Public Health Implications and Possible Sources of Lead (Pb) as a Contaminant of Poorly Regulated Kratom Products in the United States.

Kratom (Mitragyna speciosa) is a tropical tree that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression, and opioid use disorder (OUD). Recent studies from the United States Food and Drug Administration (FDA, Silver Spring, MD, USA) and our laboratory have shown that many kratom products being sold in the United States are contaminated with potentially hazardous levels of lead (Pb). In this commentary, we discuss the public health implications of the presence of Pb in kratom products, particularly as they relate to the predicted levels of Pb exposure among kratom users. We also considered the specific toxic effects of Pb and how they might relate to the known physiologic and toxicologic effects of kratom. Finally, we consider the possible sources of Pb in kratom products and suggest several areas for research on this issue.

In Vitro Nephrotoxicity and Permeation of Vancomycin Hydrochloride Loaded Liposomes.

Drugs can be toxic to the fetus depending on the amount that permeates across the maternal-fetal barrier. One way to limit the amount which penetrates this barrier is to increase the molecular size of the drug. In this study, we have achieved this by encapsulating our model antibiotic (vancomycin hydrochloride, a known nephrotoxic agent) in liposomes. PEGylated and non-PEGylated liposomes encapsulating vancomycin hydrochloride were prepared using two different methods: thin-film hydration followed by the freeze-thaw method and the reverse-phase evaporation method. These liposomes were characterized by their hydrodynamic size and zeta potential measurements, CryoTEM microscopy, loading and encapsulation efficiency studies, in vitro release measurements and in vitro cytotoxicity assays using NRK-52 E rat kidney cells. We also determined the in vitro permeability of these liposomes across the human placental cell and dog kidney cell barriers. Vancomycin hydrochloride-loaded PEGylated liposomes (VHCL-lipo) of a size less than 200 nm were prepared. The VHCL-lipo were found to have the faster release of vancomycin hydrochloride and resulted in greater viability of NRK-52E cells. In vitro, the VHCL-lipo permeated the human placental cell and dog kidney cell barriers to a lesser extent than the free vancomycin hydrochloride. The data suggest a reduction in nephrotoxicity and permeability of vancomycin hydrochloride after encapsulation in PEGylated liposomes.

Vancomycin Pharmacokinetics in a Pregnancy Rat Model.

Vancomycin usage is often unavoidable in pregnant patients; however, literature suggests vancomycin can cross the placental barrier and reach the fetus. Understanding the mass transit of vancomycin to the fetus is important in pregnancy. We aimed to (i) identify a relevant population pharmacokinetic (PK) model for vancomycin in pregnancy and (ii) estimate PK parameters and describe the mass transit of vancomycin from mother to pup kidneys. Pregnant Sprague-Dawley rats (i.e., trimester 1 and trimester 3) received 250 mg/kg vancomycin once daily for three days through intravenous injection via an internal jugular vein catheter. Vancomycin concentrations in maternal plasma and pup kidneys were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple compartment models were fitted and assessed using a nonparametric approach with Pmetrics. A total of 10 vancomycin-treated rats and 48 pups contributed PK data. A 3-compartment model adjusted for trimester fit the data well (maternal plasma Bayesian, observed versus predicted R2 = 0.978; pup kidney Bayesian, observed versus predicted R2 = 0.999). The mean rate constant for vancomycin mass transit to the pup kidney was 0.72 h-1 for trimester 1 dams and 0.75 h-1 for trimester 3 dams. Median vancomycin concentrations in pup kidneys from trimester 3 were significantly higher than those in trimester 1 (8.62 versus 0.36 µg/mL, P < 0.001). Vancomycin transited to the fetus from the mother and was; kidney accumulation differed by trimester. This model may be useful for a translational understanding of vancomycin distribution in pregnancy to ensure efficacious and safe doses to both mother and fetus.

The Use of Kratom (Mitragyna speciosa Korth.) Among People Who Co-use Heroin and Methamphetamine in Malaysia.

OBJECTIVES: Kratom (Mitragyna speciosa Korth.), an indigenous medicinal plant, has been widely used as a traditional remedy in Southeast Asia. However, its combined consumption with other substances has received scarce attention. This study investigates the use of kratom among adults with a history of using heroin and methamphetamine in Malaysia. METHODS: A total of 332 patients who were mandated to undergo drug rehabilitation participated in this cross-sectional study. The study data were collected through face-to-face interviews using a semi-structured questionnaire. RESULTS: The majority were males (95%, n = 314/332) and Malays (98%, n = 325/332) with a mean age of 32.3 years (SD = 9.16). Over two thirds of the respondents used kratom to alleviate heroin withdrawal symptoms and to reduce methamphetamine intake; 59% used it as a substitute for heroin and methamphetamine. A similar proportion used kratom to reduce heroin intake (58%), while only 15% used it for its euphoric effects. Multivariate analysis showed that previous attendees of government rehabilitation programs had lower odds of using kratom as a heroin substitute. CONCLUSIONS: The potential of kratom to alleviate heroin withdrawal symptoms, and to reduce methamphetamine and heroin intake, among people who co-use heroin and methamphetamine warrants further research.

Kratom Use Within the Context of the Evolving Opioid Crisis and the COVID-19 Pandemic in the United States.

Kratom (Mitragyna speciosa, Korth.) is an evergreen tree that is indigenous to Southeast Asia. When ingested, kratom leaves or decoctions from the leaves have been reported to produce complex stimulant and opioid-like effects. For generations, native populations in Southeast Asia have used kratom products to stave off fatigue, improve mood, alleviate pain and manage symptoms of opioid withdrawal. Despite the long history of kratom use in Asia, it is only within the past 10-20 years that kratom has emerged as an important herbal agent in the United States, where it is being used for the self-treatment of pain, opioid withdrawal symptoms, and mood disorders. The increase in the use of kratom in the United States has coincided with the serious epidemic of opioid abuse and dependence. Since 2015, efforts to restrict access to prescription opioids have resulted in a marked increase in the use of "street" opioids such as heroin and illicit fentanyl. At the same time, many patients with chronic pain conditions or opioid use disorder have been denied access to appropriate medical help. The lack of access to care for patients with chronic pain and opioid use disorder has been magnified by the emergence of the COVID-19 pandemic. In this report, we highlight how these converging factors have led to a surge in interest in kratom as a potential harm reduction agent in the treatment of pain and opioid use disorder.

Of Rats and Men: a Translational Model To Understand Vancomycin Pharmacokinetic/Toxicodynamic Relationships.

Vancomycin area under the concentration curve (AUC) is known to predict vancomycin-induced acute kidney injury (AKI). Data were analyzed from a rat model (n = 48) and two prospective clinical studies (PROVIDE [n = 263] and CAMERA2 [n = 291]). A logit-link model was used to calculate the multiplicative factors between the probability of AKI from clinical studies and in the rat. The rat was 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 and 794.3 mg·h/liter, respectively.

The Pharmacodynamic-Toxicodynamic Relationship of AUC and Cmax in Vancomycin-Induced Kidney Injury in an Animal Model.

Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received intravenous (i.v.) vancomycin doses of 300 mg/kg/day and 400 mg/kg/day, divided into once-, twice-, three-times-, or four-times-daily doses (i.e., QD, BID, TID, or QID) over 24 h. Up to 8 samples plus a terminal sample were drawn during the 24-h dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e., area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration from 0 to 24 h [Cmax0-24]) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed versus predicted concentrations; R2 = 0.96). KIM-1 values were greater in QD and BID groups (P for QD versus TID, <0.002; P for QD versus QID, <0.004; P for BID versus TID, <0.002; and P for BID versus QID, <0.004). Exposure-response relationships were observed between KIM-1 versus Cmax0-24 and AUC0-24 (R2 = 0.7 and 0.68). Corrected Akaike's information criterion showed Cmax0-24 as the most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (-5.28 versus -1.95). While PK-TD indices are often intercorrelated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.

Can Kratom (Mitragyna speciosa) Alleviate COVID-19 Pain? A Case Study.

Among the symptoms of COVID-19 fever, general malaise, pain and aches, myalgia, fatigue, and headache can affect the quality of life of patients, even after the end of the acute phase of the infection and can be long lasting. The current treatment of these symptoms, also because COVID-19 patients have been asked not to use non-steroidal anti-inflammatory drugs (NSAIDs), in particular ibuprofen are often unsatisfactory. Among the above mentioned symptoms malaise and fatigue seem the most difficult to treat. In this case report we describe the use of kratom (Mitragyna speciosa) by a patient with confirmed COVID-19 infection. What we observed was a fast and sustained relieve of the above mentioned symptoms.

Current and Future Potential Impact of COVID-19 on Kratom (Mitragyna speciosa Korth.) Supply and Use.

Kratom (Mitragyna speciosa Korth., Rubiaceae) is native to and has traditional use in Southeast Asia. The number of kratom users outside of Southeast Asia has increased significantly in recent decades with use spreading to the Unites States (US) and Europe. Because of its reputed opioid-like psychoactive effects at higher doses, kratom has been regulated in several countries and is subject to an import ban by the US Food and Drug Administration. Nonetheless, in the US it is estimated that 10-15 million people consume kratom primarily for the self-treatment of pain, psychiatric disorders, to mitigate withdrawal from or dependence on opioids, and to self-treat opioid use disorder or other substance use disorders (SUDs). Due to the global COVID-19 pandemic, a shortage in the supply of kratom products may place unexpected burdens on kratom users, potentially influencing some who use kratom for SUD self-treatment to regress to harmful drug use, hence increasing the likelihood of adverse outcomes, including overdose. Inadequate treatment, treatment barriers, and increases in the sales of adulterated kratom products on the internet or in convenience stores could exacerbate circumstances further. Although there are currently no verified indications of kratom scarcity, researchers and clinicians should be aware of and remain vigilant to this unanticipated possibility.

Evaluation of the Mitragynine Content, Levels of Toxic Metals and the Presence of Microbes in Kratom Products Purchased in the Western Suburbs of Chicago.

Kratom (Mitragyna speciosa, Korth) is a tree-like plant that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression and opioid use disorder. Recently, the United States Food and Drug Administration and Centers for Disease Control have raised concerns regarding the contamination of some kratom products with toxic metals (Pb and Ni) and microbes such as Salmonella. To further explore this issue, eight different kratom products were legally purchased from various "head"/"smoke" shops in the Western Suburbs of Chicago and then tested for microbial burden, a panel of metals (Ni, Pb, Cr, As, Hg, Cd), and levels of the main psychoactive alkaloid mitragynine. All of the samples contained significant, but variable, levels of mitragynine (3.9-62.1 mg/g), indicating that the products were, in fact, derived from kratom. All but two of the samples tested positive for the presence of various microbes including bacteria and fungi. However, none of the samples tested positive for Salmonella. Seven products showed significant levels of Ni (0.73-7.4 µg/g), Pb (0.16-1.6 µg/g) and Cr (0.21-5.7 µg/g) while the other product was negative for metals. These data indicate that many kratom products contain variable levels of mitragynine and can contain significant levels of toxic metals and microbes. These findings highlight the need for more stringent standards for the production and sale of kratom products.

Public Perceptions toward Kratom (Mitragyna Speciosa) Use in Malaysia.

Kratom (Mitragyna speciosa), an indigenous medicinal plant of Southeast Asia, is believed to be harmful. We compared the perceptions toward kratom use among kratom users and non-users in Malaysia. 356 respondents (137 kratom users and 219 non-users) were recruited for this cross-sectional study. The majority of respondents were male (60%, n = 212/356), Malays (88%), and 51% were ≥37 years old. Non-users showed higher unadjusted odds of reporting a perception that kratom use can cause addiction (OR = 6.72, CI: 3.91-11.54, p < .0001), withdrawal symptoms (OR = 7.58, CI: 4.62-12.42, p < .0001), illicit drug use problems (OR = 10.12, CI: 6.14-16.68, p < .0001), impaired social-functioning (OR = 12.05, CI: 7.24-20.05, p < .0001), and health problems (OR = 10.44, CI: 6.32-17.24, p < .0001). Similarly, non-users viewed kratom policies differently from kratom users, displaying increased odds of reporting the belief that kratom use and sales must be regulated with stringent laws (OR = 5.75, CI: 3.61-9.18, p < .0001), and kratom should be regulated instead under the Dangerous Drugs Act 1952 to overcome kratom use problems (OR = 8.26, CI: 4.94-13.82, p < .0001). Because of the disconnect in kratom use perceptions and personal experiences between kratom users and non-users, hastily criminalizing kratom without investigating carefully its scientific merits can significantly impede future kratom research.

Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model.

BACKGROUND: Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, only that serum creatinine increases. OBJECTIVES: To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies. METHODS: (i) Male Sprague-Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®. RESULTS: Urinary output increased from Day -1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P < 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P < 0.001, KIM-1; P < 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin. CONCLUSIONS: All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective.

A Method for the Evaluation of Site-Specific Nephrotoxic Injury in the Intact Rat Kidney.

In a previously published report we detailed an in situ method to quantify cell death in the renal cortex by perfusing the cell membrane impermeable fluorochrome, ethidium homodimer in situ. The objective of the present study was to use this in situ viability assay to examine cell death following the administration of nephrotoxic drugs known to produce cell death and/or injury in specific segments of the nephron. Male Sprague/Dawley rats were treated with the following nephrotoxicants: Gentamicin, amphotericin-B, and indomethacin. Results of the in situ viability assay indicated that gentamicin and amphotericin-B treatment caused cell death localized in the kidney cortex and medulla, respectively. The urinary biomarker kidney injury molecule-1 (Kim-1) showed significant increases in both gentamicin (20 fold increase) and amphotericin-B-treated (9.2 fold increase) animals. Urinary alpha glutathione-S-transferase (GST) showed significant increases for gentamicin (6.2 fold increase) only and mu GST for amphotericin-B-treated (19.1 fold increase) animals only. These results show that this in situ viability assay provides a sensitive method to identify cell death in different regions of the kidney. Furthermore, urinary alpha GST and mu GST are specific for proximal and distal tubule injury, respectively; urinary Kim-1 demonstrated greater sensitivity to both proximal and distal tubule injury.

Self-Report Data on Regular Consumption of Illicit Drugs and HIV Risk Behaviors after Kratom (Mitragyna Speciosa korth.) Initiation among Illicit Drug Users in Malaysia.

This study sought to determine the relationship between kratom (Mitragyna speciosa) initiation and regular consumption of illicit drugs and HIV risk behaviors in a cohort of illicit drug users in Malaysia. 260 illicit drug users with current kratom use were recruited through convenience sampling for this cross-sectional study. All were male, with the majority being Malays (95%, n = 246/260). Results suggest that kratom initiation was associated with significant decrease in the regular use of heroin (odds ratio (OR) = 0.50, 95% confidence interval (CI): 0.40- 0.72; p = .0001), methamphetamine (OR = 0.23, CI: 0.16- 0.35; p < .0001), and amphetamine (OR = 0.17, CI: 0.09- 0.34; p < .0001). Kratom initiation was also associated with reduction in regular HIV risk behaviors such as having sex with sex workers (OR = 0.20, CI: 0.12-0.32; p < .0001), using drugs before sexual intercourse (OR = 0.20, CI: 0.13- 0.31; p < .0001), injecting behaviors (OR = 0.10, CI: 0.04- 0.25; p < .0001), sharing of injection equipment (OR = 0.13, CI: 0.04- 0.43; p < .0001), and injecting with other injection drug users (IDUs) (OR = 0.07, CI: 0.02- 0.24; p < .0001).

Genistein diet improves body weight, serum glucose and triglyceride levels in both male and female ob/ob mice.

PURPOSE: Diabetic obesity in the leptin-deficient ob/ob mouse is associated with weight gain, and hyperglycemia, along with hyperinsulinemia. We have previously examined the effects of genistein (a naturally occurring isoflavone found in soy) on metabolic disturbances in the ob/ob mouse and demonstrated beneficial effects of genistein (600 mg genistein/kg diet, for 4-weeks) on T3 production and corticosterone status. The goal of this study was to examine whether dietary genistein could prevent, or at least lessen, the typical phenotype in this murine model of diabetic-obesity, and to assess potential sex-differences. PATIENTS AND METHODS: The ob/ob mice (male and female) aged 4-5 weeks were randomly assigned to one of two diets for a period of 4-weeks: standard rodent diet, or genistein-containing diet (600 mg genistein/kg diet). Comparisons were made to a lean control group. RESULTS: Genistein diet significantly reduced body weight by 12% in females and 9% in males. Genistein significantly lowered serum glucose levels by 18% in females and 43% in males, yet had no effect on serum insulin. Genistein diet significantly lowered serum triglyceride levels in both ob/ob male and female mice returning them to lean levels. In females only, genistein significantly reduced serum pancreatic polypeptide levels by 56% and increased serum GIP levels 2.3-fold. Genistein had sex-dependent effects on hepatic steatosis: in females, genistein further increased the % fat area and the fat droplet diameter 2.6-fold, along with additionally increasing hepatic TBARS. CONCLUSION: The results from this study indicate interesting beneficial effects of genistein diet for both male and female ob/ob mice.

Evaluation of Fetal and Maternal Vancomycin-Induced Kidney Injury during Pregnancy in a Rat Model.

Previous literature suggests that maternal vancomycin crosses the placental barrier to the fetus. Further, early animal studies indicated that kidney injury was not observed in the progeny. These studies were conducted prior to the availability of sensitive biomarkers for kidney injury. Therefore, a previous finding of no renal damage to the infant may be misleading. Vancomycin was administered intravenously to pregnant rats at a dose of 250 mg/kg of body weight/day (N = 6 per trimester) on three consecutive gestational days (GD) during trimesters 1, 2, and 3 (T1, T2, and T3, respectively) in three independent cohorts. The dams carried to term and delivered vaginally on GD 21. Kidneys were harvested from dams and pups and homogenized. Samples were prepared by protein precipitation and injected in a liquid chromatography tandem mass spectrometer, and vancomycin was quantified. The kidney tissue homogenate from dams and pups were analyzed for kidney injury molecule-1 (KIM-1). As trimesters progressed, the quantity of vancomycin increased linearly in the kidneys of both rat dams and pups (P < 0.0001 for T1 and T3, P < 0.0001 for T2 and T3, and P < 0.0001 for T3 and T3 control for both rat dams and pups). KIM-1 concentrations in pup kidneys were significantly higher when dams were administered vancomycin in trimesters 1 (P = 0.0001) and 2 (P = 0.0024) than in controls in trimester 3. Data demonstrate persistence of vancomycin in maternal and rat pup kidneys in all three trimesters of pregnancy with associated damage to the kidney, as indicated by expression of KIM-1.