When planning pharmacological experiments using small animals, the method and schedule of drug administration are critical factors that must be taken into account.
This white paper highlights the importance of choosing an appropriate drug delivery method to optimize pharmacological efficacy and reduce harm to the animal.
Compared to humans, small animals such as mice and rats distribute, metabolize and eliminate pharmacological agents much faster. If a drug’s half-life is short, administration via injection can be impractical and even harmful: a frequent injection schedule leads to excess handling, labor and planning from the researcher. This can lead to increased stress and drug toxicity in the animal, and a reduction in drug efficacy.
This white paper addresses this pharmacological challenge, discussing how continuous infusion using ALZET Osmotic Pumps can increase efficacy, reduce side effects, or both. It describes how the schedule and method of administration can influence a drug’s therapeutic index and presents 6 research case studies comparing the efficacy of different delivery methods in small animal models, primarily bolus injection and continuous infusion.
Below is a spoiler-free summary of each pharmacological case study – read the white paper here to learn how much of a difference the method of drug administration can make.
To assess the efficacy of various treatment regimens for mouse models of ovarian cancer, Dings et al. administered anginex to mice bearing MA148 tumors using osmotic pumps, locoregional injections or slow-release alginate beads. After 28 days, they compared tumor growth reduction for each method.
They also evaluated the efficacy of increasing doses of anginex using continuous infusion in mouse xenograft model of ovarian carcinoma and in another study, compared the effectiveness of single-agent administration with a combination therapy (anginex with angiostatin or carboplatin) in nude mice with established ovarian tumors.
Tajeda et al. evaluated the therapeutic efficacy of TT-232, a novel somatostatin analogue found to induce apoptosis and reduce proliferation of cancer cells. Using the P-388 mouse model of leukemia, they administed TT-232 using bolus injection or infusion and assessed their respective reductions in tumor growth and survival rate over 14–28 days.
El-Salhy et al. looked at combination therapy with octreotide (a somatostatin analogue), galanin and seratonin. After 14 days of treatment with either daily injection or continuous infusion, they found that both resulted in a reduction in tumor weight, volume and vascularization. However, the extent of the decrease varied substantially between treatment groups.
Kharitonenkov et al. used ALZET pumps to deliver 11µg/kg/h to db/db mice, resulting in a significant and prolonged reduction of glucose in the blood. In addition, they found that even at a high dose, FGF21 administration was not associated with any harmful side effects.
Coskun et al. investigated whether continuous infusion or daily injections differ in their therapeutic value. They do – significantly.
Wolfgang Loscher summarized recommendations for selecting an effective treatment protocol for chronic epilepsy studies in rats. The summary is presented as a flowchart taking into account elimination half-life, solubility and stability in tolerable solvents and bioavailability. Depending on the properties of the pharmaceutical agent, the flowchart could suggest administration via food, water, injection or infusion.
In addition, Seralta et al. assessed schedule-dependent effects of valproic acid (VPA). They comparing the relative toxicity and anticonvulsant efficacy of of the drug when administered via intracerebroventricular (ICV) infusion, ICV injection or IP injections.
Fujsawa et al. found that IL-13Rα2 is a potential target for tumor immunotherapy as it is overexpressed in many types of cancer. They created an immunotoxin linking IL-13 to a modified form of the Pseudomonas exotoxin (PE), and evaluated its efficacy when combined with gemcitabine to treat a mouse model of pancreatic cancer.
Mice were treated with a monotheraphy of IL-13-PE or gemcitabine or combination therapy with both, delivered either by twice-daily injection or continuous infusion.
Bioluminescence imaging (BLI) uses luciferase fusion reporters and its bioluminescent substrate luciferin to study molecular processes in vivo, in real time. When the luciferase reporter is expressed, light emitted by the oxidation of luciferin can be measured, allowing researchers to study, for example, disease progression in real time. However, as described by Sadikot and Blackwell, if luciferin is not present in abundance, light emission may not be an accurate indication of luciferase activity.
To address this issue, Gross et al. used ALZET pumps to maintain a consistent concentration of luciferin in a study evaluating the the ability of drug candidate PS-1145 to inhibit Iκ kinase. Nude mice bearing tumors expressing an IκBα-firefly luciferase fusion reporter were administered PS-1145, and tumour bioluminescence was measured several times before and after treatment.
This white paper is most valuable to pharmacological researchers interested in understanding how drug regimen can affect therapeutic index and learning how they can optimize drug efficacy, reduce side effects and minimize animal stress due to serial injections and handling.
To learn more about the use of implantable pumps as an alternative to serial injections for pharmacological research, watch the webinar, Implantable Infusion Pumps: Insights For Your Next Animal Dosing Study.