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.

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 < 0.05). The lung targeting is selective with no increase in uptake into the brain or the heart where the side-effects of theophylline are treatment-limiting. Selectively doubling the concentration of theophylline in the lungs could improve the benefit-risk ratio of this narrow therapeutic index medicine, which continues to be important in critical care.

The equimolar complexes of vancomycin, a broad-spectrum glycopeptides antibiotic with β- cyclodextrin were prepared to evaluate their suitability for the development of a prolongedrelease form of the antibiotic. Complex preparations were subjected to kneading and freezedrying techniques and characterized using X-ray powder diffractometry (XRD), Thermogravimetric analysis (TGA), Scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR). The uniformity obtained from all of the analyzed results, suggests the successive formation of the aforementioned binary systems. The in vitro dissolution profiles of vancomycin were determined accordingly in a simulated cerebrospinal fluid where the results showed a modified release with improved bioavailabity of vancomycin was achieved upon complexation with beta-cyclodextrin. Our results therefore demonstrated that the use of cyclodextrin could be advantageous not only for lipophilic drugs but also for hydrophilic drugs.