Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Heliyon. 2024 Oct 5;10(19):e38856. doi: 10.1016/j.heliyon.2024.e38856. 
eCollection 2024 Oct 15.

Ultrasound-assisted extraction of scopolamine and hyoscyamine from Hyoscyamus 
niger roots using central compost design.

Ahmadpour R(1), Zanjani BM(1), Garoosi GA(2), Farjaminezhad R(2), Haddad R(2).

Author information:
(1)Department of Agronomy and Plant Breeding, Faculty of Agriculture, University 
of Zanjan, Zanjan, Iran.
(2)Department of Biotechnology, Faculty of Agriculture and Natural Resources, 
Imam Khomeini International University, Qazvin, Iran.

Hyoscyamus niger is an important medicinal plant used in medicine and contains 
tropane alkaloid compounds such as hyoscyamine and scopolamine. In this study, 
after the selection of the solvent for extracting hyoscyamine and scopolamine, 
the central composite design of the response surface methodology was used to 
study the effect of solvent concentrations (0, 25, 50, 75, and 100 %), 
temperatures (25, 30, 35, 40, and 45 °C) and ultrasonication times (10, 20, 30, 
40, and 50 min). The hyoscyamine and scopolamine content were obtained by 
HPLC-DAD. The results indicated that the predicted optimal condition for 
hyoscyamine and scopolamine extraction from H. niger root was as follows. 
Hyoscyamine: 100 % methanol, temperature 45 °C and ultrasonication time 10 min, 
obtained 172.06 μg/g dry weight; and scopolamine: 98.50 % methanol, temperature 
25 °C and ultrasonication time 10 min, provided 229.48 μg/g dry weight. To 
confirm the predicted extraction conditions, a separate experiment was 
conducted, and the results showed that the hyoscyamine and scopolamine contents 
were 164.72 and 209.23 μg/g dry weight, respectively.

© 2024 The Authors.

DOI: 10.1016/j.heliyon.2024.e38856
PMCID: PMC11493190
PMID: 39435070

Conflict of interest statement: The authors declare that they have no known 
competing financial interests or personal relationships that could have appeared 
to influence the work reported in this paper.


2. J Ocul Pharmacol Ther. 2024 Oct 4. doi: 10.1089/jop.2024.0113. Online ahead of
 print.

Clinical Pharmacokinetics of Atropine Administered Ocularly Using an 
Ultrasensitive Bioanalytical Assay.

Bouhajib M(1), Tayab Z(1), Di Marco C(1), Suh DD(1).

Author information:
(1)Pharma Medica Research Inc., Mississauga, Ontario, Canada.

Purpose: Previous pharmacokinetic studies conducted on atropine sulfate 
ophthalmical solution have utilized bioanalytical assays that lacked sufficient 
sensitivity to fully characterize the complete pharmacokinetic profile. To 
address these limitations, Pharma Medica Research Inc. has developed and 
validated an ultrasensitive bioanalytical method capable of accurately 
quantifying the active enantiomer, L-hyoscyamine, with a very low limit of 
quantitation of 0.500 pg/mL. The objective of this study was to evaluate the 
pharmacokinetics of L-hyoscyamine in healthy subjects using a highly sensitive 
bioanalytical assay. Methods: Ten subjects were administered 0.3 mg of Isopto 
Atropine solution into the conjunctival sac of the eye. Blood samples were taken 
as early as 2 min and up to 24 h following administration. The plasma samples 
were assayed for L-hyoscyamine using a chiral method with an analytical range of 
0.500-500 pg/mL. The pharmacokinetic parameters were estimated using both a 
noncompartmental and compartmental approach. Results: The pharmacokinetics of 
L-hyoscyamine were fully characterized as there were no samples that were below 
the limit of quantitation following dosing. Using noncompartmental analysis, the 
mean Cmax was 467.9 ± 159.4 pg/mL with a median (range) Tmax of 0.5 (0.08-1) h. 
The mean area under the concentration-time curve was 1668.96 ± 436.02 h·pg/mL 
and the mean half-life was 3.91 ± 1.16 h. Overall, the study drug was well 
tolerated and no serious adverse events were reported. Conclusion: Through the 
utilization of a proprietary ultrasensitive bioanalytical method, a 
comprehensive investigation into the pharmacokinetics of L-hyoscyamine has been 
successfully conducted. This advanced method offers significant potential for 
optimizing study designs and facilitating in-depth examinations of the 
pharmacokinetics of ocularly administered atropine formulations.

DOI: 10.1089/jop.2024.0113
PMID: 39365886


3. Sheng Wu Gong Cheng Xue Bao. 2024 Sep 25;40(9):2786-2796. doi: 
10.13345/j.cjb.240117.

[Research progress of the multifunctional oxidase scopolamine 6β-hydroxylase].

[Article in Chinese]

Chen X(1)(2), Wu Q(1)(2), Zhu D(1)(2).

Author information:
(1)Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 
Tianjin 300308, China.
(2)National Center of Technology Innovation for Synthetic Biology, Tianjin 
300308, China.

2-ketoglutarate (2-KG)/Fe2+-dependent dioxygenases can catalyze the highly 
specific regio- and stereoselective functionalization of C(sp3)-H bond of 
complex compounds under mild reaction conditions. Hyoscyamine 6β-hydroxylase 
(H6H), a member of these dioxygenases, catalyzes two consecutive oxidation 
reactions in the synthesis of scopolamine. The first reaction is the 
hydroxylation of hyoscyamine to 6β-hydroxyhyoscyamine and the second is 
epoxidation of 6β-hydroxyhyoscyamine. This paper introduces the catalytic 
mechanism, substrate scope, and application of H6H and evaluates the possibility 
of this enzyme as a biocatalyst for the functionalization of C(sp3)-H bond in 
complex compounds with different structural characteristics via hydroxylation or 
epoxidation, providing a theoretical basis for modification and application of 
this enzyme.

DOI: 10.13345/j.cjb.240117
PMID: 39319707 [Indexed for MEDLINE]


4. Eur J Contracept Reprod Health Care. 2024 Sep 16:1-6. doi: 
10.1080/13625187.2024.2398440. Online ahead of print.

Pain relief during intrauterine device placement in nulligravid women with both 
oral ketorolac and an analgesic: a double-blinded randomised trial.

Marcelino AC(1), da Cunha Pereira P(1), Charles CM(1), Espejo-Arce X(1), 
Bahamondes L(1).

Author information:
(1)Department of Obstetrics and Gynaecology, Faculty of Medical Sciences, 
University of Campinas, Campinas, SP, Brazil.

OBJECTIVE: We assessed whether the administration of oral ketorolac with an 
analgesic provides effective pain relief during placement of an intrauterine 
device (IUD) in nulligravid women.
METHODS: We conducted a double-blinded randomised trial in the Department of 
Obstetrics and Gynaecology, University of Campinas Faculty of Medical Sciences, 
Campinas, SP, Brazil. We randomised participants who voluntarily agreed to 
participate to receive either one pill containing ketorolac 20 mg together with 
one pill containing dipyrone 300 mg, scopolamine 6.5 µg, hyoscyamine 104 µg, and 
homatropine 1 mg or placebo 60 min before IUD placement. The participants and 
providers were blinded to the randomisation group. The primary outcome was pain 
assessment (measured on a 0-10 visual analogue scale) during IUD placement.
RESULTS: We enrolled participants and randomised them 1:1 between November 7, 
2023, and January 31, 2024. We analysed 60 women in each group. There were no 
differences between the groups in the pain score during tenaculum placement, 
uterine sounding, and IUD placement, and in the overall perception of pain. 
However, the pain score was significantly lower 10 min after the procedure in 
women who received the treatment compared with women who received the placebo.
CONCLUSION: Oral ketorolac associated with an analgesic administered 60 min 
before IUD placement was not significantly better than placebo during tenaculum 
placement, uterine sounding, and IUD insertion, and did not significantly reduce 
the overall pain perception. However, this treatment did significantly reduce 
pain 10 min after the procedure.
TRIAL REGISTRATION: The trial was registered at Registro Brasileiro de Ensaios 
Clínicos (REBEC; in English: The Brazilian Registry of Clinical Trials) under 
number RBR-7phn8yv on November 6, 2023. 
https://ensaiosclinicos.gov.br/rg/RBR-7phn8yv.

Plain Language Summary: Pain at IUD placement after one pill containing 
ketorolac 20 mg together with one analgesic pill given 60 min before placement 
were similar than placebo.

DOI: 10.1080/13625187.2024.2398440
PMID: 39279687


5. J Am Chem Soc. 2024 Sep 4;146(35):24271-24287. doi: 10.1021/jacs.4c04406. Epub
 2024 Aug 22.

Optimized Substrate Positioning Enables Switches in the C-H Cleavage Site and 
Reaction Outcome in the Hydroxylation-Epoxidation Sequence Catalyzed by 
Hyoscyamine 6β-Hydroxylase.

Wenger ES(1), Martinie RJ, Ushimaru R(2), Pollock CJ, Sil D, Li A, Hoang N, 
Palowitch GM, Graham BP, Schaperdoth I, Burke EJ, Maggiolo AO, Chang WC, Allen 
BD, Krebs C, Silakov A, Boal AK, Bollinger JM Jr.

Author information:
(1)Department of Chemistry, University of Pennsylvania, Philadelphia, 
Pennsylvania 19104, United States.
(2)Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 
113-8657, Japan.

Hyoscyamine 6β-hydroxylase (H6H) is an iron(II)- and 2-oxoglutarate-dependent 
(Fe/2OG) oxygenase that produces the prolifically administered antinausea drug, 
scopolamine. After its namesake hydroxylation reaction, H6H then couples the 
newly installed C6 oxygen to C7 to produce the drug's epoxide functionality. 
Oxoiron(IV) (ferryl) intermediates initiate both reactions by cleaving C-H 
bonds, but it remains unclear how the enzyme switches the target site and 
promotes (C6)O-C7 coupling in preference to C7 hydroxylation in the second step. 
In one possible epoxidation mechanism, the C6 oxygen would─analogously to 
mechanisms proposed for the Fe/2OG halogenases and, in our more recent study, 
N-acetylnorloline synthase (LolO)─coordinate as alkoxide to the C7-H-cleaving 
ferryl intermediate to enable alkoxyl coupling to the ensuing C7 radical. Here, 
we provide structural and kinetic evidence that H6H does not employ substrate 
coordination or repositioning for the epoxidation step but instead exploits the 
distinct spatial dependencies of competitive C-H cleavage (C6 vs C7) and 
C-O-coupling (oxygen rebound vs cyclization) steps to promote the two-step 
sequence. Structural comparisons of ferryl-mimicking vanadyl complexes of 
wild-type H6H and a variant that preferentially 7-hydroxylates instead of 
epoxidizing 6β-hydroxyhyoscyamine suggest that a modest (∼10°) shift in the 
Fe-O-H(C7) approach angle is sufficient to change the outcome. The 
7-hydroxylation:epoxidation partition ratios of both proteins increase more than 
5-fold in 2H2O, reflecting an epoxidation-specific requirement for cleavage of 
the alcohol O-H bond, which, unlike in the LolO oxacyclization, is not 
accomplished by iron coordination in advance of C-H cleavage.

DOI: 10.1021/jacs.4c04406
PMCID: PMC11374477
PMID: 39172701 [Indexed for MEDLINE]