Acid-sensitive liposome has drawn much interest as drug and gene carriers that release payloads specifically at the low-pH target sites, such as in solid tumors, tissues with inflammation, and ischemia sites. Also, it helps drug/gene to escape endosome trapping and followed lysosome degradation. The goal of this thesis research is to develop novel trans-2-aminocyclohexanols based lipids and their liposome that can be switched by mildly acidic pH. NMR study · show that in certain acidic medium, the amine group on cyclohexane will attract proton and form hydrogen bond with the neighboring -OH. This change will force the bonds switch to from equatorial conformation to axial conformation. This conformational change is transmitted by the structure of the molecular, and induces consequently dramatic conformational change of the two long lipid tails. Fluorescence leakage assay was conducted on liposomes that encapsulated with ANTs/DPX fluorescence dyes. For certain special designed cyclohexane compounds, the pH triggered lipid conformation change will rupture liposome membrane, release the encapsulated content, and thus help them escape lysosome degradation. This would in tum improve the efficiency of liposome drug delivery and gene transfection. Luciferase gene transfection was conducted on B16F10 cultured cells. The lipoplex comprising trans-2-aminocyclohexanollipid 1 significantly enhanced the Luciferase gene expression. The gene transfection efficiency correlated well with the pH-triggered membrane-rupture in the trans-aminocyclohexanol-based lipoplexes.

Thesis (M. Pharm. (Pharmacology)) -- University of Limpopo, 2021 / Introduction: Zebediela Hospital in Limpopo Province is running an outreach programme as part of its chronic care initiative. In the programme, pharmacy personnel visit the feeder clinics attached to the hospital to dispense chronic medicines to patients. This study aimed at evaluating how this pharmacy chronic care outreach programme is performing, by looking at pharmacy personnel, nursing personnel and patients’ perceptions. Method: A cross-sectional descriptive study was conducted at the six feeder clinics attached to Zebediela Hospital in the Lepelle-Nkumpi municipality of the Capricorn district in Limpopo Province using a quantitative research method. This quantitative research was administered in the form of a survey. Questionnaires were used to collect data from patients, nursing personnel and pharmacy personnel. A total of 399 participants (n=399) took part in the study. The participants included 337 patients from six different clinics, 18 pharmacy personnel and 44 nursing personnel. Data was analysed using the SPSS version 25.0. Results: The pharmacy personnel showed that an allocation of more than three personnel per duty roster sufficed. Regarding transport used by pharmacy personnel when embarking on the Pharmacy Chronic Care Outreach Programme, 71.4% of pharmacy personnel indicated that they always used hospital transport in 83.3% of the cases. The study findings showed that, 71% of patients agreed they were satisfied with the pharmacy times for collecting medicines apart from the fact that 65.6% of patients travelled for more than two hours from their respective homes to their nearest clinic. Sixty eight percent of pharmacy personnel perceived the PCCOP model to be reducing patient waiting time at the clinics. Both the patients and nursing personnel were however not satisfied with the pharmacy personnel’s arrival time at the clinic. The other negative aspect reported was the space problem at the clinics where, 77.8% of pharmacy personnel and 54.5% of nursing personnel reported this as not user-friendly. The patients’ satisfaction levels regarding the PCCOP model for “very satisfied” stood at 64.2% and 0.6% for “very dissatisfied”. Both pharmacy and nursing personnel recommended that the PCCOP model be continued with recommendations towards improving human resources and infrastructure. Conclusion: In conclusion, both pharmacy personnel and nursing personnel showed that the outreach programme was a good initiative in the health system and it benefitted patients. However, the concerns mentioned by patients included long waiting times at the clinic and medicine stock outs. As the results show, the pharmacy chronic care outreach programme should be continued, as long as patients’ complaints can be attended to. Key words: Evaluation, Pharmacy Chronic care Outreach Programme, Zebediela

Development of liposome formulation of an amphiphilic anticancer peptide using the ANTS/DPX leakage assay. The effects of lipid composition on the liposomes' resistance to an amphiphilic cyclic peptide c[KS.S.S.KWL W] were studied by the ANTS/DPX leakage assay. One or more unsaturated acyl chains in the phospholipids, small phospholipid headgroup size, the presence of cholesterol, and the presence of PEG-lipid were demonstrated as critical parameters to stabilize the liposome membrane. A liposome formulation of the peptide comprising POPE/POPC/cholesterol/C16 mPEG 2000 ceramide (20.8:31.2:40:8, mol%) was thereby developed with a peptide-encapsulation efficiency of 47.8%. The liposomal cyclic peptide exhibited dose-dependent toxicity to MCF7 human breast cancer cells and stability under incubation. Design, construction and in vitro characterization of a hydrazone-based convertible liposomal system for anticancer drug delivery. A novel PEG-lipid, PEG2ooo-Hz-DHG, with an acid-labile hydrazone linker between the PEG2ooo head group and the lipidic DHG moiety was synthesized. PEG2000-Hz-DHG was relatively stable at normal physiological pH 7.4, but hydrolyzed more quickly at tumor interstitium pH 6.5-7.0 and endosomal/lysosomal pH 5.0. A novel pH-sensitive "Convertible Liposome System" (CLS) was constructed comprising PEG2ooo-Hz-DHG, positively charged lipid DOTAP, and the zwitterionic phospholipid POPC (8:15:77, mol%). CLS converted from neutrally charged "stealth" liposome to positively charged liposome at tumor interstitual pH owing to the hydrolysis ofPEG2ooo-Hz-DHG. The doxorubicin-encapsulated CLS that had been pre-incubated at pH 6.5 for 30 h exhibited more intensive binding and higher toxicity to Bl6-Fl0 murine melanoma and MDA-MB-435S human breast cancer cells than doxorubicin encapsulated in pH-insensitive stealth liposome.

Indiana University-Purdue University Indianapolis (IUPUI) / Drug-drug interactions (DDIs) refer to situations where one drug affects the pharmacokinetics or pharmacodynamics of another. DDIs represent a major cause of morbidity and mortality. A common adverse drug reaction (ADR) that can result from, or be exacerbated by DDIs is drug-induced myopathy. Identifying DDIs and understanding their underlying mechanisms is key to the prevention of undesirable effects of DDIs and to efforts to optimize therapeutic outcomes. This dissertation is dedicated to identification of clinically important myopathic DDIs and to elucidation of their underlying mechanisms. Using data mined from the published cytochrome P450 (CYP) drug interaction literature, 13,197 drug pairs were predicted to potentially interact by pairing a substrate and an inhibitor of a major CYP isoform in humans. Prescribing data for these drug pairs and their associations with myopathy were then examined in a large electronic medical record database. The analyses identified fifteen drug pairs as DDIs significantly associated with an increased risk of myopathy. These significant myopathic DDIs involved clinically important drugs including alprazolam, chloroquine, duloxetine, hydroxychloroquine, loratadine, omeprazole, promethazine, quetiapine, risperidone, ropinirole, trazodone and simvastatin. Data from in vitro experiments indicated that the interaction between quetiapine and chloroquine (risk ratio, RR, 2.17, p-value 5.29E-05) may result from the inhibitory effects of quetiapine on chloroquine metabolism by cytochrome P450s (CYPs). The in vitro data also suggested that the interaction between simvastatin and loratadine (RR 1.6, p-value 4.75E-07) may result from synergistic toxicity of simvastatin and desloratadine, the major metabolite of loratadine, to muscle cells, and from the inhibitory effect of simvastatin acid, the active metabolite of simvastatin, on the hepatic uptake of desloratadine via OATP1B1/1B3. Our data not only identified unknown myopathic DDIs of clinical consequence, but also shed light on their underlying pharmacokinetic and pharmacodynamic mechanisms. More importantly, our approach exemplified a new strategy for identification and investigation of DDIs, one that combined literature mining using bioinformatic algorithms, ADR detection using a pharmacoepidemiologic design, and mechanistic studies employing in vitro experimental models.