Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom.

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (Cmax ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and Cmax (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (KI , ~4 µM; kinact , ~0.07 min-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.

Interactive influences of meteorological and socioeconomic factors on ecosystem service values in a river basin with different geomorphic features.

Ecosystem service value (ESV) is influenced by land use and land cover (LULC), and is closely related to natural conditions and human activities. However, the interactions between human and natural systems and ESV remain unclear, especially concerning widely discussed meteorological and socioeconomic factors. In this study, three periods of LULC patterns (2000, 2010, and 2020) in the Haihe River Basin, northern China, were collected to determine the relationship between changes in LULC and ESV over time. Natural and socioeconomic data associated with ESV were obtained and the structural equation model was used to decouple interactions between these factors. Results showed that the total value of regional ecosystem services has decreased as cultivated land shrunk and artificial surfaces increased over the past two decades. The ESV was significantly decreased in the middle of the basin. The direct effects of meteorological factors and socioeconomic factors on ESV were positive (0.094) and negative (-0.203), respectively. The indirect effect of socioeconomic factors on ESV through meteorological and LULC factors was 0.149. Structural equation modeling demonstrated that under the dominance of LULC, interactions between natural and socioeconomic factors affected ESV in a complex manner. These results implied that identifying the direct and indirect effects of economic development and human activities on ESV could guide and implement effective land management policies.

Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants.

Increasing use of the botanical kratom to self-manage opioid withdrawal and pain has led to increased kratom-linked overdose deaths. Despite these serious safety concerns, rigorous fundamental pharmacokinetic knowledge of kratom in humans remains lacking. We assessed the pharmacokinetics of a single low dose (2 g) of a well-characterized kratom product administered orally to six healthy participants. Median concentration-time profiles for the kratom alkaloids examined were best described by a two-compartment model with central elimination. Pronounced pharmacokinetic differences between alkaloids with the 3S configuration (mitragynine, speciogynine, paynantheine) and alkaloids with the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) were attributed to differences in apparent intercompartmental distribution clearance, volumes of distribution, and clearance. Based on noncompartmental analysis of individual concentration-time profiles, the 3S alkaloids exhibited a shorter median time to maximum concentration (1-2 vs. 2.5-4.5 h), lower area under the plasma concentration-time curve (430-490 vs. 794-5120 nM × h), longer terminal half-life (24-45 vs. ~12-18 h), and higher apparent volume of distribution during the terminal phase (960-12,700 vs. ~46-130 L) compared to the 3R alkaloids. Follow-up mechanistic in vitro studies suggested differential hepatic/intestinal metabolism, plasma protein binding, blood-to-plasma partitioning, and/or distribution coefficients may explain the pharmacokinetic differences between the two alkaloid types. This first comprehensive pharmacokinetic characterization of kratom alkaloids in humans provides the foundation for further research to establish safety and effectiveness of this emerging botanical product.

Assessment of Regular and NPH Insulin Concentration via Two Methods of Quantification: The Washington State Insulin Concentration Study (WICS).

BACKGROUND: Recent reports have suggested that insulin vials purchased in community pharmacies do not meet the minimum required intact insulin concentration (≥95 U/mL) as defined by the United States Pharmacopeia. We sought to independently obtain multidose human insulin vials from a variety of community pharmacies across the state of Washington and quantitatively measure intact insulin. METHODS: Sixty 10-mL vials of insulin (n = 30 regular human insulin and n = 30 neutral protamine Hagedorn insulin) were purchased and assayed. To ensure random selection of lots and supply chain sources, insulin samples were purchased on a variety of calendar dates from various pharmacy locations across Washington State, inclusive of both chain and independent pharmacies. All samples were assessed for intact insulin concentration via both Ultra Performance Liquid Chromatography coupled with UV detection (UPLC-UV) and Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). RESULTS: When considering all samples (N = 60), the mean concentration was 101.8 ± 4.4and 91.5 ± 1.9 U/mL as determined by UPLC-UV and UPLC-MS, respectively. Measured concentrations ranged from 90.0 to 108.4 U/mL when assayed by UV UPLC and 86.1 to 95.4 U/mL for UPLC-MS. CONCLUSION: To our knowledge, this is the first study following the report by Carter et al that assessed human insulin concentrations by both UPLC-UV and UPLC-MS. These findings are important because they demonstrate that the results obtained from these two methods differ and that the method used must be considered when interpreting findings.

Connecting Patients to Prescription Assistance Programs: Effects on Emergency Department and Hospital Utilization.

BACKGROUND: Manufacturer prescription assistance programs (PAPs) have been developed to provide medications at little or no cost to eligible patients. There are over 200 PAPs available from pharmaceutical companies, and each may have different eligibility requirements and assistance guidelines. A formalized community-based patient prescription coordinator can help patients navigate these programs by reviewing an applicant's financial information and medication requirements to identify which PAPs are most appropriate. Little is known, however, about whether providing such guidance is associated with a reduction in acute care utilization. OBJECTIVE: To evaluate changes in emergency department and hospital utilization among patients who received care coordination and financial assistance with prescribed medications. METHODS: This single-cohort interrupted time-series study included participants in eastern Washington state who enrolled in the Spokane Prescription Assistance Network (SPAN) program between March 1, 2009, and August 31, 2012. Referrals to the SPAN patient prescription coordinator were made by a social service agency or medical provider for patients who may have difficulty paying for prescribed medications. Initial patient contact occurred while the patient was still being treated in a clinic or hospital or through a direct visit to the coordinator's community-based office. Participants were contacted 6 months after the initial appointment and then annually thereafter to review current medications and health status. A review of electronic health records provided information on hospitalizations and emergency department visits in the 12 months before and after program entry. RESULTS: Among SPAN participants (n = 310), emergency department and hospital encounters declined from 0.38 per participant in the year before enrollment to 0.20 encounters in the year following program entry. A repeated-measures mixed-effects model indicated SPAN participation was associated with a 51% decline in the rate of emergency department and hospital utilization (incidence rate ratio [IRR] = 0.49; 95% CI = 0.31-0.77; P = 0.002). Observed effects differed by prescription class. Factor interactions revealed significant reductions in utilization for participants with prescribed pulmonary medications (IRR = 0.58; 95% CI = 0.37-0.92; P = 0.019). Assistance with mental health (psychotropic) medications was associated with increased incidence of utilization (IRR = 2.07; 95% CI = 1.32-3.24; P = 0.001). At the time of SPAN enrollment, 60% of participants had prescriptions for psychotropic medications. CONCLUSIONS: A formalized patient prescription coordinator can help patients access prescribed medications at low cost and remain compliant with treatment plans. In a study of a coordination pilot program, reductions in hospital admissions and emergency department visits were observed following program participation. DISCLOSURES: This study was not supported by any outside funding. The authors declare no conflicts of interest. Study design was created by Burley, McPherson, and Daratha. Burley Daratha, Selinger, and Armstrong collected the data, with interpretation performed by Burley, Daratha, and Tuttle, assisted by McPherson. The manuscript was written by Burley, Daratha, and Selinger, with assistance from White, and revised by Burley, White, and Selinger, with assistance from Daratha and Tuttle.

Investigation of biogeochemical functional proxies in headwater streams across a range of channel and catchment alterations.

Historically, headwater streams received limited protection and were subjected to extensive alteration from logging, farming, mining, and development activities. Despite these alterations, headwater streams provide essential ecological functions. This study examines proxy measures of biogeochemical function across a range of catchment alterations by tracking nutrient cycling (i.e., inputs, processing, and stream loading) with leaf litter fall, leaf litter decomposition, and water quality parameters. Nutrient input and processing remained highest in second growth forests (the least altered areas within the region), while recently altered locations transported higher loads of nutrients, sediments, and conductivity. Biogeochemical functional proxies of C and N input and processing significantly, positively correlated with rapid assessment results (Pearson coefficient = 0.67-0.81; P = 0.002-0.016). Additionally, stream loading equations demonstrate that N and P transport, sediment, and specific conductivity negatively correlated with rapid assessment scores (Pearson coefficient = 0.56-0.81; P = 0.002-0.048). The observed increase in stream loading with lower rapid assessment scores indicates that catchment alterations impact stream chemistry and that rapid assessments provide useful proxy measures of function in headwater ecosystems. Significant differences in nutrient processing, stream loading, water quality, and rapid assessment results were also observed between recently altered (e.g., mined) headwater streams and older forested catchments (Mann-Whitney U = 24; P = 0.01-0.024). Findings demonstrate that biogeochemical function is reduced in altered catchments, and rapid assessment scores respond to a combination of alteration type and recovery time. An analysis examining time and economic requirements of proxy measurements highlights the benefits of rapid assessment methods in evaluating biogeochemical functions.

Microbial and geochemical assessment of bauxitic un-mined and post-mined chronosequence soils from Mocho Mountains, Jamaica.

Microorganisms are very sensitive to environmental change and can be used to gauge anthropogenic impacts and even predict restoration success of degraded environments. Here, we report assessment of bauxite mining activities on soil biogeochemistry and microbial community structure using un-mined and three post-mined sites in Jamaica. The post-mined soils represent a chronosequence, undergoing restoration since 1987, 1997, and 2007. Soils were collected during dry and wet seasons and analyzed for pH, organic matter (OM), total carbon (TC), nitrogen (TN), and phosphorus. The microbial community structure was assessed through quantitative PCR and massively parallel bacterial ribosomal RNA (rRNA) gene sequencing. Edaphic factors and microbial community composition were analyzed using multivariate statistical approaches and revealed a significant, negative impact of mining on soil that persisted even after greater than 20 years of restoration. Seasonal fluctuations contributed to variation in measured soil properties and community composition, but they were minor in comparison to long-term effects of mining. In both seasons, post-mined soils were higher in pH but OM, TC, and TN decreased. Bacterial rRNA gene analyses demonstrated a general decrease in diversity in post-mined soils and up to a 3-log decrease in rRNA gene abundance. Community composition analyses demonstrated that bacteria from the Proteobacteria (α, ß, γ, δ), Acidobacteria, and Firmicutes were abundant in all soils. The abundance of Firmicutes was elevated in newer post-mined soils relative to the un-mined soil, and this contrasted a decrease, relative to un-mined soils, in proteobacterial and acidobacterial rRNA gene abundances. Our study indicates long-lasting impacts of mining activities to soil biogeochemical and microbial properties with impending loss in soil productivity.

Trends in the management of type 2 diabetes: an emerging role for insulin.

OBJECTIVE: This review is intended to explore the pathophysiology of type 2 diabetes, examine the role of insulin as a means of achieving glycemic control in people with type 2 diabetes, and provide a practical approach for insulin use in type 2 diabetes in the managed care setting. DATA SOURCES: This manuscript is based on the results of a MEDLINE literature search and presentations by the authors at a symposium titled, "Emerging Changes in Diabetes Management," that took place on October, 14, 2004, at the Academy of Managed Care Pharmacy's 2004 Educational Conference in Baltimore, Maryland. CONCLUSIONS: Despite advances in oral treatment, type 2 diabetes remains a substantial source of microvascular and macrovascular complications that cause unacceptable levels of morbidity, mortality, and cost. Accumulating clinical evidence suggests that insulin treatment, both basal and prandial, can advance the treatment of type 2 diabetes and reduce the risks for serious sequelae by providing consistent and optimal glycemic control. By more closely mimicking the actions of endogenous insulin, in terms of onset and duration of action, insulin analogues offer clear advantages over their regular insulin counterparts.

Economic considerations in treating patients with type 2 diabetes mellitus.

Economic considerations in treating patients with type 2 diabetes mellitus are reviewed. Glycemic control, lipid profiles, and adherence to standards of care are less than optimal in many patients with type 2 diabetes mellitus. Diabetes has an enormous economic impact, and its related costs in the United States are expected to increase as the frequency of the disease increases. A substantial portion of diabetes-related health care expenditures is allotted to the treatment of cardiovascular disease, a major complication of diabetes. Significant health care resources are spent in a reactive manner (i.e., after complications have developed), with little emphasis on preventive care. One large study conducted in the United Kingdom demonstrated that providing intensive blood glucose control significantly reduced the risk of microvascular complications, such as retinopathy, nephropathy, and neuropathy, in patients with type 2 diabetes mellitus. Factors to consider in selecting pharmacotherapy for these patients include the magnitude of change in measures of glycemic control provided by the medication, other desired metabolic changes and outcomes (e.g., blood pressure and lipid changes), mechanism of action, adverse effects, contraindications, patient adherence, and cost. Early interventions, such as annual urinalysis and screening for microalbuminemia, annual comprehensive eye examination by an ophthalmologist or optometrist, and screening for neuropathy and foot problems are cost-effective ways of reducing diabetes-related complications. Interventions recommended for reducing the risk for cardiovascular complications in patients with type 2 diabetes mellitus include lipid control, blood pressure control, aspirin therapy, smoking cessation, and weight loss. Achieving and maintaining glycemic control in patients with type 2 diabetes mellitus improves quality of life and is cost-effective, especially among patients with comorbid heart disease, hypertension, or both.

Insulin glargine: a new basal insulin.

OBJECTIVE: To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy of insulin glargine. DATA SOURCES: Primary and review articles regarding insulin glargine were identified by MEDLINE search (1966-July 2001); abstracts were identified through Institute for Scientific Information Web of Science (1995-July 2001) and the American Diabetes Association. Additional information was obtained from the insulin glargine product information. STUDY SELECTION AND DATA EXTRACTION: All of the articles and meeting abstracts identified from the data sources were evaluated, and all information deemed relevant was included in this review. Priority was placed on data from the primary medical literature. DATA SYNTHESIS: Insulin glargine is a long-acting, recombinant human insulin analog that is given once daily as a basal source of insulin in patients with type 1 or type 2 diabetes mellitus. Modification of the basic insulin structure has produced a new insulin that is soluble at an acidic pH, but precipitates in the subcutaneous tissue and is slowly released from a depot. Insulin glargine has a slower onset of action than NPH insulin and a longer duration of action with no peak activity. Once-daily administration of insulin glargine has comparable efficacy to that of NPH insulin administered once or twice daily in basal-bolus regimens when used in combination with intermittent doses of regular insulin or insulin lispro in patients with type 1 and type 2 diabetes, and in conjunction with oral antidiabetic agents in patients with type 2 diabetes. Overall, insulin glargine has an incidence of hypoglycemia comparable to or less than that of NPH insulin, with a reduced incidence of nocturnal hypoglycemia compared with NPH insulin seen in some studies. CONCLUSIONS: Insulin glargine is a long-acting insulin analog capable of providing 24-hour basal insulin coverage when administered once daily at bedtime. Its activity profile, which lacks a pronounced peak, more closely resembles that of endogenous basal insulin than that of other intermediate- or long-acting insulins and appears more likely to be associated with a reduced incidence of hypoglycemia, particularly nocturnal hypoglycemia. Insulin glargine physiologically provides basal insulin but, for most patients, the addition of a rapid-acting insulin, like insulin lispro, before or with meals will need to be included in the treatment regimen to achieve optimal management of blood glucose concentrations.