Pharmacokinetics and Safety Assessment ofl-Tetrahydropalmatine in Cocaine Users: A Randomized, Double-Blind, Placebo-Controlled Study

Abstract

Cocaine use disorder (CUD) remains a significant public health challenge. Levo-tetrahydropalmatine (L-THP), a well-tolerated and non-addictive compound, shows promise for the management of CUD. Its pharmacologic profile includes blockade at dopamine and other monoamine receptors and attenuation of cocaine self-administration, reinstatement, and rewarding properties in rats. This study evaluated the safety of L-THP in human cocaine users and its influence on the safety and pharmacokinetics (PK) of cocaine. Twenty-four cocaine-using adult men were randomized to receive L-THP (30 mg BID orally) or placebo double-blind for 4 days, with an intranasal cocaine (40 mg) challenge on the fourth day. Safety and tolerability were evaluated using vital signs, EKG, clinical laboratory tests, and standardized self-report instruments. Peripheral venous blood was collected periodically and later assayed for L-THP and cocaine using highly sensitive and specific ultra-performance liquid chromatography-fluorescence detection (UPLC-FLD) methods. Twenty subjects completed the study, of whom 19 provided complete PK data. The short 3.5-day course of L-THP was safe and well tolerated and did not affect cocaine’s PK or its acute cardiovascular effects. The cocaine AUC0→∞ was 211.5 and 261.4 h*ng/ml, and the Cmax was 83.3 and 104.5 ng/ml for the L-THP and placebo groups respectively. In addition there were no significant difference in the number of side effects reported in each group (L-THP group: 22 [48%], Placebo group: 24 [52%]), or vital signs including, heart rate, blood pressure, complete blood count or EKG. These findings suggest that oral THP has promise for further development as a treatment for CUD.

<i>O</i>-Methylbulbocapnine and Dicentrine Suppress LPS-Induced Inflammatory Response by Blocking NF-κB and AP-1 Activation through Inhibiting MAPKs and Akt Signaling in RAW264.7 Macrophages

“…11) According to previous phytochemical investigations, several natural alkaloids, including crebanine (CN), O-methylbulbocapnine (OMP), dicentrine (DC), tetrahydropalmatine (THP), and N-methyl tetrahydropalmatine (NTHP) have been found in the tubes of S. vernosa. [12][13][14] CN, OMP, and DC are aporphine alkaloids and they show the structural differences in the position of the dimethoxy group on the D-ring. Whereas, THP and NTHP are derivatives of protoberberine alkaloids and differ only the presence or absence of methyl group on the quaternary nitrogen atom in the position 7.…”

Quality Evaluation of Corydalis yanhusuo by High-Performance Liquid Chromatography Fingerprinting Coupled with Multicomponent Quantitative Analysis

“…The similarity values of 21 samples exceeded 0.9, i.e., similar components were present in these samples regardless of geographic location. However, low similarity values of <0.9 observed for samples 14,16,20, and 21 suggested that the compositions of these samples might be different from those of samples with high similarity values. Thus, crude herbs and prepared slices were concluded to be significantly different because of the production process and the variable contents of main bioactive constituents.…”

“…Samples 1-8 and 22-23 were unprocessed (crude drugs), 9-20 were boiled (cooked drugs), and sample 21 was sulfur-fumigated. For better comparison, we used samples originating from Zhejiang, excluding those produced outside of this province (samples [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. It seemed the fingerprints of crude drugs and cooked medicines were obviously different in areas A and C (see Supplementary Fig.…”

“…Among the chromatographic fingerprinting methods used for TCM authentication and qualitative evaluation over the past decade, high-performance liquid chromatography (HPLC) fingerprinting is most widely employed to discriminate the origins of medicinal herbs and conduct TCM quality control owing to its convenience and efficiency 9,10 .The dried tuber of Corydalis yanhusuo W. T. Wang (Corydalis Rhizoma, or Yuanhu in Chinese) is a well-known TCM that has been long used to promote blood circulation, reinforce vital energy, inhibit cancer cell proliferation, and alleviate pain 11 , and can also be applied to treat cardiovascular diseases 12 . Among the hundreds of isolated C. yanhusuo metabolites such as fatty acids, organic acids, amino acids, sugars, steroids, anthraquinones, and volatile compounds [13][14][15][16] , alkaloids are known to be the major pharmacologically active compounds for the treatment of blood vessel diseases, tumors, and various pains 17,18 . The main (~60) specifically active alkaloids,…”

Metabolite profiling of l‐isocorypalmine in rat urine, plasma, and feces after oral administration using high performance liquid chromatography coupled to Fourier transform ion cyclotron resonance mass spectrometry

“…L-isocorypalmine is also one of the active metabolites of L-tetrahydropalmatine with a mono demethylation at C-2 site [7]. Several animal studies have supported the therapeutic potential of L-tetrahydropalmatine to treat addiction, and phase І clinical trial has been conducted in healthy men and cocaine users [1,2,8,9].…”