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Anti-cancer drugs gain access to solid tumors via the blood, and must penetrate tissue to reach all viable cancer cells. This thesis aims to compare the distribution of anticancer drugs in normal tissues and tumours, to examine whether drug distribution is modifiable and quantifiable in solid tumours, and to determine whether extracellular drug distribution can be improved by modifying intracellular drug distribution. The time-dependent spatial distribution of three anticancer drugs, doxorubicin, mitoxantrone and topotecan, were studied in normal tissues and tumours. Ten minutes after drug administration, there was fairly uniform distribution in the heart, kidney and liver whereas drug distribution within tumours was limited to perivascular regions. Doxorubicin distribution in P-glycoprotein (PgP) over-expressing tumours was compared to that in wild-type tumours and changes in distribution were evaluated with the use of PgP inhibitors. There was better doxorubicin distribution in PgP-over-expressing tumours compared to wild-type tumours, and pretreatment of PgP-over-expressing tumours with PgP inhibitors decreased doxorubicin distribution. These data suggest that reduced uptake of drug into cells may enhance extracellular drug distribution, and the dual effects of PgP inhibitors (increased drug uptake in proximal cells, but poorer drug distribution) may explain, in part, why these agents have not provided clinical benefit. The effect of the proton pump inhibitor pantoprozole on intracellular and extracellular drug distribution was determined. Pantoprazole increased endosomal pH in cells, leading to less sequestration of doxorubicin within them, and increased the toxicity of doxorubicin for cultured cells. In wild-type MCF7 tumours, pretreatment with pantoprazole enhanced doxorubicin distribution and tumour growth delay without apparent increase in toxicity. These studies have led to initiation of a phase I clinical trial of pantoprazole and doxorubicin for patients with solid tumours. The work completed in this thesis demonstrates that drug distribution can be modified and that these changes can be quantified, and may correlate with improved anti-tumour effects. Improving drug distribution through the use of proton pump inhibitors may be an effective strategy to improve chemotherapeutic efficacy.

Anti-cancer drugs gain access to solid tumors via the blood, and must penetrate tissue to reach all viable cancer cells. This thesis aims to compare the distribution of anticancer drugs in normal tissues and tumours, to examine whether drug distribution is modifiable and quantifiable in solid tumours, and to determine whether extracellular drug distribution can be improved by modifying intracellular drug distribution. The time-dependent spatial distribution of three anticancer drugs, doxorubicin, mitoxantrone and topotecan, were studied in normal tissues and tumours. Ten minutes after drug administration, there was fairly uniform distribution in the heart, kidney and liver whereas drug distribution within tumours was limited to perivascular regions. Doxorubicin distribution in P-glycoprotein (PgP) over-expressing tumours was compared to that in wild-type tumours and changes in distribution were evaluated with the use of PgP inhibitors. There was better doxorubicin distribution in PgP-over-expressing tumours compared to wild-type tumours, and pretreatment of PgP-over-expressing tumours with PgP inhibitors decreased doxorubicin distribution. These data suggest that reduced uptake of drug into cells may enhance extracellular drug distribution, and the dual effects of PgP inhibitors (increased drug uptake in proximal cells, but poorer drug distribution) may explain, in part, why these agents have not provided clinical benefit. The effect of the proton pump inhibitor pantoprozole on intracellular and extracellular drug distribution was determined. Pantoprazole increased endosomal pH in cells, leading to less sequestration of doxorubicin within them, and increased the toxicity of doxorubicin for cultured cells. In wild-type MCF7 tumours, pretreatment with pantoprazole enhanced doxorubicin distribution and tumour growth delay without apparent increase in toxicity. These studies have led to initiation of a phase I clinical trial of pantoprazole and doxorubicin for patients with solid tumours. The work completed in this thesis demonstrates that drug distribution can be modified and that these changes can be quantified, and may correlate with improved anti-tumour effects. Improving drug distribution through the use of proton pump inhibitors may be an effective strategy to improve chemotherapeutic efficacy.

Ph.D.

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Yes / Failure of systemic cancer treatment can be, at least in part, due to the drug not being delivered to the tumour at sufficiently high concentration and/or sufficiently homogeneous distribution; this is termed as “pharmacokinetic drug resistance”. To understand whether a drug is being adequately delivered to the tumour, “precision pharmacology” techniques are needed. Mass spectrometry imaging (MSI) is a relatively new and complex technique that allows imaging of drug distribution within tissues. In this review we address the applicability of MSI to the study of cancer drug distribution from the bench to the bedside. We address: (i) the role of MSI in pre-clinical studies to characterize anti-cancer drug distribution within the body and the tumour, (ii) the application of MSI in pre-clinical studies to define optimal drug dose or schedule, combinations or new drug delivery systems, and finally (iii) the emerging role of MSI in clinical research. / Spanish Medical Oncology Society (SEOM) for contribution with a grant for research abroad of Dr. Jove, “Instituto Carlos III” for contribution with a “Río Hortega” Grant (nº CM17/00008) for Dr. Jove

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Thesis (MPH.) -- University of Limpopo, 2015 / Background Drugs expiration in public hospital pharmacies is a concern to health professionals as the Department of Health spends a lot of money to buy drugs. The number of drugs which expire in public hospital pharmacies can give an indication of how the drugs are used, and consequently reflect on the disease prevalence for which the drugs are indicated for. Drugs cannot be used beyond expiry date. The purpose of this study was to determine the cause or causes, extent and costs of expired drugs in public hospital pharmacies of Sekhukhune District in Limpopo Province of South Africa. Methods Sekhukhune District has seven public hospital pharmacies. Data collection involved interviews conducted by the researcher from thirty-five participants with each hospital having five participants. All interviews were recorded by the use of a laptop voice recorder. Participants in each hospital involved a pharmacy manager, an additional pharmacist who had twelve months or more working experience within the facility under study, a clinical manager, a nurse who attends the hospital Drug and Therapeutics Committee and a medical practitioner who had twelve or more working experience within the facility under study. Results and conclusion In this study it was identified that, overstocking; prescribing tendencies by medical practitioners; delivery of short-dated drugs from the supplier; poor stock rotation and unreliably minimum and maximum order levels were cited as some of the reasons for stock expiration. The study found drugs expiration value to be above the set limit of 0.05% of the expenditure in a financial year. An expired stock value of R86 815 was found based on the data collected for 2010/2011 financial year.