0.001). Results reported in the neuropathic pain subgroup were similar to results reported in the total study sample. Among adults taking oxycodone CR for chronic noncancer pain (with or without a neuropathic pain component), over three-fourths reported being bothered by side effects. Respondents who reported higher levels of side-effect bother also reported greater MRU, resulting in increased payer costs. The results of this study provide further support of the econo-mic burden to payers associated with opioid-related side effects in patients with chronic noncancer pain, with and without neuropathic pain.

Comparison of epidural oxycodone and epidural morphine for post-caesarean section analgesia: A randomised controlled trial

PubMed Central

Sng, Ban Leong; Kwok, Sarah Carol; Mathur, Deepak; Ithnin, Farida; Newton-Dunn, Clare; Assam, Pryseley Nkouibert; Sultana, Rehena; Sia, Alex Tiong Heng

2016-01-01

Background and Aims: Epidural morphine after caesarean section may cause moderate to severe pruritus in women. Epidural oxycodone has been shown in non-obstetric trials to reduce pruritus when compared to morphine. We hypothesised that epidural oxycodone may reduce pruritus after caesarean section. Methods: A randomised controlled trial was conducted in pregnant women at term who underwent caesarean section with combined spinal-epidural technique initiated with intrathecal fentanyl 15 μg. Women received either epidural morphine 3 mg or epidural oxycodone 3 mg via the epidural catheter after delivery. The primary outcome was the incidence of pruritus at 24 h after caesarean section. The secondary outcomes were the pruritus scores, treatment for post-operative nausea and vomiting (PONV), pain scores and maternal satisfaction. Results: One hundred women were randomised (group oxycodone O = 50, morphine M = 50). There was no difference between Group O and M in the incidence of pruritus (n [%] 28 [56%] vs. 31 [62%], P = 0.68) and the worst pruritus scores (mean [standard deviation] 2.6 (2.8) vs. 3.3 [3.1], P = 0.23), respectively. Both groups had similar pain scores at rest (2.7 [2.3] vs. 2.0 [2.7], P = 0.16) and sitting up (5.0 [2.3] vs. 4.6 [2.4], P = 0.38) at 24 h. Pruritus scores were lower at 4–8, 8–12 and 12–24 h with oxycodone, but pain scores were higher. Both groups had a similar need for treatment of PONV and maternal satisfaction with analgesia. Conclusion: There was no difference in the incidence of pruritus at 24 h between epidural oxycodone and morphine. However, pruritus scores were lower with oxycodone between 4 and 24 h after surgery with higher pain scores in the same period. PMID:27053782

Retrospective Evaluation of a Fixed-Dose Combination of Oxycodone and Acetaminophen to Manage Moderate Pain: The Lower the Better.

PubMed

Natoli, Silvia; Lazzari, Marzia; Carpenedo, Roberta; Palombo, Elisa; Silvi, Maria Beatrice; Mammucari, Massimo; Dauri, Mario

2016-06-01

Oxycodone is one of the most commonly used opioid analgesics in the clinical management of pain. The present retrospective analysis aimed to determine the dose of oxycodone that could achieve effective control of moderate pain when combined with a fixed dose of acetaminophen, and the time required to reach a clinically relevant reduction in intensity of pain. Data of patients treated with a combination of oxycodone (5, 10, and 20 mg) and acetaminophen (325 mg) were evaluated for gender, current disease condition, basal pain intensity, total daily dose, days of controlled pain at the initial low dose, and pain intensity after treatment using a numeric pain rating scale. Data from a total of 491 patients were assessed; of these 93.5% of patients experienced persistent non-cancer pain and had an average baseline pain score of 5.68 ± 1.35. For the overall population, the pain score was reduced to 2.49 ± 1.71 with a mean dose of 8.68 ± 4.96 mg oxycodone after 21.60 ± 6.12 days of treatment with the combination. Almost 97% of the patients who reported relief of pain received 1.61 ± 0.67 doses of oxycodone 5 mg combined with 325 mg of acetaminophen. A low-dose combination of oxycodone with acetaminophen can be effective in the management of moderate pain and may help in reducing the treatment-associated adverse reactions and drug dependence. Sponsorship for article processing charges was provided by Molteni Farmaceutici, Florence, Italy.

Targinact--opioid pain relief without constipation?

PubMed

2010-12-01

Targinact (Napp Pharmaceuticals Ltd) is a modified-release combination product containing the strong opioid oxycodone plus the opioid antagonist naloxone. It is licensed for "severe pain, which can be adequately managed only with opioid analgesics".1 The summary of product characteristics (SPC) states that "naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut". Advertising for the product claims "better pain relief", "superior GI [gastrointestinal] tolerability" and "improved quality of life" "compared to previous treatment in a clinical practice study (n=7836)". Here we consider whether Targinact offers advantages over using strong opioids plus laxatives where required.

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 food (whole capsule, fed vs. fasted) or of sprinkling on applesauce (pellets vs. whole capsule, fasted) on oxycodone bioavailability. The Test/Reference ratios of adjusted geometric means for oxycodone AUCinf , AUClast , and Cmax were 99.2%, 100%, and 107%, respectively, for the effect of food; and 101%, 101%, and 97.5%, respectively, for the effect of sprinkling on applesauce. The 90% confidence intervals contained entirely within the bioequivalence limits of 80% to 125% for each comparison. Naltrexone remained sequestered during each treatment, based on the sporadic and low measurable plasma concentrations of naltrexone and 6-ß-naltrexol. Single doses of ALO-02 40 mg were well tolerated, and adverse events were mild, with no apparent difference in frequency for all 3 treatments. Results indicate that ALO-02 can be administered without regard to food. Also, the contents of ALO-02 can be sprinkled over applesauce and consumed without chewing as an alternative treatment option by subjects with difficulty swallowing. Naltrexone remained sequestered in the ALO-02 formulation under all 3 treatments. © 2015, The American College of Clinical Pharmacology.

75 FR 66149 - East Main Street Pharmacy; Affirmance of Suspension Order

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-27

... from a physician practicing in Wheelersburg, Ohio, prescriptions for 90 tablets of oxycodone 30 mg. and 60 tablets of carisoprodol (a non- controlled but highly abused drug which metabolizes into... [Respondent] as the dispensing pharmacy and several scattered oxycodone tablets * * * next to her body,'' and...

A Randomized Clinical Trial of Nefopam versus Ketorolac Combined With Oxycodone in Patient-Controlled Analgesia after Gynecologic Surgery.

PubMed

Hwang, Boo-Young; Kwon, Jae-Young; Lee, Do-Won; Kim, Eunsoo; Kim, Tae-Kyun; Kim, Hae-Kyu

2015-01-01

Nefopam is a centrally-acting non-opioid analgesic, which has no effect on bleeding time and platelet aggregation. There has been no study about nefopam and oxycodone combination for postoperative analgesia. In this study, we present efficacy and side effects of nefopam/oxycodone compared with ketorolac/oxycodone in patient-controlled analgesia (PCA) after gynecologic surgery. 120 patients undergoing gynecologic surgery were divided randomly into two groups: Nefopam group treated with oxycodone 1 mg and nefopam 1 mg bolus; and Ketorolac group treated with oxycodone 1 mg and ketorolac 1.5 mg bolus. After the operation, a blinded observer assessed the pain with a numeric rating scale (NRS), infused PCA dose and sedation score at 1, 4, 24, and 48 h, nausea, vomiting, headache, shivering, pruritus and delirium at 6, 24 and 48 h, and satisfaction at 48 h after the operation. Nefopam group showed less nausea than Ketorolac group within 6 h after the operation. There were no significant differences in demographic data and other complications between both groups. At 48 h after operation, satisfaction and the infused PCA volumes of Nefopam group (34.0± 19.7 ml) showed no significant differences compared to Ketorolac group (30.7± 18.4 ml, P-value= 0.46). Nefopam showed a similar efficacy and lower incidence of nausea within 6 h after the operation to that of ketorolac in PCA. Nefopam may be a useful analgesic drug for the opioid-based PCA after gynecologic surgery. Further evaluation of accurate equivalent dose of nefopam as well as pharmacokinetics of bolus administration is required.

Do abuse deterrent opioid formulations work?

PubMed

Dart, Richard C; Iwanicki, Janetta L; Dasgupta, Nabarun; Cicero, Theodore J; Schnoll, Sidney H

We performed a systematic review to answer the question, "Does the introduction of an opioid analgesic with abuse deterrent properties result in reduced overall abuse of the drug in the community?" We included opioid analgesics with abuse deterrent properties (hydrocodone, morphine, oxycodone) with results restricted to the metasearch term "delayed onset," English language, use in humans, and publication years 2009-2016. All articles that contained data evaluating misuse, abuse, overdose, addiction, and death were included. The results were categorized using the Bradford-Hill criteria. We included 44 reports: hydrocodone (n = 7), morphine (n = 5), or oxycodone (n = 32) with Food and Drug Administration-approved Categories 1, 2, or 3 abuse deterrent labeling. The data currently available support the Hill criteria of strength (effect size), consistency (reproducibility), temporality, plausibility, and coherence. There was insufficient or no information available for the criteria of biological gradient, experiment, and analogy. We also assessed confounding factors and bias, which indicated that both were present and substantial in magnitude. Our analysis found that only oxycodone extended release (ER) had information available to evaluate abuse deterrence in the community. In Australia, Canada, and the United States, reformulation of oxycodone ER was followed by marked reduction in measures of abuse. The precise extent of reduced abuse cannot be calculated because of heterogeneous data sets, but the reported reductions ranged from 10 to 90 percent depending on the measure and the duration of follow-up.

A Randomized Clinical Trial of Nefopam versus Ketorolac Combined With Oxycodone in Patient-Controlled Analgesia after Gynecologic Surgery

PubMed Central

Hwang, Boo-Young; Kwon, Jae-Young; Lee, Do-Won; Kim, Eunsoo; Kim, Tae-Kyun; Kim, Hae-Kyu

2015-01-01

Objectives: Nefopam is a centrally-acting non-opioid analgesic, which has no effect on bleeding time and platelet aggregation. There has been no study about nefopam and oxycodone combination for postoperative analgesia. In this study, we present efficacy and side effects of nefopam/oxycodone compared with ketorolac/oxycodone in patient-controlled analgesia (PCA) after gynecologic surgery. Methods: 120 patients undergoing gynecologic surgery were divided randomly into two groups: Nefopam group treated with oxycodone 1 mg and nefopam 1 mg bolus; and Ketorolac group treated with oxycodone 1 mg and ketorolac 1.5 mg bolus. After the operation, a blinded observer assessed the pain with a numeric rating scale (NRS), infused PCA dose and sedation score at 1, 4, 24, and 48 h, nausea, vomiting, headache, shivering, pruritus and delirium at 6, 24 and 48 h, and satisfaction at 48 h after the operation. Results: Nefopam group showed less nausea than Ketorolac group within 6 h after the operation. There were no significant differences in demographic data and other complications between both groups. At 48 h after operation, satisfaction and the infused PCA volumes of Nefopam group (34.0± 19.7 ml) showed no significant differences compared to Ketorolac group (30.7± 18.4 ml, P-value= 0.46). Conclusion: Nefopam showed a similar efficacy and lower incidence of nausea within 6 h after the operation to that of ketorolac in PCA. Nefopam may be a useful analgesic drug for the opioid-based PCA after gynecologic surgery. Further evaluation of accurate equivalent dose of nefopam as well as pharmacokinetics of bolus administration is required. PMID:26283884

Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone.

PubMed

Jacob, Joanna C; Poklis, Justin L; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L

2017-07-01

This study compared the development of tolerance to two orally bioavailable prescription opioids, oxycodone and hydrocodone, to that of morphine, and the reversal of this tolerance by ethanol. Oxycodone (s.c.) was significantly more potent in the mouse tail-withdrawal assay than either morphine or hydrocodone. Oxycodone was also significantly more potent in this assay than hydrocodone when administered orally. Tolerance was seen following chronic subcutaneous administration of each of the three drugs and by the chronic administration of oral oxycodone, but not following the chronic oral administration of hydrocodone. Ethanol (1 g/kg i.p.) significantly reversed the tolerance to the subcutaneous administration of each of the three opioids that developed when given 30 minutes prior to challenge doses. It took twice as much ethanol, when given orally, to reverse the tolerance to oxycodone. We investigated whether the observed tolerance to oxycodone and its reversal by ethanol were due to biodispositional changes or reflected a true neuronal tolerance. As expected, a relationship between brain oxycodone concentrations and activity in the tail-immersion test existed following administration of acute oral oxycodone. Following chronic treatment, brain oxycodone concentrations were significantly lower than acute concentrations. Oral ethanol (2 g/kg) reversed the tolerance to chronic oxycodone, but did not alter brain concentrations of either acute or chronic oxycodone. These studies show that there is a metabolic component of tolerance to oxycodone; however, the reversal of that tolerance by ethanol is not due to an alteration of the biodisposition of oxycodone, but rather is neuronal in nature. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Impact of pharmacists assisting with prescribing and undertaking medication review on oxycodone prescribing and supply for patients discharged from surgical wards.

PubMed

Tran, T; Taylor, S E; Hardidge, A; Findakly, D; Aminian, P; Elliott, R A

2017-10-01

Overprescribing of oxycodone is a contributor to the epidemic of prescription opioid misuse and deaths. Practice models to optimize oxycodone prescribing and supply need to be evaluated. We explored the impact of pharmacist-assisted discharge prescribing and medication review on oxycodone prescribing and supply for patients discharged from surgical wards. A retrospective audit was conducted on two surgical inpatient wards following a 16-week prospective pre- and post-intervention study. During the pre-intervention period, discharge prescriptions were prepared by hospital doctors and then reviewed by a ward pharmacist (WP) before being dispensed. Post-intervention, prescriptions were prepared by a project pharmacist in consultation with hospital doctors and then reviewed by a WP and dispensed. Proportion of patients who were prescribed, and proportion supplied, oxycodone on discharge; Median amount (milligrams) of oxycodone prescribed and supplied, for patients who were prescribed and supplied at least one oxycodone-containing preparation, respectively. A total of 320 and 341 patients were evaluated pre- and post-intervention, respectively. Pre-intervention, 75.6% of patients were prescribed oxycodone; after WP review, 60.3% were supplied oxycodone (P<.01); the median amount both prescribed and supplied was 100 milligrams/patient. Post-intervention, 68.6% of patients were prescribed oxycodone; after WP review, 57.8% were supplied oxycodone (P<.01); median amount prescribed and supplied was 50 milligrams/patient (difference in amount prescribed and supplied: 50 milligrams, P<.01). WP review of doctor-prepared prescriptions reduced the proportion of patients who were supplied oxycodone but not the amount supplied/patient. Having a pharmacist assist with prescribing reduced the amount of oxycodone supplied. © 2017 John Wiley & Sons Ltd.

Oxycodone-induced tolerance to respiratory depression: reversal by ethanol, pregabalin and protein kinase C inhibition.

PubMed

Hill, Rob; Dewey, William L; Kelly, Eamonn; Henderson, Graeme

2018-06-01

Oxycodone, a prescription opioid, is a major drug of abuse, especially in the USA, and contributes significantly to opioid overdose deaths each year. Overdose deaths result primarily from respiratory depression. We have studied respiratory depression by oxycodone and have characterized how tolerance develops on prolonged exposure to the drug. We have investigated the role of PKC in maintaining tolerance and have examined whether ethanol or pregabalin reverses oxycodone-induced tolerance. Respiration was measured in male CD-1 mice by whole-body plethysmography. Mice were preinjected with oxycodone then implanted with mini-pumps (s.c.) delivering 20, 45 or 120 mg·kg -1 ·day -1 oxycodone for 6 days and subsequently challenged with oxycodone (3 mg·kg -1 , i.p.) or morphine (10 mg·kg -1 , i.p.) to assess the level of tolerance. Oxycodone-treated mice developed tolerance to oxycodone and cross tolerance to morphine-induced respiratory depression. Tolerance was less with 20 mg·kg -1 ·day -1 than with 45 or 120 mg·kg -1 ·day -1 oxycodone treatment. At doses that do not depress respiration, ethanol (0.3 g·kg -1 ), pregabalin (20 mg·kg -1 ) and calphostin C (45 μg·kg -1 ) all reversed oxycodone-induced tolerance resulting in significant respiratory depression. Reversal of tolerance was less in mice treated with oxycodone (120 mg·kg -1 ·day -1 ). In mice receiving ethanol and calphostin C or ethanol and pregabalin, there was no greater reversal of tolerance than seen with either drug alone. These data suggest that oxycodone-induced tolerance is mediated by PKC and that reversal of tolerance by ethanol or pregabalin may be a contributory factor in oxycodone overdose deaths. © 2018 The British Pharmacological Society.

Improving postoperative tonsillectomy pain management in children--a double blinded randomised control trial of a patient analgesia information sheet.

PubMed

Bailey, Lucas; Sun, Jing; Courtney, Mark; Murphy, Paul

2015-05-01

To evaluate paediatric post-tonsillectomy pain management using oxycodone when a specific analgesia information sheet is included with standard postoperative information. Oxycodone information sheets were randomly allocated to half the study children's post-tonsillectomy information pack. The trial was double-blinded to the surgeon, anaesthetist, nursing and administrative staff. Parents and children completed the pain assessment on day 3, 5 and 7. On day 10 the parents completed a questionnaire. A postoperative analgesia information sheet provides for higher satisfaction and knowledge for parents using oxycodone (p<0.001) and children have improved postoperative pain control, most significantly at day 5 (p<0.05). Parent assessment of the child's analgesia was superior with the oxycodone information sheet, most significantly at day 3 and 7 post operatively (p<0.05). There is also a positive correlation between the parents' observed pain score and children's self reported pain score, with a low correlation efficient level observed (p<0.001). Information sheets are useful in education and use of postoperative analgesia. The primary objective to explore the efficacy of the information sheet has proved to be successful in this setting. Given risks of opioid analgesia, it is recommended that postoperative information sheets be given to all parents, to provide for improved analgesia control and safe management of children in the postoperative period. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Quantitative study of controlled substance bedside wasting, disposal and evaluation of potential ecologic effects.

PubMed

Mankes, Russell F; Silver, Charles D

2013-02-01

Drugs in wastewater arise from many sources. For health care, these include excretion and direct disposal (bedside wasting). The present study reports on the dispensing and wasting of 15 controlled substances (CS) at two health care facilities in Albany, NY over a nearly two year period. The study considered measures of ecotoxicity, drug metabolism, excretion and disposal of these CS. Potential alternatives to flushing of CS into wastewaters from healthcare facilities are discussed. Drug medication and waste collection records (12,345) included: numbers of drugs dispensed, returned and wasted. Overall, 8528 g of 15 CS were wasted. Three (midazolam, acetaminophen-codeine and fentanyl) accounted for 87.5% of the total wasted. Wasting varied by hospital, 14 CS at the academic medical center hospital and 8 at the surgical care center were wasted. Liquids were more frequently wasted than tablets or pills. Some combination drugs (acetaminophen (APAP)-codeine) were frequently (50% of drug dispensed) wasted while others were less wasted (APAP-hydrocodone-6.3%; APAP-oxycodone-1.3%). The 8 CS judged more hazardous to aquatic life were: APAP-codeine, APAP-hydrocodone, APAP-oxycodone, alprazolam, diazepam, fentanyl, midazolam, and testosterone. Ketamine, morphine, oxycodone and zolpidem were of lesser acute toxicity based on available LC50 values. These CS might provide a therapeutically equivalent alternative to the more environmentally harmful drugs. In health care facilities, professionals dispose of CS by bedside wasting into water or other receptacles. This can be avoided by returning CS to the hospital's pharmacy department, thence to a licensed distributor. Study of this process of drug wasting can identify opportunities for process improvements. We found 3 CS (APAP-codeine, midazolam and testosterone) where ½ to 1/3 of the drug was wasted and 5 others with 30 to 13% wasted. Knowledge of the adverse impacts from the release of highly toxic drugs into the environment might influence CS selection and disposal alternatives. Copyright © 2012 Elsevier B.V. All rights reserved.

77 FR 40069 - Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-06

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0563... Labeled for Human Use; Enforcement Action Dates AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing its intention to take enforcement...

Changes in the dispensing of opioid medications in Canada following the introduction of a tamper-deterrent formulation of long-acting oxycodone: a time series analysis.

PubMed

Gomes, Tara; Mastorakos, Andrea; Paterson, J Michael; Sketris, Ingrid; Caetano, Patricia; Greaves, Simon; Henry, David

2017-11-22

In February 2012, a reformulated tamper-deterrent form of long-acting oxycodone, OxyNeo, was introduced in Canada. We investigated the impact of the introduction of OxyNeo on patterns of opioid prescribing. We conducted population-based, cross-sectional analyses of opioid dispensing in Canada between 2008 and 2016. We estimated monthly community pharmacy dispensing of oral formulations of codeine, morphine, hydromorphone and oxycodone, and a transdermal formulation of fentanyl, and converted quantities to milligrams of morphine equivalents (MMEs) per 1000 population. We used time series analysis to evaluate the effect of the introduction of OxyNeo on these trends. National dispensing of long-acting opioids fell by 14.9% between February 2012 and April 2016, from 36 098 MMEs to 30 716 MMEs per 1000 population ( p < 0.01). This effect varied across Canada and was largest in Ontario (reduction of 22.8%) ( p = 0.01) and British Columbia (reduction of 30.0%) ( p = 0.01). The national rate of oxycodone dispensing fell by 46.4% after the introduction of OxyNeo ( p < 0.001); this was partially offset by an increase of 47.8% in hydromorphone dispensing ( p < 0.001). Although dispensing of immediate-release opioids was a substantial contributor to overall population opioid exposure across Canada, it was unaffected by the introduction of OxyNeo ( p > 0.05 in all provinces). The findings suggest that the introduction of a tamper-deterrent formulation of long-acting oxycodone in Canada, against a background of changing public drug benefits, was associated with sustained changes in selection of long-acting opioids but only small changes in the quantity of long-acting opioids dispensed. This illustrates the limited effect a tamper-deterrent formulation and associated coverage policy can have when other, non-tamper-deterrent alternatives are readily available. Copyright 2017, Joule Inc. or its licensors.

The danger of imperfect regulation: OxyContin use in the United States and Canada.

PubMed

Lexchin, Joel; Kohler, Jillian Clare

2011-01-01

Drug companies aggressively market their products to increase sales and economic rewards. Different countries have different regulatory regimes for controlling promotion. In the United States control rests directly with the Food and Drug Administration whereas Canada relies on a mixture of voluntary self-regulation and an autonomous agency. Each method has significant weaknesses. We examine these weaknesses by analyzing the promotion of OxyContin (the time release version of the opioid oxycodone) by Purdue in Canada and the United States. We then look at the association between promotion and the misuse and abuse of OxyContin in both countries. Finally, we advance specific recommendations for regulating promotion for drugs that may have a high abuse potential.

Involvement of α₂-adrenoceptors, imidazoline, and endothelin-A receptors in the effect of agmatine on morphine and oxycodone-induced hypothermia in mice.

PubMed

Bhalla, Shaifali; Andurkar, Shridhar V; Gulati, Anil

2013-10-01

Potentiation of opioid analgesia by endothelin-A (ET(A)) receptor antagonist, BMS182874, and imidazoline receptor/α₂-adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α₂-adrenoceptors, imidazoline, and ET(A) receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α₂-adrenoceptors, imidazoline, and ET(A) receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α₂-adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET(A) receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine-induced hypothermia. Agmatine-induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine-induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α₂-adrenoceptors are involved in agmatine-induced reversal of oxycodone hypothermia. Our findings also suggest that ET(A) receptors may be involved in blockade of oxycodone hypothermia by agmatine. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.

Cholestatic hepatitis as a possible new side-effect of oxycodone: a case report

PubMed Central

Ho, Vincent; Stewart, Maxwell; Boyd, Peter

2008-01-01

Introduction Oxycodone is a widely-used semisynthetic opioid analgesic that has been used for over eighty years. Oxycodone is known to cause side effects such as nausea, pruritus, dizziness, constipation and somnolence. As far as we are aware cholestatic hepatitis as a result of oxycodone use has not been reported so far in the world literature. Case presentation A 34-year-old male presented with cholestatic jaundice and severe pruritus after receiving oxycodone for analgesia post-T11 vertebrectomy. Extensive laboratory investigations and imaging studies did not reveal any other obvious cause for his jaundice and a liver biopsy confirmed canalicular cholestatis suggestive of drug-induced hepatotoxicity. The patient's symptoms and transaminases normalised on withdrawal of oxycodone confirming that oxycodone was the probable cause of the patient's hepatotoxicity. Conclusion We conclude that cholestatic hepatitis is possibly a rare side effect of oxycodone use. Physicians should be aware of the possibility of this potentially serious picture of drug-induced hepatotoxicity. PMID:18452597

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...

Ethanol Reversal of Oxycodone Tolerance in Dorsal Root Ganglia Neurons.

PubMed

Jacob, Joanna C; Sakakibara, Kensuke; Mischel, Ryan A; Henderson, Graeme; Dewey, William L; Akbarali, Hamid I

2018-05-01

Oxycodone is a semisynthetic opioid compound that is widely prescribed, used, and abused today, and has a well-established role in shaping the current opioid epidemic. Previously, we have shown that tolerance develops to the antinociceptive and respiratory depressive effects of oxycodone in mice, and that a moderate dose of acute ethanol or a protein kinase C (PKC) inhibitor reversed that tolerance. To investigate further if tolerance was occurring through neuronal mechanisms, our aims for this study were to assess the effects of acute and prolonged oxycodone in isolated dorsal root ganglia (DRG) neurons and to determine if this tolerance was reversed by either ethanol or a PKC inhibitor. We found that an acute exposure to 3 μ M oxycodone reduced neuronal excitability, as measured by increased threshold potentials and reduced action potential amplitude, without eliciting measurable changes in resting membrane potential. Exposure to 10 μ M oxycodone for 18-24 hours prevented oxycodone's effect on neuronal excitability, indicative of tolerance development. The development of opioid tolerance was mitigated in DRG neurons from β -arrestin 2 knockout mice. Oxycodone tolerance was reversed in isolated DRG neurons by the acute application of either ethanol (20 mM) or the PKC inhibitor, bisindolylmaleimide XI hydrochloride (Bis XI), when a challenge of 3 µ M oxycodone significantly reduced neuronal excitability following prolonged exposure. Through these studies, we concluded that oxycodone acutely reduced neuronal excitability, tolerance developed to this effect, and reversal of that tolerance occurred at the level of a single neuron, suggesting that reversal of oxycodone tolerance by either ethanol or Bis XI involves cellular mechanisms. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Potentiation of oxycodone antinociception in mice by agmatine and BMS182874 via an imidazoline I2 receptor-mediated mechanism.

PubMed

Bhalla, Shaifali; Ali, Izna; Lee, Hyaera; Andurkar, Shridhar V; Gulati, Anil

2013-01-01

The potentiation of oxycodone antinociception by BMS182874 (endothelin-A (ET(A)) receptor antagonist) and agmatine (imidazoline receptor/α(2)-adrenoceptor agonist) is well-documented. It is also known that imidazoline receptors but not α(2)-adrenoceptors are involved in potentiation of oxycodone antinociception by agmatine and BMS182874 in mice. However, the involvement of specific imidazoline receptor subtypes (I(1), I(2), or both) in this interaction is not clearly understood. The present study was conducted to determine the involvement of imidazoline I(1) and I(2) receptors in agmatine- and BMS182874-induced potentiation of oxycodone antinociception in mice. Antinociceptive (tail flick and hot-plate) latencies were determined in male Swiss Webster mice treated with oxycodone, agmatine, BMS182874, and combined administration of oxycodone with agmatine or BMS182874. Efaroxan (imidazoline I(1) receptor antagonist) and BU224 (imidazoline I(2) receptor antagonist) were used to determine the involvement of I(1) and I(2) imidazoline receptors, respectively. Oxycodone produced significant antinociceptive response in mice which was not affected by efaroxan but was blocked by BU224. Agmatine-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. Similarly, BMS182874-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. This is the first report demonstrating that BMS182874- or agmatine-induced enhancement of oxycodone antinociception is blocked by BU224 but not by efaroxan. We conclude that imidazoline I(2) receptors but not imidazoline I(1) receptors are involved in BMS182874- and agmatine-induced potentiation of oxycodone antinociception in mice. Copyright © 2012 Elsevier Inc. All rights reserved.

Oxycodone physical dependence and its oral self-administration in C57BL/6J mice.

PubMed

Enga, Rachel M; Jackson, Asti; Damaj, M Imad; Beardsley, Patrick M

2016-10-15

Abuse of prescription opioids, such as oxycodone, has markedly increased in recent decades. While oxycodone's antinociceptive effects have been detailed in several preclinical reports, surprisingly few preclinical reports have elaborated its abuse-related effects. This is particularly surprising given that oxycodone has been in clinical use since 1917. In a novel oral operant self-administration procedure, C57BL/6J mice were trained to self-administer water before introducing increasing concentrations of oxycodone (0.056-1.0mg/ml) under post-prandial conditions during daily, 3-h test sessions. As the concentration of oxycodone increased, the numbers of deliveries first increased, then decreased in an inverted U-shape fashion characteristic of the patterns of other drugs self-administered during limited access conditions. After post-prandial conditions were removed, self-administration at the highest concentration was maintained suggesting oral oxycodone served as a positive reinforcer. In other mice, using a novel regimen of physical dependence, mice were administered increasing doses of oxycodone (9.0-33.0mg/kg, s.c.) over 9 days, challenged with naloxone (0.1-10.0mg/kg, s.c.), and then observed for 30min. Naloxone dose-dependently increased the observed number of somatic signs of withdrawal, suggesting physical dependence of oxycodone was induced under this regimen. This is the first report demonstrating induction of oral operant self-administration of oxycodone and dose-dependent precipitations of oxycodone withdrawal in C57BL/6J mice. The use of oral operant self-administration as well as the novel physical dependence regimen provides useful approaches to further examine the abuse- and dependence-related effects of this highly abused prescription opioid. Copyright © 2016 Elsevier B.V. All rights reserved.

Impact of abuse-deterrent OxyContin on prescription opioid utilization.

PubMed

Hwang, Catherine S; Chang, Hsien-Yen; Alexander, G Caleb

2015-02-01

We quantified the degree to which the August 2010 reformulation of abuse-deterrent OxyContin affected its use, as well as the use of alternative extended-release and immediate-release opioids. We used the IMS Health National Prescription Audit, a nationally representative source of prescription activity in the USA, to conduct a segmented time-series analysis of the use of OxyContin and other prescription opioids. Our primary time period of interest was 12 months prior to and following August 2010. We performed model checks and sensitivity analyses, such as adjusting for marketing and promotion, using alternative lag periods, and adding extra observation points. OxyContin sales were similar before and after the August 2010 reformulation, with approximately 550 000 monthly prescriptions. After adjusting for declines in the generic extended-release oxycodone market, the formulation change was associated with a reduction of approximately 18 000 OxyContin prescription sales per month (p = 0.02). This decline corresponded to a change in the annual growth rate of OxyContin use, from 4.9% prior to the reformulation to -23.8% during the year after the reformulation. There were no statistically significant changes associated with the sales of alternative extended-release (p = 0.42) or immediate-release (p = 0.70) opioids. Multiple sensitivity analyses supported these findings and their substantive interpretation. The market debut of abuse-deterrent OxyContin was associated with declines in its use after accounting for the simultaneous contraction of the generic extended-release oxycodone market. Further scrutiny into the effect of abuse-deterrent formulations on medication use and health outcomes is vital given their popularity in opioid drug development. Copyright © 2014 John Wiley & Sons, Ltd.

Pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxycodone transdermal patch system: a Phase I study.

PubMed

Gavin, Paul D; Simon, Lee S; Schlagheck, Thomas; Smith, Alisha J; Shakib, Sepehr

2017-07-01

To characterize the pharmacokinetic profile and evaluate the safety and tolerability of a transdermal oxycodone patch containing tocopheryl phosphate mixture (TPM). Eleven healthy subjects received a single application of three TPM/oxycodone patches applied to the torso for 72 h. Oxycodone was detected 8.0 ± 2.7-h postpatch administration, reaching a mean maximum plasma concentration of 3.41 ± 1.34 ng/ml at 49.3 ± 21.2 h. The safety profile was consistent with the application method and known side-effect profile of oxycodone and naltrexone. No treatment-limiting skin irritation was observed. A 3-day application of the TPM/oxycodone patch demonstrated an acceptable safety profile and was well tolerated by healthy subjects, with limited dermal irritation following application.

Maximizing value in opioid utilization: Is oxycodone immediate release a good option for pain management?

PubMed

Pergolizzi, Joseph V; Köknel Talu, Gül; Zmponga, Gianpetrio; Erdine, Serdar; Taylor, Robert; Ayan, Burak; Raffa, Robert B

2015-01-01

The modern approach to the management of pain involves optimizing all aspects of the process. This includes utilization of pharmacologic and non-pharmacologic modalities, consideration of patient characteristics, proper matching of the physiology of the pain with the analgesic's mechanism of action (pharmacodynamics, PD), and the onset and duration of action (pharmacokinetics, PK). No single agent or formulation satisfies all of the requirements for all patients. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are effective options for inflammatory pain and, as is acetaminophen, for mild pain. Specialized agents are helpful for particular pains, such as for migraine headache. Opioids remain the standard option for severe pain. Although they are generally a safe and effective option, opioids can produce dose-limiting adverse effects and have abuse potential. The goal of pain therapy is thus to achieve the maximum pain relief with the least amount of opioid exposure. Against this background of measured approach to the use of analgesics, an immediate release (IR) oral formulation of the established opioid oxycodone has been developed to provide rapid onset of action and rate of titration, both of which could maximize temporal matching of dose with pain level and reduce total exposure to drug. This article considers the option of an immediate release (IR) oral formulation for the management of pain.

Effect of Currently Approved Carriers and Adjuvants on the Pre-Clinical Efficacy of a Conjugate Vaccine against Oxycodone in Mice and Rats

PubMed Central

Pravetoni, Marco; Vervacke, Jeffrey S.; Distefano, Mark D.; Tucker, Ashli M.; Laudenbach, Megan; Pentel, Paul R.

2014-01-01

Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund’s adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations. PMID:24797666

Role of mu, but not delta or kappa, opioid receptors in context-induced reinstatement of oxycodone seeking.

PubMed

Bossert, Jennifer M; Hoots, Jennifer K; Fredriksson, Ida; Adhikary, Sweta; Zhang, Michelle; Venniro, Marco; Shaham, Yavin

2018-05-19

Relapse to nonmedical use of prescription opioids often occurs after exposure to places previously associated with drug use. Here, we describe a rat model of context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction-induced abstinence. We also determined the role of mu, delta, and kappa opioid receptors (MOR, DOR, KOR) in this reinstatement. We trained rats to self-administer oxycodone for 6 h/d in Context A; lever pressing was paired with a discrete cue. Next, we extinguished the lever pressing in the presence of the discrete cue in Context B and then tested the rats for reinstatement of oxycodone seeking in both contexts. We retrained rats to self-administer oxycodone in Context A, re-extinguished their lever pressing in Context B, and retested them for reinstatement in both contexts. Prior to testing, we injected the rats with vehicle or antagonists of MOR (naltrexone; 0.5 or 1.0 mg/kg), DOR (naltrindole; 7.5 or 15 mg/kg), or KOR (LY2456302; 5 or 10 mg/kg). We also tested the effect of naltrexone, naltrindole, and LY2456302 on oxycodone self-administration under fixed-ratio-1 (FR1) and progressive-ratio (PR) reinforcement schedules. We observed context-induced reinstatement of oxycodone seeking after repeated cycles of drug self-administration and extinction. Naltrexone, but not naltrindole or LY2456302, injections decreased this reinstatement. Additionally, naltrexone increased oxycodone self-administration under the FR1 schedule and decreased oxycodone self-administration under the PR schedule; naltrindole and LY2456302 were ineffective. Results demonstrate a critical role of MOR, but not DOR or KOR, in context-induced reinstatement of oxycodone seeking and oxycodone self-administration. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Modeling the Frequency and Costs Associated with Postsurgical Gastrointestinal Adverse Events for Tapentadol IR versus Oxycodone IR

PubMed Central

Paris, Andrew; Kozma, Chris M.; Chow, Wing; Patel, Anisha M.; Mody, Samir H.; Kim, Myoung S.

2013-01-01

Background Few studies have estimated the economic effect of using an opioid that is associated with lower rates of gastrointestinal (GI) adverse events (AEs) than another opioid for postsurgical pain. Objective To estimate the number of postsurgical GI events and incremental hospital costs, including potential savings, associated with lower GI AE rates, for tapentadol immediate release (IR) versus oxycodone IR, using a literature-based calculator. Methods An electronic spreadsheet–based cost calculator was developed to estimate the total number of GI AEs (ie, nausea, vomiting, or constipation) and incremental costs to a hospital when using tapentadol IR 100 mg versus oxycodone IR 15 mg, in a hypothetical cohort of 1500 hospitalized patients requiring short-acting opioids for postsurgical pain. Data inputs were chosen from recently published, well-designed studies, including GI AE rates from a previously published phase 3 clinical trial of postsurgical patients who received these 2 opioids; GI event–related incremental length of stay from a large US hospital database; drug costs using wholesale acquisition costs in 2011 US dollars; and average hospitalization cost from the 2009 Healthcare Cost and Utilization Project database. The base case assumed that 5% (chosen as a conservative estimate) of patients admitted to the hospital would shift from oxycodone IR to tapentadol IR. Results In this hypothetical cohort of 1500 hospitalized patients, replacing 5% of oxycodone IR 15-mg use with tapentadol IR 100-mg use predicted reductions in the total number of GI events from 1095 to 1085, and in the total cost of GI AEs from $2,978,400 to $2,949,840. This cost reduction translates to a net savings of $22,922 after factoring in drug cost. For individual GI events, the net savings were $26,491 for nausea; $12,212 for vomiting; and $7187 for constipation. Conclusion Using tapentadol IR in place of a traditional μ-opioid shows the potential for reduced GI events and subsequent cost-savings in the postsurgical hospital setting. In the absence of sufficient real-world data, this literature-based cost calculator may assist hospital Pharmacy & Therapeutics committees in their evaluation of the costs of opioid-related GI events. PMID:24991383

Reversal of oxycodone and hydrocodone tolerance by diazepam.

PubMed

Gonek, Maciej; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L

2017-11-01

The Centers for Disease Control has declared opioid abuse to be an epidemic. Overdose deaths are largely assumed to be the result of excessive opioid consumption. In many of these cases, however, opioid abusers are often polydrug abusers. Benzodiazepines are one of the most commonly co-abused substances and pose a significant risk to opioid users. In 2016, the FDA required boxed warnings - the FDA's strongest warning - for prescription opioid analgesics and benzodiazepines about the serious risks associated with using these medications at the same time. The point of our studies was to evaluate the interactions between these two classes of drugs. We investigated whether diazepam adds to the depressant effects of opioids or do they alter the levels of tolerance to opioids. In the present study, we have found that the antinociceptive tolerance that developed to repeated administration of oxycodone was reversed by an acute dose of diazepam. Antinociceptive tolerance to hydrocodone was also reversed by acute injection of diazepam; however, a fourfold higher dose of diazepam was required when compared to reversal of oxycodone-induced tolerance. These doses of diazepam did not potentiate the acute antinociceptive effect of either opioid. The same dose of diazepam that reversed oxycodone antinociceptive tolerance also reversed oxycodone locomotor tolerance while having no potentiating effects. These studies show that diazepam does not potentiate the acute effect of prescription opioids but reverses the tolerance developed after chronic administration of the drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Stability indicating HPLC method for the estimation of oxycodone and lidocaine in rectal gel.

PubMed

Gebauer, M G; McClure, A F; Vlahakis, T L

2001-07-31

An HPLC method for the quantification of oxycodone and lidocaine in a gel matrix is described. The mobile phase consisted of methanol--water--acetic acid (35:15:1 v/v/v) and was delivered at 1.5 ml/min through a 4.6 x 250 mm Zorbax SB-C8 column. Oxycodone was detected at 285 nm and lidocaine at 264 nm. Linear calibration curves were obtained for oxycodone in the range of 0.05--1.5% (w/w) and for lidocaine in the range of 0.1--5.0% (w/w). Oxycodone and lidocaine were treated with hydrogen peroxide and the oxidation products were readily separated on the column. The method was applied to assess the stability of a gel containing oxycodone hydrochloride (0.3% w/w) and lidocaine (1.5% w/w). The gel was stored under refrigeration in ready-to-use syringes and under these conditions oxycodone and lidocaine were stable for at least 1 year. The gel is useful in the management of tenesmus in rectal cancer.

Oral oxycodone offers equivalent analgesia to intravenous patient-controlled analgesia after total hip replacement: a randomized, single-centre, non-blinded, non-inferiority study.

PubMed

Rothwell, M P; Pearson, D; Hunter, J D; Mitchell, P A; Graham-Woollard, T; Goodwin, L; Dunn, G

2011-06-01

To determine if oral oxycodone (OOXY) could provide equivalent postoperative analgesia and a similar side-effect profile to i.v. patient-controlled morphine in patients undergoing elective primary total hip replacement (THR) under spinal anaesthesia. We studied 110 consecutive patients aged 60-85 yr. After operation, patients were randomly allocated to receive either oral controlled- and immediate-release OOXY or i.v. patient-controlled analgesia (IVPCA) with morphine. Both groups received regular co-analgesia and antiemetics. The primary outcome measures were: (i) postoperative pain at rest and movement and (ii) nausea score recorded 12 hourly. The secondary outcome measures were: (i) time to first mobilization, (ii) total amount of opioid consumed, (iii) number of additional antiemetic doses, and (iv) time to analgesic discontinuation. There were no statistically significant differences in the primary outcome measures of pain at rest and movement (P>0.05, 95% confidence intervals -0.41, +0.96) or nausea score (P>0.5). The secondary outcome measures showed no significant difference in the total amount of opioid consumed (102 vs 63 mg; P>0.05) or time to mobilization (24.45 vs 26.6 h, P=0.2). The number of antiemetic doses required in the first 24 h was significantly lower in the OOXY group (1.1 vs 1.4, P<0.05). The time to analgesic discontinuation was significantly shorter in the OOXY group (50.5 vs 56.6 h, P<0.05). Oral analgesia with OOXY was approximately GBP 10 less expensive per patient than IVPCA. Oral analgesia with OOXY after THR offers non-inferior analgesia to IVPCA and may offer some logistical and cost advantages.

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.

Understanding opioid overdose characteristics involving prescription and illicit opioids: A mixed methods analysis.

PubMed

Yarborough, Bobbi Jo H; Stumbo, Scott P; Janoff, Shannon L; Yarborough, Micah T; McCarty, Dennis; Chilcoat, Howard D; Coplan, Paul M; Green, Carla A

2016-10-01

Opioid abuse and misuse are significant public health issues. The CDC estimated 72% of pharmaceutical-related overdose deaths in the US in 2012 involved opioids. While studies of opioid overdoses have identified sociodemographic characteristics, agents used, administration routes, and medication sources associated with overdoses, we know less about the context and life circumstances of the people who experience these events. We analyzed interviews (n=87) with survivors of opioid overdoses or family members of decedents. Individuals experiencing overdoses were members of a large integrated health system. Using ICD codes for opioid overdoses and poisonings, we identified participants from five purposefully derived pools of health-plan members who had: 1) prescriptions for OxyContin(®) or single-ingredient sustained-release oxycodone, 2) oxycodone single-ingredient immediate release, 3) other long-acting opioids, 4) other short-acting opioids, or 5) no active opioid prescriptions. Individuals who experienced opioid overdoses abused and misused multiple medications/drugs; experienced dose-related miscommunications or medication-taking errors; had mental health and/or substance use conditions; reported chronic pain; or had unstable resources or family/social support. Many had combinations of these risks. Most events involved polysubstance use, often including benzodiazepines. Accidental overdoses were commonly the result of abuse or misuse, some in response to inadequately treated chronic pain or, less commonly, medication-related mistakes. Suicide attempts were frequently triggered by consecutive negative life events. To identify people at greater risk of opioid overdose, efforts should focus on screening for prescribed and illicit polysubstance use, impaired cognition, and changes in life circumstances, psychosocial risks/supports, and pain control. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A comparison among tapentadol tamper-resistant formulations (TRF) and OxyContin® (non-TRF) in prescription opioid abusers

PubMed Central

Vosburg, Suzanne K.; Jones, Jermaine D.; Manubay, Jeanne M.; Ashworth, Judy B.; Shapiro, Douglas Y.; Comer, Sandra D.

2013-01-01

Aims To examine whether tamper-resistant formulations (TRFs) of tapentadol hydrochloride ER 50 mg (TAP50) and tapentadol hydrochloride 250 mg (TAP250) could be converted into forms amenable to intranasal (Study 1) or intravenous abuse (Study 2). Design Randomized, repeated-measures study designs were employed. A non-TRF of OxyContin® 40 mg (OXY40) served as a positive control. No drug was taken in either study. Setting The studies took place in an outpatient setting in New York, NY. Participants 25 experienced, healthy extended-release oxycodone abusers participated in each study. Measurements The primary outcome for Study 1 was percentage of participants who indicated they would snort the tampered tablets, while the primary outcome for Study 2 was percent yield of active drug in solution. Other descriptive variables such as time spent manipulating the tablets were also examined to better characterize tampering behaviors. Findings Tampered TRF tablets were less desirable than the tampered OXY40 tablets. Few individuals were willing to snort the TRF particles (TAP50: 24%, TAP250: 16%; OXY40: 100% p<.001). There was less drug extracted from the TAP50 tablet than from the OXY40 tablet (3.5% vs. 37.0%, p=.008), and no samples from the TAP250 tablets contained analyzable solutions of the drug. It took participants longer to tamper with the TAPs (Study 1: TAP50 vs. OXY40, p<.01; TAP250 vs. OXY40, p<.01; Study 2: TAP250 vs. OXY40, p<05). Conclusions Taptentadol TRF tablets were not well-liked by individuals who regularly tampered with extended-release oxycodone tablets. Employing tamper resistant technology may be a promising approach towards reducing the abuse potential of tapentadol ER. PMID:23316699

Opioid tolerance and urine drug testing among initiates of extended-release or long-acting opioids in Food and Drug Administration's Sentinel System.

PubMed

Larochelle, Marc R; Cocoros, Noelle M; Popovic, Jennifer; Dee, Elizabeth C; Kornegay, Cynthia; Ju, Jing; Racoosin, Judith A

A risk evaluation and mitigation strategy for extended-release and long-acting (ER/LA) opioid analgesics was approved by the Food and Drug Administration in 2012. Our objective was to assess frequency of opioid tolerance and urine drug testing for individuals initiating ER/LA opioid analgesics. Retrospective cohort study. Sentinel, a distributed database with electronic healthcare data on >190 million predominantly commercially insured members. Members under age 65 initiating ER/LA opioid analgesics between January 2009 and December 2013. We examined the proportion of opioid-tolerant-only ER/LA opioid analgesic initiates meeting tolerance criteria: receipt of ≥30 mg oxycodone equivalents per day in 7 days prior to the first opioid-tolerant-only dispensing. We separately examined the proportion of new users of extended-release oxycodone (ERO) and other ER/LA opioid analgesics with a claim for a urine drug test in the 30 days prior to, and separately for the 183 days after, dispensing. We identified 79,824 ERO, 7,343 extended-release hydromorphone, and 91,778 transdermal fentanyl opi-oid-tolerant-only episodes. Tolerance criteria were met in 64 percent of ERO, 64 percent of extended-release hydromorphone and 40 percent of transdermal fentanyl episodes. We identified 210,581 incident ERO and 311,660 other ER/LA opioid analgesic episodes. Use of urine drug testing for ERO compared with other ER/LA opioid analgesics was: 4 percent vs 14 percent respectively in the 30 days prior to initiation and 9 percent vs 23 percent respectively in the 183 days following initiation. These results suggest potential areas for improving appropriate ER/LA opioid analgesic prescribing practices.

Population pharmacokinetics of oxycodone in patients with cancer-related pain.

PubMed

Komatsu, Toshiaki; Kokubun, Hideya; Suzuki, Ai; Takayanagi, Risa; Yamada, Yasuhiko; Matoba, Motohiro; Yago, Kazuo

2012-09-01

Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

The analgesic efficacy of oxycodone hydrochloride versus fentanyl during outpatient artificial abortion operation: A randomized trial.

PubMed

Xie, Kangjie; Zhang, Wen; Fang, Wumei; Lian, Yanhong; Lin, Sufeng; Fang, Jun

2017-06-01

Problems like body movement, respiratory depression, and complained of pain are still common phenomenon in outpatient artificial abortion general anesthesia. Oxycodone hydrochloride is a semisynthetic opioid and has a good therapeutic effect on visceral pain. We hypothesize that oxycodone hydrochloride would be superior to fentanyl in outpatient artificial abortion surgery. In this clinical trial 149 American Society of Anesthesiologists (ASA) I or II female outpatients scheduled for elective artificial abortion surgeries under general anesthesia were randomly divided into 3 groups: oxycodone hydrochloride 0.06 mg/kg group (group A), oxycodone hydrochloride 0.08 mg/kg group (group B), and control group fentanyl 2 ug/kg (group C). The primary outcome was level body movement and respiratory depression during the surgery, the second outcome included the visual analogue scale (VAS) score 30 minutes after waking. A total of 120 participants completed the study, n = 40 in each group. There was no significant difference in patients' age, body mass index (BMI), preoperative heart rate, mean arterial blood pressure, consumption dose of propofol, intraoperative body movement type and times, and duration of surgery among the 3 groups (P > .05). Comparing the incidence of intraoperative respiratory depression and SPO2 < 90% among the 3 groups, group C's was significantly higher than those of groups A and B, and the difference was statistically significant (P < .05). Group A had no difference compared with group B. In VAS score 30minutes after waking, group C was the highest, followed by group A, with group B as the lowest. The difference among the 3 groups was statistically significant (P < .05), but a difference delta less than 1 on the VAS scale is not clinically significant. The analgesic effect of oxycodone hydrochloride at 0.06 mg/kg applied to painless artificial abortion surgery is not superior than that of fentanyl, but the incidence of intraoperative respiratory depression and hypoxemia is significantly lower than fentanyl.

Development and characterization of a mucoadhesive sublingual formulation for pain control: extemporaneous oxycodone films in personalized therapy.

PubMed

Parodi, Brunella; Russo, Eleonora; Baldassari, Sara; Zuccari, Guendalina; Pastorino, Sara; Yan, Mengying; Neduri, Karthik; Caviglioli, Gabriele

2017-06-01

The aim of this work was the development of mucoadhesive sublingual films, prepared using a casting method, for the administration of oxycodone. A solvent casting method was employed to prepare the mucoadhesive films. A calibrated pipette was used to deposit single aliquots of different polymeric solutions on a polystyrene plate lid. Among the various tested polymers, hydroxypropylcellulose at low and medium molecular weight (HPC) and pectin at two different degrees of esterification (PC) were chosen for preparing solutions with good casting properties, capable of producing films suitable for mucosal application. The obtained films showed excellent drug content uniformity and stability and rapid drug release, which, at 8 min, ranged from 60% to 80%. All films presented satisfactory mucoadhesive and mechanical properties, also confirmed by a test on healthy volunteers, who did not experience irritation or mucosa damages. Pectin films based on pectin at lower degrees of esterification have been further evaluated to study the influence of two different amounts of drug on the physicochemical properties of the formulation. A slight reduction in elasticity has been observed in films containing a higher drug dose; nevertheless, the formulation maintained satisfactory flexibility and resistance to elongation. HPC and PC sublingual films, obtained by a simple casting method, could be proposed to realize personalized hospital pharmacy preparations on a small scale.

Increasing deaths involving oxycodone, Victoria, Australia, 2000-09.

PubMed

Rintoul, Angela C; Dobbin, Malcolm D H; Drummer, Olaf H; Ozanne-Smith, Joan

2011-08-01

In light of an emerging epidemic identified in the United States and Canada, to identify trends in fatal drug toxicity involving oxycodone and the demographic characteristics and indicators of socioeconomic disadvantage of the deceased. Population-based observational study in Victoria, Australia. Decedents whose death was reported to the Victorian Coroner between 2000 and 2009 and where oxycodone was detected. Association between supply of oxycodone and deaths. Demographic characteristics of decedents. Rate ratios of the rural or metropolitan location and socioeconomic indicators of disadvantage of the deceased. Supply to Victoria has increased nine-fold from 7.5 mg per capita in 2000 to 67.5 mg per capita in 2009. Detection of oxycodone in deaths reported to the Victorian Coroner has increased from 4 (0.08/100,000 population) in 2000 to 97 (1.78/100,000 population) in 2009-a 21-fold increase in deaths. Of the 320 cases described, 53.8% (172) were the result of drug toxicity. Of these, 52.3% were unintentional and 19.8% intentional self-harm; the remaining 27.9% are either still under investigation by the coroner or intent is unknown. Drug toxicity deaths were overrepresented in both rural areas and areas indexed with high levels of disadvantage. The substantial increase in the number of deaths involving oxycodone is strongly and significantly associated with the increase in supply. Most drug toxicity deaths involving oxycodone were unintentional. This newly identified trend in fatalities in Victoria supports concerns that a pattern of increasing deaths involving oxycodone is emerging globally.

Effect of oxycodone hydrochloride combined with flurbiprofen axetil for intravenous patient-controlled analgesia in lower abdominal patients: A randomized trial.

PubMed

Xiang, Xiaobing; Yuan, Xiaohong; Lian, Yanhong; Fang, Jun; Wu, Yingli

2018-02-01

Problems like postoperative pain are still common phenomena after general anesthesia. Oxycodone hydrochloride is a semisynthetic opioid with a safe and excellent therapeutic effect on visceral pain. Flurbiprofen axetil has the efficacy of targeted analgesia. We hypothesize that different doses of oxycodone hydrochloride combined with flurbiprofen axetil would generate great results on postoperative intravenous analgesia in lower abdominal patients. In the clinical trial, 90 American Society of Anesthesiologists I or II patients scheduled for elective general anesthesia were randomly divided into 3 groups, 30 cases in each group. Group I: oxycodone hydrochloride 0.5 mg/kg + flurbiprofen axetil 150 mg, group II: oxycodone hydrochloride 0.75 mg/kg + flurbiprofen axetil 150 mg, group III: oxycodone hydrochloride 1.0 mg/kg + flurbiprofen axetil 150 mg. Dilute them with 0.9% saline to 150 mL, respectively, with the background dose of 2 mL/h, patient-controlled analgesia 2 mL per time, with an interval of 10 min, and the loading dose of 0.1 mL/kg. Record the preoperative situation, 24 h (T0) before surgery, postoperative situation, 1 h (T1), 4 h (T2), 8 h (T3), 12 h (T4), 24 h (T5), 48 h (T6), 72 h (T7) after the surgery, including the mean arterial pressure, heart rate, saturation of pulse oximetry, static and dynamic pain rating (NRS) and Ramsay sedation score, effective pressing and total pressing ratio (referred to as the pressing ratio), patient satisfaction, and occurrence of adverse reactions. There was no significant statistic difference in mean arterial blood pressure, heart rate, arterial oxygen saturation, and adverse reactions among the 2 groups at each time point (P > .05). Compared with group I, the static NRS rating in group II and group III were significantly lower than that in group I (P < .05) from T1 to T5. The dynamic NRS rating of group II from T1 to T4 and that of group III from T1 to T5 were significantly lower (P < .05). The effective pressing and total pressing ratio was significantly higher (P < .05). There was no significant statistic difference between group II and group III in NRS rating and the effective pressing and total pressing ratio (P > .05). Compared with group III, the Ramsay sedation scores of group I and group II were significantly lower from T1 to T4 (P < .05). The dose of 0.75 mg/kg oxycodone hydrochloride combined with flurbiprofen axetil can provide safe and effective postoperative analgesia for lower abdominal patients, with fewer adverse reactions.

Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction

PubMed Central

Leppert, Wojciech

2015-01-01

Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD, and OXN may be also considered as a preventive measure of OIBD development in patients who require opioid administration. PMID:25931815

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.

A Novel Chronic Opioid Monitoring Tool to Assess Prescription Drug Steady State Levels in Oral Fluid.

PubMed

Shaparin, Naum; Mehta, Neel; Kunkel, Frank; Stripp, Richard; Borg, Damon; Kolb, Elizabeth

2017-11-01

Interpretation limitations of urine drug testing and the invasiveness of blood toxicology have motivated the desire for the development of simpler methods to assess biologically active drug levels on an individualized patient basis. Oral fluid is a matrix well-suited for the challenge because collections are based on simple noninvasive procedures and drug concentrations better correlate to blood drug levels as oral fluid is a filtrate of the blood. Well-established pharmacokinetic models were utilized to generate oral fluid steady state concentration ranges to assess the interpretive value of the alternative matrix to monitor steady state plasma oxycodone levels. Paired oral fluid and plasma samples were collected from patients chronically prescribed oxycodone and quantitatively analyzed by liquid chromatography tandem mass spectrometry. Steady state plasma concentration ranges were calculated for each donor and converted to an equivalent range in oral fluid. Measured plasma and oral fluid oxycodone concentrations were compared with respective matrix-matched steady state ranges, using each plasma steady state classification as the control. A high degree of correlation was observed between matrices when classifying donors according to expected steady state oxycodone concentration. Agreement between plasma and oral fluid steady state classifications was observed in 75.6% of paired samples. This study supports novel application of basic pharmacokinetic knowledge to the pain management industry, simplifying and improving individualized drug monitoring and risk assessment through the use of oral fluid drug testing. Many benefits of established therapeutic drug monitoring in plasma can be realized in oral fluid for patients chronically prescribed oxycodone at steady state. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Continuous subcutaneous infusion of compound oxycodone for the relief of dyspnea in patients with terminally ill cancer: a retrospective study.

PubMed

Kawabata, Masahiro; Kaneishi, Keisuke

2013-05-01

Pain and dyspnea are the most prevalent and distressing symptoms in patients with terminally ill cancer. Evidences have accumulated for the effects of morphine on dyspnea, whereas little is known about the effects of oxycodone on dyspnea. We investigated the effectiveness of oxycodone for dyspnea in patients with terminally ill cancer. The injectable form of compound oxycodone (iOC) containing hydrocotarnine was administered continuously via subcutaneous route. We administered iOC to 136 patients. The effect on dyspnea was less conspicuous than pain, yet iOC was effective for dyspnea with varying degrees. None of the adverse effects observed were serious. These results suggest that continuous subcutaneous administration of oxycodone could be one of the reasonable alternatives in the management of dyspnea in patients with terminally ill cancer.

Lorcaserin suppresses oxycodone self-administration and relapse vulnerability in rats

PubMed Central

Neelakantan, Harshini; Holliday, Erica D.; Fox, Robert G.; Stutz, Sonja J.; Comer, Sandra D.; Haney, Margaret; Anastasio, Noelle C.; Moeller, F. Gerard; Cunningham, Kathryn A.

2017-01-01

Opioid use disorder (OUD) is a major public health problem. High relapse rates and poor treatment retention continue to pose major challenges in OUD treatment. Of the abused opioids, oxycodone is well described to maintain self-administration and evoke the durable conditioned responses (“cue reactivity”) that result from pairing of opioid-related stimuli (e.g., paraphernalia) with repeated abuse. Serotonin (5-HT) neurotransmission, particularly through the 5-HT2C receptor (5-HT2CR), regulates psychostimulant reward and cue reactivity, and in the present experiments, we investigated the hypothesis that the selective 5-HT2CR agonist lorcaserin, which is FDA-approved for the treatment of obesity, will suppress oxycodone self-administration and oxycodone-associated cue reactivity in rats. We found that lorcaserin inhibited oxycodone intake, an effect blocked by the selective 5-HT2CR antagonist SB242084. Lorcaserin also decreased responding for the discrete cue complex (“cue reactivity”) previously associated with delivery of oxycodone (i.e., stimulus lights, infusion pump sounds) in both abstinence and extinction-reinstatement models. The selected dose range of lorcaserin (0.25–1 mg/kg) does not overtly alter spontaneous behaviors nor operant responding on inactive levers in the present study. Taken together, the ability of lorcaserin to reduce the oxycodone self-administration and decrease cue reactivity associated with relapse highlights the therapeutic potential for lorcaserin in the treatment of OUD. PMID:28107783

Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self-administration: a RNA sequencing study.

PubMed

Zhang, Yong; Liang, Yupu; Levran, Orna; Randesi, Matthew; Yuferov, Vadim; Zhao, Connie; Kreek, Mary Jeanne

2017-08-01

Non-medical use of prescription opioids such as the mu opioid receptor (MOP-r) agonist oxycodone is a growing problem in the USA and elsewhere. There is limited information about oxycodone's impact on diverse gene systems in the brain. The current study was designed to examine how chronic oxycodone self-administration (SA) affects gene expression in the terminal areas of the nigrostriatal and mesolimbic dopaminergic pathways in mice. Adult male C57BL/6J mice underwent a 14-day oxycodone self-administration procedure (4 h/day, 0.25 mg/kg/infusion, FR1) and were euthanized 1 h after the last session. The dorsal and ventral striata were dissected, and total RNAs were extracted. Gene expressions were examined using RNA sequencing. We found that oxycodone self-administration exposure led to alterations of expression in numerous genes related to inflammation/immune functions in the dorsal striatum (54 upregulated genes and 1 downregulated gene) and ventral striatum (126 upregulated genes and 15 downregulated genes), with 38 upregulated genes identified in both brain regions. This study reveals novel neurobiological mechanisms underlying some of the effects of a commonly abused prescription opioid. We propose that inflammation/immune gene systems may undergo a major change during chronic self-administration of oxycodone.

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 100,000 members per quarter [95% CI, -0.01 to 0.53]). Opioid dispensing and prescription opioid overdoses decreased substantially after 2 major changes in the pharmaceutical market in late 2010. Pharmaceutical market interventions may have value in combatting the prescription opioid overdose epidemic, but heroin overdose rates continue to increase. Complementary strategies to identify and treat opioid abuse and addiction are urgently needed.

Long-term Safety and Efficacy of Tapentadol Extended Release Following up to 2 Years of Treatment in Patients With Moderate to Severe, Chronic Pain: Results of an Open-label Extension Trial.

PubMed

Buynak, Robert; Rappaport, Stephen A; Rod, Kevin; Arsenault, Pierre; Heisig, Fabian; Rauschkolb, Christine; Etropolski, Mila

2015-11-01

Tapentadol extended release (ER) has demonstrated efficacy and safety for the management of moderate to severe, chronic pain in adults. This study evaluated the long-term safety and tolerability of tapentadol ER in patients with chronic osteoarthritis or low back pain. Patients were enrolled in this 1-year, open-label extension study after completing one of two 15-week, placebo-controlled studies of tapentadol ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain (NCT00449176), a 7-week crossover study between tapentadol immediate release and tapentadol ER for low back pain (NCT00594516), or a 1-year safety study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After titrating the drug to an optimal dose, patients received tapentadol ER (100-250 mg BID) for up to 1 year (after finishing treatment in the preceding studies); patients who were previously treated with tapentadol ER in the 1-year safety study received tapentadol ER continuously for up to 2 years in total. Of the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were female; 50.1% had mild baseline pain intensity. Mean (SD) pain intensity scores (11-point numerical rating scale) were 3.9 (2.38) at baseline (end of preceding study) and 3.7 (2.42) at end point, indicating that pain relief was maintained during the extension study. Improvements in measures of quality of life (eg, EuroQol-5 Dimension and the 36-item Short Form Health Survey [SF-36]) health status questionnaires) achieved during the preceding studies were maintained during the open-label extension study. Tapentadol ER was associated with a safety and tolerability profile comparable to that observed in the preceding studies. The most common treatment-emergent adverse events (incidence ≥10%; n = 1154) were headache (13.1%), nausea (11.8%), and constipation (11.1%). Similar efficacy and tolerability results were shown for patients who received up to 2 years of tapentadol ER treatment. Pain relief and improvements in quality of life achieved during the preceding studies were maintained throughout this extension study, during which tapentadol ER was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment. (ClinicalTrials.gov identifier: NCT00487435.). Copyright © 2015. Published by Elsevier Inc.

A fatal drug interaction between oxycodone and clonazepam.

PubMed

Burrows, David L; Hagardorn, Andrea N; Harlan, Gretel C; Wallen, Ellen D B; Ferslew, Kenneth E

2003-05-01

A case is presented of a fatal drug interaction caused by ingestion of oxycodone (Oxycontin) and clonazepam (Klonapin). Oxycodone is an opium alkaloid used in long-term pain management therapy. Clonazepam is a benzodiazepine used for the treatment of seizures and panic disorders. The Drug Abuse Warning Network (DAWN) has reported an increase of 108% in the last two years of emergency department episodes related to Oxycontin. Six billion prescriptions were written for Oxycontin in the year 2000, an 18-fold increase from four years previous (1). Oxycontin has recently gained enormous notoriety at the local and national levels; however, there are very few previously documented cases of lethal drug interactions between oxycodone and clonazepam. Synergistic effects between these two drugs are postulated to arise from different agonistic mechanisms producing similar physiological changes. It is also theorized that clonazepam may inhibit the metabolism of oxycodone. A 38-year-old white female was found dead in Jefferson County, Tennessee in March of 2001. The deceased had physical evidence of previous drug abuse and positive serological findings of hepatitis B and C. Prescription pill bottles filled under the name of the deceased, as well as another name, were found with the body. Serum, urine and gastric contents from the deceased were screened for numerous drugs and metabolites using a combination of thin layer chromatography and immunoassay techniques (EMIT and FPIA). Analysis of biological specimens from the deceased revealed the presence of: benzodiazepines, opiates (oxycodone), and trazodone metabolites in the serum; cannabinoids, benzodiazepines, opiates (oxycodone), trazodone, trazodone metabolites, nicotine, and nicotine metabolite in the urine; and benzodiazepines, opiates (oxycodone), nicotine, and nicotine metabolite in the gastric contents. Quantitative analyses for clonazepam was performed by high performance liquid chromatography (HPLC) and revealed a plasma concentration of 1.41 microg/mL. Plasma oxycodone and urine 11-nor-carboxy-delta-9-tetrahydrocannabinol concentrations were determined by gas chromatography/mass spectrometry and revealed concentrations of 0.60 microg/mL and 27.9 ng/mL, respectively. The deceased had pathologies consistent with severe central nervous system (CNS) and respiratory depression produced by high concentrations of clonazepam and oxycodone including collapsed lungs, aspirated mucus, and heart failure. The pathologies were sufficient to cause death, which was officially attributed to a drug overdose; however, the manner of death was unknown.

Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats.

PubMed

Neelakantan, Harshini; Holliday, Erica D; Fox, Robert G; Stutz, Sonja J; Comer, Sandra D; Haney, Margaret; Anastasio, Noelle C; Moeller, F Gerard; Cunningham, Kathryn A

2017-05-17

Opioid use disorder (OUD) is a major public health problem. High relapse rates and poor treatment retention continue to pose major challenges in OUD treatment. Of the abused opioids, oxycodone is well described to maintain self-administration and evoke the durable conditioned responses ("cue reactivity") that result from pairing of opioid-related stimuli (e.g., paraphernalia) with repeated abuse. Serotonin (5-HT) neurotransmission, particularly through the 5-HT 2C receptor (5-HT 2C R), regulates psychostimulant reward and cue reactivity, and in the present experiments, we investigated the hypothesis that the selective 5-HT 2C R agonist lorcaserin, which is approved by the United States Food and Drug Administration (FDA) for the treatment of obesity, will suppress oxycodone self-administration and oxycodone-associated cue reactivity in rats. We found that lorcaserin inhibited oxycodone intake, an effect blocked by the selective 5-HT 2C R antagonist SB242084. Lorcaserin also decreased responding for the discrete cue complex ("cue reactivity") previously associated with delivery of oxycodone (i.e., stimulus lights, infusion pump sounds) in both abstinence and extinction-reinstatement models. The selected dose range of lorcaserin (0.25-1 mg/kg) does not overtly alter spontaneous behaviors nor operant responding on inactive levers in the present study. Taken together, the ability of lorcaserin to reduce the oxycodone self-administration and decrease cue reactivity associated with relapse highlights the therapeutic potential for lorcaserin in the treatment of OUD.

Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of mu-opioid receptors and dynamin-2.

PubMed

Pawar, Mohit; Kumar, Priyank; Sunkaraneni, Soujanya; Sirohi, Sunil; Walker, Ellen A; Yoburn, Byron C

2007-06-01

It has been proposed that opioid agonist efficacy may play a role in tolerance and the regulation of opioid receptor density. To address this issue, the present studies estimated the in vivo efficacy of three opioid agonists and then examined changes in spinal mu-opioid receptor density following chronic treatment in the mouse. In addition, tolerance and regulation of the trafficking protein dynamin-2 were determined. To evaluate efficacy, the method of irreversible receptor alkylation was employed and the efficacy parameter tau estimated. Mice were injected with the irreversible mu-opioid receptor antagonist clocinnamox (0.32-25.6 mg/kg, i.p), and 24 h later, the analgesic potency of s.c. morphine, oxycodone and etorphine were determined. Clocinnamox dose-dependently antagonized the analgesic effects of morphine, etorphine and oxycodone. The shift to the right of the dose-response curves was greater for morphine and oxycodone compared to etorphine and the highest dose of clocinnamox reduced the maximal effect of morphine and oxycodone, but not etorphine. The order of efficacy calculated from these results was etorphine>morphine>oxycodone. Other mice were infused for 7 days with oxycodone (10-150 mg/kg/day, s.c.) or etorphine (50-250 microg/kg/day, s.c.) and the analgesic potency of s.c. morphine determined. The low efficacy agonist (oxycodone) produced more tolerance than the high efficacy agonist (etorphine) at equi-effective infusion doses. In saturation binding experiments, the low efficacy opioid agonists (morphine, oxycodone) did not regulate the density of spinal mu-opioid receptors, while etorphine produced approximately 40% reduction in mu-opioid receptor density. Furthermore, etorphine increased spinal dynamin-2 abundance, while oxycodone did not produce any significant change in dynamin-2 abundance. Overall, these data indicate that high efficacy agonists produce less tolerance at equi-effective doses. Furthermore, increased efficacy was associated with mu-opioid receptor downregulation and dynamin-2 upregulation. Conversely, lower efficacy agonists produced more tolerance at equi-effective doses, but did not regulate mu-opioid receptor density or dynamin-2 abundance. Taken together, these studies indicate that agonist efficacy plays an important role in tolerance and regulation of receptors and trafficking proteins.

Determination of oxycodone and hydrocotarnine in cancer patient serum by high-performance liquid chromatography with electrochemical detection.

PubMed

Kokubun, Hideya; Ouki, Makiko; Matoba, Motohiro; Kubo, Hiroaki; Hoka, Sumio; Yago, Kazuo

2005-03-01

We developed an HPLC procedure using electrochemical detection for the quantitation of oxycodone and hydrocotarnine in cancer patients serum. An eluent of methanol:acetonitrile:5 mM pH 8 phosphate buffer (2:1:7) was used for the mobile phase. The calibration curve was linear in the range from 10 ng/mL to 100 ng/mL. The recovery of oxycodone and hydrocotarnine was 97.2% and 90.5%, respectively. The relative standard deviations within-runs and between-runs for the assay of oxycodone or hydrocotarnine were less than 4.8%. The method developed here was better than the method reported previously.

Oxycodone Self-Administration Induces Alterations in Expression of Integrin, Semaphorin and Ephrin Genes in the Mouse Striatum.

PubMed

Yuferov, Vadim; Zhang, Yong; Liang, Yupu; Zhao, Connie; Randesi, Matthew; Kreek, Mary J

2018-01-01

Oxycodone is one a commonly used medication for pain, and is also a widely abused prescription opioid, like other short-acting MOPr agonists. Neurochemical and structural adaptations in brain following chronic MOPr-agonist administration are thought to underlie pathogenesis and persistence of opiate addiction. Many axon guidance molecules, such as integrins, semaphorins, and ephrins may contribute to oxycodone-induced neuroadaptations through alterations in axon-target connections and synaptogenesis, that may be implicated in the behaviors associated with opiate addiction. However, little is known about this important area. The aim of this study is to investigate alterations in expression of selected integrin, semaphorin, ephrins, netrin, and slit genes in the nucleus accumbens (NAc) and caudate putamen (CPu) of mice following extended 14-day oxycodone self-administration (SA), using RNAseq. Methods: Total RNA from the NAc and CPu were isolated from adult male C57BL/6J mice within 1 h after the last session of oxycodone in a 14-day self-administration paradigm (4h/day, 0.25 mg/kg/infusion, FR1) or from yoked saline controls. Gene expressions were examined using RNA sequencing (RNA-Seq) technology. RNA-Seq libraries were prepared using Illumina's TruSeq® Stranded Total RNA LT kit. The reads were aligned to the mouse reference genome (version mm10) using STAR. DESeq2 was applied to the counts of protein coding genes to estimate the fold change between the treatment groups. False Discovery Rate (FDR) q < 0.1 were used to select genes that have a significant expression change. For selection of a subset of genes related to axon guidance pathway, REACTOME was used. Results: Among 38 known genes of the integrin, semaphorin, and ephrin gene families, RNA-seq data revealed up-regulation of six genes in the NAc: heterodimer receptor, integrins Itgal, Itgb2 , and Itgam , and its ligand semaphorin Sema7a , two semaphorin receptors, plexins Plxnd1 and Plxdc1 . There was down-regulation of eight genes in this region: two integrin genes Itga3 and Itgb8 , semaphorins Sema3c, Sema4g, Sema6a, Sema6d , semaphorin receptor neuropilin Nrp2 , and ephrin receptor Epha3 . In the CPu, there were five differentially expressed axon guidance genes: up-regulation of three integrin genes, Itgal, Itgb2, Itga1 , and down-regulation of Itga9 and ephrin Efna3 were thus observed. No significant alterations in expression of Netrin-1 or Slit were observed. Conclusion: We provide evidence for alterations in the expression of selective axon guidance genes in adult mouse brain following chronic self-administration of oxycodone. Further examination of oxycodone-induced changes in the expression of these specific axon guidance molecules and integrin genes in relation to behavior may provide new insights into development of addiction to oxycodone.

Do Diuretics have Antinociceptive Actions: Studies of Spironolactone, Eplerenone, Furosemide and Chlorothiazide, Individually and with Oxycodone and Morphine.

PubMed

Jokinen, Viljami; Lilius, Tuomas; Laitila, Jouko; Niemi, Mikko; Kambur, Oleg; Kalso, Eija; Rauhala, Pekka

2017-01-01

Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co-administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)- and morphine (3 mg/kg, s.c.)-induced antinociception using tail-flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Resolution of an apparent hook effect in Roche partner DRI oxycodone immunoassay.

PubMed

Colón-Franco, Jessica M; Cox, Elbert T; Crosby, David B; Dawling, Sheila

2013-01-01

A presumed hook effect in the semiquantitative DRI Oxycodone immunoassay, OXY3S (Cobas Integra, Roche Diagnostics), was investigated in 14 urine samples with gas chromatography/mass spectrometry (GC-MS) >10,000 ng/mL but OXY3S <1,000 ng/mL. These samples included the index case, a false-negative OXY3S result with >75,000 ng/mL oxycodone + oxymorphone by GC-MS confirmation. Patient samples needed 2- to 16-fold dilution to obtain the correct OXY3S response. The OXY3S test did not hook at high-spiked concentrations of oxycodone, oxymorphone or oxymorphone-3β-d-glucuronide in drug-free urine. The OXY3S test parameters were replicated in a development channel on the Cobas using DRI Reagents (Microgenics, CA, USA) and were subsequently modified. Delayed sample addition or doubling of Reagent 1 (R1: antibody/substrate/co-factor) yielded maximal immunoassay response (>10,000 ng/mL) in 12 of 14 and 14 of 14 undiluted patient samples, respectively. Supplementation of R1 with substrate alone did not correctly recover oxycodone from any of the samples, while co-factor supplementation resulted a maximal OXY3S response in 13 of 14 samples. The remaining (index) sample could only be corrected by supplemental R1. The semiquantitative utility of the DRI Oxycodone assay is questionable. Although the precise cause of the under-recovery could not be determined, the modification presented permits reliable oxycodone determination at the high concentrations frequently seen in clinical urine samples.

Choice between delayed food and immediate oxycodone in rats.

PubMed

Secci, Maria E; Factor, Julie A; Schindler, Charles W; Panlilio, Leigh V

2016-12-01

The choice to seek immediate drug effects instead of more meaningful but delayed rewards is a defining feature of addiction. To develop a rodent model of this behavior, we allowed rats to choose between immediate intravenous delivery of the prescription opioid oxycodone (50 μg/kg) and delayed delivery of palatable food pellets. Rats preferred food at delays up to 30 s, but they chose oxycodone and food equally at 60-s delay and preferred oxycodone over food at 120-s delay. Comparison of food-drug choice, food-only, and drug-only conditions indicated that food availability decreased drug intake, but drug availability increased food intake. In the food-only condition, food was effective as a reinforcer even when delayed by 120 s. Pre-session feeding with chow slowed acquisition of food and drug self-administration, but did not affect choice. To establish procedures for testing potential anti-addiction medications, noncontingent pre-treatment with oxycodone or naltrexone (analogous to substitution and antagonist therapies, respectively) were tested on a baseline in which oxycodone was preferred over delayed food. Naltrexone pre-treatment decreased drug intake and increased food intake. Oxycodone pre-treatment decreased drug intake, but also produced extended periods with no food or drug responding. These findings show that the contingencies that induce preference for drugs over more meaningful but less immediate rewards in humans can be modeled in rodents, and they suggest that the model could be useful for assessing the therapeutic potential of treatments and exploring the underlying behavioral and neural mechanisms involved in addiction.

Choice between delayed food and immediate oxycodone in rats

PubMed Central

Secci, Maria E.; Factor, Julie A.; Schindler, Charles W.; Panlilio, Leigh V.

2016-01-01

Rationale The choice to seek immediate drug effects instead of more meaningful but delayed rewards is a defining feature of addiction. Objectives To develop a rodent model of this behavior, we allowed rats to choose between immediate intravenous delivery of the prescription opioid oxycodone (50 μg/kg) and delayed delivery of palatable food pellets. Results Rats preferred food at delays up to 30 s, but they chose oxycodone and food equally at 60-s delay and preferred oxycodone over food at 120-s delay. Comparison of food-drug choice, food-only, and drug-only conditions indicated that food availability decreased drug intake, but drug availability increased food intake. In the food-only condition, food was effective as a reinforcer even when delayed by 120 s. Pre-session feeding with chow slowed acquisition of food and drug self-administration, but did not affect choice. To establish procedures for testing potential anti-addiction medications, noncontingent pretreatment with oxycodone or naltrexone (analogous to substitution and antagonist therapies, respectively) were tested on a baseline in which oxycodone was preferred over delayed food. Naltrexone pretreatment decreased drug intake and increased food intake. Oxycodone pretreatment decreased drug intake, but also produced extended periods with no food or drug responding. Conclusions These findings show that the contingencies that induce preference for drugs over more meaningful but less immediate rewards in humans can be modeled in rodents, and they suggest that the model could be useful for assessing the therapeutic potential of treatments and exploring the underlying behavioral and neural mechanisms involved in addiction. PMID:27678551

77 FR 50162 - Importer of Controlled Substances; Notice of Registration; Almac Clinical Services, Inc.

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2012-08-20

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of..., Pennsylvania 18964, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Oxycodone (9143...

76 FR 8776 - Importer of Controlled Substances; Notice of Registration

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2011-02-15

... Cocaine (9041) II Codeine (9050) II Dihydrocodeine (9120) II Oxycodone (9143) II Hydromorphone (9150) II... with United States obligations under international treaties, conventions, or protocols in effect on May...

77 FR 4831 - Importer of Controlled Substances; Notice of Application

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2012-01-31

... (8501) II Coca Leaves (9040) II Oxycodone (9143) II Hydromorphone (9150) II Hydrocodone (9193) II... crude opium, poppy straw, poppy straw concentrate, and coca leaves. As explained in the Correction to...

Exploring pharmacological activities and signaling of morphinans substituted in position 6 as potent agonists interacting with the μ opioid receptor

PubMed Central

2014-01-01

Background Opioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The μ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures. Results This study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone. Conclusion Development of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects. PMID:25059282

Comparative Analgesic Efficacy of Oxycodone/Acetaminophen Versus Hydrocodone/Acetaminophen for Short-term Pain Management in Adults Following ED Discharge.

PubMed

Chang, Andrew K; Bijur, Polly E; Holden, Lynne; Gallagher, E John

2015-11-01

The objective was to test the hypothesis that oxycodone/acetaminophen provides superior analgesia to hydrocodone/acetaminophen for the treatment of acute extremity pain following emergency department (ED) discharge. This was a prospective, randomized, double-blind clinical trial of nonelderly adult ED patients with acute musculoskeletal extremity pain, randomly allocated at discharge to receive oxycodone/acetaminophen (5 mg/325 mg) or hydrocodone/acetaminophen (5 mg/325 mg). The primary outcome was the between-group difference in improvement in numerical rating scale (NRS) pain scores over a 2-hour period following the most recent ingestion of study drug, obtained during telephone contact 24 hours after ED discharge. Secondary outcomes included proportionate decrease in pain, comparative side-effect profiles, and patient satisfaction. A total of 240 patients were enrolled. The final sample consisted of 220 patients, 107 randomly allocated to oxycodone/acetaminophen and 113 to hydrocodone/acetaminophen. At 24 hours after ED discharge, the mean NRS pain scores prior to the most recent dose of outpatient pain medication were 7.8 and 7.9 in the oxycodone/acetaminophen and hydrocodone/acetaminophen groups, respectively. The mean decreases in pain scores over 2 hours were 4.4 NRS units in the oxycodone/acetaminophen group versus 4.0 NRS units in the hydrocodone/acetaminophen group, for a difference of 0.4 NRS units (95% confidence interval = -0.2 to 1.1 NRS units). Satisfaction with the analgesics was similar. This study design could not detect a clinically or statistically significant difference in analgesic efficacy between oxycodone/acetaminophen (5 mg/325 mg) and hydrocodone/acetaminophen (5 mg/325 mg) for treatment of acute musculoskeletal extremity pain in adults following ED discharge. Both opioids reduced pain scores by approximately 50%. © 2015 by the Society for Academic Emergency Medicine.

Scoring the best deal: Quantity discounts and street price variation of diverted oxycodone and oxymorphone.

PubMed

Lebin, Jacob A; Murphy, David L; Severtson, Stevan Geoffrey; Bau, Gabrielle E; Dasgupta, Nabarun; Dart, Richard C

2018-05-15

Diverted prescription opioids are significant contributors to drug overdose mortality. Street price has been suggested as an economic metric of the diverted prescription opioid black market. This study examined variables that may influence the street price of diverted oxycodone and oxymorphone. A cross-sectional study was conducted utilizing data from the previously validated, crowdsourcing website StreetRx. Street price reports of selected oxycodone and oxymorphone products, between August 22, 2014 and June 30, 2016, were considered for analysis. Geometric means and 95% confidence intervals were calculated comparing prices per milligram of drug in US dollars. Univariate and multivariable regressions were used to examine the influence of dosage strength, drug formulation, and bulk purchasing on street price. A total of 5611 oxycodone and 1420 oxymorphone reports were analyzed. Across various dosages and formulations, geometric mean prices per milligram ranged between $0.12 and $1.07 for oxycodone and $0.73 and $2.90 for oxymorphone. For a 2-fold increase in dosage strength, there is a 24.0% (95% CI: -28.1%, -19.6%, P < 0.001) and a 22.5% (95% CI: -24.2%, -20.8%, P < 0.001) decrease on average in price per milligram for oxycodone and oxymorphone, respectively. Lower potency, high dosage strength, crush-resistant opioids, and those purchased in bulk were significantly cheaper. Street prices for diverted oxycodone and oxymorphone are influenced by multiple factors including potency, dosage, formulation, and bulk purchasing. Buyers who purchase large quantities of low potency, large dosage, crush-resistant formulation prescription opioids can expect to achieve the lowest price. Copyright © 2018 John Wiley & Sons, Ltd.

Separate and combined psychopharmacological effects of alprazolam and oxycodone in healthy volunteers.

PubMed

Zacny, James P; Paice, Judith A; Coalson, Dennis W

2012-08-01

There are epidemiological data indicating that medical and/or nonmedical use of prescription opioids oftentimes involves concurrent use of other substances. One of those substances is benzodiazepines. It would be of relevance to characterize the effects of an opioid and a benzodiazepine when taken together to determine if measures related to abuse liability-related effects and psychomotor performance impairment are increased compared to when the drugs are taken alone. Twenty volunteers participated in a crossover, randomized, double-blind study in which they received placebo, 0.5mg alprazolam, 10mg oxycodone, and 0.5mg alprazolam combined with 10 mg oxycodone, all p.o. Subjective, psychomotor, and physiological measures were assessed during each of the four sessions. Oxycodone by itself increased drug liking and "take again" ratings relative to placebo, but these ratings were not increased when oxycodone was taken with alprazolam, which by itself did not increase either of these ratings. The two drugs in combination produced stronger effects (larger in magnitude or longer lasting) than when either was taken alone on a number of measures, including psychomotor performance impairment. In healthy volunteers, abuse liability-related subjective effects of oxycodone were not enhanced by alprazolam. There was enhanced behavioral toxicity when the drugs were taken together, and thus, this is of significant concern from a public safety standpoint. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Separate and combined psychopharmacological effects of alprazolam and oxycodone in healthy volunteers

PubMed Central

Zacny, James P.; Paice, Judith A.; Coalson, Dennis W.

2013-01-01

Background There are epidemiological data indicating that medical and/or nonmedical use of prescription opioids oftentimes involves concurrent use of other substances. One of those substances is benzodiazepines. It would be of relevance to characterize the effects of an opioid and a benzodiazepine when taken together to determine if measures related to abuse liability-related effects and psychomotor performance impairment are increased compared to when the drugs are taken alone. Methods Twenty volunteers participated in a crossover, randomized, double-blind study in which they received placebo, 0.5 mg alprazolam, 10mg oxycodone, and 0.5 mg alprazolam combined with 10mg oxycodone, all p.o. Subjective, psychomotor, and physiological measures were assessed during each of the four sessions. Results Oxycodone by itself increased drug liking and “take again” ratings relative to placebo, but these ratings were not increased when oxycodone was taken with alprazolam, which by itself did not increase either of these ratings. The two drugs in combination produced stronger effects (larger in magnitude or longer lasting) than when either was taken alone on a number of measures, including psychomotor performance impairment. Conclusions In healthy volunteers, abuse liability-related subjective effects of oxycodone were not enhanced by alprazolam. There was enhanced behavioral toxicity when the drugs were taken together, and thus, this is of significant concern from a public safety standpoint. PMID:22365897

Oxycodone

MedlinePlus

... this type of medication for at least one week. Oxycodone is in a class of medications called ... have stopped taking them within the past two weeks: isocarboxazid (Marplan), linezolid (Zyvox), methylene blue, phenelzine (Nardil), ...

Assessment of the abuse of tapentadol immediate release: the first 24 months.

PubMed

Dart, Richard C; Cicero, Theodore J; Surratt, Hilary L; Rosenblum, Andrew; Bartelson, Becki Bucher; Adams, Edgar H

2012-01-01

Prescription opioid analgesics play an important role in the management of moderate to severe pain. An unintended consequence of prescribing opioid analgesics is the abuse and diversion of these medications. The authors estimated abuse and diversion rates for tapentadol immediate release (IR) compared with oxycodone, hydrocodone, and tramadol during the first 24 months of tapentadol IR availability. The Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System measures rates of prescription opioid abuse and diversion throughout the United States. Quarterly data from the Poison Center, Drug Diversion, Opioid Treatment, and Survey of Key Informants' Patients (SKIP) programs were plotted to visually compare the rates of tapentadol IR abuse and diversion with those of other opioid analgesics from July 2009 through June 2011 using both cases per 100,000 population and per 1,000 unique recipients of dispensed drug (URDD) as denominators. Trends in abuse and diversion rates over time were determined using a linear regression model of rate versus time. During the 24 months following its introduction, tapentadol IR had very low population-based rates of abuse and diversion that were similar to rates for tramadol and lower than rates for oxycodone and hydrocodone. Rates of tapentadol IR abuse and diversion based on URDD were variable by program due to changes in market share and had not stabilized as of June 2011. Rates of tapentadol IR abuse and diversion have been low during the first 24 months after its launch. Continued monitoring of trends in these data is warranted.

78 FR 54913 - Importer of Controlled Substances; Notice of Registration; United States Pharmacopeial Convention

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-06

... (9010) II Anileridine (9020) II Cocaine (9041) II Codeine (9050) II Dihydrocodeine (9120) II Oxycodone... obligations under international treaties, conventions, or protocols in effect on May 1, 1971. DEA has...

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 in activity impairment due to low back pain subscale of the WPAI:SHP significantly favored ALO-02 compared with placebo for the ITT population when considering the overall study period (p = 0.0040). HRQL, work productivity, and activity impairment may be improved with ALO-02 treatment. ClinicalTrials.gov NCT01571362 , registered April 3, 2012.

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

PubMed Central

Largent-Milnes, Tally M.; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H.; Vanderah, Todd W.

2017-01-01

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)–G protein coupling from Gi/o to Gs that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L5/L6 spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to Gs in the damaged (ipsilateral) spinal dorsal horn. This MOR-Gs coupling occurred without changing Gi/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-Gs coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-Gs coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this Gs coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-Gs coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. PMID:18468954

Short-term oxycodone treatment does not affect electrogenic ion transport in isolated mucosa from the human rectosigmoid colon.

PubMed

Nilsson, Matias; Brock, Christina; Poulsen, Jakob Lykke; Bindslev, Niels; Hansen, Mark Berner; Louring Christrup, Lona; Drewes, A M

2016-01-01

Opioid therapy is associated with altered secretion and motility of the gut. The relative contribution of decreased secretion to the development of opioid-induced constipation remains unknown. Twenty-five healthy males were treated with oxycodone for 5 d in a placebo-controlled, randomised cross-over design. Gastrointestinal adverse effects were assessed with validated questionnaires (bowel function index and gastrointestinal symptom rating scale). Rectosigmoid mucosal biopsies were taken at baseline and on day 5 during both treatments and mounted in Ussing chambers. Electrogenic ion transport parameters (short circuit current (SCC) and slope conductance) were measured after addition of secretagogues (prostaglandin E2 (PGE2) (6 μm), theophylline (400 μm)), and an inhibitor (ouabain (200 μm)). Additionally, morphine (50 μm) was added to investigate the direct opioid effect on colonic mucosa. Questionnaires showed pronounced bowel symptoms, including constipation during oxycodone treatment (eight-fold increase in bowel function index score from day 1 to day 5 (p < 0.001) while no significant change occurred during placebo treatment (p = 0.47). Basal SCC and slope conductance did not differ between treatments (all p > 0.05) and application with PGE2, theophylline, and ouabain yielded comparable results on all examinations (all p > 0.05). Morphine application consistently did not evoke a change in ion transport. Compared to placebo, epithelial electrogenic ion transport is not altered in mucosal biopsies from the rectosigmoid colon following 5-d oxycodone treatment. The secretory mechanisms in isolated mucosa appear to play a negligible role in the development of opioid-induced constipation.

Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans

PubMed Central

Lofwall, Michelle R.; Babalonis, Shanna; Nuzzo, Paul A.; Elayi, Samy Claude; Walsh, Sharon L.

2016-01-01

Background The cannabinoid (CB) system is a rational novel target for treating opioid dependence, a significant public health problem around the world. This proof-of-concept study examined the potential efficacy of a CB1 receptor partial agonist, dronabinol, in relieving signs and symptoms of opioid withdrawal. Methods Twelve opioid dependent adults participated in this 5-week, inpatient, double-blind, randomized, placebo-controlled study. Volunteers were maintained on double-blind oxycodone (30mg oral, four times/day) and participated in a training session followed by 7 experimental sessions, each testing a single oral test dose (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Placebo was substituted for oxycodone maintenance doses for 21 hours before each session in order to produce measurable opioid withdrawal. Outcomes included observer- and participant-ratings of opioid agonist, opioid withdrawal and psychomotor/cognitive performance. Results Oxycodone produced prototypic opioid agonist effects (i.e., suppressing withdrawal and increasing subjective effects indicative of abuse liability). Dronabinol 5 and 10mg produced effects most similar to placebo, while the 20 and 30mg doses produced modest signals of withdrawal suppression that were accompanied by dose-related increases in high, sedation, bad effects, feelings of heart racing, and tachycardia. Dronabinol was not liked more than placebo, showed some impairment in cognitive performance, and was identified as marijuana with increasing dose. Conclusion CB1 receptor activation is a reasonable strategy to pursue for the treatment of opioid withdrawal; however, dronabinol is not a likely candidate given its modest withdrawal suppression effects of limited duration and previously reported tachycardia during opioid withdrawal. PMID:27234658

Opioid-induced bowel dysfunction in healthy volunteers assessed with questionnaires and MRI.

PubMed

Nilsson, Matias; Poulsen, Jakob L; Brock, Christina; Sandberg, Thomas H; Gram, Mikkel; Frøkjær, Jens B; Krogh, Klaus; Drewes, Asbjørn M

2016-05-01

Opioid treatment is associated with numerous gastrointestinal adverse effects collectively known as opioid-induced bowel dysfunction (OIBD). Most current knowledge of the pathophysiology derives from animal studies limited by species differences and clinical studies, which have substantial confounders that make evaluation difficult. An experimental model of OIBD in healthy volunteers in a controlled setting is therefore highly warranted. The aim of this study was to assess bowel function in healthy volunteers during opioid treatment using subjective and objective methods. Twenty-five healthy men were assigned randomly to oxycodone or placebo for 5 days in a cross-over design. The analgesic effect was assessed with muscle pressure algometry and adverse effects were measured using questionnaires including the bowel function index, gastrointestinal symptom rating scale, patient assessment of constipation symptoms and the Bristol stool form scale. Colorectal volumes were determined using a newly developed MRI method. Compared with baseline, oxycodone increased pain detection thresholds by 8% (P=0.02). Subjective OIBD was observed as increased bowel function index (464% increase; P<0.001), gastrointestinal symptom rating scale (37% increase; P<0.001) and patient assessment of constipation symptoms (198% increase; P<0.001). Objectively, stools were harder and drier during oxycodone treatment (P<0.001) and segmental colorectal volumes increased in the caecum/ascending colon by 41% (P=0.005) and in the transverse colon by 20% (P=0.005). No associations were detected between questionnaire scores and colorectal volumes. Experimental OIBD in healthy volunteers was induced during oxycodone treatment. This model has potential for future interventional studies to discriminate the efficacies of different laxatives, peripheral morphine antagonists and opioid treatments.

78 FR 5498 - Importer of Controlled Substances; Notice of Registration; R & D Systems, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-25

...) II Cocaine (9041) II Oxycodone (9143) II Thebaine (9333) II Fentanyl (9801) II The company plans to..., conventions, or protocols in effect on May 1, 1971, at this time. DEA has investigated R & D Systems, Inc., to...

Comparative Analgesic Efficacy of Oxycodone/Acetaminophen vs Codeine/Acetaminophen for Short-Term Pain Management Following ED Discharge.

PubMed

Chang, Andrew K; Bijur, Polly E; Lupow, Jason B; Gallagher, E John

2015-12-01

To test the hypothesis that oxycodone/acetaminophen provides analgesia superior to codeine/acetaminophen following emergency department (ED) discharge. Prospective, randomized, double-blind, trial. Adult inner city ED. ED patients with acute extremity pain who were discharged home. Patients randomized to oxycodone/acetaminophen (5 mg/325 mg) or codeine/acetaminophen (30 mg/300 mg). The primary outcome, obtained via telephone one day after ED discharge, was the between-group difference in improvement in numerical rating scale (NRS) pain scores over a 2-hour period following the most recent ingestion of study drug. Secondary outcomes included proportion of patients with >50% pain reduction, side-effect profile, and patient satisfaction. Two hundred and forty patients were enrolled. Mean baseline NRS scores were 7.9 in both groups. Mean decrease over 2 hours was 4.5 NRS units in the oxycodone/acetaminophen group vs 4.2 NRS units in the codeine/acetaminophen group, for a clinically and statistically nonsignificant difference of 0.2 NRS units (95% CI -0.4-0.9 NRS units). Similarly, 66% vs 61% achieved >50% pain relief for a nonsignificant difference of 5% (95% CI -8% to 17%). Side-effect profile and patient satisfaction were similar. Our hypothesis that oxycodone/acetaminophen provides analgesia superior to codeine/acetaminophen was rejected. Although pain within each group was reduced by more than half, the between-group difference was not significant. Pending independent validation, these unexpected findings suggest that codeine/acetaminophen, a Schedule III agent, may be a clinically reasonable outpatient opioid alternative to oxycodone/acetaminophen, a more tightly restricted Schedule II agent thought to be more prone to misuse. Wiley Periodicals, Inc.

Consumption of three strong opioids (morphine, oxycodone and fentanyl) in seven European countries during seven years (2003-2009).

PubMed

Hudec, R; Tisonova, J; Foltan, V; Kristova, V

2013-01-01

The aim was to analyse the consumption of selected strong opioid analgesics during a seven-year period of 2003-2009 in order to compare Slovak consumption with that in six other European countries and to determine our position. Drug consumption data from the State Institute for Drug Control in Slovak Republic were used. As to the data from other countries, annual health statistics published on websites were used in comparison. Obviously the consumption of one of studied opioid drugs with transdermal aplication route, particularly fentanyl, tended to increase in all countries during the observed period. Oxycodone tends to yield a rapid increase in consumption as well. As opposed to the latter drugs, the consumption of morphine was decreasing throughout the observed period. The consumption of these drugs in Slovakia remains low (except for that of fentanyl). Our analysis confirmed a clear shift from oral to transdermal therapy as well as usage of newer drugs. Drug consumption data are a relatively new source of information for health research. Our analysis showed increasing trends in fentanyl (patch opioid) consumption in all compared countries as well as an increasing consumption of oxycodone and decreasing consumption of morphine (Fig. 3, Ref. 17).

Increasing availability of illicit and prescription opioids among people who inject drugs in a Canadian setting, 2010-2014.

PubMed

Ho, Joel; DeBeck, Kora; Milloy, M-J; Dong, Huiru; Wood, Evan; Kerr, Thomas; Hayashi, Kanna

2018-01-01

Nonmedical use of prescription opioid and illicit opioid has been increasing at an alarming rate in North America over the past decade. We sought to examine the temporal trends and correlates of the availability of illicit and prescription opioids among people who inject drugs (PWID) in Vancouver, Canada. Data were derived from three prospective cohort studies of PWID in Vancouver between 2010 and 2014. In semiannual interviews, participants reported the availability of five sets of illicit and prescription opioids: (1) heroin; (2) Percocet (oxycodone/acetaminophen), Vicodin (hydrocodone/acetaminophen), or Demerol (meperidine); (3) Dilaudid (hydromorphone); (4) Morphine; (5) oxycontin/OxyNEO (controlled-release oxycodone). We defined perceived availability as immediate (e.g., available within 10 minutes) versus no availability/available after 10 minutes. The trend and correlation of immediate availability were identified by multivariable generalized estimating equations logistic regression. Among 1584 participants, of which 564 (35.6%) were female, the immediate availability of all illicit and prescribed opioids (except for oxycontin/OxyNEO) increased over time, independent of potential confounders. The Adjusted Odds Ratios of immediate availability associated with every calendar year increase were between 1.09 (95% confidence interval 1.05-1.12) (morphine and Dilaudid) and 1.13 (95% confidence interval 1.09-1.17) (Percocet/Vicodin/Demerol) (all p-values <0.05). The availability of most prescription opioids had continued to increase in recent years among our sample of PWID in Vancouver. Concurrent increases in the availability of heroin were also observed, raising concerns regarding combination of both illicit and prescription opioid use among PWID that could potentially increase the risk of overdose.

mu-Opioid receptor-independent fashion of the suppression of sodium currents by mu-opioid analgesics in thalamic neurons.

PubMed

Hashimoto, Keisuke; Amano, Taku; Kasakura, Akiko; Uhl, George R; Sora, Ichiro; Sakai, Norio; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru

2009-03-27

Most reports in the literature have shown that the effects of opioid analgesics are primarily mediated by mu-opioid receptor (MOR), whereas other potential targets of opioid analgesics have not been thoroughly characterized. In this study, we found that extracellular application of morphine, fentanyl or oxycodone, which are all considered to be MOR agonists, at relatively high concentrations, but not endogenous mu-opioid peptides, produced a concentration-dependent suppression of sodium currents in cultured thalamic neurons. These effects of opioids were not affected by either a MOR antagonist naloxone or a deletion of MOR gene. Among these opioids, fentanyl strongly suppressed sodium currents to the same degree as lidocaine, and both morphine and oxycodone slightly but significantly reduced sodium currents when they were present extracellularly. In contrast, the intracellular application of morphine, but not oxycodone, fentanyl or lidocaine, reduced sodium currents. These results suggest that morphine, fentanyl and oxycodone each produce the MOR-independent suppression of sodium currents by distinct mechanisms in thalamic neurons.

Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone

PubMed Central

Dhalla, Irfan A.; Mamdani, Muhammad M.; Sivilotti, Marco L.A.; Kopp, Alex; Qureshi, Omar; Juurlink, David N.

2009-01-01

Introduction Opioid-related mortality appears to be increasing in Canada. We examined the true extent of the problem and the impact of the introduction of long-acting oxycodone. Methods We examined trends in the prescribing of opioid analgesics in the province of Ontario from 1991 to 2007. We reviewed all deaths related to opioid use between 1991 and 2004. We linked 3271 of these deaths to administrative data to examine the patients’ use of health care services before death. Using time-series analysis, we determined whether the addition of long-acting oxycodone to the provincial drug formulary in January 2000 was associated with an increase in opioid-related mortality. Results From 1991 to 2007, annual prescriptions for opioids increased from 458 to 591 per 1000 individuals. Opioid-related deaths doubled, from 13.7 per million in 1991 to 27.2 per million in 2004. Prescriptions of oxycodone increased by 850% between 1991 and 2007. The addition of long-acting oxycodone to the drug formulary was associated with a 5-fold increase in oxycodone-related mortality (p < 0.01) and a 41% increase in overall opioid-related mortality (p = 0.02). The manner of death was deemed unintentional by the coroner in 54.2% and undetermined in 21.9% of cases. Use of health care services in the month before death was common: for example, of the 3066 patients for whom data on physician visits were available, 66.4% had visited a physician in the month before death; of the 1095 patients for whom individual-level prescribing data were available, 56.1% had filled a prescription for an opioid in the month before death. Interpretation Opioid-related deaths in Ontario have increased markedly since 1991. A significant portion of the increase was associated with the addition of long-acting oxycodone to the provincial drug formulary. Most of the deaths were deemed unintentional. The frequency of visits to a physician and prescriptions for opioids in the month before death suggests a missed opportunity for prevention. PMID:19969578

Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling.

PubMed

Largent-Milnes, Tally M; Guo, Wenhong; Wang, Hoau-Yan; Burns, Lindsay H; Vanderah, Todd W

2008-08-01

Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in mu-opioid receptor (MOR)-G protein coupling from G(i/o) to G(s) that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L(5)/L(6) spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G(s) in the damaged (ipsilateral) spinal dorsal horn. This MOR-G(s) coupling occurred without changing G(i/o) coupling levels and without changing the expression of MOR or Galpha proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G(s) coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G(s) coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G(s) coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G(s) coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain. The current study investigates whether Oxytrex (oxycodone with an ultra-low dose of naltrexone) alleviates mechanical and thermal hypersensitivities in an animal model of neuropathic pain over a period of 7 days, given locally or systemically. In this report, we first describe an injury-induced shift in mu-opioid receptor coupling from G(i/o) to G(s), suggesting why a mu-opioid agonist may have reduced efficacy in the nerve-injured state. These data present a novel approach to neuropathic pain therapy.

Oxycodone Ingestion Patterns in Acute Fracture Pain With Digital Pills.

PubMed

Chai, Peter R; Carreiro, Stephanie; Innes, Brendan J; Chapman, Brittany; Schreiber, Kristin L; Edwards, Robert R; Carrico, Adam W; Boyer, Edward W

2017-12-01

Opioid analgesics are commonly prescribed on an as-needed (PRN) basis for acute painful conditions. Uncertainty of how patients actually take PRN opioids, coupled with a desire to completely cover pain, leads to variable and overly generous opioid prescribing practices, resulting in a surplus of opioids. This opioid surplus becomes a source for diversion and nonmedical opioid use. Understanding patterns of actual opioid ingestion after acute painful conditions can help clinicians counsel patients on safe opioid use, and allow timely recognition and intervention when escalating opioid self-dosing occurs, to prevent tolerance and addiction. We used a novel oxycodone digital pill system (ingestible biosensor within a standard gelatin capsule combined with 5-mg oxycodone) that when ingested, is activated by the chloride ion gradient in the stomach thereby emitting a radiofrequency signal captured by a wearable reader. The reader relays ingestion data to a cloud-based server that displays ingestion events to the study team. We deployed the oxycodone digital pill among opioid-naive individuals discharged from the emergency department with acute fracture pain. Participants were trained on digital pill operation and discharged with twenty-one 5-mg oxycodone digital pills. They were instructed to take digital pills PRN for pain on discharge. We conducted a brief interview 7 days after study enrollment, at which point participants returned the digital pill system. We identified oxycodone ingestion events in real time by data from the digital pill system and performed pill counts at the return visit to validate digital pill reporting of medication ingestion. In this study, 26 individuals were approached; 16 enrolled with 15 completing the study. Participants ingested a median of 6 (3-9.5) oxycodone digital pills over the course of 7 days, with 82% of the oxycodone dose ingested in the first 3 days. In individuals who required operative repair, 86% (N = 6) continued to ingest opioids at 1 week. There was substantial variability in ingestion patterns between individuals. The utilization patterns of individuals with acute fracture pain could be captured using a digital pill system and revealed a median opioid ingestion of 45-mg morphine equivalents for acute pain over 7 days. Seven participants ceased using opioids within 4 days after discharge from the emergency department, although operative repair was associated with longer use. This digital pill system was able to measure changes in and patterns of opioid self-dosing, which varied between patients.

Behavioral Flexibility and Response Selection Are Impaired after Limited Exposure to Oxycodone

ERIC Educational Resources Information Center

Seip-Cammack, Katharine M.; Shapiro, Matthew L.

2014-01-01

Behavioral flexibility allows individuals to adapt to situations in which rewards and goals change. Potentially addictive drugs may impair flexible decision-making by altering brain mechanisms that compute reward expectancies, thereby facilitating maladaptive drug use. To investigate this hypothesis, we tested the effects of oxycodone exposure on…

Doctor shopping of opioid analgesics relative to benzodiazepines: A pharmacoepidemiological study among 11.7 million inhabitants in the French countries.

PubMed

Ponté, Camille; Lepelley, Marion; Boucherie, Quentin; Mallaret, Michel; Lapeyre Mestre, Maryse; Pradel, Vincent; Micallef, Joëlle

2018-06-01

The abuse of prescription opioids and its subsequent consequences is an important public concern particularly in the USA. The literature on opioid analgesic abuse is scarce. We assess the extent and risk of opioid analgesics abuse relative to benzodiazepines (BZD) using the doctor shopping method, taken into account the pharmacological characteristics (dosage, route of administration, extended or immediate release). We used SNIIRAM database covering 11.7 million inhabitants. All individuals with at least one reimbursement for non-injectable opioid analgesic or BZD in 2013 were included. Opioids for mild to moderate pain and for moderately severe to severe pain were studied. The Doctor Shopping Quantity (DSQ) is the quantity obtained by overlapping prescriptions from several prescribers. The Doctor Shopping Indicator (DSI) is the DSQ divided by the total dispensed quantity. The strong opioid analgesics have the highest DSI (2.79%) versus 2.06% for BZD hypnotics. Flunitrazepam ranked first according to its DSI (13.2%), followed by morphine (4%), and zolpidem (2.2%). The three-strong opioids having the highest DSI were morphine, oxycodone and fentanyl (respectively 4%, 1.7% and 1.5%). The highest DSI was observed for the highest dosages of morphine (DSI = 8.4% for 200 mg) and oxycodone (DSI = 2.8% for 80 mg). The highest DSI for fentanyl was described with nasal and transmucosal forms (4.1% and 3.3% respectively). The highest DSI for morphine was described for extended-release (4.1%). There is a need to reinforce surveillance systems to track opioid misuse and to increase awareness of healthcare professionals. Copyright © 2018 Elsevier B.V. All rights reserved.

Opioid abusers’ ability to differentiate an opioid from placebo in laboratory challenge testing*

PubMed Central

Antoine, Denis G.; Strain, Eric C.; Tompkins, D. Andrew; Bigelow, George E.

2013-01-01

Background Abuse liability assessments influence drug development, federal regulation, and clinical care. One suggested procedure to reduce variability of assessments is a qualification phase, which assesses whether study applicants adequately distinguish active drug from placebo; applicants failing to make this distinction are disqualified. The present analyses assessed differences between qualification phase qualifiers and non-qualifiers. Methods Data were collected from 23 completers of the qualification phase of an abuse liability study. Opioid abusing participants received 30 mg oxycodone and placebo orally on separate days, and were characterized as qualifiers (vs. non-qualifiers) if their peak visual analog scale liking rating for oxycodone was at least 20 points higher than placebo’s peak rating. Groups were compared on demographic characteristics, drug history, and physiologic, subject and observer ratings. Results 61% of participants were qualifiers and 39% were non-qualifiers. Groups had similar demographic characteristics, drug use histories, and pupillary constriction responses. However, unlike qualifiers, non-qualifiers had an exaggerated placebo response for the liking score (p=0.03) and an attenuated oxycodone response for the liking score (p<.0001). Non-qualifiers’ failure to differentiate oxycodone versus placebo was evident for subject and observer ratings. Conclusion Different subjective responses to identical stimuli support the use of a qualification phase in abuse liability assessments. Further research should explore objective measures that may better account for these differences, determine optimal qualification criteria, and explore the developmental course of drug use. This study also documents certain opioid abusers fail to differentiate 30 mg of oxycodone from placebo, a phenomenon deserving further study. PMID:23369645

In Vitro Drug Release After Crushing: Evaluation of Xtampza® ER and Other ER Opioid Formulations.

PubMed

Mayock, Stephen P; Saim, Said; Fleming, Alison B

2017-12-01

Extended-release (ER) opioids are associated with high rates of abuse. Recreational opioid users often manipulate ER formulations to achieve a high plasma concentration in a short amount of time, resulting in a more rapid and intense high. Patients may also manipulate ER tablets to facilitate swallowing, without recognizing that manipulation could increase release rate. The goal of this study was to assess the ability of oxycodone DETERx (Xtampza ® ER, Collegium Pharmaceutical, Inc., Canton, MA, USA) and other commercially available ER opioid formulations with and without physicochemical abuse-deterrent characteristics to be manipulated by crushing in an in vitro setting. In vitro dissolution techniques were used to compare the opioid release from a variety of ER opioid formulations. Dissolution was assessed for intact and crushed dosage forms. Opioid release was quantified using high-performance liquid chromatography. Intact formulations exhibited drug release rates characteristic of 12- or 24-h dosage forms. After crushing using commonly available household tools, only Xtampza ER maintained ER of opioid. Xtampza ER maintained its ER characteristics after crushing, unlike many other commercially available opioid formulations, including some formulated with abuse-deterrent properties. As such, Xtampza ER may be less appealing to abusers and offer a margin of safety for patients who manipulate dosage forms to facilitate swallowing.

A rapid recovery program: early home and pain free.

PubMed

Lombardi, Adolph V; Berend, Keith R; Adams, Joanne B

2010-09-07

Enhancement of our perioperative pain management protocols has resulted in accelerated rehabilitation. At our facility, the majority of patients undergoing total and partial knee arthroplasty are treated with a single-shot spinal anesthetic consisting of a combination of bupivacaine and duramorph. The bupivacaine affords the immediate perioperative anesthetic while the duramorph results in sustained analgesia for a period of 12 to 24 hours. We use intra-articular injections delivered directly into the soft tissue of the knee. Our current intra-articular injection is 60 mL of 0.5% ropivacaine with 0.5 mg of epinephrine. In patients with a normal renal function, 30 mg of ketorolac is added. The injection is administered throughout all of the soft tissues in and around the knee. Prophylactic antiemetics are administered in the form of dexamethasone, ondansetron, and a scopolamine patch. The use of this perioperative anesthesia provides effective pain relief with no motor blockade. Patients are able to participate in physiotherapy within several hours of the operative procedure, performing active range of motion and ambulating with assistive devices. Patients with no significant cardiovascular history are given celecoxib preoperatively, which is continued for approximately 2 weeks postoperatively. Additionally, all patients are treated with oxycodone, either preoperatively or within 2 hours of arrival to the floor postoperatively. Patients younger than 70 years are given 20 mg of oxycodone while those older than 70 years are given 10 mg of oxycodone. The oxycodone is continued for the first 24 hours of the hospital stay. Patients are then managed with oxycodone and hydrocodone. Length of stay has decreased and currently averages <2 days. Copyright 2010, SLACK Incorporated.

A retrospective cohort study of long-term immediate-release hydrocodone/acetaminophen use and acetaminophen dosing above the Food and Drug Administration recommended maximum daily limit among commercially insured individuals in the United States (2008-2013).

PubMed

DeVeaugh-Geiss, Angela; Kadakia, Aditi; Chilcoat, Howard; Alexander, Louis; Coplan, Paul

2015-06-01

Immediate-release (IR) hydrocodone/acetaminophen is the most prescribed opioid in the United States; however, patterns of use, including long-term treatment and dose, are not well described. Duration of use, including the percentage of patients on long-term treatment (>90 days of continuous use), was assessed for patients newly prescribed IR hydrocodone/acetaminophen compared to other opioid analgesics in a national commercial insurance database (January 2008-September 2013). Though only a small percentage of IR hydrocodone/acetaminophen patients continued treatment long-term (1.7%), the number was large (104,839) and was nearly 5 times the number receiving extended-release (ER) morphine (n = 22,338) and nearly 4 times the number receiving ER oxycodone (n = 26,946) long-term. Using a less conservative allowable gap in treatment increased the number of patients meeting the criteria for long-term use (approximately 160,000 for IR hydrocodone/acetaminophen vs <30,000 for ER morphine and ER oxycodone). Most patients meeting these criteria received IR hydrocodone doses between >20 and ≤60 mg/d (n = 56,220, 53.6%) in month 4; 5.5% (n = 5,743) received doses >60 mg/d. Moreover, approximately 15% of IR hydrocodone/acetaminophen patients (n > 900,000) were prescribed total daily acetaminophen doses exceeding 4 g (the limit recommended by the U.S. Food and Drug Administration) at their initial IR hydrocodone/acetaminophen prescription or any time during therapy. Although most patients were prescribed IR hydrocodone/acetaminophen for acute pain, the number of patients prescribed long-term therapy exceeds the number of patients prescribed ER opioids. It is important to consider the benefits and risks inherent with long-term opioid therapy, whether with IR or ER opioids, to ensure safe use of these products. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Effect size comparison of ketorolac nasal spray and commonly prescribed oral combination opioids for pain relief after third molar extraction surgery.

PubMed

Niebler, Gwendolyn; Dayno, Jeffrey

2016-01-01

Opioids are frequently used for treatment of moderate to severe short-term pain, but concerns exist about this treatment approach. Ketorolac tromethamine nasal spray, a nonsteroidal anti-inflammatory, is indicated for the short-term management of moderate to moderately severe pain requiring analgesia at the opioid level. However, there are no direct comparison studies between ketorolac nasal spray and opioids. The objective of this study was to use an effect size analysis to compare the effectiveness of ketorolac nasal spray with oral combination opioid formulations in treating moderate to severe short-term pain. An effect size analysis of three randomized, double-blind, placebo-controlled studies of third molar extraction surgery compared pain relief with ketorolac nasal spray and commonly prescribed combination opioids including hydrocodone/acetaminophen (APAP), oxycodone/APAP, oxycodone/ibuprofen and tramadol HCl/APAP. Effect size comparisons were made using total pain relief scores (TOTPAR6 or TOTPAR8; the weighted sum of pain relief scores through 6 or 8 h). Pain relief was measured using a five-point categorical rating scale (0 = none; 4 = complete). The effect size equivalent correlation, r, was determined using an online effect size calculator. The treatment effect size r compared with placebo was classified using established criteria (small = 0.20-0.49, moderate = 0.50-0.79 and large = ≥ 0.80). TOTPAR6 data indicated a moderate effect size for ketorolac nasal spray 31.5 mg (0.51) and oxycodone/ibuprofen 5/400 mg (0.64) and a small effect size for hydrocodone/APAP 7.5/500 mg (0.24) and oxycodone/APAP 5/325 mg (0.32). TOTPAR8 data indicated small effect sizes for ketorolac nasal spray (0.48), hydrocodone/APAP 10/650 mg (0.43), tramadol HCl/APAP 75/650 mg (0.35) and tramadol HCl/APAP 37.5/325 mg (0.17). The treatment effect sizes of ketorolac nasal spray were similar to or higher than the opioid comparators after third molar surgery, a well-accepted pain model. These results support ketorolac nasal spray as an effective treatment for moderate to moderately severe short-term pain.

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.

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.

Abuse Liability and Reinforcing Efficacy of Oral Tramadol in Humans

PubMed Central

Babalonis, Shanna; Lofwall, Michelle R.; Nuzzo, Paul A.; Siegel, Anthony J.; Walsh, Sharon L.

2012-01-01

BACKGROUND Tramadol, a monoaminergic reuptake inhibitor, is hepatically metabolized to an opioid agonist (M1). This atypical analgesic is generally considered to have limited abuse liability. Recent reports of its abuse have increased in the U.S., leading to more stringent regulation in some states, but not nationally. The purpose of this study was to examine the relative abuse liability and reinforcing efficacy of tramadol in comparison to a high (oxycodone) and low efficacy (codeine) opioid agonist. METHODS Nine healthy, non-dependent prescription opioid abusers (6 male, 3 female) participated in this within-subject, randomized, double blind, placebo-controlled study. Participants completed 14 paired sessions (7 sample, 7 self-administration). During each sample session, an oral dose of tramadol (200, 400 mg), oxycodone (20, 40 mg), codeine (100, 200 mg) or placebo was administered, and a full array of abuse liability measures was collected. During self-administration sessions, volunteers were given the opportunity to work (via progressive ratio) for the sample dose or money. RESULTS All active doses were self-administered; placebo engendered no responding. The high doses of tramadol and oxycodone were readily self-administered (70%, 59% of available drug, respectively); lower doses and both codeine doses maintained intermediate levels of drug taking. All three drugs dose-dependently increased measures indicative of abuse liability, relative to placebo; however, the magnitude and time course of these and other pharmacodynamic effects varied qualitatively across drugs. CONCLUSIONS This study demonstrates that, like other mu opioids, higher doses of tramadol function as reinforcers in opioid abusers, providing new empirical data for regulatory evaluation. PMID:23098678

Cancer Pain Management and Bone Metastases: An Update for the Clinician

PubMed Central

Schneider, Guido; Voltz, Raymond; Gaertner, Jan

2012-01-01

Breast cancer patients with bone metastases often suffer from cancer pain. In general, cancer pain treatment is far from being optimal for many patients. To date, morphine remains the gold standard as first-line therapy, but other pure μ agonists such as hydromorphone, fentanyl, or oxycodone can be considered. Transdermal opioids are an important option if the oral route is impossible. Due to its complex pharmacology, methadone should be restricted to patients with difficult pain syndromes. The availability of a fixed combination of oxycodone and naloxone is a promising development for the reduction of opioid induced constipation. Especially bone metastases often result in breakthrough pain episodes. Thus, the provision of an on-demand opioid (e.g., immediate-release morphine or rapid-onset fentanyl) in addition to the baseline (regular) opioid therapy (e.g., sustained-release morphine tablets) is mandatory. Recently, rapid onset fentanyls (buccal or nasal) have been strongly recommended for breakthrough cancer pain due to their fast onset and their shorter duration of action. If available, metamizole is an alternative non-steroid-anti-inflammatory-drug. The indication for bisphosphonates should always be checked early in the disease. In advanced cancer stages, glucocorticoids are an important treatment option. If bone metastases lead to neuropathic pain, coanalgetics (e.g., pregabalin) should be initiated. In localized bone pain, radiotherapy is the gold standard for pain reduction in addition to pharmacologic pain management. In diffuse bone pain radionuclids (such as samarium) can be beneficial. Invasive measures (e.g., neuroaxial blockage) are rarely necessary but are an important option if patients with cancer pain syndromes are refractory to pharmacologic management and radiotherapy as described above. Clinical guidelines agree that cancer pain management in incurable cancer is best provided as part of a multiprofessional palliative care approach and all other domains of suffering (psychosocial, spiritual, and existential) need to be carefully addressed («total pain»). PMID:22740797

False-positive buprenorphine EIA urine toxicology results due to high dose morphine: a case report.

PubMed

Tenore, Peter L

2012-01-01

In monitoring a patient with chronic pain who was taking high-dose morphine and oxycodone with weekly urine enzymatic immunoassay (EIA) toxicology testing, the authors noted consistent positives for buprenorphine. The patient was not taking buprenorphine, and gas chromatography/mass spectroscopy (GCMS) testing on multiple samples revealed no buprenorphine, indicating a case of false-positive buprenorphine EIAs in a high-dose opiate case. The authors discontinued oxycodone for a period of time and then discontinued morphine. Urine monitoring with EIAs and GCMS revealed false-positive buprenorphine EIAs, which remained only when the patient was taking morphine. When taking only oxycodone and no morphine, urine samples became buprenorphine negative. When morphine was reintroduced, false-positive buprenorphine results resumed. Medical practitioners should be aware that high-dose morphine (with morphine urine levels turning positive within the 15,000 to 28,000 mg/mL range) may produce false-positive buprenorphine EIAs with standard urine EIA toxicology testing.

Patient characteristics and risks factors for development of dependence on hydrocodone and oxycodone.

PubMed

Miller, Norman S; Greenfeld, Andrea

2004-01-01

The purpose of the study was to document the substantial increase in problematic use of hydrocodone and oxycodone in an addiction treatment population. Our study consisted of a retrospective review of medical records from all patients admitted and discharged in 2000 from Sparrow/St. Lawrence Addiction Detoxification Unit (N = 534). A literature review was conducted in medical journals, governmental groups, and reports including Drug Abuse Warning Network, Pharmacy Times, and National Household Survey on Drug Abuse. More than 144 patients (27%) were dependent on prescription opiate medications. The most frequently mentioned medication was Vicodin (hydrocodone) (53% of the users) followed by OxyContin (oxycodone) (19%). Physicians commonly prescribed these medications (75% of the cases). Predictors of dependence on opiate medications included substance-related diagnoses, positive toxicology for opiates, and other medical diagnoses. Patients under the care of physicians who have other drug dependence diagnoses and medical complaints appear at risk of developing dependence on prescription opiate medications. Proper evaluation and intervention can limit adverse consequences of prescription opiate medications.

Parent and Metabolite Opioid Drug Concentrations in Unintentional Deaths Involving Opioid and Benzodiazepine Combinations*†‡

PubMed Central

Fields, Marcia D.; Abate, Marie A.; Hu, Lan; Long, D. Leann; Blommel, Matthew L.; Haikal, Nabila A.; Kraner, James C.

2016-01-01

Effects of benzodiazepines on postmortem opioid parent and parent/metabolite blood concentration ratios were determined for fentanyl-, hydrocodone-, methadone-, or oxycodone-related accidental deaths. These opioids are partially metabolized by the CYP3A4 enzyme system, which is also affected by diazepam and alprazolam. Opioid/metabolite combinations examined were as follows: fentanyl/norfentanyl, hydrocodone/dihydrocodeine, methadone/EDDP, and oxycodone/oxymorphone. Parent opioid concentrations were analyzed for 877 deaths. Parent/metabolite concentration ratios were analyzed for 349 deaths, excluding cases with co-intoxicants present known to interfere with opioid elimination. Alprazolam in combination with diazepam significantly decreased median hydrocodone concentrations by 48% (p = 0.01) compared to hydrocodone alone. The methadone parent/metabolite concentration ratio was reduced by 35% in the presence of diazepam compared to methadone alone (p = 0.03). Benzodiazepines did not statistically significantly affect fentanyl or oxycodone concentrations. Possible factors affecting opioid concentrations and possible toxicity development, including any differential effects on specific opioids, should continue to be explored. PMID:26223761

[Interindividual variation of pharmacokinetic disposition of and clinical responses to opioid analgesics in cancer pain patients].

PubMed

Naito, Takafumi; Kawakami, Junichi

2015-01-01

Use of prescription opioids for cancer pain according to the World Health Organization analgesic ladder has been accepted in Japan. Although oxycodone and fentanyl are commonly used as first-line analgesics, a few clinical reports have been published on interindividual variations in their pharmacokinetics and clinical responses in cancer patients. (1) Some factors relating to CYP2D6, CYP3A, ATP-binding cassette sub-family B member 1 (ABCB1), and opioid receptor mu 1 (OPRM1) involve oxycodone pharmacokinetics and sensitivity in humans. The relations between their genetic variations and clinical responses to oxycodone are being revealed in limited groups. In our study, the impact of genetic variants and pharmacokinetics on clinical responses to oxycodone were evaluated in Japanese populations. (2) Opioid switching improves the opioid tolerance related to the balance between analgesia and adverse effects. Some patients have difficulty in obtaining better opioid tolerance in recommended conversion ratios. The activities of CYP3A, ABCB1, and OPRM1 contribute to the interindividual variations in clinical responses to fentanyl in cancer patients. However, the variations in opioid switching remain to be clarified in clinical settings. In our study, genetic factors related to interindividual variations in clinical responses in opioid switching to fentanyl were revealed in Japanese populations. In this symposium review, the possibility of approaches to personalized palliative care using opioids based on genetic variants of CYP2D6, CYP3A5, ABCB1, and OPRM1 is discussed.

Effect of preemptive analgesia with intravenous oxycodone in the patients undergoing laparoscopic resection of ovarian tumor

PubMed Central

Wang, Na; Wang, Yuantao; Pang, Lei; Wang, Jinguo

2015-01-01

Objective: To evaluate the efficacy of preemptive intravenous oxycodone in the patients undergoing laparoscopic resection of ovarian tumor. Methods: Sixty ASA I or II patients undergoing elective laparoscopic resection of ovarian tumor were randomly allocated to one of two groups: Group O (n=30) received intravenous oxycodone (0.1 mg·kg-1) 10 minutes before surgery over 2 minutes, and Group N (n=30) received an equivalent volume of normal saline. All patients received a standardized general anesthesia. MBP and HR at the time of arrival of the operating room (T1), 5 min before pneumoperitoneum (T2), 5 minutes (T3), 10 minutes (T4), and 15 minutes after pneumoperitoneum (T5), and VAS scores at postoperative 2, 4, 8, 12 and 24 hour were recorded. The tramadol consumption and side effects in 24 h after surgery were recorded. Results: VAS pain scores at 2, 4, 8 and 12 hour after operation were significantly lower in Group O (P<0.05). MBP and HR increased significantly due to pneumoperitoneum at T3, T4 and T5, compared with T1 and T2 within Group N, and were higher at T3, T4 and T5 in Group N than at the same time points in Group O. Tramadol consumption was statistically lower in Group O (P=0.0003). Conclusions: Preemptive intravenous oxycodone was an efficient and safe method to reduce intraoperative haemodynamic effect and postoperative pain. PMID:26101479

Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)§.

PubMed

Winkelmann, Juliane; Allen, Richard P; Högl, Birgit; Inoue, Yuichi; Oertel, Wolfgang; Salminen, Aaro V; Winkelman, John W; Trenkwalder, Claudia; Sampaio, Cristina

2018-05-14

The objective of the current review was to update the previous evidence-based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, gabapentin enacarbil, and oxycodone/naloxone, which did not appear in the previous review, have accrued data to be considered efficacious. Likewise, new data enable the modification of the level of efficacy for rotigotine from likely efficacious to efficacious. Intravenous ferric carboxymaltose and pneumatic compression devices are considered likely efficacious in idiopathic restless legs syndrome. Bupropion and clonidine were reviewed, but the lack of data determined a rating of insufficient evidence for efficacy. The following interventions continue to be considered efficacious as in 2008: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Bromocriptine, oxycodone, carbamazepine, and valproic acid are considered likely efficacious. Oral iron is nonefficacious in iron-sufficient subjects, but its benefit for patients with low peripheral iron status has not been adequately evaluated. Restless legs syndrome augmentation has been identified as a significant long-term treatment complication for pramipexole more than pregabalin and possibly for all dopaminergic agents more than α2δ ligands. Therefore, special monitoring for augmentation is required for all dopaminergic medications as well as tramadol. Other drugs also require special safety monitoring: cabergoline, pergolide, oxycodone, methadone, tramadol, carbamazepine, and valproic acid. Finally, we also highlighted gaps and needs for future clinical research and studies of restless legs syndrome. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

Safety of Oral Dronabinol During Opioid Withdrawal in Humans

PubMed Central

Jicha, Crystal J.; Lofwall, Michelle R.; Nuzzo, Paul A.; Babalonis, Shanna; Elayi, Samy Claude; Walsh, Sharon L.

2015-01-01

Background Opioid dependence remains a significant public health problem worldwide with only three FDA-approved treatments, all targeting the mu-opioid receptor. Dronabinol, a cannabinoid (CB) 1 receptor agonist, is currently under investigation as a novel opioid withdrawal treatment. This study reports on safety outcomes of dronabinol among adults in opioid withdrawal. Methods Twelve adults physically dependent on short-acting opioids participated in this 5-week within-subject, randomized, double blind, placebo-controlled inpatient study. Volunteers were maintained on oral oxycodone 30mg qid. Double-blind placebo substitutions occurred for 21 hours before each of 7 experimental sessions in order to produce opioid withdrawal. A single oral test dose was administered each session (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Heart rate, blood pressure, respiratory outcomes and pupil diameter were assessed repeatedly. Results Dronabinol 40mg produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30mg. Sinus tachycardia and anxiety also occurred in one volunteer after dronabinol 20mg. Compared to placebo, dronabinol 20 and 30mg produced significant increases in heart rate beginning 1 hour after drug administration that lasted approximately two hours (p<0.05). Dronabinol 5 and 10mg produced placebo-like effects. Oxycodone produced prototypic mu-opioid agonist effects (e.g., miosis). Conclusion Dronabinol 20mg and higher increased heart rate among healthy adults at rest who were in a state of opioid withdrawal, raising concern about its safety. These results have important implications for future dosing strategies and may limit the utility of dronabinol as a treatment for opioid withdrawal. PMID:26483357

Effect of estrogen on morphine- and oxycodone-induced antinociception in a female femur bone cancer pain model.

PubMed

Ono, Hiroko; Nakamura, Atsushi; Kanemasa, Toshiyuki; Sakaguchi, Gaku; Shinohara, Shunji

2016-02-15

Although estrous cycle has been reported to influence antiociceptive effect of morphine in several pain conditions, its effect on cancer pain is not well established. We investigated the effect of estrogen on morphine antinociception using a bone cancer pain model and compared its potency with that of oxycodone. Female mice were ovariectomized (OVX) for preparation of a femur bone cancer pain (FBC) model. β-estradiol was subcutaneously (s.c.) administered and antinociceptive effects of opioids was assessed using the von Frey monofilament test. Although morphine (5-20mg/kg, s.c.) did have significant antinociceptive effects in the FBC-OVX group, its effects in the FBC-OVX+β-estradiol (OVX+E) group was limited. Oxycodone (1-5mg/kg, s.c.) exhibited significant effects in both groups. Expression changes in opioid-related genes (μ-, κ-, δ-opioid receptors, prodynorphin, proenkephalin, proopiomelanocortin) in the spinal and supraspinal sites were examined among the sham-OVX, sham-OVX+E, FBC-OVX, and FBC-OVX+E groups by in situ hybridization. These studies detected a significant increase in prodynorphin in the spinal dorsal horn of the FBC-OVX+E group. Spinal injection of a dynorphin-A antibody to FBC-OVX+E mice restored antinociception of morphine. In conclusion, we detected a differential effect of estrogen on morphine- and oxycodone-induced antinociception in a female FBC model. The effect of morphine was limited with estrogen exposure, which may be due to estrogen- and pain-mediated spinal expression of dynorphin-A. Copyright © 2016 Elsevier B.V. All rights reserved.

Cost-Effectiveness of Tramadol and Oxycodone in the Treatment of Knee Osteoarthritis.

PubMed

Smith, Savannah R; Katz, Jeffrey N; Collins, Jamie E; Solomon, Daniel H; Jordan, Joanne M; Suter, Lisa G; Yelin, Edward H; David Paltiel, A; Losina, Elena

2017-02-01

To evaluate the cost-effectiveness of incorporating tramadol or oxycodone into knee osteoarthritis (OA) treatment. We used the Osteoarthritis Policy Model to evaluate long-term clinical and economic outcomes of knee OA patients with a mean age of 60 years with persistent pain despite conservative treatment. We evaluated 3 strategies: opioid-sparing (OS), tramadol (T), and tramadol followed by oxycodone (T+O). We obtained estimates of pain reduction and toxicity from published literature and annual costs for tramadol ($600) and oxycodone ($2,300) from Red Book Online. Based on published data, in the base case, we assumed a 10% reduction in total knee arthroplasty (TKA) effectiveness in opioid-based strategies. Outcomes included quality-adjusted life years (QALYs), lifetime cost, and incremental cost-effectiveness ratios (ICERs) and were discounted at 3% per year. In the base case, T and T+O strategies delayed TKA by 7 and 9 years, respectively, and led to reduction in TKA utilization by 4% and 10%, respectively. Both opioid-based strategies increased cost and decreased QALYs compared to the OS strategy. Tramadol's ICER was highly sensitive to its effect on TKA outcomes. Reduction in TKA effectiveness by 5% (compared to base case 10%) resulted in an ICER for the T strategy of $110,600 per QALY; with no reduction in TKA effectiveness, the ICER was $26,900 per QALY. When TKA was not considered a treatment option, the ICER for T was $39,600 per QALY. Opioids do not appear to be cost-effective in OA patients without comorbidities, principally because of their negative impact on pain relief after TKA. The influence of opioids on TKA outcomes should be a research priority. © 2016, American College of Rheumatology.

The introduction of a potentially abuse deterrent oxycodone formulation: Early findings from the Australian National Opioid Medications Abuse Deterrence (NOMAD) study.

PubMed

Degenhardt, Louisa; Bruno, Raimondo; Ali, Robert; Lintzeris, Nicholas; Farrell, Michael; Larance, Briony

2015-06-01

There is increasing concern about tampering of pharmaceutical opioids. We describe early findings from an Australian study examining the potential impact of the April 2014 introduction of an abuse-deterrent sustained-release oxycodone formulation (Reformulated OxyContin(®)). Data on pharmaceutical opioid sales; drug use by people who inject drugs regularly (PWID); client visits to the Sydney Medically Supervised Injecting Centre (MSIC); and last drug injected by clients of inner-Sydney needle-syringe programmes (NSPs) were obtained, 2009-2014. A cohort of n=606 people tampering with pharmaceutical opioids was formed pre-April 2014, and followed up May-August 2014. There were declines in pharmacy sales of 80mg OxyContin(®) post-introduction of the reformulated product, the dose most commonly diverted and injected by PWID. Reformulated OxyContin(®) was among the least commonly used and injected drugs among PWID. This was supported by Sydney NSP data. There was a dramatic reduction in MSIC visits for injection of OxyContin(®) post-introduction of the new formulation (from 62% of monthly visits pre-introduction to 5% of visits, August 2014). The NOMAD cohort confirmed a reduction in OxyContin(®) use/injection post-introduction. Reformulated OxyContin(®) was cheaper and less attractive for tampering than Original OxyContin(®). These data suggest that, in the short term, introduction of an abuse-deterrent formulation of OxyContin(®) in Australia was associated with a reduction in injection of OxyContin(®), with no clear switch to other drugs. Reformulated OxyContin(®), in this short follow-up, does not appear to be considered as attractive for tampering. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Pain, opioids, and sleep: implications for restless legs syndrome treatment.

PubMed

Trenkwalder, Claudia; Zieglgänsberger, Walter; Ahmedzai, Sam H; Högl, Birgit

2017-03-01

Opioid receptor agonists are known to relieve restless legs syndrome (RLS) symptoms, including both sensory and motor events, as well as improving sleep. The mechanisms of action of opioids in RLS are still a matter of speculation. The mechanisms by which endogenous opioids contribute to the pathophysiology of this polygenetic disorder, in which there are a number of variants, including developmental factors, remains unknown. A summary of the cellular mode of action of morphine and its (partial) antagonist naloxone via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and the involvement of dendritic spine activation is described. By targeting pain and its consequences, opioids are the first-line treatment in many diseases and conditions with both acute and chronic pain and have thus been used in both acute and chronic pain conditions over the last 40 years. Addiction, dependence, and tolerability of opioids show a wide variability interindividually, as the response to opioids is influenced by a complex combination of genetic, molecular, and phenotypic factors. Although several trials have now addressed opioid treatment in RLS, hyperalgesia as a complication of long-term opioid treatment, or opioid-opioid interaction have not received much attention so far. Therapeutic opioids may act not only on opioid receptors but also via histamine or N-methyl-d-aspartate (NMDA) receptors. In patients with RLS, one of the few studies investigating opioid bindings found that possible brain regions involved in the severity of RLS symptoms are similar to those known to be involved in chronic pain, such as the medial pain system (medial thalamus, amygdala, caudate nucleus, anterior cingulate gyrus, insular cortex, and orbitofrontal cortex). The results of this diprenorphine positron emission tomography study suggested that the more severe the RLS, the greater the release of endogenous opioids. Since 1993, when the first small controlled study was performed with oxycodone in RLS, opioids have been considered an efficacious off-label therapy in patients with severe RLS. A recent trial has proved the efficacy of a combination of prolonged release oxycodone/naloxone in patients with severe RLS as second-line therapy, with a mean dosage of 10/5 mg twice daily (mean difference of International Restless Legs Syndrome Study Group Rating Scale (IRLS) score between groups at 12 weeks: 8.15), and has now been licensed as the first opioid therapy in Europe. The current results from both short- and long-term trials and studies with opioids encourage optimism in alleviating RLS symptoms in patients with severe RLS, or possibly during or after augmentation. Copyright © 2016 Elsevier B.V. All rights reserved.

Opioid overdose mortality in Kansas, 2001-2011: toxicologic evaluation of intent.

PubMed

Okic, Merisa; Cnossen, Leslie; Crifasi, Joseph A; Long, Christopher; Mitchell, Erik K

2013-01-01

Drug concentration is a factor in the determination of the manner of death, but considerable overlap exists between therapeutic and toxic concentrations. This study aims to quantify opioid mortality in Kansas from use of fentanyl, methadone and oxycodone and to evaluate utility of drug concentrations for the determination of the manner of death. Cases referred to a forensic pathology practice in Kansas for autopsy from 1 January 2001 to 31 December 2011 were considered. The criterion for inclusion was detection of fentanyl, methadone and/or oxycodone in postmortem toxicology. Of 9,789 cases, 3,315 had positive toxicology: 180 of fentanyl, 299 of methadone and 310 of oxycodone. There were 207 single opioid fatalities, 264 polydrug overdoses and 318 deaths where an opioid was present but not contributory to the mechanism of death. In line with published studies, incidence of opioid overdose deaths increased over the time of the study. Drug concentrations within each cause and manner of death covered broad ranges. Non-natural and natural manners had less overlap than existed within non-natural manners in limited comparisons. This study shows that drug concentration is independent of manner for non-natural deaths and although insufficient to identify intent, can provide a guideline in differentiating non-natural from natural deaths.

Long-term efficacy, safety and tolerability of Remoxy for the management of chronic pain.

PubMed

Pergolizzi, Joseph V; Zampogna, Gianpietro; Taylor, Robert; Raffa, Robert B

2015-03-01

Historically, chronic pain generally went under-treated for a variety of objective and subjective reasons, including difficulty to objectively diagnose and manage over a long period of time, potential serious adverse effects of commonly available medications, and patient, healthcare and societal concerns over opioid medications. More recently, in an effort to redress the under-treatment of pain, the number of prescriptions of opioid analgesics has risen dramatically. However, paralleling the increased legitimate use has been a concomitant increase in opioid abuse, misuse and diversion. Pharmaceutical companies have responded by developing a variety of opioid formulations designed to deter abuse by making the products more difficult to tamper with. One such product is Remoxy(®), an extended-release formulation of the strong opioid oxycodone. We review the efficacy, safety and tolerability of this formulation based on the available published literature.

Determination of oxycodone and its major metabolites noroxycodone and oxymorphone by ultra-high-performance liquid chromatography tandem mass spectrometry in plasma and urine: application to real cases.

PubMed

Pantano, Flaminia; Brauneis, Stefano; Forneris, Alexandre; Pacifici, Roberta; Marinelli, Enrico; Kyriakou, Chrystalla; Pichini, Simona; Busardò, Francesco Paolo

2017-08-28

Oxycodone is a narcotic drug widely used to alleviate moderate and severe acute and chronic pain. Variability in analgesic efficacy could be explained by inter-subject variations in plasma concentrations of parent drug and its active metabolite, oxymorphone. To evaluate patient compliance and to set up therapeutic drug monitoring (TDM), an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay was developed and validated for the parent drug and its major metabolites noroxycodone and oxymorphone. Extraction of analytes from plasma and urine samples was obtained by simple liquid-liquid extraction. The chromatographic separation was achieved with a reversed phase column using a linear gradient elution with two solvents: acetic acid 1% in water and methanol. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode via positive electrospray ionization (ESI). Separation of analytes was obtained in less than 5 min. Linear calibration curves for all the analytes under investigation in urine and plasma samples showed determination coefficients (r2) equal or higher than 0.990. Mean absolute analytical recoveries were always above 86%. Intra- and inter-assay precision (measured as coefficient of variation, CV%) and accuracy (measured as % error) values were always better than 13%. Limit of detection at 0.06 and 0.15 ng/mL and limit of quantification at 0.2 and 0.5 ng/mL for plasma and urine samples, respectively, were adequate for the purpose of the present study. Rapid extraction, identification and quantification of oxycodone and its metabolites both in urine and plasma by UHPLC-MS/MS assay was tested for its feasibility in clinical samples and provided excellent results for rapid and effective drug testing in patients under oxycodone treatment.

A preclinical physiological assay to test modulation of knee joint pain in the spinal cord: effects of oxycodone and naproxen.

PubMed

Miranda, Jason A; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.

A Preclinical Physiological Assay to Test Modulation of Knee Joint Pain in the Spinal Cord: Effects of Oxycodone and Naproxen

PubMed Central

Miranda, Jason A.; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain. PMID:25157947

Evaluation of a targeted prescriber education intervention on emergency department discharge oxycodone prescribing.

PubMed

Donaldson, Síne R; Harding, Andrew M; Taylor, Simone E; Vally, Hassan; Greene, Shaun L

2017-08-01

The objective of this study was to evaluate the impact of an educational intervention on ED discharge opioid analgesic (OA) prescribing. A brief, one-on-one, educational intervention was delivered to ED OA prescribers by an ED clinical champion. The percentage of patients receiving (i) written advice regarding appropriate oxycodone use, (ii) written or verbal advice regarding appropriate post-discharge follow up and (iii) written general practitioner notification that oxycodone had been prescribed were determined pre- and post-intervention, through review of electronic patient records and structured patient telephone interviews conducted 3-7 days after ED attendance. Secondary outcomes included total amount prescribed and use of non-OA therapies. ED OA prescribers were surveyed to evaluate perceived effectiveness and intervention acceptability. A total of 30 ED OA prescribers received the 5-min intervention. Pre- and post-intervention, 80 and 81 patients were interviewed, respectively. Percentage of patients given written OA information increased from 10% to 22% (P = 0.04) and those receiving follow-up advice increased from 61 to 94% (P < 0.01). General practitioner notification of OA prescription increased from 15% to 88% (P < 0.01). Risk ratio for achieving all three end-points was 7.5 (95% confidence interval 1.8-32, P = 0.01). Median total amount of oxycodone prescribed/patient decreased from 100mg to 50mg (P = 0.04). Non-OA therapies were used by 49% of pre-intervention and 85% of post-intervention patients (P = <0.01). All ED OA prescribers agreed the intervention would change their prescribing practices; 70% deemed the intervention appropriate for delivery in their work environment. A brief, one-on-one educational intervention targeting ED OA prescribers was well received by clinicians and associated with improved quality of OA prescribing. © 2017 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

Pharmaceutical Formulation Facilities as Sources of Opioids and Other Pharmaceuticals to Wastewater Treatment Plant Effluents

PubMed Central

2010-01-01

Facilities involved in the manufacture of pharmaceutical products are an under-investigated source of pharmaceuticals to the environment. Between 2004 and 2009, 35 to 38 effluent samples were collected from each of three wastewater treatment plants (WWTPs) in New York and analyzed for seven pharmaceuticals including opioids and muscle relaxants. Two WWTPs (NY2 and NY3) receive substantial flows (>20% of plant flow) from pharmaceutical formulation facilities (PFF) and one (NY1) receives no PFF flow. Samples of effluents from 23 WWTPs across the United States were analyzed once for these pharmaceuticals as part of a national survey. Maximum pharmaceutical effluent concentrations for the national survey and NY1 effluent samples were generally <1 μg/L. Four pharmaceuticals (methadone, oxycodone, butalbital, and metaxalone) in samples of NY3 effluent had median concentrations ranging from 3.4 to >400 μg/L. Maximum concentrations of oxycodone (1700 μg/L) and metaxalone (3800 μg/L) in samples from NY3 effluent exceeded 1000 μg/L. Three pharmaceuticals (butalbital, carisoprodol, and oxycodone) in samples of NY2 effluent had median concentrations ranging from 2 to 11 μg/L. These findings suggest that current manufacturing practices at these PFFs can result in pharmaceuticals concentrations from 10 to 1000 times higher than those typically found in WWTP effluents. PMID:20521847

Medicines for back pain

MedlinePlus

... direct care, they can be effective in reducing pain. Examples of narcotics include: Codeine Fentanyl -- available as a patch Hydrocodone Hydromorphone Morphine Oxycodone Tramadol Possible side effects of these drugs include: Drowsiness ...

77 FR 3777 - Draft and Revised Draft Guidances for Industry Describing Product-Specific Bioequivalence...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-25

... Potassium (multiple RLDs) Aripiprazole Aspirin; Butalbital; Caffeine (multiple RLDs) Aspirin; Dipyridamole Aspirin; Oxycodone Aspirin; Butalbital; Caffeine; Codeine Phosphate Atovaquone Auranofin Azelaic Acid...

Trends in the Distribution of Opioids in Puerto Rico, 1999-2013.

PubMed

El Burai Félix, Sausan; Mack, Karin A; Jones, Christopher M

2016-09-01

Limited information has been published about opioid prescribing practices in Puerto Rico. The objective of this study was to create baseline trends of opioids distributed over a period of fourteen years in Puerto Rico. We examined data from the U.S. Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS) for the period 1999-2013. ARCOS data reflects the amount of controlled substances legally dispensed. Analyses include the distribution of opioids (in morphine milligram equivalent kg per 10,000 persons) by year and entity (pharmacy, hospital, practitioner). The distribution of four drugs (fentanyl, hydromorphone, methadone, oxycodone) increased over 100% between 1999 and 2013. The distribution of two drugs (hydrocodone and meperidine) declined between 1999 and 2013. Oxycodone distribution grew from 0.13 MME kg grams per 10,000 persons in 1999 to 0.29 MME kg in 2013. ARCOS data showed that the overall amount of opioid pain relievers distributed in Puerto Rico increased by 68% between 1999 and 2013. Currently, prescription opioid pain reliever overdose deaths in Puerto Rico do not appear to be skyrocketing as they are in the mainland U.S. However, the ongoing problem with prescription opioid pain reliever overdoses in certain areas should serve as a warning to monitor consumption of opioid pain relievers, as well as changes in prescription drug abuse, overdoses, and deaths.

Neonatal abstinence syndrome

MedlinePlus

... takes drugs such as heroin, codeine, oxycodone (Oxycontin), methadone or buprenorphine. These and other substances pass through ... babies with severe symptoms need medicines such as methadone and morphine to treat withdrawal symptoms. These babies ...

Hydrocodone/oxycodone overdose

MedlinePlus

... often found in prescription painkillers. The most common painkillers that include these two ingredients are: Norco OxyContin Percocet Percodan Vicodin Vicodin ES These medicines may also be combined with the non-narcotic medicine, acetaminophen (Tylenol).

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.

Desomorphine Screening Using Commercial Enzyme-Linked Immunosorbent Assays.

PubMed

Winborn, Jessica; Kerrigan, Sarah

2017-06-01

Desomorphine ("Krokodil") is a semi-synthetic opioid that has drawn attention as a recreational drug, particularly in Russia, neighboring former Soviet Republics, Eastern and Central Europe. It has no accepted medicinal uses and is currently a schedule I drug in the United States. In clandestine environments, desomorphine is synthesized from codeine using red phosphorous, hydroiodic acid and gasoline. Residual starting materials in illicit preparations have been associated with severe dermatological effects and extensive tissue necrosis. Desomorphine is not well studied, and there are limited reports concerning its pharmacology or detection in biological matrices. Immunoassays are widely relied upon for both antemortem and postmortem toxicology screening. Although desomorphine is an opioid of the phenanthrene-type, its ability to bind to conventional opioid antibodies has not been described. In this report we describe the cross-reactivity of desomorphine using six commercially available enzyme-linked immunosorbent assays (Immunalysis Opiates Direct ELISA, Immunalysis Oxycodone/Oxymorphone Direct ELISA, Randox Opiate ELISA, OraSure Technologies OTI Opiate Micro-plate EIA, Neogen Opiate Group ELISA and Neogen Oxycodone/Oxymorphone ELISA). Cross-reactivites were highly variable between assays, ranging from 77 to <2.5%. In general, assays directed towards morphine produced greater cross-reactivity with desomorphine than those directed towards oxycodone. The Immunalysis Opiates Direct ELISA produced the greatest cross-reactivity, although several of the assays evaluated produced cross-reactivity of a sufficient magnitude to be effective for desomorphine screening. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Efficacy and Clinical Safety of Various Analgesic Combinations for Post-Operative Pain after Third Molar Surgery: A Systematic Review and Meta-Analysis

PubMed Central

Au, Alvin Ho Yeung; Choi, Siu Wai; Cheung, Chi Wai; Leung, Yiu Yan

2015-01-01

Objectives To run a systematic review and meta-analysis of randomized clinical trials aiming to answer the clinical question “which analgesic combination and dosage is potentially the most effective and safe for acute post-operative pain control after third molar surgery?”. Materials and Methods A systematic search of computer databases and journals was performed. The search and the evaluations of articles were performed by 2 independent reviewers in 3 rounds. Randomized clinical trials related to analgesic combinations for acute post-operative pain control after lower third molar surgery that matched the selection criteria were evaluated to enter in the final review. Results Fourteen studies with 3521 subjects, with 10 groups (17 dosages) of analgesic combinations were included in the final review. The analgesic efficacy were presented by the objective pain measurements including sum of pain intensity at 6 hours (SPID6) and total pain relief at 6 hours (TOTPAR6). The SPID6 scores and TOTPAR6 scores of the reported analgesic combinations were ranged from 1.46 to 6.44 and 3.24 – 10.3, respectively. Ibuprofen 400mg with oxycodone HCL 5mg had superior efficacy (SPID6: 6.44, TOTPAR6: 9.31). Nausea was the most common adverse effect, with prevalence ranging from 0-55%. Ibuprofen 200mg with caffeine 100mg or 200mg had a reasonable analgesic effect with fewer side effects. Conclusion This systematic review and meta-analysis may help clinicians in their choices of prescribing an analgesic combination for acute post-operative pain control after lower third molar surgery. It was found in this systematic review Ibuprofen 400mg combined with oxycodone HCL 5mg has superior analgesic efficacy when compared to the other analgesic combinations included in this study. PMID:26053953

Methadone, Morphine, or Oxycodone in Treating Pain in Patients With Cancer

ClinicalTrials.gov

2012-11-09

Brain and Central Nervous System Tumors; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Pain; Precancerous Condition; Unspecified Adult Solid Tumor, Protocol Specific

Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part II.

PubMed

Armstrong, Scott C; Cozza, Kelly L

2003-01-01

Pharmacokinetic drug-drug interactions with codeine, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine are reviewed in this column. These compounds have a very similar chemical structure to morphine. Unlike morphine, which is metabolized chiefly through conjugation reactions with uridine diphosphate glucuronosyl transferase (UGT) enzymes, these five drugs are metabolized both through oxidative reactions by the cytochrome P450 (CYP450) enzyme and conjugation by UGT enzymes. There is controversy as to whether codeine, dihydrocodeine, and hydrocodone are actually prodrugs requiring activation by the CYP450 2D6 enzyme or UGT enzymes. Oxycodone and buprenorphine, however, are clearly not prodrugs and are metabolized by the CYP450 2D6 and 3A4 enzymes, respectively. Knowledge of this metabolism assists in the understanding for the potential of drug-drug interactions with these drugs. This understanding is important so that clinicians can choose the proper dosages for analgesia and anticipate potential drug-drug interactions.

Trends and changes in prescription opioid analgesic dispensing in Canada 2005–2012: an update with a focus on recent interventions

PubMed Central

2014-01-01

Background Prescription opioid analgesic (POA) utilization has steeply increased globally, yet is far higher in established market economies than elsewhere. Canada features the world’s second-highest POA consumption rates. Following increases in POA-related harm, several POA control interventions have been implemented since 2010. Methods We examined trends and patterns in POA dispensing in Canada by province for 2005–2012, including a focus on the potential effects of interventions. Data on annual dispensing of individual POA formulations – categorized into ‘weak opioids’ and ‘strong opioids’ – from a representative sub-sample of 5,700 retail pharmacies across Canada (from IMS Brogan’s Compuscript) were converted into Defined Daily Doses (DDD), and examined intra- and inter-provincially as well as for Canada (total). Results Total POA dispensing – driven by strong opioids – increased across Canada until 2011; four provinces indicated decreases in strong opioid dispensing; seven provinces indicated decreases specifically in oxycodone dispensing, 2011–2012. The dispensing ratio weak/strong opioids decreased substantively. Major inter-provincial differences in POA dispensing levels and qualitative patterns of POA formulations dispensed persisted. Previous increasing trends in POA dispensing were reversed in select provinces 2011–2012, coinciding with POA-related interventions. Conclusions Further examinations regarding the sustained nature, drivers and consequences of the recent trend changes in POA dispensing – including possible ‘substitution effects’ for oxycodone reductions – are needed. PMID:24572005

Prescription opioid abuse based on representative postmortem toxicology.

PubMed

Häkkinen, Margareeta; Vuori, Erkki; Ojanperä, Ilkka

2014-12-01

Opioids are important medications for pain and opioid maintenance treatment. Increasing use and abuse of prescription opioids has, however, caused worldwide concern. Our aim was to estimate the ratio between prescription opioid abuse and total use, based on representative postmortem toxicology. Our material included all the medico-legally examined deaths in Finland during 2010-2011 involving positive findings involving buprenorphine, codeine, fentanyl, methadone, oxycodone, or tramadol. We studied drug abuse by age group, with "abuse" meaning licit opioids used illicitly as narcotics. Drug-abuse history, drug injecting, or laboratory findings of illicit drugs defined an abuser case. We then compared abuser cases and other opioid-related cases between the opioids with the number of fatal poisonings, accidents, suicides, alcohol findings, concomitant opioid use, and median postmortem blood opioid concentrations. Opioid findings numbered 2499 in 2088 cases. Drug abuse involved 545 opioid-positive cases, which in Finland represented 0.5% of those deceased. The proportion of abuser cases among all opioid-related cases for buprenorphine was 85.5%, for methadone 82.4%, for tramadol 29.4%, for codeine 16.3%, for fentanyl 14.5%, and for oxycodone 6.9%. Abuse in age-groups >60 was rare. Concomitant other opioid findings were more frequent in abuser- than in other cases for codeine, oxycodone, and tramadol, whereas alcohol findings were more frequent in buprenorphine, codeine, and fentanyl abuse. Buprenorphine and methadone were most often related to drug abuse. Every other opioid studied involved some abuse, and especially tramadol. Abuse and fatal poisonings were concentrated in men aged 20-49. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Tricyclic Antidepressants Found in Pilots Fatally Injured in Civil Aviation Accidents

DTIC Science & Technology

2014-11-01

had only nortriptyline value. 4 oxycodone, propoxyphene/norpropoxyphene, salicylate, and tramadol ), anticholinergic/ parasympatholytic agent...amitriptyline, one nortriptyline, and one imipramine), for pain in two cases (one imipramine and one amitriptyline), and for chronic insomnia in one case

Preoperative versus postoperative ultrasound-guided rectus sheath block for improving pain, sleep quality and cytokine levels of patients with open midline incisions undergoing transabdominal gynaecological operation: study protocol for a randomised controlled trial.

PubMed

Jin, Feng; Li, Xiao-Qian; Tan, Wen-Fei; Ma, Hong; Lu, Huang-Wei

2015-12-10

Rectus sheath block (RSB) is used for postoperative pain relief in patients undergoing abdominal surgery with midline incision. Preoperative RSB has been shown to be effective, but it has not been compared with postoperative RSB. The aim of the present study is to evaluate postoperative pain, sleep quality and changes in the cytokine levels of patients undergoing gynaecological surgery with RSB performed preoperatively versus postoperatively. This study is a prospective, randomised, controlled (randomised, parallel group, concealed allocation), single-blinded trial. All patients undergoing transabdominal gynaecological surgery will be randomised 1:1 to the treatment intervention with general anaesthesia as an adjunct to preoperative or postoperative RSB. The objective of the trial is to evaluate postoperative pain, sleep quality and changes in the cytokine levels of patients undergoing gynaecological surgery with RSB performed preoperatively (n = 32) versus postoperatively (n = 32). All of the patients, irrespective of group allocation, will receive patient-controlled intravenous analgesia (PCIA) with oxycodone. The primary objective is to compare the interval between leaving the post-anaesthesia care unit and receiving the first PCIA bolus injection on the first postoperative night between patients who receive preoperative versus postoperative RSB. The secondary objectives will be to compare (1) cumulative oxycodone consumption at 24 hours after surgery; (2) postoperative sleep quality, as measured using a BIS-Vista monitor during the first night after surgery; and (3) cytokine levels (interleukin-1, interleukin-6, tumour necrosis factor-α and interferon-γ) during surgery and at 24 and 48 hours postoperatively. Clinical experience has suggested that RSB is a very effective postoperative analgesic technique, and we will answer the following questions with this trial. Do preoperative block and postoperative block have the same duration of analgesic effects? Can postoperative block extend the analgesic time? The results of this study could have actual clinical applications that could help to reduce postoperative pain and shorten hospital stays. Current Controlled Trials NCT02477098 15 June 2015.

[Selection of an optimum solvent for administration of oxinorm powder through a tube].

PubMed

Fukawa, Misako; Kokubun, Hideya; Sasaki, Hisako; Matsubara, Hajime; Yago, Kazuo

2008-05-01

Oxinorm powder is a rapid-release preparation of oxycodone hydrochloride for oral administration recently marketed for the first time in Japan. Administration of a powdered drug through a nasal tube is known to involve the risk of tube obstruction by the drug. For narcotic preparations like oxinorm powder, it is desirable from the perspective of drug control, that the drug administered be unlikely to remain in the cup, syringe or catheter used, and that the drug be dispensable in precise amounts. The present study was undertaken to identify problems associated with administration of oxinorm powder through a nasal tube and to determine an appropriate method for its administration. First, the solubility of the powder in various solvents was evaluated macroscopically to select initially appropriate solvents. Then, the drug dissolved in each of these solvents was administered through 3 types of catheters with different raw materials and forms, to simulate drug administration through a nasal tube. Percent residual drug remaining on/within the cup, syringe, and catheter was measured by HPLC, to evaluate the adhesiveness of the drug. When dissolved in distilled water, black vinegar, or milk, the drug was easy to administer through the catheter, with a low percentage of drug remaining on the cup, syringe, and catheter, suggesting that these fluids can be used as solvents for oxinorm powder. Semidigested nutrients such as Ensure.H were found to be unsuitable solvents for oxinorm powder.

[Role of intensive medical training on Law 38 to improve pain management in primary care].

PubMed

Mammucari, Massimo; Muscas, Fabrizio; Arpino, Giovanni; Aronica, Alberto; Russo, Pasquale; Visconti, Marco

2014-04-01

The Italian Law no. 38/2010 requires that the physician reports in the medical record the type and the intensity of pain, analgesic therapies and clinical results. We developed a training model for 256 primary care physicians (GPs). After a period of intensive training on the content of the law no. 38, diagnostic and pharmacological approach of pain, we carried out a clinical audit by a web based clinical record to assess doctor's compliance to Law no. 38 and the use of opioids. 2631 patients were assessed (age 71,5±13,7 years; median 74). The mean of chronic non oncologic pain intesity was 5.41±2.0 (static) and 6.10±2.32 (dynamic). After a systematic measurement of pain, a better control of patients was achieved (2.22±2.12 points lower for static, 2.37±2.34 lower for dynamic pain (p<0.001 vs basal time). An increased use of opioids have been detected. GPs have also used strong opioids in opioid-naïve patients, avoiding the first or the second step if intensity of pain detected was severe. In fact, a greater pain control was achieved with oxycodone compared to tramadol or codeine (all of them with normal release and combined with acetaminophen). Chronic non cancer pain remains one of the major clinical problems in the primary care setting, especially in the elderly. The standard measurement of parameters related to pain and the proper use of opioids depends on the scientific update and how this is delivered. GPs are crucial to implement the Law 38 and to increase the degree of complexity of the patient to be properly admitted to a SPOKE/HUB center.

Prescription of opioid analgesics for nontraumatic dental conditions in emergency departments.

PubMed

Okunseri, Christopher; Dionne, Raymond A; Gordon, Sharon M; Okunseri, Elaye; Szabo, Aniko

2015-11-01

Opioid analgesics prescribed for nontraumatic dental conditions (NTDCs) by emergency physicians continue to receive attention because of the associated potential for misuse, abuse and addiction. This study examined rates of prescription of opioid analgesics and types of opioid analgesics prescribed for NTDC visits in U.S. emergency departments. Data from the National Hospital Ambulatory Medical Care Survey from 2007 to 2010 were analyzed. Descriptive statistics and logistic regression analysis were performed and adjusted for the survey design. NTDCs made up 1.7% of all ED visits from 2007 to 2010. The prescription of opioid analgesics was 50.3% for NTDC and 14.8% for non-NTDC visits. The overall rate of opioid analgesics prescribed for NTDCs remained fairly stable from 2007 through 2010. Prescription of opioids was highest among patients aged 19-33 years (56.8%), self-paying (57.1%), and non-Hispanic Whites (53.2%). The probability of being prescribed hydrocodone was highest among uninsured patients (68.7%) and for oxycodone, it was highest among private insurance patients (33.6%). Compared to 34-52 year olds, children 0-4 years were significantly more likely to be prescribed codeine and less likely to be prescribed oxycodone. Compared to non-Hispanic Whites, non-Hispanic Blacks had significantly higher odds of been prescribed codeine and somewhat lower odds of been prescribed oxycodone, but it was not statistically significant. There was no significant change in the rates of opioid analgesics prescribed over time for NTDC visits to EDs. Age, payer type and race/ethnicity were significant predictors for the prescription of different opioid analgesics by emergency physicians for NTDC visits. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Active surveillance of abused and misused prescription opioids using poison center data: a pilot study and descriptive comparison.

PubMed

Hughes, Alice A; Bogdan, Gregory M; Dart, Richard C

2007-01-01

Prescription opioids are abused throughout the United States. Several monitoring programs are in existence, however, none of these systems provide up-to-date information on prescription opioid abuse. This article describes the use of poison centers as a real-time, geographically specific, surveillance system for prescription opioid abuse and compares our system with an existing prescription drug abuse monitoring program, the Drug Abuse Warning Network (DAWN). Data were collected from eight geographically dispersed poison centers for a period of twelve months. Any call involving buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, and oxycodone was considered a case. Any case coded as intentional exposure (abuse, intentional misuse, suicide, or intentional unknown) was regarded as misuse and abuse. Comparative data were obtained from DAWN. Poison center rates of abuse and misuse were highest for hydrocodone at 3.75 per 100,000 population, followed by oxycodone at 1.81 per 100,000 population. DAWN emergency department (ED) data illustrate a similar pattern of abuse with most mentions involving hydrocodone and oxycodone. Poison center data indicate that people aged 18 to 25 had the highest rates of abuse. DAWN reported the majority of ED mentions among 35 to 44-year-olds. Geographically, Kentucky had the uppermost rates of abuse and misuse for all opioids combined at 20.69 per 100,000 population. CONCLUSIONS. Comparing poison center data to DAWN yielded mostly comparable results, including hydrocodone as the most commonly mentioned drug. Our results suggest poison center data can be used as an indicator for prescription opioid abuse and misuse and can provide timely, geographically specific information on prescription drug abuse.

Characterization of Adolescent Prescription Drug Abuse and Misuse Using the Researched Abuse Diversion and Addiction-Related Surveillance (RADARS®) System

PubMed Central

Zosel, Amy; Bartelson, Becki Bucher; Bailey, Elise; Lowenstein, Steven; Dart, Rick

2013-01-01

Objective To describe the characteristics and health effects of adolescent (age 13–19 years) prescription drug abuse and misuse using the Researched Abuse Diversion and Addiction-Related Surveillance (RADARS®) System. Method Secondary analysis of data collected from RADARS System participating poison centers was performed. Data for all intentional exposures from 2007 through 2009 were used to describe adolescent prescription opioid (oxycodone, fentanyl, hydrocodone, hydromorphone, morphine, methadone, buprenorphine, and tramadol) and stimulant (methylphenidate and amphetamines) exposures. Results A total of 16,209 intentional adolescent exposures to prescription drugs were identified, 68% to opioids and 32% to stimulants. The mean age was 16.6 years (SD ± 1.7 years). Slightly more than half (52.4%) of drug mentions involved females. The five most frequently misused or abused drugs were hydrocodone (32%), amphetamines (18%), oxycodone (15%), methylphenidate (14%), and tramadol (11%). Of all exposures, 38%were classified as suspected suicidal. Of adolescents who intentionally exposed themselves to prescription drugs, 30% were treated in a health care facility, 2,792 of whom were admitted to the hospital, including 1,293 to the intensive care unit. A total of 17.2% of intentional exposures were associated with no effect, 38.9% minor effects, 23.3% moderate effects, 3.6% major effects, and 0.1% were associated with death. Oxycodone and methadone were associated with the most deaths. No deaths were associated with exposures to stimulants. Conclusions Prescription drug misuse and abuse poses an important health problem and results in thousands of hospitalizations of adolescents per year. Further work is needed to develop focused interventions and educational programs to prevent prescription drug abuse and misuse by adolescents. PMID:23357446

NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential.

PubMed

Miyazaki, Takahiro; Choi, Irene Y; Rubas, Werner; Anand, Neel K; Ali, Cherie; Evans, Juli; Gursahani, Hema; Hennessy, Marlene; Kim, Grace; McWeeney, Daniel; Pfeiffer, Juergen; Quach, Phi; Gauvin, David; Riley, Timothy A; Riggs, Jennifer A; Gogas, Kathleen; Zalevsky, Jonathan; Doberstein, Stephen K

2017-10-01

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Characterization of adolescent prescription drug abuse and misuse using the Researched Abuse Diversion and Addiction-related Surveillance (RADARS(®)) System.

PubMed

Zosel, Amy; Bartelson, Becki Bucher; Bailey, Elise; Lowenstein, Steven; Dart, Rick

2013-02-01

To describe the characteristics and health effects of adolescent (age 13-19 years) prescription drug abuse and misuse using the Researched Abuse Diversion and Addiction-Related Surveillance (RADARS(®)) System. Secondary analysis of data collected from RADARS System participating poison centers was performed. Data for all intentional exposures from 2007 through 2009 were used to describe adolescent prescription opioid (oxycodone, fentanyl, hydrocodone, hydromorphone, morphine, methadone, buprenorphine, and tramadol) and stimulant (methylphenidate and amphetamines) exposures. A total of 16,209 intentional adolescent exposures to prescription drugs were identified, 68% to opioids and 32% to stimulants. The mean age was 16.6 years (SD ± 1.7 years). Slightly more than half (52.4%) of drug mentions involved females. The five most frequently misused or abused drugs were hydrocodone (32%), amphetamines (18%), oxycodone (15%), methylphenidate (14%), and tramadol (11%). Of all exposures, 38% were classified as suspected suicidal. Of adolescents who intentionally exposed themselves to prescription drugs, 30% were treated in a health care facility, 2,792 of whom were admitted to the hospital, including 1,293 to the intensive care unit. A total of 17.2% of intentional exposures were associated with no effect, 38.9% minor effects, 23.3% moderate effects, 3.6% major effects, and 0.1% were associated with death. Oxycodone and methadone were associated with the most deaths. No deaths were associated with exposures to stimulants. Prescription drug misuse and abuse poses an important health problem and results in thousands of hospitalizations of adolescents per year. Further work is needed to develop focused interventions and educational programs to prevent prescription drug abuse and misuse by adolescents. Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Comparative Analysis of Opioid Queries on Erowid.org: An Opportunity to Advance Harm Reduction.

PubMed

Wightman, Rachel S; Perrone, Jeanmarie; Erowid, Fire; Erowid, Earth; Meisel, Zachary F; Nelson, Lewis S

2017-08-24

Many individuals who use opioids turn to online resources to gather information on effects, availability, and safety. Describe opioid index page views on Erowid.org to assess trends in public interest in particular opioids. Retrospective analysis of Erowid.org site traffic was performed to identify unique average daily visits to opioid pages. All data was normalized to that of visits to the heroin index page. Average daily visits to the index pages of each of 6 commonly abused opioids were assessed during the period of 2009 to 2015. Similarly, visits to 15 distinct opioid index pages at 5 time points (July, October 2014 and Jan, April, and July 2015) were described. From 2009 to 2015 a decrease in the number of page visits versus heroin (1.00) occurred for hydrocodone (0.87 to 0.59, -32%), oxycodone (1.38 to 0.99, -28%), and morphine (0.26 to 0.25, -6%). Increases in page visits compared to heroin occurred for fentanyl (0.18 to 0.47, +157%), tramadol (0.43 to 0.88, +106%), hydromorphone (0.19 to 0.24, +29%), and oxymorphone (0.11 to 0.13, +18%). Indexed to heroin (1.00) average opioid page visit frequencies from July 2014 to July 2015 were highest for oxycodone (1.02) and tramadol (0.81). Conclusion/Importance: Oxycodone and tramadol represent the greatest number of Erowid.org opioid page visits compared to heroin. The largest increase in visits over the study periods was for fentanyl and tramadol. The relationship of page visits on Erowid.org creates a unique opportunity for real-time evaluation of emerging drug trends and epidemiological study.

Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target

PubMed Central

Yin, Kathleen; Deuis, Jennifer R; Lewis, Richard J

2016-01-01

Burn injury is a cause of significant mortality and morbidity worldwide and is frequently associated with severe and long-lasting pain that remains difficult to manage throughout recovery. We characterised a mouse model of burn-induced pain using pharmacological and transcriptomic approaches. Mechanical allodynia elicited by burn injury was partially reversed by meloxicam (5 mg/kg), gabapentin (100 mg/kg) and oxycodone (3 and 10 mg/kg), while thermal allodynia and gait abnormalities were only significantly improved by amitriptyline (3 mg/kg) and oxycodone (10 mg/kg). The need for relatively high opioid doses to elicit analgesia suggested a degree of opioid resistance, similar to that shown clinically in burn patients. We thus assessed the gene expression changes in dorsal root ganglion neurons and pathophysiological mechanisms underpinning burn injury-induced pain using a transcriptomic approach. Burn injury was associated with significantly increased expression of genes associated with axon guidance, neuropeptide signalling, behavioural defence response and extracellular signalling, confirming a mixed neuropathic and inflammatory aetiology. Notably, among the pain-related genes that were upregulated post-injury was the cholecystokinin 2 receptor (Cckbr), a G protein-coupled receptor known as a pain target involved in reducing opioid effectiveness. Indeed, the clinically used cholecystokinin receptor antagonist proglumide (30 mg/kg) was effective at reversing mechanical allodynia, with additional analgesia evident in combination with low-dose oxycodone (1 mg/kg), including significant reversal of thermal allodynia. These findings highlight the complex pathophysiological mechanisms underpinning burn injury-induced pain and suggest that cholecystokinin-2 receptor antagonists may be useful clinically as adjuvants to decrease opioid requirements and improve analgesic management. PMID:27573516

The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction.

PubMed

Grønlund, Debbie; Poulsen, Jakob L; Krogh, Klaus; Brock, Christina; Liao, Donghua; Gregersen, Hans; Drewes, Asbjørn M; Olesen, Anne E

2018-05-30

Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting μ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo. In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale. During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (-45.9 vs -38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01). In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

Social Media Mining for Toxicovigilance: Automatic Monitoring of Prescription Medication Abuse from Twitter.

PubMed

Sarker, Abeed; O'Connor, Karen; Ginn, Rachel; Scotch, Matthew; Smith, Karen; Malone, Dan; Gonzalez, Graciela

2016-03-01

Prescription medication overdose is the fastest growing drug-related problem in the USA. The growing nature of this problem necessitates the implementation of improved monitoring strategies for investigating the prevalence and patterns of abuse of specific medications. Our primary aims were to assess the possibility of utilizing social media as a resource for automatic monitoring of prescription medication abuse and to devise an automatic classification technique that can identify potentially abuse-indicating user posts. We collected Twitter user posts (tweets) associated with three commonly abused medications (Adderall(®), oxycodone, and quetiapine). We manually annotated 6400 tweets mentioning these three medications and a control medication (metformin) that is not the subject of abuse due to its mechanism of action. We performed quantitative and qualitative analyses of the annotated data to determine whether posts on Twitter contain signals of prescription medication abuse. Finally, we designed an automatic supervised classification technique to distinguish posts containing signals of medication abuse from those that do not and assessed the utility of Twitter in investigating patterns of abuse over time. Our analyses show that clear signals of medication abuse can be drawn from Twitter posts and the percentage of tweets containing abuse signals are significantly higher for the three case medications (Adderall(®): 23 %, quetiapine: 5.0 %, oxycodone: 12 %) than the proportion for the control medication (metformin: 0.3 %). Our automatic classification approach achieves 82 % accuracy overall (medication abuse class recall: 0.51, precision: 0.41, F measure: 0.46). To illustrate the utility of automatic classification, we show how the classification data can be used to analyze abuse patterns over time. Our study indicates that social media can be a crucial resource for obtaining abuse-related information for medications, and that automatic approaches involving supervised classification and natural language processing hold promises for essential future monitoring and intervention tasks.

Assessment of Tapentadol API Abuse Liability With the Researched Abuse, Diversion and Addiction-Related Surveillance System.

PubMed

Vosburg, Suzanne K; Severtson, S Geoffrey; Dart, Richard C; Cicero, Theodore J; Kurtz, Steven P; Parrino, Mark W; Green, Jody L

2018-04-01

Tapentadol, a Schedule II opioid with a combination of µ-opioid activity and norepinephrine reuptake inhibition, is used for the management of moderate to severe acute and chronic pain. Its dual mechanism of action is thought to reduce opioid-related side effects that can complicate pain management. Since approval, tapentadol has been tracked across multiple outcomes suggesting abuse liability, and a pattern of relatively low, although not absent, abuse liability has been found. This retrospective cohort study further details the abuse liability of tapentadol as an active pharmaceutical ingredient (API) when immediate-release as well as extended-release formulations were on the market together (fourth quarter of 2011 to second quarter of 2016). Tapentadol (API) was compared with tramadol, hydrocodone, morphine, oxycodone, hydromorphone, and oxymorphone across Poison Center, Drug Diversion, and Treatment Center Programs Combined data streams from the Researched Abuse, Diversion and Addiction-Related Surveillance system. Findings suggest the public health burden related to tapentadol to date is low, but present. Event rates of abuse per population-level denominators were significantly lower than all other opioids examined. However, when adjusted for drug availability, event rates of abuse were lower than most Schedule II opioids studied, but were not the lowest. Disentangling these 2 sets of findings further by examining various opioid formulations, such as extended-release and the role of abuse-deterrent formulations, is warranted. This article presents the results from an examination of tapentadol API across the Researched Abuse, Diversion and Addiction-Related Surveillance System: a broad and carefully designed postmarketing mosaic. Data to date from Poison Center, Drug Diversion, and Treatment Centers combined suggest a low, but present public health burden related to tapentadol. Copyright © 2018. Published by Elsevier Inc.

Opioid doses required for pain management in lung cancer patients with different cholesterol levels: negative correlation between opioid doses and cholesterol levels.

PubMed

Huang, Zhenhua; Liang, Lining; Li, Lingyu; Xu, Miao; Li, Xiang; Sun, Hao; He, Songwei; Lin, Lilong; Zhang, Yixin; Song, Yancheng; Yang, Man; Luo, Yuling; Loh, Horace H; Law, Ping-Yee; Zheng, Dayong; Zheng, Hui

2016-03-08

Pain management has been considered as significant contributor to broad quality-of-life improvement for cancer patients. Modulating serum cholesterol levels affects analgesia abilities of opioids, important pain killer for cancer patients, in mice system. Thus the correlation between opioids usages and cholesterol levels were investigated in human patients with lung cancer. Medical records of 282 patients were selected with following criteria, 1) signed inform consent, 2) full medical records on total serum cholesterol levels and opioid administration, 3) opioid-naïve, 4) not received/receiving cancer-related or cholesterol lowering treatment, 5) pain level at level 5-8. The patients were divided into different groups basing on their gender and cholesterol levels. Since different opioids, morphine, oxycodone, and fentanyl, were all administrated at fixed low dose initially and increased gradually only if pain was not controlled, the percentages of patients in each group who did not respond to the initial doses of opioids and required higher doses for pain management were determined and compared. Patients with relative low cholesterol levels have larger percentage (11 out of 28 in female and 31 out of 71 in male) to not respond to the initial dose of opioids than those with high cholesterol levels (0 out of 258 in female and 8 out of 74 in male). Similar differences were obtained when patients with different opioids were analyzed separately. After converting the doses of different opioids to equivalent doses of oxycodone, significant correlation between opioid usages and cholesterol levels was also observed. Therefore, more attention should be taken to those cancer patients with low cholesterol levels because they may require higher doses of opioids as pain killer.

78 FR 62676 - Anthony E. Wicks, M.D. Decision and Order

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-22

... registration BW7987184, while listing his address as Pain Management of Winter Springs, 165 W. SR 434, Winter... practice address. Id. at 2, ] 5. \\2\\ Documentary evidence, which the Government acquired through... prescriptions for oxycodone,\\4\\ diazepam, and lorazepam.\\5\\ GX 15, at 2, ] 7; GX 13. \\3\\ The documentary...

Exploring trends of nonmedical use of prescription drugs and polydrug abuse in the Twittersphere using unsupervised machine learning.

PubMed

Kalyanam, Janani; Katsuki, Takeo; R G Lanckriet, Gert; Mackey, Tim K

2017-02-01

Nonmedical use of prescription medications/drugs (NMUPD) is a serious public health threat, particularly in relation to the prescription opioid analgesics abuse epidemic. While attention to this problem has been growing, there remains an urgent need to develop novel strategies in the field of "digital epidemiology" to better identify, analyze and understand trends in NMUPD behavior. We conducted surveillance of the popular microblogging site Twitter by collecting 11 million tweets filtered for three commonly abused prescription opioid analgesic drugs Percocet® (acetaminophen/oxycodone), OxyContin® (oxycodone), and Oxycodone. Unsupervised machine learning was applied on the subset of tweets for each analgesic drug to discover underlying latent themes regarding risk behavior. A two-step process of obtaining themes, and filtering out unwanted tweets was carried out in three subsequent rounds of machine learning. Using this methodology, 2.3M tweets were identified that contained content relevant to analgesic NMUPD. The underlying themes were identified for each drug and the most representative tweets of each theme were annotated for NMUPD behavioral risk factors. The primary themes identified evidence high levels of social media discussion about polydrug abuse on Twitter. This included specific mention of various polydrug combinations including use of other classes of prescription drugs, and illicit drug abuse. This study presents a methodology to filter Twitter content for NMUPD behavior, while also identifying underlying themes with minimal human intervention. Results from the study track accurately with the inclusion/exclusion criteria used to isolate NMUPD-related risk behaviors of interest and also provides insight on NMUPD behavior that has a high level of social media engagement. Results suggest that this could be a viable methodology for use in big data substance abuse surveillance, data collection, and analysis in comparison to other studies that rely upon content analysis and human coding schemes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sources of Pharmaceutical Opioids for Non-Medical Use Among Young Adults

PubMed Central

Daniulaityte, Raminta; Falck, Russel; Carlson, Robert G.

2014-01-01

The study uses qualitative and quantitative data to describe sources of pain pills for illicit use among young adult (18–23 year-old) users. Respondent driven sampling was used to recruit 390 individuals in the Columbus, Ohio area. The sample was almost 50% white and about 55% male. Qualitative interview participants (n=45) were selected from the larger sample. Qualitative data suggest that pharmaceutical opioid availability was so pervasive that most individuals did not have to venture outside of their immediate social networks to find people who sold or shared pills. Participants emphasized differences between those who are actively involved in obtaining pills, and those who play a more passive role. Active involvement was described as going out searching for pills and paying money to obtain them. In contrast, passive role included obtaining pills when somebody offered or shared them free of charge. Multiple logistic regression analysis indicates that a more active role in obtaining pharmaceutical opioids was related to being white, more frequent use of pharmaceutical opioids, extended-release oxycodone use, and using pharmaceutical opioids to get high, as opposed to self-treating a health problem. The study results can help inform drug use epidemiology, interventions and policy. PMID:25052878

Intramuscular Fentanyl and Ketorolac Associated with Superior Pain Control After Pediatric Bilateral Myringotomy and Tube Placement Surgery: A Retrospective Cohort Study.

PubMed

Stricker, Paul A; Muhly, Wallis T; Jantzen, Ellen C; Li, Yue; Jawad, Abbas F; Long, Alexander S; Polansky, Marcia; Cook-Sather, Scott D

2017-01-01

Bilateral myringotomy and pressure equalization tube insertion (BMT) is the most common surgery in children. Multiple anesthetic techniques for BMT have been proposed, but that which reliably promotes ideal recovery remains unclear. We sought to assess associations between anesthetic regimens that included single-agent (fentanyl or ketorolac) or dual-agent (fentanyl and ketorolac) analgesic therapy and the primary outcome of maximal postanesthesia care unit (PACU) pain score. Secondary outcomes included in-hospital rescue analgesic administration, recovery time, and emesis incidence. Principal analysis was conducted on a retrospective cohort of 3669 children aged 6 months to <7 years who underwent BMT over a 16-month period and received intraoperative fentanyl and/or ketorolac. Routine anesthetic care included preoperative oral midazolam, general anesthesia via a mask maintained with sevoflurane and N2O or air in O2, and intramuscular analgesic administration. Multivariable analyses were performed examining relationships between analgesic regimen with the following outcomes: maximum PACU Face, Legs, Activity, Cry, and Consolability (FLACC) score = 0 or 7 to 10, oxycodone administration, and time to discharge readiness. Demographic variables, midazolam exposure, and location (main hospital vs ambulatory surgery center) were included in the multivariable analyses as potential confounders. Associations with postoperative vomiting were studied separately in 2725 children from a subsequent, nonoverlapping 12-month period using similar inclusion criteria. Fentanyl and ketorolac dose-response relationships were evaluated for selected outcome variables. Maximum FLACC = 0, maximum FLACC score of 7 to 10, and oxycodone rescue were most strongly associated with dual-agent therapy versus single-agent ketorolac: odds ratios 4.89 (95% confidence interval [CI], 4.04-5.93), 0.13 (95% CI, 0.10-0.16), and 0.11 (98.3% CI, 0.09-0.14), respectively, P < .001 for each). Minor associations were found for age, Hispanic ethnicity, midazolam, and location, and none for sex or race. For subjects managed with higher dose fentanyl (≥1.5 µg/kg) and ketorolac (≥0.75 mg/kg), 90% had no demonstrable pain, agitation, or distress. Mean discharge readiness times were 21 ± 11 minutes (ketorolac), 26 ± 16 minutes (fentanyl), and 24 ± 14 minutes (dual) (P < .0001). Postoperative emesis incidences associated with ketorolac (2.7%) versus dual therapy (4.5%) were not different (P = .08). In this large retrospective pediatric BMT study, combination intramuscular fentanyl/ketorolac was strongly associated with superior PACU analgesia and reduced need for oxycodone rescue without clinically significant increases in recovery time or emesis incidence. Combination fentanyl at 1.5 to 2 µg/kg and 1 mg/kg ketorolac was associated with optimal outcomes. Dual therapy appears similarly effective in children of either European Caucasian or African ancestry or of Hispanic ethnicity.

Surveillance of Suicidal Behavior January through December 2013

DTIC Science & Technology

2015-06-01

primarily for cannabis and cocaine.  The prevalence of being screened for ASAP was: - 19%, suicide cases; of those, 57% enrolled in the program...year of their death. Positive tests were primarily for cannabis (50%), cocaine (35%), and amphetamines (18%). Of suicide cases from 2001...their death.  Drugs with Positive Tests: Positive tests were for cannabis (50%), oxycodone (33%) and cocaine (17%).  ASAP Screening

Twitter-Based Detection of Illegal Online Sale of Prescription Opioid.

PubMed

Mackey, Tim K; Kalyanam, Janani; Katsuki, Takeo; Lanckriet, Gert

2017-12-01

To deploy a methodology accurately identifying tweets marketing the illegal online sale of controlled substances. We first collected tweets from the Twitter public application program interface stream filtered for prescription opioid keywords. We then used unsupervised machine learning (specifically, topic modeling) to identify topics associated with illegal online marketing and sales. Finally, we conducted Web forensic analyses to characterize different types of online vendors. We analyzed 619 937 tweets containing the keywords codeine, Percocet, fentanyl, Vicodin, Oxycontin, oxycodone, and hydrocodone over a 5-month period from June to November 2015. A total of 1778 tweets (< 1%) were identified as marketing the sale of controlled substances online; 90% had imbedded hyperlinks, but only 46 were "live" at the time of the evaluation. Seven distinct URLs linked to Web sites marketing or illegally selling controlled substances online. Our methodology can identify illegal online sale of prescription opioids from large volumes of tweets. Our results indicate that controlled substances are trafficked online via different strategies and vendors. Public Health Implications. Our methodology can be used to identify illegal online sellers in criminal violation of the Ryan Haight Online Pharmacy Consumer Protection Act.

Comparison of abuse, suspected suicidal intent, and fatalities related to the 7-day buprenorphine transdermal patch versus other opioid analgesics in the National Poison Data System.

PubMed

Coplan, Paul M; Sessler, Nelson E; Harikrishnan, Venkatesh; Singh, Richa; Perkel, Charles

2017-01-01

Prescription opioid related abuse, suicide and death are significant public health problems. This study compares rates of poison center calls categorized as intentional abuse, suspected suicidal intent or fatality for the 7-day buprenorphine transdermal system/patch (BTDS) with other extended-release and long-acting (ER/LA) opioids indicated for chronic pain. Retrospective 24-month cohort study using National Poison Data System data from July 2012 through June 2014. BTDS was introduced in the United States in January 2011. Numbers and rates of calls of intentional abuse, suspected suicidal intent and fatalities were evaluated for BTDS, ER morphine, ER oxycodone, fentanyl patch, ER oxymorphone and methadone tablets/capsules, using prescription adjustment to account for community availability. Rate ratios (RR) and 95% confidence intervals (CI) were calculated. Absolute numbers and prescription-adjusted rates of intentional abuse and suspected suicidal intent with BTDS were significantly lower (p < .0001) than for all other ER/LA opioid analgesics examined. No fatalities associated with BTDS exposure were reported. This post-marketing evaluation of BTDS indicates infrequent poison center calls for intentional abuse and suspected suicidal intent events, suggesting lower rates of these risks with BTDS compared to other ER/LA opioids.

Emerging analgesic drugs for Parkinson's disease.

PubMed

Perez-Lloret, Santiago; Rey, María Verónica; Dellapina, Estelle; Pellaprat, Jean; Brefel-Courbon, Christine; Rascol, Olivier

2012-06-01

Pain affects between 40 and 85% of Parkinson's disease (PD) patients. It is a frequently disabling and overlooked feature, which can significantly reduce health-related quality of life. Unfortunately, there are no universally recommended treatments for this condition. Evidence about the efficacy and safety of available analgesic treatments is summarized in this review. Potential targets for upcoming therapies are then discussed in light of what is currently known about the physiopathology of pain in PD. Protocols for efficacy and safety assessment of novel analgesic therapies are discussed. Finally, critical aspects of study protocol design such as patient selection or outcomes to be evaluated are discussed. Preliminary results indicate that duloxetine, cranial electrotherapy stimulation, rotigotine, subthalamic or pallidum nuclei stimulation or lesion or levodopa could be effective for treating pain in PD. Similarly, some case reports indicate that repetitive transcranial magnetic stimulation (rTMS) or apomorphine could be effective for relieving painful off-period dystonia. Clinical trials with rTMS or oxycodone/naloxone prolonged-release tablets for neuropathic pain or botulinum toxin for off-period dystonia are underway. Success of clinical trials about analgesic strategies in PD will depend on the selection of the right PD population to be treated, according to the type of pain, and the proper selection of study outcomes and follow-up of international recommendations.

Compulsive-like responding for opioid analgesics in rats with extended access.

PubMed

Wade, Carrie L; Vendruscolo, Leandro F; Schlosburg, Joel E; Hernandez, Daniel O; Koob, George F

2015-01-01

The abuse of prescription opioids that are used for the treatment of chronic pain is a major public health concern, costing ∼$53.4 billion annually in lost wages, health-care costs, and criminal costs. Although opioids remain a first-line therapy for the treatment of severe chronic pain, practitioners remain cautious because of the potential for abuse and addiction. Opioids such as heroin are considered very rewarding and reinforcing, but direct and systematic comparisons of compulsive intake between commonly prescribed opioids and heroin in animal models have not yet been performed. In the present study, we evaluated the potential for compulsive-like drug seeking and taking, using intravenous self-administration of oxycodone, fentanyl, and buprenorphine in rats allowed long access sessions (12 h). We measured compulsive-like intake using an established escalation model and responding on a progressive ratio schedule of reinforcement. We compared the potential for compulsive-like self-administration of these prescription opioids and heroin, which has been previously established to induce increasing intake that models the transition to addiction in humans. We found that animals that self-administered oxycodone, fentanyl, or heroin, but not buprenorphine had similar profiles of escalation and increases in breakpoints. The use of extended access models of prescription opioid intake will help better understand the biological factors that underlie opioid dependence.

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.

Changes in drug use patterns reported on the web after the introduction of ADF OxyContin: findings from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Web Monitoring Program.

PubMed

Vosburg, Suzanne K; Haynes, Colleen; Besharat, Andrea; Green, Jody L

2017-09-01

This qualitative study summarizes information that individuals shared online about use of OxyContin following the August 2010 introduction of the abuse deterrent formulation (ADF). The primary objective was to study online posts that endorsed continued use of OxyContin or a switch from OxyContin to another formulation of oxycodone or another substance altogether following the introduction of the ADF. A secondary objective was to determine whether posts revealed that the ADF led to cessation of OxyContin use. Data were collected with the Researched Abuse, Diversion, and Addiction-Related Surveillance System Web Monitoring Program, an online surveillance system that collects and organizes posts about prescription drugs from social media websites, blogs, and forums from 3Q2009 to 4Q2014 using a commercially available web platform. Posts were categorized by whether they conveyed a switch to drugs other than reformulated OxyContin or a continuation of reformulated OxyContin abuse. "Switch posts" primarily discussed switching to immediate-release opioids. "Continue abusing" posts identified tampering strategies for alternate routes of administration, oral use, and continued use although post authors were generally unhappy with the experience. No reference to OxyContin cessation as a function of the introduction of the ADF was found; however, discontinued use was discussed. Web Monitoring data are useful for capturing cross sections of Internet conversation reflecting reactions to new drug formulations. These data support the notion that users will gravitate to non-ADFs generally, and to immediate-release non-ADF opioid formulations, specifically, as long as these options remain on the market. Copyright © 2017 John Wiley & Sons, Ltd.

Important statistical considerations in the evaluation of post-market studies to assess whether opioids with abuse-deterrent properties result in reduced abuse in the community.

PubMed

By, Kunthel; McAninch, Jana K; Keeton, Stephine L; Secora, Alex; Kornegay, Cynthia J; Hwang, Catherine S; Ly, Thomas; Levenson, Mark S

2018-05-01

Abuse, misuse, addiction, overdose, and death associated with non-medical use of prescription opioids have become a serious public health concern. Reformulation of these products with abuse-deterrent properties is one approach for addressing this problem. FDA has approved several extended-release opioid analgesics with abuse-deterrent labeling, the bases of which come from pre-market studies. As all opioid analgesics must be capable of delivering the opioid in order to reduce pain, abuse-deterrent properties do not prevent abuse, nor do pre-market evaluations ensure that there will be reduced abuse in the community. Utilizing data from various surveillance systems, some recent post-market studies suggest a decline in abuse of extended-release oxycodone after reformulation with abuse-deterrent properties. We discuss challenges stemming from the use of such data. We quantify the relationship between the sample, the population, and the underlying sampling mechanism and identify the necessary conditions if valid statements about the population are to be made. The presence of other interventions in the community necessitates the use of comparators. We discuss the principles under which the use of comparators can be meaningful. Results based on surveillance data need to be interpreted with caution as the underlying sampling mechanisms can bias the results in unpredictable ways. The use of comparators has the potential to disentangle the effect due to the abuse-deterrence properties from those due to other interventions. However, identifying a comparator that is meaningful can be very difficult. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Evaluation of Patient Migration Patterns and Related Health Care Costs Within a National Medicare Advantage Prescription Drug Plan After Implementation of an Oxycodone HCl Extended-Release Access Restriction.

PubMed

Chen, Chi-Chang; De, Ajita P; Sweet, Brian; Wade, Rolin L

2017-08-01

Health plans use formulary restrictions (e.g., prior authorization, step therapy, tier change, nonformulary status) in an effort to control cost and promote quality, safety, and appropriate prescription utilization. Some Medicare payers perceive that the inclusion of certain agents, such as branded oxycodone HCl extended-release tablets (OERs), on their formularies is associated with attracting high-cost members to the plan. To evaluate disenrollment rates, patient migration, and subsequent health care costs among OER users who disenrolled from a national Medicare Advantage Prescription Drug plan (study-MAPD) in the plan year following OER nonformulary restriction. A retrospective, longitudinal cohort study using IMS pharmacy and medical claims data between July 1, 2011, and December 31, 2014, was conducted. In the study-MAPD, adults aged ≥ 18 years who were chronic OER users with ≥ 2 OER claims 6 months before the nonformulary restriction date on January 1, 2013 (index date) and with continuous activity in pharmacy and medical claims for 6 months pre- and post-index were included in the study. Comparison years of 2012 and 2014 prerestriction/postrestriction were selected. All groups were followed for 6 months postindex. Year-to-year disenrollment rates of OER patients and the overall plan, as well as patient characteristics and costs of those who disenrolled from and those who remained with the plan, were measured. Costs were compared using a difference-in-differences approach. This study identified 2,935 eligible OER users from the study-MAPD population after imposing nonformulary restrictions on OERs on January 1, 2013. Mean age was 62.1 years, and 59.8% were female. The mean Charlson Comorbidity Index score was 1.83 for those 1,001 patients with medical claims data. For comparison years 2012 (prerestriction) and 2014 (postrestriction), 2,248 and 2,222 OER patients were identified, respectively. Patient characteristics were similar across patient cohorts in all 3 study years. Disenrollment rates for OER users (12.9%, 5.5%, and 14.3% for years 2012, 2013, and 2014, respectively) were lower or similar to those of the overall plan (18.3%, 7.6%, and 14.1%, respectively, for the same 3 years). Approximately 40% of OER users who disenrolled from the study-MAPD migrated to plans also imposing a nonformulary restriction on OERs, while about 25% moved to plans with less restrictive OER coverage. The majority (59.9%) of patients continued OER use irrespective of their disenrollment from the study-MAPD in 2013. Although a nonsignificant decrease ($117; P = 0.340) in per patient per month (PPPM) cost was observed among OER patients postrestriction (from 2012 to 2013), the difference-in-difference analysis indicated a net postrestriction increase of $124 (P = 0.461) in PPPM for OER patients. This study found little evidence to support any consistent directional effect on patient enrollment behavior as a result of an OER non-formulary restriction. Implementation of an OER nonformulary restriction did not lead to higher OER patient disenrollment or lower patient costs in the study-MAPD. Funding for this study was provided by Purdue Pharma. De, Chen, and Wade are employees of QuintilesIMS, a for-profit company that was contracted by Purdue Pharma to undertake this research. Sweet was a paid consultant for Purdue Pharma at the time of this study. Study concept and design were contributed by Chen, Wade, and De. Chen, De, and Wade collected the data, which were interpreted by all the authors. The manuscript was written by Chen and De, along with Sweet and Wade, and revised by all the authors.

Clearing the smoke around medical marijuana.

PubMed

Ware, M A

2011-12-01

The hazy world of "medical marijuana" continues to cry out for clear data on which to base medical decision making and rational policy design. In this issue of Clinical Pharmacology & Therapeutics, Abrams and colleagues report that vaporized cannabis does not meaningfully affect opioid plasma levels and may even augment the efficacy of oxycodone and morphine in patients with chronic non-cancer pain. This Commentary considers the implications of this work for clinical practice and further research initiatives.

The use of a prescription drug monitoring program to develop algorithms to identify providers with unusual prescribing practices for controlled substances.

PubMed

Ringwalt, Christopher; Schiro, Sharon; Shanahan, Meghan; Proescholdbell, Scott; Meder, Harold; Austin, Anna; Sachdeva, Nidhi

2015-10-01

The misuse, abuse and diversion of controlled substances have reached epidemic proportion in the United States. Contributing to this problem are providers who over-prescribe these substances. Using one state's prescription drug monitoring program, we describe a series of metrics we developed to identify providers manifesting unusual and uncustomary prescribing practices. We then present the results of a preliminary effort to assess the concurrent validity of these algorithms, using death records from the state's vital records database pertaining to providers who wrote prescriptions to patients who then died of a medication or drug overdose within 30 days. Metrics manifesting the strongest concurrent validity with providers identified from these records related to those who co-prescribed benzodiazepines (e.g., valium) and high levels of opioid analgesics (e.g., oxycodone), as well as those who wrote temporally overlapping prescriptions. We conclude with a discussion of a variety of uses to which these metrics may be put, as well as problems and opportunities related to their use.

Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care.

PubMed

Candy, Bridget; Jones, Louise; Vickerstaff, Victoria; Larkin, Philip J; Stone, Patrick

2018-06-05

Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care. To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data. We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced. Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE. We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (RR 2.77, 95% CI 1.91 to 4.04. I² = 0%; moderate-quality evidence). In combined analysis, we found methylnaltrexone induced more laxation responses over two weeks (RR 9.98, 95% CI 4.96 to 20.09. I² = 0%; moderate-quality evidence). The proportion of participants who had a rescue-free laxation response within 24 hours of the first dose was 59.1% in the methylnaltrexone arms and 19.1% in the placebo arm. There was moderate-quality evidence that the rate of opioid withdrawal was not affected. Methylnaltrexone did not increase the likelihood of a serious adverse event; there were fewer in the intervention arm (RR 0.59, 95% CI 0.38 to 0.93; I² = 0%; moderate-quality evidence). There was no difference in the proportion of participants experiencing an adverse event (RR 1.17, 95% CI 0.94 to 1.45; I² = 74%; low-quality evidence). Methylnaltrexone increased the likelihood of abdominal pain and flatulence.Two trials compared differing methylnaltrexone schedules of higher doses with lower doses. For early laxation, there was low-quality evidence of no clear difference between doses on analgesia and adverse events. Both trials measured laxation response within 24 hours of first dose (trial one: RR 0.82, 95% CI 0.41 to 1.66; trial two: RR 1.07, 95% CI 0.81 to 1.42). In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.

Method Description, Quality Assurance, Environmental Data, and other Information for Analysis of Pharmaceuticals in Wastewater-Treatment-Plant Effluents, Streamwater, and Reservoirs, 2004-2009

USGS Publications Warehouse

Phillips, Patrick J.; Smith, Steven G.; Kolpin, Dana W.; Zaugg, Steven D.; Buxton, Herbert T.; Furlong, Edward T.

2010-01-01

Abstract Wastewater-treatment-plant (WWTP) effluents are a demonstrated source of pharmaceuticals to the environment. During 2004-09, a study was conducted to identify pharmaceutical compounds in effluents from WWTPs (including two that receive substantial discharges from pharmaceutical formulation facilities), streamwater, and reservoirs. The methods used to determine and quantify concentrations of seven pharmaceuticals are described. In addition, the report includes information on pharmaceuticals formulated or potentially formulated at the two pharmaceutical formulation facilities that provide substantial discharge to two of the WWTPs, and potential limitations to these data are discussed. The analytical methods used to provide data on the seven pharmaceuticals (including opioids, muscle relaxants, and other pharmaceuticals) in filtered water samples also are described. Data are provided on method performance, including spike data, method detection limit results, and an estimation of precision. Quality-assurance data for sample collection and handling are included. Quantitative data are presented for the seven pharmaceuticals in water samples collected at WWTP discharge points, from streams, and at reservoirs. Occurrence data also are provided for 19 pharmaceuticals that were qualitatively identified. Flow data at selected WWTP and streams are presented. Between 2004-09, 35-38 effluent samples were collected from each of three WWTPs in New York and analyzed for seven pharmaceuticals. Two WWTPs (NY2 and NY3) receive substantial inflows (greater than 20 percent of plant flow) from pharmaceutical formulation facilities (PFF) and one (NY1) receives no PFF flow. Samples of effluents from 23 WWTPs across the United States were analyzed once for these pharmaceuticals as part of a national survey. Maximum pharmaceutical effluent concentrations for the national survey and NY1 effluent samples were generally less than 1 ug/L. Four pharmaceuticals (methadone, oxycodone, butalbital and metaxalone) in samples of NY3 effluent had median concentrations ranging from 3.4 to greater than 400 ug/L. Maximum concentrations of oxycodone (1,700 ug/L) and metaxalone (3,800 ug/L) in samples from NY3 effluent exceeded 1,000 ug/L. Three pharmaceuticals (butalbital, carisoprodol, and oxycodone) in samples of NY2 effluent had median concentrations ranging from 2 to 11 ug/L. These findings suggest that current 2 manufacturing practices at these PFFs can result in pharmaceutical concentrations from 10 to 1,000 times higher than those typically found in WWTP effluents.

Opioid management and dependency among adult patients with sickle cell disease.

PubMed

Feliu, Miriam H; Wellington, Chante; Crawford, Regina D; Wood, Mary; Edwards, Lekisha; Byrd, Goldie; Edwards, Christopher L

2011-01-01

While pain is one of the most debilitating symptoms of sickle cell disease, narcotics remain an effective although controversial widely practiced intervention. Vaso-occlusive crises are the most common cause for seeking pharmacological treatment. The influence of stigmatization and pseudo addiction in emergency departments and outpatient clinics was reviewed. We analyzed patterns of narcotic utilization in a sample of 63 adult patients with sickle cell disease to determine if their psychological functioning and reports of pain differed as a function of the primary narcotics they were taking for oral pain management. Fifty-one percent of patients reported treatment of Oxycodone, 35% OxyContin, 24% methadone and 11% morphine. Patients who were treated with Oxycodone reported greater sensory reactions to pain (p = 0.001), visual analog scale (VAS) (p = 0.02), and averaged weekly pain intensity ratings than patients who did not use this medication. There were no differences in pain or affective response in patients treated with OxyContin, methadone or morphine. We suggest there are clear differences between the reports of pain in patients with sickle cell disease taking short-acting narcotics for pain management as compared to those who are not, a pattern that does not distinguish patients who are managed with long-acting preparations. We discuss the relevance of addressing narcotic management in the context of the perception of health care providers and patients with sickle cell disease.

Simultaneous detection of seventeen drugs of abuse and metabolites in hair using solid phase micro extraction (SPME) with GC/MS.

PubMed

Aleksa, Katarina; Walasek, Paula; Fulga, Netta; Kapur, Bhushan; Gareri, Joey; Koren, Gideon

2012-05-10

The analysis of pediatric and adult hair is a useful non-invasive biomarker to effectively detect long term exposure to various xenobiotics, specifically drugs of abuse such as cocaine, opiates and amphetamines. Very often individuals are using, or are exposed to multiple drugs simultaneously and therefore it is important to be able to detect them in the same analysis. We have developed a sensitive and specific solid phase micro extraction (SPME) coupled with gas chromatography mass spectrometry (GC/MS) to detect 17 different analytes in hair using a single extraction method. Five milligrams of hair is extracted overnight, subjected to solid phase extraction (SPE) and then to SPME-GC/MS. The aimed analytes include amphetamine, methamphetamine, MDA, MDMA, cocaine, benzoylecognine, norcocaine, cocaethylene, methadone, codeine, morphine, 6-AM, oxycodone, oxymorphone, hydrocodone, hydromorphone and meperidone. The following are the LOD of the various drugs: 0.2ng/mg hair for amphetamine, methamphetamine, MDA, MDMA, morphine, codeine, 6-AM, oxycodone, oxymorphone, hydromorphone, hydrocodone, meperidine and 0.13ng/mg hair for cocaine, benzoylecognine, cocaethylene, norcocaine and methadone. This GC/MS method is sensitive and specific to detect the presence of these 17 analytes in as little as 5mg of hair and is especially useful for newborn and child hair analysis where the amount of hair is often very limited. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose?

PubMed

Bannwarth, Bernard

2012-09-10

During the last 2 decades, there has been a dramatic increase in the use of strong opioids for chronic non-cancer pain. This increase has been accompanied by a steep increase in abuse, misuse, and both fatal and non-fatal overdoses involving prescription opioids. The situation is already alarming in the US. Prescription opioid-related harm is a complex, multifactorial issue that requires a multifaceted solution. In this respect, formulations of opioid analgesics designed to resist or deter abuse may be a useful component of a comprehensive opioid risk minimization programme. Such formulations have or are being developed. Abuse-resistant opioids include those that use some kind of physical barrier to prevent tampering with the formulation. Abuse-deterrent opioids are not necessarily resistant to tampering, but contain substances that are designed to make the formulation less attractive to abusers. This article focuses on two products intended to deter abuse that were reviewed by the US Food and Drug Administration (FDA). The first (Embeda®) consists of extended-release morphine with sequestered naltrexone, an opioid antagonist that is released if the tablet is compromised by chewing or crushing. Although Embeda® exhibited abuse-deterrent features, its label warns that it can be abused in a manner similar to other opioid agonists. Furthermore, tampering with Embeda® will result in the release of naltrexone, which may precipitate withdrawal in opioid-tolerant individuals. In March 2011, all dosage forms of Embeda® were recalled because the product failed to meet routine stability standards, and its return date to the market is currently unknown. The second product (Acurox®) was intended to be both tamper resistant and abuse deterrent. It consisted of an immediate-release oxycodone tablet with subtherapeutic niacin as an aversive agent and used a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The new drug application for Acurox® was rejected in 2010 by the FDA because of concerns about the potential abuse-deterrent benefits of niacin. While acknowledging that no one formulation can be expected to deter all types of opioid-abusive behaviours and no product is likely to be abuse proof in the hands of clear and determined abusers, the reductions in abuse these new products would provide may be an incremental step towards safer prescription opioids.

Postoperative Pain Management After Primary Total Knee Arthroplasty: The Value of Liposomal Bupivacaine.

PubMed

Sporer, Scott M; Rogers, Thea

2016-11-01

Multimodal pain protocols have been proposed to achieve improved long-acting postoperative analgesia. Controlling postoperative pain after joint arthroplasty is especially important as it relates to patient satisfaction and outcomes. The purpose of this study was to compare the postoperative pain, time to ambulation, and overall narcotic usage between patients who received either a femoral nerve block with a periarticular bupivacaine injection or a periarticular bupivacaine and extended-release liposomal bupivacaine injection after primary total knee arthroplasty. A total of 597 consecutive primary total knee arthroplasties performed between September 1, 2012 and August 31, 2014 received preoperative celecoxib, oxycodone, and transdermal scopolamine. Intraoperatively, patients either received a single-dose bupivacaine femoral nerve block along with 30-mL 0.25% bupivacaine periarticular injection (group A) or a 60-mL periarticular injection alone (20-mL liposomal bupivacaine, 30-mL 0.25% bupivacaine, and 10-mL saline; group B). The postoperative pain scores, narcotic usage, and time to ambulation were retrospectively collected from the electronic medical record. These outcomes were compared between treatment groups. There were 325 patients in group A compared with 272 in group B during the time frame. There was no difference among age, gender, race, and body mass index between the groups. Group B demonstrated a decreased need for breakthrough pain medication (16.9% vs 36.3% P < .001), decreased pain 12 hours postoperatively (3.2 vs 3.6 P < .003), and an earlier time to ambulation (29.5 hours vs 32.2 hours, P < .017). There was no difference in hospital length of stay (2.8 vs 2.6 days, P = .123). On controlling for demographic factors, patients in group B were able to ambulate 2.3 hours earlier than those in group A (coefficient = -2.3, P = .049). Liposomal bupivacaine resulted in a decrease need for breakthrough pain medication, improved pain scores at 12 hours, and an earlier time to ambulation compared to a combined femoral nerve block and periarticular bupivacaine injection. Copyright © 2016 Elsevier Inc. All rights reserved.

New developments in managing opioid addiction: impact of a subdermal buprenorphine implant

PubMed Central

Itzoe, MariaLisa; Guarnieri, Michael

2017-01-01

Opioid addiction to prescription and illicit drugs is a serious and growing problem. In the US alone, >2.4 million people suffer from opioid use disorder. Government and pharmaceutical agencies have begun to address this crisis with recently released and revised task forces and medication-assisted therapies (MAT). For decades, oral or intravenous (IV) MATs have helped patients in their recovery by administration of opioid agonists (methadone, buprenorphine, oxycodone), antagonists (naltrexone, naloxone), and combinations of the two (buprenorphine/naloxone). While shown to be successful, particularly when combined with psychological counseling, oral and IV forms of treatment come with constraints and challenges. Patients can become addicted to the agonists themselves, and there is increased risk for diversion, abuse, or missed dosages. Consequently, long-acting implants have begun to be developed as a potentially preferable method of agonist delivery. To date, the newest implant approved by the US Food and Drug Administration (May 2016) is Probuphine®, which delivers steady-state levels of buprenorphine over the course of 6 months. Numerous studies have demonstrated its efficacy and safety. Yet, implants come with their own risks such as surgical site irritation, possible movement, and protrusion of implant out of skin. This review introduces the opioid abuse epidemic, examines existing medications used for therapy, and highlights Probuphine as a new treatment option. Costs associated with MATs are also discussed. PMID:28546740

New developments in managing opioid addiction: impact of a subdermal buprenorphine implant.

PubMed

Itzoe, MariaLisa; Guarnieri, Michael

2017-01-01

Opioid addiction to prescription and illicit drugs is a serious and growing problem. In the US alone, >2.4 million people suffer from opioid use disorder. Government and pharmaceutical agencies have begun to address this crisis with recently released and revised task forces and medication-assisted therapies (MAT). For decades, oral or intravenous (IV) MATs have helped patients in their recovery by administration of opioid agonists (methadone, buprenorphine, oxycodone), antagonists (naltrexone, naloxone), and combinations of the two (buprenorphine/naloxone). While shown to be successful, particularly when combined with psychological counseling, oral and IV forms of treatment come with constraints and challenges. Patients can become addicted to the agonists themselves, and there is increased risk for diversion, abuse, or missed dosages. Consequently, long-acting implants have begun to be developed as a potentially preferable method of agonist delivery. To date, the newest implant approved by the US Food and Drug Administration (May 2016) is Probuphine ® , which delivers steady-state levels of buprenorphine over the course of 6 months. Numerous studies have demonstrated its efficacy and safety. Yet, implants come with their own risks such as surgical site irritation, possible movement, and protrusion of implant out of skin. This review introduces the opioid abuse epidemic, examines existing medications used for therapy, and highlights Probuphine as a new treatment option. Costs associated with MATs are also discussed.

Effectiveness of opioids in the treatment of chronic non-cancer pain.

PubMed

Trescot, Andrea M; Glaser, Scott E; Hansen, Hans; Benyamin, Ramsin; Patel, Samir; Manchikanti, Laxmaiah

2008-03-01

For thousands of years, opioids have been used to treat pain, and they continue to be one of the most commonly prescribed medications for pain. It is estimated that 90% of patients presenting to pain centers and receiving treatment in such facilities are on opioids. Opioids can be considered broad-spectrum analgesics that act at multiple points along the pain pathway. Unfortunately, opioids also have the potential for great harm, with multiple side effects and potential complications, some of which are lethal. They are also uniquely addictive, which can lead to misuse and diversion. We reviewed the relevant English literature and did thorough manual searches of the bibliographies of known primary and review articles. We utilized pain relief as the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, improvement in work status, and evidence of addiction. Short-term use and improvement was defined as less than 6 months and long-term relief was defined as 6 months or longer. The 3 systematic reviews evaluating long-term effectiveness of opioids for chronic non-cancer pain provided unclear and weak evidence. The results of this review showed that many patients in the included studies were dissatisfied with adverse events or insufficient pain relief from opioids and withdrew from the studies. For patients able to continue on opioids, evidence was weak suggesting that their pain scores were lower than before therapy and that this relief could be maintained long-term (> 6 months). There was also weak evidence that long-term opioid therapy with morphine and transdermal fentanyl not only decreases pain but also improves functioning. Limited evidence was available for the most commonly used opioids, oxycodone and hydrocodone. Evidence for the ability to drive on chronic opioid therapy was moderate without major side effects or complications. It is concluded that, for long-term opioid therapy of 6 months or longer in managing chronic non-cancer pain, with improvement in function and reduction in pain, there is weak evidence for morphine and transdermal fentanyl. However, there is limited or lack of evidence for all other controlled substances, including the most commonly used drugs, oxycodone and hydrocodone.

Case report: efficacy and tolerability of ketamine in opioid-refractory cancer pain.

PubMed

Amin, Priya; Roeland, Eric; Atayee, Rabia

2014-09-01

A 36-year-old female with metastatic breast cancer involving bones, liver, lung, and pleura/chest wall with worsening back pain received weight-based intravenous (IV) ketamine and was transitioned to oral ketamine for cancer-related neuropathic pain. She had responded poorly to outpatient pain regimen of oxycodone sustained and immediate release, hydromorphone, gabapentin, and duloxetine (approximate 480 mg total oral morphine equivalents [OME]), reporting an initial pain score of 10/10. She was started on hydromorphone parenteral patient-controlled analgesia (PCA) bolus dose in addition to her outpatient regimen. Despite escalating doses of opioids and the addition of a lidocaine 5% patch, the patient's pain remained uncontrolled 6 days after admission. On hospital day 7, utilizing a hospital weight-based ketamine protocol, the patient was started on subanesthetic doses of ketamine at 0.2 mg/kg/h (288 mg/24 h) and titrated over 2 days to 0.4 mg/kg/h (576 mg/24 h). Then, a 3-day rotation from intravenous to oral ketamine was initiated, and the patient was discharged on ketamine oral solution, 75 mg every 8 hours. When the patient's dose was increased to 0.4 mg/kg/h, adequate pain relief was charted by the nurse within 120 minutes, "patient pain free and resting comfortably." Her pain continued to be well managed, with an average pain score of 5/10 with the ketamine continuous infusion and sustained with conversion to oral ketamine without any report of side effects. This was a 37% reduction in pain scores. With the patient's stabilized dose of ketamine, opioid requirements decreased by 61.4% (1017.5 mg reduction in total OME). The use of weight-based dosing of IV continuous infusion and transition to oral ketamine was effective and tolerable in the management of opioid-refractory, neuropathic cancer pain. It is hoped that this case report promotes a discussion regarding ketamine dosing in refractory neuropathic cancer pain.

The development of a comprehensive risk-management program for prescription opioid analgesics: researched abuse, diversion and addiction-related surveillance (RADARS).

PubMed

Cicero, Theodore J; Dart, Richard C; Inciardi, James A; Woody, George E; Schnoll, Sidney; Muñoz, Alvaro

2007-03-01

OBJECTIVE. Beginning in the late 1990's a marked increase in abuse of OxyContin emerged, which led to the development and establishment of a proactive surveillance program to monitor and characterize abuse, named the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS) System. The main goal of RADARS was to develop proactive, timely and geographically sensitive methods to assess the abuse and diversion of OxyContin, along with a number of other Schedule II and III opioids with the aim of using this information to guide risk reduction interventions. Thus, its major focus was the detection of abuse of OxyContin and other commonly prescribed opioid analgesics at the three-digit ZIP code level across the country utilizing a number of different detection systems. The detection systems selected were: (1) Quarterly-surveys of drug abuse experts who are knowledgeable about cases of prescription drug abuse; (2) Surveys of law enforcement agencies that detect diversion of prescription drugs; and (3) Poison Control Center reports of intentional misuse or abuse of prescription opioids. Collectively, the three systems provide overlapping coverage of over 80% of the nation's 973 three-digit ZIP codes. Preliminary results indicate that prescription drug abuse is prevalent nationwide, but it seems to be heavily localized in rural, suburban and small urban areas. Our results also indicate that hydrocodone and extended and immediate release oxycodone products are by far the most widely abused drugs in the country, but the abuse of all prescription opioids seems to have grown over the 14 quarters since the inception of RADARS. The next step in these studies is to develop regionally specific, risk-minimization-strategies, which is the goal of all risk-management programs. If successful, RADARS will serve as a prototype of such programs for any new drug approved that has measurable abuse potential.

Effects of oxycodone on brain responses to emotional images.

PubMed

Wardle, Margaret C; Fitzgerald, Daniel A; Angstadt, Michael; Rabinak, Christine A; de Wit, Harriet; Phan, K Luan

2014-11-01

Evidence from animal and human studies suggests that opiate drugs decrease emotional responses to negative stimuli and increase responses to positive stimuli. Such emotional effects may motivate misuse of oxycodone (OXY), a widely abused opiate. Yet, we know little about how OXY affects neural circuits underlying emotional processing in humans. We examined effects of OXY on brain activity during presentation of positive and negative visual emotional stimuli. We predicted that OXY would decrease amygdala activity to negative stimuli and increase ventral striatum (VS) activity to positive stimuli. Secondarily, we examined the effects of OXY on other emotional network regions on an exploratory basis. In a three-session study, healthy adults (N = 17) received placebo, 10 and 20 mg OXY under counterbalanced, double-blind conditions. At each session, participants completed subjective and cardiovascular measures and underwent functional MRI (fMRI) scanning while completing two emotional response tasks. Our emotional tasks reliably activated emotional network areas. OXY produced subjective effects but did not alter either behavioral responses to emotional stimuli or activity in our primary areas of interest. OXY did decrease right medial orbitofrontal cortex (MOFC) responses to happy faces. Contrary to our expectations, OXY did not affect behavioral or neural responses to emotional stimuli in our primary areas of interest. Further, the effects of OXY in the MOFC would be more consistent with a decrease in value for happy faces. This may indicate that healthy adults do not receive emotional benefits from opiates, or the pharmacological actions of OXY differ from other opiates.

Increased use of heroin as an initiating opioid of abuse.

PubMed

Cicero, Theodore J; Ellis, Matthew S; Kasper, Zachary A

2017-11-01

Given the relatively recent growth in access to heroin and a more permissive atmosphere surrounding its use, we hypothesized that an increasing number of persons with limited experience and tolerance to opioids would experiment with heroin as their first opioid rather than more common prescription opioid analgesics. Individuals entering substance abuse treatment for an opioid use disorder in the period 2010-2016 (N=5885) were asked about the specific opioid they first regularly used to get high. To limit long-term recall and survival bias, analyses was restricted to opioid initiation that occurred in the past ten years (2005-2015). In 2005, only 8.7% of opioid initiators started with heroin, but this sharply increased to 33.3% (p<0.001) in 2015, with no evidence of stabilization. The use of commonly prescribed opioids, oxycodone and hydrocodone, dropped from 42.4% and 42.3% of opioid initiators, respectively, to 24.1% and 27.8% in 2015, such that heroin as an initiating opioid was now more frequently endorsed than prescription opioid analgesics. Our data document that, as the most commonly prescribed opioids - hydrocodone and oxycodone - became less accessible due to supply-side interventions, the use of heroin as an initiating opioid has grown at an alarming rate. Given that opioid novices have limited tolerance to opioids, a slight imprecision in dosing inherent in heroin use is likely to be an important factor contributing to the growth in heroin-related over dose fatalities in recent years. Copyright © 2017. Published by Elsevier Ltd.

Drug Take Back in Hawai‘i: Partnership Between the University of Hawai‘i Hilo College of Pharmacy and the Narcotics Enforcement Division

PubMed Central

Batz, Forrest; Juarez, Deborah Taira; Ladao, Lani C

2014-01-01

Unused/unwanted medications in households and patient care facilities expose vulnerable populations, including children, elders, and pets, to potential harm through inadvertent ingestion, as well as the potential for theft and assault. Hawai‘i Administrative Rules prohibit the return of any prescription medications to retail pharmacies after dispensing. The Hawai‘i Narcotics Enforcement Division (NED) partnered with the University of Hawai‘i at Hilo Daniel K. Inouye College of Pharmacy (CoP) in eleven Drug Take Back events throughout the state. Most participants heard of the events via newspaper and television marketing. The most common methods of medication disposal are via trash or down household drains. Over 8,000 lbs of unused/unwanted medications was collected, identified and logged from 2011 through 2012. The majority of returned drugs were non-controlled substances (90%). Commonly returned medications included prescription cardiac medications such as simvastatin and lisinopril, non-prescription analgesics such as aspirin and ibuprofen, and dietary supplements such as vitamins and iron. Commonly returned controlled substance medications included narcotics such as hydrocodone/acetaminophen combinations and oxycodone, and sedative hypnotics such as zolpidem and lorazepam. PMID:24470984

Drug take back in Hawai'i: partnership between the University of Hawai'i Hilo College of Pharmacy and the Narcotics Enforcement Division.

PubMed

Ma, Carolyn S; Batz, Forrest; Juarez, Deborah Taira; Ladao, Lani C

2014-01-01

Unused/unwanted medications in households and patient care facilities expose vulnerable populations, including children, elders, and pets, to potential harm through inadvertent ingestion, as well as the potential for theft and assault. Hawai'i Administrative Rules prohibit the return of any prescription medications to retail pharmacies after dispensing. The Hawai'i Narcotics Enforcement Division (NED) partnered with the University of Hawai'i at Hilo Daniel K. Inouye College of Pharmacy (CoP) in eleven Drug Take Back events throughout the state. Most participants heard of the events via newspaper and television marketing. The most common methods of medication disposal are via trash or down household drains. Over 8,000 lbs of unused/unwanted medications was collected, identified and logged from 2011 through 2012. The majority of returned drugs were non-controlled substances (90%). Commonly returned medications included prescription cardiac medications such as simvastatin and lisinopril, non-prescription analgesics such as aspirin and ibuprofen, and dietary supplements such as vitamins and iron. Commonly returned controlled substance medications included narcotics such as hydrocodone/acetaminophen combinations and oxycodone, and sedative hypnotics such as zolpidem and lorazepam.

"Every 'never' I ever said came true": transitions from opioid pills to heroin injecting.

PubMed

Mars, Sarah G; Bourgois, Philippe; Karandinos, George; Montero, Fernando; Ciccarone, Daniel

2014-03-01

This qualitative study documents the pathways to injecting heroin by users in Philadelphia and San Francisco before and during a pharmaceutical opioid pill epidemic. Data was collected through in-depth, semi-structured interviews (conducted between 2010 and 2012) that were, conducted against a background of longer-term participant-observation, ethnographic studies of street-based drug users and dealers in Philadelphia (2007-12) and San Francisco (1994-2007, 2012). Philadelphia and San Francisco were selected for their contrasting political economies, immigration patterns and source type of heroin. In Philadelphia the ethnographers found heroin injectors, usually white users, who had started their opiate using careers with prescription opioids rather than transitioning from other drugs. In both Philadelphia and San Francisco, most of the young heroin injectors interviewed began, their drug-use trajectories with opioid pills--usually Percocet (oxycodone and acetaminophen), generic short acting oxycodone or, OxyContin (long-acting oxycodone)--before transitioning to heroin, usually by nasal inhalation (sniffing) or smoking at first, followed by injecting. While most of the Philadelphia users were born in the city or its suburbs and had started using both opioid pills and heroin there, many of the San Francisco users had initiated their pill and sometimes heroin use elsewhere and had migrated to the city from around the country. Nevertheless, patterns of transition of younger injectors were similar in both cities suggesting an evolving national pattern. In contrast, older users in both Philadelphia and San Francisco were more likely to have graduated to heroin injection from non-opiate drugs such as cannabis, methamphetamine and cocaine. Pharmaceutical opioid initiates typically reported switching to heroin for reasons of cost and ease-of-access to supply after becoming physically and emotionally dependent on opioid pills. Many expressed surprise and dismay at their progression to sniffing and subsequently to injecting heroin. Historically and structurally these users found themselves caught at the intersection of two major developments in the opiate supply: (1) an over 500% increase in opiate pill prescription from 1997 to 2005 resulting in easy access to diverted supplies of less stigmatized opiates than heroin and (2) a heroin supply glut, following the US entry of Colombian-sourced, heroin in the early 1990s, that decreased cost and increased purity at the retail level. A nationwide up-cycle of heroin use may be occurring among young inner city, suburban and rural youth fueled by widespread prescription opioid pill use. Copyright © 2013 Elsevier B.V. All rights reserved.

Two-step iron(0)-mediated N-demethylation of N-methyl alkaloids.

PubMed

Kok, Gaik B; Pye, Cory C; Singer, Robert D; Scammells, Peter J

2010-07-16

A mild and simple two-step Fe(0)-mediated N-demethylation of a number of tertiary N-methyl alkaloids is described. The tertiary N-methylamine is first oxidized to the corresponding N-oxide, which is isolated as the hydrochloride salt. Subsequent treatment of the N-oxide hydrochloride with iron powder readily provides the N-demethylated amine. Representative substrates include a number of opiate and tropane alkaloids. Key intermediates in the synthesis of semisynthetic 14-hydroxy pharmaceutical opiates such as oxycodone and oxymorphone are also readily N-demethylated using this method.

A Study of Outpatient Pharmacy Utilization at Naval Hospital, Camp Lejeune

DTIC Science & Technology

2002-07-01

5,468.87 LAMOTRIGINE 19 $4,907.53 ROSIGLITAZONE MALEATE 43 $4,849.93 ATORVASTATIN CALCIUM 47 $4,761.28 Table 10. Pharmacy Utilization 45 The Top 20 NHCL... ATORVASTATIN CALCIUM 246 $19,647.89 OXYCODONE HCL 132 $17,217.78 LANSOPRAZOLE 118 $16,499.98 PIOGLITAZONE HCL 83 $11,250.99 LORATADINE 150 $10,138.27...2,564.48 ATORVASTATIN CALCIUM 17 $2,276.93 LANSOPRAZOLE 13 $2,268.28 Table 13. Pharmacy Utilization 48 The Top 20 Drugs Utilized by NHCL Non-Prime

Reimbursement of analgesics for chronic pain.

PubMed

Pedersen, Line; Hansen, Anneli Borge; Svendsen, Kristian; Skurtveit, Svetlana; Borchgrevink, Petter C; Fredheim, Olav Magnus S

2012-11-27

The prevalence of chronic non-malignant pain in Norway is between 24% and 30%. The proportion of the population using opioids for non-malignant pain on a long-term basis is around 1%. The purpose of our study was to investigate how many were prescribed analgesics on reimbursable prescription under reimbursement code -71 (chronic non-malignant pain) in 2009 and 2010, which analgesics were prescribed and whether prescribing practices were in accordance with national guidelines. We retrieved pseudonymised data from the National Prescription Database on all those who received drugs with reimbursement code -71 in 2009 and 2010. The data contain information on drug, dosage, formulation, reimbursement code and date of issue. 90,731 patients received reimbursement for drugs indicated for chronic non-malignant pain in 2010. Of these, 6,875 were given opioids, 33,242 received paracetamol, 25,865 non-steroid inflammatory drugs (NSAIDs), 20,654 amitryptiline and 16,507 gabapentin. Oxycodone was the most frequently prescribed opioid, followed by buprenorphine, tramadol and codeine/paracetamol. Of those who were prescribed opioids, 4,047 (59%) received mainly slow-release opioids, 2,631 (38%) also received benzodiazepines and 2,418 (35%) received benzodiazepine-like sleep medications. The number of patients who received analgesics and opioids on reimbursable prescriptions was low compared to the proportion of the population with chronic pain and the proportion using opioids long-term. 38% of those reimbursed for opioids also used benzodiazepines, which is contrary to official Norwegian guidelines.

Does expecting more pain make it more intense? Factors associated with the first week pain trajectories after breast cancer surgery

PubMed Central

Sipilä, Reetta M.; Haasio, Lassi; Meretoja, Tuomo J.; Ripatti, Samuli; Estlander, Ann-Mari; Kalso, Eija A.

2017-01-01

Abstract The aim of this study was to identify clinical risk factors for unfavorable pain trajectories after breast cancer surgery, to better understand the association between pain expectation, psychological distress, and acute postoperative pain. This prospective study included 563 women treated for breast cancer. Psychological data included questionnaires for depressive symptoms and anxiety. Experimental pain tests for heat and cold were performed before surgery. The amount of oxycodone needed for satisfactory pain relief after surgery was recorded. Pain intensity in the area of operation before surgery and during the first postoperative week and expected intensity of postoperative pain were recorded using the Numerical Rating Scale (NRS 0-10). Pain trajectories were formed to describe both initial intensity (the intercept) and the direction of the pain path (the slope). Factors associated with higher initial pain intensity (the intercept) were the amount of oxycodone needed for adequate analgesia, psychological distress, type of axillary surgery, preoperative pain in the area of the operation, and expectation of postoperative pain. The higher the pain initially was, the faster it resolved over the week. Expectation of severe postoperative pain was associated with higher scores of both experimental and clinical pain intensity and psychological factors. The results confirm that acute pain after breast cancer surgery is a multidimensional phenomenon. Psychological distress, pain expectation, and the patients' report of preoperative pain in the area to be operated should be recognized before surgery. Patients having axillary clearance need more efficient analgesic approaches. PMID:28134654

A Retrospective Analysis of Urine Drugs of Abuse Immunoassay True Positive Rates at a National Reference Laboratory.

PubMed

Johnson-Davis, Kamisha L; Sadler, Aaron J; Genzen, Jonathan R

2016-03-01

Urine drug screens are commonly performed to identify drug use or monitor adherence to drug therapy. The purpose of this retrospective study was to evaluate the true positive and false positive rates of one of our in-house urine drug screen panels. The urine drugs of abuse panel studied consists of screening by immunoassay then positive immunoassay results were confirmed by mass spectrometry. Reagents from Syva and Microgenics were used for the immunoassay screen. The screen was performed on a Beckman AU5810 random access automated clinical analyzer. The percent of true positives for each immunoassay was determined. Agreement with previously validated GC-MS or LC-MS-MS confirmatory methods was also evaluated. There were 8,825 de-identified screening results for each of the drugs in the panel, except for alcohol (N = 2,296). The percent of samples that screened positive were: 10.0% for amphetamine/methamphetamine/3,4-methylenedioxy-methamphetamine (MDMA), 12.8% for benzodiazepines, 43.7% for opiates (including oxycodone) and 20.3% for tetrahydrocannabinol (THC). The false positive rate for amphetamine/methamphetamine was ∼14%, ∼34% for opiates (excluding oxycodone), 25% for propoxyphene and 100% for phencyclidine and MDMA immunoassays. Based on the results from this retrospective study, the true positive rate for THC drug use among adults were similar to the rate of illicit drug use in young adults from the 2013 National Survey; however, our positivity rate for cocaine was higher than the National Survey. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Choice between delayed food and immediate opioids in rats: treatment effects and individual differences.

PubMed

Panlilio, Leigh V; Secci, Maria E; Schindler, Charles W; Bradberry, Charles W

2017-11-01

Addiction involves maladaptive choice behavior in which immediate drug effects are valued more than delayed nondrug rewards. To model this behavior and extend our earlier work with the prescription opioid oxycodone, we allowed rats to choose between immediate intravenous delivery of the short-acting opioid remifentanil and delayed delivery of highly palatable food pellets. Treatment drugs were tested on a baseline where remifentanil was preferred over food. Treatment with a high dose of the opioid antagonist naltrexone decreased but did not reverse the preference for remifentanil. Treatment with the serotonin 5-HT 2C agonist lorcaserin decreased remifentanil and food self-administration nonselectively. Across conditions in which the alternative to delayed food was either a moderate dose of oxycodone, a moderate or high dose of remifentanil, a smaller more immediate delivery of food, or timeout with no primary reinforcement, choice was determined by both the length of the delay and the nature of the alternative option. Delayed food was discounted most steeply when the alternative was a high dose of remifentanil, which was preferred over food when food was delayed by 30 s or more. Within-subject comparisons showed no evidence for trait-like impulsivity or sensitivity to delay across these conditions. Choice was determined more by the current contingencies of reinforcement than by innate individual differences. This finding suggests that people might develop steep delay-discounting functions because of the contingencies in their environment, and it supports the use of contingency management to enhance the relative value of delayed nondrug reinforcers.

Opioids in people with cancer-related pain

PubMed Central

2008-01-01

Introduction Up to 80% of people with cancer experience pain at some time during their illness, and most will need opioid analgesics. This review assesses how different opioid analgesics compare, in terms of both pain control and adverse effects, in people with cancer. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical question: what are the effects of opioids in treating cancer-related pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: codeine, dihydrocodeine, transdermal fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. PMID:19445735

Pain Management of Malignant Psoas Syndrome Under Epidural Analgesia During Palliative Radiotherapy.

PubMed

Ota, Takayo; Makihara, Masaru; Tsukuda, Hiroshi; Kajikawa, Ryuji; Inamori, Masayuki; Miyatake, Nozomi; Tanaka, Noriko; Tokunaga, Masahiro; Hasegawa, Yoshikazu; Tada, Takuhito; Fukuoka, Masahiro

2017-06-01

Malignant psoas syndrome is a rare malignant condition presenting as lumbosacral plexopathy and painful fixed flexion of the hip. Metastasis to the psoas muscle is observed, which damages the nerve bundles in the lumbosacral plexuses. The syndrome presents as refractory lower back pain with several other neurological symptoms. The pain is difficult to control because it is a mixture of nociceptive and neuropathic pain, which indicates that treatment requires a versatile approach. The authors report a case of severe back pain caused by metastasis to the psoas muscle of advanced gastric cancer in a patient who underwent palliative radiotherapy under epidural analgesia. Despite conventional analgesics and subcutaneous oxycodone, he had difficulties in maintaining supine position because of the back pain and had a problem to receive radiotherapy, which required him to stay still in the same position during the treatment. By epidural analgesia, he could remain in supine position and complete radiotherapy without increasing opioid administration. His back pain was improved after the radiotherapy. Epidural analgesia is an effective treatment choice for a patient who is unable to keep the position during palliative radiotherapy.

Assessment of the trends in medical use and misuse of opioid analgesics from 2004 to 2011.

PubMed

Atluri, Sairam; Sudarshan, Gururau; Manchikanti, Laxmaiah

2014-01-01

The epidemic of medical use and abuse of opioid analgesics is linked to the economic burden of opioid-related abuse and fatalities in the United States. Multiple studies have estimated the extent to which prescription opioid analgesics contribute to the national drug abuse problem; studies also assessing the trends in medical use and abuse of opioid analgesics have confirmed the relationship between increasing medical use of opioids and increasing fatalities.The available data is limited until 2002. Retrospective analysis of data from 2004 to 2011 from 2 databases: Automation of Reports and Consolidated Orders System (ARCOS) for opioid use data and Drug Abuse Warning Network (DAWN) for drug misuse data. To determine the proportion of drug abuse related to opioid analgesics and the various trends in the medical use and abuse of 8 opioid analgesics commonly used to treat pain: buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, and oxycodone. The data obtained from DAWN is a nationally representative sample of hospital emergency department admissions resulting from drug abuse. Main outcome measure was the identification of trends in the medical use and misuse of opioid analgesics from 2004 to 2011. From 2004 to 2011, there was an increase in the medical use of all opioids except for a 20% decrease in codeine. The abuse of all opioids including codeine increased during this period. Increases in medical use ranged from 2,318% for buprenorphine to 35% for fentanyl, including 140% for hydromorphone, 117% for oxycodone, 73% for hydrocodone, 64% for morphine, and 37% for methadone. The misuse increased 384% for buprenorphine with available data from 2006 to 2011, whereas from 2004 to 2011, it increased 438% for hydromorphone, 263% for oxycodone, 146% for morphine, 107% for hydrocodone, 104% for fentanyl, 82% for methadone, and 39% for codeine. Comparison of opioid use showed an overall increase of 1,448% from 1996 to 2011, with increases of 690% from 1996 to 2004 and 100% from 2004 to 2011. In contrast, misuse increased more dramatically: 4,680% from 1996 to 2011, with increases of 1,372% from 1996 through 2004 and 245% from 2004 to 2011. The number of patients seeking rehabilitation for substance abuse also increased 187% for opioids, whereas it increased 87% for heroin, 40% for marijuana, and decreased 7% for cocaine. Limitations of this assessment include the lack of data from 2003, lack of data available on meperidine, and that the aggregate data systems used in the study did not identify specific formulations or commercial products. The present trend of continued increase in the medical use of opioid analgesics appears to contribute to increases in misuse, resulting in multiple health consequences.

An Analysis of 34,218 Pediatric Outpatient Controlled Substance Prescriptions.

PubMed

George, Jessica A; Park, Paul S; Hunsberger, Joanne; Shay, Joanne E; Lehmann, Christoph U; White, Elizabeth D; Lee, Benjamin H; Yaster, Myron

2016-03-01

Prescription errors are among the most common types of iatrogenic errors. Because of a previously reported 82% error rate in handwritten discharge narcotic prescriptions, we developed a computerized, web-based, controlled substance prescription writer that includes weight-based dosing logic and alerts to reduce the error rate to (virtually) zero. Over the past 7 years, >34,000 prescriptions have been created by hospital providers using this platform. We sought to determine the ongoing efficacy of the program in prescription error reduction and the patterns with which providers prescribe controlled substances for children and young adults (ages 0-21 years) at hospital discharge. We examined a database of 34,218 controlled substance discharge prescriptions written by our institutional providers from January 1, 2007 to February 14, 2014, for demographic information, including age and weight, type of medication prescribed based on patient age, formulation of dispensed medication, and amount of drug to be dispensed at hospital discharge. In addition, we randomly regenerated 2% (700) of prescriptions based on stored data and analyzed them for errors using previously established error criteria. Weights that were manually entered into the prescription writer by the prescriber were compared with the patient's weight in the hospital's electronic medical record. Patients in the database averaged 9 ± 6.1 (range, 0-21) years of age and 36.7 ± 24.9 (1-195) kg. Regardless of age, the most commonly prescribed opioid was oxycodone (73%), which was prescribed as a single agent uncombined with acetaminophen. Codeine was prescribed to 7% of patients and always in a formulation containing acetaminophen. Liquid formulations were prescribed to 98% of children <6 years of age and to 16% of children >12 years of age (the remaining 84% received tablet formulations). Regardless of opioid prescribed, the amount of liquid dispensed averaged 106 ± 125 (range, 2-3240) mL, and the number of tablets dispensed averaged 51 ± 51 (range, 1-1080). Of the subset of 700 regenerated prescriptions, all were legible (drug, amount dispensed, dose, patient demographics, and provider name) and used best prescribing practice (e.g., no trailing zero after a decimal point, leading zero for doses <1). Twenty-five of the 700 (3.6%) had incorrectly entered weights compared with the most recent weight in the chart. Of these, 14 varied by 10% or less and only 2 varied by >15%. Of these, 1 resulted in underdosing (true weight 80 kg prescribed for a weight of 50 kg) and the other in overdosing (true weight 10 kg prescribed for a weight of 30 kg). A computerized prescription writer eliminated most but not all the errors common to handwritten prescriptions. Oxycodone has supplanted codeine as the most commonly prescribed oral opioid in current pediatric pain practice and, independent of formulation, is dispensed in large quantities. This study underscores the need for liquid opioid formulations in the pediatric population and, because of their abuse potential, the urgent need to determine how much of the prescribed medication is actually used by patients.

Pain Management After Outpatient Shoulder Arthroscopy: A Systematic Review of Randomized Controlled Trials.

PubMed

Warrender, William J; Syed, Usman Ali M; Hammoud, Sommer; Emper, William; Ciccotti, Michael G; Abboud, Joseph A; Freedman, Kevin B

2017-06-01

Effective postoperative pain management after shoulder arthroscopy is a critical component to recovery, rehabilitation, and patient satisfaction. This systematic review provides a comprehensive overview of level 1 and level 2 evidence regarding postoperative pain management for outpatient arthroscopic shoulder surgery. Systematic review. We performed a systematic review of the various modalities reported in the literature for postoperative pain control after outpatient shoulder arthroscopy and analyzed their outcomes. Analgesic regimens reviewed include regional nerve blocks/infusions, subacromial/intra-articular injections or infusions, cryotherapy, and oral medications. Only randomized control trials with level 1 or level 2 evidence that compared 2 or more pain management modalities or placebo were included. We excluded studies without objective measures to quantify postoperative pain within the first postoperative month, subjective pain scale measurements, or narcotic consumption as outcome measures. A combined total of 40 randomized control trials met our inclusion criteria. Of the 40 included studies, 15 examined nerve blocks, 4 studied oral medication regimens, 12 studied subacromial infusion, 8 compared multiple modalities, and 1 evaluated cryotherapy. Interscalene nerve blocks (ISBs) were found to be the most effective method to control postoperative pain after shoulder arthroscopy. Increasing concentrations, continuous infusions, and patient-controlled methods can be effective for more aggressively controlling pain. Dexamethasone, clonidine, intrabursal oxycodone, and magnesium have all been shown to successfully improve the duration and adequacy of ISBs when used as adjuvants. Oral pregabalin and etoricoxib administered preoperatively have evidence supporting decreased postoperative pain and increased patient satisfaction. On the basis of the evidence in this review, we recommend the use of ISBs as the most effective analgesic for outpatient arthroscopic shoulder surgery.

Modified in vivo comet assay detects the genotoxic potential of 14-hydroxycodeinone, an α,β-unsaturated ketone in oxycodone.

PubMed

Pant, Kamala; Roden, Nicholas; Zhang, Charles; Bruce, Shannon; Wood, Craig; Pendino, Kimberly

2015-12-01

14-Hydroxycodeinone (14-HC) is an α,β-unsaturated ketone impurity found in oxycodone drug substance and has a structural alert for genotoxicity. 14-HC was tested in a combined Modified and Standard Comet Assay to determine if the slight decrease in % Tail DNA noted in a previously conducted Standard Comet Assay with 14-HC could be magnified to clarify if the response was due to cross-linking activity. One limitation of the Standard Comet Assay is that DNA cross-links cannot be reliably detected. However, under certain modified testing conditions, DNA cross-links and chemical moieties that elicit such cross-links can be elucidated. One such modification involves the induction of additional breakages of DNA strands by gamma or X-ray irradiation. To determine if 14-HC is a DNA crosslinker in vivo, a Modified Comet Assay was conducted using X-ray irradiation as the modification to visualize crosslinking activity. In this assay, 14-HC was administered orally to mice up to 320 mg/kg/day. Results showed a statistically significant reduction in percent tail DNA in duodenal cells at 320 mg/kg/day, with a nonstatistically significant but dose-related reduction in percent tail DNA also observed at the mid dose of 160 mg/kg/day. Similar decreases were not observed in cells from the liver or stomach, and no increases in percent tail DNA were noted for any tissue in the concomitantly conducted Standard Comet Assay. Taken together, 14-HC was identified as a cross-linking agent in the duodenum in the Modified Comet Assay. © 2015 Wiley Periodicals, Inc.

Pharmacogenomics and Patient Treatment Parameters to Opioid Treatment in Chronic Pain: A Focus on Morphine, Oxycodone, Tramadol, and Fentanyl.

PubMed

Lloyd, Renae A; Hotham, Elizabeth; Hall, Catherine; Williams, Marie; Suppiah, Vijayaprakash

2017-12-01

Opioids are one of the most commonly prescribed medicines for chronic pain. However, their use for chronic pain has been controversial. The objective of this literature review was to identify the role of genetic polymorphisms on patient treatment parameters (opioid dose requirements, response, and adverse effects) for opioids used in malignant and nonmalignant chronic pain. The opioids that this review focuses on are codeine, morphine, oxycodone, tramadol, and fentanyl. A literature search of databases Medline and Embase was carried out, and studies up to April 2016 were included in this review. Studies were included based on a combination of key words: chronic pain and related terms, pharmacogenetics and related terms, and opioids and related terms. Among the 1,408 individual papers retrieved from the search in Medline and Embase, 32 original articles were included in this review, with none related to codeine. The 32 papers reported various study designs, opioids, and polymorphisms being studied for associations with treatment outcomes. This literature review reveals that variants in ABCB1, OPRM1, and COMT have been replicated for opioid dosing and variants in ABCB1 have been replicated for both treatment response and adverse effects. Currently, there are few validated studies to form a strong evidence base to support pharmacogenomics testing when initiating opioid therapy. However, the field of pharmacogenomics in chronic pain is likely to expand over the coming years, with the increasing number of treatment options available and larger cohorts being assembled in order to identify true associations. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Dose and Duration of Opioid Use in Patients with Cancer and Noncancer Pain at an Outpatient Hospital Setting in Malaysia.

PubMed

Zin, Che S; Rahman, Norny A; Ismail, Che R; Choy, Leong W

2017-07-01

There are currently limited data available on the patterns of opioid prescribing in Malaysia. This study investigated the patterns of opioid prescribing and characterized the dosing and duration of opioid use in patients with noncancer and cancer pain. This retrospective, cross-sectional study was conducted at an outpatient hospital setting in Malaysia. All prescriptions for opioids (dihydrocodeine, fentanyl, morphine, and oxycodone) issued between January 2013 and December 2014 were examined. The number of prescriptions and patients, the distribution of mean daily dose, annual total days covered with opioids, and annual total opioid dose at the individual level were calculated and stratified by noncancer and cancer groups. A total of 1015 opioid prescriptions were prescribed for 347 patients from 2013 to 2014. Approximately 41.5% of patients (N = 144/347) and 58.5% (N = 203/347) were associated with noncancer and cancer diagnosis, respectively. Oxycodone (38.0%) was the highest prescribed primarily for the noncancer group. The majority of patients in both noncancer (74.3%) and cancer (60.4%) groups were receiving mean daily doses of < 50 mg morphine equivalents. The chronic use of opioids (> 90 days per year) was associated with 21.8% of patients in the noncancer group and 17.5% in the cancer group. The finding from this study showed that 41.5% of opioid users at an outpatient hospital setting in Malaysia received opioids for noncancer pain and 21.8% of these users were using opioids for longer than 90 days. The average daily dose in the majority of patients in both groups of noncancer and cancer was modest. © 2016 World Institute of Pain.

Twenty‐five years of prescription opioid use in Australia: a whole‐of‐population analysis using pharmaceutical claims

PubMed Central

Karanges, Emily A.; Blanch, Bianca; Buckley, Nicholas A.

2016-01-01

Aim The aim of this paper is to investigate 25‐year trends in community use of prescribed opioid analgesics in Australia, and to map these trends against major changes to opioid registration and subsidy. Methods We obtained dispensing data from 1990 to 2014 from two sources: dispensing claims processed under Australia's national drug subsidy programme, the Pharmaceutical Benefits Scheme, including under co‐payment records from 2012; and estimates of non‐subsidized medicine use from a survey of Australian pharmacies (until 2011). Utilization was expressed in defined daily doses (DDD)/1000 population/day. Results Opioid dispensing increased almost four‐fold between 1990 and 2014, from 4.6 to 17.4 DDD/1000 pop/day. In 1990, weak, short‐acting or orally administered opioids accounted for over 90% of utilization. Use of long‐acting opioids increased over 17‐fold between 1990 and 2000, due primarily to the subsidy of long‐acting morphine and increased use of methadone for pain management. Between 2000 and 2011, oxycodone, fentanyl, buprenorphine, tramadol and hydromorphone use increased markedly. Use of strong opioids, long‐acting and transdermal preparations also increased, largely following the subsidy of various opioids for noncancer pain. In 2011, the most dispensed opioids were codeine (41.1% of total opioid use), oxycodone (19.7%) and tramadol (16.1%); long‐acting formulations comprised approximately half, and strong opioids 40%, of opioid dispensing. Conclusions Opioid utilization in Australia is increasing, although these figures remain below levels reported in the US and Canada. The increased use of opioids was largely driven by the subsidy of long‐acting formulations and opioids for the treatment of noncancer pain. PMID:26991673

Broad-spectrum drug screening of meconium by liquid chromatography with tandem mass spectrometry and time-of-flight mass spectrometry.

PubMed

Ristimaa, Johanna; Gergov, Merja; Pelander, Anna; Halmesmäki, Erja; Ojanperä, Ilkka

2010-09-01

Analysis of the major drugs of abuse in meconium has been established in clinical practice for detecting fetal exposure to illicit drugs, particularly for the ready availability of the sample and ease of collection from diapers, compared with neonatal hair and urine. Very little is known about the occurrence and detection possibilities of therapeutic and licit drugs in meconium. Meconium specimens (n = 209) were collected in delivery hospitals, from infants of mothers who were suspected to be drug abusers. A targeted analysis method by liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) was developed for abused drugs: amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, morphine, codeine, 6-monoacetylmorphine, oxycodone, methadone, tramadol, buprenorphine, and norbuprenorphine. A separate LC-MS/MS method was developed for 11-nor-∆(9)-tetrahydrocannabinol-9-carboxylic acid. A screening method based on LC coupled to time-of-flight MS was applied to a broad spectrum of drugs. As a result, a total of 77 different compounds were found. The main drug findings in meconium were as follows: local anesthetics 82.5% (n = 172), nicotine or its metabolites 61.5% (n = 129), opioids 48.5% (n = 101), stimulants 21.0% (n = 44), hypnotics and sedatives 19.0% (n = 40), antidepressants 18.0% (n = 38), antipsychotics 5.5% (n = 11), and cannabis 3.0% (n = 5). By revealing drugs and metabolites beyond the ordinary scope, the present procedure helps the pediatrician in cases where maternal denial is strong but the infant seems to suffer from typical drug-withdrawal symptoms. Intrapartum drug administration cannot be differentiated from gestational drug use by meconium analysis, which affects the interpretation of oxycodone, tramadol, fentanyl, pethidine, and ephedrine findings.

Practice guideline summary: Treatment of restless legs syndrome in adults

PubMed Central

Winkelman, John W.; Armstrong, Melissa J.; Allen, Richard P.; Chaudhuri, K. Ray; Ondo, William; Trenkwalder, Claudia; Zee, Phyllis C.; Gronseth, Gary S.; Gloss, David; Zesiewicz, Theresa

2016-01-01

Objective: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults. Methods: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength. Results and recommendations: In moderate to severe primary RLS, clinicians should consider prescribing medication to reduce RLS symptoms. Strong evidence supports pramipexole, rotigotine, cabergoline, and gabapentin enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use (Level B). Clinicians may consider prescribing levodopa (Level C). Few head-to-head comparisons exist to suggest agents preferentially. Cabergoline is rarely used (cardiac valvulopathy risks). Augmentation risks with dopaminergic agents should be considered. When treating periodic limb movements of sleep, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For subjective sleep measures, clinicians should consider prescribing cabergoline or gabapentin enacarbil (Level A), or ropinirole, pramipexole, rotigotine, or pregabalin (Level B). For patients failing other treatments for RLS symptoms, clinicians may consider prescribing prolonged-release oxycodone/naloxone where available (Level C). In patients with RLS with ferritin ≤75 μg/L, clinicians should consider prescribing ferrous sulfate with vitamin C (Level B). When nonpharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C). Clinicians may consider prescribing vibrating pads to improve subjective sleep (Level C). In patients on hemodialysis with secondary RLS, clinicians should consider prescribing vitamin C and E supplementation (Level B) and may consider prescribing ropinirole, levodopa, or exercise (Level C). PMID:27856776

Impact of capillary flow hydrodynamics on carrier-mediated transport of opioid derivatives at the blood-brain barrier, based on pH-dependent Michaelis-Menten and Crone-Renkin analyses.

PubMed

Yusof, Siti R; Abbott, N Joan; Avdeef, Alex

2017-08-30

Most studies of blood-brain barrier (BBB) permeability and transport are conducted at a single pH, but more detailed information can be revealed by using multiple pH values. A pH-dependent biophysical model was applied to the mechanistic analysis of published pH-dependent BBB luminal uptake data from three opioid derivatives in rat: pentazocine (Suzuki et al., 2002a, 2002b), naloxone (Suzuki et al., 2010a), and oxycodone (Okura et al., 2008). Two types of data were processed: in situ brain perfusion (ISBP) and brain uptake index (BUI). The published perfusion data were converted to apparent luminal permeability values, P app , and analyzed by the pCEL-X program (Yusof et al., 2014), using the pH-dependent Crone-Renkin equation (pH-CRE) to determine the impact of cerebrovascular flow on the Michaelis-Menten transport parameters (Avdeef and Sun, 2011). For oxycodone, the ISBP data had been measured at pH7.4 and 8.4. The present analysis indicates a 7-fold lower value of the cerebrovascular flow velocity, F pf , than that expected in the original study. From the pyrilamine-inhibited data, the flow-corrected passive intrinsic permeability value was determined to be P 0 =398×10 -6 cm·s -1 . The uptake data indicate that the neutral form of oxycodone is affected by a transporter at pH8.4. The extent of the cation uptake was less certain from the available data. For pentazocine, the brain uptake by the BUI method had been measured at pH5.5, 6.5, and 7.4, in a concentration range 0.1-40mM. Under similar conditions, ISBP data were also available. The pH-CRE determined values of F pf from both methods were nearly the same, and were smaller than the expected value in the original publication. The transport of the cationic pentazocine was not fully saturated at pH5.5 at 40mM. The transport of the neutral species at pH7.4 appeared to reach saturation at 40mM pentazocine concentration, but not at 12mM. In the case of naloxone, a pH-dependent Michaelis-Menten equation (pH-MME) analysis of the data indicated a smooth sigmoidal transition from a higher capacity uptake process affecting cationic naloxone (pH5.0-7.0) to a lower capacity uptake process affecting the neutral drug (pH8.0-8.5), with cross-over point near pH7.4. Evidently, measurements at multiple pH values can reveal important information about both cerebrovascular flow and BBB transport kinetics. Copyright © 2017 Elsevier B.V. All rights reserved.

Impact of Release Rates on the Effectiveness of Augmentative Biological Control Agents

PubMed Central

Crowder, David W.

2007-01-01

To access the effect of augmentative biological control agents, 31 articles were reviewed that investigated the impact of release rates of 35 augmentative biological control agents on the control of 42 arthropod pests. In 64% of the cases, the release rate of the biological control agent did not significantly affect the density or mortality of the pest insect. Results where similar when parasitoidsor predators were utilized as the natural enemy. Within any order of natural enemy, there were more cases where release rates did not affect augmentative biological control than cases where release rates were significant. There were more cases in which release rates did not affect augmentative biological control when pests were from the orders Hemiptera, Acari, or Diptera, but not with pests from the order Lepidoptera. In most cases, there was an optimal release rate that produced effective control of a pest species. This was especially true when predators were used as a biological control agent. Increasing the release rate above the optimal rate did not improve control of the pest and thus would be economically detrimental. Lower release rates were of ten optimal when biological control was used in conjunction with insecticides. In many cases, the timing and method of biological control applications were more significant factors impacting the effectiveness of biological control than the release rate. Additional factors that may limit the relative impact of release rates include natural enemy fecundity, establishment rates, prey availability, dispersal, and cannibalism. PMID:20307240

[Oral controlled release dosage forms].

PubMed

Mehuys, Els; Vervaet, Chris

2010-06-01

Several technologies to control drug release from oral dosage forms have been developed. Drug release can be regulated in several ways: sustained release, whereby the drug is released slowly over a prolonged period of time, postponed release, whereby drug release is delayed until passage from the stomach into the intestine (via enteric coating), and targeted release, whereby the drug is targeted to a specific location of the gastrointestinal tract. This article reviews the various oral controlled release dosage forms on the market.

Investigational opioid antagonists for treating opioid-induced bowel dysfunction.

PubMed

Mozaffari, Shilan; Nikfar, Shekoufeh; Abdollahi, Mohammad

2018-03-01

Opioids have been highlighted for their role in pain relief among cancer and non-cancer patients. Novel agents have been investigated to reduce opioid-induced constipation (OIC) as the main adverse effect that may lead to treatment discontinuation. Development of peripherally acting mu-opioid receptor antagonists (PAMORA) has resulted in a novel approach to preserve the efficacy of pain control along with less OIC. Areas covered: Clinical evidence for investigational PAMORAs was reviewed and clinical trials on investigational agents to reduce OIC were included. TD-1211 is currently being evaluated in Phase II clinical trial. Oxycodone-naltrexone and ADL-5945 went through Phase III clinical trials, but have been discontinued. Expert opinion: There is a substantial need to develop agents with specific pharmacokinetic properties to meet the needs of patients with underlying diseases. Holding the efficacy of a medicine with the highest selectivity on targeted receptors and the least adverse effects is the main approach in upcoming investigations to improve patients' quality of life (QoL). Novel agents to reduce opioid-induced bowel dysfunction (OIBD) that do not reverse peripherally mediated pain analgesia are of great interest. Direct comparison of available agents in this field is lacking in the literature.

Dual-controlled release system of drugs for bone regeneration.

PubMed

Kim, Yang-Hee; Tabata, Yasuhiko

2015-11-01

Controlled release systems have been noted to allow drugs to enhance their ability for bone regeneration. To this end, various biomaterials have been used as the release carriers of drugs, such as low-molecular-weight drugs, growth factors, and others. The drugs are released from the release carriers in a controlled fashion to maintain their actions for a long time period. Most research has been focused on the controlled release of single drugs to demonstrate the therapeutic feasibility. Controlled release of two combined drugs, so-called dual release systems, are promising and important for tissue regeneration. This is because the tissue regeneration process of bone formation is generally achieved by multiple bioactive molecules, which are produced from cells by other molecules. If two types of bioactive molecules, (i.e., drugs), are supplied in an appropriate fashion, the regeneration process of living bodies will be efficiently promoted. This review focuses on the bone regeneration induced by dual-controlled release of drugs. In this paper, various dual-controlled release systems of drugs aiming at bone regeneration are overviewed explaining the type of drugs and their release materials. Copyright © 2015 Elsevier B.V. All rights reserved.

Controlling the Release of Indomethacin from Glass Solutions Layered with a Rate Controlling Membrane Using Fluid-Bed Processing. Part 2: The Influence of Formulation Parameters on Drug Release.

PubMed

Dereymaker, Aswin; Pelgrims, Jirka; Engelen, Frederik; Adriaensens, Peter; Van den Mooter, Guy

2017-04-03

This study aimed to investigate the pharmaceutical performance of an indomethacin-polyvinylpyrrolidone (PVP) glass solution applied using fluid bed processing as a layer on inert sucrose spheres and subsequently top-coated with a release rate controlling membrane consisting of either ethyl cellulose or Eudragit RL. The implications of the addition of a pore former (PVP) and the coating medium (ethanol or water) on the diffusion and release behavior were also considered. In addition, the role of a charge interaction between drug and controlled release polymer on the release was investigated. Diffusion experiments pointed to the influence of pore former concentration, rate controlling polymer type, and coating solvent on the permeability of the controlled release membranes. This can be translated to drug release tests, which show the potential of diffusion tests as a preliminary screening test and that diffusion is the main factor influencing release. Drug release tests also showed the effect of coating layer thickness. A charge interaction between INDO and ERL was demonstrated, but this had no negative effect on drug release. The higher diffusion and release observed in ERL-based rate controlling membranes was explained by a higher hydrophilicity, compared to EC.

"It's bad around here now": tobacco, alcohol and other drug use among American Indians living on a rural reservation.

PubMed

Dennis, Mary Kate; Momper, Sandra L

2012-01-01

Using data about members of a midwestern American Indian reservation in eight focus groups that were conducted like "talking circles," the authors describe the participants' (N = 49) views of the current use and abuse of tobacco, alcohol, and other drugs. Results indicate that the use of tobacco is pervasive; that the use of alcohol and other drugs, especially marijuana and oxycodone, are problems on this reservation because they are detrimental to health and well-being; and appropriate, available, and accessible treatment is scarce, nonexistent, or underfunded. Culturally sensitive substance abuse treatment and increased funding for treatment are major health issues for this population.

Poly (lactic-co-glycolic acid) controlled release systems: experimental and modeling insights

PubMed Central

Hines, Daniel J.; Kaplan, David L.

2013-01-01

Poly-lactic-co-glycolic acid (PLGA) has been the most successful polymeric biomaterial for use in controlled drug delivery systems. There are several different chemical and physical properties of PLGA that impact the release behavior of drugs from PLGA delivery devices. These properties must be considered and optimized in drug release device formulation. Mathematical modeling is a useful tool for identifying, characterizing, and predicting the mechanisms of controlled release. The advantages and limitations of poly (lactic-co-glycolic acid) for controlled release are reviewed, followed by a review of current approaches in controlled release technology that utilize PLGA. Mathematical modeling applied towards controlled release rates from PLGA-based devices will also be discussed to provide a complete picture of state of the art understanding of the control achievable with this polymeric system, as well as the limitations. PMID:23614648

Characteristics of Opioid-Users Whose Death Was Related to Opioid-Toxicity: A Population-Based Study in Ontario, Canada

PubMed Central

Madadi, Parvaz; Hildebrandt, Doris; Lauwers, Albert E.; Koren, Gideon

2013-01-01

Background The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity. Methods This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed. Results Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359). Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch), 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer. Significance/Conclusion These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users. PMID:23577131

Ephemeral profiles of prescription drug and formulation tampering: evolving pseudoscience on the Internet.

PubMed

Cone, Edward J

2006-06-01

The magnitude of non-therapeutic use, or misuse of prescription pharmaceuticals now rivals that of illicit drug abuse. Drug and formulation tampering enables misusers to administer higher doses by intended and non-intended routes. Perceived motives appear to be a combination of interests in achieving a faster onset and enhancing psychoactive effects. Narcotic analgesics, stimulants, and depressants are widely sought, examined, and tampered with for recreational use. This review examines tampering methods reported on the Internet for selected pharmaceutical products. The Internet provides broad and varied guidance on tampering methods that are specific to drug classes and unique formulations. Instructions are available on crushing, separating, purifying and chemically altering specific formulations to allow changes in dosage, route of administration, and time course of effects. Many pharmaceutical formulations contain features that serve as "barriers" to tampering. The nature and effectiveness of formulation barriers vary widely with many being overcome by adventurous misusers. Examples of successes and failures in tampering attempts are frequently described on Internet sites that support recreational drug use. Successful tampering methods that have widespread appeal evolve into recipes and become archived on multiple websites. Examples of tampering methods include: (1) how to separate narcotic drugs (codeine, hydrocodone, oxycodone) from excipients and non-desirable actives (aspirin, acetaminophen, ibuprofen); (2) overcoming time-release formulations (beads, layers, matrices); (3) removal of active drug from high-dose formulations (patches, pills); (4) alteration of dosage forms for alternate routes of administration. The development of successful formulations that inhibit or prevent drug/formulation tampering with drugs of abuse should take into consideration the scope and practice of tampering methods available to recreational drug users on the Internet.

Characteristics of opioid-users whose death was related to opioid-toxicity: a population-based study in Ontario, Canada.

PubMed

Madadi, Parvaz; Hildebrandt, Doris; Lauwers, Albert E; Koren, Gideon

2013-01-01

The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity. This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed. Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359). Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch), 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer. These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users.

Patient-Controlled Epidural Analgesia or Multimodal Pain Regimen with Periarticular Injection After Total Hip Arthroplasty

PubMed Central

Jules-Elysee, Kethy M.; Goon, Amanda K.; Westrich, Geoffrey H.; Padgett, Douglas E.; Mayman, David J.; Ranawat, Amar S.; Ranawat, Chitranjan S.; Lin, Yi; Kahn, Richard L.; Bhagat, Devan D.; Goytizolo, Enrique A.; Ma, Yan; Reid, Shane C.; Curren, Jodie; YaDeau, Jacques T.

2015-01-01

Background: The optimal postoperative analgesia after primary total hip arthroplasty remains in question. This randomized, double-blind, placebo-controlled study compared the use of patient-controlled epidural analgesia (PCEA) with use of a multimodal pain regimen including periarticular injection (PAI). We hypothesized that PAI would lead to earlier readiness for discharge, decreased opioid consumption, and lower pain scores. Methods: Forty-one patients received PAI, and forty-three patients received PCEA. Preoperatively, both groups were administered dexamethasone (6 mg, orally). The PAI group received a clonidine patch and sustained-release oxycodone (10 mg), while the PCEA group had placebo. Both groups received combined spinal-epidural anesthesia and used an epidural pain pump postoperatively; the PAI group had normal saline solution, while the PCEA group had bupivacaine and hydromorphone. The primary outcome, readiness for discharge, required the discontinuation of the epidural, a pain score of <4 (numeric rating scale) without parenteral narcotics, normal eating, minimal nausea, urination without a catheter, a dry surgical wound, no acute medical problems, and the ability to independently transfer and walk 12.2 m (40 ft). Results: The mean time to readiness for discharge (and standard deviation) was 2.4 ± 0.7 days (PAI) compared with 2.3 ± 0.8 days (PCEA) (p = 0.86). The mean length of stay was 3.0 ± 0.8 days (PAI) compared with 3.1 ± 0.7 days (PCEA) (p = 0.46). A significant mean difference in pain score of 0.74 with ambulation (p = 0.01; 95% confidence interval [CI], 0.18 to 1.31) and 0.80 during physical therapy (p = 0.03; 95% CI, 0.09 to 1.51) favored the PCEA group. The mean opioid consumption (oral morphine equivalents in milligrams) was significantly higher in the PAI group on postoperative day 0 (43 ± 21 compared with 28 ± 23; p = 0.002) and postoperative days 0 through 2 (136 ± 59 compared with 90 ± 79; p = 0.004). Opioid-Related Symptom Distress Scale (ORSDS) composite scores for severity and bothersomeness as well as scores for nausea, vomiting, and itchiness were significantly higher in the PCEA group (p < 0.05). Quality of Recovery-40 scores and patient satisfaction were similar. Conclusions: PAI did not decrease the time to discharge and was associated with higher pain scores and greater opioid consumption but lower ORSDS scores compared with PCEA. The choice for analgesic regimen may depend on a particular patient’s threshold for pain and the potential side effects. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID:25995489

Controlled-release tablet formulation of isoniazid.

PubMed

Jain, N K; Kulkarni, K; Talwar, N

1992-04-01

Guar (GG) and Karaya gums (KG) alone and in combination with hydroxy-propylmethylcellulose (HPMC) were evaluated as release retarding materials to formulate a controlled-release tablet dosage form of isoniazid (1). In vitro release of 1 from tablets followed non-Fickian release profile with rapid initial release. Urinary excretion studies in normal subjects showed steady-state levels of 1 for 13 h. In vitro and in vivo data correlated (r = 0.9794). The studies suggested the potentiality of GG and KG as release retarding materials in formulating controlled-release tablet dosage forms of 1.

Critical review of controlled release packaging to improve food safety and quality.

PubMed

Chen, Xi; Chen, Mo; Xu, Chenyi; Yam, Kit L

2018-03-19

Controlled release packaging (CRP) is an innovative technology that uses the package to release active compounds in a controlled manner to improve safety and quality for a wide range of food products during storage. This paper provides a critical review of the uniqueness, design considerations, and research gaps of CRP, with a focus on the kinetics and mechanism of active compounds releasing from the package. Literature data and practical examples are presented to illustrate how CRP controls what active compounds to release, when and how to release, how much and how fast to release, in order to improve food safety and quality.

Calcium modified edible Canna (Canna edulis L) starch for controlled released matrix

NASA Astrophysics Data System (ADS)

Putri, A. P.; Ridwan, M.; Darmawan, T. A.; Darusman, F.; Gadri, A.

2017-07-01

Canna edulis L starch was modified with calcium chloride in order to form controlled released matrix. Present study aim to analyze modified starch characteristic. Four different formulation of ondansetron granules was used to provide dissolution profile of controlled released, two formula consisted of 15% and 30% modified starch, one formula utilized matrix reference standards and the last granules was negative control. Methocel-hydroxypropyl methyl cellulose was used as controlled released matrix reference standards in the third formula. Calcium starch was synthesized in the presence of sodium hydroxide to form gelatinized mass and calcium chloride as the cross linking agent. Physicochemical and dissolution properties of modified starch for controlled released application were investigated. Modified starch has higher swelling index, water solubility and compressibility index. Three of four different formulation of granules provide dissolution profile of controlled released. The profiles indicate granules which employed calcium Canna edulis L starch as matrix are able to resemble controlled drug released profile of matrix reference, however their bigger detain ability lead to lower bioavailability.

Comparative Rates of Mortality and Serious Adverse Effects Among Commonly Prescribed Opioid Analgesics.

PubMed

Murphy, David L; Lebin, Jacob A; Severtson, Stevan G; Olsen, Heather A; Dasgupta, Nabarun; Dart, Richard C

2018-03-26

The epidemic of prescription opioid overdose and mortality parallels the dispensing rates of prescription opioids, and the availability of increasingly potent opioid analgesics. The common assumption that more potent opioid analgesics are associated with higher rates of adverse outcomes has not been adequately substantiated. We compared the rate of serious adverse events among commonly prescribed opioid analgesics of varying potency. Serious adverse events (SAEs; defined as death, major medical effect, or hospitalization) resulting from exposure to tablets containing seven opioid analgesics (oxycodone, hydrocodone, morphine, hydromorphone, oxymorphone, tapentadol, and tramadol) captured by the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS ® ) System Poison Center Program were evaluated from 2010 through 2016. Rates of SAEs were adjusted for availability through outpatient dispensing data and regressed on morphine milligram equivalents (MME). There were 19,480 cases of SAE during the 7-year study period. Hydrocodone and oxycodone contributed to 77% of SAE cases. Comparing rates of outcome by relative potency, a hierarchy was observed with hydromorphone (8.02 SAEs/100 kg) and tapentadol (0.27 SAE/100 kg) as the highest and lowest rates, reflecting a 30-fold difference among individual opioid products. SAE rate and potency were related linearly-SAEs increased 2.04 per 100 kg drug dispensed for each 1-unit rise in MME (p = 0.004). Linear regression of SAE/100 kg drug dispensed and drug potency identified that MME comprised 96% of the variation observed. In contrast, potency did not explain variation seen using other study denominators (prescriptions dispensed, dosage units dispensed, and the number of individuals filling a prescription). Potency of a prescription opioid analgesic demonstrates a significant, highly positive linear relationship with exposures resulting in SAEs per 100 kg drug dispensed reported to poison centers. Potency should be carefully considered from both individual provider and public health perspectives.

Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats.

PubMed

Merlos, Manuel; Portillo-Salido, Enrique; Brenchat, Alex; Aubel, Bertrand; Buxens, Jordi; Fisas, Angels; Codony, Xavier; Romero, Luz; Zamanillo, Daniel; Vela, José Miguel

2018-06-19

Drug combination for the treatment of pain is common clinical practice. Co-crystal of Tramadol-Celecoxib (CTC) consists of two active pharmaceutical ingredients (APIs), namely the atypical opioid tramadol and the preferential cyclooxygenase-2 inhibitor celecoxib, at a 1:1 molecular ratio. In this study, a non-formulated 'raw' form of CTC administered in suspension (referred to as ctc susp ) was compared with both tramadol and celecoxib alone in a rat plantar incision postoperative pain model. For comparison, the strong opioids morphine and oxycodone, and a tramadol plus acetaminophen combination at a molecular ratio of 1:17 were also tested. Isobolographic analyses showed that ctc susp exerted synergistic mechanical antiallodynic (experimental ED 50 =2.0±0.5mg/kg, i.p.; theoretical ED 50 =3.8±0.4mg/kg, i.p.) and thermal (experimental ED 50 =2.3±0.5mg/kg, i.p.; theoretical ED 50 =9.8±0.8mg/kg, i.p.) antihyperalgesic effects in the postoperative pain model. In contrast, the tramadol and acetaminophen combination showed antagonistic effects on both mechanical allodynia and thermal hyperalgesia. No synergies between tramadol and celecoxib on locomotor activity, motor coordination, ulceration potential and gastrointestinal transit were observed after the administration of ctc susp . Overall, rat efficacy and safety data revealed that ctc susp provided synergistic analgesic effects compared with each API alone, without enhancing adverse effects. Moreover, ctc susp showed similar efficacy but improved safety ratio (80, measured as gastrointestinal transit vs postoperative pain ED 50 ratios) compared with the strong opioids morphine (2.5) and oxycodone (5.8). The overall in vivo profile of ctc susp supports the further investigation of CTC in the clinical management of moderate-to-severe acute pain as an alternative to strong opioids. Copyright © 2018. Published by Elsevier B.V.

Can variability in the effect of opioids on refractory breathlessness be explained by genetic factors?

PubMed Central

Currow, David C; Quinn, Stephen; Ekstrom, Magnus; Kaasa, Stein; Johnson, Miriam J; Somogyi, Andrew A; Klepstad, Päl

2015-01-01

Objectives Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness. Setting 17 hospice/palliative care services (tertiary services) in 11 European countries. Participants 2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment. Primary outcome measures The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588). Secondary outcome measures The same measures for people on oxycodone (n=402) or fentanyl (n=429). Results SNPs not in Hardy-Weinberg equilibrium or with allele frequencies (<5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the β-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone. Conclusions This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy. PMID:25948405

Sustained release of methotrexate through liquid-crystalline folate nanoparticles.

PubMed

Misra, Rahul; Mohanty, Sanat

2014-09-01

To make chemotherapy more effective, sustained release of the drug is desirable. By controlling the release rates, constant therapeutic levels can be achieved which can avoid re-administration of drug. This helps to combat tumors more effectively with minimal side effects. The present study reports the control release of methotrexate through liquid-crystalline folate nanoparticles. These nanoparticles are composed of highly ordered folate self-assembly which encapsulate methotrexate molecules. These drug molecules can be released in a controlled manner by disrupting this assembly in the environment of monovalent cations. The ordered structure of folate nanoparticles offers low drug losses of about 4-5%, which is significant in itself. This study reports the size-control method of forming methotrexate encapsulated folate nanoparticles as well as the release of methotrexate through these nanoparticles. It has been demonstrated that methotrexate release rates can be controlled by controlling the size of the nanoparticles, cross-linking cation and cross-linking concentration. The effect of different factors like drug loading, release medium, and pH of the medium on methotrexate release rates was also studied.

Nanostructured aligned CNT platforms enhance the controlled release of a neurotrophic protein from polypyrrole

NASA Astrophysics Data System (ADS)

Thompson, Brianna C.; Chen, Jun; Moulton, Simon E.; Wallace, Gordon G.

2010-04-01

An aligned CNT array membrane electrode has been used as a nanostructured supporting platform for polypyrrole (PPy) films, exhibiting significant improvement in the controlled release of neurotrophin. In terms of linearity of release, stimulated to unstimulated control of NT-3 release and increased mass and % release of incorporated NT-3, the nanostructured material performed more favourably than the flat PPy film.

A Voltage-Responsive Free-Blockage Controlled-Release System Based on Hydrophobicity Switching.

PubMed

Jiao, Xiangyu; Sun, Ruijuan; Cheng, Yaya; Li, Fengyu; Du, Xin; Wen, Yongqiang; Song, Yanlin; Zhang, Xueji

2017-05-19

Controlled-release systems based on mesoporous silica nanomaterials (MSNs) have drawn great attention owing to their potential biomedical applications. Various switches have been designed to control the release of cargoes through the construction of physical blocking units on the surface of MSNs. However, such physical blockages are limited by poor sealing ability and low biocompatibility, and most of them lack closure ability. Herein, a voltage-responsive controlled-release system was constructed by functionalizing the nanopore of MSNs with ferrocene. The system realized free-blockage controlled release and achieved pulsatile release. The nanopores of the ferrocene-functionalized MSNs were hydrophobic enough to prevent invasion of the solution. Once a suitable voltage was applied, the nanopores became hydrophilic, which was followed by invasion of the solution and the release of the cargos. Moreover, pulsatile release was realized, which avoided unexpected release after the stimulus disappeared. Thus, we believe that our studies provide new insight into highly effective blockage for MSNs. Furthermore, the voltage-responsive release system is expected to find use in electrical stimulation combination therapy and bioelectricity-responsive release. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Controlled release of cyclosporine A self-nanoemulsifying systems from osmotic pump tablets: near zero-order release and pharmacokinetics in dogs.

PubMed

Zhang, Xi; Yi, Yueneng; Qi, Jianping; Lu, Yi; Tian, Zhiqiang; Xie, Yunchang; Yuan, Hailong; Wu, Wei

2013-08-16

It is very important to enhance the absorption simultaneously while designing controlled release delivery systems for poorly water-soluble and poorly permeable drugs (BCS IV). In this study, controlled release of cyclosporine (CyA) was achieved by the osmotic release strategy taking advantage of the absorption-enhancing capacity of self-nanoemulsifying drug delivery systems (SNEDDSs). The liquid SNEDDS consisting of Labrafil M 1944CS, Transcutol P and Cremophor EL was absorbed by the osmotic tablet core excipients (sucrose, lactose monohydrate, polyethylene oxide, and partly pregelatinized starch) and then transformed into osmotic tablets. Near zero-order release could be achieved for CyA-loaded nanoemulsions reconstituted from the SNEDDS. In general, the influencing factor study indicated that the release rate increased with increase of inner osmotic pressure, ratio of osmotic agent to suspending agent, content of pore-forming agent, and size of release orifice, whereas the thickness of the membrane impeded the release of CyA nanoemulsion. Pharmacokinetic study showed steady blood CyA profiles with prolonged Tmax and MRT, and significantly reduced Cmax for self-nanoemulsifying osmotic pump tablet (SNEOPT) in comparison with highly fluctuating profiles of the core tablet and Sandimmune Neoral(®). However, similar oral bioavailability was observed for either controlled release or non-controlled release formulations. It was concluded that simultaneous controlling on CyA release and absorption-enhancing had been achieved by a combination of osmotic tablet and SNEDDS. Copyright © 2013 Elsevier B.V. All rights reserved.

PREVENTION REFERENCE MANUAL: CONTROL TECHNOLOGIES, VOL. 2. POST-RELEASE MITIGATION MEASURES FOR CONTROLLING ACCIDENTAL RELEASES OF AIR TOXICS

EPA Science Inventory

The volume discusses prevention and protection measures for controlling accidental releases of air toxics. The probability of accidental releases depends on the extent to which deviations (in magnitude and duration) in the process can be tolerated before a loss of chemical contai...

How controlled release technology can aid gene delivery.

PubMed

Jo, Jun-Ichiro; Tabata, Yasuhiko

2015-01-01

Many types of gene delivery systems have been developed to enhance the level of gene expression. Controlled release technology is a feasible gene delivery system which enables genes to extend the expression duration by maintaining and releasing them at the injection site in a controlled manner. This technology can reduce the adverse effects by the bolus dose administration and avoid the repeated administration. Biodegradable biomaterials are useful as materials for the controlled release-based gene delivery technology and various biodegradable biomaterials have been developed. Controlled release-based gene delivery plays a critical role in a conventional gene therapy and genetic engineering. In the gene therapy, the therapeutic gene is released from biodegradable biomaterial matrices around the tissue to be treated. On the other hand, the intracellular controlled release of gene from the sub-micro-sized matrices is required for genetic engineering. Genetic engineering is feasible for cell transplantation as well as research of stem cells biology and medicine. DNA hydrogel containing a sequence of therapeutic gene and the exosome including the individual specific nucleic acids may become candidates for controlled release carriers. Technologies to deliver genes to cell aggregates will play an important role in the promotion of regenerative research and therapy.

Preparation and characterization of controlled-release fertilizers coated with marine polysaccharide derivatives

NASA Astrophysics Data System (ADS)

Wang, Jing; Liu, Song; Qin, Yukun; Chen, Xiaolin; Xing, Rong'e.; Yu, Huahua; Li, Kecheng; Li, Pengcheng

2017-09-01

Encapsulation of water-soluble nitrogen fertilizers by membranes can be used to control the release of nutrients to maximize the fertilization effect and reduce environmental pollution. In this research, we formulated a new double-coated controlled-release fertilizer (CRF) by using food-grade microcrystalline wax (MW) and marine polysaccharide derivatives (calcium alginate and chitosan-glutaraldehyde copolymer). The pellets of water-soluble nitrogen fertilizer were coated with the marine polysaccharide derivatives and MW. A convenient and eco-friendly method was used to prepare the CRF. Scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) were used to characterize the morphology and composition of the products. The nitrogen-release properties were determined in water using UV-Vis spectrophotometry. The controlled-release properties of the fertilizer were improved dramatically after coating with MW and the marine polysaccharide derivatives. The results show that the double-coated CRFs can release nitrogen in a controlled manner, have excellent controlled-release features, and meet the European Standard for CRFs.

Controlled Release Applications of Organometals.

ERIC Educational Resources Information Center

Thayer, John S.

1981-01-01

Reviews two classes of controlled release organometals: (1) distributional, to distribute bioactive materials to control a certain target organism; and (2) protective, to protect surface or interior of some structure from attach by organisms. Specific examples are given including a discussion of controlled release for schistosomiasis. (SK)

Pocket-size near-infrared spectrometer for narcotic materials identification

NASA Astrophysics Data System (ADS)

Pederson, Christopher G.; Friedrich, Donald M.; Hsiung, Chang; von Gunten, Marc; O'Brien, Nada A.; Ramaker, Henk-Jan; van Sprang, Eric; Dreischor, Menno

2014-05-01

While significant progress has been made towards the miniaturization of Raman, mid-infrared (IR), and near-infrared (NIR) spectrometers for homeland security and law enforcement applications, there remains continued interest in pushing the technology envelope for smaller, lower cost, and easier to use analyzers. In this paper, we report on the use of the MicroNIR Spectrometer, an ultra-compact, handheld near infrared (NIR) spectrometer, the, that weighs less than 60 grams and measures < 50mm in diameter for the classification of 140 different substances most of which are controlled substances (such as cocaine, heroin, oxycodone, diazepam), as well as synthetic cathinones (also known as bath salts), and synthetic cannabinoids. A library of the materials was created from a master MicroNIR spectrometer. A set of 25 unknown samples were then identified with three other MicroNIRs showing: 1) the ability to correctly identify the unknown with a very low rate of misidentification, and 2) the ability to use the same library with multiple instruments. In addition, we have shown that through the use of innovative chemometric algorithms, we were able to identify the individual compounds that make up an unknown mixture based on the spectral library of the individual compounds only. The small size of the spectrometer is enabled through the use of high-performance linear variable filter (LVF) technology.

Palliative Care Development in Mongolia.

PubMed

Davaasuren, Odontuya; Ferris, Frank D

2018-02-01

Since the year 2000, Mongolia has established the foundation measures for a national palliative care program and has made several significant achievements. Systematic reviews and observational studies on palliative care development in Mongolia have taken place over the past 16 years. Mongolia began palliative care development in 2000 with the creation of the Mongolian Palliative Care Society and the Palliative Care Department. Palliative care is included in the Mongolia's Health Law, Health Insurance Law, Social Welfare Law, National Cancer Control Program, and the National Program for Non-Communicable Diseases, and has approved Palliative Care Standards and Pain Management Guidelines. Palliative care education is included in the undergraduate and postgraduate curriculum in all medical universities. Six hospice units in Ulaanbaatar have 50 beds; each of the nine districts and all 21 provinces have up to four to five palliative beds, and there are 36 palliative care units, for a total 190 beds for three million people. In 2014, a pediatric palliative care inpatient unit was established with five beds. Essential drugs for palliative care have been available in Mongolia since 2015. The pharmaceutical company IVCO produces morphine, codeine, pethidine, and oxycodone in Ulaanbaatar. Mongolia has made real progress in integrating palliative care into the health system. Copyright © 2017. Published by Elsevier Inc.

28 CFR 541.50 - Release from a control unit.

Code of Federal Regulations, 2010 CFR

2010-07-01

... general population of the institution which has a control unit. [49 FR 32991, Aug. 17, 1984, as amended at... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Release from a control unit. 541.50... INMATE DISCIPLINE AND SPECIAL HOUSING UNITS Control Unit Programs § 541.50 Release from a control unit...

28 CFR 541.50 - Release from a control unit.

Code of Federal Regulations, 2013 CFR

2013-07-01

... general population of the institution which has a control unit. [49 FR 32991, Aug. 17, 1984, as amended at... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Release from a control unit. 541.50... INMATE DISCIPLINE AND SPECIAL HOUSING UNITS Control Unit Programs § 541.50 Release from a control unit...

28 CFR 541.50 - Release from a control unit.

Code of Federal Regulations, 2012 CFR

2012-07-01

... general population of the institution which has a control unit. [49 FR 32991, Aug. 17, 1984, as amended at... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Release from a control unit. 541.50... INMATE DISCIPLINE AND SPECIAL HOUSING UNITS Control Unit Programs § 541.50 Release from a control unit...

28 CFR 541.50 - Release from a control unit.

Code of Federal Regulations, 2011 CFR

2011-07-01

... general population of the institution which has a control unit. [49 FR 32991, Aug. 17, 1984, as amended at... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Release from a control unit. 541.50... INMATE DISCIPLINE AND SPECIAL HOUSING UNITS Control Unit Programs § 541.50 Release from a control unit...

28 CFR 541.50 - Release from a control unit.

Code of Federal Regulations, 2014 CFR

2014-07-01

... general population of the institution which has a control unit. [49 FR 32991, Aug. 17, 1984, as amended at... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Release from a control unit. 541.50... INMATE DISCIPLINE AND SPECIAL HOUSING UNITS Control Unit Programs § 541.50 Release from a control unit...

Application of tumbling melt granulation (TMG) method to prepare controlled-release fine granules.

PubMed

Maejima, T; Kubo, M; Osawa, T; Nakajima, K; Kobayashi, M

1998-03-01

The tumbling melt granulation (TMG) method was applied to prepare controlled-release fine granules of diltiazem hydrochloride (DH). The entire process, from the preparation of the cores by the adherence of DH to the sucrose crystal to the subsequent coating of the controlled-release layer, was performed without using any solvent. A mixture of meltable material, talc, and ethylcellulose was used for the controlled-release layer and controlled-release fine granules approximately 400 microns in diameter were obtained with excellent producibility. The dissolution rate of DH from these fine granules was similar to that of a once-a-day dosage form obtained in the market; further, the dependency of the dissolution profile on pH of the media was less. Thus, it was concluded that this TMG method was very useful for preparing not only controlled-release beads of granule size (usually 500 to 1400 microns) but also fine granules.

Bioinspired nanovalves with selective permeability and pH sensitivity

NASA Astrophysics Data System (ADS)

Zheng, Z.; Huang, X.; Schenderlein, M.; Moehwald, H.; Xu, G.-K.; Shchukin, D. G.

2015-01-01

Biological systems with controlled permeability and release functionality, which are among the successful examples of living beings to survive in evolution, have attracted intensive investigation and have been mimicked due to their broad spectrum of applications. We present in this work, for the first time, an example of nuclear pore complexes (NPCs)-inspired controlled release system that exhibits on-demand release of angstrom-sized molecules. We do so in a cost-effective way by stabilizing porous cobalt basic carbonates as nanovalves and realizing pH-sensitive release of entrapped subnano cargo. The proof-of-concept work also consists of the establishment of two mathematical models to explain the selective permeability of the nanovalves. Finally, gram-sized (or larger) quantities of the bio-inspired controlled release system can be synthesized through a scaling-up strategy, which opens up opportunities for controlled release of functional molecules in wider practical applications.Biological systems with controlled permeability and release functionality, which are among the successful examples of living beings to survive in evolution, have attracted intensive investigation and have been mimicked due to their broad spectrum of applications. We present in this work, for the first time, an example of nuclear pore complexes (NPCs)-inspired controlled release system that exhibits on-demand release of angstrom-sized molecules. We do so in a cost-effective way by stabilizing porous cobalt basic carbonates as nanovalves and realizing pH-sensitive release of entrapped subnano cargo. The proof-of-concept work also consists of the establishment of two mathematical models to explain the selective permeability of the nanovalves. Finally, gram-sized (or larger) quantities of the bio-inspired controlled release system can be synthesized through a scaling-up strategy, which opens up opportunities for controlled release of functional molecules in wider practical applications. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06378c

Control-release microcapsule of famotidine loaded biomimetic synthesized mesoporous silica nanoparticles: Controlled release effect and enhanced stomach adhesion in vitro.

PubMed

Li, Jing; Wang, Hongyu; Yang, Baixue; Xu, Lu; Zheng, Nan; Chen, Hongtao; Li, Sanming

2016-01-01

In the present work, control-release microcapsule of famotidine (FMT) loaded biomimetic synthesized mesoporous silica nanoparticles (B-MSNs) was developed, and controlled release effect and stomach adhesion of this formulation in vitro were mainly investigated. B-MSN was previously synthesized and it was amorphous mesoporous nanoparticles with helical channels. Cytotoxicity of B-MSN was studied using human breast cancer cells (MCF-7) and the result indicated that cytotoxicity of B-MSN can be neglected. After loading FMT into B-MSN, specific surface area, pore volume and pore diameter of B-MSN were obviously reduced. In vitro dissolution test showed that B-MSN had the ability to slow down FMT release for 15 min. In order to prolong controlled release effect and remained the advantage of B-MSN (improve drug stability due to its rigid silica framework), the combined application of control-release microcapsule (using cellulose and hydroxypropyl methylcellulose K15M as excipients) with B-MSN was designed. It was obvious that newly designed formulation significantly controlled FMT release with Fickian diffusion mechanism and showed enhanced stomach adhesion in vitro, which has significant value in widening the application of B-MSN in formulation design. Copyright © 2015 Elsevier B.V. All rights reserved.

Development and experimental design of a novel controlled-release matrix tablet formulation for indapamide hemihydrate.

PubMed

Antovska, Packa; Ugarkovic, Sonja; Petruševski, Gjorgji; Stefanova, Bosilka; Manchevska, Blagica; Petkovska, Rumenka; Makreski, Petre

2017-11-01

Development, experimental design and in vitro in vivo correlation (IVIVC) of controlled-release matrix formulation. Development of novel oral controlled delivery system for indapamide hemihydrate, optimization of the formulation by experimental design and evaluation regarding IVIVC on a pilot scale batch as a confirmation of a well-established formulation. In vitro dissolution profiles of controlled-release tablets of indapamide hemihydrate from four different matrices had been evaluated in comparison to the originator's product Natrilix (Servier) as a direction for further development and optimization of a hydroxyethylcellulose-based matrix controlled-release formulation. A central composite factorial design had been applied for the optimization of a chosen controlled-release tablet formulation. The controlled-release tablets with appropriate physical and technological properties had been obtained with a matrix: binder concentration variations in the range: 20-40w/w% for the matrix and 1-3w/w% for the binder. The experimental design had defined the design space for the formulation and was prerequisite for extraction of a particular formulation that would be a subject for transfer on pilot scale and IVIV correlation. The release model of the optimized formulation has shown best fit to the zero order kinetics depicted with the Hixson-Crowell erosion-dependent mechanism of release. Level A correlation was obtained.

Effect of preemptive intra-articular morphine and ketamine on pain after arthroscopic rotator cuff repair: a prospective, double-blind, randomized controlled study.

PubMed

Khashan, M; Dolkart, O; Amar, E; Chechik, O; Sharfman, Z; Mozes, G; Maman, E; Weinbroum, A A

2016-02-01

Rotator cuff tear is a leading etiology of shoulder pain and disability. Surgical treatment is indicated in patients with persistent pain who fail a trial of non-surgical treatment. Pain reduction following rotator cuff repair, particularly within the first 24-48 h, is a major concern to both doctors and patients. This study aimed to compare the postoperative antinociceptive additive effects of pre-incisional intra-articular (IA) ketamine when combined with morphine with two times the dose of morphine or saline. In this prospective, randomized, double blind, controlled trial patients undergoing arthroscopic rotator cuff tear repair (ARCR) under general anesthesia were enrolled. Patients were randomly assigned to one of the three intervention groups. Twenty minutes prior to incision, morphine (20 mg/10 ml), ketamine (50 mg + morphine 10 mg/10 ml), or saline (0.9 % 10 ml) (n = 15/group), were administered to all patients. First 24 h postoperative analgesia consisted of intravenous patient controlled analgesia (IV-PCA) morphine and oral rescue paracetamol 1000 mg or oxycodone 5 mg. 24-h, 2-week and 3-month patient rated pain numeric rating scale (NRS) and analgesics consumption were documented. Patients' demographic and perioperative data were similar among all groups. The 24-h and the 2-week NRSs were significantly (p < 0.05) lower in both treatment groups compared to placebo, but were not significantly different between the two intervention groups. PCA-morphine and oral analgesics were consumed similarly among the groups throughout the study phases. Pre-incisional intra-articular morphine reduced pain in the first 2 weeks after arthroscopic rotator cuff repair. Further research is warranted to elucidate the optimal timing and dosing of IA ketamine and morphine for postoperative analgesic effects.

A history of being prescribed controlled substances and risk of drug overdose death.

PubMed

Paulozzi, Leonard J; Kilbourne, Edwin M; Shah, Nina G; Nolte, Kurt B; Desai, Hema A; Landen, Michael G; Harvey, William; Loring, Larry D

2012-01-01

The abuse of prescription drugs has increased dramatically since 1990. Persons who overdose on such drugs frequently consume large doses and visit multiple providers. The risk of fatal overdose for different patterns of use of opioid analgesics and sedative/hypnotics has not been fully quantified. Matched case-control study. Cases were 300 persons who died of unintentional drug overdoses in New Mexico during 2006-2008, and controls were 5,993 patients identified through the state prescription monitoring program with matching 6-month exposure periods. Death from drug overdose or death from opioid overdose. Exposures were demographic variables and characteristics of prescription history. Crude and adjusted odds ratios (AOR) were calculated. Increased risk was associated with male sex (AOR 2.4, 95% confidence interval [CI] 1.8-3.1), one or more sedative/hypnotic prescriptions (AOR 3.0, CI 2.2-4.2), greater age (AOR 1.3, CI 1.2-1.4 for each 10-year increment), number of prescriptions (AOR 1.1, CI 1.1-1.1 for each additional prescription), and a prescription for buprenorphine (AOR 9.5, CI 3.0-30.0), fentanyl (AOR 3.5, CI 1.7-7.0), hydromorphone (AOR 3.3, CI 1.4-7.5), methadone (AOR 4.9, CI 2.5-9.6), or oxycodone (AOR 1.9, CI 1.4-2.6). Patients receiving a daily average of >40 morphine milligram equivalents had an OR of 12.2 (CI 9.2-16.0). Patients being prescribed opioid analgesics frequently or at high dosage face a substantial overdose risk. Prescription monitoring programs might be the best way for prescribers to know their patients' prescription histories and accurately assess overdose risk. Wiley Periodicals, Inc.

Controlled release of folic acid through liquid-crystalline folate nanoparticles.

PubMed

Misra, Rahul; Katyal, Henna; Mohanty, Sanat

2014-11-01

The present study explores folate nanoparticles as nano-carriers for controlled drug delivery. Cross-linked nanoparticles of liquid crystalline folates are composed of ordered stacks. This paper shows that the folate nanoparticles can be made with less than 5% loss in folate ions. In addition, this study shows that folate nanoparticles can disintegrate in a controlled fashion resulting in controlled release of the folate ions. Release can be controlled by the size of nanoparticles, the extent of cross-linking and the choice of cross-linking cation. The effect of different factors like agitation, pH, and temperature on folate release was also studied. Studies were also carried out to show the effect of release medium and role of ions in the release medium on disruption of folate assembly. Copyright © 2014. Published by Elsevier B.V.

[Studies on preparation of sustained-release Shuxiong formulation, a traditional Chinese medicine compound recipe, using time-controlled release techniques].

PubMed

Song, Hong-Tao; Zhang, Qian; Jiang, Peng; Guo, Tao; Chen, Da-Wei; He, Zhong-Gui

2006-09-01

To prepare a sustained-release formulation of traditional Chinese medicine compound recipe by adopting time-controlled release techniques. Shuxiong tablets were chosen as model drug. The prescription and technique of core tablets were formulated with selecting disintegrating time and swelling volume of core tablets in water as index. The time-controlled release tablets were prepared by adopting press-coated techniques, using PEG6000, HCO and EVA as coating materials. The influences of compositions, preparation process and dissolution conditions in vitro on the lag time (T(lag)) of drug release were investigated. The composition of core tablets was as follow: 30% of drug, 50% MCC and 20% CMS-Na. The T(lag) of time-controlled release tablets was altered remarkably by PEG6000 content of the outer layer, the amount of outer layer and hardness of tablet. The viscosity of dissolution media and basket rotation had less influence on the T(lag) but more on rate of drug release. The core tablets pressed with the optimized composition had preferable swelling and disintegrating properties. The shuxiong sustained-release formulations which contained core tablet and two kinds of time-controlled release tablets with 3 h and 6 h of T(lag) could release drug successively at 0 h, 3 h and 6 h in vitro. The technique made it possible that various components with extremely different physicochemical properties in these preparations could release synchronously.

Chemical release module facility

NASA Technical Reports Server (NTRS)

Reasoner, D. L.

1980-01-01

The chemical release module provides the capability to conduct: (1) thermite based metal vapor releases; (2) pressurized gas releases; (3) dispersed liquid releases; (4) shaped charge releases from ejected submodules; and (5) diagnostic measurements with pi supplied instruments. It also provides a basic R-F and electrical system for: (1) receiving and executing commands; (2) telemetering housekeeping data; (3) tracking; (4) monitoring housekeeping and control units; and (5) ultrasafe disarming and control monitoring.

Investigation of the effect of tablet surface area/volume on drug release from hydroxypropylmethylcellulose controlled-release matrix tablets.

PubMed

Reynolds, Thomas D; Mitchell, Shawn A; Balwinski, Karen M

2002-04-01

The purpose of this study was to investigate the influence of tablet surface area/volume (SA/Vol) on drug release from controlled-release matrix tablets containing hydroxypropylmethylcellulose (HPMC). Soluble drugs (promethazine HCl, diphenhydramine HCl, and propranolol HCl) were utilized in this study to give predominantly diffusion-controlled release. Drug release from HPMC matrix tablets with similar values of SA/Vol was comparable within the same tablet shape (i.e., flat-faced round tablets) and among different shapes (i.e., oval, round concave, flat-faced beveled-edge, and flat-faced round tablets). Tablets having the same surface area but different SA/Vol values did not result in similar drug release; tablets with larger SA/Vol values hadfaster release profiles. Utility of SA/Vol to affect drug release was demonstrated by changing drug doses, and altering tablet shape to adjust SA/Vol. When SA/Vol was held constant, similar release profiles were obtained with f2 metric values greater than 70. Thus, surface area/volume is one of the key variables in controlling drug release from HPMC matrix tablets. Proper use of this variable has practical application by formulators who may need to duplicate drug release profiles from tablets of different sizes and different shapes.

Limited mobility of target pests crucially lowers controllability when sterile insect releases are spatiotemporally biased.

PubMed

Ikegawa, Yusuke; Himuro, Chihiro

2017-05-21

The sterile insect technique (SIT) is a genetic pest control method wherein mass-reared sterile insects are periodically released into the wild, thereby impeding the successful reproduction of fertile pests. In Okinawa Prefecture, Japan, the SIT has been implemented to eradicate the West Indian sweet potato weevil Euscepes postfasciatus (Fairmaire), which is a flightless agricultural pest of sweet potatoes. It is known that E. postfasciatus is much less mobile than other insects to which the SIT has been applied. However, previous theoretical studies have rarely examined effects of low mobility of target pests and variation in the spatiotemporal evenness of sterile insect releases. To theoretically examine the effects of spatiotemporal evenness on the regional eradication of less mobile pests, we constructed a simple two-patch population model comprised of a pest and sterile insect moving between two habitats, and numerically simulated different release strategies (varying the number of released sterile insects and release intervals). We found that spatially biased releases allowed the pest to spatially escape from the sterile insect, and thus intensively lowered its controllability. However, we showed that the temporally counterbalancing spatially biased releases by swapping the number of released insects in the two habitats at every release (called temporal balancing) could greatly mitigate this negative effect and promote the controllability. We also showed that the negative effect of spatiotemporally biased releases was a result of the limited mobility of the target insect. Although directed dispersal of the insects in response to habitats of differing quality could lower the controllability in the more productive habitat, the temporal balancing could promote and eventually maximize the controllability as released insects increased. Copyright © 2017 Elsevier Ltd. All rights reserved.

Materials for pharmaceutical dosage forms: molecular pharmaceutics and controlled release drug delivery aspects.

PubMed

Mansour, Heidi M; Sohn, Minji; Al-Ghananeem, Abeer; Deluca, Patrick P

2010-09-15

Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development.

Materials for Pharmaceutical Dosage Forms: Molecular Pharmaceutics and Controlled Release Drug Delivery Aspects

PubMed Central

Mansour, Heidi M.; Sohn, MinJi; Al-Ghananeem, Abeer; DeLuca, Patrick P.

2010-01-01

Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development. PMID:20957095

Release of betaine and dexpanthenol from vitamin E modified silicone-hydrogel contact lenses.

PubMed

Hsu, Kuan-Hui; de la Jara, Percy Lazon; Ariyavidana, Amali; Watling, Jason; Holden, Brien; Garrett, Qian; Chauhan, Anuj

2015-03-01

To develop a contact lens system that will control the release of an osmoprotectant and a moisturizing agent with the aim to reduce symptoms of ocular dryness. Profiles of the release of osmoprotectant betaine and moisturizing agent dexpanthenol from senofilcon A and narafilcon B contact lenses were determined in vitro under sink conditions. Both types of lenses were also infused with vitamin E to increase the duration of drug release due to the formation of the vitamin E diffusion barriers in the lenses. The release profiles from vitamin E-infused lenses were compared with those from the control lenses. Both dexpanthenol and betaine are released from commercial silicone hydrogel lenses for only about 10 min. Vitamin E loadings into contact lenses at about 20-23% can increase the release times to about 10 h, which is about 60 times larger compared to the control unmodified lenses. Vitamin E-loaded silicone hydrogel contact lenses released betaine and dexpanthenol in a controlled fashion.

Effect of Nisin's Controlled Release on Microbial Growth as Modeled for Micrococcus luteus.

PubMed

Balasubramanian, Aishwarya; Lee, Dong Sun; Chikindas, Michael L; Yam, Kit L

2011-06-01

The need for safe food products has motivated food scientists and industry to find novel technologies for antimicrobial delivery for improving food safety and quality. Controlled release packaging is a novel technology that uses the package to deliver antimicrobials in a controlled manner and sustain antimicrobial stress on the targeted microorganism over the required shelf life. This work studied the effect of controlled release of nisin to inhibit growth of Micrococcus luteus (a model microorganism) using a computerized syringe pump system to mimic the release of nisin from packaging films which was characterized by an initially fast rate and a slower rate as time progressed. The results show that controlled release of nisin was strikingly more effective than instantly added ("formulated") nisin. While instant addition experiments achieved microbial inhibition only at the beginning, controlled release experiments achieved complete microbial inhibition for a longer time, even when as little as 15% of the amount of nisin was used as compared to instant addition.

Photoresponsive lipid-polymer hybrid nanoparticles for controlled doxorubicin release

NASA Astrophysics Data System (ADS)

Yao, Cuiping; Wu, Ming; Zhang, Cecheng; Lin, Xinyi; Wei, Zuwu; Zheng, Youshi; Zhang, Da; Zhang, Zhenxi; Liu, Xiaolong

2017-06-01

Currently, photoresponsive nanomaterials are particularly attractive due to their spatial and temporal controlled drug release abilities. In this work, we report a photoresponsive lipid-polymer hybrid nanoparticle for remote controlled delivery of anticancer drugs. This hybrid nanoparticle comprises three distinct functional components: (i) a poly(D,L-lactide-co-glycolide) (PLGA) core to encapsulate doxorubicin; (ii) a soybean lecithin monolayer at the interface of the core and shell to act as a molecular fence to prevent drug leakage; (iii) a photoresponsive polymeric shell with anti-biofouling properties to enhance nanoparticle stability, which could be detached from the nanoparticle to trigger the drug release via a decrease in the nanoparticle’s stability under light irradiation. In vitro results revealed that this core-shell nanoparticle had excellent light-controlled drug release behavior (76% release with light irradiation versus 10% release without light irradiation). The confocal microscopy and flow cytometry results also further demonstrated the light-controlled drug release behavior inside the cancer cells. Furthermore, a CCK8 assay demonstrated that light irradiation could significantly improve the efficiency of killing cancer cells. Meanwhile, whole-animal fluorescence imaging of a tumor-bearing mouse also confirmed that light irradiation could trigger drug release in vivo. Taken together, our data suggested that a hybrid nanoparticle could be a novel light controlled drug delivery system for cancer therapy.

14-Amino-4,5-Epoxymorphinan Derivatives and Their Pharmacological Actions

NASA Astrophysics Data System (ADS)

Lewis, John W.; Husbands, Stephen M.

14-Hydroxy-7,8-dihydromorphinone (oxymorphone) and its derivatives (oxycodone, naloxone, naltrexone) have become among the most important clinical agents to have been produced from opium. 14-Aminocodeinone and its 7,8-dihydro and morphinone derivatives are of more recent origin thanks to the work of Professor Gordon Kirby and his collaborators. The 14-amino parent compounds have proved of limited interest but their 14-acylamino- and 14-alkylamino derivatives have been extensively studied. The 4'-substituted cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronormorphinones, C-CAM and M-CAM are the best available selective MOR irreversible antagonists and the related dihydrocodeinone MC-CAM, 4'-chlorocinnamoylamino-17-cyclopropylmethyl-7,8-dihydronorcodeinone, is a long-acting MOR partial agonist with extended MOR-pseudoirreversible antagonist activity that could be a candidate for pharmacotherapy of opiate abuse/dependence.

Dual-opioid therapy: changing the paradigm. Introduction.

PubMed

Nicholson, Bruce D

2012-03-01

Morphine sulfate and oxycodone hydrochloride are commonly used for pain management because of their pharmacologic profile, pharmacokinetics, and analgesic potency. However, opioids are associated with a significant adverse event (AE) burden that limits their use in both the acute and the chronic pain settings. Co-administration of opioids demonstrated synergistic analgesia and reduced side effects. Thus, dual-opioid therapy has the potential to enhance the positive analgesic benefits of opioids, while limiting the burden of opioid-related AEs. This symposium proceedings was based on presentations at the 13th World Congress on Pain in August 2010. This program will review the rationale for dual-opioid therapy based on preclinical findings and data from clinical studies showing the efficacy and tolerability profile of a dual-opioid formulation when used to treat acute postoperative pain. Wiley Periodicals, Inc.

Bioavailability and in vivo release behavior of controlled-release multiple-unit theophylline dosage forms in beagle dogs, cynomolgus monkeys, and göttingen minipigs.

PubMed

Ikegami, Kengo; Tagawa, Kozo; Osawa, Takashi

2006-09-01

To determine the usefulness of monkey as an animal model, bioavailability and in vivo release behaviors of theophylline (TP) after oral administration of controlled-release beads in dogs, monkeys, and minipigs were evaluated. Controlled-release beads were prepared using a centrifugal-fluid type granulator, that is, CF-granulator, and Ethylcellulose (EC) was used as controlled-release coating agent. Aqueous solution and EC-coated beads, which contained TP were orally administered to animals after at least 1-week intervals. In dogs and minipigs, their relative bioavailabilities of EC-coated beads were 33.1% and 47.0%, respectively, and in vivo TP release from EC-coated beads in the gastrointestinal tract of dogs and minipigs were not reflected in vitro data. In monkeys, relative bioavailability of EC-coated beads was 80.0% and the highest among the three species, and release amount of TP from EC-coated beads at 24 h after oral administration was 82.8% and 92.4%, which was almost correlated to in vitro data. Therefore, the discrepancy of the relative bioavailability in three species is considered to be due to the difference of in vivo release behavior of TP. The monkey may be useful animal model for bioavailability studies of controlled-release dosage forms of TP from the viewpoint of in vitro-in vivo release correlation. (c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association.

Controlled release of glaucocalyxin - a self-nanoemulsifying system from osmotic pump tablets with enhanced bioavailability.

PubMed

Yanfei, Miao; Guoguang, Chen; Lili, Ren; Pingkai, Ouyang

2017-03-01

The purpose of this study was to develop a new formulation to enhance the bioavailability simultaneously with controlled release of glaucocalyxin A (GLA). In this study, controlled release of GLA was achieved by the osmotic release strategy taking advantage of the bioavailability enhancing capacity of self-nanoemulsifying drug delivery systems (SNEDDS). The formulation of GLA-SNEDDS was selected by the solubility and pseudoternary-phase diagrams studies. The prepared GLA-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis and zeta potential. The optimized GLA-SNEDDS were used to prepare GLA-SNEDDS osmotic pump tablet via direct powder compression method. The effect of formulation variables on the release characteristic was investigated. GLA-SNEDDS osmotic pump tablets were administered to beagle dogs and their pharmacokinetics were compared to GLA and GLA-SNEDDS as a control. In vitro drug release studies indicated that the GLA-SNEDDS osmotic pump tablet showed sustained release profiles with 90% released within 12 h. Pharmacokinetic study showed steady blood GLA with prolonged T max and mean residence time (MRT), and enhanced bioavailability for GLA-SNEDDS osmotic pump tablet. It was concluded that simultaneous controlling on GLA release and enhanced bioavailability had been achieved by a combination of osmotic pump tablet and SNEDDS.

21 CFR 1312.29 - Domestic release prohibited.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Domestic release prohibited. 1312.29 Section 1312... OF CONTROLLED SUBSTANCES Exportation of Controlled Substances § 1312.29 Domestic release prohibited. An exporter or a forwarding agent acting for an exporter must either deliver the controlled...

Use of a Fish Transportation Barge for Increasing Returns of Steelhead Imprinted for Homing, Final Report.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harmon, Jerrel R.

1989-08-01

The objective of this 7-year National Fisheries Service study, which began is 1982, was to determine if transporting juvenile steelhead (Oncorhynchus mykiss) by truck and barge from Dworshak National Fish Hatchery (NFH), on the Clearwater River, to a release site on the Columbia River below Bonneville Dam would result in increased returns of adults to the various fisheries and to the hatchery homing site. During 1982 and 1983, over 500,000 marked juvenile steelhead were serially released as controls from the hatchery or barged as test fish to below Bonneville Dam. Recoveries of marked adults to various recovery sites are complete.more » Fish released in 1983 showed a stronger homing ability and more rapid upstream migration than test fish released in 1982. Most adults from both control and test releases in 1983 and control releases in 1982 migrated a considerable distance upstream and overwintered in the Snake and Clearwater Rivers--behavior similar to Clearwater River fish previously transported from Lower Granite Dam. In contrast, many of the adults from test releases in 1982 failed to migrate upstream during the fall, overwintered in the Columbia River, and migrated upstream the following spring. Survival of control fish released at Dworshak NFH in late April 1982 was substantially higher than survival of those released in mid-May. Survival and homing of control fish released in late April and early May 1983 were over 10 times that for fish released in late May. Return of adults from normal hatchery releases in 1982 was the highest ever observed at Dworshak NFH.« less

A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents.

PubMed

O'Neill, Hugh S; Herron, Caroline C; Hastings, Conn L; Deckers, Roel; Lopez Noriega, Adolfo; Kelly, Helena M; Hennink, Wim E; McDonnell, Ciarán O; O'Brien, Fergal J; Ruiz-Hernández, Eduardo; Duffy, Garry P

2017-01-15

Lysolipid-based thermosensitive liposomes (LTSL) embedded in a chitosan-based thermoresponsive hydrogel matrix (denoted Lipogel) represents a novel approach for the spatiotemporal release of therapeutic agents. The entrapment of drug-loaded liposomes in an injectable hydrogel permits local liposome retention, thus providing a prolonged release in target tissues. Moreover, release can be controlled through the use of a minimally invasive external hyperthermic stimulus. Temporal control of release is particularly important for complex multi-step physiological processes, such as angiogenesis, in which different signals are required at different times in order to produce a robust vasculature. In the present work, we demonstrate the ability of Lipogel to provide a flexible, easily modifiable release platform. It is possible to tune the release kinetics of different drugs providing a passive release of one therapeutic agent loaded within the gel and activating the release of a second LTSL encapsulated agent via a hyperthermic stimulus. In addition, it was possible to modify the drug dosage within Lipogel by varying the duration of hyperthermia. This can allow for adaption of drug dosing in real time. As an in vitro proof of concept with this system, we investigated Lipogels ability to recruit stem cells and then elevate their production of vascular endothelial growth factor (VEGF) by controlling the release of a pro-angiogenic drug, desferroxamine (DFO) with an external hyperthermic stimulus. Initial cell recruitment was accomplished by the passive release of hepatocyte growth factor (HGF) from the hydrogel, inducing a migratory response in cells, followed by the delayed release of DFO from thermosensitive liposomes, resulting in a significant increase in VEGF expression. This delayed release could be controlled up to 14days. Moreover, by changing the duration of the hyperthermic pulse, a fine control over the amount of DFO released was achieved. The ability to trigger the release of therapeutic agents at a specific timepoint and control dosing level through changes in duration of hyperthermia enables sequential multi-dose profiles. This paper details the development of a heat responsive liposome loaded hydrogel for the controlled release of pro-angiogenic therapeutics. Lysolipid-based thermosensitive liposomes (LTSLs) embedded in a chitosan-based thermoresponsive hydrogel matrix represents a novel approach for the spatiotemporal release of therapeutic agents. This hydrogel platform demonstrates remarkable flexibility in terms of drug scheduling and sequencing, enabling the release of multiple agents and the ability to control drug dosing in a minimally invasive fashion. The possibility to tune the release kinetics of different drugs independently represents an innovative platform to utilise for a variety of treatments. This approach allows a significant degree of flexibility in achieving a desired release profile via a minimally invasive stimulus, enabling treatments to be tuned in response to changing symptoms and complications. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Simulated food effects on drug release from ethylcellulose: PVA-PEG graft copolymer-coated pellets.

PubMed

Muschert, Susanne; Siepmann, Florence; Leclercq, Bruno; Carlin, Brian; Siepmann, Juergen

2010-02-01

Food effects might substantially alter drug release from oral controlled release dosage forms in vivo. The robustness of a novel type of controlled release film coating was investigated using various types of release media and two types of release apparatii. Importantly, none of the investigated conditions had a noteworthy impact on the release of freely water-soluble diltiazem HCl or slightly water-soluble theophylline from pellets coated with ethylcellulose containing small amounts of PVA-PEG graft copolymer. In particular, the presence of significant amounts of fats, carbohydrates, surfactants, bile salts, and calcium ions in the release medium did not alter drug release. Furthermore, changes in the pH and differences in the mechanical stress the dosage forms were exposed to did not affect drug release from the pellets. The investigated film coatings allowing for oral controlled drug delivery are highly robust in vitro and likely to be poorly sensitive to classical food effects in vivo.

Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations.

PubMed

Gesquiere, Ina; Darwich, Adam S; Van der Schueren, Bart; de Hoon, Jan; Lannoo, Matthias; Matthys, Christophe; Rostami, Amin; Foulon, Veerle; Augustijns, Patrick

2015-11-01

The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB. A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6-8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB. After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC(0-24 h)) was shown, although a tendency towards an increased oral exposure could be observed as the AUC(0-24 h) was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity. The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation. © 2015 The British Pharmacological Society.

Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations

PubMed Central

Gesquiere, Ina; Darwich, Adam S; Van der Schueren, Bart; de Hoon, Jan; Lannoo, Matthias; Matthys, Christophe; Rostami, Amin; Foulon, Veerle; Augustijns, Patrick

2015-01-01

Aims The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB. Methods A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6–8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB. Results After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC0–24 h) was shown, although a tendency towards an increased oral exposure could be observed as the AUC0–24 h was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity. Conclusions The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation. PMID:25917170

The sustaining effect of three polymers on the release of chlorhexidine from a controlled release drug device for root canal disinfection.

PubMed

Lee, Doug-Youn; Spångberg, Larz S W; Bok, Young-Bin; Lee, Chang-Young; Kum, Kee-Yeon

2005-07-01

The aim of this in vitro study was to evaluate the suitability of using chitosan, poly (lactide-co-glycolide) (PLGA), and polymethyl methacrylate (PMMA) to control the release of chlorhexidine digluconate (CHX) from a prototype of controlled release drug device for root canal disinfection. Four different prototypes with different formulations were prepared. Group A (n = 12): the device (absorbent paper point) was loaded with CHX as control. Group B (n = 12): same as group A, but the device was coated with chitosan (Texan MedTech). In Groups C and D, the device was treated in the same way as group A and then coated 3 times with 5% PMMA (Group C, n = 12, Aldrich), or coated 3 times with 3% PLGA (Group D, n = 12, Sigma). The devices were randomly allocated to experimental groups of 12 each. All the prototypes of controlled release drug device were soaked in 3 mL distilled water. The concentrations of CHX were determined using a UV spectrophotometer. The surface characteristics of each prototype were observed using a scanning electron microscope. The result showed that release rate of CHX was the greatest in the noncoated group, followed by the chitosan-coated group, the PLGA-coated group, and the PMMA-coated group (P < 0.05). Pores were observed on the surface of the prototypes that were coated with PLGA and PMMA. When the pore size was smaller, the release rate was lower. These data indicate that polymer coating can control the release rate of CHX from the prototypes of controlled release drug device.

Modulation of the release of ( sup 3 H)norepinephrine from the base and body of the rat urinary bladder by endogenous adrenergic and cholinergic mechanisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Somogyi, G.T.; de Groat, W.C.

Modulation of (3H)NE release was studied in rat urinary bladder strips prelabeled with (3H)NE. (3H)NE uptake occurred in strips from the bladder base and body, but was very prominent in the base where the noradrenergic innervation is most dense. Electrical field stimulation markedly increased (3H)NE outflow from the superfused tissue. The quantity of (3H)NE release was approximately equal during three consecutive periods of stimulation. Activation of presynaptic muscarinic receptors by 1.0 microM oxotremorine reduced (3H)NE release to 46% of the control. Atropine (1 microM) blocked the effect of oxotremorine and increased the release to 147% of predrug control levels. Activationmore » of presynaptic alpha-2 adrenoceptors by 1 microM clonidine reduced (3H)NE release to 55% of control. Yohimbine blocked the action of clonidine and increased the release to 148% of control. The release of (3H)NE from the bladder base and body was increased by both 1 microM atropine (to 167% and 174% of control, respectively) and 1 microM yohimbine (to 286% and 425% of control, respectively). Atropine and yohimbine administered in combination had similar facilitatory effects as when administered alone. We conclude that the release of (3H)NE from adrenergic nerve endings in electrically stimulated bladder strips is modulated via endogenous transmitters acting on both muscarinic and alpha-2 adrenergic presynaptic receptors and that the latter provide the most prominent control.« less

49 CFR 236.506 - Release of brakes after automatic application.

Code of Federal Regulations, 2010 CFR

2010-10-01

... INSTALLATION, INSPECTION, MAINTENANCE, AND REPAIR OF SIGNAL AND TRAIN CONTROL SYSTEMS, DEVICES, AND APPLIANCES Automatic Train Stop, Train Control and Cab Signal Systems Standards § 236.506 Release of brakes after automatic application. The automatic train stop or train control apparatus shall prevent release of the...

49 CFR 236.506 - Release of brakes after automatic application.

Code of Federal Regulations, 2011 CFR

2011-10-01

... INSTALLATION, INSPECTION, MAINTENANCE, AND REPAIR OF SIGNAL AND TRAIN CONTROL SYSTEMS, DEVICES, AND APPLIANCES Automatic Train Stop, Train Control and Cab Signal Systems Standards § 236.506 Release of brakes after automatic application. The automatic train stop or train control apparatus shall prevent release of the...

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.

Opioid Prescription, Morbidity, and Mortality in United States Dialysis Patients.

PubMed

Kimmel, Paul L; Fwu, Chyng-Wen; Abbott, Kevin C; Eggers, Anne W; Kline, Prudence P; Eggers, Paul W

2017-12-01

Aggressive pain treatment was advocated for ESRD patients, but new Centers for Disease Control and Prevention guidelines recommend cautious opioid prescription. Little is known regarding outcomes associated with ESRD opioid prescription. We assessed opioid prescriptions and associations between opioid prescription and dose and patient outcomes using 2006-2010 US Renal Data System information in patients on maintenance dialysis with Medicare Part A, B, and D coverage in each study year ( n =671,281, of whom 271,285 were unique patients). Opioid prescription was confirmed from Part D prescription claims. In the 2010 prevalent cohort ( n =153,758), we examined associations of opioid prescription with subsequent all-cause death, dialysis discontinuation, and hospitalization controlled for demographics, comorbidity, modality, and residence. Overall, >60% of dialysis patients had at least one opioid prescription every year. Approximately 20% of patients had a chronic (≥90-day supply) opioid prescription each year, in 2010 usually for hydrocodone, oxycodone, or tramadol. In the 2010 cohort, compared with patients without an opioid prescription, patients with short-term (1-89 days) and chronic opioid prescriptions had increased mortality, dialysis discontinuation, and hospitalization. All opioid drugs associated with mortality; most associated with worsened morbidity. Higher opioid doses correlated with death in a monotonically increasing fashion. We conclude that opioid drug prescription is associated with increased risk of death, dialysis discontinuation, and hospitalization in dialysis patients. Causal relationships cannot be inferred, and opioid prescription may be an illness marker. Efforts to treat pain effectively in patients on dialysis yet decrease opioid prescriptions and dose deserve consideration. Copyright © 2017 by the American Society of Nephrology.

Double loaded self-decomposable SiO2 nanoparticles for sustained drug release

NASA Astrophysics Data System (ADS)

Zhao, Saisai; Zhang, Silu; Ma, Jiang; Fan, Li; Yin, Chun; Lin, Ge; Li, Quan

2015-10-01

Sustained drug release for a long duration is a desired feature of modern drugs. Using double-loaded self-decomposable SiO2 nanoparticles, we demonstrated sustained drug release in a controllable manner. The double loading of the drugs was achieved using two different mechanisms--the first one via a co-growth mechanism, and the second one by absorption. A two-phase sustained drug release was firstly revealed in an in vitro system, and then further demonstrated in mice. After a single intravenous injection, the drug was controllably released from the nanoparticles into blood circulation with a Tmax of about 8 h, afterwards a long lasting release pattern was achieved to maintain drug systemic exposure with a plasma elimination half-life of approximately 28 h. We disclosed that the absorbed drug molecules contributed to the initial fast release for quickly reaching the therapeutic level with relatively higher plasma concentrations, while the ``grown-in'' drugs were responsible for maintaining the therapeutic level via the later controlled slow and sustained release. The present nanoparticle carrier drug configuration and the loading/maintenance release mechanisms provide a promising platform that ensures a prolonged therapeutic effect by controlling drug concentrations within the therapeutic window--a sustained drug delivery system with a great impact on improving the management of chronic diseases.Sustained drug release for a long duration is a desired feature of modern drugs. Using double-loaded self-decomposable SiO2 nanoparticles, we demonstrated sustained drug release in a controllable manner. The double loading of the drugs was achieved using two different mechanisms--the first one via a co-growth mechanism, and the second one by absorption. A two-phase sustained drug release was firstly revealed in an in vitro system, and then further demonstrated in mice. After a single intravenous injection, the drug was controllably released from the nanoparticles into blood circulation with a Tmax of about 8 h, afterwards a long lasting release pattern was achieved to maintain drug systemic exposure with a plasma elimination half-life of approximately 28 h. We disclosed that the absorbed drug molecules contributed to the initial fast release for quickly reaching the therapeutic level with relatively higher plasma concentrations, while the ``grown-in'' drugs were responsible for maintaining the therapeutic level via the later controlled slow and sustained release. The present nanoparticle carrier drug configuration and the loading/maintenance release mechanisms provide a promising platform that ensures a prolonged therapeutic effect by controlling drug concentrations within the therapeutic window--a sustained drug delivery system with a great impact on improving the management of chronic diseases. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr03029c

Fabrication, Characterization, and Biological Activity of Avermectin Nano-delivery Systems with Different Particle Sizes

NASA Astrophysics Data System (ADS)

Wang, Anqi; Wang, Yan; Sun, Changjiao; Wang, Chunxin; Cui, Bo; Zhao, Xiang; Zeng, Zhanghua; Yao, Junwei; Yang, Dongsheng; Liu, Guoqiang; Cui, Haixin

2018-01-01

Nano-delivery systems for the active ingredients of pesticides can improve the utilization rates of pesticides and prolong their control effects. This is due to the nanocarrier envelope and controlled release function. However, particles containing active ingredients in controlled release pesticide formulations are generally large and have wide size distributions. There have been limited studies about the effect of particle size on the controlled release properties and biological activities of pesticide delivery systems. In the current study, avermectin (Av) nano-delivery systems were constructed with different particle sizes and their performances were evaluated. The Av release rate in the nano-delivery system could be effectively controlled by changing the particle size. The biological activity increased with decreasing particle size. These results suggest that Av nano-delivery systems can significantly improve the controllable release, photostability, and biological activity, which will improve efficiency and reduce pesticide residues.

Clinical translation of controlled protein delivery systems for tissue engineering.

PubMed

Spiller, Kara L; Vunjak-Novakovic, Gordana

2015-04-01

Strategies that utilize controlled release of drugs and proteins for tissue engineering have enormous potential to regenerate damaged organs and tissues. The multiple advantages of controlled release strategies merit overcoming the significant challenges to translation, including high costs and long, difficult regulatory pathways. This review highlights the potential of controlled release of proteins for tissue engineering and regenerative medicine. We specifically discuss treatment modalities that have reached preclinical and clinical trials, with emphasis on controlled release systems for bone tissue engineering, the most advanced application with several products already in clinic. Possible strategies to address translational and regulatory concerns are also discussed.

Clinical translation of controlled protein delivery systems for tissue engineering

PubMed Central

Spiller, Kara L.; Vunjak-Novakovic, Gordana

2013-01-01

Strategies that utilize controlled release of drugs and proteins for tissue engineering have enormous potential to regenerate damaged organs and tissues. The multiple advantages of controlled release strategies merit overcoming the significant challenges to translation, including high costs and long, difficult regulatory pathways. This review highlights the potential of controlled release of proteins for tissue engineering and regenerative medicine. We specifically discuss treatment modalities that have reached preclinical and clinical trials, with emphasis on controlled release systems for bone tissue engineering, the most advanced application with several products already in clinic. Possible strategies to address translational and regulatory concerns are also discussed. PMID:25787736

Inocluative release of an exotic predator for the biological control of the black turpentine beetle

Treesearch

John C. Moser

1989-01-01

An inoculative release of the Eurasian predatorial beetle, Rhizophagus grandis, was made for control of the black turpentine beetle, Dendroctonus terebrans Olivier, a prominent native pest of southern pines. If this central Louisiana release proves successful, and rearing programs are prefectied, further releases should expand the...

Use of natural and biobased materials for controlled-release of urea in water: Environmental applications

USDA-ARS?s Scientific Manuscript database

Urea pearls were encapsulated in cloisite-based matrices using different natural materials (lignin, beeswax and latex) to control the release of urea over time. It was found that all cloisite-based fertilizer tablets showed better release profiles than neat urea tablets. The best release profile was...

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.

Enzyme-triggered compound release using functionalized antimicrobial peptide derivatives† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c6sc04435b Click here for additional data file.

PubMed Central

Kashibe, Masayoshi; Matsumoto, Kengo; Hori, Yuichiro

2017-01-01

Controlled release is one of the key technologies for medical innovation, and many stimulus-responsive nanocarriers have been developed to utilize this technology. Enzyme activity is one of the most useful stimuli, because many enzymes are specifically activated in diseased tissues. However, controlled release stimulated by enzyme activity has not been frequently reported. One of the reasons for this is the lack of versatility of carriers. Most of the reported stimulus-responsive systems involve a sophisticated design and a complicated process for the synthesis of stimulus-responsive nanocarrier components. The purpose of this study was to develop versatile controlled release systems triggered by various stimuli, including enzyme activity, without modifying the nanocarrier components. We developed two controlled release systems, both of which comprised a liposome as the nanocarrier and a membrane-damaging peptide, temporin L (TL), and its derivatives as the release-controllers. One system utilized branched peptides for proteases, and the other utilized phosphopeptides for phosphatases. In our systems, the target enzymes converted the non-membrane-damaging TL derivatives into membrane-damaging peptides and released the liposome inclusion. We demonstrated the use of our antimicrobial peptide-based controlled release systems for different enzymes and showed the promise of this technology as a novel theranostic tool. PMID:28451373

Wax-based sustained release matrix pellets prepared by a novel freeze pelletization technique II. In vitro drug release studies and release mechanisms.

PubMed

Cheboyina, Sreekhar; Wyandt, Christy M

2008-07-09

A novel freeze pelletization technique was evaluated for the preparation of wax-based sustained release matrix pellets. Pellets containing water-soluble drugs were successfully prepared using a variety of waxes. The drug release significantly depended on the wax type used and the aqueous drug solubility. The drug release decreased as the hydrophobicity of wax increased and the drug release increased as the aqueous drug solubility increased. In glyceryl monostearate (GMS) pellets, drug release rate decreased as the loading of theophylline increased. On the contrary, the release rate increased as the drug loading of diltiazem HCl increased in Precirol pellets. Theophylline at low drug loads existed in a dissolved state in GMS pellets and the release followed desorption kinetics. At higher loads, theophylline existed in a crystalline state and the release followed dissolution-controlled constant release for all the waxes studied. However, with the addition of increasing amounts of Brij 76, theophylline release rate increased and the release mechanism shifted to diffusion-controlled square root time kinetics. But the release of diltiazem HCl from Precirol pellets at all drug loads, followed diffusion-controlled square root time kinetics. Therefore, pellets capable of providing a variety of release profiles for different drugs can be prepared using this freeze pelletization technique by suitably modifying the pellet forming matrix compositions.

Controlled release of insect sex pheromones from paraffin wax and emulsions.

PubMed

Atterholt, C A; Delwiche, M J; Rice, R E; Krochta, J M

1999-02-22

Paraffin wax and aqueous paraffin emulsions can be used as controlled release carriers for insect sex pheromones for mating disruption of orchard pests. Paraffin can be applied at ambient temperature as an aqueous emulsion, adheres to tree bark or foliage, releases pheromone for an extended period of time, and will slowly erode from bark and biodegrade in soil. Pheromone emulsions can be applied with simple spray equipment. Pheromone release-rates from paraffin were measured in laboratory flow-cell experiments. Pheromone was trapped from an air stream with an adsorbent, eluted periodically, and quantified by gas chromatography. Pheromone release from paraffin was partition-controlled, providing a constant (zero-order) release rate. A typical paraffin emulsion consisted of 30% paraffin, 4% pheromone, 4% soy oil, 1% vitamin E, 2% emulsifier, and the balance water. Soy oil and vitamin E acted as volatility suppressants. A constant release of oriental fruit moth pheromone from paraffin emulsions was observed in the laboratory for more than 100 days at 27 degreesC, with release-rates ranging from 0.4 to 2 mg/day, depending on the concentration and surface area of the dried emulsion. The use of paraffin emulsions is a viable method for direct application of insect pheromones for mating disruption. Sprayable formulations can be designed to release insect pheromones to the environment at a rate necessary for insect control by mating disruption. At temperatures below 38 degreesC, zero-order release was observed. At 38 degreesC and higher, pheromone oxidation occurred. A partition-controlled release mechanism was supported by a zero-order pheromone release-rate, low air/wax partition coefficients, and pheromone solubility in paraffin.

75 FR 2845 - ArborGen, LLC; Availability of an Environmental Assessment for Controlled Release of a...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-19

... Engineered Eucalyptus Hybrid AGENCY: Animal and Plant Health Inspection Service, USDA. ACTION: Notice... for a proposed controlled field release of a genetically engineered clone of a Eucalyptus hybrid. This... proposed controlled field release of a genetically engineered clone of a Eucalyptus hybrid. \\1\\ To view the...

Effects of release procedures on the primary stress response and post-release survival and growth of hatchery-reared spotted seatrout Cynoscion nebulosus.

PubMed

Guest, T W; Rakocinski, C F; Evans, A N; Blaylock, R B

2017-03-01

To help explain the apparent poor post-release success of hatchery-reared (HR) spotted seatrout Cynoscion nebulosus, this study examined the effects of handling, transport and release procedures on the stress response of two age classes [48 and 80 day post-hatch (dph)] of HR C. nebulosus, as measured by cortisol concentrations and the post-release survival and growth of 48 and 80 dph HR C. nebulosus. As a proxy for stress, tissue cortisol was measured at various times during the handling, tagging (80 dph), transport, acclimation and release process. To consider the implications of the pre-release stressors, growth and survival were monitored in separate field experiments for each age class of acclimated post-transport C. nebulosus using control C. nebulosus that only experienced anaesthesia, transport, acclimation and a net release v. experimental C. nebulosus that underwent the entire routine procedure, including anaesthesia, tagging, transport, acclimation and gravity release through a pipe. For 48 dph C. nebulosus, mean cortisol varied significantly throughout handling and transport, increasing more than six-fold from controls before decreasing in mean concentration just prior to release. For 80 dph C. nebulosus, cortisol varied throughout handling, tagging and transport, first increasing more than three-fold compared with control C. nebulosus, before decreasing and rising slightly just prior to release. For 48 dph C. nebulosus within field enclosures, survival was high and similar for control and experimental groups; experimental C. nebulosus, however, were shorter, lighter and lower in condition than control C. nebulosus. For 80 dph C. nebulosus within field enclosures, fewer experimental C. nebulosus survived and those that did survive were of lower condition than C. nebulosus from the control group. Small untagged C. nebulosus may survive the release procedure better than larger C. nebulosus carrying a coded-wire tag. These findings document some ways in which pre-release practices may translate into detrimental effects on post-release success of HR C. nebulosus. © 2016 The Fisheries Society of the British Isles.

The Smart Aerial Release Machine, a Universal System for Applying the Sterile Insect Technique

PubMed Central

Mubarqui, Ruben Leal; Perez, Rene Cano; Kladt, Roberto Angulo; Lopez, Jose Luis Zavala; Parker, Andrew; Seck, Momar Talla; Sall, Baba; Bouyer, Jérémy

2014-01-01

Background Beyond insecticides, alternative methods to control insect pests for agriculture and vectors of diseases are needed. Management strategies involving the mass-release of living control agents have been developed, including genetic control with sterile insects and biological control with parasitoids, for which aerial release of insects is often required. Aerial release in genetic control programmes often involves the use of chilled sterile insects, which can improve dispersal, survival and competitiveness of sterile males. Currently available means of aerially releasing chilled fruit flies are however insufficiently precise to ensure homogeneous distribution at low release rates and no device is available for tsetse. Methodology/Principal Findings Here we present the smart aerial release machine, a new design by the Mubarqui Company, based on the use of vibrating conveyors. The machine is controlled through Bluetooth by a tablet with Android Operating System including a completely automatic guidance and navigation system (MaxNav software). The tablet is also connected to an online relational database facilitating the preparation of flight schedules and automatic storage of flight reports. The new machine was compared with a conveyor release machine in Mexico using two fruit flies species (Anastrepha ludens and Ceratitis capitata) and we obtained better dispersal homogeneity (% of positive traps, p<0.001) for both species and better recapture rates for Anastrepha ludens (p<0.001), especially at low release densities (<1500 per ha). We also demonstrated that the machine can replace paper boxes for aerial release of tsetse in Senegal. Conclusions/Significance This technology limits damages to insects and allows a large range of release rates from 10 flies/km2 for tsetse flies up to 600 000 flies/km2 for fruit flies. The potential of this machine to release other species like mosquitoes is discussed. Plans and operating of the machine are provided to allow its use worldwide. PMID:25036274

The smart aerial release machine, a universal system for applying the sterile insect technique.

PubMed

Leal Mubarqui, Ruben; Perez, Rene Cano; Kladt, Roberto Angulo; Lopez, Jose Luis Zavala; Parker, Andrew; Seck, Momar Talla; Sall, Baba; Bouyer, Jérémy

2014-01-01

Beyond insecticides, alternative methods to control insect pests for agriculture and vectors of diseases are needed. Management strategies involving the mass-release of living control agents have been developed, including genetic control with sterile insects and biological control with parasitoids, for which aerial release of insects is often required. Aerial release in genetic control programmes often involves the use of chilled sterile insects, which can improve dispersal, survival and competitiveness of sterile males. Currently available means of aerially releasing chilled fruit flies are however insufficiently precise to ensure homogeneous distribution at low release rates and no device is available for tsetse. Here we present the smart aerial release machine, a new design by the Mubarqui Company, based on the use of vibrating conveyors. The machine is controlled through Bluetooth by a tablet with Android Operating System including a completely automatic guidance and navigation system (MaxNav software). The tablet is also connected to an online relational database facilitating the preparation of flight schedules and automatic storage of flight reports. The new machine was compared with a conveyor release machine in Mexico using two fruit flies species (Anastrepha ludens and Ceratitis capitata) and we obtained better dispersal homogeneity (% of positive traps, p<0.001) for both species and better recapture rates for Anastrepha ludens (p<0.001), especially at low release densities (<1500 per ha). We also demonstrated that the machine can replace paper boxes for aerial release of tsetse in Senegal. This technology limits damages to insects and allows a large range of release rates from 10 flies/km2 for tsetse flies up to 600,000 flies/km2 for fruit flies. The potential of this machine to release other species like mosquitoes is discussed. Plans and operating of the machine are provided to allow its use worldwide.

Core/shell PLGA microspheres with controllable in vivo release profile via rational core phase design.

PubMed

Yu, Meiling; Yao, Qing; Zhang, Yan; Chen, Huilin; He, Haibing; Zhang, Yu; Yin, Tian; Tang, Xing; Xu, Hui

2018-02-27

Highly soluble drugs tend to release from preparations at high speeds, which make them need to be taken at frequent intervals. Additionally, some drugs need to be controlled to release in vivo at certain periods, so as to achieve therapeutic effects. Thus, the objective of this study is to design injectable microparticulate systems with controllable in vivo release profile. Biodegradable PLGA was used as the matrix material to fabricate microspheres using the traditional double emulsification-solvent evaporation method as well as improved techniques, with gel (5% gelatine or 25% F127) or LP powders as the inner phases. Their physicochemical properties were systemically investigated. Microspheres prepared by modified methods had an increase in drug loading (15.50, 16.72, 15.66%, respectively) and encapsulation efficiencies (73.46, 79.42, 74.40%, respectively) when compared with traditional methods (12.01 and 57.06%). The morphology of the particles was characterized by optical microscope (OM) and scanning electron microscopy (SEM), and the amorphous nature of the encapsulated drug was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. To evaluate their release behaviour, the in vitro degradation, in vitro release and in vivo pharmacodynamics were subsequently studied. Traditional microspheres prepared in this study with water as the inner phase had a relatively short release period within 16 d when compared with modified microspheres with 5% gelatine as the inner phase, which resulted in a smooth release profile and appropriate plasma LP concentrations over 21 d. Thus this type of modified microspheres can be better used in drugs requiring sustained release. The other two formulations containing 25% F127 and LP micropowders presented two-stage release profiles, resulting in fluctuant plasma LP concentrations which may be suitable for drugs requiring controlled release. All the results suggested that drug release rates from the microspheres prepared by various methods were mainly controlled by either the porosity inside the microspheres or the degradation of materials, which could, therefore, lead to different release behaviours. This results indicated great potential of the PLGA microsphere formulation as an injectable depot for controllable in vivo release profile via rational core phase design. Core/shell microspheres fabricated by modified double emulsification-solvent evaporation methods, with various inner phases, to obtain high loading drugs system, as well as appropriate release behaviours. Accordingly, control in vivo release profile via rational core phase design.

Pregabalin misuse in methadone maintenance treatment patients in Israel: Prevalence and risk factors.

PubMed

Sason, Anat; Adelson, Miriam; Schreiber, Shaul; Peles, Einat

2018-05-29

Drug users reportedly abuse pregabalin, and its combination with opiates was related to fatalities. We aimed to estimate the prevalence of pregabalin misuse and risk factors among patients in methadone maintenance treatment (MMT). A cross-sectional study included all current MMT patients (n = 300) after excluding 9 with prescriptions, from a large tertiary medical center university-affiliated MMT clinic in Israel. Pregabalin was tested in one of the routine urine tests for other substances in December 2017. Data on urine results and patients' characteristics were retrieved from the patients' records. Pregabalin was detected among 53 (17.7%) patients. The group had higher depressive symptoms severity score (21-HAM-D) (11.1 ± 8.4 vs. 8.3 ± 7.8, p = 0.03), a higher prevalence of sero-positive HIV (13.7% vs. 4.2%, p = 0.02), sero-positive hepatitis C (66.7% vs. 50.4%, p = 0.04), DSM-IV-TR Axis I psychiatric diagnosis (54.0% vs. 41.7%, p = 0.03), and positive urine for opiates (22.6% vs. 8.9%, p = 0.008), cannabis (39.6% vs. 4.0 p < 0.0005) benzodiazepine (BDZ) (77.4% vs. 18.2%, p < 0.0005) and oxycodone (11.3% vs. 0.4%, p < 0.0005). Logistic regression found pregabalin group as more likely to be urine positive to BDZ (OR = 12.8 95%CI 5.0-32.5) cannabis (OR = 22.7, 95%CI 6.3-81.6) and oxycodone (OR = 43.9, 95%CI 3.6-541.4), with higher 21-HAM-D scores (OR = 1.1, 95%CI 1.04-1.2) and hepatitis C sera-positive (OR = 4.1, 95% CI 1.5-11.4). Unexpectedly, 13.2% of the pregabalin group had take-home dose privileges, which are rewards to non-drug abusers. High prevalence of pregabalin misuse among both BDZ abusers and non-abusers and patients with depressive symptoms supports both the inclusion of routine monitoring for pregabalin and intervention in MMT population. Copyright © 2018. Published by Elsevier B.V.

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

PubMed Central

Moore, Kelsey; Madularu, Dan; Iriah, Sade; Yee, Jason R.; Kulkarni, Praveen; Darcq, Emmanuel; Kieffer, Brigitte L.; Ferris, Craig F.

2016-01-01

Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (μ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high μ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala, and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex, and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala, and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the μ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the μ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other μ opioid agonists. PMID:27857679

Effects of the NOP receptor agonist Ro65-6570 on the acquisition of opiate- and psychostimulant-induced conditioned place preference in rats.

PubMed

Rutten, Kris; De Vry, Jean; Bruckmann, Walter; Tzschentke, Thomas M

2010-10-25

Activation of the Nociceptin/Orphanin FQ (NOP) receptor may have anti-abuse effects. The present study examined the consequence of NOP receptor activation on the rewarding effect of opiates and psychostimulants in the conditioned place preference task in rats. First, the motivational effect of the NOP receptor agonists Ro64-6198 (0.316-3.16 mg/kg i.p.) and Ro65-6570 (1-10mg/kg i.p.) when administered alone, was assessed. Ro65-6570 was selected for further drug combination studies since, unlike Ro64-6198, it was devoid of an intrinsic motivational effect. Next, the minimal effective dose to induce reward for the opiates heroin (0.1-3.16 mg/kg i.p.), morphine (1-10mg/kg i.p.), hydrocodone (0.316-10mg/kg i.p.), tilidine (1-31.6 mg/kg i.p.), hydromorphone (0.1-10mg/kg i.p.), and oxycodone (0.0316-10mg/kg i.p.), as well as for the psychostimulants cocaine (3.16-31.6 mg/kg i.p.) and dexamphetamine (0.316-3.16 mg/kg i.p.) in combination with Ro 65-6570 (0 or 3.16 mg/kg i.p.) was determined. All drugs produced conditioned place preference, and for opiates and cocaine, but not for dexamphetamine, the minimal effective dose was higher when combined with Ro65-6570 (3.16 mg/kg i.p.). Attenuation of the rewarding effect of tilidine (3.16 mg/kg i.p.) and oxycodone (1mg/kg i.p.) by Ro65-6570 (3.16 mg/kg i.p.) could be reversed by pre-treatment with the NOP receptor antagonist J-113397 (4.64 mg/kg i.p.), suggesting that the attenuating effect of Ro65-6570 on opiates is due to activation of the NOP receptor. Taken together, the present study suggests that activation of NOP receptors effectively attenuates the rewarding effect of opiates, but may be less effective in reducing psychostimulant-induced reward. Copyright © 2010 Elsevier B.V. All rights reserved.

Six-Year Follow-Up of Impact of Co-proxamol Withdrawal in England and Wales on Prescribing and Deaths: Time-Series Study

PubMed Central

Hawton, Keith; Bergen, Helen; Simkin, Sue; Wells, Claudia; Kapur, Navneet; Gunnell, David

2012-01-01

Background The analgesic co-proxamol (paracetamol/dextropropoxyphene combination) has been widely involved in fatal poisoning. Concerns about its safety/effectiveness profile and widespread use for suicidal poisoning prompted its withdrawal in the UK in 2005, with partial withdrawal between 2005 and 2007, and full withdrawal in 2008. Our objective in this study was to assess the association between co-proxamol withdrawal and prescribing and deaths in England and Wales in 2005–2010 compared with 1998–2004, including estimation of possible substitution effects by other analgesics. Methods and Findings We obtained prescribing data from the NHS Health and Social Care Information Centre (England) and Prescribing Services Partneriaeth Cydwasanaethau GIG Cymru (Wales), and mortality data from the Office for National Statistics. We carried out an interrupted time-series analysis of prescribing and deaths (suicide, open verdicts, accidental poisonings) involving single analgesics. The reduction in prescribing of co-proxamol following its withdrawal in 2005 was accompanied by increases in prescribing of several other analgesics (co-codamol, paracetamol, codeine, co-dydramol, tramadol, oxycodone, and morphine) during 2005–2010 compared with 1998–2004. These changes were associated with major reductions in deaths due to poisoning with co-proxamol receiving verdicts of suicide and undetermined cause of −21 deaths (95% CI −34 to −8) per quarter, equating to approximately 500 fewer suicide deaths (−61%) over the 6 years 2005–2010, and −25 deaths (95% CI −38 to −12) per quarter, equating to 600 fewer deaths (−62%) when accidental poisoning deaths were included. There was little observed change in deaths involving other analgesics, apart from an increase in oxycodone poisonings, but numbers were small. Limitations were that the study was based on deaths involving single drugs alone and changes in deaths involving prescribed morphine could not be assessed. Conclusions During the 6 years following the withdrawal of co-proxamol in the UK, there was a major reduction in poisoning deaths involving this drug, without apparent significant increase in deaths involving other analgesics. Please see later in the article for the Editors' Summary PMID:22589703

RANKL release from self-assembling nanofiber hydrogels for inducing osteoclastogenesis in vitro.

PubMed

Xing, James Z; Lu, Lei; Unsworth, Larry D; Major, Paul W; Doschak, Michael R; Kaipatur, Neelambar R

2017-02-01

To develop a nanofiber hydrogel (NF-hydrogel) for sustained and controlled release of the recombinant receptor activator of NF-kB ligand; (RANKL) and to characterize the release kinetics and bioactivity of the released RANKL. Various concentrations of fluorescently-labelled RANKL protein were added to NF-hydrogels, composed of Acetyl-(Arg-Ala-Asp-Ala) 4 -CONH 2 [(RADA) 4 ] of different concentrations, to investigate the resulting in vitro release rates. The nano-structures of NF-hydrogel, with and without RANKL, were determined using atomic force microscopy (AFM). Released RANKL was further analyzed for changes in secondary and tertiary structure using CD spectroscopy and fluorescent emission spectroscopy, respectively. Bioactivity of released RANKL protein was determined using NFATc1 gene expression and tartrate resistant acid phosphatase (TRAP) activity of osteoclast cells as biomarkers. NF-hydrogel concentration dependent sustained release of RANKL protein was measured at concentrations between 0.5 and 2%(w/v). NF-hydrogel at 2%(w/v) concentration exhibited a sustained and slow-release of RANKL protein up to 48h. Secondary and tertiary structure analyses confirmed no changes to the RANKL protein released from NF-hydrogel in comparison to native RANKL. The results of NFATc1 gene mRNA expression and TRAP activities of osteoclast, showed that the release process did not affect the bioactivity of released RANKL. This novel study is the first of its kind to attempt in vitro characterization of NF-hydrogel based delivery of RANKL protein to induce osteoclastogenesis. We have shown the self-assembling NF-hydrogel peptide system is amenable to the sustained and controlled release of RANKL locally; that could in turn increase local concentration of RANKL to induce osteoclastogenesis, for application to the controlled mobilization of tooth movement in orthodontic procedures. Orthodontic tooth movement (OTM) occurs through controlled application of light forces to teeth, facilitating the required changes in the surrounding alveolar bone through the process of bone remodelling. The RANKL system regulates alveolar bone remodelling and controls root resorption during OTM. The use of exogenous RANKL to accelerate OTM has not been attempted to date because large quantities of RANKL for systemic therapy may subsequently cause serious systemic loss of skeletal bone. The controlled and sustained local release of RANKL from a carrier matrix could maximize its therapeutic benefit whilst minimizing systemic side effects. In this study a NF-hydrogel was used for sustained and controlled release of RANKL and the release kinetics and biofunctionality of the released RANKL was characterized. Our results provide fundamental insight for further investigating the role of RANKL NF-hydrogel release systems for inducing osteoclastogenesis in vivo. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Antifouling composites with self-adaptive controlled release based on an active compound intercalated into layered double hydroxides

NASA Astrophysics Data System (ADS)

Yang, Miaosen; Gu, Lianghua; Yang, Bin; Wang, Li; Sun, Zhiyong; Zheng, Jiyong; Zhang, Jinwei; Hou, Jian; Lin, Cunguo

2017-12-01

This paper reports a novel method to prepare the antifouling composites with properties of self-adaptive controlled release (defined as control the release rate autonomously and adaptively according to the change of environmental conditions) by intercalation of sodium paeonolsilate (PAS) into MgAl and ZnAl layered double hydroxide (LDH) with the molar ratio (M2+/M3+) of 2:1 and 3:1, respectively. The powder X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) confirm the intercalation of PAS into the galleries of LDH. The controlled release behavior triggered by temperature for the PAS-LDH composites has been investigated, and the results show that the release rate of all PAS-LDH composites increases as the increase of temperature. However, the MgAl-PAS-LDH composites (Mg2Al-PAS-LDH and Mg3Al-PAS-LDH) exhibit the increased release rate of 0.21 ppm/°C from 15 to 30 °C in 3.5% NaCl solution, more than three times of the ZnAl-PAS-LDH composites (0.06 ppm/°C), owing to the confined microenvironment influenced by metal types in LDH layers. In addition, a possible diffusion-controlled process with surface diffusion, bulk diffusion and heterogeneous flat surface diffusion has been revealed via fitting four kinetic equations. Moreover, to verify the practical application of the PAS-LDH composites, a model coating denoted as Mg2Al-PAS-LDH coating was fabricated. The release result displays that the release rate increases or decreases as temperature altered at 15 and 25 °C alternately, indicating its self-adaptive controlled release behavior with temperature. Moreover, the superior resistance to the settlement of Ulva spores at 15 and 25 °C was observed for the Mg2Al-PAS-LDH coating, as a result of the controllable release of antifoulant. Therefore, this work provides a facile and effective method for the fabrication of antifouling composites with self-adaptive controlled release behavior in response to temperature, which can be used to prolong the lifetime of antifouling coatings.

Quick release latch for reactor scram

DOEpatents

Johnson, Melvin L.; Shawver, Bruce M.

1976-01-01

A simple, reliable, and fast-acting means for releasing a control element and allowing it to be inserted rapidly into the core region of a nuclear reactor for scram purposes. A latch mechanism grips a coupling head on a nuclear control element to connect the control element to the control drive assembly. The latch mechanism is closed by tensioning a cable or rod with an actuator. The control element is released by de-energizing the actuator, providing fail-safe, rapid release of the control element to effect reactor shutdown. A sensing rod provides indication that the control element is properly positioned in the latch. Two embodiments are illustrated, one involving a collet-type latch mechanism, the other a pliers-type latch mechanism with the actuator located inside the reactor vessel.

Quick release latch for reactor scram

DOEpatents

Johnson, M.L.; Shawver, B.M.

1975-09-16

A simple, reliable, and fast-acting means for releasing a control element and allowing it to be inserted rapidly into the core region of a nuclear reactor for scram purposes is described. A latch mechanism grips a coupling head on a nuclear control element to connect the control element to the control drive assembly. The latch mechanism is closed by tensioning a cable or rod with an actuator. The control element is released by de-energizing the actuator, providing fail-safe, rapid release of the control element to effect reactor shutdown. A sensing rod provides indication that the control element is properly positioned in the latch. Two embodiments are illustrated, one involving a collet- type latch mechanism, the other a pliers-type latch mechanism with the actuator located inside the reactor vessel. (auth)

Microencapsulation: A promising technique for controlled drug delivery.

PubMed

Singh, M N; Hemant, K S Y; Ram, M; Shivakumar, H G

2010-07-01

MICROPARTICLES OFFER VARIOUS SIGNIFICANT ADVANTAGES AS DRUG DELIVERY SYSTEMS, INCLUDING: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed.

Microencapsulation: A promising technique for controlled drug delivery

PubMed Central

Singh, M.N.; Hemant, K.S.Y.; Ram, M.; Shivakumar, H.G.

2010-01-01

Microparticles offer various significant advantages as drug delivery systems, including: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed. PMID:21589795

Novel system for reducing leaching of the herbicide metribuzin using clay-gel-based formulations.

PubMed

Maqueda, Celia; Villaverde, Jaime; Sopeña, Fátima; Undabeytia, Tomás; Morillo, Esmeralda

2008-12-24

Metribuzin is an herbicide widely used for weed control that has been identified as a groundwater pollutant. It contaminates the environment even when it is used according to the manufacturer's instructions. To reduce herbicide leaching and increase weed control, new controlled release formulations were developed by entrapping metribuzin within a sepiolite-gel-based matrix using two clay/herbicide proportions (0.5/0.2 and 1/0.2) (loaded at 28.6 and 16.7% a.i.) as a gel (G28, G16) or as a powder after freeze-drying (LF28, LF16). The release of metribuzin from the control released formulations into water was retarded, when compared with commercial formulation (CF) except in the case of G28. The mobility of metribuzin from control released formulations into soil columns of sandy soil was greatly diminished in comparison with CF. Most of the metribuzin applied as control released formulations (G16, LF28 and LF16) was found at a depth of 0-8 cm depth. In contrast, residues from CF and G28 along the column were almost negligible. Bioassays from these control released formulations showed high efficacy at 0-12 cm depth. The use of these novel formulations could minimize the risk of groundwater contamination while maintaining weed control for a longer period.

10 CFR 50.34a - Design objectives for equipment to control releases of radioactive material in effluents-nuclear...

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Design objectives for equipment to control releases of..., Certifications, and Regulatory Approvals; Form; Contents; Ineligibility of Certain Applicants § 50.34a Design objectives for equipment to control releases of radioactive material in effluents—nuclear power reactors. (a...

10 CFR 50.34a - Design objectives for equipment to control releases of radioactive material in effluents-nuclear...

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Design objectives for equipment to control releases of..., Certifications, and Regulatory Approvals; Form; Contents; Ineligibility of Certain Applicants § 50.34a Design objectives for equipment to control releases of radioactive material in effluents—nuclear power reactors. (a...

10 CFR 50.34a - Design objectives for equipment to control releases of radioactive material in effluents-nuclear...

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false Design objectives for equipment to control releases of..., Certifications, and Regulatory Approvals; Form; Contents; Ineligibility of Certain Applicants § 50.34a Design objectives for equipment to control releases of radioactive material in effluents—nuclear power reactors. (a...

10 CFR 50.34a - Design objectives for equipment to control releases of radioactive material in effluents-nuclear...

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Design objectives for equipment to control releases of..., Certifications, and Regulatory Approvals; Form; Contents; Ineligibility of Certain Applicants § 50.34a Design objectives for equipment to control releases of radioactive material in effluents—nuclear power reactors. (a...

10 CFR 50.34a - Design objectives for equipment to control releases of radioactive material in effluents-nuclear...

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Design objectives for equipment to control releases of..., Certifications, and Regulatory Approvals; Form; Contents; Ineligibility of Certain Applicants § 50.34a Design objectives for equipment to control releases of radioactive material in effluents—nuclear power reactors. (a...

Controlled release properties of zein-fatty acid blend films for multiple bioactive compounds.

PubMed

Arcan, Iskender; Yemenicioğlu, Ahmet

2014-08-13

To develop edible films having controlled release properties for multiple bioactive compounds, hydrophobicity and morphology of zein films were modified by blending zein with oleic (C18:1)Δ⁹, linoleic (C18:2)Δ(9,12), or lauric (C₁₂) acids in the presence of lecithin. The blend zein films showed 2-8.5- and 1.6-2.9-fold lower initial release rates for the model active compounds, lysozyme (LYS) and (+)-catechin (CAT), than the zein control films, respectively. The change of fatty acid chain length affected both CAT and LYS release rates while the change of fatty acid double bond number affected only the CAT release rate. The film morphologies suggested that the blend films owe their controlled release properties mainly to the microspheres formed within their matrix and encapsulation of active compounds. The blend films showed antilisterial activity and antioxidant activity up to 81 μmol Trolox/cm². The controlled release of multiple bioactive compounds from a single film showed the possibility of combining application of active and bioactive packaging technologies and improving not only safety and quality but also health benefits of packed food.

In Vivo Analytical Performance of Nitric Oxide-Releasing Glucose Biosensors

PubMed Central

2015-01-01

The in vivo analytical performance of percutaneously implanted nitric oxide (NO)-releasing amperometric glucose biosensors was evaluated in swine for 10 d. Needle-type glucose biosensors were functionalized with NO-releasing polyurethane coatings designed to release similar total amounts of NO (3.1 μmol cm–2) for rapid (16.0 ± 4.4 h) or slower (>74.6 ± 16.6 h) durations and remain functional as outer glucose sensor membranes. Relative to controls, NO-releasing sensors were characterized with improved numerical accuracy on days 1 and 3. Furthermore, the clinical accuracy and sensitivity of rapid NO-releasing sensors were superior to control and slower NO-releasing sensors at both 1 and 3 d implantation. In contrast, the slower, extended, NO-releasing sensors were characterized by shorter sensor lag times (<4.2 min) in response to intravenous glucose tolerance tests versus burst NO-releasing and control sensors (>5.8 min) at 3, 7, and 10 d. Collectively, these results highlight the potential for NO release to enhance the analytical utility of in vivo glucose biosensors. Initial results also suggest that this analytical performance benefit is dependent on the NO-release duration. PMID:24984031

In vivo analytical performance of nitric oxide-releasing glucose biosensors.

PubMed

Soto, Robert J; Privett, Benjamin J; Schoenfisch, Mark H

2014-07-15

The in vivo analytical performance of percutaneously implanted nitric oxide (NO)-releasing amperometric glucose biosensors was evaluated in swine for 10 d. Needle-type glucose biosensors were functionalized with NO-releasing polyurethane coatings designed to release similar total amounts of NO (3.1 μmol cm(-2)) for rapid (16.0 ± 4.4 h) or slower (>74.6 ± 16.6 h) durations and remain functional as outer glucose sensor membranes. Relative to controls, NO-releasing sensors were characterized with improved numerical accuracy on days 1 and 3. Furthermore, the clinical accuracy and sensitivity of rapid NO-releasing sensors were superior to control and slower NO-releasing sensors at both 1 and 3 d implantation. In contrast, the slower, extended, NO-releasing sensors were characterized by shorter sensor lag times (<4.2 min) in response to intravenous glucose tolerance tests versus burst NO-releasing and control sensors (>5.8 min) at 3, 7, and 10 d. Collectively, these results highlight the potential for NO release to enhance the analytical utility of in vivo glucose biosensors. Initial results also suggest that this analytical performance benefit is dependent on the NO-release duration.

Controlled release of silyl ether camptothecin from thiol-ene click chemistry-functionalized mesoporous silica nanoparticles.

PubMed

Yan, Yue; Fu, Jie; Wang, Tianfu; Lu, Xiuyang

2017-03-15

As efficient drug carriers, stimuli-responsive mesoporous silica nanoparticles are at the forefront of research on drug delivery systems. An acid-responsive system based on silyl ether has been applied to deliver a hybrid prodrug. Thiol-ene click chemistry has been successfully utilized for tethering this prodrug to mesoporous silica nanoparticles. Here, by altering the steric bulk of the substituent on the silicon atom, the release rate of a model drug, camptothecin, was controlled. The synthesized drug delivery system was investigated by analytical methods to confirm the functionalization and conjugation of the mesoporous silica nanoparticles. Herein, trimethyl silyl ether and triethyl silyl ether were selected to regulate the release rate. Under normal plasma conditions (pH 7.4), both types of camptothecin-loaded mesoporous silica nanoparticles (i.e., MSN-Me-CPT and MSN-Et-CPT) did not release the model drug. However, under in vitro acidic conditions (pH 4.0), based on a comparison of the release rates, camptothecin was released from MSN-Me-CPT more rapidly than from MSN-Et-CPT. To determine the biocompatibility of the modified mesoporous silica nanoparticles and the in vivo camptothecin uptake behavior, MTT assays with cancer cells and confocal microscopy observations were conducted, with positive results. These functionalized nanoparticles could be useful in clinical treatments requiring controlled drug release. As the release rate of drug from drug-carrier plays important role in therapy effects, trimethyl silyl ether (TMS) and triethyl silyl ether (TES) were selected as acid-sensitive silanes to control the release rates of model drugs conjugated from MSNs by thiol-ene click chemistry. The kinetic profiles of TMS and TES materials have been studied. At pH 4.0, the release of camptothecin from MSN-Et-CPT occurred after 2h, whereas MSN-Me-CPT showed immediate drug release. The results showed that silyl ether could be used to control release rates of drugs from MSNs under acid environment, which could be useful in clinical treatments requiring controlled drug release. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Controlled release of chlorhexidine digluconate using β-cyclodextrin and microfibrillated cellulose.

PubMed

Lavoine, Nathalie; Tabary, Nicolas; Desloges, Isabelle; Martel, Bernard; Bras, Julien

2014-09-01

This study aims to develop a high-performance delivery system using microfibrillated cellulose (MFC)-coated papers as a controlled release system combined with the well-known drug delivery agent, β-cyclodextrin (βCD). Chlorhexidine digluconate (CHX), an antibacterial molecule, was mixed with a suspension of MFC or a βCD solution or mixed with both the substances, before coating onto a cellulosic substrate. The intermittent diffusion of CHX (i.e., diffusion interrupted by the renewal of the release medium periodically) was conducted in an aqueous medium, and the release mechanism of CHX was elucidated by field emission gun-scanning electron microscopy, SEM, NMR, and Fourier transform infrared analyses. According to the literature, both βCD and MFC are efficient controlled delivery systems. This study indicated that βCD releases CHX more gradually and over a longer period of time compared to MFC, which is mainly due to the ability of βCD to form an inclusion complex with CHX. Furthermore from the release study, a complementary action when the two compounds were combined was deduced. MFC mainly affected the burst effect, while βCD primarily controlled the amount of CHX released over time. In this paper, two different types of controlled release systems are proposed and compared. Depending on the final application, the use of βCD alone would release low amounts of active molecules over time (slow delivery), whereas the combination of β-cyclodextrin and MFC would be more suitable for the release of higher amounts of active molecules over time (rapid delivery). Copyright © 2014 Elsevier B.V. All rights reserved.

Floating tablets for controlled release of ofloxacin via compression coating of hydroxypropyl cellulose combined with effervescent agent.

PubMed

Qi, Xiaole; Chen, Haiyan; Rui, Yao; Yang, Fengjiao; Ma, Ning; Wu, Zhenghong

2015-07-15

To prolong the residence time of dosage forms within gastrointestinal trace until all drug released at desired rate was one of the real challenges for oral controlled-release drug delivery system. Herein, we developed a fine floating tablet via compression coating of hydrophilic polymer (hydroxypropyl cellulose) combined with effervescent agent (sodium bicarbonate) to achieve simultaneous control of release rate and location of ofloxacin. Sodium alginate was also added in the coating layer to regulate the drug release rate. The effects of the weight ratio of drug and the viscosity of HPC on the release profile were investigated. The optimized formulations were found to immediately float within 30s and remain lastingly buoyant over a period of 12 h in simulated gastric fluid (SGF, pH 1.2) without pepsin, indicating a satisfactory floating and zero-order drug release profile. In addition, the oral bioavailability experiment in New Zealand rabbits showed that, the relative bioavailability of the ofloxacin after administrated of floating tablets was 172.19%, compared to marketed common release tablets TaiLiBiTuo(®). These results demonstrated that those controlled-released floating tables would be a promising gastro-retentive delivery system for drugs acting in stomach. Copyright © 2015 Elsevier B.V. All rights reserved.

Development of 5-Substituted N-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile.

PubMed

Schmidhammer, Helmut; Spetea, Mariana

2012-01-01

One of the most important functions of the opioid system is the control of pain. Among the three main opioid receptor classes (μ, δ, κ), the μ (MOR) is the main type targeted for pharmacotherapy of pain. Opioid analgesics such as morphine, oxycodone and fentanyl are agonists at the MOR and are the mainstay for the treatment of moderate-to-severe pain. However, adverse effects related to opioid use are severe and often lead to early discontinuation and inadequate analgesia. The development of more effective and safer medications for the management of pain still remains a major direction in pharmaceutical research. Chemical approaches towards the identification of novel MOR analgesics with reduced side effects include structural modifications of 14-alkoxy-N-methylmorphinan-6-ones in key positions that are important for binding, selectivity, potency, and efficacy at opioid receptors. This paper describes a representative strategy to improve the therapeutic usefulness of opioid analgesics from the morphinan class of drugs by targeting position 5. The focus is on chemical and biological studies and structure-activity relationships of this series of ligands. We report on 14-alkoxymorphinan-6-ones having a methyl and benzyl group at position 5 as strong opioid antinociceptive agents with reduced propensity to cause undesired effects compared to morphine although interacting selectively with MORs.

ATP during early bladder stretch is important for urgency in detrusor overactivity patients.

PubMed

Cheng, Y; Mansfield, K J; Allen, W; Chess-Williams, R; Burcher, E; Moore, K H

2014-01-01

ATP is an important mediator of urgency in women with detrusor overactivity (DO). In order to understand how different degrees of bladder stretch elicited ATP release in DO patients compared with controls, sequential aliquots were collected during cystometry and ATP release was measured at each degree of bladder filling, in female patients with DO and controls. In both DO and control groups, ATP release was induced during bladder filling, suggesting that stretch stimulated further ATP release. However, the luminal ATP concentrations were already high at early filling stage (200 mL), which was even greater than those at the later filling stages (400 mL and maximum cystometric capacity, MCC), indicating that a substantial ATP release has been induced during early filling (200 mL) in both DO and controls. In DO, ATP release at 200 mL was significantly higher in those with low first desire to void (FDV) (≤ 200 mL) than in those with higher FDV (> 200 mL); this may suggest that ATP release at early stretch may play an important role in urgency (early sensation) in DO. ATP concentrations remained unchanged after voiding, suggesting that voiding did not further induce ATP release into intraluminal fluid.

A simple and rapid approach to evaluate the in vitro in vivo role of release controlling agent ethyl cellulose ether derivative polymer.

PubMed

Akhlaq, Muhammad; Khan, Gul Majid; Jan, Syed Umer; Wahab, Abdul; Hussain, Abid; Nawaz, Asif; Abdelkader, Hamdy

2014-11-01

Diclofenac sodium (DCL-Na) conventional oral tablets exhibit serious side effects when given for a longer period leading to noncompliance. Controlled release matrix tablets of diclofenac sodium were formulated using simple blending (F-1), solvent evaporation (F-2) and co-precipitation techniques (F-3). Ethocel® Standard 7 FP Premium Polymer (15%) was used as a release controlling agent. Drug release study was conducted in 7.4 pH phosphate buffer solutions as dissolution medium in vitro. Pharmacokinetic parameters were evaluated using albino rabbits. Solvent evaporation technique was found to be the best release controlling technique thereby prolonging the release rate up to 24 hours. Accelerated stability studies of the optimized test formulation (F-2) did not show any significant change (p<0.05) in the physicochemical characteristics and release rate when stored for six months. A simple and rapid method was developed for DCL-Na active moiety using HPLC-UV at 276nm. The optimized test tablets (F-2) significantly (p<0.05) exhibited peaks plasma concentration (cmax=237.66±1.98) and extended the peak time (tmax=4.63±0.24). Good in-vitro in vivo correlation was found (R(2)=0.9883) against drug absorption and drug release. The study showed that once-daily controlled release matrix tablets of DCL-Na were successfully developed using Ethocel® Standard 7 FP Premium.

Release and control of hydrogen sulfide during sludge thermal drying.

PubMed

Weng, Huanxin; Dai, Zhixi; Ji, Zhongqiang; Gao, Caixia; Liu, Chongxuan

2015-10-15

The release of hydrogen sulfide (H2S) during sludge drying is a major environmental problem because of its toxicity to human health. A series of experiments were performed to investigate the mechanisms and factors controlling the H2S release. Results of this study show that: (1) the biomass and activity of sulfate-reducing bacteria (SRB) in sludge were the major factors controlling the amount of H2S release, (2) the sludge drying temperature had an important effect on both the extent and the timing of H2S release from the sludge, and (3) decreasing sludge pH increased the H2S release. Based on the findings from this study, a new system that integrates sludge drying and H2S gas treatment was developed, by which 97.5% of H2S and 99.7% of smoke released from sludge treatments was eliminated. Copyright © 2015 Elsevier B.V. All rights reserved.

Release and control of hydrogen sulfide during sludge thermal drying

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weng, Huanxin; Dai, Zhixin; Ji, Zhongqiang

2015-04-15

The release of hydrogen sulfide (H2S) during sludge drying is a major environmental problem because of its toxicity to human health. A series of experiments were performed to investigate the mechanisms and factors controlling the H2S release. Results of this study show that: 1) the biomass and activity of sulfate-reducing bacteria (SRB) in sludge were the major factors controlling the amount of H2S release, 2) the sludge drying temperature had an important effect on both the extent and the timing of H2S release from the sludge, and 3) decreasing sludge pH increased the H2S release. Based on the findings frommore » this study, a new system that integrates sludge drying and H2S gas treatment was developed to reduce the amount of H2S released from sludge treatments.« less

Modeling transport kinetics in clinoptilolite-phosphate rock systems

NASA Technical Reports Server (NTRS)

Allen, E. R.; Ming, D. W.; Hossner, L. R.; Henninger, D. L.

1995-01-01

Nutrient release in clinoptilolite-phosphate rock (Cp-PR) systems occurs through dissolution and cation-exchange reactions. Investigating the kinetics of these reactions expands our understanding of nutrient release processes. Research was conducted to model transport kinetics of nutrient release in Cp-PR systems. The objectives were to identify empirical models that best describe NH4, K, and P release and define diffusion-controlling processes. Materials included a Texas clinoptilolite (Cp) and North Carolina phosphate rock (PR). A continuous-flow thin-disk technique was used. Models evaluated included zero order, first order, second order, parabolic diffusion, simplified Elovich, Elovich, and power function. The power-function, Elovich, and parabolic-diffusion models adequately described NH4, K, and P release. The power-function model was preferred because of its simplicity. Models indicated nutrient release was diffusion controlled. Primary transport processes controlling nutrient release for the time span observed were probably the result of a combination of several interacting transport mechanisms.

Active bio-based food-packaging: Diffusion and release of active substances through and from cellulose nanofiber coating toward food-packaging design.

PubMed

Lavoine, Nathalie; Guillard, Valérie; Desloges, Isabelle; Gontard, Nathalie; Bras, Julien

2016-09-20

Cellulose nanofibers (CNFs) were recently investigated for the elaboration of new functional food-packaging materials. Their nanoporous network was especially of interest for controlling the release of active species. Qualitative release studies were conducted, but quantification of the diffusion phenomenon observed when the active species are released from and through CNF coating has not yet been studied. Therefore, this work aims to model CNF-coated paper substrates as controlled release system for food-packaging using release data obtained for two model molecules, namely caffeine and chlorhexidine digluconate. The applied mathematical model - derived from Fickian diffusion - was validated for caffeine only. When the active species chemically interacts with the release device, another model is required as a non-predominantly diffusion-controlled release was observed. From caffeine modeling data, a theoretical active food-packaging material was designed. The use of CNFs as barrier coating was proved to be the ideal material configuration that best meets specifications. Copyright © 2016. Published by Elsevier Ltd.

Outpatient CPOE orders discontinued due to 'erroneous entry': prospective survey of prescribers' explanations for errors.

PubMed

Hickman, Thu-Trang T; Quist, Arbor Jessica Lauren; Salazar, Alejandra; Amato, Mary G; Wright, Adam; Volk, Lynn A; Bates, David W; Schiff, Gordon

2018-04-01

Computerised prescriber order entry (CPOE) systems users often discontinue medications because the initial order was erroneous. To elucidate error types by querying prescribers about their reasons for discontinuing outpatient medication orders that they had self-identified as erroneous. During a nearly 3 year retrospective data collection period, we identified 57 972 drugs discontinued with the reason 'Error (erroneous entry)." Because chart reviews revealed limited information about these errors, we prospectively studied consecutive, discontinued erroneous orders by querying prescribers in near-real-time to learn more about the erroneous orders. From January 2014 to April 2014, we prospectively emailed prescribers about outpatient drug orders that they had discontinued due to erroneous initial order entry. Of 2 50 806 medication orders in these 4 months, 1133 (0.45%) of these were discontinued due to error. From these 1133, we emailed 542 unique prescribers to ask about their reason(s) for discontinuing these mediation orders in error. We received 312 responses (58% response rate). We categorised these responses using a previously published taxonomy. The top reasons for these discontinued erroneous orders included: medication ordered for wrong patient (27.8%, n=60); wrong drug ordered (18.5%, n=40); and duplicate order placed (14.4%, n=31). Other common discontinued erroneous orders related to drug dosage and formulation (eg, extended release versus not). Oxycodone (3%) was the most frequent drug discontinued error. Drugs are not infrequently discontinued 'in error.' Wrong patient and wrong drug errors constitute the leading types of erroneous prescriptions recognised and discontinued by prescribers. Data regarding erroneous medication entries represent an important source of intelligence about how CPOE systems are functioning and malfunctioning, providing important insights regarding areas for designing CPOE more safely in the future. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Control of drug release through the in situ assembly of stimuli-responsive ordered mesoporous silica with magnetic particles.

PubMed

Zhu, Shenmin; Zhou, Zhengyang; Zhang, Di

2007-12-03

A site-selective controlled delivery system for controlled drug release is fabricated through the in situ assembly of stimuli-responsive ordered SBA-15 and magnetic particles. This approach is based on the formation of ordered mesoporous silica with magnetic particles formed from Fe(CO)5 via the surfactant-template sol-gel method and control of transport through polymerization of N-isopropyl acrylamide inside the pores. Hydrophobic Fe(CO)5 acts as a swelling agent as well as being the source of the magnetic particles. The obtained system demonstrates a high pore diameter (7.1 nm) and pore volume (0.41 cm(3) g(-1)), which improves drug storage for relatively large molecules. Controlled drug release through the porous network is demonstrated by measuring the uptake and release of ibuprofen (IBU). The delivery system displays a high IBU storage capacity of 71.5 wt %, which is almost twice as large as the highest value based on SBA-15 ever reported. In vitro testing of IBU loading and release exhibits a pronounced transition at around 32 degrees C, indicating a typical thermosensitive controlled release.

Controlling Release Kinetics of PLG Microspheres Using a Manufacturing Technique

NASA Astrophysics Data System (ADS)

Berchane, Nader

2005-11-01

Controlled drug delivery offers numerous advantages compared with conventional free dosage forms, in particular: improved efficacy and patient compliance. Emulsification is a widely used technique to entrap drugs in biodegradable microspheres for controlled drug delivery. The size of the formed microspheres has a significant influence on drug release kinetics. Despite the advantages of controlled drug delivery, previous attempts to achieve predetermined release rates have seen limited success. This study develops a tool to tailor desired release kinetics by combining microsphere batches of specified mean diameter and size distribution. A fluid mechanics based correlation that predicts the average size of Poly(Lactide-co-Glycolide) [PLG] microspheres from the manufacturing technique, is constructed and validated by comparison with experimental results. The microspheres produced are accurately represented by the Rosin-Rammler mathematical distribution function. A mathematical model is formulated that incorporates the microsphere distribution function to predict the release kinetics from mono-dispersed and poly-dispersed populations. Through this mathematical model, different release kinetics can be achieved by combining different sized populations in different ratios. The resulting design tool should prove useful for the pharmaceutical industry to achieve designer release kinetics.

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.

Evaluation of the resistance of a geopolymer-based drug delivery system to tampering.

PubMed

Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne

2014-04-25

Tamper-resistance is an important property of controlled-release formulations of opioid drugs. Tamper-resistant formulations aim to increase the degree of effort required to override the controlled release of the drug molecules from extended-release formulations for the purpose of non-medical use. In this study, the resistance of a geopolymer-based formulation to tampering was evaluated by comparing it with a commercial controlled-release tablet using several methods commonly used by drug abusers. Because of its high compressive strength and resistance to heat, much more effort and time was required to extract the drug from the geopolymer-based formulation. Moreover, in the drug-release test, the geopolymer-based formulation maintained its controlled-release characteristics after milling, while the drug was released immediately from the milled commercial tablets, potentially resulting in dose dumping. Although the tampering methods used in this study does not cover all methods that abuser could access, the results obtained by the described methods showed that the geopolymer matrix increased the degree of effort required to override the controlled release of the drug, suggesting that the formulation has improved resistance to some common drug-abuse tampering methods. The geopolymer matrix has the potential to make the opioid product less accessible and attractive to non-medical users. Copyright © 2014 Elsevier B.V. All rights reserved.

Apparatus for controlling system state based on unique identifiers

DOEpatents

Drotning, William D.

2002-01-01

An apparatus allows workers to assert and release control over the energization of a system. The apparatus does not require the workers to carry any additional paraphernalia, and is not be easily defeated by other workers. Users asserting and releasing control present tokens uniquely identifying each user to a reader, and the apparatus prevents transition of the system to an undesired state until an appropriate number of users are currently asserting control. For example, a dangerous manufacturing robot can be prevented from energizing until all the users that have asserted control when entering the robot's controlled space have subsequently released control when leaving the robot's controlled space.

Best Practices for Controlling Lead and Copper Release

EPA Science Inventory

Presentation draft, covering summary of current state-of-the-art knowledge for the best treatment strategies for minimizing lead release and controlling copper release. The presentation is intended to aid with compliance with the Lead and Copper Rule, but also provide a guide to...

Reducing the Use of Agrochemicals: A Simple Experiment

ERIC Educational Resources Information Center

Vidal, M. M.; Filipe, Olga M. S.; Costa, M. C. Cruz

2006-01-01

An experiment was performed on polymeric-based controlled-release agrochemicals that minimize leaching into groundwater while maintaining an adequate quantity for the desired agrochemical benefits. Gelatin gel containing inorganic Phosphorous provides controlled-release of an agrochemical where release curves show a linear relationship between…

Development of formulations to improve the controlled-release of linalool to be applied as an insecticide.

PubMed

Lopez, M D; Maudhuit, A; Pascual-Villalobos, M J; Poncelet, D

2012-02-08

In recent studies, insecticide activity of a monoterpene, linalool, has been demonstrated, finding, however, limitations in application because of its rapid volatilization. Potential effectiveness of microcapsules and effects of various types of matrices on its stability as controlled-release systems for the slow volatilization of linalool to be applied as insecticide were evaluated. To study controlled-release, linalool was entrapped into microcapsules, inclusion complexes, and beads, obtained by different methods, inverse gelation (IG1, IG2, IG3, IG4, and IG5), oil-emulsion-entrapment (OEE), interfacial coacervation (INCO), and chemical precipitation (Cyc5 and Cyc10). The encapsulation yield turned out to be different for each formulation, reaching the maximum retention for IG1 and OEE. In controlled-release, OEE followed by INCO presented a long time necessary for releasing as a result of the presence of glycerol or chitosan. These results pointed out remarkable differences in the release behavior of linalool depending on matrix composition and the method of encapsulation.

Exploitation of novel gum Prunus cerasoides as mucoadhesive beads for a controlled-release drug delivery.

PubMed

Seelan, T Veenus; Kumari, Henry Linda Jeeva; Kishore, Narra; Selvamani, Palanisamy; Lalhlenmawia, H; Thanzami, K; Pachuau, Lalduhsanga; Ruckmani, Kandasamy

2016-04-01

The present study deals with the formulation of pH-sensitive mucoadhesive beads using natural gum isolated from Prunus cerasoides (PC) in combination with sodium alginate (SA) for the controlled release of diclofenac sodium (DS). PC and SA composite (PC-SA), DS loaded SA (DS-SA) and DS loaded PC-SA (DS-PC-SA) beads were prepared by ionotropic gelation method. The absence of interaction between DS and PC-SA was shown by FTIR, DSC and TGA analyses. The optimized DS-PC-SA formulation exhibited mucoadhesive property and the controlled release of DS was achieved 68% in 12h. The in vitro release kinetics follows zero order with anomalous diffusion mechanism. Therefore, the formulated mucoadhesive beads with the novel gum are preferable for the controlled release of DS by prolonging the residence time of the drug in the gastrointestinal tract, overcoming the problems associated with the immediate release dosage forms of DS. Copyright © 2016 Elsevier B.V. All rights reserved.

Encapsulation-free controlled release: Electrostatic adsorption eliminates the need for protein encapsulation in PLGA nanoparticles

PubMed Central

Pakulska, Malgosia M.; Elliott Donaghue, Irja; Obermeyer, Jaclyn M.; Tuladhar, Anup; McLaughlin, Christopher K.; Shendruk, Tyler N.; Shoichet, Molly S.

2016-01-01

Encapsulation of therapeutic molecules within polymer particles is a well-established method for achieving controlled release, yet challenges such as low loading, poor encapsulation efficiency, and loss of protein activity limit clinical translation. Despite this, the paradigm for the use of polymer particles in drug delivery has remained essentially unchanged for several decades. By taking advantage of the adsorption of protein therapeutics to poly(lactic-co-glycolic acid) (PLGA) nanoparticles, we demonstrate controlled release without encapsulation. In fact, we obtain identical, burst-free, extended-release profiles for three different protein therapeutics with and without encapsulation in PLGA nanoparticles embedded within a hydrogel. Using both positively and negatively charged proteins, we show that short-range electrostatic interactions between the proteins and the PLGA nanoparticles are the underlying mechanism for controlled release. Moreover, we demonstrate tunable release by modifying nanoparticle concentration, nanoparticle size, or environmental pH. These new insights obviate the need for encapsulation and offer promising, translatable strategies for a more effective delivery of therapeutic biomolecules. PMID:27386554

Controlled release of tocopherols from polymer blend films

NASA Astrophysics Data System (ADS)

Obinata, Noe

Controlled release packaging has great potential to increase storage stability of foods by releasing active compounds into foods continuously over time. However, a major limitation in development of this technology is the inability to control the release and provide rates useful for long term storage of foods. Better understanding of the factors affecting active compound release is needed to overcome this limitation. The objective of this research was to investigate the relationship between polymer composition, polymer processing method, polymer morphology, and release properties of active compounds, and to provide proof of principle that compound release is controlled by film morphology. A natural antioxidant, tocopherol was used as a model active compound because it is natural, effective, heat stable, and soluble in most packaging polymers. Polymer blend films were produced from combination of linear low density polyethylene (LLDPE) and high density polyethylene (HDPE), polypropylene (PP), or polystyrene (PS) with 3000 ppm mixed tocopherols using conventional blending method and innovative blending method, smart blending with a novel mixer using chaotic advection. Film morphologies were visualized with scanning electron microscopy (SEM). Release of tocopherols into 95% ethanol as a food simulant was measured by UV/Visible spectrophotometry or HPLC, and diffusivity of tocopherols in the polymers was estimated from this data. Polymer composition (blend proportions) and processing methods have major effects on film morphology. Four different types of morphologies, dispersed, co-continuous, fiber, and multilayer structures were developed by either conventional extrusion or smart blending. With smart blending of fixed polymer compositions, different morphologies were progressively developed with fixed polymer composition as the number of rod rotations increased, providing a way to separate effects of polymer composition and morphology. The different morphologies obtained using conventional and smart blending greatly affected tocopherol release. Strong correlation was observed between morphology and release rate: multilayer, slow release; co-continuous and fiber, moderate; disperse: fast release. Results indicate that morphology can be manipulated by polymer composition and processing method, and release rates of tocopherols are varied with polymer morphology. Manipulating polymer compositions and film morphologies may provide a means to control the release of tocopherols from food contact films.

Ibuprofen-loaded poly(lactic-co-glycolic acid) films for controlled drug release.

PubMed

Pang, Jianmei; Luan, Yuxia; Li, Feifei; Cai, Xiaoqing; Du, Jimin; Li, Zhonghao

2011-01-01

Ibuprofen- (IBU) loaded biocompatible poly(lactic-co-glycolic acid) (PLGA) films were prepared by spreading polymer/ibuprofen solution on the nonsolvent surface. By controlling the weight ratio of drug and polymer, different drug loading polymer films can be obtained. The synthesized ibuprofen-loaded PLGA films were characterized with scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry. The drug release behavior of the as-prepared IBU-loaded PLGA films was studied to reveal their potential application in drug delivery systems. The results show the feasibility of the as-obtained films for controlling drug release. Furthermore, the drug release rate of the film could be controlled by the drug loading content and the release medium. The development of a biodegradable ibuprofen system, based on films, should be of great interest in drug delivery systems.

Effects of formulation variables and post-compression curing on drug release from a new sustained-release matrix material: polyvinylacetate-povidone.

PubMed

Shao, Z J; Farooqi, M I; Diaz, S; Krishna, A K; Muhammad, N A

2001-01-01

A new commercially available sustained-release matrix material, Kollidon SR, composed of polyvinylacetate and povidone, was evaluated with respect to its ability to modulate the in vitro release of a highly water-soluble model compound, diphenhydramine HCl. Kollidon SR was found to provide a sustained-release effect for the model compound, with certain formulation and processing variables playing an important role in controlling its release kinetics. Formulation variables affecting the release include the level of the polymeric material in the matrix, excipient level, as well as the nature of the excipients (water soluble vs. water insoluble). Increasing the ratio of a water-insoluble excipient, Emcompress, to Kollidon SR enhanced drug release. The incorporation of a water-soluble excipient, lactose, accelerated its release rate in a more pronounced manner. Stability studies conducted at 40 degrees C/75% RH revealed a slow-down in dissolution rate for the drug-Kollidon SR formulation, as a result of polyvinylacetate relaxation. Further studies demonstrated that a post-compression curing step effectively stabilized the release pattern of formulations containing > or = 47% Kollidon SR. The release mechanism of Kollidon-drug and drug-Kollidon-Emcompress formulations appears to be diffusion controlled, while that of the drug-Kollidon-lactose formulation appears to be controlled predominantly by diffusion along with erosion.

Laser-activated nano-biomaterials for tissue repair and controlled drug release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matteini, P; Ratto, F; Rossi, F

2014-07-31

We present recent achievements of minimally invasive welding of biological tissue and controlled drug release based on laser-activated nano-biomaterials. In particular, we consider new advancements in the biomedical application of near-IR absorbing gold nano-chromophores as an original solution for the photothermal repair of surgical incisions and as nanotriggers of controlled drug release from hybrid biopolymer scaffolds. (laser biophotonics)

Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropylmethylcellulose.

PubMed

Yi, Tao; Wan, Jiangling; Xu, Huibi; Yang, Xiangliang

2008-08-07

The objective of this work was the development of a controlled release system based on self-microemulsifying mixture aimed for oral delivery of poorly water-soluble drugs. HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) of low water solubility and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system (SMES) consisting of ethyl oleate, Cremophor RH 40 and Labrasol. Based on investigation by transmission electron microscopy (TEM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction, differences were found in the particle structure between both types of formulations. In vitro release was performed and characterized by the power law. Nimodipine release from both types of formulations showed a controlled release profile and the two power law parameters, n and K, correlated to the viscosity of HPMC. The parameters were also influenced by the presence of SMES. For the controlled release solid SMES, oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. Thus, it is possible to control the in vitro release of poorly soluble drugs from solid oral dosage forms containing SMES.

A Simple Approach for Molecular Controlled Release based on Atomic Layer Deposition Hybridized Organic-Inorganic Layers

PubMed Central

Boehler, Christian; Güder, Firat; Kücükbayrak, Umut M.; Zacharias, Margit; Asplund, Maria

2016-01-01

On-demand release of bioactive substances with high spatial and temporal control offers ground-breaking possibilities in the field of life sciences. However, available strategies for developing such release systems lack the possibility of combining efficient control over release with adequate storage capability in a reasonably compact system. In this study we present a new approach to target this deficiency by the introduction of a hybrid material. This organic-inorganic material was fabricated by atomic layer deposition of ZnO into thin films of polyethylene glycol, forming the carrier matrix for the substance to be released. Sub-surface growth mechanisms during this process converted the liquid polymer into a solid, yet water-soluble, phase. This layer permits extended storage for various substances within a single film of only a few micrometers in thickness, and hence demands minimal space and complexity. Improved control over release of the model substance Fluorescein was achieved by coating the hybrid material with a conducting polymer film. Single dosage and repetitive dispensing from this system was demonstrated. Release was controlled by applying a bias potential of ±0.5 V to the polymer film enabling or respectively suppressing the expulsion of the model drug. In vitro tests showed excellent biocompatibility of the presented system. PMID:26791399

An Exclusion Zone for Ca2+ Channels around Docked Vesicles Explains Release Control by Multiple Channels at a CNS Synapse

PubMed Central

Keller, Daniel; Babai, Norbert; Kochubey, Olexiy; Han, Yunyun; Markram, Henry; Schürmann, Felix; Schneggenburger, Ralf

2015-01-01

The spatial arrangement of Ca2+ channels and vesicles remains unknown for most CNS synapses, despite of the crucial importance of this geometrical parameter for the Ca2+ control of transmitter release. At a large model synapse, the calyx of Held, transmitter release is controlled by several Ca2+ channels in a "domain overlap" mode, at least in young animals. To study the geometrical constraints of Ca2+ channel placement in domain overlap control of release, we used stochastic MCell modelling, at active zones for which the position of docked vesicles was derived from electron microscopy (EM). We found that random placement of Ca2+ channels was unable to produce high slope values between release and presynaptic Ca2+ entry, a hallmark of domain overlap, and yielded excessively large release probabilities. The simple assumption that Ca2+ channels can be located anywhere at active zones, except below a critical distance of ~ 30 nm away from docked vesicles ("exclusion zone"), rescued high slope values and low release probabilities. Alternatively, high slope values can also be obtained by placing all Ca2+ channels into a single supercluster, which however results in significantly higher heterogeneity of release probabilities. We also show experimentally that high slope values, and the sensitivity to the slow Ca2+ chelator EGTA-AM, are maintained with developmental maturation of the calyx synapse. Taken together, domain overlap control of release represents a highly organized active zone architecture in which Ca2+ channels must obey a certain distance to docked vesicles. Furthermore, domain overlap can be employed by near-mature, fast-releasing synapses. PMID:25951120

Oral Drug Delivery Systems Comprising Altered Geometric Configurations for Controlled Drug Delivery

PubMed Central

Moodley, Kovanya; Pillay, Viness; Choonara, Yahya E.; du Toit, Lisa C.; Ndesendo, Valence M. K.; Kumar, Pradeep; Cooppan, Shivaan; Bawa, Priya

2012-01-01

Recent pharmaceutical research has focused on controlled drug delivery having an advantage over conventional methods. Adequate controlled plasma drug levels, reduced side effects as well as improved patient compliance are some of the benefits that these systems may offer. Controlled delivery systems that can provide zero-order drug delivery have the potential for maximizing efficacy while minimizing dose frequency and toxicity. Thus, zero-order drug release is ideal in a large area of drug delivery which has therefore led to the development of various technologies with such drug release patterns. Systems such as multilayered tablets and other geometrically altered devices have been created to perform this function. One of the principles of multilayered tablets involves creating a constant surface area for release. Polymeric materials play an important role in the functioning of these systems. Technologies developed to date include among others: Geomatrix® multilayered tablets, which utilizes specific polymers that may act as barriers to control drug release; Procise®, which has a core with an aperture that can be modified to achieve various types of drug release; core-in-cup tablets, where the core matrix is coated on one surface while the circumference forms a cup around it; donut-shaped devices, which possess a centrally-placed aperture hole and Dome Matrix® as well as “release modules assemblage”, which can offer alternating drug release patterns. This review discusses the novel altered geometric system technologies that have been developed to provide controlled drug release, also focusing on polymers that have been employed in such developments. PMID:22312236

Use of fibrin sealants for the localized, controlled release of cefazolin

PubMed Central

Tredwell, Stephen; Jackson, John K.; Hamilton, Donald; Lee, Vivian; Burt, Helen M.

2006-01-01

Background Fibrin sealants are used increasingly in surgery to reduce bleeding and improve wound healing. They have great potential as biocompatible, biodegradable drug delivery systems, because the sealant may adhere to the target tissue and allow controlled release of the drug over an extended period. We investigated the encapsulation, stability and controlled release of erythromycin and cefazolin from Beriplast fibrin sealants (Aventis Behring Canada). Methods Drug-loaded clots were cast in glass vials and allowed to set. We observed the clots for drug precipitation and aggregation, and we assessed the effect of drug encapsulation on clot strength. Drug stability and release from the clots in phosphate buffered saline (PBS) was quantified by ultraviolet and visible violet absorbance spectroscopy and high-performance liquid chromatography. Results Erythromycin was found to release slowly from the fibrin clots over the first 2 hours but then degrade rapidly. Cefazolin was found to be very stable in clots in PBS (97% stable at 2 d and 93% stable at 5 d). The drug released in a controlled manner over 2 days, with most being released during the first day. The dose of drug released could be varied by changing the amount placed in the thrombin solution. Clot thickness had no effect on the rate of cefazolin release. Conclusion Overall, the 2-day release profile and the excellent stability of the drug suggest that cefazolin-loaded fibrin sealants may offer an effective route of postoperative antibiotic delivery. PMID:17152573

Controlled Release from Recombinant Polymers

PubMed Central

Price, Robert; Poursaid, Azadeh; Ghandehari, Hamidreza

2014-01-01

Recombinant polymers provide a high degree of molecular definition for correlating structure with function in controlled release. The wide array of amino acids available as building blocks for these materials lend many advantages including biorecognition, biodegradability, potential biocompatibility, and control over mechanical properties among other attributes. Genetic engineering and DNA manipulation techniques enable the optimization of structure for precise control over spatial and temporal release. Unlike the majority of chemical synthetic strategies used, recombinant DNA technology has allowed for the production of monodisperse polymers with specifically defined sequences. Several classes of recombinant polymers have been used for controlled drug delivery. These include, but are not limited to, elastin-like, silk-like, and silk-elastinlike proteins, as well as emerging cationic polymers for gene delivery. In this article, progress and prospects of recombinant polymers used in controlled release will be reviewed. PMID:24956486

Controlled Release of Imidacloprid from Poly Styrene-Diacetone - Nanoformulation

NASA Astrophysics Data System (ADS)

Qian, Kun; Guo, Yanzhen; He, Lin

2012-01-01

Imidacloprid is a neonicotinoids insecticide, which is important for the cash crops such as tomato, rape and so on. The conventional formulation does not only increase the loss of pesticide but also leads to environmental pollution. Controlled-release formulations of pesticide are highly desirable not only for attaining the most effective utilization of the pesticide, but also for reducing environmental pollution. Pesticide imidacloprid was incorporated in poly (styrene-diacetone crylamide)-based formulation to obtain controlled release properties, and the imidacloprid nanocontrolled release formulation was characterized by infrared (IR) and field emission scanning electron microscope (FESEM). Factors related to loading efficiency, swelling and release behaviors of the formulation were investigated. It showed that the loading efficiency could reach about 40% (w/w). The values for the diffusion exponent "n" were in the range of 0.31-0.58, which indicated that the release of imidacloprid was diffusion-controlled. The time taken for 50% of the active ingredient to be released into water, T50, was also calculated for the comparison of formulations in different conditions. The results showed that the formulation with higher temperature and more diacetone crylamide had lower value of T50, which means a quicker release of the active ingredient. This study highlighted some pieces of evidence that improved pesticide incorporation and slower release were linked to potential interactions between the pesticide and the polymer.

pH dependent silver nanoparticles releasing titanium implant: A novel therapeutic approach to control peri-implant infection.

PubMed

Dong, Yiwen; Ye, Hui; Liu, Yi; Xu, Lihua; Wu, Zuosu; Hu, Xiaohui; Ma, Jianfeng; Pathak, Janak L; Liu, Jinsong; Wu, Gang

2017-10-01

Peri-implant infection control is crucial for implant fixation and durability. Antimicrobial administration approaches to control peri-implant infection are far from satisfactory. During bacterial infection, pH level around the peri-implant surface decreases as low as pH 5.5. This change of pH can be used as a switch to control antimicrobial drug release from the implant surface. Silver nanoparticles (AgNPs) have broad-spectrum antimicrobial properties. In this study, we aimed to design a pH-dependent AgNPs releasing titania nanotube arrays (TNT) implant for peri-implant infection control. The nanotube arrays were fabricated on the surface of titanium implant as containers; AgNPs were grafted on TNT implant surface via a low pH-sensitive acetal linker (TNT-AL-AgNPs). SEM, TEM, AFM, FTIR as well as XPS data showed that AgNPs have been successfully linked to TNT via acetal linker without affecting the physicochemical characteristics of TNT. The pH 5.5 enhanced AgNPs release from TNT-AL-AgNPs implant compared with pH 7.4. AgNPs released at pH 5.5 robustly increased antimicrobial activities against gram-positive and gram-negative bacteria compared with AgNPs released at pH 7.4. TNT-AL-AgNPs implant enhanced osteoblast proliferation, differentiation, and did not affect osteoblast morphology in vitro. In conclusion, incorporation of AgNPs in TNT via acetal linker maintained the surface characteristics of TNT. TNT-AL-AgNPs implant was biocompatible to osteoblasts and showed osteoinductive properties. AgNPs were released from TNT-AL-AgNPs implant in high dose at pH 5.5, and this release showed strong antimicrobial properties in vitro. Therefore, this novel design of low pH-triggered AgNPs releasing TNT-AL-AgNPs could be an infection-triggered antimicrobial releasing implant model to control peri-implant infection. Copyright © 2017 Elsevier B.V. All rights reserved.

A diels-alder modulated approach to control and sustain the release of dexamethasone and induce osteogenic differentiation of human mesenchymal stem cells

PubMed Central

Koehler, Kenneth C.; Alge, Daniel L.; Anseth, Kristi S.; Bowman, Christopher N.

2013-01-01

We report a new approach to controlled drug release based upon exploiting the dynamic equilibrium that exists between Diels-Alder reactants and products, demonstrating the release of a furan containing dexamethasone peptide (dex-KGPQG-furan) from a maleimide containing hydrogel. Using a reaction-diffusion model, the release kinetics were tuned to achieve sustained concentrations conducive to osteogenic differentiation of human mesenchymal stem cells (hMSCs). Efficacy was first demonstrated in a 2D culture model, in which dexamethasone release induced significant increases in alkaline phosphatase (ALP) activity and mineral deposition in hMSCs compared to a dexamethasone-free treatment. The results were similar to that observed with a soluble dexamethasone treatment. More dramatic differences were observed in 3D culture, where co-encapsulation of a dexamethasone releasing hydrogel depot within an hMSC-laden extracellular matrix mimetic poly(ethylene glycol) hydrogel resulted in a local and robust osteogenic differentiation. ALP activity reached levels that were up to six times higher than the dexamethasone free treatment. Interestingly, at 5 and 10 day time points, the ALP activity exceeded the dexamethasone positive control, suggesting a potential benefit of sustained release in 3D culture. After 21 days, substantial mineralization comparable to the positive control was also observed in the hydrogels. Collectively, these results demonstrate Diels-Alder modulated release as an effective and versatile new platform for controlled drug delivery that may prove especially beneficial for sustaining the release of low molecular weight molecules in hydrogel systems. PMID:23465826

Regulating Drug Release Behavior and Kinetics from Matrix Tablets Based on Fine Particle-Sized Ethyl Cellulose Ether Derivatives: An In Vitro and In Vivo Evaluation

PubMed Central

Shah, Kifayat Ullah; Khan, Gul Majid

2012-01-01

The design and fabrication of sustained/controlled release dosage forms, employing new excipients capable of extending/controlling the release of drugs from the dosage forms over prolonged periods, has worked well in achieving optimally enhanced therapeutic levels of the drugs. In this sense, the objective of this study was to investigate the suitability of selected cellulose ether derivatives for use in direct compression (DC) and as efficient drug release controlling agents. Controlled release matrix tablets of ciprofloxacin were prepared at different drug-to-polymer (D : P) ratios by direct compression using a fine particle sized ethylcellulose ether derivative (ETHOCEL Standard Premium 7FP) as rate controlling polymer. The tablets obtained were evaluated for various physico-chemical characteristics and in-vitro drug release studies were conducted in phosphate buffer (pH 7.4) using PharmaTest dissolution apparatus at constant temperature of 37°C ± 0.1. Similarity factor f 2 was employed to the release profiles of test formulations and were compared with marketed ciprofloxacin conventional tablets. Drug release mechanism and the kinetics involved were investigated by fitting the release profile data to various kinetic models. It was found that with increasing the proportion of ethylcellulose ether derivative in the matrix, the drug release was significantly extended up to 24 hours. The tablets exhibited zero order or nearly zero order drug transport mechanism. In vivo drug release performance of the developed controlled release tablets and reference conventional tablets containing ciprofloxacin were determined in rabbit serum according to randomized two-way crossover study design using High Performance Liquid Chromatography. Several bioavailability parameters of both the test tablets and conventional tablets including C max⁡, T max⁡ and AUC0-t were compared which showed an optimized C max⁡ and T max⁡ (P < 0.05). A good correlation was obtained between in vitro drug release and in vivo drug absorption with correlation value (R 2 = 0.934). Relative bioavailability was found to be 93%. Reproducibility of manufacturing process and accelerated stability of the developed tablets were performed in stability chamber at 40 ± 2°C and 75 ± 5% relative humidity for a period of 6 months and were found to be stable throughout the stability period. PMID:22649325

Controlled release hydrophilic matrix tablet formulations of isoniazid: design and in vitro studies.

PubMed

Hiremath, Praveen S; Saha, Ranendra N

2008-01-01

The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer-Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f (2) metric values. The release profiles found to follow Higuchi's square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.

Coordination responsive tellurium-containing multilayer film for controlled delivery.

PubMed

Cao, Wei; Wang, Lu; Xu, Huaping

2015-03-28

A coordination-responsive tellurium containing film was fabricated for controlled release. The coordination chemistry between telluride molecules and cisplatin was utilized for the loading of cisplatin, while competitive ligands were used for triggered release. This work could enrich the coordination responsive system and further tune the release kinetics of cisplatin.

PREVENTION REFERENCE MANUAL: OVERVIEWS ON PREVENTING AND CONTROLLING ACCIDENTIAL RELEASES OF SELECTED TOXIC CHEMICALS

EPA Science Inventory

The manual can be used to orient personnel involved in inspecting and otherwise evaluating potential toxic chemical release hazards to the fundamentals of release hazard control for 13 of the specific chemicals chosen for evaluation under Section 305(b) of the Superfund Amendment...

Pectin gel vehicles for controlled fragrance delivery.

PubMed

Liu, LinShu; Chen, Guoying; Fishman, Marshall L; Hicks, Kevin B

2005-01-01

Using citronellal as a model compound, pectin gels formulations were evaluated for the controlled fragrance release by kinetic and static methods. The pectins with higher degrees of esterification induced a stronger molecular association with the nonpolar fragrance. This resulted in a prolonged duration of fragrance release and the limitation of fragrance adsorption to the receptor skin layers. The increase in pectin concentrations suppressed the fragrance release by a diffusion mechanism. Blocking the carboxyl groups of pectin with calcium ions reduces the hydrophilicity of pectin and provides physical barriers for citronellal diffusion. The pectin/calcium microparticles are promising materials for controlled fragrance release.

Development and Evaluation of Oral Controlled Release Chlorpheniramine-Ion Exchange Resinate Suspension

PubMed Central

Kadam, A. U.; Sakarkar, D. M.; Kawtikwar, P. S.

2008-01-01

An oral controlled release suspension of chlorpheniramine maleate was prepared using ion-exchange resin technology. A strong cation exchange resin Indion 244 was utilized for the sorption of the drug and the drug resinates was evaluated for various physical and chemical parameters. The drug-resinate complex was microencapsulated with a polymer Eudragit RS 100 to further retard the release characteristics. Both the drug-resinate complex and microencapsulated drug resinate were suspended in a palatable aqueous suspension base and were evaluated for controlled release characteristic. Stability study indicated that elevated temperature did not alter the sustained release nature of the dosage form indicating that polymer membrane surrounding the core material remained intact throughout the storage period. PMID:20046790

Controlling Release of Integral Lipid Nanoparticles Based on Osmotic Pump Technology.

PubMed

Tian, Zhiqiang; Yu, Qin; Xie, Yunchang; Li, Fengqian; Lu, Yi; Dong, Xiaochun; Zhao, Weili; Qi, Jianping; Wu, Wei

2016-08-01

To achieve controlled release of integral nanoparticles by the osmotic pump strategy using nanostructured lipid carriers (NLCs) as model nanoparticles. NLCs was prepared by a hot-homogenization method, transformed into powder by lyophilization, and formulated into osmotic pump tablets (OPTs). Release of integral NLCs was visualized by live imaging after labeling with a water-quenching fluorescent probe. Effects of formulation variables on in vitro release characteristics were evaluated by measuring the model drug fenofibrate. Pharmacokinetics were studied in beagle dogs using the core tablet and a micronized fenofibrate formulation as references. NLCs are released through the release orifices of the OPTs as integral nanoparticles. Near zero-order kinetics can be achieved by optimizing the influencing variables. After oral administration, decreased C max and steady drug levels for as long as over 24 h are observed. NLC-OPTs show an oral bioavailability of the model drug fenofibrate similar to that of the core tablets, which is about 1.75 folds that of a fast-release formulation. Controlled release of integral NLCs is achieved by the osmotic pump strategy.

Synthesis and characterization of emamectin-benzoate slow-release microspheres with different surfactants.

PubMed

Wang, Yan; Wang, Anqi; Wang, Chunxin; Cui, Bo; Sun, Changjiao; Zhao, Xiang; Zeng, Zhanghua; Shen, Yue; Gao, Fei; Liu, Guoqiang; Cui, Haixin

2017-10-06

Pesticide slow-release formulations provide a way to increase the efficiency of active components by reducing the amount of pesticide that needs to be applied. Slow-release formulations also increase the stability and prolong the control effect of photosensitive pesticides. Surfactants are an indispensable part of pesticide formulations, and the choice of surfactant can strongly affect formulation performance. In this study, emamectin-benzoate (EMB) slow-release microspheres were prepared by the microemulsion polymerization method. We explored the effect of different surfactants on the particle size and dispersity of EMB in slow-release microspheres. The results indicated that the samples had uniform spherical shapes with an average diameter of 320.5 ±5.24 nm and good dispersity in the optimal formulation with the polymeric stabilizer polyvinyl alcohol (PVA) and composite non-ionic surfactant polyoxyethylene castor oil (EL-40). The optimal EMB pesticide slow-release microspheres had excellent anti-photolysis performance, stability, controlled release properties, and good leaf distribution. These results demonstrated that EMB slow-release microspheres are an attractive candidate for improving pesticide efficacy and prolonging the control effect of EMB in the environment.

A modified SILCS contraceptive diaphragm for long-term controlled release of the HIV microbicide dapivirine.

PubMed

Major, Ian; Boyd, Peter; Kilbourne-Brook, Maggie; Saxon, Gene; Cohen, Jessica; Malcolm, R Karl

2013-07-01

There is considerable interest in developing new multipurpose prevention technologies to address women's reproductive health needs. This study describes an innovative barrier contraceptive device--based on the SILCS diaphragm--that also provides long-term controlled release of the lead candidate anti-HIV microbicide dapivirine. Diaphragm devices comprising various dapivirine-loaded polymer spring cores overmolded with a nonmedicated silicone elastomer sheath were fabricated by injection molding processes. In vitro release testing, thermal analysis and mechanical characterization were performed on the devices. A diaphragm device containing a polyoxymethylene spring core loaded with 10% w/w dapivirine provided continuous and controlled release of dapivirine over a 6-month period, with a mean in vitro daily release rate of 174 mcg/day. The mechanical properties of the new diaphragm were closely matched to the SILCS diaphragm. The study demonstrates proof of concept for a dapivirine-releasing diaphragm with daily release quantities potentially capable of preventing HIV transmission. In discontinuous clinical use, release of dapivirine may be readily extended over 1 or more years. Copyright © 2013 Elsevier Inc. All rights reserved.

Modelling Aedes aegypti mosquito control via transgenic and sterile insect techniques: endemics and emerging outbreaks.

PubMed

Seirin Lee, S; Baker, R E; Gaffney, E A; White, S M

2013-08-21

The invasion of pest insects often changes or destroys a native ecosystem, and can result in food shortages and disease endemics. Issues such as the environmental effects of chemical control methods, the economic burden of maintaining control strategies and the risk of pest resistance still remain, and mosquito-borne diseases such as malaria and dengue fever prevail in many countries, infecting over 100 million worldwide in 2010. One environmentally friendly method for mosquito control is the Sterile Insect Technique (SIT). This species-specific method of insect control relies on the mass rearing, sterilization and release of large numbers of sterile insects. An alternative transgenic method is the Release of Insects carrying a Dominant Lethal (RIDL). Our objective is to consider contrasting control strategies for two invasive scenarios via SIT and RIDL: an endemic case and an emerging outbreak. We investigate how the release rate and size of release region influence both the potential for control success and the resources needed to achieve it, under a range of conditions and control strategies, and we discuss advantageous strategies with respect to reducing the release resources and strategy costs (in terms of control mosquito numbers) required to achieve complete eradication of wild-type mosquitoes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Control of accidental releases of hydrogen selenide in vented storage cabinets

NASA Astrophysics Data System (ADS)

Fthenakis, V. M.; Moskowitz, P. D.; Sproull, R. D.

1988-07-01

Highly toxic hydrogen selenide and hydrogen sulfide gases are used in the production of copper-indium-diselenide photovoltaic cells by reactive sputtering. In the event of an accident, these gases may be released to the atmosphere and pose hazards to public and occupational safety and health. This paper outlines an approach for designing systems for the control of these releases given the uncertainty in release conditions and lack of data on the chemical systems involved. Accidental releases of these gases in storage cabinets can be controlled by either a venturi and packed-bed scrubber and carbon adsorption bed, or containment scrubbing equipment followed by carbon adsorption. These systems can effectively reduce toxic gas emissions to levels needed to protect public health. The costs of these controls (˜0.012/Wp) are samll in comparison with current (˜6/Wp) and projected (˜I/Wp) production costs.

Synthesis and characterization of superabsorbent polymer prepared by radiation-induced graft copolymerization of acrylamide onto carboxymethyl cellulose for controlled release of agrochemicals

NASA Astrophysics Data System (ADS)

Hemvichian, Kasinee; Chanthawong, Auraruk; Suwanmala, Phiriyatorn

2014-10-01

Superabsorbent polymer (SAP) was synthesized by radiation-induced grafting of acrylamide (AM) onto carboxymethyl cellulose (CMC) in the presence of a crosslinking agent, N,N‧-methylenebisacrylamide (MBA). The effects of various parameters, such as dose, the amount of CMC, AM, MBA and ionic strength on the swelling ratio were investigated. In order to evaluate its controlled release potential, SAP was loaded with potassium nitrate (KNO3) as an agrochemical model and its potential for controlled release of KNO3 was studied. The amount of released KNO3 was analyzed by an inductively coupled plasma mass spectrometry (ICP-MS). The results from controlled release experiment agreed very well with the results from swelling experiment. The synthesized SAP was characterized by Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). The obtained SAP exhibited a swelling ratio of 190 g/g of dry gel.

X-ray Radiation-Controlled NO-Release for On-Demand Depth-Independent Hypoxic Radiosensitization.

PubMed

Fan, Wenpei; Bu, Wenbo; Zhang, Zhen; Shen, Bo; Zhang, Hui; He, Qianjun; Ni, Dalong; Cui, Zhaowen; Zhao, Kuaile; Bu, Jiwen; Du, Jiulin; Liu, Jianan; Shi, Jianlin

2015-11-16

Multifunctional stimuli-responsive nanotheranostic systems are highly desirable for realizing simultaneous biomedical imaging and on-demand therapy with minimized adverse effects. Herein, we present the construction of an intelligent X-ray-controlled NO-releasing upconversion nanotheranostic system (termed as PEG-USMSs-SNO) by engineering UCNPs with S-nitrosothiol (R-SNO)-grafted mesoporous silica. The PEG-USMSs-SNO is designed to respond sensitively to X-ray radiation for breaking down the S-N bond of SNO to release NO, which leads to X-ray dose-controlled NO release for on-demand hypoxic radiosensitization besides upconversion luminescent imaging through UCNPs in vitro and in vivo. Thanks to the high live-body permeability of X-ray, our developed PEG-USMSs-SNO may provide a new technique for achieving depth-independent controlled NO release and positioned radiotherapy enhancement against deep-seated solid tumors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The controlled release of tilmicosin from silica nanoparticles.

PubMed

Song, Meirong; Li, Yanyan; Fai, Cailing; Cui, Shumin; Cui, Baoan

2011-06-01

The aim of this study was to use silica nanoparticles as the carrier for controlled release of tilmicosin. Tilmicosin was selected as a drug model molecule because it has a lengthy elimination half-life and a high concentration in milk after subcutaneous administration. Three samples of tilmicosin-loaded silica nanoparticles were prepared with different drug-loading weight. The drug-loading weight in three samples, as measured by thermal gravimetric analysis, was 29%, 42%, and 64%, respectively. With increased drug-loading weight, the average diameter of the drug-loaded silica nanoparticles was increased from 13.4 to 25.7 nm, and the zeta potential changed from-30.62 to-6.78 mV, indicating that the stability of the drug-loaded particles in the aqueous solution decreases as drug-loading weight increases. In vitro release studies in phosphate-buffered saline showed the sample with 29% drug loading had a slow and sustained drug release, reaching 44% after 72 h. The release rate rose with increased drug-loading weight; therefore, the release of tilmicosin from silica nanoparticles was well-controlled by adjusting the drug loading. Finally, kinetics analysis suggested that drug released from silica nanoparticles was mainly a diffusion-controlled process.

Controlling protein release using biodegradable microparticles

NASA Astrophysics Data System (ADS)

Kline, Benjamin Patrick

Research in the field of protein therapeutics has exploded over the past decade and continues to grow in both academia and in industry. Protein drugs have advantages of being highly specific and highly active making them coveted targets for high profile disease states like cancer and multiple sclerosis. Unfortunately, their many advantages are complemented by their obstacles. Because proteins are highly active and highly specific, the window between efficacy and toxicity is very narrow and drug development can be long and arduous. In addition, protein activity is dependent on its specific folding conformation that is easily disrupted by a variety of development processes. This research aimed to identify microparticle formulations to control protein release and also to determine which formulation parameters affected burst release, encapsulation, and steady-state release the most. It was found that polymer type and composition were two of the most important factors. Long-term controlled release of bovine serum albumin (BSA) was achieved as well as a wide variety of release profiles. A method was identified for micronizing protein at low cost to retain activity and coacervation was evaluated as a method for preparing protein loaded microspheres. This research provides a basis from which researchers can create better controlled release formulations for future protein therapeutics.

Development of controlled release formulations of azadirachtin-A employing poly(ethylene glycol) based amphiphilic copolymers.

PubMed

Kumar, Jitendra; Shakil, Najam A; Singh, Manish K; Singh, Mukesh K; Pandey, Alka; Pandey, Ravi P

2010-05-01

Controlled release (CR) formulations of azadirachtin-A, a bioactive constituent derived from the seed of Azadirachta indica A. Juss (Meliaceae), have been prepared using commercially available polyvinyl chloride, polyethylene glycol (PEG) and laboratory synthesized poly ethylene glycol-based amphiphilic copolymers. Copolymers of polyethylene glycol and various dimethyl esters, which self assemble into nano micellar aggregates in aqueous media, have been synthesized. The kinetics of azadirachtin-A, release in water from the different formulations was studied. Release from the commercial polyethylene glycol (PEG) formulation was faster than the other CR formulations. The rate of release of encapsulated azadirachtin-A from nano micellar aggregates is reduced by increasing the molecular weight of PEG. The diffusion exponent (n value) of azadirachtin-A, in water ranged from 0.47 to 1.18 in the tested formulations. The release was diffusion controlled with a half release time (t(1/2)) of 3.05 to 42.80 days in water from different matrices. The results suggest that depending upon the polymer matrix used, the application rate of azadirachtin-A can be optimized to achieve insect control at the desired level and period.

Drug Loading and Release Behavior Depending on the Induced Porosity of Chitosan/Cellulose Multilayer Nanofilms.

PubMed

Park, Sohyeon; Choi, Daheui; Jeong, Hyejoong; Heo, Jiwoong; Hong, Jinkee

2017-10-02

The ability to control drug loading and release is the most important feature in the development of medical devices. In this research, we prepared a functional nanocoating technology to incorporate a drug-release layer onto a desired substrate. The multilayer films were prepared using chitosan (CHI) and carboxymethyl cellulose (CMC) polysaccharides by the layer-by-layer (LbL) method. By using chemical cross-linking to change the inner structure of the assembled multilayer, we could control the extent of drug loading and release. The cross-linked multilayer film had a porous structure and enhanced water wettability. Interestingly, more of the small-molecule drug was loaded into and released from the non-cross-linked multilayer film, whereas more of the macromolecular drug was loaded into and released from the cross-linked multilayer film. These results indicate that drug loading and release can be easily controlled according to the molecular weight of the desired drug by changing the structure of the film.

Controlled release of curcumin from poly(HEMA-MAPA) membrane.

PubMed

Caka, Müşerref; Türkcan, Ceren; Aktaş Uygun, Deniz; Uygun, Murat; Akgöl, Sinan; Denizli, Adil

2017-05-01

In this work, poly(HEMA-MAPA) membranes were prepared by UV-polymerization technique. These membranes were characterized by SEM, FTIR, and swelling studies. Synthesized membranes had high porous structure. These membranes were used for controlled release of curcumin which is already used as folk remedy and used as drug for some certain diseases and cancers. Curcumin release was investigated for various pHs and temperatures. Optimum drug release yield was found to be as 70% at pH 7.4 and 37 °C within 2 h period. Time-depended release of curcumin was also investigated and its slow release from the membrane demonstrated within 48 h.

Programmable release of multiple protein drugs from aptamer-functionalized hydrogels via nucleic acid hybridization.

PubMed

Battig, Mark R; Soontornworajit, Boonchoy; Wang, Yong

2012-08-01

Polymeric delivery systems have been extensively studied to achieve localized and controlled release of protein drugs. However, it is still challenging to control the release of multiple protein drugs in distinct stages according to the progress of disease or treatment. This study successfully demonstrates that multiple protein drugs can be released from aptamer-functionalized hydrogels with adjustable release rates at predetermined time points using complementary sequences (CSs) as biomolecular triggers. Because both aptamer-protein interactions and aptamer-CS hybridization are sequence-specific, aptamer-functionalized hydrogels constitute a promising polymeric delivery system for the programmable release of multiple protein drugs to treat complex human diseases.

Modulation of drug release kinetics of shellac-based matrix tablets by in-situ polymerization through annealing process.

PubMed

Limmatvapirat, Sontaya; Limmatvapirat, Chutima; Puttipipatkhachorn, Satit; Nunthanid, Jurairat; Luangtana-anan, Manee; Sriamornsak, Pornsak

2008-08-01

A new oral-controlled release matrix tablet based on shellac polymer was designed and developed, using metronidazole (MZ) as a model drug. The shellac-based matrix tablets were prepared by wet granulation using different amounts of shellac and lactose. The effect of annealing temperature and pH of medium on drug release from matrix tablets was investigated. The increased amount of shellac and increased annealing temperature significantly affected the physical properties (i.e., tablet hardness and tablet disintegration) and MZ release from the matrix tablets. The in-situ polymerization played a major role on the changes in shellac properties during annealing process. Though the shellac did not dissolve in acid medium, the MZ release in 0.1N HCl was faster than in pH 7.3 buffer, resulting from a higher solubility of MZ in acid medium. The modulation of MZ release kinetics from shellac-based matrix tablets could be accomplished by varying the amount of shellac or annealing temperature. The release kinetics was shifted from relaxation-controlled release to diffusion-controlled release when the amount of shellac or the annealing temperature was increased.

Control of lipopolysaccharide biosynthesis and release by Escherichia coli and Salmonella typhimurium.

PubMed Central

Ishiguro, E E; Vanderwel, D; Kusser, W

1986-01-01

The influence of the relA gene on lipopolysaccharide (LPS) biosynthesis and release by Escherichia coli and Salmonella typhimurium was investigated. Similar results were obtained with both species. The incorporation of [3H]galactose into LPS by galE mutants was inhibited by at least 50% (as compared with normal growing controls) during amino acid deprivation of relA+ strains. This inhibition could be prevented by the treatment of the amino acid-deprived relA+ bacteria with chloramphenicol, a known antagonist of the stringent control mechanism. Furthermore, LPS biosynthesis was not inhibited during amino acid deprivation of isogenic relA mutant strains. These results indicate that LPS synthesis is regulated by the stringent control mechanism. Normal growing cells of both relA+ and relA strains released LPS into the culture fluid at low rates. Amino acid deprivation stimulated the rate of LPS release by relA mutants but not by relA+ bacteria. Chloramphenicol treatment markedly stimulated the release of cell-bound LPS by amino acid-deprived relA+ cells. Thus, a low rate of LPS release was characteristic of normal growth and could be increased in nongrowing cells by relaxing the control of LPS synthesis. Images PMID:3531174

Magnetic field activated lipid-polymer hybrid nanoparticles for stimuli-responsive drug release.

PubMed

Kong, Seong Deok; Sartor, Marta; Hu, Che-Ming Jack; Zhang, Weizhou; Zhang, Liangfang; Jin, Sungho

2013-03-01

Stimuli-responsive nanoparticles (SRNPs) offer the potential of enhancing the therapeutic efficacy and minimizing the side-effects of chemotherapeutics by controllably releasing the encapsulated drug at the target site. Currently controlled drug release through external activation remains a major challenge during the delivery of therapeutic agents. Here we report a lipid-polymer hybrid nanoparticle system containing magnetic beads for stimuli-responsive drug release using a remote radio frequency (RF) magnetic field. These hybrid nanoparticles show long-term stability in terms of particle size and polydispersity index in phosphate-buffered saline (PBS). Controllable loading of camptothecin (CPT) and Fe(3)O(4) in the hybrid nanoparticles was demonstrated. RF-controlled drug release from these nanoparticles was observed. In addition, cellular uptake of the SRNPs into MT2 mouse breast cancer cells was examined. Using CPT as a model anticancer drug the nanoparticles showed a significant reduction in MT2 mouse breast cancer cell growth in vitro in the presence of a remote RF field. The ease of preparation, stability, and controllable drug release are the strengths of the platform and provide the opportunity to improve cancer chemotherapy. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Controlled release of metronidazole from composite poly-ε-caprolactone/alginate (PCL/alginate) rings for dental implants.

PubMed

Lan, Shih-Feng; Kehinde, Timilehin; Zhang, Xiangming; Khajotia, Sharukh; Schmidtke, David W; Starly, Binil

2013-06-01

Dental implants provide support for dental crowns and bridges by serving as abutments for the replacement of missing teeth. To prevent bacterial accumulation and growth at the site of implantation, solutions such as systemic antibiotics and localized delivery of bactericidal agents are often employed. The objective of this study was to demonstrate a novel method of controlled localized delivery of antibacterial agents to an implant site using a biodegradable custom fabricated ring. The study involved incorporating a model antibacterial agent (metronidazole) into custom designed poly-ε-caprolactone/alginate (PCL/alginate) composite rings to produce the intended controlled release profile. The rings can be designed to fit around the body of any root form dental implants of various diameters, shapes and sizes. In vitro release studies indicate that pure (100%) alginate rings exhibited an expected burst release of metronidazole in the first few hours, whereas Alginate/PCL composite rings produced a medium burst release followed by a sustained release for a period greater than 4 weeks. By varying the PCL/alginate weight ratios, we have shown that we can control the amount of antibacterial agents released to provide the minimal inhibitory concentration (MIC) needed for adequate protection. The fabricated composite rings have achieved a 50% antibacterial agent release profile over the first 48 h and the remaining amount slowly released over the remainder of the study period. The PCL/alginate agent release characteristic fits the Ritger-Peppas model indicating a diffusion-based mechanism during the 30-day study period. The developed system demonstrates a controllable drug release profile and the potential for the ring to inhibit bacterial biofilm growth for the prevention of diseases such as peri-implantitis resulting from bacterial infection at the implant site. Copyright © 2013 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Long-term Controlled Drug Release from bi-component Electrospun Fibers

NASA Astrophysics Data System (ADS)

Xu, Shanshan; Zhang, Zixin; Xia, Qinghua; Han, Charles

Multi-drug delivery systems with timed programmed release are hard to be produced due to the complex drug release kinetics which mainly refers to the diffusion of drug molecules from the fiber and the degradation of the carrier. This study focused on the whole life-time story of the long-term drug releasing fibrous systems. Electrospun membrane utilizing FDA approved polymers and broad-spectrum antibiotics showed specific drug release profiles which could be divided into three stages based on the profile slope. With throughout morphology observation, cumulative release amount and releasing duration, releasing kinetics and critical factors were fully discussed during three stages. Through changing the second component, approximately linear drug release profile and a drug release duration about 13 days was prepared, which is perfect for preventing post-operative infection. The addition of this semi-crystalline polymer in turn influenced the fiber swelling and created drug diffusion channels. In conclusion, through adjusting and optimization of the blending component, initial burst release, delayed release for certain duration, and especially the sustained release profile could all be controlled, as well as specific anti-bacterial behavior could be obtained.

Adsorption and release of biocides with mesoporous silica nanoparticles

NASA Astrophysics Data System (ADS)

Popat, Amirali; Liu, Jian; Hu, Qiuhong; Kennedy, Michael; Peters, Brenton; Lu, Gao Qing (Max); Qiao, Shi Zhang

2012-01-01

In this proof-of-concept study, an agricultural biocide (imidacloprid) was effectively loaded into the mesoporous silica nanoparticles (MSNs) with different pore sizes, morphologies and mesoporous structures for termite control. This resulted in nanoparticles with a large surface area, tunable pore diameter and small particle size, which are ideal carriers for adsorption and controlled release of imidacloprid. The effect of pore size, surface area and mesoporous structure on uptake and release of imidacloprid was systematically studied. It was found that the adsorption amount and release profile of imidacloprid were dependent on the type of mesoporous structure and surface area of particles. Specifically, MCM-48 type mesoporous silica nanoparticles with a three dimensional (3D) open network structure and high surface area displayed the highest adsorption capacity compared to other types of silica nanoparticles. Release of imidacloprid from these nanoparticles was found to be controlled over 48 hours. Finally, in vivo laboratory testing on termite control proved the efficacy of these nanoparticles as delivery carriers for biopesticides. We believe that the present study will contribute to the design of more effective controlled and targeted delivery for other biomolecules.In this proof-of-concept study, an agricultural biocide (imidacloprid) was effectively loaded into the mesoporous silica nanoparticles (MSNs) with different pore sizes, morphologies and mesoporous structures for termite control. This resulted in nanoparticles with a large surface area, tunable pore diameter and small particle size, which are ideal carriers for adsorption and controlled release of imidacloprid. The effect of pore size, surface area and mesoporous structure on uptake and release of imidacloprid was systematically studied. It was found that the adsorption amount and release profile of imidacloprid were dependent on the type of mesoporous structure and surface area of particles. Specifically, MCM-48 type mesoporous silica nanoparticles with a three dimensional (3D) open network structure and high surface area displayed the highest adsorption capacity compared to other types of silica nanoparticles. Release of imidacloprid from these nanoparticles was found to be controlled over 48 hours. Finally, in vivo laboratory testing on termite control proved the efficacy of these nanoparticles as delivery carriers for biopesticides. We believe that the present study will contribute to the design of more effective controlled and targeted delivery for other biomolecules. Electronic supplementary information (ESI) available. See DOI: 10.1039/c2nr11691j

Duloxetine and Subacute Pain after Knee Arthroplasty when Added to a Multimodal Analgesic Regimen: A Randomized, Placebo-controlled, Triple-blinded Trial.

PubMed

YaDeau, Jacques T; Brummett, Chad M; Mayman, David J; Lin, Yi; Goytizolo, Enrique A; Padgett, Douglas E; Alexiades, Michael M; Kahn, Richard L; Jules-Elysee, Kethy M; Fields, Kara G; Goon, Amanda K; Gadulov, Yuliya; Westrich, Geoffrey

2016-09-01

Duloxetine is effective for chronic musculoskeletal and neuropathic pain, but there are insufficient data to recommend the use of antidepressants for postoperative pain. The authors hypothesized that administration of duloxetine for 15 days would reduce pain with ambulation at 2 weeks after total knee arthroplasty. In this triple-blinded, randomized, placebo-controlled trial, patients received either duloxetine or placebo for 15 days, starting from the day of surgery. Patients also received a comprehensive multimodal analgesic regimen including neuraxial anesthesia, epidural analgesia, an adductor canal block, meloxicam, and oxycodone/acetaminophen as needed. The primary outcome was the pain score (0 to 10 numeric rating scale) with ambulation on postoperative day 14. One hundred six patients were randomized and analyzed. On day 14, duloxetine had no effect on pain with ambulation; mean pain was 3.8 (SD, 2.3) for placebo versus 3.5 (SD, 2.1) for duloxetine (difference in means [95% CI], 0.4 [-0.5 to 1.2]; P = 0.386). Symptoms potentially attributable to duloxetine discontinuation at study drug completion (nausea, anxiety) occurred among nine patients (duloxetine) and five patients (placebo); this was not statistically significant (P = 0.247). Statistically significant secondary outcomes included opioid consumption (difference in mean milligram oral morphine equivalents [95% CI], 8.7 [3.3 to 14.1], P = 0.002 by generalized estimating equation) over the postoperative period and nausea on day 1 (P = 0.040). There was no difference in other side effects or in anxiety and depression scores. When included as a part of a multimodal analgesic regimen for knee arthroplasty, duloxetine does not reduce subacute pain with ambulation.

Overprescription of postoperative narcotics: a look at postoperative pain medication delivery, consumption and disposal in urological practice.

PubMed

Bates, Cory; Laciak, Robert; Southwick, Andrew; Bishoff, Jay

2011-02-01

Prescription narcotic abuse is a significant social problem. Surplus medication following surgery is 1 source of prescription diversion. We assessed prescribing practices, consumption and disposal of prescribed narcotics after urological surgery. Surveys were administered to a 3-month consecutive sample of adult patients who underwent surgery performed by full and adjunct University of Utah Urology faculty. Surveys were performed 2 to 4 weeks postoperatively. With the exception of the investigators, prescribing physicians had no prior knowledge of the study. Data collected included perception of pain control, type and quantity of medication prescribed, quantity of leftover medication, refills needed, disposal instructions and surplus medication disposition. Overall 47% of 586 patients participated in the study. Hydrocodone was prescribed most commonly (63%), followed by oxycodone (35%), and 86% of the patients were satisfied with pain control. Of the dispensed narcotics 58% was consumed and 12% of patients requested refills. A total of 67% of patients had surplus medication from the initial prescription and 92% received no disposal instructions for surplus medication. Of those patients with leftover medication 91% kept the medication at home while 6% threw it in the trash, 2% flushed it down the toilet and less than 1% returned it to a pharmacy. Overprescription of narcotics is common and retained surplus medication presents a readily available source of opioid diversion. It appears that no entity on the prescribing or dispensing ends of prescription opioid delivery is fulfilling the responsibility to accurately educate patients on proper surplus medication disposal. Surgeons should analyze prescribing practices and consider decreasing the quantity of postoperative narcotics prescribed. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics of pericyte involvement in small-molecular drug transport across the blood-brain barrier.

PubMed

Mihajlica, Nebojsa; Betsholtz, Christer; Hammarlund-Udenaes, Margareta

2018-06-19

Pericytes are perivascular cells that play important roles in the regulation of the blood-brain barrier (BBB) properties. Pericyte-deficiency causes compromised BBB integrity and increase in permeability to different macromolecules mainly by upregulated transcytosis. The aim of the present study was to investigate pericyte involvement in the extent of small-molecular drug transport across the BBB. This was performed with five compounds: diazepam, digoxin, levofloxacin, oxycodone and paliperidone. Compounds were administered at low doses via subcutaneous injections as a cassette (simultaneously) to pericyte-deficient Pdgfb ret/ret mice and corresponding WT controls. Total drug partitioning across the BBB was calculated as the ratio of total drug exposures in brain tissue and plasma (K p,brain ). In addition, equilibrium dialysis experiments were performed to estimate unbound drug fractions in brain (f u,brain ) and plasma (f u,plasma ). This enabled estimation of unbound drug partitioning coefficients (K p,uu,brain ). The results indicated slight tendencies towards increase of total brain exposures in Pdgfb ret/ret mice as reflected in K p,brain values, which were within the 2-fold limit. Part of these differences could be explained by differences in plasma protein binding. No difference was found in brain tissue binding. The combined in vivo and in vitro data resulted in no differences in BBB transport in pericyte-deficiency, as described by similar K p,uu,brain values in Pdgfb ret/ret and control mice. In conclusion, these findings imply no influence of pericytes on the extent of BBB transport of small-molecular drugs, and suggest preserved BBB features relevant for handling of this type of molecules irrespective of pericyte presence at the brain endothelium. Copyright © 2018. Published by Elsevier B.V.

Comparison of ultrasonic shears and traditional suture ligature for vaginal hysterectomy: randomized controlled trial.

PubMed

Fitz-Gerald, Alison Louise; Tan, Jason; Chan, Kok-Weng; Polyakov, Alex; Edwards, Geoff N; Najjar, Haider; Tsaltas, Jim; Vollenhoven, Beverley

2013-01-01

To compare operating time, intraoperative blood loss, postoperative analgesia, and length of hospital stay using ultrasonic shears vs traditional suture ligature in vaginal hysterectomy. Randomized controlled trial (Canadian Task Force classification I). Gynecology units within a single health network, university hospital. Forty women requiring vaginal hysterectomy because of benign disease. Vaginal hysterectomy performed using either ultrasonically activated shears (USS) or traditional suture ligatures. Twenty-one patients were randomized to the USS arm, and 19 patients to the traditional suture ligature arm. Patient characteristics were comparable. Mean (SD) hysterectomy time and was similar in both the USS and traditional arms, 28.66 (4.0) minutes vs 32.37 (3.18) minutes (p = .47), as was total operating time, 97.38 (8.9) minutes vs 91.63 (7.69) minutes (p = .63). Operative blood loss was significantly decreased in the USS group: 62.63 (12.46) mL vs 136.05 (21.54) mL (p = .006). There was, however, no significant change in hemoglobin concentration between the 2 groups: 19.53 (1.79) g/L vs -16.72 (2.5) g/L. There was no significant difference in mean oxycodone use: 9.29 (2.66) mg vs 8.06 (3.19) mg (p = .77). Length of hospital stay was similar in both groups: 58.98 (3.27) hours vs 60.05 (6.48) hours (p = .88). There was no significant difference in overall complication rates between the groups. Although the Harmonic scalpel system, compared with the traditional suture ligation method, seems to be a safe alternative for securing the pedicles in vaginal hysterectomy, it offers no benefit insofar as operative time, reduction in clinically significant blood loss, and analgesic requirements. Copyright © 2013 AAGL. Published by Elsevier Inc. All rights reserved.

Fine spatiotemporal control of nitric oxide release by infrared pulse-laser irradiation of a photolabile donor.

PubMed

Nakagawa, Hidehiko; Hishikawa, Kazuhiro; Eto, Kei; Ieda, Naoya; Namikawa, Tomotaka; Kamada, Kenji; Suzuki, Takayoshi; Miyata, Naoki; Nabekura, Jun-ichi

2013-11-15

Two-photon-excitation release of nitric oxide (NO) from our recently synthesized photolabile NO donor, Flu-DNB, was confirmed to allow fine spatial and temporal control of NO release at the subcellular level in vitro. We then evaluated in vivo applications. Femtosecond near-infrared pulse laser irradiation of predefined regions of interest in living mouse brain treated with Flu-DNB induced NO-release-dependent, transient vasodilation specifically at the irradiated site. Photoirradiation in the absence of Flu-DNB had no effect. Further, NO release from Flu-DNB by pulse laser irradiation was shown to cause chemoattraction of microglial processes to the irradiated area in living mouse brain. To our knowledge, this is the first demonstration of induction of biological responses in vitro and in vivo by means of precisely controlled, two-photon-mediated release of NO.

Organosilane functionalization of halloysite nanotubes for enhanced loading and controlled release.

PubMed

Yuan, Peng; Southon, Peter D; Liu, Zongwen; Kepert, Cameron J

2012-09-21

The surfaces of naturally occurring halloysite nanotubes were functionalized with γ-aminopropyltriethoxysilane (APTES), which was found to have a substantial effect on the loading and subsequent release of a model dye molecule. APTES was mostly anchored at the internal lumen surface of halloysite through covalent grafting, forming a functionalized surface covered by aminopropyl groups. The dye loading of the functionalized halloysite was 32% greater than that of the unmodified sample, and the release from the functionalized halloysite was dramatically prolonged as compared to that from the unmodified one. Dye release was prolonged at low pH and the release at pH 3.5 was approximately three times slower than that at pH 10.0. These results demonstrate that organosilane functionalization makes pH an external trigger for controlling the loading of guest on halloysite and the subsequent controlled release.

Recidivism Among Licensed-Released Prisoners Who Participated in the EM Program in Israel.

PubMed

Shoham, Efrat; Yehosha-Stern, Shirley; Efodi, Rotem

2015-08-01

Toward the end of 2006, a pilot program was launched in Israel wherein licensed-released prisoners were put under electronic monitoring (EM). In addition to EM, the pilot program, operated by the Prisoners' Rehabilitation Authority, provides programs of occupational supervision and personal therapy and is designed to allow for early release of those prisoners who, without increased supervision, would have been found unsuitable for early release. The aim of this study was to ascertain whether participation in the EM program among licensed-released prisoners in Israel might bring about lessened recidivism. For that matter, rates of arrests and incarceration were examined during a follow-up period of up to 4 years, among the entirety of licensed-released prisoners participating in the EM program between the years 2007 and 2009 (n = 155). To compare recidivism rates, a control group was assembled from among the entirety of released prisoners who were found unsuitable for early release in judicial conditions, and had therefore served the full term of their incarceration, to be released between the years 2005 and 2006 (a period of time during which an EM program was not yet operated among licensed-released prisoners in Israel). Study findings clearly show that while among the control group, 42% of released prisoners were re-incarcerated, at the end of a 4-year follow-up period, only 15% among the study group had returned to prison. These findings can be explained by combining the Social Control theory and the Self-Control theory which consider the period of time under EM program and the occupational and familial integration tools for reducing criminal connections and enhancing pro-social behavior. © The Author(s) 2014.

Metal-organic framework tethering PNIPAM for ON-OFF controlled release in solution.

PubMed

Nagata, Shunjiro; Kokado, Kenta; Sada, Kazuki

2015-05-21

A smart metal-organic framework (MOF) exhibiting controlled release was achieved by modification with a thermoresponsive polymer (PNIPAM) via a surface-selective post-synthetic modification technique. Simple temperature variation readily switches "open" (lower temperature) and "closed" (higher temperature) states of the polymer-modified MOF through conformational change of PNIPAM grafted onto the MOF, resulting in controlled release of the included guest molecules such as resorufin, caffeine, and procainamide.

Photocatalytic thin films coupled with polymeric microcapsules for the controlled-release of volatile agents upon solar activation

NASA Astrophysics Data System (ADS)

Oliveira, L. F.; Marques, J.; Coutinho, P. J. G.; Parpot, P.; Tavares, C. J.

2013-06-01

This work reportson the application of solar-activated photocatalytic thin films that allow the controlled-release of volatile agents (e.g., insecticides, repellents) from the interior of adsorbedpolymericmicrocapsules. In order to standardize the tests, a quantification of the inherent controlled-release of a particular volatile agent is determined by gas chromatography coupled to mass spectroscopy, so that an application can be offered to a wide range of supports from various industrial sectors, such as in textiles (clothing, curtains, mosquito nets). This technology takes advantage of the established photocatalytic property of titanium dioxide (TiO2) for the use as an active surface/site to promote the controlled-release of a specific vapor (volatile agentfrom within the aforementioned microcapsules.

Effect of chronic treatment with the GABA transaminase inhibitors gamma-vinyl GABA and ethanolamine O-sulphate on the in vitro GABA release from rat hippocampus.

PubMed

Qume, M; Fowler, L J

1997-10-01

1. The effects of 2, 8 and 21 day oral treatment with the specific gamma-aminobutyric acid transaminase (GABA-T) inhibitors gamma-vinyl GABA (GVG) and ethanolamine O-sulphate (EOS) on brain GABA levels, GABA-T activity, and basal and stimulated GABA release from rat cross-chopped brain hippocampal slices was investigated. 2. Treatment with GABA-T inhibitors lead to a reduction in brain GABA-T activity by 65-80% compared with control values, with a concomitant increase in brain GABA content of 40-100%. 3. Basal hippocampal GABA release was increased to 250-450% of control levels following inhibition of GABA-T activity. No Ca2+ dependence was observed in either control or treated tissues. 4. GVG and EOS administration led to a significant elevation in the potassium stimulated release of GABA from cross-chopped hippocampal slices compared with that of controls. Although stimulated GABA release from control tissues was decreased in the presence of a low Ca2+ medium, GVG and EOS treatment abolished this Ca2+ dependency. 5. GABA compartmentalization, Na+ and Cl- coupled GABA uptake carriers and glial release may provide explanations for the loss of the Ca2+ dependency of stimulated GABA release observed following GVG and EOS treatment. 6. Administration of GABA-T inhibitors led to increases in both basal and stimulated hippocampal GABA release. However, it is not clear which is the most important factor in the anticonvulsant activity of these drugs, the increased GABA content 'leaking' out of neurones and glia leading to widespread inhibition, or the increase in stimulated GABA release which may occur following depolarization caused by an epileptic discharge.

Effect of chronic treatment with the GABA transaminase inhibitors γ-vinyl GABA and ethanolamine O-sulphate on the in vitro GABA release from rat hippocampus

PubMed Central

Qume, M; Fowler, L J

1997-01-01

The effects of 2, 8 and 21 day oral treatment with the specific γ-aminobutyric acid transaminase (GABA-T) inhibitors γ-vinyl GABA (GVG) and ethanolamine O-sulphate (EOS) on brain GABA levels, GABA-T activity, and basal and stimulated GABA release from rat cross-chopped brain hippocampal slices was investigated. Treatment with GABA-T inhibitors lead to a reduction in brain GABA-T activity by 65–80% compared with control values, with a concomitant increase in brain GABA content of 40–100%. Basal hippocampal GABA release was increased to 250–450% of control levels following inhibition of GABA-T activity. No Ca2+ dependence was observed in either control or treated tissues. GVG and EOS administration led to a significant elevation in the potassium stimulated release of GABA from cross-chopped hippocampal slices compared with that of controls. Although stimulated GABA release from control tissues was decreased in the presence of a low Ca2+ medium, GVG and EOS treatment abolished this Ca2+ dependency. GABA compartmentalization, Na+ and Cl− coupled GABA uptake carriers and glial release may provide explanations for the loss of the Ca2+ dependency of stimulated GABA release observed following GVG and EOS treatment. Administration of GABA-T inhibitors led to increases in both basal and stimulated hippocampal GABA release. However, it is not clear which is the most important factor in the anticonvulsant activity of these drugs, the increased GABA content ‘leaking' out of neurones and glia leading to widespread inhibition, or the increase in stimulated GABA release which may occur following depolarization caused by an epileptic discharge. PMID:9351512

Facile preparation of antibacterial chitosan/graphene oxide-Ag bio-nanocomposite hydrogel beads for controlled release of doxorubicin.

PubMed

Rasoulzadehzali, Monireh; Namazi, Hassan

2018-04-27

The present project describes the facile preparation of novel pH-sensitive bio-nanocomposite hydrogel beads based on chitosan (CH) and GO-Ag nanohybrid particles for controlled release of anti-cancer drugs such as doxorubicin (DOX). The loading efficiency of doxorubicin into test beads was measured via UV-vis spectroscopy analysis and was found to be high. The formation of silver nanoparticles on the GO sheets and structural characteristics were evaluated via FT-IR, TEM, XRD, and SEM techniques. In addition, the antibacterial activity, swelling and drug release profiles of prepared nanocomposite beads were evaluated. Also, in vitro drug release test was performed in order to investigate the efficiency of CH/GO-Ag nanocomposite hydrogel beads as a drug carrier for controlled release of anti-cancer drugs such as doxorubicin (DOX). A more sustained and controlled drug release profile was observed for CH/GO-Ag nanocomposite hydrogel beads that enhanced by increasing the GO-Ag nanohybrid particles content. Copyright © 2018 Elsevier B.V. All rights reserved.

Development of a novel drug release system, time-controlled explosion system (TES). I. Concept and design.

PubMed

Ueda, S; Hata, T; Asakura, S; Yamaguchi, H; Kotani, M; Ueda, Y

1994-01-01

A novel controlled drug release system. Time-Controlled Explosion System (TES) has been developed. TES has a four-layered spherical structure, which consists of core, drug, swelling agent and water insoluble polymer membrane. TES is characterized by a rapid drug release with a precisely programmed lag time; i.e. expansion of the swelling agent by water penetrating through the outer membrane, destruction of the membrane by stress due to swelling force and subsequent rapid drug release. For establishing the concept and development strategy, TES was designed using metoprolol and polystyrene balls (size: 3.2 mm in diameter) as a model drug and core particles. Among the polymers screened, low-substituted hydroxypropylcellulose (L-HPC) and ethylcellulose (EC) were selected for a swelling agent and an outer water insoluble membrane, respectively. The release profiles of metoprolol from the system were not affected by the pH of the dissolution media. Lag time was controlled by the thickness of the outer EC membrane; thus, a combination of TES particles possessing different lag times could offer any desired release profile of the model compound, metoprolol.

Online NASTRAN documentation

NASA Technical Reports Server (NTRS)

Turner, Horace Q.; Harper, David F.

1991-01-01

The distribution of NASTRAN User Manual information has been difficult because of the delay in printing and difficulty in identification of all the users. This has caused many users not to have the current information for the release of NASTRAN that could be available to them. The User Manual updates have been supplied with the NASTRAN Releases, but distribution within organizations was not coordinated with access to releases. The Executive Control, Case Control, and Bulk Data sections are supplied in machine readable format with the 91 Release of NASTRAN. This information is supplied on the release tapes in ASCII format, and a FORTRAN program to access this information is supplied on the release tapes. This will allow each user to have immediate access to User Manual level documentation with the release. The sections on utilities, plotting, and substructures are expected to be prepared for the 92 Release.

Guidance for Evaluating the Safety of Experimental Releases of Mosquitoes, Emphasizing Mark-Release-Recapture Techniques.

PubMed

Benedict, Mark Q; Charlwood, J Derek; Harrington, Laura C; Lounibos, L Philip; Reisen, William K; Tabachnick, Walter J

2018-01-01

Experimental releases of mosquitoes are performed to understand characteristics of populations related to the biology, ability to transmit pathogens, and ultimately their control. In this article, we discuss considerations related to the safety of experimental releases of living mosquitoes, applying principles of good practice in vector biology that protect human health and comfort. We describe specific factors of experimental releases of mosquitoes that we believe are critical to inform institutional biosafety committees and similar review boards to which proposals to conduct mosquito release experiments have been submitted. In this study, "experimental releases" means those that do not significantly increase vector capacity or nuisance biting relative to the unperturbed natural baseline. This document specifically does not address releases of mosquitoes for ongoing control programs or trials of new control methods for which broader assessments of risk are required. It also does not address releases of transgenic or exotic (non-native) mosquito species, both of which require particular regulatory approval. Experimental releases may include females and males and evaluation must consider their effects based on the number released, their genotype and phenotype, the environment into which they are released, and postrelease collection activities. We consider whether increases of disease transmission and nuisance biting might result from proposed experimental releases against the backdrop of natural population size variation. We recommend that experimental releases be conducted in a manner that can be reasonably argued to have insignificant negative effects. Reviewers of proposals for experimental releases should expect applicants to provide such an argument based on evidence from similar studies and their planned activities. This document provides guidance for creating and evaluating such proposals.

Biophysical characterization of hydrogel-core, lipid-shell nanoparticles (nanolipogels) for HIV chemoprophylaxis

NASA Astrophysics Data System (ADS)

Mahadevan, Reena

Nanoparticles are emerging as versatile vehicles for drug delivery, providing targeting, protection, and controlled-release capabilities to encapsulated cargo. Polymeric nanoparticles made from poly(lactide-co-glycolide) (PLGA) are biodegradable, exhibit tunable drug release, and have encapsulated a wide variety of biological agents. However, PLGA nanoparticles are relatively inefficient at encapsulating small-molecule hydrophilic drugs. Liposomes encapsulate greater amounts of hydrophilic agents and demonstrate good cellular affinity; however, they lack controlled-release functionality. Hydrogel-core lipid-shell nanoparticles, or nanolipogels, combine the controlled-release capability of polymeric nanocarriers with the hydrophilic and cellular affinity of liposomes into a single drug delivery vehicle. This study establishes a facile, reproducible synthetic protocol for nanolipogels and evaluates hydrogel swelling as a mechanism for release of the small hydrophilic antiretroviral azidothymidine from nanolipogels.

Opioid Deaths in Milwaukee County, Wisconsin 2013-2017: The Primacy of Heroin and Fentanyl.

PubMed

Peterson, Brian L; Schreiber, Sara; Fumo, Nicole; Brooke Lerner, E

2018-04-23

Heroin and fentanyl are the overwhelming and increasing cause of opioid deaths in Milwaukee County, Wisconsin. We reviewed all drug and opioid deaths from 2013 to 2017 to delineate the specific opioid drugs involved and changes in their incidence. From 2013 to 2017, 980 deaths were due to opioids, rising from 184 in 2013 to 337 in 2017. In 2017, opioid deaths exceeded combined non-natural deaths from homicide and suicide. Illicit heroin and fentanyl/analogs caused 84% of opioid deaths and 80% of drug deaths, with no increase in deaths due to oral prescription drugs such as oxycodone and hydrocodone. Any approach to decreasing this dramatic increase in opioid deaths should first focus on interdicting the supply and cheap availability of these illicit opioids. Fentanyl and its analogs represent the most deadly opioids and the greatest threat to human life in our population. © 2018 American Academy of Forensic Sciences.

Effects of amphetamine, morphine, and CP 55, 940 on Go/No-Go task performance in rhesus monkeys.

PubMed

Koek, Wouter; Gerak, Lisa R; France, Charles P

2015-08-01

In humans, impulsivity measured as false alarms in a Go/No-Go task is reportedly decreased by amphetamine and is not affected by oxycodone and delta(9)-tetrahydrocannabinol. To model these findings in animals, three rhesus monkeys were trained to perform a food-reinforced Go/No-Go task. In this task, amphetamine was found to decrease false alarms (i.e. responding during No-Go trials), but only at doses that also decreased hits (i.e. responding during Go trials). Morphine generally decreased hits but not false alarms. The cannabinoid receptor agonist CP 55, 940 decreased both false alarms and hits, but only at doses that also decreased the number of trials completed. Additional studies in animals and humans are necessary to delineate the conditions under which amphetamine and other psychoactive drugs affect impulsivity in Go/No-Go tasks.

46 CFR 160.170-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 6 2014-10-01 2014-10-01 false Production inspections, tests, quality control, and..., quality control, and conformance of release mechanisms. (a) Unless the Commandant directs otherwise, an... prescribe additional production tests and inspections necessary to maintain quality control and to monitor...

46 CFR 160.170-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 6 2012-10-01 2012-10-01 false Production inspections, tests, quality control, and..., quality control, and conformance of release mechanisms. (a) Unless the Commandant directs otherwise, an... prescribe additional production tests and inspections necessary to maintain quality control and to monitor...

46 CFR 160.133-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 6 2014-10-01 2014-10-01 false Production inspections, tests, quality control, and..., quality control, and conformance of release mechanisms. (a) Unless the Commandant directs otherwise, an... prescribe additional production tests and inspections necessary to maintain quality control and to monitor...

46 CFR 160.170-15 - Production inspections, tests, quality control, and conformance of release mechanisms.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 6 2013-10-01 2013-10-01 false Production inspections, tests, quality control, and..., quality control, and conformance of release mechanisms. (a) Unless the Commandant directs otherwise, an... prescribe additional production tests and inspections necessary to maintain quality control and to monitor...

Parachute deploy/Release mechanism

NASA Technical Reports Server (NTRS)

Robelen, D. B.

1979-01-01

Mechanism operated by signals from single radio-control channel deploy and releases small drogue parachute from flying aircraft. Technique has uses in industrial process control and in recreational hobby applications.

[Characteristics of ammonia volatilization and nitrous oxide emission from a paddy soil under continuous application of different slow/controlled release urea.

PubMed

Sun, Xiang Xin; Li, Dong Po; Wu, Zhi Jie; Cui, Ya Lan; Han, Mei; Li, Yong Hua; Yang, De Fu; Cui, Yong Kun

2016-06-01

The characteristics of ammonia volatilization and nitrous oxide emission from a paddy soil were examined under 9-year application of different slow/controlled release urea with the common large granule urea (U) as the control. The results showed that compared with the control, all slow/controlled release urea treatments, except 25.8% increase of ammonia volatilization under 1% 3,4-dimethylpyrazole phosphate (DMPP)+U, could decrease the ammonia volatilization. Polymer coated urea (PCU) dominated the highest reduction of 73.4% compared to U, followed by sulfur coated urea (SCU) (72.2%), 0.5% N-(N-butyl) thiophosphoric triamide (NBPT)+1% DMPP+U (71.9%), 1% hydroquinone (HQ)+3% dicyandiamide (DCD)+U (46.9%), 0.5% NBPT+U (43.2%), 1% HQ +U (40.2%), 3% DCD+U (25.5%), and the ammonia volatilization under different slow/controlled release urea treatments were statistically lower than that of U (P<0.05). 1% DMPP+U caused the lowest emission of N 2 O under different slow/controlled release urea treatments. The slow/controlled release urea also had a significant potential of N 2 O emission reduction: 1% DMPP+U showed the highest reduction of 74.9% compared to U, followed by PCU (62.1%), 1% HQ+3% DCD+U (54.7%), 0.5% NBPT+1% DMPP+U (42.2%), 3% DCD+U (35.9%), 1% HQ +U (28.9%), 0.5% NBPT+U (17.7%), SCU (14.5%), and N 2 O emissions under different slow/controlled release urea treatments were statistically lower than that of U (P<0.05). The comprehensive analysis showed that 0.5% NBPT+1% DMPP+U, SCU and PCU had similar effects on decreasing the ammonia volatilization and N 2 O emission and were remarkably better than the other treatments. The slow release urea with the combination of urease and nitrification inhibitors should be the first choice for reducing N loss and environmental pollution in paddy field, in view of the higher costs of coated urea fertilizers.

Rate-programming of nano-particulate delivery systems for smart bioactive scaffolds in tissue engineering.

PubMed

Izadifar, Mohammad; Haddadi, Azita; Chen, Xiongbiao; Kelly, Michael E

2015-01-09

Development of smart bioactive scaffolds is of importance in tissue engineering, where cell proliferation, differentiation and migration within scaffolds can be regulated by the interactions between cells and scaffold through the use of growth factors (GFs) and extra cellular matrix peptides. One challenge in this area is to spatiotemporally control the dose, sequence and profile of release of GFs so as to regulate cellular fates during tissue regeneration. This challenge would be addressed by rate-programming of nano-particulate delivery systems, where the release of GFs via polymeric nanoparticles is controlled by means of the methods of, such as externally-controlled and physicochemically/architecturally-modulated so as to mimic the profile of physiological GFs. Identifying and understanding such factors as the desired release profiles, mechanisms of release, physicochemical characteristics of polymeric nanoparticles, and externally-triggering stimuli are essential for designing and optimizing such delivery systems. This review surveys the recent studies on the desired release profiles of GFs in various tissue engineering applications, elucidates the major release mechanisms and critical factors affecting release profiles, and overviews the role played by the mathematical models for optimizing nano-particulate delivery systems. Potentials of stimuli responsive nanoparticles for spatiotemporal control of GF release are also presented, along with the recent advances in strategies for spatiotemporal control of GF delivery within tissue engineered scaffolds. The recommendation for the future studies to overcome challenges for developing sophisticated particulate delivery systems in tissue engineering is discussed prior to the presentation of conclusions drawn from this paper.

Acoustically-Responsive Scaffolds: Control of Growth Factor Release for Tissue Regeneration Using Ultrasound

NASA Astrophysics Data System (ADS)

Moncion, Alexander

Administration of exogenous growth factors (GFs) is a proposed method of stimulating tissue regeneration. Conventional administration routes, such as at-site or systemic injections, have yielded problems with efficacy and/or safety, thus hindering the translation of GF-based regenerative techniques. Hydrogel scaffolds are commonly used as biocompatible delivery vehicles for GFs. Yet hydrogels do not afford spatial or temporal control of GF release - two critical parameters for tissue regeneration. Controlled delivery of GFs is critical for angiogenesis, which is a crucial process in tissue engineering that provides oxygen and nutrients to cells within an implanted hydrogel scaffold. Angiogenesis requires multiple GFs that are presented with distinct spatial and temporal profiles. Thus, controlled release of GFs with spatiotemporal modulation would significantly improve tissue regeneration by recapitulating endogenous GF presentation. In order to achieve this goal, we have developed acoustically-responsive scaffolds (ARSs), which are fibrin hydrogels doped with sonosensitive perfluorocarbon (PFC) emulsions capable of encapsulating various payloads. Focused, mega-Hertz range, ultrasound (US) can modulate the release of a payload non-invasively and in an on-demand manner from ARSs via physical mechanisms termed acoustic droplet vaporization (ADV) and inertial cavitation (IC). This work presents the relationship between the ADV/IC thresholds and various US and hydrogel parameters. These physical mechanisms were used for the controlled release of fluorescent dextran in vitro and in vivo to determine the ARS and US parameters that yielded optimal payload release. The optimal ARS and US parameters were used to demonstrate the controlled release of basic fibroblast growth factor from an in vivo subcutaneous implant model - leading to enhanced angiogenesis and perfusion. Additionally, different acoustic parameters and PFCs were tested and optimized to demonstrate the controlled release of two encapsulated payloads within an ARS. Overall, ARSs are a promising platform for GF delivery in tissue regeneration applications.

Laser-triggered release of encapsulated molecules from polylactic-co-glycolic acid microcapsules

NASA Astrophysics Data System (ADS)

Ariyasu, Kazumasa; Ishii, Atsuhiro; Umemoto, Taiga; Terakawa, Mitsuhiro

2016-08-01

The controlled release of encapsulated molecules from a microcapsule is a promising method of targeted drug delivery. Laser-triggered methods for the release of encapsulated molecules have the advantage of spatial and temporal controllability. In this study, we demonstrated the release of encapsulated molecules from biodegradable polymer-based microcapsules using near-infrared femtosecond laser pulses. The polylactic-co-glycolic acid microcapsules encapsulating fluorescein isothiocyanate-dextran molecules were fabricated using a dual-coaxial nozzle system. Irradiation of femtosecond laser pulses enhanced the release of the molecules from the microcapsules, which was accompanied by a decrease in the residual ratio of the microcapsules. The laser-induced modification of the surface of the shell of the microcapsules indicated the potential for sustained release as well as burst release.

Birth control - slow release methods

MedlinePlus

Contraception - slow-release hormonal methods; Progestin implants; Progestin injections; Skin patch; Vaginal ring ... might want to consider a different birth control method. SKIN PATCH The skin patch is placed on ...

Light Control of Insulin Release and Blood Glucose Using an Injectable Photoactivated Depot.

PubMed

Sarode, Bhagyesh R; Kover, Karen; Tong, Pei Y; Zhang, Chaoying; Friedman, Simon H

2016-11-07

In this work we demonstrate that blood glucose can be controlled remotely through light stimulated release of insulin from an injected cutaneous depot. Human insulin was tethered to an insoluble but injectable polymer via a linker, which was based on the light cleavable di-methoxy nitrophenyl ethyl (DMNPE) group. This material was injected into the skin of streptozotocin-treated diabetic rats. We observed insulin being released into the bloodstream after a 2 min trans-cutaneous irradiation of this site by a compact LED light source. Control animals treated with the same material, but in which light was blocked from the site, showed no release of insulin into the bloodstream. We also demonstrate that additional pulses of light from the light source result in additional pulses of insulin being absorbed into circulation. A significant reduction in blood glucose was then observed. Together, these results demonstrate the feasibility of using light to allow for the continuously variable control of insulin release. This in turn has the potential to allow for the tight control of blood glucose without the invasiveness of insulin pumps and cannulas.

Water-based polyurethane 3D printed scaffolds with controlled release function for customized cartilage tissue engineering.

PubMed

Hung, Kun-Che; Tseng, Ching-Shiow; Dai, Lien-Guo; Hsu, Shan-hui

2016-03-01

Conventional 3D printing may not readily incorporate bioactive ingredients for controlled release because the process often involves the use of heat, organic solvent, or crosslinkers that reduce the bioactivity of the ingredients. Water-based 3D printing materials with controlled bioactivity for customized cartilage tissue engineering is developed in this study. The printing ink contains the water dispersion of synthetic biodegradable polyurethane (PU) elastic nanoparticles, hyaluronan, and bioactive ingredients TGFβ3 or a small molecule drug Y27632 to replace TGFβ3. Compliant scaffolds are printed from the ink at low temperature. These scaffolds promote the self-aggregation of mesenchymal stem cells (MSCs) and, with timely release of the bioactive ingredients, induce the chondrogenic differentiation of MSCs and produce matrix for cartilage repair. Moreover, the growth factor-free controlled release design may prevent cartilage hypertrophy. Rabbit knee implantation supports the potential of the novel 3D printing scaffolds in cartilage regeneration. We consider that the 3D printing composite scaffolds with controlled release bioactivity may have potential in customized tissue engineering. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fabrication of Plasmonic Nanorod-Embedded Dipeptide Microspheres via the Freeze-Quenching Method for Near-Infrared Laser-Triggered Drug-Delivery Applications.

PubMed

Erdogan, Hakan; Yilmaz, Mehmet; Babur, Esra; Duman, Memed; Aydin, Halil M; Demirel, Gokhan

2016-05-09

Control of drug release by an external stimulus may provide remote controllability, low toxicity, and reduced side effects. In this context, varying physical external stimuli, including magnetic and electric fields, ultrasound, light, and pharmacological stimuli, have been employed to control the release rate of drug molecules in a diseased region. However, the design and development of alternative on-demand drug-delivery systems that permit control of the dosage of drug released via an external stimulus are still required. Here, we developed near-infrared laser-activatable microspheres based on Fmoc-diphenylalanine (Phe-Phe) dipeptides and plasmonic gold nanorods (AuNRs) via a simple freeze-quenching approach. These plasmonic nanoparticle-embedded microspheres were then employed as a smart drug-delivery platform for native, continuous, and pulsatile doxorubicin (DOX) release. Remarkable sustained, burst, and on-demand DOX release from the fabricated microspheres were achieved by manipulating the laser exposure time. Our results demonstrate that AuNR-embedded dipeptide microspheres have great potential for controlled drug-delivery systems.

A review of mathematical modeling and simulation of controlled-release fertilizers.

PubMed

Irfan, Sayed Ameenuddin; Razali, Radzuan; KuShaari, KuZilati; Mansor, Nurlidia; Azeem, Babar; Ford Versypt, Ashlee N

2018-02-10

Nutrients released into soils from uncoated fertilizer granules are lost continuously due to volatilization, leaching, denitrification, and surface run-off. These issues have caused economic loss due to low nutrient absorption efficiency and environmental pollution due to hazardous emissions and water eutrophication. Controlled-release fertilizers (CRFs) can change the release kinetics of the fertilizer nutrients through an abatement strategy to offset these issues by providing the fertilizer content in synchrony with the metabolic needs of the plants. Parametric analysis of release characteristics of CRFs is of paramount importance for the design and development of new CRFs. However, the experimental approaches are not only time consuming, but they are also cumbersome and expensive. Scientists have introduced mathematical modeling techniques to predict the release of nutrients from the CRFs to elucidate fundamental understanding of the dynamics of the release processes and to design new CRFs in a shorter time and with relatively lower cost. This paper reviews and critically analyzes the latest developments in the mathematical modeling and simulation techniques that have been reported for the characteristics and mechanisms of nutrient release from CRFs. The scope of this review includes the modeling and simulations techniques used for coated, controlled-release fertilizers. Copyright © 2017 Elsevier B.V. All rights reserved.

Influence of poloxamers on the dissolution performance and stability of controlled-release formulations containing Precirol ATO 5.

PubMed

Jannin, V; Pochard, E; Chambin, O

2006-02-17

Lipid excipients are usually used for the development of sustained-release formulations. When used in relatively high quantities, Precirol ATO 5 imparts sustained-release properties to solid oral dosage forms, by forming a lipid matrix. To control or adjust the drug release kinetics from such lipid matrix however, one must often resort to complementary ingredients or techniques. This study investigates the influence of poloxamers (Lutrol) included in lipid matrices composed of glyceryl palmitostearate (Precirol ATO 5) on their dissolution performance and their stability. The addition of these hydrophilic polymers in the lipid matrix increased the amount of theophylline released thanks to the swelling of the hydrophilic polymer and the creation of a porous network into the inert lipid matrix. The grade and the quantity of Lutrol could modulate the extent of drug release. Theophylline was released mainly by the matrix erosion but also by diffusion through the pores as suggested by the Peppas' model. Moreover, the addition of Lutrol enhanced the stability during storage. The theophylline release was quite steady after 6 months in different conditions (temperature and humidity). Thus, the mixture of glyceryl palmitostearate and poloxamers is an approach with many advantages for the development of controlled-release formulations by capsule molding.

Guidance for Evaluating the Safety of Experimental Releases of Mosquitoes, Emphasizing Mark-Release-Recapture Techniques

PubMed Central

Charlwood, J. Derek; Harrington, Laura C.; Lounibos, L. Philip; Reisen, William K.; Tabachnick, Walter J.

2018-01-01

Abstract Experimental releases of mosquitoes are performed to understand characteristics of populations related to the biology, ability to transmit pathogens, and ultimately their control. In this article, we discuss considerations related to the safety of experimental releases of living mosquitoes, applying principles of good practice in vector biology that protect human health and comfort. We describe specific factors of experimental releases of mosquitoes that we believe are critical to inform institutional biosafety committees and similar review boards to which proposals to conduct mosquito release experiments have been submitted. In this study, “experimental releases” means those that do not significantly increase vector capacity or nuisance biting relative to the unperturbed natural baseline. This document specifically does not address releases of mosquitoes for ongoing control programs or trials of new control methods for which broader assessments of risk are required. It also does not address releases of transgenic or exotic (non-native) mosquito species, both of which require particular regulatory approval. Experimental releases may include females and males and evaluation must consider their effects based on the number released, their genotype and phenotype, the environment into which they are released, and postrelease collection activities. We consider whether increases of disease transmission and nuisance biting might result from proposed experimental releases against the backdrop of natural population size variation. We recommend that experimental releases be conducted in a manner that can be reasonably argued to have insignificant negative effects. Reviewers of proposals for experimental releases should expect applicants to provide such an argument based on evidence from similar studies and their planned activities. This document provides guidance for creating and evaluating such proposals. PMID:29337660

Release behavior and bioefficacy of imazethapyr formulations based on biopolymeric hydrogels.

PubMed

Kumar, Vikas; Singh, Anupama; Das, T K; Sarkar, Dhruba Jyoti; Singh, Shashi Bala; Dhaka, Rashmi; Kumar, Anil

2017-06-03

Controlled release formulations of imazethapyr herbicide have been developed employing guar gum-g-cl-polyacrylate/bentonite clay hydrogel composite (GG-HG) and guar gum-g-cl-PNIPAm nano hydrogel (GG-NHG) as carriers, to assess the suitability of biopolymeric hydrogels as controlled herbicide release devices. The kinetics of imazethapyr release from the developed formulations was studied in water and it revealed that the developed formulations of imazethapyr behaved as slow release formulations as compared to commercial formulation. The calculated diffusion exponent (n) values showed that Fickian diffusion was the predominant mechanism of imazethapyr release from the developed formulations. Time for release of half of the loaded imazethapyr (t 1/2 ) ranged between 0.06 and 4.8 days in case of GG-NHG and 4.4 and 12.6 days for the GG-HG formulations. Weed control index (WCI) of GG-HG and GG-NHG formulations was similar to that of the commercial formulation and the herbicidal effect was observed for relatively longer period. Guar gum-based biopolymeric hydrogels in both macro and nano particle size range can serve as potential carriers in developing slow release herbicide formulations.

A Drug-Eluting Contact Lens

PubMed Central

Ciolino, Joseph B.; Hoare, Todd R.; Iwata, Naomi G.; Behlau, Irmgard; Dohlman, Claes H.; Langer, Robert; Kohane, Daniel S.

2014-01-01

Purpose To formulate and characterize a drug-eluting contact lens designed to provide extended, controlled release of a drug. Methods Prototype contact lenses were created by coating PLGA (poly[lactic-co-glycolic acid]) films containing test compounds with pHEMA (poly[hydroxyethyl methacrylate]) by ultraviolet light polymerization. The films, containing encapsulated fluorescein or ciprofloxacin, were characterized by scanning electron microscopy. Release studies were conducted in phosphate-buffered saline at 37°C with continuous shaking. Ciprofloxacin eluted from the contact lens was studied in an antimicrobial assay to verify antimicrobial effectiveness. Results After a brief and minimal initial burst, the prototype contact lenses demonstrated controlled release of the molecules studied, with zero-order release kinetics under infinite sink conditions for over 4 weeks. The rate of drug release was controlled by changing either the ratio of drug to PLGA or the molecular mass of the PLGA used. Both the PLGA and the pHEMA affected release kinetics. Ciprofloxacin released from the contact lenses inhibited ciprofloxacin-sensitive Staphylococcus aureus at all time-points tested. Conclusions A prototype contact lens for sustained drug release consisting of a thin drug-PLGA film coated with pHEMA could be used as a platform for ocular drug delivery with widespread therapeutic applications. PMID:19136709

Novel Polyurethane Matrix Systems Reveal a Particular Sustained Release Behavior Studied by Imaging and Computational Modeling.

PubMed

Campiñez, María Dolores; Caraballo, Isidoro; Puchkov, Maxim; Kuentz, Martin

2017-07-01

The aim of the present work was to better understand the drug-release mechanism from sustained release matrices prepared with two new polyurethanes, using a novel in silico formulation tool based on 3-dimensional cellular automata. For this purpose, two polymers and theophylline as model drug were used to prepare binary matrix tablets. Each formulation was simulated in silico, and its release behavior was compared to the experimental drug release profiles. Furthermore, the polymer distributions in the tablets were imaged by scanning electron microscopy (SEM) and the changes produced by the tortuosity were quantified and verified using experimental data. The obtained results showed that the polymers exhibited a surprisingly high ability for controlling drug release at low excipient concentrations (only 10% w/w of excipient controlled the release of drug during almost 8 h). The mesoscopic in silico model helped to reveal how the novel biopolymers were controlling drug release. The mechanism was found to be a special geometrical arrangement of the excipient particles, creating an almost continuous barrier surrounding the drug in a very effective way, comparable to lipid or waxy excipients but with the advantages of a much higher compactability, stability, and absence of excipient polymorphism.

Composite poly(vinyl alcohol)/poly(vinyl acetate) electrospun nanofibrous mats as a novel wound dressing matrix for controlled release of drugs

PubMed Central

Jannesari, Marziyeh; Varshosaz, Jaleh; Morshed, Mohammad; Zamani, Maedeh

2011-01-01

The aim of this study was to develop novel biomedicated nanofiber electrospun mats for controlled drug release, especially drug release directly to an injury site to accelerate wound healing. Nanofibers of poly(vinyl alcohol) (PVA), poly(vinyl acetate) (PVAc), and a 50:50 composite blend, loaded with ciprofloxacin HCl (CipHCl), were successfully prepared by an electrospinning technique for the first time. The morphology and average diameter of the electrospun nanofibers were investigated by scanning electron microscopy. X-ray diffraction studies indicated an amorphous distribution of the drug inside the nanofiber blend. Introducing the drug into polymeric solutions significantly decreased solution viscosities as well as nanofiber diameter. In vitro drug release evaluations showed that both the kind of polymer and the amount of drug loaded greatly affected the degree of swelling, weight loss, and initial burst and rate of drug release. Blending PVA and PVAc exhibited a useful and convenient method for electrospinning in order to control the rate and period of drug release in wound healing applications. Also, the thickness of the blend nanofiber mats strongly influenced the initial release and rate of drug release. PMID:21720511

Development of novel sustained-release system, disintegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilvadipine.

PubMed

Tanaka, Nobuyuki; Imai, Keiji; Okimoto, Kazuto; Ueda, Satoshi; Tokunaga, Yuji; Ohike, Atsuo; Ibuki, Rinta; Higaki, Kazutaka; Kimura, Toshikiro

2005-11-28

The goal of this study is to develop a novel sustained-release (SR) system for poorly water-soluble drugs by applying solid dispersion (SD) technique for improving the solubility. The developed SR system, disintegration-controlled matrix tablet (DCMT), consists of hydrogenated soybean oil (HSO) as wax and SD granules containing low-substituted hydroxypropylcellulose (L-HPC) as a disintegrant. In this study, nilvadipine (NiD) was chosen as a model compound. Sustained-release profiles of NiD from DCMT were identically controlled in several dissolution mediums in spite of varying pH and agitation speed. The release of NiD from DCMT was sustained more effectively by increasing the amount of wax or by decreasing the amount of disintegrant, and supersaturation of NiD was achieved without any re-crystallization in dissolution medium. The release rate of NiD from DCMT was controlled by the disintegration rate of tablet. The release profile of NiD was described by the Hixson-Crowell's model better than zero-order kinetics, first-order kinetics and Higuchi's model, which supports that the release of NiD from DCMT is regulated by the disintegration of the tablet. From this study, it was clarified that DCMT was one of the promising SR systems applying SD for the poorly water-soluble drugs.

The Impact of Bubbles on Measurement of Drug Release from Echogenic Liposomes

PubMed Central

Kopechek, Jonathan A.; Haworth, Kevin J.; Radhakrishnan, Kirthi; Huang, Shaoling; Klegerman, Melvin E.; McPherson, David D.; Holland, Christy K.

2013-01-01

Echogenic liposomes (ELIP) encapsulate gas bubbles and drugs within lipid vesicles, but the mechanisms of ultrasound-mediated drug release from ELIP are not well understood. The effect of cavitation activity on drug release from ELIP was investigated in flowing solutions using two fluorescent molecules: a lipophilic drug (rosiglitazone) and a hydrophilic drug substitute (calcein). ELIP samples were exposed to pulsed Doppler ultrasound from a clinical diagnostic ultrasound scanner at pressures above and below the inertial and stable cavitation thresholds. Control samples were exposed to a surfactant, Triton X-100 (positive control), or to flow alone (negative control). Fluorescence techniques were used to detect release. Encapsulated microbubbles reduced the measured fluorescence intensity and this effect should be considered when assessing drug release from ELIP. The origin of this effect is not specific to ELIP. Release of rosiglitazone or calcein compared to the negative control was only observed with detergent treatment, but not with ultrasound exposure, despite the presence of stable and inertial cavitation activity. Release of rosiglitazone or calcein from ELIP exposed to diagnostic ultrasound was not observed, even in the presence of cavitation activity. Ultrasound-mediated drug delivery strategies with ELIP will thus rely on passage of the drug-loaded liposomes to target tissues. PMID:23357288

Preparation and In Vitro/In Vivo Evaluation of Vinpocetine Elementary Osmotic Pump System

PubMed Central

Ning, Meiying; Zhou, Yue; Chen, Guojun; Mei, Xingguo

2011-01-01

Preparation and in vitro and in vivo evaluation of vinpocetine (VIN) elementary osmotic pump (EOP) formulations were investigated. A method for the preparation of VIN elementary osmotic pump tablet was obtained by adding organic acid additives to increase VIN solubility. VIN was used as the active pharmaceutical ingredient, lactose and mannitol as osmotic agent. Citric acid was used as increasing API solubility and without resulting in the API degradation. It is found that the VIN release rate was increasing with the citric acid amount at a constant range. Cellulose acetate 398-3 was employed as semipermeable membrane containing polyethylene glycol 6000 and diethyl-o-phthalate as pore-forming agent and plasticizer for controlling membrane permeability. In addition, a clear difference between the pharmacokinetic patterns of VIN immediate release and VIN elementary osmotic pump formulations was revealed. The area under the plasma concentration-time curve after oral administration of elementary osmotic pump formulations was equivalent to VIN immediate release formulation. Furthermore, significant differences found for mean residence time, elimination half-life, and elimination rate constant values corroborated prolonged release of VIN from elementary osmotic pump formulations. These results suggest that the VIN osmotic pump controlled release tablets have marked controlled release characters and the VIN osmotic pump controlled release tablets and the normal tablets were bioequivalent. PMID:21577257

Using polymer-coated controlled-release fertilizers in the nursery and after outplanting

Treesearch

Thomas D. Landis; R. Kasten Dumroese

2009-01-01

Controlled-release fertilizers (CRF) are the newest and most technically advanced way of supplying mineral nutrients to nursery crops. Compared to conventional fertilizers, their gradual pattern of nutrient release better meets plant needs, minimizes leaching, and therefore improves fertilizer use efficiency. In our review of the literature, we found many terms used...

Controlled release of linalool using nanofibrous membranes of poly(lactic acid) obtained by electrospinning and solution blow spinning: A comparative study

USDA-ARS?s Scientific Manuscript database

The controlled-release of natural plant oils such as linalool is of interest in therapeutics, cosmetics, and antimicrobial and larvicidal products. The present study reports the release characteristics of linalool encapsulated at three concentrations (10, 15 and 20 wt.%) in poly(lactic acid) nanofib...

Conjugated Polymer for Voltage-Controlled Release of Molecules.

PubMed

Liu, Shenghua; Fu, Ying; Li, Guijun; Li, Li; Law, Helen Ka-Wai; Chen, Xianfeng; Yan, Feng

2017-09-01

Conjugated polymers are attractive in numerous biological applications because they are flexible, biocompatible, cost-effective, solution-processable, and electronic/ionic conductive. One interesting application is for controllable drug release, and this has been realized previously using organic electronic ion pumps. However, organic electronic ion pumps show high operating voltages and limited transportation efficiency. Here, the first report of low-voltage-controlled molecular release with a novel organic device based on a conjugated polymer poly(3-hexylthiophene) is presented. The releasing rate of molecules can be accurately controlled by the duration of the voltage applied on the device. The use of a handy mobile phone to remotely control the releasing process and its application in delivering an anticancer drug to treat cancer cells are also successfully demonstrated. The working mechanism of the device is attributed to the unique switchable permeability of poly(3-hexylthiophene) in aqueous solutions under a bias voltage that can tune the wettability of poly(3-hexylthiophene) via oxidation or reduction processes. The organic devices are expected to find many promising applications for controllable drug delivery in biological systems. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Preparation and release characteristics of polymer-coated and blended alginate microspheres.

PubMed

Lee, D W; Hwang, S J; Park, J B; Park, H J

2003-01-01

To prevent a rapid drug release from alginate microspheres in simulated intestinal media, alginate microspheres were coated or blended with polymers. Three polymers were selected and evaluated such as HPMC, Eudragit RS 30D and chitosan, as both coating materials and additive polymers for controlling the drug release. This study focused on the release characteristics of polymer-coated and blended alginate microspheres, varying the type of polymer and its concentration. The alginate microspheres were prepared by dropping the mixture of drug and sodium alginate into CaCl(2) solution using a spray-gun. Polymer-coated microspheres were prepared by adding alginate microspheres into polymer solution with mild stirring. Polymer-blended microspheres were prepared by dropping the mixture of drug, sodium alginate and additive polymer with plasticizer into CaCl(2) solution. In vitro release test was carried out to investigate the release profiles in 500 ml of phosphate buffered saline (PBS, pH 7.4). As the amount of polymer in sodium alginate or coating solution increase, the drug release generally decreased. HPMC-blended microspheres swelled but withstood the disintegration, showing an ideal linear release profiles. Chitosan-coated microspheres showed smooth and round surface and extended the release of drug. In comparison with chitosan-coated microspheres, HPMC-blended alginate microspheres can be easily made and used for controlled drug delivery systems due to convenient process and controlled drug release.

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.

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

A controlled release of ibuprofen by systematically tailoring the morphology of mesoporous silica materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qu Fengyu; Chemistry and Pharmaceutical College, Jiamusi University, Jiamusi 154007; Zhu Guangshan

2006-07-15

A series of mesoporous silica materials with similar pore sizes, different morphologies and variable pore geometries were prepared systematically. In order to control drug release, ibuprofen was employed as a model drug and the influence of morphology and pore geometry of mesoporous silica on drug release profiles was extensively studied. The mesoporous silica and drug-loaded samples were characterized by X-ray diffraction, Fourier transform IR spectroscopy, N{sub 2} adsorption and desorption, scanning electron microscopy, and transmission electron microscopy. It was found that the drug-loading amount was directly correlated to the Brunauer-Emmett-Teller surface area, pore geometry, and pore volume; while the drugmore » release profiles could be controlled by tailoring the morphologies of mesoporous silica carriers. - Graphical abstract: The release of ibuprofen is controlled by tailoring the morphologies of mesoporous silica. The mesoporous silica and drug-loaded samples are characterized by powder X-ray diffraction, Fourier transform IR spectroscopy, N{sub 2} adsorption and desorption, scanning electron microscopy, and transmission electron microscopy. The drug-loading amount is directly correlated to the Brunauer-Emmett-Teller surface area, pore geometry, and pore volume; while the drug release profiles can be controlled by tailoring the morphologies of mesoporous silica carriers.« less

Non-Toxic, Self Cleaning Silicone Fouling Release Coatings

DTIC Science & Technology

1997-10-07

Attempts to microencapsulate silicone oils for enhanced fouling release coatings with thermoset wall structures were unsuccessful: Microcapsule ...filled coatings failed abrasion resistance tests and had mediocre fouling release properties, despite having controlled release rates. Microcapsules with

Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules V. Release properties of ethylcellulose layered matrix granules.

PubMed

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

2008-04-01

In the pharmaceutical preparation of a controlled release drug, it is very important and necessary to understand the release properties. In previous papers, a combination of the square-root time law and cube-root law equations was confirmed to be a useful equation for qualitative treatment. It was also confirmed that the combination equation could analyze the release properties of layered granules as well as matrix granules. The drug release property from layered granules is different from that of matrix granules. A time lag occurs before release, and the entire release property of layered granules was analyzed using the combination of the square-root time law and cube-root law equations. It is considered that the analysis method is very useful and efficient for both matrix and layered granules. Comparing the granulation methods, it is easier to control the manufacturing process by tumbling granulation (method B) than by tumbling-fluidized bed granulation (method C). Ethylcellulose (EC) layered granulation by a fluidized bed granulator might be convenient for the preparation of controlled release dosage forms as compared with a tumbling granulator, because the layered granules prepared by the fluidized bed granulator can granulate and dry at the same time. The time required for drying by the fluidized bed granulator is shorter than that by the tumbling granulator, so the fluidized bed granulator is convenient for preparation of granules in handling and shorter processing time than the tumbling granulator. It was also suggested that the EC layered granules prepared by the fluidized bed granulator were suitable for a controlled release system as well as the EC matrix granules.

Histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP)-induced histamine release is enhanced with SHIP-1 knockdown in cultured human mast cell and basophil models

PubMed Central

Langdon, Jacqueline M.; Schroeder, John T.; Vonakis, Becky M.; Bieneman, Anja P.; Chichester, Kristin; MacDonald, Susan M.

2008-01-01

Previously, we demonstrated a negative correlation between histamine release to histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP) and protein levels of SHIP-1 in human basophils. The present study was conducted to investigate whether suppressing SHIP-1 using small interfering (si)RNA technology would alter the releasability of culture-derived mast cells and basophils, as determined by HRF/TCTP histamine release. Frozen CD34+ cells were obtained from the Fred Hutchinson Cancer Research Center (Seattle, WA, USA). Cells were grown in StemPro-34 medium containing cytokines: mast cells with IL-6 and stem cell factor (100 ng/ml each) for 6–8 weeks and basophils with IL-3 (6.7 ng/ml) for 2–3 weeks. siRNA transfections were performed during Week 6 for mast cells and Week 2 for basophils with siRNA for SHIP-1 or a negative control siRNA. Changes in SHIP-1 expression were determined by Western blot. The functional knockdown was measured by HRF/TCTP-induced histamine release. siRNA knockdown of SHIP-1 in mast cells ranged from 31% to 82%, mean 65 ± 12%, compared with control (n=4). Histamine release to HRF/TCTP was increased only slightly in two experiments. SHIP-1 knockdown in basophils ranged from 34% to 69%, mean 51.8 ± 7% (n=4). Histamine release to HRF/TCTP in these basophils was dependent on the amount of SHIP knockdown. Mast cells and basophils derived from CD34+ precursor cells represent suitable models for transfection studies. Reducing SHIP-1 protein in cultured mast cells and in cultured basophils increases releasability of the cells. PMID:18625911

Preparation of Porous γ-Fe2O3@mWO3 Multifunctional Nanoparticles for Drug Loading and Controlled Release.

PubMed

Peng, Hongxia; Huang, Qin; Wu, Tengyan; Wen, Jin; He, Hengping

2018-02-14

The use of chemotherapy drug is hindered by relatively low selectivity toward cancer cells and severe side effects from uptake by noncancerous cells and tissue. Thus, targeted drug delivery systems are preferred to increase the efficiency of drug delivery to specific tissues as well as to decrease its side effects. The aims of this paper are develop microwave-triggered controlled-release drug delivery systems using porous γ-Fe2O3@mWO3 multifunctional core-shell nanoparticles. We also studied its magnetic- microwave to heat responsive properties and large specific surface area. We chose ibuprofen (IBU) as a model drug to evaluate the loading and release function of the γ- Fe2O3@mWO3 nanoparticles. We used a direct precipitation method and thermal decomposition of CTAB template method to synthesize core-shell structured γ-Fe2O3@mWO3 nanoparticles. The specific surface areas were calculated by the Brunauer-Emmett-Teller (BET) method. The load drug and controlled release of the γ-Fe2O3@mWO3 triggered by microwave was determined with ultraviolet-visible spectroscopic analysis. The γ-Fe2O3@mWO3 nanoparticles possesses high surface area of 100.09 m2/g, provides large accessible pore diameter of 6.0 nm for adsorption of drug molecules, high magnetization saturation value of 43.6 emu/g for drug targeting under foreign magnetic fields, quickly convert electromagnetic energy into thermal energy for controlled release by microwave-triggered which was caused by mWO3 shell. The IBU release of over 78% under microwave discontinuous irradiation out classes the 0.15% within 20s only stirring release. This multifunctional material shows good performance for targeting delivery and mWO3 microwave controlled release of anticancer drugs based on all the properties they possess. The porous shell and the introduction of absorbing material not only increased the drug loading efficiency of the nanoparticles but also realized the microwave-stimulated anticancer drug controlled release. The nanoparticles would be very promising for microwave-induced controlled drug release, targeted drug delivery and hyperthermia therapy using microwave. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Designing in vivo concentration gradients with discrete controlled release: a computational model

NASA Astrophysics Data System (ADS)

Walker, Edgar Y.; Barbour, Dennis L.

2010-08-01

One promising neurorehabilitation therapy involves presenting neurotrophins directly into the brain to induce growth of new neural connections. The precise control of neurotrophin concentration gradients deep within neural tissue that would be necessary for such a therapy is not currently possible, however. Here we evaluate the theoretical potential of a novel method of drug delivery, discrete controlled release (DCR), to control effective neurotrophin concentration gradients in an isotropic region of neocortex. We do so by constructing computational models of neurotrophin concentration profiles resulting from discrete release locations into the cortex and then optimizing their design for uniform concentration gradients. The resulting model indicates that by rationally selecting initial neurotrophin concentrations for drug-releasing electrode coatings in a square 16-electrode array, nearly uniform concentration gradients (i.e. planar concentration profiles) from one edge of the electrode array to the other should be obtainable. DCR therefore represents a promising new method of precisely directing neuronal growth in vivo over a wider spatial profile than would be possible with single release points.

Utilization of wheat straw for the preparation of coated controlled-release fertilizer with the function of water retention.

PubMed

Xie, Lihua; Liu, Mingzhu; Ni, Boli; Wang, Yanfang

2012-07-18

With the aim of improving fertilizer use efficiency and minimizing the negative impact on the environment, a new coated controlled-release fertilizer with the function of water retention was prepared. A novel low water solubility macromolecular fertilizer, poly(dimethylourea phosphate) (PDUP), was "designed" and formulated from N,N'-dimethylolurea (DMU) and potassium dihydrogen phosphate. Simultaneously, an eco-friendly superabsorbent composite based on wheat straw (WS), acrylic acid (AA), 2-acryloylamino-2-methyl-1-propanesulfonic acid (AMPS), and N-hydroxymethyl acrylamide (NHMAAm) was synthesized and used as the coating to control the release of nutrient. The nitrogen release profile and water retention capacity of the product were also investigated. The degradation of the coating material in soil solution was studied. Meanwhile, the impact of the content of N-hydroxymethyl acrylamide on the degradation extent was examined. The experimental data showed that the product with good water retention and controlled-release capacities, being economical and eco-friendly, could be promising for applications in agriculture and horticulture.

Optimum timing for integrated pest management: modelling rates of pesticide application and natural enemy releases.

PubMed

Tang, Sanyi; Tang, Guangyao; Cheke, Robert A

2010-05-21

Many factors including pest natural enemy ratios, starting densities, timings of natural enemy releases, dosages and timings of insecticide applications and instantaneous killing rates of pesticides on both pests and natural enemies can affect the success of IPM control programmes. To address how such factors influence successful pest control, hybrid impulsive pest-natural enemy models with different frequencies of pesticide sprays and natural enemy releases were proposed and analyzed. With releasing both more or less frequent than the sprays, a stability threshold condition for a pest eradication periodic solution is provided. Moreover, the effects of times of spraying pesticides (or releasing natural enemies) and control tactics on the threshold condition were investigated with regard to the extent of depression or resurgence resulting from pulses of pesticide applications. Multiple attractors from which the pest population oscillates with different amplitudes can coexist for a wide range of parameters and the switch-like transitions among these attractors showed that varying dosages and frequencies of insecticide applications and the numbers of natural enemies released are crucial. To see how the pesticide applications could be reduced, we developed a model involving periodic releases of natural enemies with chemical control applied only when the densities of the pest reached the given Economic Threshold. The results indicate that the pest outbreak period or frequency largely depends on the initial densities and the control tactics. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Magnetic molecularly imprinted polymer for aspirin recognition and controlled release

NASA Astrophysics Data System (ADS)

Kan, Xianwen; Geng, Zhirong; Zhao, Yao; Wang, Zhilin; Zhu, Jun-Jie

2009-04-01

Core-shell structural magnetic molecularly imprinted polymers (magnetic MIPs) with combined properties of molecular recognition and controlled release were prepared and characterized. Magnetic MIPs were synthesized by the co-polymerization of methacrylic acid (MAA) and trimethylolpropane trimethacrylate (TRIM) around aspirin (ASP) at the surface of double-bond-functionalized Fe3O4 nanoparticles in chloroform. The obtained spherical magnetic MIPs with diameters of about 500 nm had obvious superparamagnetism and could be separated quickly by an external magnetic field. Binding experiments were carried out to evaluate the properties of magnetic MIPs and magnetic non-molecularly imprinted polymers (magnetic NIPs). The results demonstrated that the magnetic MIPs had high adsorption capacity and selectivity to ASP. Moreover, release profiles and release rate of ASP from the ASP-loaded magnetic MIPs indicated that the magnetic MIPs also had potential applications in drug controlled release.

Development of an osmotic pump system for controlled delivery of diclofenac sodium.

PubMed

Emara, L H; Taha, N F; Badr, R M; Mursi, N M

2012-10-01

Based on an elementary osmotic pump, controlled release systems of diclofenac sodium (DS) were designed to deliver the drug in a zero-order release pattern. Osmotic pump tablets containing 100 mg DS were prepared and coated with either semipermeable (SPM) or microporous (PM) membranes. The tablet coats were composed of hydrophobic triacetin (TA) or hydrophilic polyethylene glycol 400 (PEG 400) incorporated in cellulose acetate (CA) solution, for SPM and PM, respectively. Variable tablet core compositions such as swelling polymers (PEO and HPMC) and osmotic agents (lactose, NaCl, and KCl) were studied. An optimized, sensitive and well controlled in vitro release design, based on the flow-through cell (FTC), was utilized to discriminate between preparations. The results revealed that the presence of PEG 400 in the coating membrane accelerated the drug release rate, while TA suppressed the release rate of DS. In the case of SPM, the amount of DS released was inversely proportional to the membrane thickness, where 5% (w/w) weight gain gave a higher DS release rate than 10% (w/w). Results of different tablet core compositions revealed that the release rate of DS decreased as PEO molecular weight increased. HPMC K15M showed the lowest DS release rate. The presence of lactose, KCl, or NaCl pronouncedly affected DS release rate depending on polymer type in the core. Scanning electron microscopy (SEM) confirmed formation of pores in the membrane that accounts for faster DS release rate. These results revealed that DS could be formulated as an osmotic pump system with a prolonged, zero-order release pattern.

Genipin-modified gelatin nanocarriers as swelling controlled drug delivery system for in vitro release of cytarabine.

PubMed

Khan, Huda; Shukla, R N; Bajpai, A K

2016-04-01

The aim of the present investigation was to design biocompatible gelatin nanoparticles, capable of releasing the cytarabine drug in a controllable way by regulating the extent of swelling of nanoparticles. In order to achieve the proposed objectives, gelatin (Type A, derived from acid cured tissue) was modified by crosslinking with genipin and nanoparticles of crosslinked gelatin were prepared using single water in oil (W/O) emulsion technique. The nanoparticles were characterized by techniques like FTIR, SEM, TEM, particles size analysis, and surface potential measurements. The nanoparticle chemical architecture was found to influence drug-releasing capacity. The influence of experimental conditions such as pH and simulated physiological fluids as the release medium was also investigated on the release profiles of cytarabine. It is possible to fabricate high-performance materials, by designing of controlled size gelatin nanoparticles with good biocompatible properties along with desired drug release profiles. Copyright © 2015 Elsevier B.V. All rights reserved.

Adaptive release of natural enemies in a pest-natural enemy system with pesticide resistance.

PubMed

Liang, Juhua; Tang, Sanyi; Cheke, Robert A; Wu, Jianhong

2013-11-01

Integrated pest management options such as combining chemical and biological control are optimal for combating pesticide resistance, but pose questions if a pest is to be controlled to extinction. These questions include (i) what is the relationship between the evolution of pesticide resistance and the number of natural enemies released? (ii) How does the cumulative number of natural enemies dying affect the number of natural enemies to be released? To address these questions, we developed two novel pest-natural enemy interaction models incorporating the evolution of pesticide resistance. We investigated the number of natural enemies to be released when threshold conditions for the extinction of the pest population in two different control tactics are reached. Our results show that the number of natural enemies to be released to ensure pest eradication in the presence of increasing pesticide resistance can be determined analytically and depends on the cumulative number of dead natural enemies before the next scheduled release time.

Action potential-independent and pharmacologically unique vesicular serotonin release from dendrites

PubMed Central

Colgan, Lesley A.; Cavolo, Samantha L.; Commons, Kathryn G.; Levitan, Edwin S.

2012-01-01

Serotonin released within the dorsal raphe nucleus (DR) induces feedback inhibition of serotonin neuron activity and consequently regulates mood-controlling serotonin release throughout the forebrain. Serotonin packaged in vesicles is released in response to action potentials by the serotonin neuron soma and terminals, but the potential for release by dendrites is unknown. Here three-photon (3P) microscopy imaging of endogenous serotonin in living rat brain slice, immunofluorescence and immuno-gold electron microscopy detection of VMAT2 (vesicular monoamine transporter 2) establish the presence of vesicular serotonin within DR dendrites. Furthermore, activation of glutamate receptors is shown to induce vesicular serotonin release from dendrites. However, unlike release from the soma and terminals, dendritic serotonin release is independent of action potentials, relies on L-type Ca2+ channels, is induced preferentially by NMDA, and displays distinct sensitivity to the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. The unique control of dendritic serotonin release has important implications for DR physiology and the antidepressant action of SSRIs, dihydropyridines and NMDA receptor antagonists. PMID:23136413

Effect of decrease in both postprandial blood glucose (PBG) and fasting blood glucose (FBG) levels in normal beagle dogs with nateglinide enteric coated granules and immediate release tablets.

PubMed

Makino, Chisato; Ninomiya, Nobutaka; Sakai, Hidetoshi; Orita, Haruo; Okano, Akira; Yabuki, Akira

2006-04-01

Nateglinide is a new quick action/short duration (QRSD) type of oral blood glucose regulator, and nateglinide immediate release tablets are used for patients with mild diabetes under the trade name of Fastic((R)) tablets. In this study, we attempted to determine if it was possible to control both post-prandial blood glucose level (PBG) and fasting blood glucose level (FBG) for moderate or severe diabetes through controlled release of nateglinide. Enteric coated granules were selected for the administration form for controlled release of nateglinide, and three types of enteric coated granules were prepared having dissolution pH values of 5.5, 6.5 and 7.2. The three types of enteric coated granules were each administered separately or the enteric coated granules having an dissolution pH of 6.5 were administered simultaneous to administration of nateglinide immediate release tablets to normal beagle dogs just before feeding followed by measurement of plasma nateglinide concentration, plasma insulin concentration and blood glucose level. In the case of administering enteric coated granules alone (nateglinide: 9 mg/kg), the absorption of nateglinide was confirmed to tend to be delayed as the dissolution pH increased. In the case of an dissolution pH of 5.5, decreases in both PBG and FBG were observed. In the case of dissolution pH values of 6.5 and 7.2, only decrease in FBG was observed. In case of nateglinide immediate release tablets (nateglinide: 9 mg/kg), only decrease in PBG was observed. Decreases in both PBG and FBG were observed in the case of simultaneous administration of dissolution pH 6.5 enteric coated granules and nateglinide immediate release tablets just before feeding (nateglinide: 90 mg/head+60 mg/head). A correlation was observed between plasma nateglinide concentrations and blood glucose levels. On the other hand, there were no correlations observed between changes in plasma insulin concentrations and blood glucose levels. In case of nateglinide immediate release tablets (nateglinide: 150 mg/head), Decreases in both PBG and FBG were observed. However, the nateglinide controlled release formulation is more useful than the nateglinide immediate release tablets from the view point of avoidance of side effect, or of easy control of both PBG and FBG. On the basis of these results, the design of a controlled release formulation that contains nateglinide was suggested to enable control of both PBG and FBG for moderate and severe diabetes patients.

40 CFR 68.39 - Documentation.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., and the rationale for selection; assumptions shall include use of any administrative controls and any... include the anticipated effect of the controls and mitigation on the release quantity and rate. (b) For... administrative controls and any mitigation that were assumed to limit the quantity that could be released...

40 CFR 68.39 - Documentation.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., and the rationale for selection; assumptions shall include use of any administrative controls and any... include the anticipated effect of the controls and mitigation on the release quantity and rate. (b) For... administrative controls and any mitigation that were assumed to limit the quantity that could be released...

40 CFR 68.39 - Documentation.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., and the rationale for selection; assumptions shall include use of any administrative controls and any... include the anticipated effect of the controls and mitigation on the release quantity and rate. (b) For... administrative controls and any mitigation that were assumed to limit the quantity that could be released...

40 CFR 68.39 - Documentation.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., and the rationale for selection; assumptions shall include use of any administrative controls and any... include the anticipated effect of the controls and mitigation on the release quantity and rate. (b) For... administrative controls and any mitigation that were assumed to limit the quantity that could be released...

40 CFR 68.39 - Documentation.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., and the rationale for selection; assumptions shall include use of any administrative controls and any... include the anticipated effect of the controls and mitigation on the release quantity and rate. (b) For... administrative controls and any mitigation that were assumed to limit the quantity that could be released...

Munc13 controls the location and efficiency of dense-core vesicle release in neurons.

PubMed

van de Bospoort, Rhea; Farina, Margherita; Schmitz, Sabine K; de Jong, Arthur; de Wit, Heidi; Verhage, Matthijs; Toonen, Ruud F

2012-12-10

Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2-null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically.

Slow Release Of Reagent Chemicals From Gel Matrices

NASA Technical Reports Server (NTRS)

Debnam, William J.; Barber, Patrick G.; Coleman, James

1988-01-01

Procedure developed for slow release of reagent chemicals into solutions. Simple and inexpensive and not subject to failure of equipment. Use of toothpaste-type tube or pump dispenser conceivably provides more controlled technique for storage and dispensation of gel matrix. Possible uses include controlled, slow release of reagents in chemical reactions, crystal growth, space-flight experiments, and preformed gel medications from packets.

Releases of natural enemies in Hawaii since 1980 for classical biological control of weeds

Treesearch

P. Conant; J. N. Garcia; M. T. Johnson; W. T. Nagamine; C. K. Hirayama; G. P. Markin; R. L. Hill

2013-01-01

A comprehensive review of biological control of weeds in Hawaii was last published in 1992, covering 74 natural enemy species released from 1902 through 1980. The present review summarizes releases of 21 natural enemies targeting seven invasive weeds from 1981 to 2010. These projects were carried out by Hawaii Department of Agriculture (HDOA), USDA Forest Service (USFS...

Leachate Concentrations of Ammonium, Nitrate, and Phosphorus as Affected by Nutrient Release from Four Different Types of Controlled-Release Fertilizers and Crop Development of Containerized Waxleaf Privet.

USDA-ARS?s Scientific Manuscript database

Concentrations of ammonium, nitrate, and phosphorus in irrigation leachate were measured weekly over a 47-week period from a high-fertility, neutral-pH substrate into which four types of 12-month controlled-release fertilizers (Osmocote, Nutricote, Polyon, or Multicote) were incorporated. Containers...

Leachate Concentrations of Ammonium, Nitrate, and Phosphorus as Affected by Nutrient Release From Four Different Types of Controlled-Release Fertilizers and Crop Development of Containerized Azaleas

USDA-ARS?s Scientific Manuscript database

Concentrations of ammonium, nitrate, and phosphorus in irrigation leachate were measured weekly over a 47-week period from a low-fertility, acid-based substrate into which four types of 12-month controlled-release fertilizers (Osmocote, Nutricote, Polyon, or Multicote) were incorporated. Containers ...

Trends in opioid use and dosing among socio-economically disadvantaged patients

PubMed Central

Gomes, Tara; Juurlink, David N; Dhalla, Irfan A; Mailis-Gagnon, Angela; Paterson, J Michael; Mamdani, Muhammad M

2011-01-01

Background Opioid therapy for patients with chronic nonmalignant pain remains controversial, primarily because of safety concerns and the potential for abuse. The objective of this study was to examine trends in opioid utilization for nonmalignant pain among recipients of social assistance and to explore the relation between dose of analgesic and mortality. Methods Using a cross-sectional study design, we characterized annual trends in prescriptions for and daily dose of opioid analgesics between 2003 and 2008 for beneficiaries (aged 15 to 64 years) of Ontario’s public drug plan. We defined moderate, high and very high dose thresholds as daily doses of up to 200, 201 to 400, and more than 400 mg oral morphine (or equivalent), respectively. In an exploratory cohort study, we followed, over a 2-year period, patients who received at least one prescription for an opioid in 2004 to investigate the relation between opioid dose and opioid-related mortality. Results Over the study period, opioid prescribing rates rose by 16.2%, and 180 974 individuals received nearly 1.5 million opioid prescriptions in 2008. Also by 2008, the daily dose dispensed exceeded 200 mg morphine equivalent for almost a third (32.6%) of recipients of long-acting oxycodone but only 20.3% of those treated with fentanyl or other long-acting opioids. Among patients for whom high or very high doses of opioids were dispensed in 2004, 19.3% of deaths during the subsequent 2 years were opioid-related, occurring at a median age of 46 years. Two-year opioid-related mortality rates were 1.63 per 1000 population (95% confidence interval [CI] 1.42–1.85) among people with moderate-dose prescriptions, 7.92 per 1000 population (95% CI 5.25–11.49) among those with high-dose prescriptions, and 9.94 per 1000 population (95% CI 2.78–25.12) among those with very-high-dose prescriptions. Interpretation Among socio-economically disadvantaged patients in Ontario, the use and dose of opioids for nonmalignant pain has increased substantially, driven primarily by the use of long-acting oxycodone and, to a lesser extent, fentanyl. The findings of our exploratory study suggested a strong association between opioid-related mortality and the dose of opioid dispensed. PMID:22046214

Oxycodone recycling: a novel hypothesis of opioid tolerance development in humans.

PubMed

Linares, Oscar A; Fudin, Jeffrey; Schiesser, William E; Linares, Annemarie Daly; Boston, Raymond C

2014-09-01

We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC's exposure to local μ-opioid receptors (μORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is TΩ. TΩ estimates OC's tolerance recovery in days; It is defined as the rate of recovery of OC's pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t1/2 = 4.5h)-after which time steady-state was assumed. Repetitive OC dose TΩ fell 61% compared to single OC dose TΩ (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p = 0.001). The fall in TΩ was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravascular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of μORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface μOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance development to include OC recycling. OC recycling is a novel hypothesis of OC tolerance development in humans. Copyright © 2014 Elsevier Ltd. All rights reserved.

Bioavailability of ambroxol sustained release preparations. Part II: Single and multiple oral dose studies in man.

PubMed

Janssen, T J; Guelen, P J; Vree, T B; Botterblom, M H; Valducci, R

1988-01-01

The bioavailability of a new ambroxol sustained release preparation (75 mg) based on a dialyzing membrane for controlled release was studied in healthy volunteers after single and multiple oral dose in comparison with a standard sustained release formulation in a cross-over study under carefully controlled conditions. Plasma concentrations of ambroxol were measured by means of a HPLC method. Based on AUC data both preparations are found to be bioequivalent, but show different plasma concentration profiles. The test preparation showed a more pronounced sustained release profile than the reference preparation (single dose) resulting in significantly higher steady state plasma levels.

Letrozole dispersed on poly (vinyl alcohol) anchored maleic anhydride grafted low density polyethylene: a controlled drug delivery system for treatment of breast cancer.

PubMed

Siddiqa, Akhtar Jahan; Chaudhury, Koel; Adhikari, Basudam

2014-04-01

The present work focuses on the design of a drug delivery system for systemic, controlled release of the poorly soluble breast cancer drug, letrozole. The drug delivery system was prepared in two steps: a low density polyethylene (LDPE) substrate surface was grafted with maleic anhydride (MA) via solution grafting technique. Next, the grafted substrate was used to anchor a hydrophilic polymeric drug release system consisting of poly (vinyl alcohol) (PVA). The PVA anchored MA grafted LDPE (PVA/MA-g-LDPE) drug release system was used for the controlled release of letrozole. This system was characterized using ATR-FTIR spectrophotometry, surface profilometry, and scanning electron microscopy. Biocompatibility studies were also carried out. In vitro release studies of letrozole from the system were performed in distilled water and phosphate buffer saline (PBS) at 37°C. Release of ∼90% letrozole from hydrophilic PVA matrix was observed within a period of 35 days. A high correlation coefficient (R(2)=0.99) was seen between the release of letrozole in distilled water and PBS. Cytotoxicity studies using MTT colorimetric assay suggested that all samples were biocompatible. It is concluded that the letrozole delivery system appears to overcome the limitations associated with letrozole by providing enhanced drug dissolution rate, controlled release and improved bioavailability of the incorporated drug and, therefore, seems to have extended therapeutic effects. Copyright © 2014 Elsevier B.V. All rights reserved.

Intercalation and controlled release properties of vitamin C intercalated layered double hydroxide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Xiaorui, E-mail: gxr_1320@sina.com; School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189; Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA

Two drug-inorganic composites involving vitamin C (VC) intercalated in Mg–Al and Mg–Fe layered double hydroxides (LDHs) have been synthesized by the calcination–rehydration (reconstruction) method. Powder X-ray diffraction (XRD), Fourier transform infrared (FTIR), and UV–vis absorption spectroscopy indicate a successful intercalation of VC into the interlayer galleries of the LDH host. Studies of VC release from the LDHs in deionised water and in aqueous CO{sub 3}{sup 2−} solutions imply that Mg{sub 3}Al–VC LDH is a better controlled release system than Mg{sub 3}Fe–VC LDH. Analysis of the release profiles using a number of kinetic models suggests a solution-dependent release mechanism, and amore » diffusion-controlled deintercalation mechanism in deionised water, but an ion exchange process in CO{sub 3}{sup 2−} solution. - Graphical abstract: Vitamin C anions have been intercalated in the interlayer space of layered double hydroxide and released in CO{sub 3}{sup 2−} solution and deionised water. - Highlights: • Vitamin C intercalated Mg–Al and Mg–Fe layered double hydroxides were prepared. • Release property of vitamin C in aqueous CO{sub 3}{sup 2−} solution is better. • Avrami-Erofe’ev and first-order models provide better fit for release results. • Diffusion-controlled and ion exchange processes occur in deionised water. • An ion exchange process occurs in CO{sub 3}{sup 2−} solution.« less

Physician Dispensing of Oxycodone and Other Commonly Used Opioids, 2000-2015, United States.

PubMed

Mack, Karin Ann; Jones, Christopher McCall; McClure, Roderick John

2018-05-01

An average of 91 people in the United States die every day from an opioid-related overdose (including prescription opioids and heroin). The direct dispensing of opioids from health care practitioner offices has been linked to opioid-related harms. The objective of this study is to describe the changing nature of the volume of this type of prescribing at the state level. This descriptive study examines the distribution of opioids by practitioners using 1999-2015 Automation of Reports and Consolidated Orders System data. Analyses were restricted to opioids distributed to practitioners. Amount distributed (morphine milligram equivalents [MMEs]) and number of practitioners are presented. Patterns of distribution to practitioners and the number of practitioners varied markedly by state and changed dramatically over time. Comparing 1999 with 2015, the MME distributed to dispensing practitioners decreased in 16 states and increased in 35. Most notable was the change in Florida, which saw a peak of 8.94 MMEs per 100,000 persons in 2010 (the highest distribution in all states in all years) and a low of 0.08 in 2013. This study presents the first state estimates of office-based dispensing of opioids. Increases in direct dispensing in recent years may indicate a need to monitor this practice and consider whether changes are needed. Using controlled substances data to identify high prescribers and dispensers of opioids, as well as examining overall state trends, is a foundational activity to informing the response to potentially high-risk clinical practices.

Controlled porosity osmotic pump-based controlled release systems of pseudoephedrine. I. Cellulose acetate as a semipermeable membrane.

PubMed

Makhija, Sapna N; Vavia, Pradeep R

2003-04-14

A controlled porosity osmotic pump-based drug delivery system has been described in this study. Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channeling agents in the coating. The usual dose of pseudoephedrine is 60 mg to be taken three or four times daily. It has a short plasma half life of 5-8 h. Hence, pseudoephedrine was chosen as a model drug with an aim to develop a controlled release system for a period of 12 h. Sodium bicarbonate was used as the osmogent. The effect of different ratios of drug:osmogent on the in-vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. Different channeling agents tried were diethylphthalate (DEP), dibutylphthalate (DBP), dibutylsebacate (DBS) and polyethyleneglycol 400 (PEG 400). The effect of polymer loading on in-vitro drug release was studied. It was found that drug release rate increased with the amount of osmogent due to the increased water uptake, and hence increased driving force for drug release. This could be retarded by the proper choice of channeling agent in order to achieve the desired zero order release profile. Also the lag time seen with tablets coated using diethylphthalate as channeling agent was reduced by using a hydrophilic plasticizer like polyethyleneglycol 400 in combination with diethylphthalate. This system was found to deliver pseudoephedrine at a zero order rate for 12 h. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per ICH guidelines at different temperature and humidity conditions.

Dual turn-on fluorescence signal-based controlled release system for real-time monitoring of drug release dynamics in living cells and tumor tissues.

PubMed

Kong, Xiuqi; Dong, Baoli; Song, Xuezhen; Wang, Chao; Zhang, Nan; Lin, Weiying

2018-01-01

Controlled release systems with capabilities for direct and real-time monitoring of the release and dynamics of drugs in living systems are of great value for cancer chemotherapy. Herein, we describe a novel dual turn-on fluorescence signal-based controlled release system ( CDox ), in which the chemotherapy drug doxorubicin ( Dox ) and the fluorescent dye ( CH ) are conjugated by a hydrazone moiety, a pH-responsive cleavable linker. CDox itself shows nearly no fluorescence as the fluorescence of CH and Dox is essentially quenched by the C=N isomerization and N-N free rotation. However, when activated under acidic conditions, CDox could be hydrolyzed to afford Dox and CH , resulting in dual turn-on signals with emission peaks at 595 nm and 488 nm, respectively. Notably, CDox exhibits a desirable controlled release feature as the hydrolysis rate is limited by the steric hindrance effect from both the Dox and CH moieties. Cytotoxicity assays indicate that CDox shows much lower cytotoxicity relative to Dox , and displays higher cell inhibition rate to cancer than normal cells. With the aid of the dual turn-on fluorescence at different wavelengths, the drug release dynamics of CDox in living HepG2 and 4T-1 cells was monitored in double channels in a real-time fashion. Importantly, two-photon fluorescence imaging of CDox in living tumor tissues was also successfully performed by high-definition 3D imaging. We expect that the unique controlled release system illustrated herein could provide a powerful means to investigate modes of action of drugs, which is critical for development of much more robust and effective chemotherapy drugs.

Kinetics and mechanism of release from glyceryl monostearate-based implants: evaluation of release in a gel simulating in vivo implantation.

PubMed

Allababidi, S; Shah, J C

1998-06-01

The overall objective of the study was to design an implantable delivery system based on glyceryl monostearate (GMS) for the site-specific delivery of antibiotics for the prevention of surgical wound infection. To design the implant, a release method had to be developed that simulate the in vivo implantation conditions to be able to predict the release characteristics from the implants when they are actually used in vivo. Also, identifying the release kinetics and mechanism and evaluating the factors that influence the release of drugs from the GMS-based matrix were necessary to allow further design of implants that could yield a desired release rate. The release of cefazolin was monitored from GMS matrixes implanted into agar gel, simulating subcutaneous tissues with respect to viscosity and water content. The gel method resulted in observation of spatial and temporal concentration profiles in the immediate vicinity of the implants, indicating the benefits of local drug delivery; however, there was no significant difference between the cumulative release profiles by the gel method or the vial release method. The release of cefazolin from the GMS-based matrix with the vial method followed Higuchi's square root of time kinetics. The release rate was found to be directly proportional to cefazolin load (A) and the surface area (SA) of the matrix as expressed by the following equation: = 0.24ASA. On the basis of this equation, one can design a variety of GMS matrixes that would result in a desired release rate or release duration. This also indicated that cefazolin release followed the release kinetics of a freely soluble drug from an insoluble matrix and hence it is a diffusion-controlled process. The effect of drug solubility on the release kinetics was determined by comparing the release kinetics of the poorly water soluble ciprofloxacin (0.16 mg/mL) to that of the highly water soluble cefazolin (325 mg/mL). The release duration of ciprofloxacin (80 h) was longer than that of cefazolin (25 h) from identical GMS matrixes. Although ciprofloxacin release was initially controlled by the matrix, agitation accelerated disintegration of the matrix and release due to its poor solubility, and ciprofloxacin release appeared to be a dissolution-controlled process following zero-order release kinetics.

49 CFR 229.135 - Event recorders.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) Locomotive position in consist (lead or trail); (xxiii) Tractive effort; (xxiv) Cruise control on/off, if so...; (xviii) Brakes apply summary train line; (xix) Brakes released summary train line; (xx) Cruise control on... determining, that a brake application or release resulted from manipulation of brake controls at the position...

49 CFR 229.135 - Event recorders.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) Locomotive position in consist (lead or trail); (xxiii) Tractive effort; (xxiv) Cruise control on/off, if so...; (xviii) Brakes apply summary train line; (xix) Brakes released summary train line; (xx) Cruise control on... determining, that a brake application or release resulted from manipulation of brake controls at the position...

49 CFR 229.135 - Event recorders.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) Locomotive position in consist (lead or trail); (xxiii) Tractive effort; (xxiv) Cruise control on/off, if so...; (xviii) Brakes apply summary train line; (xix) Brakes released summary train line; (xx) Cruise control on... determining, that a brake application or release resulted from manipulation of brake controls at the position...

49 CFR 229.135 - Event recorders.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) Locomotive position in consist (lead or trail); (xxiii) Tractive effort; (xxiv) Cruise control on/off, if so...; (xviii) Brakes apply summary train line; (xix) Brakes released summary train line; (xx) Cruise control on... determining, that a brake application or release resulted from manipulation of brake controls at the position...

Synchronized and sustained release of multiple components in silymarin from erodible glyceryl monostearate matrix system.

PubMed

Lu, Cheng; Lu, Yi; Chen, Jian; Zhang, Wentong; Wu, Wei

2007-05-01

Development of sustained delivery systems for herbal medicines was very difficult because of their complexity in composition. The concept of synchronized release from sustained release systems, which is characterized by release of multiple components in their original ratio that defines a herbal medicine, served as the basis for keeping the original pharmacological activity. In this study, erodible matrix systems based on glyceryl monostearate and polyethylene glycol 6000 or poloxamer 188 were prepared to perform strict control on synchronized release of the five active components of silymarin, i.e. taxifolin, silychrystin, silydianin, isosilybin and silybin. The matrix system was prepared by a melt fusion method. Synchronized release was achieved with high similarity factor f(2) values between each two of the five components. Erosion profiles of the matrix were in good correlation with release profiles of the five components, showing erosion-controlled release mechanisms. Through tuning some of the formulation variables, the system can be adjusted for synchronized and sustained release of silymarin for oral administration. In vitro hemolysis study indicated that the synchronized release samples showed a much better stabilizing effect on erythrocyte membrane.

A biodegradable device for the controlled release of Piper nigrum (Piperaceae) standardized extract to control Aedes aegypti (Diptera, Culicidae) larvae.

PubMed

Custódio, Kauê Muller; Oliveira, Joice Guilherme de; Moterle, Diego; Zepon, Karine Modolon; Prophiro, Josiane Somariva; Kanis, Luiz Alberto

2016-01-01

The significant increase in dengue, Zika, and chikungunya and the resistance of the Aedes aegypti mosquito to major insecticides emphasize the importance of studying alternatives to control this vector. The aim of this study was to develop a controlled-release device containing Piper nigrum extract and to study its larvicidal activity against Aedes aegypti. Piper nigrum extract was produced by maceration, standardized in piperine, and incorporated into cotton threads, which were inserted into hydrogel cylinders manufactured by the extrusion of carrageenan and carob. The piperine content of the extract and thread reservoirs was quantified by chromatography. The release profile from the device was assessed in aqueous medium and the larvicidal and residual activities of the standardized extract as well as of the controlled-release device were examined in Aedes aegypti larvae. The standardized extract contained 580mg/g of piperine and an LC50 value of 5.35ppm (24h) and the 3 cm thread reservoirs contained 13.83 ± 1.81mg of piperine. The device showed zero-order release of piperine for 16 days. The P. nigrum extract (25ppm) showed maximum residual larvicidal activity for 10 days, decreasing progressively thereafter. The device had a residual larvicidal activity for up to 37 days. The device provided controlled release of Piper nigrum extract with residual activity for 37 days. The device is easy to manufacture and may represent an effective alternative for the control of Aedes aegypti larvae in small water containers.

Remote modulation of neural activities via near-infrared triggered release of biomolecules.

PubMed

Li, Wei; Luo, Rongcong; Lin, Xudong; Jadhav, Amol D; Zhang, Zicong; Yan, Li; Chan, Chung-Yuan; Chen, Xianfeng; He, Jufang; Chen, Chia-Hung; Shi, Peng

2015-10-01

The capability to remotely control the release of biomolecules provides an unique opportunity to monitor and regulate neural signaling, which spans extraordinary spatial and temporal scales. While various strategies, including local perfusion, molecular "uncaging", or photosensitive polymeric materials, have been applied to achieve controlled releasing of neuro-active substances, it is still challenging to adopt these technologies in many experimental contexts that require a straightforward but versatile loading-releasing mechanism. Here, we develop a synthetic strategy for remotely controllable releasing of neuro-modulating molecules. This platform is based on microscale composite hydrogels that incorporate polypyrrole (PPy) nanoparticles as photo-thermal transducers and is triggered by near-infrared-light (NIR) irradiation. Specifically, we first demonstrate the utility of our technology by recapitulating the "turning assay" and "collapse assay", which involve localized treatment of chemotactic factors (e.g. Netrin or Semaphorin 3A) to subcellular neural elements and have been extensively used in studying axonal pathfinding. On a network scale, the photo-sensitive microgels are also validated for light-controlled releasing of neurotransmitters (e.g. glutamate). A single NIR-triggered release is sufficient to change the dynamics of a cultured hippocampal neuron network. Taking the advantage of NIR's capability to penetrate deep into live tissue, this technology is further shown to work similarly well in vivo, which is evidenced by synchronized spiking activity in response to NIR-triggered delivery of glutamate in rat auditory cortex, demonstrating remote control of brain activity without any genetic modifications. Notably, our nano-composite microgels are capable of delivering various molecules, ranging from small chemicals to large proteins, without involving any crosslinking chemistry. Such great versatility and ease-of-use will likely make our optically-controlled delivery technology a general and important tool in cell biology research. Copyright © 2015 Elsevier Ltd. All rights reserved.

77 FR 46373 - Field Release of Aphelinus glycinis for the Biological Control of the Soybean Aphid in the...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-03

... Inspection Service [Docket No APHIS-2012-0061] Field Release of Aphelinus glycinis for the Biological Control... for the biological control of the soybean aphid, Aphis glycines, in the continental United States. We... glycinis for the Biological Control of the Soybean Aphid in the Continental United States'' (March 2012...

Advances in Targeted Pesticides with Environmentally Responsive Controlled Release by Nanotechnology

PubMed Central

Huang, Bingna; Chen, Feifei; Shen, Yue; Wang, Yan; Sun, Changjiao; Zhao, Xiang; Cui, Bo; Gao, Fei; Zeng, Zhanghua; Cui, Haixin

2018-01-01

Pesticides are the basis for defending against major biological disasters and important for ensuring national food security. Biocompatible, biodegradable, intelligent, and responsive materials are currently an emerging area of interest in the field of efficient, safe, and green pesticide formulation. Using nanotechnology to design and prepare targeted pesticides with environmentally responsive controlled release via compound and chemical modifications has also shown great potential in creating novel formulations. In this review, special attention has been paid to intelligent pesticides with precise controlled release modes that can respond to micro-ecological environment changes such as light-sensitivity, thermo-sensitivity, humidity sensitivity, soil pH, and enzyme activity. Moreover, establishing intelligent and controlled pesticide release technologies using nanomaterials are reported. These technologies could increase pesticide-loading, improve the dispersibility and stability of active ingredients, and promote target ability. PMID:29439498

Synthesis and Properties of pH-, Thermo-, and Salt-Sensitive Modified Poly(aspartic acid)/Poly(vinyl alcohol) IPN Hydrogel and Its Drug Controlled Release.

PubMed

Lu, Jingqiong; Li, Yinhui; Hu, Deng; Chen, Xiaoling; Liu, Yongmei; Wang, Liping; Zhao, Yansheng

2015-01-01

Modified poly(aspartic acid)/poly(vinyl alcohol) interpenetrating polymer network (KPAsp/PVA IPN) hydrogel for drug controlled release was synthesized by a simple one-step method in aqueous system using poly(aspartic acid) grafting 3-aminopropyltriethoxysilane (KH-550) and poly(vinyl alcohol) (PVA) as materials. The hydrogel surface morphology and composition were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The thermal stability was analyzed by thermogravimetric analysis (TGA). The swelling properties and pH, temperature, and salt sensitivities of KPAsp, KPAsp/PVA semi-interpenetrating polymer network (semi-IPN), and KPAsp/PVA IPN hydrogels were also investigated. All of the three hydrogels showed ampholytic pH-responsive properties, and swelling behavior was also extremely sensitive to the temperature, ionic strength, and cationic species. Finally, the drug controlled release properties of the three hydrogels were evaluated and results indicated that three hydrogels could control drug release by external surroundings stimuli. The drug controlled release properties of KPAsp/PVA IPN hydrogel are the most outstanding, and the correlative measured release profiles of salicylic acid at 37°C were 32.6 wt% at pH = 1.2 (simulated gastric fluid) and 62.5 wt% at pH = 7.4 (simulated intestinal fluid), respectively. These results indicated that KPAsp/PVA IPN hydrogels are a promising carrier system for controlled drug delivery.

Responsiveness of blood and sputum inflammatory cells in Japanese COPD patients, non-COPD smoking controls, and non-COPD nonsmoking controls

PubMed Central

Kawayama, Tomotaka; Kinoshita, Takashi; Matsunaga, Kazuko; Kobayashi, Akihiro; Hayamizu, Tomoyuki; Johnson, Malcolm; Hoshino, Tomoaki

2016-01-01

Purpose To compare pulmonary and systemic inflammatory mediator release, pre- and poststimulation, ex vivo, in cells from Japanese patients with chronic obstructive pulmonary disease (COPD), non-COPD smoking controls, and non-COPD nonsmoking controls (NSC). Patients and methods This was a nontreatment study with ten subjects per group. Inflammatory biomarker release, including interleukin (IL)-6 and -8, matrix metalloproteinase-9, and tumor necrosis factor (TNF)-α, was measured in peripheral blood mononuclear cells (PBMC) and sputum cells with and without lipopolysaccharide or TNF-α stimulation. Results In PBMC, basal TNF-α release (mean ± standard deviation) was significantly different between COPD (81.6±111.4 pg/mL) and nonsmoking controls (9.5±5.2 pg/mL) (P<0.05). No other significant differences were observed. Poststimulation biomarker release tended to increase, with the greatest changes in the COPD group. The greatest mean increases were seen in the lipopolysaccharide-induced release of matrix metalloproteinase-9, TNF-α, and IL-6 from PBMC. Pre- and poststimulation data from sputum samples were more variable and less conclusive than from PBMC. In the COPD group, induced sputum neutrophil levels were higher and macrophage levels were lower than in either control group. Significant correlations were seen between the number of sputum cells (macrophages and neutrophils) and biomarker levels (IL-8, IL-6, and TNF-α). Conclusion This was the first study to compare cellular inflammatory mediator release before and after stimulation among Japanese COPD, smoking controls, and nonsmoking controls populations. Poststimulation levels tended to be higher in patients with COPD. The results suggest that PBMC are already preactivated in the circulation in COPD patients. This provides further evidence that COPD is a multicomponent disease, involving both airway and systemic inflammation. PMID:26929615

Responsiveness of blood and sputum inflammatory cells in Japanese COPD patients, non-COPD smoking controls, and non-COPD nonsmoking controls.

PubMed

Kawayama, Tomotaka; Kinoshita, Takashi; Matsunaga, Kazuko; Kobayashi, Akihiro; Hayamizu, Tomoyuki; Johnson, Malcolm; Hoshino, Tomoaki

2016-01-01

To compare pulmonary and systemic inflammatory mediator release, pre- and poststimulation, ex vivo, in cells from Japanese patients with chronic obstructive pulmonary disease (COPD), non-COPD smoking controls, and non-COPD nonsmoking controls (NSC). This was a nontreatment study with ten subjects per group. Inflammatory biomarker release, including interleukin (IL)-6 and -8, matrix metalloproteinase-9, and tumor necrosis factor (TNF)-α, was measured in peripheral blood mononuclear cells (PBMC) and sputum cells with and without lipopolysaccharide or TNF-α stimulation. In PBMC, basal TNF-α release (mean ± standard deviation) was significantly different between COPD (81.6±111.4 pg/mL) and nonsmoking controls (9.5±5.2 pg/mL) (P<0.05). No other significant differences were observed. Poststimulation biomarker release tended to increase, with the greatest changes in the COPD group. The greatest mean increases were seen in the lipopolysaccharide-induced release of matrix metalloproteinase-9, TNF-α, and IL-6 from PBMC. Pre- and poststimulation data from sputum samples were more variable and less conclusive than from PBMC. In the COPD group, induced sputum neutrophil levels were higher and macrophage levels were lower than in either control group. Significant correlations were seen between the number of sputum cells (macrophages and neutrophils) and biomarker levels (IL-8, IL-6, and TNF-α). This was the first study to compare cellular inflammatory mediator release before and after stimulation among Japanese COPD, smoking controls, and nonsmoking controls populations. Poststimulation levels tended to be higher in patients with COPD. The results suggest that PBMC are already preactivated in the circulation in COPD patients. This provides further evidence that COPD is a multicomponent disease, involving both airway and systemic inflammation.

Thermoresponsive magnetic composite nanomaterials for multimodal cancer therapy.

PubMed

Purushotham, S; Ramanujan, R V

2010-02-01

The synthesis, characterization and property evaluation of drug-loaded polymer-coated magnetic nanoparticles (MNPs) relevant to multimodal cancer therapy has been studied. The hyperthermia and controlled drug release characteristics of these particles was examined. Magnetite (Fe(3)O(4))-poly-n-(isopropylacrylamide) (PNIPAM) composite MNPs were synthesized in a core-shell morphology by dispersion polymerization of n-(isopropylacrylamide) chains in the presence of a magnetite ferrofluid. These core-shell composite particles, with a core diameter of approximately 13nm, were loaded with the anti-cancer drug doxorubicin (dox), and the resulting composite nanoparticles (CNPs) exhibit thermoresponsive properties. The magnetic properties of the composite particles are close to those of the uncoated magnetic particles. In an alternating magnetic field (AMF), composite particles loaded with 4.15 wt.% dox exhibit excellent heating properties as well as simultaneous drug release. Drug release testing confirmed that release was much higher above the lower critical solution temperature (LCST) of the CNP, with a release of up to 78.1% of bound dox in 29h. Controlled drug release testing of the particles reveals that the thermoresponsive property can act as an on/off switch by blocking drug release below the LCST. Our work suggests that these dox-loaded polymer-coated MNPs show excellent in vitro hyperthermia and drug release behavior, with the ability to release drugs in the presence of AMF, and the potential to act as agents for combined targeting, hyperthermia and controlled drug release treatment of cancer.

Controls on Fe(II)-Activated Trace Element Release from Goethite and Hematite

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frierdich, Andrew J.; Catalano, Jeffrey G.

2012-03-26

Electron transfer and atom exchange (ETAE) between aqueous Fe(II) and Fe(III) oxides induces surface growth and dissolution that affects trace element fate and transport. We have recently demonstrated Ni(II) cycling through goethite and hematite (adsorbed Ni incorporates into the mineral structure and preincorporated Ni releases to solution) during Fe(II)-Fe(III) ETAE. However, the chemical parameters affecting net trace element release remain unknown. Here, we examine the chemical controls on Ni(II) and Zn(II) release from Ni- and Zn-substituted goethite and hematite during reaction with Fe(II). Release follows a rate law consistent with surface reaction limited mineral dissolution and suggests that release occursmore » near sites of Fe(III) reductive dissolution during Fe(II)-Fe(III) ETAE. Metal substituent type affects reactivity; Zn release is more pronounced from hematite than goethite, whereas the opposite trend occurs for Ni. Buildup of Ni or Zn in solution inhibits further release but this resumes upon fluid exchange, suggesting that sustained release is possible under flow conditions. Mineral and aqueous Fe(II) concentrations as well as pH strongly affect sorbed Fe(II) concentrations, which directly control the reaction rates and final metal concentrations. Our results demonstrate that structurally incorporated trace elements are mobilized from iron oxides into fluids without abiotic or microbial net iron reduction. Such release may affect micronutrient availability, contaminant transport, and the distribution of redox-inactive trace elements in natural and engineered systems.« less

Chronic nicotine administration differentially affects neurotransmitter release from rat striatal slices.

PubMed

Yu, Z J; Wecker, L

1994-07-01

The objective of these experiments was to determine whether the chronic administration of nicotine, at a dose regimen that increases the density of nicotine binding sites, alters the nicotine-induced release of [3H]-dopamine ([3H]DA), [3H]norepinephrine ([3H]NE), [3H]-serotonin ([3H]5-HT), or [3H]acetylcholine ([3H]ACh) from rat striatal slices. For these experiments, rats received subcutaneous injections of either saline or nicotine bitartrate [1.76 mg (3.6 mumol)/kg, dissolved in saline] twice daily for 10 days, and neurotransmitter release was measured following preloading of the tissues with [3H]DA, [3H]NE, [3H]5-HT, or [3H]choline. Chronic nicotine administration did not affect the accumulation of tritium by striatal slices, the basal release of radioactivity, or the 25 mM KCl-evoked release of neurotransmitter. Superfusion of striatal slices with 1, 10, and 100 microM nicotine increased [3H]DA release in a concentration-dependent manner, and release from slices from nicotine-injected animals was significantly (p < 0.05) greater than release from saline-injected controls; release from the former increased to 132, 191, and 172% of release from the controls following superfusion with 1, 10, and 100 microM nicotine, respectively. Similarly, [3H]5-HT release increased in a concentration-related manner following superfusion with nicotine, and release from slices from nicotine-injected rats was significantly (p < 0.05) greater than that from controls. [3H]5-HT release from slices from nicotine-injected rats evoked by superfusion with 1 and 10 microM nicotine increased to 453 and 217%, respectively, of release from slices from saline-injected animals. The nicotine-induced release of [3H]NE from striatal slices was also concentration dependent but was unaffected by chronic nicotine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Development and evaluation of accelerated drug release testing methods for a matrix-type intravaginal ring.

PubMed

Externbrink, Anna; Eggenreich, Karin; Eder, Simone; Mohr, Stefan; Nickisch, Klaus; Klein, Sandra

2017-01-01

Accelerated drug release testing is a valuable quality control tool for long-acting non-oral extended release formulations. Currently, several intravaginal ring candidates designed for the long-term delivery of steroids or anti-infective drugs are being in the developing pipeline. The present article addresses the demand for accelerated drug release methods for these formulations. We describe the development and evaluation of accelerated release methods for a steroid releasing matrix-type intravaginal ring. The drug release properties of the formulation were evaluated under real-time and accelerated test conditions. Under real-time test conditions drug release from the intravaginal ring was strongly affected by the steroid solubility in the release medium. Under sufficient sink conditions that were provided in release media containing surfactants drug release was Fickian diffusion driven. Both temperature and hydro-organic dissolution media were successfully employed to accelerate drug release from the formulation. Drug release could be further increased by combining the temperature effect with the application of a hydro-organic release medium. The formulation continued to exhibit a diffusion controlled release kinetic under the investigated accelerated conditions. Moreover, the accelerated methods were able to differentiate between different prototypes of the intravaginal ring that exhibited different release profiles under real-time test conditions. Overall, the results of the present study indicate that both temperature and hydro-organic release media are valid parameters for accelerating drug release from the intravaginal ring. Variation of either a single or both parameters yielded release profiles that correlated well with real-time release. Copyright © 2016 Elsevier B.V. All rights reserved.

Ristocetin induces phosphorylated-HSP27 (HSPB1) release from the platelets of type 2 DM patients: Anti-platelet agent-effect on the release.

PubMed

Tokuda, Haruhiko; Kuroyanagi, Gen; Onuma, Takashi; Enomoto, Yukiko; Doi, Tomoaki; Iida, Hiroki; Otsuka, Takanobu; Ogura, Shinji; Iwama, Toru; Kojima, Kumi; Kozawa, Osamu

2018-04-01

It has been previously reported that HSP27 is released from platelets in type 2 diabetes mellitus (DM) patients according to phosphorylation. In the present study, we investigated the effect of ristocetin, a glycoprotein (GP)Ib/IX/V activator, on the release of HSP27 and the effect of anti-platelet agents, such as acetylsalicylic acid (ASA), on this release. Forty-six patients with type 2 DM were recruited, and classified into two groups depending on administration of anti-platelet agents, resulting in 31 patients without these agents (control group) and 15 patients with them (anti-platelet group). Ristocetin potently induced the aggregation of platelets in the two groups. Ristocetin-induced changes of the area under the curve of light transmittance and the ratio of the size of platelet aggregates in the anti-platelet group were slightly different from those in the control group. On the other hand, the levels of phosphorylated-HSP27 induced by ristocetin in the platelets from a patient of the anti-platelet group taking ASA were significantly lower than those from a patient of the control group. The levels of HSP27 release from the ristocetin-stimulated platelets were significantly correlated with the levels of phosphorylated-HSP27 in the platelets from patients in the two groups. The levels of HSP27 release and those of platelet-derived growth factor-AB (PDGF-AB) secretion stimulated by ristocetin in the anti-platelet group were lower than those in the control group. In addition, the levels of HSP27 release and those of PDGF-AB secretion stimulated by ADP in the anti-platelet group were lower than those in the control group. These results strongly suggest that anti-platelet agents inhibit the HSP27 release from platelets stimulated by ristocetin but not the aggregation in type 2 DM patients.

Improving the controlled release of water-insoluble emodin from amino-functionalized mesoporous silica

NASA Astrophysics Data System (ADS)

Xu, Yunqiang; Wang, Chunfeng; Zhou, Guowei; Wu, Yue; Chen, Jing

2012-06-01

Several types of amino-functionalized mesoporous silica, including F5-SBA-15, F10-SBA-15, and F15-SBA-15 were prepared through co-condensation of tetraethoxysilane (TEOS) and (3-aminopropyl)triethoxysilane (APTES) in varying molar ratios (5 mol%, 10 mol%, and 15 mol%) via a hydrothermal process. The materials obtained were characterized by means of small-angle X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, N2 adsorption-desorption, Fourier transformed infrared spectra, and X-ray photoelectron spectroscopy. Increasing APTES molar ratios decreased the degree of orderliness of the functionalized mesoporous silica. Pure and amino-functionalized SBA-15 samples were employed as supports for the controlled release of water-insoluble drug emodin. Loading experiments showed that drug loading capacities mainly depended on the surface areas and pore diameters of the carriers. Controlled release profiles of emodin-loaded samples were studied in phosphate buffered saline (PBS, pH 7.4), and results indicated that the emodin release rate could be controlled by surface amino-functionalized carriers. Emodin loaded on functionalized mesoporous supports exhibited a lower release rate than that of loaded on pure SBA-15, emodin loaded on F10-SBA-15 showed the smallest release amount (71.74 wt%) after stirring in PBS for 60 h. Findings suggest that functionalized mesoporous SBA-15 is a promising carrier for achieving prolonged release time periods.

Controlled-release Hydrogen Peroxide for On-site Treatment of Organic Pollutants in Urban Storm Runoff

NASA Astrophysics Data System (ADS)

Lee, E.; Sun, S.; Kim, Y.

2011-12-01

Nonpoint source (NPS) pollutants are the remaining cause of the environment problems, significantly impairing the hydrologic and biologic function of urban water systems and human health. Managing the NPS loads to urban aquatic systems remains a challenge because of ubiquitous contaminant sources and large pollutants loads in the first flush. Best management practices (BMPs) exist for reducing the NPS pollutants in urban storm waters, but the remedial efficiencies of these passive schemes are unpredictable. This study aims to develop a controlled-release system as part of an in situ chemical oxidation scheme designed for on-site treatment of organic pollutants in urban runoff. Controlled-release hydrogen peroxide (CR-HP) solids were manufactured by dispersing fine sodium percarbonate granules in paraffin wax matrices. Release kinetics and treatment efficiencies of CR-HP for BTEX and MTBE were investigated through a series of column tests. Release data indicated that the CR-HP could continually release hydrogen peroxide (H2O2) in flowing water at controlled rates over 276-1756 days, and the release rates could be adjusted by changing the mixing ratios of sodium percarbonate and wax matrices. Additional column tests and model calculations demonstrated that CR-HP/UV systems can provide low-cost, target-specific, and persistent source of oxidants for efficient treatment of organic compounds in urban storm runoff.

Nanostructured DPA-MPC-DPA triblock copolymer gel for controlled drug release of ketoprofen and spironolactone.

PubMed

Azmy, Bahaa; Standen, Guy; Kristova, Petra; Flint, Andrew; Lewis, Andrew L; Salvage, Jonathan P

2017-08-01

Uncontrolled rapid release of drugs can reduce their therapeutic efficacy and cause undesirable toxicity; however, controlled release from reservoir materials helps overcome this issue. The aims of this study were to determine the release profiles of ketoprofen and spironolactone from a pH-responsive self-assembling DPA-MPC-DPA triblock copolymer gel and elucidate underlying physiochemical properties. Drug release profiles from DPA 50 -MPC 250 -DPA 50 gel (pH 7.5), over 32 h (37 °C), were determined using UV-Vis spectroscopy. Nanoparticle size was measured by dynamic light scattering (DLS) and critical micelle concentration (CMC) by pyrene fluorescence. Polymer gel viscosity was examined via rheology, nanoparticle morphology investigated using scanning transmission electron microscopy (STEM) and the gel matrix observed using cryo-scanning electron microscopy (Cryo-SEM). DPA 50 -MPC 250 -DPA 50 copolymer (15% w/v) formed a free-standing gel (pH 7.5) that controlled drug release relative to free drugs. The copolymer possessed a low CMC, nanoparticle size increased with copolymer concentration, and DLS data were consistent with STEM. The gel displayed thermostable viscosity at physiological temperatures, and the gel matrix was a nanostructured aggregation of smaller nanoparticles. The DPA 50 -MPC 250 -DPA 50 copolymer gel could be used as a drug delivery system to provide the controlled drug release of ketoprofen and spironolactone. © 2017 Royal Pharmaceutical Society.

[Testing of medicinal products produced from pooled plasma].

PubMed

Unkelbach, U; Hunfeld, A; Breitner-Ruddock, S

2014-10-01

Medicinal products produced from human plasma fall under the administrative batch release procedure of the competent authority. In Germany, this has been carried out since 1995 by the Paul Ehrlich Institute (PEI), the responsible state control agency for blood products. Medicinal products released for the European and national market are tested for quality, efficacy and safety. Experimental testing of the final product and the starting materials, the plasma pools, as well as control of the production documentation guarantee a constantly high product safety. In the 28,000 batches tested since the beginning of the state controlled batch release testing of these blood products at the PEI, there has been no transmission of infectious viruses (HIV, HBV and HCV) to any patient. The batch release has made a contribution to the improvement of product quality. This procedure is still an important tool to ensure safety of blood products. The PEI is integrated in the batch release network of the European Directorate for the Quality of Medicines & Health Care (EDQM) in Strasbourg. Regulations and guidelines for official control authority batch release (OCABR) ensure harmonized procedures for mutual recognition of batch release on the European level. The EU certificates and German national certificates are requested and accepted in over 70 countries worldwide. Experimental testing in the EU and the requisite certificates have developed into a seal of quality for the world market.

Controlled release of chlorhexidine antiseptic from microporous amorphous silica applied in open porosity of an implant surface.

PubMed

Verraedt, Els; Braem, Annabel; Chaudhari, Amol; Thevissen, Karin; Adams, Erwin; Van Mellaert, Lieve; Cammue, Bruno P A; Duyck, Joke; Anné, Jozef; Vleugels, Jef; Martens, Johan A

2011-10-31

Amorphous microporous silica (AMS) serving as a reservoir for controlled release of a bioactive agent was applied in the open porosity of a titanium coating on a Ti-6Al-4V metal substrate. The pores of the AMS emptied by calcination were loaded with chlorhexidine diacetate (CHX) via incipient wetness impregnation with CHX solution, followed by solvent evaporation. Using this CHX loaded AMS system on titanium substrate sustained release of CHX into physiological medium was obtained over a 10 day-period. CHX released from the AMS coating was demonstrated to be effective in killing planktonic cultures of the human pathogens Candida albicans and Staphylococcus epidermidis. This surface modification of titanium bodies with AMS controlled release functionality for a bioactive compound potentially can be applied on dental and orthopaedic implants to abate implant-associated microbial infection. Copyright © 2011 Elsevier B.V. All rights reserved.

Controlled release in transdermal pressure sensitive adhesives using organosilicate nanocomposites.

PubMed

Shaikh, Sohel; Birdi, Anil; Qutubuddin, Syed; Lakatosh, Eric; Baskaran, Harihara

2007-12-01

Polydimethyl siloxane (PDMS) based pressure sensitive adhesives (PSA) incorporating organo-clays at different loadings were fabricated via solution casting. Partially exfoliated nanocomposites were obtained for the hydroxyl terminated PDMS in ethyl acetate solvent as determined by X-ray diffraction and atomic force microscopy. Drug release studies showed that the initial burst release was substantially reduced and the drug release could be controlled by the addition of organo-clay. Shear strength and shear adhesion failure temperature (SAFT) measurements indicated substantial improvement in adhesive properties of the PSA nanocomposite adhesives. Shear strength showed more than 200% improvement at the lower clay loadings and the SAFT increased by about 21% due to the reinforcement provided by the nano-dispersed clay platelets. It was found that by optimizing the level of the organosilicate additive to the polymer matrix, superior control over drug release kinetics and simultaneous improvements in adhesive properties could be attained for a transdermal PSA formulation.

Smart Electrospun Nanofibers for Controlled Drug Release: Recent Advances and New Perspectives

PubMed Central

Weng, Lin; Xie, Jingwei

2017-01-01

In biological systems, chemical molecules or ions often release upon certain conditions, at a specific location, and over a desired period of time. Electrospun nanofibers that undergo alterations in the physicochemical characteristics corresponding to environmental changes have gained considerable interest for various applications. Inspired by biological systems, therapeutic molecules have been integrated with these smart electrospun nanofibers, presenting activation-modulated or feedback-regulated control of drug release. Compared to other materials like smart hydrogels, environment-responsive nanofiber-based drug delivery systems are relatively new but possess incomparable advantages due to their greater permeability, which allows shorter response time and more precise control over the release rate. In this article, we review the mechanisms of various environmental parameters functioning as stimuli to tailor the release rates of smart electrospun nanofibers. We also illustrate several typical examples in specific applications. We conclude this article with a discussion on perspectives and future possibilities in this field. PMID:25732665

Smart electrospun nanofibers for controlled drug release: recent advances and new perspectives.

PubMed

Weng, Lin; Xie, Jingwei

2015-01-01

In biological systems, chemical molecules or ions often release upon certain conditions, at a specific location, and over a desired period of time. Electrospun nanofibers that undergo alterations in the physicochemical characteristics corresponding to environmental changes have gained considerable interest for various applications. Inspired by biological systems, therapeutic molecules have been integrated with these smart electrospun nanofibers, presenting activation-modulated or feedback-regulated control of drug release. Compared to other materials like smart hydrogels, environment-responsive nanofiber-based drug delivery systems are relatively new but possess incomparable advantages due to their greater permeability, which allows shorter response time and more precise control over the release rate. In this article, we review the mechanisms of various environmental parameters functioning as stimuli to tailor the release rates of smart electrospun nanofibers. We also illustrate several typical examples in specific applications. We conclude this article with a discussion on perspectives and future possibilities in this field.