Publications by authors named "Abhisheak Sharma"

54 Publications

Oral Pharmacokinetics in Beagle Dogs of the Mitragynine Metabolite, 7-Hydroxymitragynine.

Eur J Drug Metab Pharmacokinet 2021 May 13;46(3):459-463. Epub 2021 Apr 13.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Background And Objectives: 7-Hydroxymitragynine (7-HMG) is an oxidative metabolite of mitragynine, the most abundant alkaloid in the leaves of Mitragyna speciosa (otherwise known as kratom). While mitragynine is a weak partial µ-opioid receptor (MOR) agonist, 7-HMG is a potent and full MOR agonist. It is produced from mitragynine by cytochrome P450 (CYP) 3A, a drug-metabolizing CYP isoform predominate in the liver that is also highly expressed in the intestine. Given the opioidergic potency of 7-HMG, a single oral dose pharmacokinetic and safety study of 7-HMG was performed in beagle dogs.

Methods: Following a single oral dose (1 mg/kg) of 7-HMG, plasma samples were obtained from healthy female beagle dogs. Concentrations of 7-HMG were determined using ultra-performance liquid chromatography coupled with a tandem mass spectrometer (UPLC-MS/MS). Pharmacokinetic parameters were calculated using a model-independent non-compartmental analysis of plasma concentration-time data.

Results: Absorption of 7-HMG was rapid, with a peak plasma concentration (C, 56.4 ± 1.6 ng/ml) observed within 15 min post-dose. In contrast, 7-HMG elimination was slow, exhibiting a mono-exponential distribution and mean elimination half-life of 3.6 ± 0.5 h. Oral dosing of 1 mg/kg 7-HMG was well tolerated with no observed adverse events or significant changes to clinical laboratory tests.

Conclusions: These results provide the first pharmacokinetic and safety data for 7-HMG in the dog and therefore contribute to the understanding of the putative pharmacologic role of 7-HMG resulting from an oral delivery of mitragynine from kratom.
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http://dx.doi.org/10.1007/s13318-021-00684-2DOI Listing
May 2021

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Drug Metab Dispos 2021 Apr 2. Epub 2021 Apr 2.

Department of Pharmacodynamics, University of Florida, United States of America.

Sodium dichloroacetate (DCA) is an investigational drug that shows promise in the treatment of acquired and congenital mitochondrial diseases, including myocardial ischemia and failure. DCA activates the pyruvate dehydrogenase complex (PDC) to increase energy production and decrease circulating lactate concentrations. In a sheep model of chronic hypercortisolemia in pregnancy, PDK4 mRNA was increased and fetal bradycardia was evident at birth in the affected fetuses. The current study shows DCA crosses the placenta and can be measured in fetal blood, following its intravenous administration to pregnant ewes during late gestation and in labor. Sustained administration of DCA to the mother over 72h decreased the hepatic expression of the DCA-metabolizing enzyme GSTZ1 in the fetuses exposed to the drug, leading to higher fetal plasma DCA concentrations during continued dosing, and reduced plasma lactate levels. Multi-compartmental pharmacokinetics modeling indicated drug metabolism in the fetal and maternal compartments is best described by the autoinhibition of metabolism in both compartments. We provide the first evidence that DCA can cross the placental compartment to enter the fetal circulation, inhibit its own hepatic metabolism and decrease fetal plasma lactate concentrations. This study was the first to administer Sodium Dichloroacetate (DCA) to pregnant animals (sheep). It showed that DCA administered to the mother can cross the placental barrier and achieve concentrations in fetus to decrease the fetal lactate concentrations. Like other reported species, DCA mediated inhibition of GSTZ1 was also observed in ewes which resulted in the reduced metabolism of DCA after a prolonged administration.
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http://dx.doi.org/10.1124/dmd.120.000330DOI Listing
April 2021

Exploring the Chemistry of Alkaloids from Malaysian (Kratom) and the Role of Oxindoles on Human Opioid Receptors.

J Nat Prod 2021 Apr 26;84(4):1034-1043. Epub 2021 Feb 26.

Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.

Ten indole and oxindole alkaloids (-) were isolated from the freshly collected leaves of Malaysian (Kratom). The chemical structures of these compounds were established on the basis of extensive 1D and 2D NMR and HRMS data analysis. The spectroscopic data of mitragynine oxindole B () are reported herein for the first time. The spatial configuration of mitragynine oxindole B () was confirmed by single-crystal X-ray diffraction. Simultaneous quantification of the isolated alkaloids in the leaf specimens collected from different locations in the northern region of Peninsular Malaysia was also performed using UPLC-MS/MS. The oxindole alkaloids (-) and the indole alkaloid () were assessed for binding affinity at opioid receptors. Corynoxine () showed high binding affinity to μ-opioid receptors with a value of 16.4 nM. Further, corynoxine () was 1.8-fold more potent than morphine in rats subjected to a nociceptive hot plate assay. These findings have important implications for evaluating the combined effects of the minor oxindole alkaloids in the overall therapeutic activity of .
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http://dx.doi.org/10.1021/acs.jnatprod.0c01055DOI Listing
April 2021

Pharmacokinetics of Eleven Kratom Alkaloids Following an Oral Dose of Either Traditional or Commercial Kratom Products in Rats.

J Nat Prod 2021 Apr 23;84(4):1104-1112. Epub 2021 Feb 23.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.

Kratom, Korth., is being widely consumed in the United States for pain management and the reduction of opioid withdrawal symptoms. The central nervous system (CNS) active alkaloids of kratom, including mitragynine, 7-hydroxymitragynine, and numerous additional compounds, are believed to derive their effects through opioid receptor activity. There is no literature describing the systemic exposure of many of these alkaloids after the consumption of kratom. Therefore, we have developed and validated a bioanalytical method for the simultaneous quantitation of 11 kratom alkaloids (mitragynine, 7-hydroxymitragynine, corynantheidine, speciogynine, speciociliatine, paynantheine, corynoxine, corynoxine-B, mitraphylline, ajmalicine, and isospeciofoline) in rat plasma. The validated method was used to analyze oral pharmacokinetic study samples of lyophilized kratom tea (LKT) and a marketed product, OPMS liquid shot, in rats. Among the 11 alkaloids, only mitragynine, 7-hydroxymitragynine, speciociliatine, and corynantheidine showed systemic exposure 8 h postdose, and the dose-normalized systemic exposure of these four alkaloids was higher (1.6-2.4-fold) following the administration of the commercial OPMS liquid. Paynantheine and speciogynine levels were quantifiable up to 1 h postdose, whereas none of the other alkaloids were detected. In summary, the method was successfully applied to quantify the exposure of individual kratom alkaloids after an oral dose of traditional or commercial products. This information will contribute to understanding the role of each alkaloid in the overall pharmacology of kratom and elucidating the pharmacokinetic differences between traditional and commercial kratom products.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01163DOI Listing
April 2021

Exploring 1-adamantanamine as an alternative amine moiety for metabolically labile azepane ring in newly synthesized benzo[]thiazol-2(3)one σ receptor ligands.

Med Chem Res 2020 Sep 8;29(9):1697-1706. Epub 2020 Jul 8.

Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA.

In this work we report the structure-activity relationships, binding properties, and metabolic stability studies of a series of benzo[]thiazol-2(3)one as sigma receptors (σRs) ligands. Specifically, to improve the metabolic stability of the cyclic amine fragment of our lead compound (), the metabolically unstable azepane ring was replaced with a 1-adatamantamine moiety. Within the synthesized analogs, compound had low nanomolar affinity for the σR ( = 7.2 nM) and moderate preference (61-fold) over the σR. metabolic stability studies showed a slight improvement of the metabolic stability for -, even though an extensive metabolism in rat liver microsomes is being observed. Furthermore, metabolic soft spot identification of suggested that the -methyl group of the adamantyl moiety is a major site of metabolism.
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http://dx.doi.org/10.1007/s00044-020-02597-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880169PMC
September 2020

Regulatory sampling of industrial hemp plant samples (Cannabis sativa L.) using UPLC-MS/MS method for detection and quantification of twelve cannabinoids.

J Cannabis Res 2020 Dec 10;2(1):42. Epub 2020 Dec 10.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Background: In 2018, the Farm Bill mandated the United States Department of Agriculture to develop regulations governing the cultivation, processing, and marketing of industrial hemp. Industrial hemp is defined as Cannabis sativa L. with a total Δ-9-tetrahydrocannabinol (Δ-9-THC) content ≤0.3%. Therefore, for hemp to become an agricultural commodity, it is important to regulate production by developing standard methods for sampling and testing of the plant material.

Methods: An ultra-performance liquid chromatography-tandem mass spectrometry analytical method for the quantification of twelve cannabinoids was developed. The method was applied to a regulatory sampling trial of three hemp varieties cultivated for cannabidiol (CBD) production. Two samples were taken from 28 plants with one sample being flower only while the other was a composite sample that included flowers, leaves, and stems.

Results: The assay method was validated for specificity, range, repeatability, reproducibility, and recovery in accordance with all applicable standards for analytical methods. The results of the regulatory study indicated a significant decrease in the concentration of total Δ-9-THC and total CBD of 0.09% and 1.32%, respectively, between a flower only and a composite sample.

Conclusions: There are many factors that may influence reported total Δ-9-THC content in industrial hemp. A robust analytical method was developed to analyze hemp samples in a trial regulatory study. The results indicate that the way hemp is sampled and analyzed may influence the legality of a crop, which could have negative economic and legal consequences.
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http://dx.doi.org/10.1186/s42238-020-00050-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819288PMC
December 2020

Effects of Nutrient Fertility on Growth and Alkaloidal Content in (Kratom).

Front Plant Sci 2020 21;11:597696. Epub 2020 Dec 21.

Mid-Florida Research and Education Center, Department of Environmental Horticulture, Institute of Food and Agricultural Sciences, University of Florida, Apopka, FL, United States.

Leaves harvested from the Southeast Asian tree (kratom) have a history of use as a traditional ethnobotanical source of medicine to combat fatigue, improve work productivity, and to reduce opioid-related withdrawal symptoms. Kratom leaves contain an array of alkaloids thought to be responsible for the bioactivity reported by users. Interest in the consumptive effects of kratom has led to its recent popularity and use in North America, Western Europe, and Australia. Although the chemistry and pharmacology of select kratom alkaloids are understood, studies have not examined the influence of production environment on growth and alkaloidal content. To directly address this need, 68 kratom trees were vegetatively propagated from a single mother stock to reduce genetic variability and subjected to four varying fertilizer application rates. Leaves were analyzed for chlorophyll concentration, biomass, and alkaloidal content to understand the physiological response of the plant. While increasing rates of fertilizer promoted greater plant growth, relationships with alkaloidal content within leaves were highly variable. Fertility rate had little influence on the concentration of mitragynine, paynantheine, speciociliatine, mitraphylline, and corynoxine per leaf dry mass. 7-Hydroxymitragynine was below the lower limit of quantification in all the analyzed leaf samples. Low to medium rates of fertilizer, however, maximized concentrations of speciogynine, corynantheidine, and isocorynantheidine per leaf dry mass, suggesting a promotion of nitrogen allocation for secondary metabolism occurred for these select alkaloids. Strong correlations ( = 0.86) between extracted leaf chlorophyll and rapid, non-destructive chlorophyll evaluation (SPAD) response allowed for development of a reliable linear model that can be used to diagnose nutrient deficiencies and allow for timely adjustment of fertilization programs to more accurately manage kratom cultivation efforts. Results from this study provide a greater understanding of the concentration and synthesis of nine bioactive alkaloids in fresh kratom leaves and provide foundational information for kratom cultivation and production.
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http://dx.doi.org/10.3389/fpls.2020.597696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779599PMC
December 2020

Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy.

ACS Pharmacol Transl Sci 2020 Dec 31;3(6):1063-1068. Epub 2020 Jul 31.

Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, Florida 32610-7011, United States.

Kratom is widely consumed in the United States for self-treatment of pain and opioid withdrawal symptoms. Mitragynine is the most abundant alkaloid in kratom and is a μ-opioid receptor agonist. 7-Hydroxymitragynine (7-HMG) is a mitragynine metabolite that is a more potent and efficacious opioid than its parent mitragynine. 7-HMG contributes to mitragynine's antinociceptive effects in mice, but evidence suggests it may also have a higher abuse potential. This study demonstrates that 7-HMG is stable in rodent and monkey plasma but is unstable in human plasma. Surprisingly, in human plasma 7-HMG is converted to mitragynine pseudoindoxyl, an opioid that is even more potent than either mitragynine or 7-HMG. This novel metabolite is formed in human plasma to a much greater extent than in the preclinical species tested (mouse, rat, dog, and cynomolgus monkey) and due to its μ-opioid potency may substantially contribute to the pharmacology of kratom in humans to a greater extent than in other tested species.
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http://dx.doi.org/10.1021/acsptsci.0c00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737207PMC
December 2020

Preclinical pharmacokinetic study of speciociliatine, a kratom alkaloid, in rats using an UPLC-MS/MS method.

J Pharm Biomed Anal 2021 Feb 21;194:113778. Epub 2020 Nov 21.

Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA. Electronic address:

Speciociliatine is a minor indole alkaloid found in kratom, a southeast Asian medicinal plant, used for centuries to increase energy, enhance mood, and mitigate pain and opioid dependence. An ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated to quantify speciociliatine in rat plasma. The quantitation range was 3-600 ng/mL. The validated method was applied to a preclinical pharmacokinetic study in male Sprague-Dawley rats after 2.5 mg/kg intravenous (I.V.) and 20 mg/kg oral (P.O.) dosing. The plasma was analyzed to obtain concentration-time profiles and results were subjected to non-compartmental analysis to determine pharmacokinetic parameters including volume of distribution (6.2 ± 2.3 L/kg I.V.), clearance (0.7 ± 0.2 L/hr/kg), and absolute oral bioavailability (20.7 %). Speciociliatine had higher systemic exposure and lower clearance compared to the other kratom alkaloids mitragynine and corynantheidine. The speciociliatine pharmacokinetic parameters described here will help to better understand the overall effects reported with kratom product use.
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http://dx.doi.org/10.1016/j.jpba.2020.113778DOI Listing
February 2021

Assessing the therapeutic potential and toxicity of in opioid use disorder.

Expert Opin Drug Metab Toxicol 2021 Mar 11;17(3):255-257. Epub 2020 Dec 11.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

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http://dx.doi.org/10.1080/17425255.2021.1853706DOI Listing
March 2021

Lyophilized Kratom Tea as a Therapeutic Option for Opioid Dependence.

Drug Alcohol Depend 2020 11 22;216:108310. Epub 2020 Sep 22.

Department of Medicinal Chemistry, University of Florida, Gainesville, FL, United States. Electronic address:

Background: Made as a tea, the Thai traditional drug "kratom" reportedly possesses pharmacological actions that include both a coca-like stimulant effect and opium-like depressant effect. Kratom has been used as a substitute for opium in physically-dependent subjects. The objective of this study was to evaluate the antinociception, somatic and physical dependence produced by kratom tea, and then assess if the tea ameliorated withdrawal in opioid physically-dependent subjects.

Methods: Lyophilized kratom tea (LKT) was evaluated in C57BL/6J and opioid receptor knockout mice after oral administration. Antinociceptive activity was measured in the 55 °C warm-water tail-withdrawal assay. Potential locomotor impairment, respiratory depression and locomotor hyperlocomotion, and place preference induced by oral LKT were assessed in the rotarod, Comprehensive Lab Animal Monitoring System, and conditioned place preference assays, respectively. Naloxone-precipitated withdrawal was used to determine potential physical dependence in mice repeatedly treated with saline or escalating doses of morphine or LKT, and LKT amelioration of morphine withdrawal. Data were analyzed using one- and two-way ANOVA.

Results: Oral administration of LKT resulted in dose-dependent antinociception (≥1 g/kg, p.o.) absent in mice lacking the mu-opioid receptor (MOR) and reduced in mice lacking the kappa-opioid receptor. These doses of LKT did not alter coordinated locomotion or induce conditioned place preference, and only briefly reduced respiration. Repeated administration of LKT did not produce physical dependence, but significantly decreased naloxone-precipitated withdrawal in morphine dependent mice.

Conclusions: The present study confirms the MOR agonist activity and therapeutic effect of LKT for the treatment of pain and opioid physical dependence.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108310DOI Listing
November 2020

Bioanalytical method development and pharmacokinetics of MCI-92, a sigma-1 receptor ligand.

J Pharm Biomed Anal 2020 Nov 13;191:113610. Epub 2020 Sep 13.

Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA. Electronic address:

Sigma-1 receptors are found throughout the nervous system and play a role in regulating nociception. They are highly expressed in nerve injury, making them a potential target for the treatment of neuropathic pain. Although sigma-1 receptor antagonists have been shown to have anti-nociceptive and anti-allodynic effects, improved selectivity of these ligands is needed to further investigate their potential to treat neuropathic pain. MCI-92 is a novel, selective sigma-1 receptor ligand developed to address this need. A sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of MCI-92 in mouse plasma and brain homogenate. A structural analog of the analyte, MCI-147, was used as the internal standard (IS). The chromatographic separation was achieved on an Acquity UPLC BEH C column using a mobile phase consisting of water acidified with 0.1 % v/v formic acid and acetonitrile with gradient elution over 3.2 min. The method was linear over a concentration range of 1-200 ng/mL. Multiple reaction monitoring in the positive ionization mode was used for the mass spectrometric quantitation using m/z transitions 369.2 > 126.0 for MCI-92 and 448.9 > 350.1 for the IS. The method was successfully applied to the analysis of plasma and brain samples obtained in the course of oral and intravenous pharmacokinetic studies in CD-1 mice. MCI-92 showed a high volume of distribution (11.3 ± 0.6 L/kg) and rapid clearance (6.1 ± 0.8 L/h/kg) from systemic circulation. The concentration of the MCI-92 was higher in the brain than in plasma throughout all terminal time points, indicating high blood-to-brain partitioning and slow brain clearance.
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http://dx.doi.org/10.1016/j.jpba.2020.113610DOI Listing
November 2020

Evaluation of the rewarding effects of mitragynine and 7-hydroxymitragynine in an intracranial self-stimulation procedure in male and female rats.

Drug Alcohol Depend 2020 10 18;215:108235. Epub 2020 Aug 18.

Department of Psychiatry, University of Florida, Gainesville, FL, USA. Electronic address:

Background: Kratom (Mitragyna speciosa Korth.) has been used in Southeast Asia for hundreds of years to increase energy, for relaxation, and to diminish opioid withdrawal. Kratom use has recently spread to Western countries. Kratom could potentially be used for the treatment of opioid withdrawal and pain, but more insight is needed into its abuse potential. Therefore, we investigated the rewarding properties of the primary kratom alkaloid mitragynine and its active metabolite 7-hydroxymitragynine, and morphine as a reference drug in male and female rats. These compounds have agonist activity at mu-opioid receptors.

Methods: The compounds were tested in an intracranial self-stimulation (ICSS) procedure, which allows for the evaluation of the rewarding/aversive and sedative effects of drugs. Rewarding doses of drugs decrease the brain reward thresholds, and aversive drug doses have the opposite effect.

Results: Mitragynine, 7-hydroxymitragynine, and morphine affected the brain reward thresholds. A high dose of 7-hydroxymitragynine (3.2 mg/kg) increased the brain reward thresholds, whereas an intermediate dose of morphine (10 mg/kg) decreased the reward thresholds. 7-Hydroxymitragynine and morphine affected the response latencies. Five mg/kg of morphine increased response latencies. 7-Hydroxymitragynine tended to increase the response latencies, but the post hoc analyses did not reveal a significant effect. There were no sex differences in the effects of mitragynine, 7-hydroxymitragynine, and morphine on the reward thresholds and the response latencies.

Conclusions: These initial findings indicate that mitragynine and 7-hydroxymitragynine are not rewarding in the ICSS procedure. The present results suggest that these kratom alkaloids do not have abuse potential.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542979PMC
October 2020

Adolescent nicotine and tobacco smoke exposure enhances nicotine self-administration in female rats.

Neuropharmacology 2020 10 20;176:108243. Epub 2020 Jul 20.

Department of Psychiatry, University of Florida, Gainesville, FL, USA. Electronic address:

Most people start experimenting with tobacco products or e-cigarettes in early adolescence and become habitual smokers in late adolescence or adulthood. These studies investigated if exposure to tobacco smoke or nicotine during early and mid-adolescence affects nicotine intake in late adolescence and early adulthood. Male and female rats were exposed to tobacco smoke from low- and high-nicotine SPECTRUM cigarettes or nicotine (0.3 mg/kg, twice a day) from postnatal day (P) 24-42. The self-administration sessions started at P55. The rats self-administered nicotine for 14-15 days under a fixed-ratio 1 schedule, and on the first day, the maximum number of infusions was twenty. Exposure to smoke from high, but not low, nicotine cigarettes during adolescence increased nicotine self-administration in female but not male rats. Adolescent treatment with nicotine facilitated nicotine self-administration. On the first day of nicotine self-administration, nicotine-treated rats reached the maximum number of infusions before the saline-treated control rats. Nicotine intake was also higher in the nicotine-treated female rats than in the saline-treated females. There was no sex difference in nicotine intake in controls when the data from the studies were combined. Smoke exposure led to a dose-dependent increase in plasma nicotine and cotinine levels in adolescent rats. Exposure to smoke from high-nicotine cigarettes and 0.3 mg/kg of nicotine led to plasma nicotine and cotinine levels that are similar to those in tobacco users. These findings indicate that in females, but not males, exposure to nicotine during adolescence may facilitate smoking and e-cigarette use later in life.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660018PMC
October 2020

Pharmacokinetics and Safety of Mitragynine in Beagle Dogs.

Planta Med 2020 Nov 21;86(17):1278-1285. Epub 2020 Jul 21.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Mitragynine is the most abundant psychoactive alkaloid derived from the leaves of (kratom), a tropical plant indigenous to regions of Southeast Asia. Mitragynine displays a moderate affinity to opioid receptors, and kratom is often self-prescribed to treat pain and/or opioid addiction. The purpose of this study was to investigate the safety and pharmacokinetic properties of mitragynine in the dog. Single dose oral (5 mg/kg) and intravenous (0.1 mg/kg) pharmacokinetic studies of mitragynine were performed in female beagle dogs. The plasma concentrations of mitragynine were measured using ultra-performance liquid chromatography coupled with a tandem mass spectrometer, and the pharmacokinetic properties were analyzed using non-compartmental analysis. Following intravenous administration, mitragynine showed a large volume of distribution (V, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (C, 278.0 ± 47.4 ng/mL) concentrations were observed within 0.5 h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a C of 31.5 ± 3.3 ng/mL and a T of 1.7 ± 0.6 h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1 ng/mL) for the intravenous study. The absolute oral bioavailability of mitragynine was 69.6%. Administration of mitragynine was well tolerated, although mild sedation and anxiolytic effects were observed. These results provide the first detailed pharmacokinetic information for mitragynine in a non-rodent species (the dog) and therefore also provide significant information for allometric scaling and dose predictions when designing clinical studies.
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http://dx.doi.org/10.1055/a-1212-5475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907416PMC
November 2020

Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo.

AAPS J 2020 07 20;22(5):94. Epub 2020 Jul 20.

Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, 32610, USA.

The sigma-2 receptor has been cloned and identified as Tmem97, which is a transmembrane protein involved in intracellular Ca regulation and cholesterol homeostasis. Since its discovery, the sigma-2 receptor has been an extremely controversial target, and many efforts have been made to elucidate the functional role of this receptor during physiological and pathological conditions. Recently, this receptor has been proposed as a potential target to treat neuropathic pain due to the ability of sigma-2 receptor agonists to relieve mechanical hyperalgesia in mice model of chronic pain. In the present work, we developed a highly selective sigma-2 receptor ligand (sigma-1/sigma-2 selectivity ratio > 1000), 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H- benzo[d]imidazol-2(3H)-one (CM398), with an encouraging in vitro and in vivo pharmacological profile in rodents. In particular, radioligand binding studies demonstrated that CM398 had preferential affinity for sigma-2 receptor compared with sigma-1 receptor and at least four other neurotransmitter receptors sites, including the norepinephrine transporter. Following oral administration, CM398 showed rapid absorption and peak plasma concentration (Cmax) occurred within 10 min of dosing. Moreover, the compound showed adequate, absolute oral bioavailability of 29.0%. Finally, CM398 showed promising anti-inflammatory analgesic effects in the formalin model of inflammatory pain in mice. The results collected in this study provide more evidence that selective sigma-2 receptor ligands can be useful tools in the development of novel pain therapeutics and altogether, these data suggest that CM398 is a suitable lead candidate for further evaluation.
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http://dx.doi.org/10.1208/s12248-020-00472-xDOI Listing
July 2020

Bioanalytical method development and validation of corynantheidine, a kratom alkaloid, using UPLC-MS/MS, and its application to preclinical pharmacokinetic studies.

J Pharm Biomed Anal 2020 Feb 5;180:113019. Epub 2019 Dec 5.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA; Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, FL, 32610, USA.

Corynantheidine, a minor alkaloid found in Mitragyna speciosa (Korth.) Havil, has been shown to bind to opioid receptors and act as a functional opioid antagonist, but its unique contribution to the overall properties of kratom remains relatively unexplored. The first validated bioanalytical method for the quantification of corynantheidine in rat plasma is described. The method was linear in the dynamic range from 1-500 ng/mL, requires a small plasma sample volume (25 μL), and a simple protein precipitation method for extraction of the analyte. The separation was achieved with Waters BEH C18 2.1 × 50 mm column and the 3-minute gradient of 10 mM ammonium acetate buffer (pH = 3.5) and acetonitrile as mobile phase. The method was validated in terms of accuracy, precision, selectivity, sensitivity, recovery, stability, and dilution integrity. It was applied to the analysis of the male Sprague Dawley rat plasma samples obtained during pharmacokinetic studies of corynantheidine administered both intravenously (I.V.) and orally (P.O.) (2.5 mg/kg and 20 mg/kg, respectively). The non-compartmental analysis performed in Certara Phoenix® yielded the following parameters: clearance 884.1 ± 32.3 mL/h, apparent volume of distribution 8.0 ± 1.2 L, exposure up to the last measured time point 640.3 ± 24.0 h*ng/mL, and a mean residence time of 3.0 ± 0.2 h with I.V. dose. The maximum observed concentration after a P.O. dose of 213.4 ± 40.4 ng/mL was detected at 4.1 ± 1.3 h with a mean residence time of 8.8 ± 1.8 h. Absolute oral bioavailability was 49.9 ± 16.4 %. Corynantheidine demonstrated adequate oral bioavailability, prolonged absorption and exposure, and an extensive extravascular distribution. In addition, imaging mass spectrometry analysis of the brain tissue was performed to evaluate the distribution of the compound in the brain. Corynantheidine was detected in the corpus callosum and some regions of the hippocampus.
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http://dx.doi.org/10.1016/j.jpba.2019.113019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350276PMC
February 2020

Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids.

J Med Chem 2020 01 27;63(1):433-439. Epub 2019 Dec 27.

Department of Medicinal Chemistry , College of Pharmacy, University of Florida , Gainesville , Florida 32610 , United States.

Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding, and metabolic stability. Mitragynine, the major alkaloid in (kratom), had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676998PMC
January 2020

Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users.

J Ethnopharmacol 2020 Mar 7;249:112462. Epub 2019 Dec 7.

Centre for Drug Research, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia.

Ethnopharmacological Relevance: Kratom (Mitragyna speciosa) is a native medicinal plant of Southeast Asia widely reported to be used to reduce opioid dependence and mitigate withdrawal symptoms. There is also evidence to suggest that opioid poly-drug users were using kratom to abstain from opioids.

Aim Of The Study: To determine the patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia.

Materials And Methods: A total of 204 opioid poly-drug users (142 current users vs. 62 former users) with current kratom use history were enrolled into this cross-sectional study. A validated UPLC-MS/MS method was used to evaluate the alkaloid content of a kratom street sample.

Results: Results from Chi-square analysis showed that there were no significant differences in demographic characteristics between current and former opioid poly-drug users except with respect to marital status. Current users had higher odds of being single (OR: 2.2: 95%CI: 1.21-4.11; p < 0.009). Similarly, there were no significant differences in the duration (OR: 1.1: 0.62-2.03; p < 0.708), daily quantity (OR: 1.5: 0.85-2.82; p < 0.154) or frequency of kratom use between current and former opioid poly-drug users (OR: 1.1: 0.62-2.06; p < 0.680). While both current and former opioid users reported using kratom to ameliorate opioid withdrawal, current users had significantly higher likelihood of using kratom for that purpose (OR: 5.4: 95%CI: 2.81-10.18; p < 0.0001). In contrast, former opioid users were more likely to be using kratom for its euphoric (mood elevating) effects (OR: 1.9: 95%CI: 1.04-3.50; p < 0.035). Results from the UPLC-MS/MS analysis indicated the major alkaloids present in the representative kratom street sample (of approximately 300 mL of brewed kratom) were mitragynine, followed by paynantheine, speciociliatine and speciogynine, as well as low levels of 7-hydroxymitragynine.

Conclusions: Both current and former opioid poly-drug users regularly used kratom (three glasses or about 900 mL daily or the equivalent of 170.19 mg of mitragynine) to overcome opioid poly-drug use problems.
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http://dx.doi.org/10.1016/j.jep.2019.112462DOI Listing
March 2020

A selective BCL-X PROTAC degrader achieves safe and potent antitumor activity.

Nat Med 2019 12 2;25(12):1938-1947. Epub 2019 Dec 2.

Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA.

B-cell lymphoma extra large (BCL-X) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-X inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-X proteolysis-targeting chimera (PROTAC), that targets BCL-X to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-X-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-X.
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http://dx.doi.org/10.1038/s41591-019-0668-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785PMC
December 2019

Bioanalytical method development and validation of MES207, a neuropeptide FF receptor antagonist, and its application in preclinical pharmacokinetics.

J Chromatogr B Analyt Technol Biomed Life Sci 2019 Dec 12;1134-1135:121875. Epub 2019 Nov 12.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA; Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.

The nonpeptide small molecule, MES207, exhibits 17-fold preferential binding to the neuropeptide FF receptor 1 (NPFFR1) over NPFFR2 and shows antagonist functionality at NPFF receptors. In order to further the development of MES207 as a NPFFR1 probe, an UPLC-MS/MS bioanalytical method was developed and validated to quantify MES207 in rat plasma for a linearity range of 3-200 ng/mL. The method was applied in the analysis of the plasma, brain, and urine samples collected during pharmacokinetic studies in healthy male and female Sprague Dawley rats. The animals were dosed through oral gavage (50 mg/kg) and intravenously (2.5 mg/kg). Test samples were analyzed using the validated bioanalytical method to generate plasma concentration-time profiles. The results were further subjected to non-compartmental analysis using Phoenix 6.4®. MES207 exhibits a large volume of distribution (1.2 ± 0.6 L), high clearance (0.8 ± 0.1 L/h), and a poor oral bioavailability (1.7 ± 0.4%). The compound also showed a multiple peak phenomenon with a very short absorption phase. It appears that gender does not significantly influence the differences in pharmacokinetic parameters of this NPFF probe.
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http://dx.doi.org/10.1016/j.jchromb.2019.121875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027589PMC
December 2019

Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids.

Toxicol Lett 2020 Feb 7;319:148-154. Epub 2019 Nov 7.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA; Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA.

In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform-specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC) data were generated for each of these isoforms. In addition, the type of inhibition and estimation of the inhibition constants (K) of MTG and COR were determined. Among the tested alkaloids, MTG and COR were potent inhibitors of CYP2D6 (IC, 2.2 and 4.2 μM, respectively). Both MTG and COR exhibited competitive inhibition of CYP2D6 activity and the K were found to be 1.1 and 2.8 μM, respectively. SPG and PAY showed moderate inhibition of CYP2D6 activity. Additionally, moderate inhibitory effects by SPC, MTG, and SPG were observed on CYP2C19 activity. Interestingly, inhibition of only midazolam hydroxylase CYP3A4/5 activity by COR, PAY, and MTG was observed while no inhibitory effect was observed when testosterone was used as a probe substrate. In conclusion, MTG and COR may lead to clinically significant adverse drug interactions upon coadministration of drugs that are substantially metabolized by CYP2D6.
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http://dx.doi.org/10.1016/j.toxlet.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902086PMC
February 2020

Simultaneous quantification of ten key Kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometry.

Drug Test Anal 2019 Aug 15;11(8):1162-1171. Epub 2019 May 15.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Kratom (Mitragyna speciosa) is a psychoactive plant popular in the United States for the self-treatment of pain and opioid addiction. For standardization and quality control of raw and commercial kratom products, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of ten key alkaloids, namely: corynantheidine, corynoxine, corynoxine B, 7-hydroxymitragynine, isocorynantheidine, mitragynine, mitraphylline, paynantheine, speciociliatine, and speciogynine. Chromatographic separation of diastereomers, or alkaloids sharing same ion transitions, was achieved on an Acquity BEH C18 column with a gradient elution using a mobile phase containing acetonitrile and aqueous ammonium acetate buffer (10mM, pH 3.5). The developed method was linear over a concentration range of 1-200 ng/mL for each alkaloid. The total analysis time per sample was 22.5 minutes. The analytical method was validated for accuracy, precision, robustness, and stability. After successful validation, the method was applied for the quantification of kratom alkaloids in alkaloid-rich fractions, ethanolic extracts, lyophilized teas, and commercial products. Mitragynine (0.7%-38.7% w/w), paynantheine (0.3%-12.8% w/w), speciociliatine (0.4%-12.3% w/w), and speciogynine (0.1%-5.3% w/w) were the major alkaloids in the analyzed kratom products/extracts. Minor kratom alkaloids (corynantheidine, corynoxine, corynoxine B, 7-hydroxymitragynine, isocorynantheidine) were also quantified (0.01%-2.8% w/w) in the analyzed products; however mitraphylline was below the lower limit of quantification in all analyses.
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http://dx.doi.org/10.1002/dta.2604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927418PMC
August 2019

A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers.

Oncogene 2019 05 4;38(22):4264-4282. Epub 2019 Feb 4.

Department of Pharmacology, University of Florida, Gainesville, FL, 32610, USA.

While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.
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http://dx.doi.org/10.1038/s41388-019-0717-6DOI Listing
May 2019

Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of (kratom).

Xenobiotica 2019 Nov 7;49(11):1279-1288. Epub 2019 Jan 7.

a Department of Pharmaceutics, University of Florida , Gainesville , FL , USA.

1. Mitragynine is the major indole-based alkaloid of (kratom). Decoctions (teas) of the plant leaves have been used traditionally for cough, diarrhoea, pain, hypertension and for the treatment of opioid addiction. In the West, kratom has become increasingly utilized for mood elevation, pain treatment and as a means of self-treating opioid addiction. 2. Metabolic pathways of mitragynine were identified in human liver microsomes (HLM) and S9 fractions. A total of thirteen metabolites were identified, four oxidative metabolites and a metabolite formed by demethylation at the 9-methoxy group were the major metabolites of mitragynine. 3. The cytochrome P450 enzymes involved in the metabolism of mitragynine were identified using selective chemical inhibitors of HLM and recombinant cytochrome P450. The metabolism of mitragynine was predominantly carried out through the CYP3A4 with minor contributions by CYP2D6 and CYP2C9. The formation of five oxidative metabolites (Met2, Met4, Met6, Met8 and Met11) was catalyzed by the CYP3A4. 4. In summary, mitragynine was extensively metabolized in HLM primarily to -demethylated and mono-oxidative metabolites. The CYP3A4 enzyme plays a predominant role in the metabolic clearance of mitragynine and also in the formation of 7-hydroxymitragynine (Met2), a known active minor alkaloid identified in the leaf material.
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http://dx.doi.org/10.1080/00498254.2018.1552819DOI Listing
November 2019

Comparative Pharmacokinetics of Mitragynine after Oral Administration of Mitragyna speciosa (Kratom) Leaf Extracts in Rats.

Planta Med 2019 Mar 16;85(4):340-346. Epub 2018 Nov 16.

Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS, USA.

Kratom () has been examined for its opioid activity, especially for the treatment of opioid withdrawal and pain. Mitragynine, the most abundant alkaloid in kratom, is thought to be the major psychoactive alkaloid. An HPLC method was developed for the quantification of mitragynine in kratom leaf extracts. In addition, a multiple reaction mode based UPLC-MS/MS method was developed and validated for the quantification of mitragynine in rat plasma. Pharmacokinetic studies were performed by comparing a single intravenous dose of mitragynine (5 mg/kg, mitragynine hydrochloride) to a single oral dose of mitragynine (20 mg/kg, mitragynine hydrochloride), lyophilized kratom tea, and the organic fraction of the lyophilized kratom tea at an equivalent mitragynine dose of 20 mg/kg in rats. After intravenous administration, mitragynine exhibited a biexponential decrease in the concentration-time profile, indicating the fast distribution of mitragynine from the systemic circulation or central compartment to the peripheral compartments. Mitragynine hydrochloride, lyophilized kratom tea, and the lyophilized kratom tea organic fraction were dosed orally and the absolute oral bioavailability of mitragynine in rats was found to be 1.5- and 1.8-fold higher than that of mitragynine dosed alone. The results provide evidence that an equivalent oral dose of the traditional preparation (lyophilized kratom tea) and formulated/manufactured products (organic fraction) of kratom leaves provide better systemic exposure of mitragynine than that of mitragynine dosed alone.
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http://dx.doi.org/10.1055/a-0770-3683DOI Listing
March 2019

Improved chemotherapy against breast cancer through immunotherapeutic activity of fucoidan decorated electrostatically assembled nanoparticles bearing doxorubicin.

Int J Biol Macromol 2019 Feb 13;122:1100-1114. Epub 2018 Sep 13.

Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research, New Delhi 110025, India. Electronic address:

Immunotherapeutic nanoparticles (NPs) could be a viable option for delivering cytotoxic agents in a manner which suppresses their toxic manifestations. Doxorubicin (DOX) loaded NPs were prepared using fucoidan (FCD), an immunomodulatory polysaccharide and evaluated against cancer. FCD was electrostatically assembled with cationic polyethylenimine (PEI) through intermolecular electrostatic interactions to develop an immunomodulatory platform to deliver DOX. FCD NPs offered improved cytotoxicity (2.64 folds), cell cycle arrest in G1-S phase (34.65%) and apoptosis (66.12%) in tumor cells compared to free DOX. The enhanced apoptosis was due to raised mitochondrial depolarization (88.00%). In vivo anticancer activity in 4T1 induced tumor bearing BALB/c mice demonstrated a 2.95 folds enhanced efficacy of NPs. Importantly, NPs treatment generated an immunotherapeutic response indicated by gradual increment of the plasma IL-12 levels and reversed polarization of tumor associated macrophages (TAMs) towards M1 subtype. Furthermore, pharmacokinetic study suggested that NPs administration in tumor infested mice caused serum DOX levels to vary in a biphasic pattern, with twin peaks occurring at 1 h and 6 h which help in maintaining preferential drug localization in tumor. Developed NPs would be an excellent approach for improved immune-chemotherapy (in terms of efficacy, safety and immunocompetency) against cancer.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.09.059DOI Listing
February 2019

A stable isotope dilution tandem mass spectrometry method of major kavalactones and its applications.

PLoS One 2018 24;13(5):e0197940. Epub 2018 May 24.

Department of Medicinal Chemistry, University of Florida, Gainesville, Florida, United States of America.

Kava is regaining its popularity with detailed characterizations warranted. We developed an ultraperformance liquid chromatography high-resolution tandem mass spectrometry (UPLC-MS/MS) method for major kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin and desmethoxyyangonin) with excellent selectivity and specificity. The method has been validated for different matrices following the Food and Drug Administration guidance of analytical procedures and methods validation. The scope of this method has been demonstrated by quantifying these kavalactones in two kava products, characterizing their tissue distribution and pharmacokinetics in mice, and detecting their presence in human urines and plasmas upon kava intake. As expected, the abundances of these kavalactones differed significantly in kava products. All of them exhibited a large volume of distribution with extensive tissue affinity and adequate mean residence time (MRT) in mice. This method also successfully quantified these kavalactones in human body fluids upon kava consumption at the recommended human dose. This UPLC-MS/MS method therefore can be used to characterize kava products and its pharmacokinetics in animals and in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197940PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993114PMC
December 2018

Model based population PK-PD analysis of furosemide for BP lowering effect: A comparative study in primary and secondary hypertension.

Eur J Pharm Sci 2017 Nov 15;109:253-261. Epub 2017 Aug 15.

Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, Mathura Road, New Delhi 110025, India. Electronic address:

Though numerous reports have demonstrated multiple mechanisms by which furosemide can exert its anti-hypertensive response. However, lack of studies describing PK-PD relationship for furosemide featuring its anti-hypertensive property has limited its usage as a blood pressure (BP) lowering agent. Serum concentrations and mean arterial BP were monitored following 40 and 80mgkg multiple oral dose of furosemide in spontaneously hypertensive rats (SHR) and DOCA-salt induced hypertensive (DOCA-salt) rats. A simultaneous population PK-PD relationship using E model with effect compartment was developed to compare the anti-hypertensive efficacy of furosemide in these rat models. A two-compartment PK model with Weibull-type absorption and first-order elimination best described the serum concentration-time profile of furosemide. In the present study, post dose serum concentrations of furosemide were found to be lower than the EC. The EC predicted in DOCA-salt rats was found to be lower (4.5-fold), whereas the tolerance development was higher than that in SHR model. The PK-PD parameter estimates, particularly lower values of EC, K and Q in DOCA-salt rats as compared to SHR, pinpointed the higher BP lowering efficacy of furosemide in volume overload induced hypertensive conditions. Insignificantly altered serum creatinine and electrolyte levels indicated a favorable side effect profile of furosemide. In conclusion, the final PK-PD model described the data well and provides detailed insights into the use of furosemide as an anti-hypertensive agent.
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http://dx.doi.org/10.1016/j.ejps.2017.08.009DOI Listing
November 2017

Effect of arteether and pyrimethamine coadministration on the pharmacokinetic and pharmacodynamic profile of ormeloxifene.

Naunyn Schmiedebergs Arch Pharmacol 2017 Sep 8;390(9):971-976. Epub 2017 Jul 8.

Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.

The study was intended to investigate the effect of concomitant administration of antimalarial drug (pyrimethamine or arteether) on pharmacokinetic and post coitus contraceptive efficacy of ormeloxifene in female Sprague-Dawley rats. A serial sampling technique coupled with LC-MS/MS detection was utilized for quantification of ormeloxifene in plasma samples collected from female rats treated with ormeloxifene only and ormeloxifene with pyrimethamine or arteether. Coitus-proven female rats were utilized to investigate the effect of pyrimethamine or arteether coadministration on contraceptive efficacy of ormeloxifene by investigating the presence or absence of implantations and status of corpora lutea on day 10 post coitum. None of the sperm-positive rats treated with ormeloxifene with or without coadministration of pyrimethamine or arteether showed any sign of pregnancy, confirming that concomitant administration of antimalarial drugs (pyrimethamine or arteether) did not affect the pharmacodynamic profile of ormeloxifene. Although there was no sign of pharmacodynamic interaction, the volume of distribution of ormeloxifene increased significantly on cotreatment with pyrimethamine. However, coadministration of arteether did not affect any of the pharmacokinetic parameters of ormeloxifene. The compiled results of preliminary study in female rats support that pyrimethamine or arteether can be prescribed with ormeloxifene.
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http://dx.doi.org/10.1007/s00210-017-1401-4DOI Listing
September 2017