Browsing by Subject "Delayed-Action Preparations"
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Item Open Access A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.(J Control Release, 2013-10-10) Sinclair, S Michael; Bhattacharyya, Jayanta; McDaniel, Jonathan R; Gooden, David M; Gopalaswamy, Ramesh; Chilkoti, Ashutosh; Setton, Lori ARadiculopathy, a painful neuroinflammation that can accompany intervertebral disc herniation, is associated with locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in the local delivery of anti-inflammatory drugs to treat this pathology as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antagonist of TNFα in multiple cell types and tissues, was chemically modified and conjugated to a thermally responsive elastin-like polypeptide (ELP) to create an injectable depot for sustained, local delivery of curcumin to treat neuroinflammation. ELPs are biopolymers capable of thermally-triggered in situ depot formation that have been successfully employed as drug carriers and biomaterials in several applications. ELP-curcumin conjugates were shown to display high drug loading, rapidly release curcumin in vitro via degradable carbamate bonds, and retain in vitro bioactivity against TNFα-induced cytotoxicity and monocyte activation with IC50 only two-fold higher than curcumin. When injected proximal to the sciatic nerve in mice via intramuscular (i.m.) injection, ELP-curcumin conjugates underwent a thermally triggered soluble-insoluble phase transition, leading to in situ formation of a depot that released curcumin over 4days post-injection and decreased plasma AUC 7-fold.Item Open Access Advances in opioid antagonist treatment for opioid addiction.(The Psychiatric clinics of North America, 2012-06) Ling, Walter; Mooney, Larissa; Wu, Li-TzyItem Open Access Bupropion and Naltrexone in Methamphetamine Use Disorder.(The New England journal of medicine, 2021-01) Trivedi, Madhukar H; Walker, Robrina; Ling, Walter; Dela Cruz, Adriane; Sharma, Gaurav; Carmody, Thomas; Ghitza, Udi E; Wahle, Aimee; Kim, Mora; Shores-Wilson, Kathy; Sparenborg, Steven; Coffin, Phillip; Schmitz, Joy; Wiest, Katharina; Bart, Gavin; Sonne, Susan C; Wakhlu, Sidarth; Rush, A John; Nunes, Edward V; Shoptaw, StevenBackground
The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied.Methods
We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.Results
A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial.Conclusions
Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).Item Open Access Controlled Release of Vancomycin and Tigecycline from an Orthopaedic Implant Coating Prevents Staphylococcus aureus Infection in an Open Fracture Animal Model.(BioMed research international, 2019-01) Stavrakis, AI; Zhu, S; Loftin, AH; Weixian, X; Niska, J; Hegde, V; Segura, T; Bernthal, NMIntroduction:Treatment of open fractures routinely involves multiple surgeries and delayed definitive fracture fixation because of concern for infection. If implants were made less susceptible to infection, a one-stage procedure with intramedullary nailing would be more feasible, which would reduce morbidity and improve outcomes. Methods:In this study, a novel open fracture mouse model was developed using Staphylococcus aureus (S. aureus) and single-stage intramedullary fixation. The model was used to evaluate whether implants coated with a novel "smart" polymer coating containing vancomycin or tigecycline would be colonized by bacteria in an open fracture model infected with S. aureus. In vivo bioluminescence, ex vivo CFUs, and X-ray images were evaluated over a 42-day postoperative period. Results:We found evidence of a markedly decreased bacterial burden with the local release of vancomycin and tigecycline from the PEG-PPS polymer compared to polymer alone. Vancomycin was released in a controlled fashion and maintained local drug concentrations above the minimum inhibition concentration for S. aureus for greater than 7 days postoperatively. Bacteria were reduced 139-fold from implants containing vancomycin and undetected from the bone and soft tissue. Tigecycline coatings led to a 5991-fold reduction in bacteria isolated from bone and soft tissue and 15-fold reduction on the implants compared to polymer alone. Antibiotic coatings also prevented osteomyelitis and implant loosening as observed on X-ray. Conclusion:Vancomycin and tigecycline can be encapsulated in a polymer coating and released over time to maintain therapeutic levels during the perioperative period. Our results suggest that antibiotic coatings can be used to prevent implant infection and osteomyelitis in the setting of open fracture. This novel open fracture mouse model can be used as a powerful in vivo preclinical tool to evaluate and optimize the treatment of open fractures before further studies in humans.Item Open Access Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial.(Drug and alcohol dependence, 2014-05) Mannelli, Paolo; Wu, Li-Tzy; Peindl, Kathleen S; Swartz, Marvin S; Woody, George EThe approval of extended release injectable naltrexone (XR-NTX; Vivitrol(®)) has introduced a new option for treating opioid addiction, but studies are needed to identify its place within the spectrum of available therapies. The absence of physiological opioid dependence is a necessary and challenging first step for starting XR-NTX. Outpatient detoxification gives poor results and inpatient detoxification is either unavailable or too brief for the physiological effects of opioids to resolve. Here we present findings from an open label study that tested whether the transition from opioid addiction to XR-NTX can be safely and effectively performed in an outpatient setting using very low dose naltrexone and buprenorphine.Twenty treatment seeking opioid addicted individuals were given increasing doses of naltrexone starting at 0.25mg with decreasing doses of buprenorphine starting at 4 mg during a 7-day outpatient XR-NTX induction procedure. Withdrawal discomfort, craving, drug use, and adverse events were assessed daily until the XR-NTX injection, then weekly over the next month.Fourteen of the 20 participants received XR-NTX and 13 completed weekly assessments. Withdrawal, craving, and opioid or other drug use were significantly lower during induction and after XR-NTX administration compared with baseline, and no serious adverse events were recorded.Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with downward titration of low dose buprenorphine was safe, well tolerated, and completed by most participants. Further studies with larger numbers of subjects are needed to see if this approach is useful for naltrexone induction.Item Open Access Extended-release ranolazine: critical evaluation of its use in stable angina.(Vasc Health Risk Manag, 2011) Truffa, Adriano Am; Newby, L Kristin; Melloni, ChiaraCoronary heart disease is the major cause of morbidity and mortality throughout the world, and is responsible for approximately one of every six deaths in the US. Angina pectoris is a clinical syndrome characterized by discomfort, typically in the chest, neck, chin, or left arm, induced by physical exertion, emotional stress, or cold, and relieved by rest or nitroglycerin. The main goals of treatment of stable angina pectoris are to improve quality of life by reducing the severity and/or frequency of symptoms, to increase functional capacity, and to improve prognosis. Ranolazine is a recently developed antianginal with unique methods of action. In this paper, we review the pharmacology of ranolazine, clinical trials supporting its approval for clinical use, and studies of its quality of life benefits. We conclude that ranolazine has been shown to be a reasonable and safe option for patients who have refractory ischemic symptoms despite the use of standard medications (for example, nitrates, beta-adrenergic receptor antagonists, and calcium channel antagonists) for treatment of anginal symptoms, and also provides a modestly improved quality of life.Item Open Access Resilience as a predictor of treatment response in patients with posttraumatic stress disorder treated with venlafaxine extended release or placebo.(Journal of psychopharmacology (Oxford, England), 2012-06) Davidson, Jonathan; Stein, Dan J; Rothbaum, Barbara O; Pedersen, Ron; Szumski, Annette; Baldwin, David SThis post-hoc analysis evaluated resilience as a predictor of treatment response in patients with posttraumatic stress disorder (PTSD). Data were pooled from two randomized, double-blind studies conducted with adult outpatients treated with flexible doses of venlafaxine extended release (ER) 37.5 to 300 mg/day or placebo. The 17-item Clinician-Administered Posttraumatic Stress Disorder Scale (CAPS-SX(17)) was the primary outcome measure. Baseline Connor-Davidson Resilience Scale (CD-RISC) scores for the 25-, 10-, and 2-item versions were used to predict changes in PTSD symptom severity at week 12 and symptomatic remission (CAPS-SX(17) ≤ 20). Analyses were conducted for the overall population and separately for the individual treatment groups. In total, pretreatment resilience predicted a positive treatment response. For the overall population, all versions of the CD-RISC predicted CAPS-SX(17) change scores and remission after controlling for variables such as treatment group and baseline symptom severity. For venlafaxine ER-treated patients, all versions of the CD-RISC were predictive of remission, but only the 10-item version was predictive of CAPS-SX(17) change score. Our results suggest that higher pretreatment resilience is generally associated with a positive treatment response. Future research may be warranted to explore the relationship between response to active treatment and the spectrum of resiliency.Item Open Access What to Expect When Switching to a Second Antidepressant Medication Following an Ineffective Initial SSRI: A Report From the Randomized Clinical STAR*D Study.(The Journal of clinical psychiatry, 2020-08-11) Rush, A John; South, Charles; Jha, Manish K; Jain, Shailesh Bobby; Trivedi, Madhukar HOBJECTIVE:An antidepressant medication switch often follows a failed initial trial with selective serotonin reuptake inhibitors (SSRIs). When, for whom, and how often second-step response and remission occur are unclear, as is preferred second-step trial duration. As more treatments are approved for use following 2 failed "adequate" trials, researchers and clinicians require an evidence-based definition of "adequate." METHODS:Following citalopram in the randomized Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial (which ran July 2001-September 2006), participants with score ≥ 11 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR₁₆) were randomized to bupropion sustained release, sertraline, or venlafaxine extended release (up to 14 weeks). The QIDS-SR₁₆ defined response, remission, and no clinically meaningful benefit based on the modified intent-to-treat sample. RESULTS:About 80% of 438 participants completed ≥ 6 weeks of treatment with the switch medication. All treatments had comparable outcomes. Overall, 21% (91/438) remitted, 9% (40/438) responded without remission, and 58% (255/438) had no meaningful benefit. Half of the responses and two-thirds of remissions occurred after 6 weeks of treatment. Overall, 33% of responses (43/131) occurred after ≥ 9 weeks of treatment. No baseline features differentiated early from later responders or remitters. No early triage point was found, but those with at least 20% reduction from baseline in QIDS-SR₁₆ score around week 2 were 6 times more likely to respond or remit than those without this reduction. CONCLUSIONS:Following nonefficacy with an initial SSRI, only about 20% remit and more than half achieve no meaningful benefit with a second-step switch to another monoaminergic antidepressant. A 12-week trial duration seems necessary to capture as many second-step switch responders as possible. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00021528.Item Open Access Withdrawal severity and early response to treatment in the outpatient transition from opioid use to extended release naltrexone.(The American journal on addictions, 2018-09) Mannelli, Paolo; Swartz, Marvin; Wu, Li-TzyBACKGROUND AND OBJECTIVES:Long acting naltrexone has improved the therapy of opioid use disorder (OUD), and safe and effective withdrawal management during naltrexone induction may help advance treatment. Despite the uncertain role of opioid withdrawal in predicting successful outcomes, early symptom control may favor detoxification completion. METHODS:We explored withdrawal severity and early response to treatment, safety, and clinical measures in 35 adult patients with DSM-5 OUD during a 7-day office-based buprenorphine-naltrexone and ancillary medications transition to extended-release naltrexone (XR-NTX). RESULTS:Subjective and objective measures of withdrawal intensity improved consistently throughout treatment in the whole sample. Participants who went on to receive XR-NTX (n = 27, 77%) reported a greater attenuation of symptoms by treatment day 2 (r = .595, p = .001), and were less likely to be injection drug users (r = -.501, p = .004). Adverse events (AEs) were recorded in 20% of participants: the majority (n = 6, 85.7%) consisted of single episodes of increased withdrawal which were well controlled using ancillary medications. One serious AE was unrelated to treatment. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE:Early opioid withdrawal changes may be a useful indicator of treatment response, helping adjust the transition protocol to the individual patients' need and gather valuable information for a better understanding of the relationship between initiating and remaining in treatment. (Am J Addict 2018;27:471-476).