Thesis (Ph.D)-Cairo University, 2023.

Bibliography: pages 128-140.

Drug incompatibilities are considered one of the most critical problems in intensive care units (ICUs). Hospitalized patients in ICUs receive multiple intravenous medications at different doses in various vehicles through a limited number of venous access points. Administration of multiple IV therapies via the same venous port increases the risk of drug incompatibilities and compromises the safety and efficacy of the administrated drugs.
Several clinical complications of concomitant administration of incompatible drug solutions are well known, including lumen occlusion, tissue ischemia, hypoxia, tissue irritation, thrombophlebitis, pulmonary embolism, modulation of immune response, and even death. In addition, these incompatibilities result in reduced therapeutic outcomes, higher costs and prolonged hospitalization stay.
Healthcare practitioners have pursued various strategies to encounter drug incompatibilities, either at the preparation stage or during drug administration. Nevertheless, most of these preventive measures are labor-intensive and time-consuming, with insufficient clinical evidence related to their successful management. Therefore, there is a growing need for a unique strategy that can tackle and overcome the problems associated with the administration of incompatible drugs, thus improving their clinical outcomes.
Acid-base reactions are the most common mechanism of physical drug incompatibilities since most of the injectable drugs (> 90%) are organic weak electrolytes in predominantly ionized or salt forms, and thus precipitation-based incompatibilities frequently happen due to the pH change that occurs upon mixing the incompatible drugs. An example is the physical incompatibility that arises upon mixing IV solutions of furosemide and midazolam. Furosemide and midazolam are widely used drugs in anesthesia and ICUs, with a well-documented incompatibility Furosemide is a short-acting loop diuretic that is used in the treatment of edematous states associated with cardiac, hepatic and renal failure as well as hypertension. Midazolam is a short-acting preoperative anesthetic agent that exhibits anticonvulsant, anxiolytic, muscle relaxant and sedative properties. Furosemide is available as a sodium salt with a pH of 8.7, while midazolam is available as midazolam hydrochloride with a pH of 3.47 upon reconstitution. Mixing both drug solutions alters the pH of the final mixture sufficiently to cause the immediate precipitation of unionized insoluble drugs.
Nanocarriers have attracted much attention in the pharmaceutical field as they have demonstrated efficiency in loading several therapeutic and diagnostic agents with control over their navigation within the body and target sites. Moreover, they can protect several drugs from degradation in the biological environment. Despite the numerous biomedical applications of nanocarriers, they have not been sufficiently explored for their ability to prevent physicochemical interactions that occur between incompatible drugs. Therefore, the aim of the work in this thesis is to explore the ability of nanocarriers to limit the physical incompatibility that occurs upon mixing IV solutions of furosemide and midazolam. It was proposed that the nanosized vesicles would isolate the incompatible drugs from each other and from the surrounding media, release the drugs slowly over time, and thus, reduce the overall particulate load (i.e., size and number of the precipitated particles), with the additional benefit of further improving the pharmacokinetic profiles of the incompatible drugs.

لقد حظيت الحوامل متناهية الصغر بالاهتمام الكبير في الآونة الأخيرة نظرًا لما أبدته من فاعلية كبيرة في حمل العديد من الأدوية العلاجية والتشخيصية والتحكم في تنقلها وإيصالها إلى المواقع المستهدفة داخل الجسم. وعلى الرغم من التطبيقات الطبية العديدة للحوامل متناهية الصغر إلا إنها لم يتم اختبارها بالشكل الكافي لمنع التداخلات الكيميائية والفيزيائية التى تحدث بين الأدوية. لذلك فإن الهدف من هذه الرسالة هو استكشاف قدرة الحوامل المتناهية الصغر(النيوزومات) على التغلب على عدم التوافق الذي يحدث بين دوائي الفوروسيميد والميدازولام.

Issues also as CD.

Text in English and abstract in Arabic & English.