Urinary catheterization is a common procedure, particularly among patients with neurogenic bladder secondary to spinal cord injury. Urethral catheterization is associated with the well-recognized complications of catheter-associated urinary tract infections and limited genitourinary trauma. Unintentional ureteral cannulation represents a rare complication of urethral catheterization and has been previously described in only eight cases within the literature. We describe two cases of aberrant ureteral cannulation involving two patients with quadriplegia. These cases along with prior reports identify the spastic, insensate bladder and altered pelvic sensorium found in upper motor neuron syndromes as major risk factors for ureteral cannulation with a urinary catheter.
ABSTRACT. Background: Synthetic cannabinoids (SCs) are a class of drugs of abuse with deleterious consequences. Despite governmental regulations related to distribution and sale, SC variants are still available online. More research is needed to determine SC use prevalence and factors associated with SC use, especially among young adults. Methods: One thousand eighty individuals, 18-25 years old, were surveyed, between January 2012 and July 2013, during recruitment for a randomized controlled trial investigating health behaviors in young adults. Advertisements were placed online and in community locations seeking individuals "who had recently used marijuana or alcohol." Respondents were queried about their use of alcohol and drugs, including SCs, in the last month. Results: Participants averaged 21.4 years old and were 53.4% male. Nearly 59% were Non-Hispanic White, 15% were African American, 15% were Hispanic, 11% identified as Other. Approximately 9% reported SC use in the last month, a level higher than the reported use of opioids, cocaine, or hallucinogens. SC use was significantly associated with male gender, not being enrolled in school, and with use of cigarettes, binge alcohol drinking, daily and weekly marijuana use, and other drugs of abuse. There was a significant decrease in SC use after the federal ban in July, 2012. Conclusions: SC use was common in the past month and often overlaps with other drug use, particularly marijuana use, and should be asked about during clinical encounters with young adults.
When used in general medical practices, buprenorphine is an effective treatment for opioid dependence, yet little is known about how use of buprenorphine affects the utilization and cost of health care in commercial health systems.
The most widely used illicit drug in the United States continues to be marijuana, and its use among emerging adults continues to increase. Marijuana use can result in a range of negative consequences and has been associated with other drug use in adolescents and emerging adults. This study examined the relationship between marijuana use frequency and the use of six other drug classes (opiates, cocaine, stimulants, hallucinogens, inhalants, and sleep medications) among emerging adults. A cross-sectional interview design was used with a community sample of 1,075 emerging adults in the northeastern United States. Using logistic regression analysis controlling for age, ethnicity, gender, and frequency of binge alcohol, daily marijuana use was found to be associated with a significant increase in the expected odds of opiate, cocaine, stimulant, hallucinogen, inhalant, and tobacco use. The findings identify a subgroup of emerging adult marijuana users-those who use daily-that may be vulnerable to additional negative consequences associated with polysubstance use.
Buprenorphine opioid agonist treatment (OAT) has established efficacy for treating opioid dependency among persons seeking addiction treatment. However, effectiveness for out-of-treatment, hospitalized patients is not known.
Injection drug users (IDUs) are at increased risk of contracting HIV. From a clinical trial assessing an intervention to enhance the linkage of hospitalized patients to opioid treatment after discharge, we conducted multivariate analysis of baseline data from hospitalized IDUs with a history of opioid dependence (n = 104) to identify differences in factors predicting HIV drug and sex risk behaviors. Factors significantly associated with HIV drug risk were being non-Hispanic Caucasian and recent cocaine use. Being female, binge drinking, and poorer mental health were significantly associated with higher sex risk. Because factors predicting HIV sex risk behaviors differ from those predicting HIV drug risk, interventions aimed at specific HIV risks should have different behavioral and substance use targets.
This study explored life concerns of prescription opioid (PO) and heroin users. Persons entering opioid detoxification rated their level of concern about 43 health and welfare items. Using exploratory factor analysis and conceptual rationale, we identified ten areas of concern. Participants (N=529) were 69.9% male, 87.5% non-Hispanic Caucasian, and 24.2% PO users. Concern about drug problems was perceived as the most serious concern, followed by money problems, relationship problems, mental health, and cigarette smoking. PO users expressed significantly lower concern about drug problems (p=.017) and transmissible diseases (p<.001), but were more concerned about alcohol use (p<.001) than heroin users. There were no significant differences with regard to the other 7 areas of concern. Recognition of the daily worries of opioid dependent persons could allow providers to better tailor their services to the context of their patients' lives.
Methadone maintenance treatment (MMT) patients have an exceedingly high prevalence of tobacco use, and interventions that have been specifically developed for this vulnerable subpopulation have struggled to attain even modest rates of cessation. A significant barrier has been an inability to initiate a quit attempt early in the treatment process and adherence to treatment.
Molecular models for HPMCAS polymer have been developed for molecular dynamics (MD) simulation that attempt to mimic the complex substitution patterns in HPMCAS observed experimentally. These molecular models were utilized to create amorphous HPMCAS solids by cooling of the polymeric melts at different water contents to explore the influence of water on molecular mobility, which plays a critical role in stability and drug release from HPMCAS-based solid matrices. The densities found for the simulated amorphous HPMCAS were 1.295, 1.287, and 1.276 g/cm(3) at 0.7, 5.7, and 13.2% w/w water, indicating swelling of the polymer with increasing water content. These densities compare favorably with the experimental density of 1.285 g/cm(3) for commercial HPMCAS-(AQOAT AS-MF) supporting the present HPMCAS models as a realistic representation of amorphous HPMCAS solids. Water molecules were observed to be mostly isolated from each other at a low water content (0.7% w/w), while clusters or strands of water were pervasive and broadly distributed in size at 13.2% w/w water. The average number of first-shell water molecules (n(w)) increased from 0.17 to 3.5, though the latter is still far below that (8.9) expected for the onset of a separate water phase. Increasing water content from 0.7 to 13.2% w/w was found to reduce the T(g) by ~81 K, similar to experimental observations. Plasticization with increasing water content resulted in increasing polymer mobility and water diffusivity. From 0.7 to 13.2% w/w water, the apparent water diffusivity increased from 1.1 × 10(-9) to 7.0 × 10(-8) cm(2)/s, though non-Einsteinian behavior persisted at all water contents explored. This and the water trajectories in the polymers suggest that water diffusion at 0.7% w/w water follows a "hopping" mechanism. At a higher water content (13.2% w/w) water diffusion follows dual diffusive processes: (1) fast water motions within water clusters; and (2) slower diffusion through the more rigid polymer matrix.
Intimate partner violence (IPV) is a highly prevalent and concerning problem among methadone maintenance populations, and previous studies have shown a relationship between a history of IPV and increased substance use and affective disturbances.
This study quantitatively explores the mechanisms underpinning the effects of model pharmaceutical polymeric precipitation inhibitors (PPIs) on the crystal growth and, in turn, maintenance of supersaturation of indomethacin, a model poorly water-soluble drug. A recently developed second-derivative UV spectroscopy method and a first-order empirical crystal growth model were used to determine indomethacin crystal growth rates in the presence of model PPIs. All three model PPIs including HP-?-CD, PVP, and HPMC inhibited indomethacin crystal growth at both high and low degrees of supersaturation (S). The bulk viscosity changes in the presence of model PPIs could not explain their crystal growth inhibitory effects. At 0.05% w/w, PVP (133-fold) and HPMC (28-fold) were better crystal growth inhibitors than HP-?-CD at high S. The inhibitory effect of HP-?-CD on the bulk diffusion-controlled indomethacin crystal growth at high S was successfully modeled using reactive diffusion layer theory, which assumes reversible complexation in the diffusion layer. Although HP-?-CD only modestly inhibited indomethacin crystal growth at either high S (?15%) or low S (?2-fold), the crystal growth inhibitory effects of PVP and HPMC were more dramatic, particularly at high S (0.05% w/w). The superior crystal growth inhibitory effects of PVP and HPMC as compared with HP-?-CD at high S were attributed to a change in the indomethacin crystal growth rate-limiting step from bulk diffusion to surface integration. Indomethacin crystal growth inhibitory effects of all three model PPIs at low S were attributed to retardation of the rate of surface integration of indomethacin, a phenomenon that may reflect the adsorption of PPIs onto the growing crystal surface. The quantitative approaches outlined in this study should be useful in future studies to develop tools to predict supersaturation maintenance effects of PPIs.
Drug release from liposomal formulations is governed by a complex interplay of kinetic (i.e., drug permeability) and thermodynamic factors (i.e., drug partitioning to the bilayer surface). Release studies under sink conditions that attempt to mimic physiological conditions are insufficient to decipher these separate contributions. The present study explores release studies performed under nonsink conditions coupled with appropriate mathematical models to describe both the release kinetics and the conditions in which equilibrium is established. Liposomal release profiles for a model anticancer agent, topotecan, under nonsink conditions provided values for both the first-order rate constant for drug release and the bilayer/water partition coefficient. These findings were validated by conducting release studies under sink conditions via dynamic dialysis at the same temperature and buffer pH. A nearly identical rate constant for drug release could be obtained from dynamic dialysis data when appropriate volume corrections were applied and a mechanism-based mathematical model was employed to account for lipid bilayer binding and dialysis membrane transport. The usefulness of the nonsink method combined with mathematical modeling was further explored by demonstrating the effects of topotecan dimerization and bilayer surface charge potential on the bilayer/water partition coefficient at varying suspension concentrations of lipid and drug.
The synthesis of electron-poor PCP pincer ligands 1,3-((C6F5)2PO)2C6H4, 1,3-((C6F5)2PCH2)2C6H4, and 1-((C6F5)2PO)-3-(tBu2PCH2)C6H4, and their coordination chemistry to platinum and palladium is described. The most electron-poor ligand 1,3-((C6F5)2PO)2C6H4 (POCOPH) reacts with Group?10 metal chloride precursors to form a range of unusual cis, trans-dimers of the type ?(2)-P,P-[(POCOPH)MCl(L)]2 (M = Pt, Pd; L = Cl, Me), which undergo metallation to form [(POCOP)MCl] pincer complexes only under prolonged thermolysis. The formation of such cis,trans-dimers during pincer complex formation can be mitigated through the use of starting materials with more strongly binding ancillary ligands, improving the overall rate of ligand metallation. Carbonyl complexes of the type [(PCP)M(CO)](+) were synthesised from the pincer chloride complexes by halide abstraction, and displayed large ?(C-O) values, from 2170-2111?cm(-1), confirming the electron-poor nature of the compounds. The [(PCP)Pd(CO)](+) complexes also demonstrated the ability to reversibly bind carbon monoxide both in solution and the solid state, with the rate of decarbonylation increasing with increasing wavenumber for the C-O stretch.
Few studies have assessed associations between craving and subsequent opioid use. We prospectively evaluated the relative utility of two craving questionnaires to predict opioid use among opioid-dependent patients in outpatient treatment.
Those who have experienced abuse may be prone to engaging in risky sexual behavior and risky drug use. The relationship between sexual abuse and risky behavior has been well established in the literature, but the association between physical abuse and risky drug use has been equivocal. We hypothesize that the experience of PTSD symptoms following physical abuse leads to risky drug use. Therefore, we examined the associations among physical abuse history, PTSD symptoms, and HIV-related drug risk in a sample of 121 opioid-dependent persons to determine whether PTSD symptoms mediated the relationship between physical abuse history and drug risk. Participants were recruited during an acute care hospital inpatient stay. Physical abuse history was associated with increased drug risk, and PTSD symptoms were associated with increased drug risk. However, PTSD symptoms were not found to be a mediator of the association between physical abuse history and HIV-related drug risk. These findings highlight the importance of assessing abuse history in high-risk samples of opioid users.
An explicit all-atom computational model for amorphous poly(lactide) (PLA) was developed. Molecular dynamics simulations of PLA glasses were conducted to explore various molecular interactions and predict certain physical properties. The density of a newly formed PLA glass aged for 100 ns at 298 K was 1.23 g/cm(3), close to the experimental range (1.24-1.25 g/cm(3)). The glass transition temperature (Tg = 364 K) was higher than experimental values because of the fast cooling rate (0.03 K/ps) in the simulation. The solubility parameter (20.6 MPa(1/2)) compared favorably to the literature. The water sorption isotherm obtained by relating the excess chemical potential of water in PLA to the Henry's law constant for water sorption was close to the experiment. At 0.6% (w/w), water molecules localize next to polar ester groups in PLA because of hydrogen bonding. Local mobility in PLA as characterized by the atomic fluctuation was sharply reduced near the Tg , decreasing further with aging at 298 K. The non-Einsteinian diffusion of water was found to correlate with the rotational ?-relaxation of PLA C=O groups at 298 K. A relaxation-diffusion coupling model proposed recently by the authors gave a diffusion coefficient (1.3 × 10(-8) cm(2) /s at 298 K) which is comparable to reported experimental values.
Most young adult women who smoke marijuana also drink alcohol. Marijuana-related problems are associated with marijuana use frequency. We hypothesized that increased alcohol use frequency potentiates the association between frequency of marijuana use and marijuana-related problem severity.
The use of liposomal delivery systems for the treatment of cancer has been extensively researched because of their passive targeting to the vasculature of solid tumors. While their potential to provide prolonged retention and high drug encapsulation is desirable for anticancer agents, a mechanistic understanding is required to optimize and design liposomal drug delivery systems capable of controllable release tailored to tumor type and patient. Topotecan (TPT) is a topoisomerase I inhibitor that undergoes reversible, pH-sensitive ring-opening hydrolysis. TPT may benefit from liposomal formulation using active loading strategies to generate low intravesicular pH to prolong drug retention and increase drug encapsulation. This paper develops a mathematical model to describe TPTs permeability as a function of pH by accounting for the drugs ionization state, membrane binding, and ring-opening interconversion kinetics. Studies were conducted to determine the acid dissociation constant of TPTs phenolic -OH and interconversion kinetics between TPTs lactone and carboxylate forms. Using the constants determined from these studies and release studies conducted at varying pH, permeability coefficients and membrane binding constants for each species of TPT were determined. Based on this model, three permeable species were observed. Interestingly, the two most permeable species were zwitterionic forms of TPT, and the permeability of the lactone zwitterion was comparable to that of the neutral form of another camptothecin analogue. Furthermore, release was affected by based-catalyzed interconversion kinetics between TPTs lactone and carboxylate forms. At neutral pH, release was rate-limited by formation of the TPT lactone from the ring-opened carboxylate form. Based on these findings, the developed model describing liposomal release of TPT may be used in the future to evaluate and optimize loading and subsequent release of liposomal TPT formulations utilizing active loading strategies.
Qualified physicians may prescribe buprenorphine to treat opioid dependence, but medication use remains controversial. We examined adoption of buprenorphine in two not-for-profit integrated health plans, over time, completing 101 semi-structured interviews with clinicians and clinician-administrators from primary and specialty care. Transcripts were reviewed, coded, and analyzed. A strong leader championing the new treatment was critical for adoption in both health plans. Once clinicians began using buprenorphine, patients and other clinicians experiences affected decisions more than did the champion. With experience, protocols developed to manage unsuccessful patients and changed to support maintenance rather than detoxification. Diffusion outside addiction and mental health settings was nonexistent; primary care clinicians cited scope-of-practice issues and referred patients to specialty care. With greater diffusion came questions about long-term use and safety. Recognizing how implementation processes develop may suggest where, when, and how to best expend resources to increase adoption of such treatments.
Sedentary behavior has been linked to many physical and mental health disorders including heightened risk for depression. Methadone-maintained individuals are at increased risk for depression and have been shown to be physically active at lower rates than the general population.
A 55-year-old man was hospitalized for a neurologic and infectious workup after having hallucinations and productive cough for 2 days. During hospitalization, he experienced dark stools with an acute drop in hemoglobin. Upper endoscopy and colonoscopy were negative for an identifiable source of bleed. Capsule endoscopy was later done and subsequently an anteroposterior abdominal radiograph confirmed the presence of a retained capsule near the junction of the descending and distal transverse colon, likely contained within a colonic diverticulum. In the interim, the patient developed acute right-sided lumbar radiculopathy prompting emergent lumbar spine magnetic resonance imaging (MRI). During the scanning process, the retained capsule was seen and the test was immediately terminated without harm to the patient. Device retention is a complication unique to capsule endoscopy, occurring at a rate of 1% to 1.7%; retained devices are considered a danger and contraindication to MRI.
Dynamic dialysis is one of the most common methods for the determination of release kinetics from nanoparticle drug delivery systems. Drug appearance in the "sink" receiver compartment is a consequence of release from the nanoparticles into the dialysis chamber followed by diffusion across the dialysis membrane. This dual barrier nature inherent in the method complicates data interpretation and may lead to incorrect conclusions regarding nanoparticle release half-lives. Although the need to consider the barrier properties of the dialysis membrane has long been recognized, there is insufficient quantitative appreciation for the role of the driving force for drug transport across that membrane. Reversible nanocarrier binding of the released drug reduces the driving force for drug transport across the dialysis membrane leading to a slower overall apparent release rate. This may lead to the conclusion that a given nanoparticle system will provide a sustained release in vivo when it will not. This study demonstrates these phenomena using model lipophilic drug-loaded liposomes varying in lipid composition to provide variations in bilayer permeability and membrane binding affinities. Model simulations of liposomal transport as measured by dynamic dialysis were conducted to illustrate the interplay between the liposome concentration, membrane/water partition coefficient, and the apparent release rate. Reliable determination of intrinsic liposomal bilayer permeability coefficients for lipophilic drugs by dynamic dialysis requires validation of drug release kinetics at varying nanoparticle concentration and the determination of membrane binding coefficients along with appropriate mechanism-based mathematical modeling to ensure the reliability and proper interpretation of the data.
Assessing motivation to quit substance use is recommended as part of brief interventions. The purpose of this study was to determine correlates of desire to quit marijuana use among young adult women enrolled in a brief motivational intervention trial.
In methadone maintenance treatment programs (MMTPs), 80-90% of participants smoke cigarettes. Patients in MMTPs are at particular risk for life stress, and nicotine, as well as other substances like alcohol, benzodiazepines, cocaine, marijuana, and opiates have been shown to reduce the effects of stress. Use of these addictive substances to cope with stress may precipitate illicit opiate relapse in MMTP patients. In the current study, we examined the relationship between perceived stress and substance abuse.
Age-associated skeletal muscle mass loss curtails quality of life and may contribute to defects in metabolic homeostasis in older persons. The onset of sarcopenia occurs in middle age in rhesus macaques although the trigger has yet to be identified. Here, we show that a shift in metabolism occurs in advance of the onset of sarcopenia in rhesus vastus lateralis. Multiphoton laser-scanning microscopy detects a shift in the kinetics of photon emission from autofluorescent metabolic cofactors NADH and FAD. Lifetime of both fluorophores is shortened at mid-age, and this is observed in both free and bound constituent pools. Levels of FAD and free NADH are increased and the NAD/NADH redox ratio is lower. Concomitant with this, expression of fiber-type myosin isoforms is altered resulting in a shift in fiber-type distribution, activity of cytochrome c oxidase involved in mitochondrial oxidative phosphorylation is significantly lower, and the subcellular organization of mitochondria in oxidative fibers is compromised. A regulatory switch involving the transcriptional coactivator PGC-1? directs metabolic fuel utilization and governs the expression of structural proteins. Age did not significantly impact total levels of PGC-1?; however, its subcellular localization was disrupted, suggesting that PGC-1? activities may be compromised. Consistent with this, intracellular lipid storage is altered and there is shift to larger lipid droplet size that likely reflects a decline in lipid turnover or a loss in efficiency of lipid metabolism. We suggest that changes in energy metabolism contribute directly to skeletal muscle aging in rhesus monkeys.
This study examined associations between substance use behaviors and self-reported health among hospitalized heroin users. Of the 112 participants, 53 (47%) reported good or better health. In multivariable logistic regression models, each day of heroin use in the last month was associated with an 8% lower odds of reporting health as good or better (OR=.92; 95% CI 0.87, 0.97, p<.05). Cocaine, cannabis, cigarettes, alcohol use, unintentional overdose, nor injection drug use was associated with health status.
A cocktail of six lytic bacteriophages, SalmoFresh™, significantly (p < 0.05) reduced the number of surface-applied Salmonella Kentucky and Brandenburg from stainless steel and glass surfaces by > 99% (2.1-4.3 log). Both strains were susceptible to SalmoFresh™ in the spot-test assay. Conversely, SalmoFresh™ was unable to reduce surface contamination with a Salmonella Paratyphi B strain that was not susceptible to the phage cocktail in the spot-test assay. However, by replacing two SalmoFresh™ component phages with two new phages capable of lysing the Paratyphi B strain in the spot-test assay, the target range of the cocktail was shifted to include the Salmonella Paratyphi B strain. The modified cocktail, SalmoLyse™, was able to significantly (p < 0.05) reduce surface contamination of the Paratyphi B strain by > 99% (2.1-4.1 log). The data show that both phage cocktails were effective in significantly reducing the levels of Salmonella on hard surfaces, provided the contaminating strains were susceptible in the spot-test (i.e., spot-test susceptibility was indicative of efficacy in subsequent surface decontamination studies). The data also support the concept that phage preparations can be customized to meet the desired antibacterial application.
This study compares the kinetics of crystal growth of indomethacin from supersaturated suspensions at varying degrees of supersaturation (2 ? S ? 9) in the presence of seed crystals of the ?-form of indomethacin, the lowest energy polymorph. At high S (6 ? S ? 9), the crystal growth was first order with rate coefficients (kG ) that were nearly constant and consistent with the value predicted for bulk-diffusion control. At lower S (<6), kG values were significantly smaller, decreasing approximately linearly with a decrease in S. The decline in kG at low S was attributed to a prolonged period during the initial stages of crystal growth in which surface integration was rate limiting. The apparent solubility of indomethacin after crystal growth for 3 days increased by ?1.6-fold at both low (S = 2) and high (S = 6) degrees of supersaturation suggesting that a higher energy surface layer was deposited on the ?-form seed crystals during crystal growth. When growth experiments were repeated at low S in the presence of indomethacin seed crystals isolated from a previous crystal growth experiment (i.e., seed crystals having higher energy surface), kG matched the higher values observed for bulk diffusion-controlled crystal growth. Crystal growth experiments were also conducted at S < 1.6 using a constant infusion of an indomethacin solution in the presence of ?-form seed crystals to obtain kG under conditions where deposition of a higher energy surface could not occur. At these conditions, the smaller value of kG indicative of surface integration control was again observed and the apparent solubility of indomethacin after crystal growth matched that of the ?-form. A quantitative mechanistic understanding of the crystal growth kinetics of indomethacin derived from experiments at high and low S may be useful in future studies aimed at understanding the inhibitory effects of pharmaceutical excipients on the crystal growth of poorly soluble compounds and their utility in maintaining drug supersaturation during oral absorption.
The current standard for posttraumatic stress disorder (PTSD) diagnosis is a 3-factor model (re-experiencing, avoidance, and hyperarousal). Two 4-factor models of PTSD, the emotional numbing model (re-experiencing, avoidance, emotional numbing, and hyperarousal) and the dysphoria model (re-experiencing, avoidance, dysphoria, and hyperarousal), have considerable empirical support in the extant literature. However, a newer 5-factor model of PTSD has been introduced that is receiving interest. The 5-factor model differs from the four-factor models in its placement of three symptoms (irritability, sleep disturbance, and concentration difficulties) into a separate cluster termed dysphoric arousal. We empirically compared the theoretical factor structures of 3-, 4-, and 5-factor models of PTSD symptoms to find the best fitting model in a sample of opioid-dependent hospitalized patients.
Models to predict membrane-water partition coefficients (Kp) as a function of drug structure, membrane composition, and solution properties would be useful. This study explores the partitioning of dexamethasone (Dex) and its ionizable 21-phosphate (Dex-P) in liposomes varying in acyl chain length, physical state, and pH.
Molecular interactions and orientations responsible for differences in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer partitioning of three structurally related drug-like molecules (4-ethylphenol, phenethylamine, and tyramine) were investigated. This work is based on previously reported molecular dynamics (MD) simulations that determined their transverse free energy profiles across the bilayer. Previously, the location where the transfer free energy of the three solutes is highest, which defines the barrier domain for permeability, was found to be the bilayer center, while the interfacial region was found to be the preferred binding region. Contributions of the amino (NH2) and hydroxyl (OH) functional groups to the transfer free energies from water to the interfacial region were found to be very small both experimentally and by MD simulation, suggesting that the interfacial binding of these solutes is hydrophobically driven and occurs with minimal loss of hydrogen-bonding interactions of the polar functional groups which can occur with either water or phospholipid head groups. Therefore, interfacial binding is relatively insensitive to the number or type of polar functional groups on the solute. In contrast, the relative solute free energy in the barrier domain is highly sensitive to the number of polar functional groups on the molecule. The number and types of hydrogen bonds formed between the three solutes and polar phospholipid atoms or with water molecules were determined as a function of solute position in the bilayer. Minima were observed in the number of hydrogen bonds formed by each solute at the center of the bilayer, coinciding with a decrease in the number of water molecules in DOPC as a function of distance away from the interfacial region. In all regions, hydrogen bonds with water molecules account for the majority of hydrogen-bonding interactions observed for each solute. Significant orientational preferences for the solutes are evident in certain regions of the bilayer (e.g., within the ordered chain region and near the interfacial region 20-25 Å from the bilayer center). The preferred orientations are those that preserve favorable molecular interactions for each solute, which vary with the solute structure.
Camptothecin analogues are anticancer drugs effective when dosed in protracted schedules. Such treatment is best suited for oral formulations. AR-67 is a novel lipophilic analogue with potent efficacy in preclinical models. Here we assessed factors that may influence its oral bioavailability in rats.
This pilot study tested the efficacy of a brief intervention using motivational interviewing (MI) plus mindfulness meditation (MM) to reduce marijuana use among young adult females. Thirty-four female marijuana users between the ages of 18 and 29 were randomized to either the intervention group (n = 22), consisting of two sessions of MI-MM, or an assessment-only control group (n = 12). The participants marijuana use was assessed at baseline and at 1, 2, and 3 months posttreatment. Fixed-effects regression modeling was used to analyze treatment effects. Participants randomized to the intervention group were found to use marijuana on 6.15 (z = -2.42, p = .015), 7.81 (z = -2.78, p = .005), and 6.83 (z = -2.23, p = .026) fewer days at Months 1, 2, and 3, respectively, than controls. Findings from this pilot study provide preliminary evidence for the feasibility and effectiveness of a brief MI-MM for young adult female marijuana users.
More than 1% of adults in the Dominican Republic are HIV-infected and most infections are acquired sexually. We studied sexual risk behaviors in a group of HIV-positive patients treated in Santiago, Dominican Republic. Interviews were conducted with 129 participants seen in May 2006 at one of the countrys largest public hospital HIV clinics. Questions included demographics, sexual history, condom use, and focused on patients last sexual encounter. Most patients (72.4%) had been sexually active since their HIV diagnosis. Following their diagnosis, 72.8% of sexually active patients used condoms more frequently, 21.7% used condoms with the same frequency, and 5.4% used condoms less often. The most common reason cited for not using a condom after HIV diagnosis differed by gender; men cited decreased sexual pleasure (70.0%) and women reported that their partner had refused to use a condom (71.8%). Sexually active patients who believed that their partner did not have HIV were much more likely to report using a condom at their last sexual encounter than those who did not know their partners HIV status (odds ratio [OR] = 16.9). HIV-positive patients reported using condoms more frequently following their HIV diagnosis and were more likely to use a condom if they believed their partner did not have HIV. Increased HIV testing may lead to reduced sexual risk behavior in the Dominican Republic.
In this case series of 5 alcohol-dependent patients with insomnia who had initiated abstinence, a 4-week course of ramelteon 8 mg nightly was associated with markedly improved insomnia scores, increased total sleep time, and decreased time to fall asleep. Given its lack of abuse potential and evidence of low melatonin levels in alcoholism, ramelteon deserves further study as a treatment for insomnia in this group of patients.
It is unknown whether infection with hepatitis C is a risk factor for pain among people who have used injection drugs. Multivariate regression was used to determine whether hepatitis C was associated with greater likelihood of reporting significant chronic pain and discomfort intolerance in a cohort of 97 injection drug users dependent on opioids. Study results suggest that participants with hepatitis C may be more likely to experience chronic pain (aOR=1.98; 95% confidence interval=0.76 to 5.12, p=0.16). Furthermore, hepatitis C was found to be associated with a higher discomfort intolerance scale score, reflecting intolerance to physical discomfort (?=2.34; 95% confidence interval=0.06 to 4.62; p=0.04). Hepatitis C may be a cause for chronic pain and discomfort intolerance that is overlooked among injection drug users dependent on opioids.
Asparagine containing peptides and proteins undergo deamidation via a succinimide intermediate. This study examines the role of the succinimide in the formation of covalent, amide-linked adducts in amorphous peptide formulations.
Pain is common among opioid-dependent patients, yet pharmacologic strategies are limited. The aim of this study was to explore whether escitalopram, a selective serotonin reuptake inhibitor, was associated with reductions in pain. The study used longitudinal data from a randomized, controlled trial that evaluated the effects of escitalopram on treatment retention in patients with depressive symptoms who were initiating buprenorphine/naloxone for treatment of opioid dependence. Participants were randomized to receive escitalopram 10 mg or placebo daily. Changes in pain severity, pain interference, and depression were assessed at 1-, 2-, and 3-month visits with the visual analog scale, Brief Pain Inventory, and the Beck Depression Inventory II, respectively. Fixed-effects estimators for panel regression models were used to assess the effects of intervention on changes in outcomes over time. Additional models were estimated to explore whether the intervention effect was mediated by within-person changes in depression. In this sample of 147 adults, we found that participants randomized to escitalopram had significantly larger reductions on both pain severity (b=-14.34, t=-2.66, P<.01) and pain interference (b=-1.20, t=-2.23, P<.05) between baseline and follow-up. After adjusting for within-subject changes in depression, the estimated effects of escitalopram on pain severity and pain interference were virtually identical to the unadjusted effects. This study of opioid-dependent patients with depressive symptoms found that treatment with escitalopram was associated with clinically meaningful reductions in pain severity and pain interference during the first 3 months of therapy.
To test whether trazodone, one of the most commonly prescribed medications for treatment of insomnia, improves subjective and/or objective sleep among methadone-maintained persons with sleep complaints, we performed a randomized, double-blind, placebo-controlled trial with 6-month follow-up.
This study evaluated time to first drink in women being released from jail to determine predictors of early relapse among women with hazardous drinking and HIV risk behaviors. Between February 2004 and June 2007, 245 participants were recruited from the Rhode Island Department of Corrections. Following the baseline assessment, participants were randomized to a motivational intervention group or to a control condition. Follow-up assessments at 1, 3, and 6 months were completed for 210 participants. Alcohol use during follow-up occurred in 86.7% of participants, 42.4% initiated alcohol use on Day 1. The rate of initiation was associated with norms favorable to using alcohol (p < .01) and having a partner with an alcohol problem (hazard ratio [HR] = 1.62, p < .01). The rate of drink initiation decreased significantly (HR = 0.82, p < .05) as length of incarceration increased. The intervention was not associated with decreased drinking. Interventions to maintain abstinence need to reach women within their first days postrelease.
Formulations that produce supersaturated solutions after their oral administration have received increased attention as a means to improve bioavailability of poorly water-soluble drugs. Although it is widely recognized that excipients can prolong supersaturation, the mechanisms by which these beneficial effects are realized are generally unknown. Difficulties in separately measuring the kinetics of nucleation and crystal growth have limited progress in understanding the mechanisms by which excipients contribute to the supersaturation maintenance. This paper describes the crystal growth kinetic modeling of indomethacin, a poorly water-soluble drug, from supersaturated aqueous suspensions using a newly developed, online second-derivative ultraviolet spectroscopic method. The apparent indomethacin equilibrium solubility after crystal growth at a high degree of supersaturation (S=6) was approximately 55% higher than the indomethacin equilibrium solubility determined prior to growth, which was attributed to the deposition of a higher energy indomethacin form on the seed crystals. The indomethacin crystal growth kinetics (S=6) was of first order. By comparing the mass transfer coefficients from indomethacin dissolution and crystal growth, it was shown that the indomethacin crystal growth kinetics at S=6 was bulk diffusion controlled. The change in indomethacin seed crystal size distribution before and after crystal growth was determined and modeled using a mass-balance relationship.
Bacteriophages are increasingly being utilized and considered for various practical applications, ranging from decontaminating foods and inanimate surfaces to human therapy; therefore, it is important to determine their concentrations quickly and reliably. Traditional plaque assay (PA) is the current "gold standard" for quantitating phage titers. However, it requires at least 18 h before results are obtained, and they may be significantly influenced by various factors. Therefore, two alternative assays based on the quantitative real-time polymerase chain reaction (QPCR) and NanoSight Limited (NS) technologies were recently proposed for enumerating phage particles. The present study compared the three approaches abilities to quantitate Listeria monocytogenes-, Escherichia coli O157:H7- and Yersinia pestis-specific lytic phages quickly and reproducibly. The average coefficient of variation (CVS) of the PA method including all three phages was 0.15. The reproducibility of the PA method decreased dramatically when multiple investigators performed the assays, and mean differences of as much as 0.33 log were observed. The QPC R method required costly equipment and the synthesis of phage-specific oligonucleotide primers, but it determined phage concentrations faster (within about 4 h) and more precisely than did PA (CVS = 0.13). NS technology required costly equipment, was less precise (CVS = 0.28) than the PA and QPCR methods, and only worked when the phages were suspended in clear medium. However, it provided results within 5 min. After the overall correlation is established with the PA method, either of the two assays may be useful for quickly and reproducibly determining phage concentrations.
Dickeya dadantii is a plant-pathogenic enterobacterium responsible for the soft rot disease of many plants of economic importance. We present here the sequence of strain 3937, a strain widely used as a model system for research on the molecular biology and pathogenicity of this group of bacteria.
Atomic-level molecular dynamics simulations of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayers containing small, amphiphilic, drug-like molecules were carried out to examine the influence of polar functionality on membrane partitioning and transport. Three related molecules (tyramine, phenethylamine, and 4-ethylphenol) were chosen to allow a detailed study of the isolated effects of the amine and hydroxyl functionalities on the preferred solute location, free energies of transfer, and the effect of combining both functional groups in a same molecule. Transfer free energy profiles (from water) generated from molecular dynamics (MD) simulations as a function of bilayer depth compared favorably to comparable experimental results. The simulations allowed the determination of the location of the barrier domain for permeability where the transfer free energy is highest and the preferred binding region at which the free energy is a minimum for each of the three solutes. Comparisons of the free energy profiles reveal that the hydrocarbon chain interior is the region most selective to chemical structure of different solutes because the free energies of transfer in that region vary to a significantly greater extent than in other regions of the bilayer. The contributions of the hydroxyl and amino groups to the free energies of solute transfer from water to the interfacial region were close to zero in both the MD simulations and experimental measurements. This suggests that the free energy decrease observed for solute transfer into the head group region occurs with minimal loss in solvation by hydrogen bonding to polar functional groups on the solute and is largely driven by hydrophobicity. Overall, the joint experimental and simulation studies suggest that the assumption of additivity of free energy contributions from multiple polar functional groups on the same molecule may hold for predictions of passive bilayer permeability coefficients providing that the groups are well isolated. However, this assumption does not hold for predictions of relative liposome-binding affinities.
The number of women incarcerated within the United States has risen dramatically in recent decades, and high rates of alcohol problems are evident among this population. Although little is known about the patterns of help utilization and efficacy for alcohol problems, preliminary evidence suggests that Alcoholics Anonymous (AA) is a widely available resource for this population.
This study tests the acquired preparedness model (APM) to explain associations among trait impulsivity, social learning principles, and marijuana use outcomes in a community sample of female marijuana users. The APM states that individuals with high-risk dispositions are more likely to acquire certain types of learning that, in turn, instigate problematic substance use behaviors. In this study, three domains of psychosocial learning were tested: positive and negative marijuana use expectancies, and marijuana refusal self-efficacy. Participants were 332 community-recruited women aged 18-24 enrolled in a study of motivational interviewing for marijuana use reduction. The present analysis is based on participant self-reports of their impulsivity, marijuana use expectancies, marijuana refusal self-efficacy, marijuana use frequency, marijuana use-related problems, and marijuana dependence. In this sample, impulsivity was significantly associated with marijuana use frequency, marijuana-related problems, and marijuana dependence. Results also indicate that the effect of impulsivity on all three marijuana outcomes was fully mediated by the three principles of psychosocial learning tested in the model, namely, positive and negative marijuana expectancies, and marijuana refusal self-efficacy. These findings lend support to the APM as it relates to marijuana use. In particular, they extend the applicability of the theory to include marijuana refusal self-efficacy, suggesting that, among high-impulsives, those who lack appropriate strategies to resist the temptation to use marijuana are more likely to exhibit more frequent marijuana use and use-related negative consequences.
Comparisons of subjective and objective sleep measures have shown discrepancies between reported sleep and polysomnography (PSG) in non-drug dependent individuals with and without insomnia. Sleep may affect behavioral and physiologic aspects of drug abuse and dependence; patients in methadone maintenance therapy (MMT) for opioid dependence frequently report sleep problems. Whether subjective sleep reflects objective sleep in MMT patients is unknown. We undertook these analyses to establish the correlations among subjective and objective sleep measures in MMT patients.
We randomized 332 women, 18-24 years old, who were not explicitly seeking treatment for their marijuana use to either a two-session motivationally focused intervention or an assessment-only condition. Assessed by timeline follow-back methodology, participants reported using marijuana 57% of days in the 3 months prior to study entry. Intervention effects on the likelihood of marijuana use were not statistically significant at 1 month (odds ratio [OR] = 0.77, p = .17), significant at 3 months (OR = 0.53, p = .01), and no longer significant at 6 months (OR = 0.74, p = .20). Among the 61% of participants endorsing any desire to quit using marijuana at baseline, significant intervention effects on the likelihood of marijuana use days were observed at 1 month (OR = 0.42, p = .03), 3 months (OR = 0.31, p = .02), and 6 months (OR = 0.35, p = .03). A two-session brief motivational intervention reduced marijuana use among young women not seeking treatment. Women with a desire to quit showed a greater and more durable response.
Chronic diseases and injuries are elevated among people with substance use problems/dependence, yet heavier drinkers use fewer routine and preventive health services than non-drinkers and moderate drinkers, while former drinkers and abstainers use more than moderate drinkers. Researchers hypothesize that drinking clusters with attitudes and practices that produce better health among moderate drinkers and that heavy drinkers avoid doctors until becoming ill, subsequently quitting and using more services. Gender differences in alcohol consumption, health-related attitudes, practices, and prevention-services use may affect these relationships.
This study examined associations between the endorsement of drug use expectancies and the frequency and severity of marijuana use in a community sample of 332 women aged 18-24years who were not explicitly seeking treatment for their marijuana use. Participants were enrolled in a larger intervention study of motivational interviewing for various health behaviors and provided self-reports of their current and past marijuana use, marijuana abuse/dependence symptoms, and marijuana use expectancies. Marijuana use expectancies were measured using the six subscales of the Marijuana Effects Expectancy Questionnaire (MEEQ). Use frequency was defined as the number of use days in the past month, severity as the total number of DSM-IV marijuana abuse or dependence symptom criteria met. Replicating and extending prior research, expectations regarding Relaxation and Tension Reduction emerged as a robust belief in this cohort, predicting not only frequency (p<.01) but also severity (p<.01) of marijuana use in multivariate analyses. Severity of marijuana use was further predicted by expectations regarding loss of control, affective changes following marijuana use, and other aspects of emotion dysregulation (Global Negative Effects, p<.01). These findings document meaningful associations between substance-related cognitions and use behavior and suggest that marijuana users who hold certain beliefs regarding marijuana use may be particularly susceptible to clinically significant problems associated with their substance use. As such, marijuana use expectancies may represent a clinical target that could be incorporated into future interventions.
To test the hypothesis that among hazardously drinking incarcerated women who are returning to the community, a brief alcohol intervention will result in less alcohol use at follow-up relative to standard of care.
This study determined the frequency of reporting being introduced to opioids by a physician among opioid-dependent patients. Cross-sectional analyses were performed using baseline data from a cohort of opioid addicts seeking treatment with buprenorphine. The primary outcome was a response to the question: "Who introduced you to opiates?" Covariates included sociodemographics, depression, pain, and current and prior substance use. Of 140 participants, 29% reported that they had been introduced to opioids by a physician. Of those who were introduced to opioids by a physician, all indicated that they had initially used opioids for pain, versus only 11% of those who did not report being introduced to opioids by a physician (p < .01). There was no difference in current pain (78% vs. 85%, p = .29); however, participants who were introduced to opioids by a physician were more likely to have chronic pain (63% vs. 43%, p = .04). A substantial proportion of individuals with opioid dependence seeking treatment may have been introduced to opioids by a physician.
Our goal was to determine whether treatment of depressive symptoms with escitalopram during buprenorphine treatment for opioid dependence would improve treatment retention compared to placebo in a 12-week, randomized, double-blind trial. Treatment dropout was defined as missing seven consecutive buprenorphine dosing days. Participants were 76% male, 80% non-Hispanic Caucasian, and 64% heroin users. At baseline, the mean Beck Depression Inventory II (BDI-II) score was 28.4 (+/-9.7). Sixty-one percent of participants completed the 12-week buprenorphine protocol. Dropout rates were 33.3% and 44.0% among those randomized to escitalopram or placebo, respectively (p = .19). Relative to baseline, mean BDI-II scores were significantly lower at all follow-up assessments, but the Treatment x Time interaction effect was not statistically significant (p = .18). Participants randomized to escitalopram also did not have a significantly lower likelihood of testing positive for either opiates or other drugs during follow-up. Depressive symptoms often resolved with buprenorphine treatment, and the immediate initiation of escitalopram does not improve treatment retention, depression outcomes, or illicit drug use. Clinicians should determine the need for antidepressant treatment later in buprenorphine care.
Despite considerable research, relationships among gender, alcohol consumption, and health remain controversial, due to potential confounding by health-related attitudes and practices associated with drinking, measurement challenges, and marked gender differences in drinking. We examined gender/alcohol consumption differences in health-related attitudes and practices, and evaluated how these factors affected relationships among gender, alcohol consumption, and health status.
The narrow efficacy-toxicity window of anticancer agents necessitates understanding of factors contributing to their disposition. This is especially true for camptothecins as they exist in the lactone and carboxylate forms with each moiety differentially interacting with efflux or uptake transporters. Here we determined the disposition of the lactone and carboxylate forms of AR-67, a 3(rd) generation camptothecin analogue.
Opioid-dependent patients treated with methadone have subjective sleep complaints and disrupted sleep on polysomnography (PSG). Previous studies of sleep-disordered breathing (SDB) in this population have focused on central sleep apnea (CSA). Our objectives were to: (1) characterize obstructive sleep apnea (OSA) and CSA in patients in methadone maintenance treatment (MMT) for opioid dependence; (2) examine factors associated with SDB in this population; and (3) investigate whether SDB was related to severity of subjective sleep complaints in MMT patients with subjective sleep disturbances.
To test whether a four-session motivational intervention would reduce hepatitis C virus (HCV) seroincidence among injection and non-injection drug users compared to an assessment-only condition, we performed a randomized 24-month clinical trial. At baseline, 277 participants reported using heroin or cocaine at least three times weekly were HCV antibody negative, 65% were male and 46% were Caucasian and 39% reported having injected drugs. Of the 15 (5.4%) individuals who seroconverted, all reported injecting drugs either at baseline or during follow-up. Seroconversion rates did not differ significantly by treatment assignment (p =.79). The annual HCV incident rate was 8.20 (95% confidence interval [CI] = 4.76-14.13) for injectors and 0.74 (95% CI = 0.19-2.98) for non-injectors per 100 person-years. Significantly fewer participants in the intervention group initiated injection drug use behaviors (p =.009). This intervention was no more effective at reducing HCV seroconversion than assessment alone but did decrease injection initiation.
Computational methods to predict pK(a) values and partition coefficients of drug molecules based on linear free energy relationships (LFERs) rely largely on the principles of independence and additivity of the functional group contributions in each molecule to the overall free energy. Nonadditivities in functional group contributions are often seen when multiple polar functional groups are in close proximity and in cases where conformational flexibility allows widely separated polar functional groups to interact. The degree to which long-range interactions may alter group contributions in more conformationally constrained molecules such as p-(aminoethyl)phenol and structurally similar analogs is more difficult to predict. In this study, both macroscopic and microscopic ionization constants and decadiene/water partition coefficients as a function of pH at 25 degrees C were obtained for p-(aminoethyl)phenol and six structurally related compounds to explore the reliability of the independence and additivity assumptions necessary in using the LFERs for predictions. A long-range interaction between the phenol and amine groups in the series has been found to affect the pK(a) values of both groups and to alter species-specific partition coefficients. Pronounced shifts in microscopic ionization constants involving zwitterion forms are clearly indicative of amplified long-range interactions between ionized substituents.
The dinuclear osmium polyhydride [Os(2)H(7)(PPh(i)Pr(2))(4)][HC(SO(2)CF(3))(2)] (1) was synthesized by the protonation of [OsH(6)(PPh(i)Pr(2))(2)] with bis(trifluoromethylsulfonyl)methane. Treatment with amine bases was not able to deprotonate 1, but reaction with potassium hydride gave the corresponding neutral polyhydride [Os(2)H(6)(PPh(i)Pr(2))(4)] (2). Single crystal X-ray diffraction revealed that 1 and 2 both crystallize in the P2(1)/c space group and are classical polyhydrides containing similar Os(mu-H)(3)Os cores with Os-Os distances of 2.5431(1) A and 2.5448(2) A, respectively. These structures represent rare examples of dinuclear osmium polyhydrides with six or more hydride ligands.
The aim of this study was to test if a motivational intervention would reduce cocaine use. We performed a randomized trial with 6-month follow-up for 198 persons who used cocaine at least weekly. Participants were randomly assigned to a four-session motivational intervention or an assessment control group. We performed an intent-to-treat analysis of past 30-day self-reported cocaine use at 6 months, with those lost to follow-up assumed to use cocaine at their baseline level. Participants were 62% male, 40% Caucasian, and used cocaine an average of 13.8 days over the past month. In the full cohort, there were no significant intervention effects on mean change in cocaine use days (p = .21), past 30-day abstinence (33% vs. 26%, p = .26), or >50% reduction in cocaine use days from baseline (55.7% vs. 46.5%, p = .20). However, among those using cocaine on 15 or more of the 30 days prior to baseline, motivational interviewing participants had a significantly larger mean reduction in cocaine use days (p = .023). There were also no significant group differences in days of employment, quality of life, or substance abuse treatment entry. We conclude that this motivational intervention was more effective than assessment alone at reducing cocaine days among the heaviest community-based users. Both study conditions induced positive effects on cocaine use.
Screening methods for hazardous drinking have not been evaluated in a population of incarcerated women. This study examines abbreviated versions of the Alcohol Use Disorders Identification Test (AUDIT) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) heavy episodic drinking criterion in a sample of female detainees.
A growing literature has identified associations between impulsivity and negative behaviors such as sexual risk-taking among high-risk and/or vulnerable populations, but few studies have linked impulsivity to biological outcomes of sexual risk-taking. The main purpose of this study was to document associations among impulsivity, sexual risk-taking, and biological measures of sexually transmitted infection (STI+) in a sample of hazardously drinking incarcerated women.
Amorphous drug dispersions are frequently employed to enhance solubility and dissolution of poorly water-soluble drugs and thereby increase their oral bioavailability. Because these systems are metastable, phase separation of the amorphous components and subsequent drug crystallization may occur during storage. Computational methods to determine the likelihood of these events would be very valuable, if their reliability could be validated. This study investigates amorphous systems of indomethacin (IMC) in poly(vinylpyrrolidone) (PVP) and their molecular interactions by means of molecular dynamics (MD) simulations. IMC and PVP molecules were constructed using X-ray diffraction data, and force-field parameters were assigned by analogy with similar groups in Amber-ff03. Five assemblies varying in PVP and IMC composition were equilibrated in their molten states then cooled at a rate of 0.03 K/ps to generate amorphous glasses. Prolonged aging dynamic runs (100 ns) at 298 K and 1 bar were then carried out, from which solubility parameters, the Flory-Huggins interaction parameter, and associated hydrogen bonding properties were obtained. Calculated glass transition temperature (T(g)) values were higher than experimental results because of the faster cooling rates in MD simulations. Molecular mobility as characterized by atomic fluctuations was substantially reduced below the T(g) with IMC-PVP systems exhibiting lower mobilities than that found in amorphous IMC, consistent with the antiplasticizing effect of PVP. The number of IMC-IMC hydrogen bonds (HBs) formed per IMC molecule was substantially lower in IMC-PVP mixtures, particularly the fractions of IMC molecules involved in two or three HBs with other IMC molecules that may be potential precursors for crystal growth. The loss of HBs between IMC molecules in the presence of PVP was largely compensated for by the formation of IMC-PVP HBs. The difference (6.5 MPa(1/2)) between the solubility parameters in amorphous IMC (25.5 MPa(1/2)) and PVP (19.0 MPa(1/2)) suggests a small, positive free energy of mixing, although it is close to the criterion for miscibility (<7 MPa(1/2)). In contrast to the solubility-parameter method, the calculated Flory-Huggins interaction parameter (-0.61 ± 0.25), which takes into account the IMC-PVP interaction energy, predicts complete miscibility at all PVP compositions, in agreement with experimental observations. These results from MD simulations were combined with experimental values for the crystalline ?-polymorph of IMC and amorphous IMC to estimate the solubility of IMC in amorphous PVP dispersions and the theoretical enhancement in the aqueous solubility of IMC molecularly dispersed in PVP at various volume fractions.
Methadone-maintained persons are at increased risk for many physical and mental health disorders compared to the general population. Increased physical activity could offset these risks. We assessed physical activity level, and perceived benefits and barriers to exercise in a group of 305 methadone-maintained smokers. Mean participant age was 39.9 years, 50.2% were male, 79.7% were non-Hispanic White, and mean body mass index was 29.8. Nearly 45% endorsed fair or poor physical health. Although participants perceived many benefits of exercise and few barriers, only 38% of participants met weekly recommendations for physical activity, and nearly 25% reported no physical activity. Those who met recommended guidelines were significantly more likely to endorse relapse prevention as a benefit of exercise. Motivating MMT patients to increase physical activity could have important physical, mental health, and drug treatment benefits.
trans-2,6-Difluoro-4-N,N-dimethylaminostilbene (DFS), a synthetic stilbene, displayed potent pre-clinical anti-cancer activities exceeding that observed for naturally occurring resveratrol. In this study, a simple and sensitive HPLC method was developed and validated to quantify DFS in rat plasma. The lower limit of quantification (LLOQ) was 5 ng/ml. The intra- and inter-day variation in terms of relative standard deviation (RSD) was all less than 10%. The bias rate ranged from -11.5% to 6.2% while the absolute recovery ranged from 94.1 ± 2.3 to 97.3 ± 4.4%. The pharmacokinetic profiles of DFS were examined in Sprague-Dawley rats after intravenous administration (2 mg/kg). DFS displayed moderate clearance (Cl=61.5 ± 17.7 ml/min/kg) and a relatively prolonged terminal elimination half-life (t(1/2 ?z)) of 351 ± 180 min. Aqueous solubility played a crucial role in the oral absorption of DFS. When DFS was given as a suspension (6 mg/kg), the absolute oral bioavailability (F) was almost negligible. However, when DFS was given in a solution prepared with hydroxypropyl-?-cyclodextrin (6 mg/kg), the F was 12.4 ± 10.7%. Dose-escalation to 15 mg/kg resulted in much higher systemic exposure (F=40.2 ± 10.0%). As DFS is orally available after formulation with hydroxypropyl-?-cyclodextrin and pharmacologically active systemic concentrations could be achieved after a single oral dose, the use of DFS as a cancer chemopreventive/chemotherapeutic agent is possible.
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