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Pentylenetetrazol-like stimulus is not produced following naloxone-precipitated mitragynine withdrawal in rats

Johari IS, Harun N, Sofian ZM, Shoaib M

Psychopharmacology (Berl), 2021 Nov;238(11):3183-3191.
PMID: 34333672 DOI: 10.1007/s00213-021-05934-4

RATIONALE: Kratom (Mitragyna speciosa Korth), a native medicinal plant of Southeast Asia, is proposed to exhibit potential therapeutic value as an opioid substitute. However, studies of its negative emotional states resulting from withdrawal particularly of its main psychoactive compound, mitragynine (MG), are limited.
OBJECTIVES: Using the pentylenetetrazol (PTZ) discrimination assay, this study aims to investigate the effects of MG in responding to the PTZ stimulus and to assess the generalisation effects of withdrawal from MG to the PTZ stimulus.
METHODS: Rats (n = 20) were trained on a tandem (FR-10, VI-15) schedule of food reinforcement to press one lever after administration of the anxiogenic compound PTZ (16 mg/kg, i.p.) and an alternate lever after vehicle. Following acute tests, training was suspended, and rats were chronically treated with MG or morphine at 8-h intervals for 9 days and withdrawal was precipitated on the tenth day using naloxone (1 mg/kg, i.p.). The rats were tested for generalisation to PTZ at 2, 8 and 24 h after the last dose of MG or morphine administration.
RESULTS: Unlike morphine that produced dose-related PTZ-like stimulus, MG at 3, 10, 30 and 45 mg/kg doses showed no substitution to the PTZ discriminative stimulus. In contrast to morphine which produced a time-dependent generalisation to the PTZ stimulus, naloxone did not precipitate withdrawal effects in MG-treated rats as they selected the vehicle lever at three withdrawal time points.
CONCLUSION: These results demonstrate that MG produces a very different response to morphine withdrawal that is not associated with anxiogenic-like subjective symptoms. These characteristics of MG may provide further support for use as a novel pharmacotherapeutic intervention for managing opioid use disorder.
Cytotoxicity evaluation of vancomycin and its complex with beta-cyclodextrin on human glial cell line

Sofian ZM, Abdullah JM, Rahim AA, Shafee SS, Mustafa Z, Razak SA

Pak J Pharm Sci, 2012 Oct;25(4):831-7.
PMID: 23010001

The possible cytotoxic effects of vancomycin and its complex with beta-cyclodextrin (β-CD) on human glial cell line (CRL 8621) were studied accordingly by means of MTS assay. The cultured cells were incubated with various concentrations of vancomycin, β-CD as well as β-CD/vancomycin complex ranging from 4.69 to 300 ug/ml. A linear dose-dependency cytotoxicity followed by hermetic-like biphasic dose-dependence was observed after incubation period of 72 hours. In general, significant increase (p<0.001) of cell proliferation was observed at lower concentrations: <18.75 μg/ml for cells treated with β-CD and their complex while < 9.38 μg/ml for cells treated with vancomycin. In contrary, regardless of the treatments given, significant (p<0.001) reduce in cell survival was found at higher concentrations >150 μg/ml. In particular, 50 % inhibitory in vitro was achieved at the concentrations of 115.95 μg/ml (for β-CD), 116.48 μg/ml (for vancomycin) and 115.44 μg/ml (for β-CD/vancomycin complex).
Self-assembled chitosan-insulin oral nanoparticles - A critical perspective review

Chellathurai MS, Yong CL, Sofian ZM, Sahudin S, Hasim NBM, Mahmood S

Int J Biol Macromol, 2023 Jul 15;243:125125.
PMID: 37263321 DOI: 10.1016/j.ijbiomac.2023.125125

Chitosan is an abundant natural cationic polysaccharide with excellent biodegradability, bioadhesion, and biocompatibility. Chitosan is extensively researched for various particulate oral insulin drug delivery systems. Oral insulin is economically efficient and more convenient than injections, with greater patient compliance. Electrostatic ionic interaction between cationic chitosan and anionic polymer or insulin leads to the formation of spontaneously self-assembled nanoparticles. This simple technique attracted many researchers as it can be carried out quickly in mild conditions without harmful solvents, such as surfactants or chemical cross-linkers that might degrade the insulin structure. The formulated chitosan nanoparticles help to protect the core insulin from enzymatic degradation in the digestive system and improve paracellular intestinal uptake from the enterocytes due to mucoadhesion and reversible tight junction opening. Moreover, functionalized chitosan nanoparticles create newer avenues for targeted and prolonged delivery. This review focuses on modified chitosan-insulin nanoparticles and their implications on oral insulin delivery. Dependent variables and their optimal concentration ranges used in self-assembly techniques for chitosan-insulin nanoparticular synthesis are summarized. This review provides a comprehensive guide to fine-tune the essential factors to formulate stable insulin-chitosan nanoparticles using mild ionic interactions.
Pharmaceutical chitosan hydrogels: A review on its design and applications

Chellathurai MS, Chung LY, Hilles AR, Sofian ZM, Singha S, Ghosal K, et al.

Int J Biol Macromol, 2024 Nov;280(Pt 2):135775.
PMID: 39307491 DOI: 10.1016/j.ijbiomac.2024.135775

Chitosan (CS) has become a focal point of extensive research in the pharmaceutical industry due to its remarkable biodegradability, biocompatibility and sustainability. Chitosan hydrogels (CS HGs) are characterized by their viscoelasticity, flexibility and softness. The polar surfaces exhibit properties that mitigate interfacial tension between the hydrogel and body fluids. The inherent compatibility of CS HGs with body tissues and fluids positions them as outstanding polymers for delivering therapeutic proteins, peptides, DNA, siRNA, and vaccines. Designed to release drugs through mechanisms such as swelling-based diffusion, bioerosion, and responsiveness to stimuli, CS HGs offer a versatile platform for drug delivery. CS HGs play pivotal roles in serving purposes such as prolonging the duration of preprogrammed drug delivery, enabling stimuli-responsive smart delivery to target sites, protecting encapsulated drugs within the mesh network from adverse environments, and facilitating mucoadhesion and penetration through cell membranes. This review comprehensively outlines various novel preparation methods of CS HGs, delving into the parameters influencing drug delivery system design, providing a rationale for CS HG utilization in drug delivery, and presenting diverse applications across the pharmaceutical landscape. In synthesizing these facets, the review seeks to contribute to a nuanced understanding of the multifaceted role that CS HGs play in advancing drug delivery methodologies.
Evaluation of the Cytotoxicity of Levodopa and its Complex with Hydroxypropyl-ß-Cyclodextrin (HP-ß-CD) to an Astrocyte Cell Line

Sofian ZM, Shafee SS, Abdullah JM, Osman H, Razak SA

Malays J Med Sci, 2014 Dec;21(Spec Issue):6-11.
PMID: 25941458

A simple, reliable a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium, (MTS) assay was conducted to evaluate the potential cytotoxic effects of levodopa, a "gold standard therapy" for Parkinsonism, and its complex with Hydroxypropyl-β-Cyclodextrin (HP-β-CD) on an astrocyte cell line. The cells were incubated in a range of concentrations from 4.69 to 300 μg/mL levodopa, HP-β-CD or the complex for up to 72 hours. At every 24-hour interval, the optical density (OD), which reflects the number of viable cells, was recorded. In general, linear dose-dependent cytotoxicity profiles were observed for the cells subjected to levodopa or the complex, whereas a slightly triphasic response was observed for the cells exposed to HP-β-CD. A significant difference (P < 0.05) in cytotoxicity was detected between the HP-β-CD-treated group and the levodopa-treated group. In particular, we observed that the cells treated with the complex, even at the highest concentrations (> 200 μg/mL), exhibited improved tolerability in a time-dependent manner, which may indicate the potential ability of HP-β-CD to mask the toxic effects of levodopa via complexation.
Fulltext A Cyclodextrin-Stabilized Spermine-Tagged Drug Triplex that Targets Theophylline to the Lungs Selectively in Respiratory Emergency

Sofian ZM, Benaouda F, Wang JT, Lu Y, Barlow DJ, Royall PG, et al.

Adv Ther (Weinh), 2020 Dec;3(12):2000153.
PMID: 33043128 DOI: 10.1002/adtp.202000153

Ion-pairing a lifesaving drug such as theophylline with a targeting moiety could have a significant impact on medical emergencies such as status asthmaticus or COVID-19 induced pneumomediastinum. However, to achieve rapid drug targeting in vivo the ion-pair must be protected against breakdown before the entry into the target tissue. This study aims to investigate if inserting theophylline, when ion-paired to the polyamine transporter substrate spermine, into a cyclodextrin (CD), to form a triplex, could direct the bronchodilator to the lungs selectively after intravenous administration. NMR demonstrates that upon the formation of the triplex spermine protruded from the CD cavity and this results in energy-dependent uptake in A549 cells (1.8-fold enhancement), which persists for more than 20 min. In vivo, the triplex produces a 2.4-fold and 2.2-fold increase in theophylline in the lungs 20 min after injection in rats and mice, respectively (p