Translational Research

ALZET Research Alert - April 2013

Translational research is a bi-directional process in which scientific knowledge is used to direct clinical development and clinical knowledge used to drive basic research. This strategy aims to accelerate the pace at which novel research discoveries are translated into safe and effective clinical therapies.

Effective translation of therapeutic strategies from the experimental phase into the clinic is often dependent on the availability of suitable animal models that closely mimic clinical features. Equally important is the use of reliable research tools to ensure reproducible study results. ALZET Osmotic Pumps are useful drug delivery tools for translational research and drug development. These small infusion pumps have been used in translational research studies designed to evaluate drug pharmacokinetics, safety and tolerability. They are also used in dose escalation studies designed to determine the maximum starting dose or effective therapeutic dose. Compared to conventional dosing methods, ALZET pumps allow greater control and accuracy in drug delivery, thus reducing dosing errors, ensuring stable dose levels and minimizing adverse effects. Most importantly, they help generate reliable preclinical data that can then be applied to clinical studies with greater confidence.

Listed below are sample research publicatons describing the use of ALZET pumps in Translational Research studies. Contact ALZET Technical Services for more information at 800.692.2990 or alzet@durect.com.

Metabolic regulators: FGF19 & FGF21
Lilly Research Laboratory scientists designed studies to understand the mechanism of action for FGF19 and FGF21 as regulators of energy metabolism. Mice were treated with either FGF19 or FGF21 for 7 days via continuous infusion using ALZET pumps. While slight differences were seen in vitro, both proteins showed comparable in vivo effects on body weight reduction and serum glucose regulation in DIO and ob/ob mice. The study supports the use of FGF21 and FGF19 as potential therapeutics for obesity and diabetes.
PLoS ONE 2012;7(5):e38438

Antipsychotic drug treatment
Steward et al. evaluated the impact of chronic atypical (clozapine) and typical (haloperidol) antipsychotic drug (APD) treatment on phencyclidine-induced schizophrenia in rats. ALZET pumps were used to mimic the human dosing regimen and eliminate the drug fluctuations seen in previous injection dosing studies. Therapeutic drug effects were correlated to muscarinic receptor (MR) modulation in the rat brain. The study showed that M1R activation is linked to antipsychotic action, with different APDs affecting different regions of the brain. Thus suggesting different modes of action for typical and atypical APDs and further validating data obtained from schizophrenia patients.
Neuropharmacology 2012;62:1554-1563

Anti-tumor activity of PF-04217903
Researchers at Pfizer, Inc. (PGRD-La Jolla) in collaboration with the Sanford Burnham Medical Research Institute evaluated the antitumor efficacy of PF-04217903, a selective c-met kinase inhibitor, in mice. ALZET minipumps were used to achieve steady-state plasma levels of PF-04217903. Tumor bearing mice were separated into groups and implanted with ALZET minipumps containing different drug concentrations. PF-04217903 demonstrated dose-dependent antitumor activity and was well-tolerated in vivo over the 14-day treatment period. 
Mol Cancer Ther. 2012;11:1036-1047

Somatostatin analogs and glucose homeostasis
Researchers at Novartis Pharma AG evaluated the effects of pasireotide and octreotide on blood glucose, insulin, and glucagon levels in rats. The agents were administered to rats at various doses by injection or continuous infusion using ALZET pumps (Model 2ML2). Pasireotide and octreotide inhibited insulin to a similar degree, but only pasireotide was associated with hyperglycemia. Various long-term phase III studies are ongoing to further understand the effects of somatostatin analogs on glucose homeostasis in humans.
J Endocrinology 2012;212:49–60

Antidepressive action of Lu AA21004
A study by Mork et al. used ALZET pumps (Model 2ML1) for 3-day continuous administration of Lu AA21004, a 5-HT receptor antagonist, to evaluate its pharmacological action in rats. The study demonstrated that Lu AA21004 mediates its antidepressive effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. This multimodal activity profile is different from that of current antidepressants, suggesting a unique therapeutic profile.
J Pharmacol Exp Ther. 2012;340(3):666-75

Risperidone and paliperidone D2 receptor occupancy
Muly et al. investigated the relationship between atypical antipsychotic (risperidone and paliperidone) drug dose and D2 receptor (D2R) occupancy in brain regions of non-human primates. Due to their short half-life in monkeys, the drugs were administered by constant, intragastric infusion using ALZET pumps. The study showed dose-dependent D2R occupancy across striatal and extrastriatal brain regions for both drugs. The study suggests that serum drug levels from 40-80 ng/ml result in D2R occupancy in the desired therapeutic window of 60-80%.
J Pharmacol Exp Ther. 2012;341(1):81-89

Ischemia revascularization therapy
Syndecan-4 proteoliposomes enhanced neovascularization by FGF-2 in a rat model of limb ischemia. Researchers at Harvard, MIT and the University of Texas used ALZET pumps to deliver FGF-2 with or without the syndecan-4 proteoliposomes. Combined therapy almost completely resolved the ischemia within about 7 days. This combined approach holds clinical promise where growth factor therapy alone has so far not been successful.
PNAS 2012;109(5):1679-1684

Links to Additional Resources

 

 

Since 1977, scientist around the world have used ALZET pumps to conduct their research, publishing their results in high-impact journals. The ALZET bibliography now contains over 16,000 publications! We can perform a custom search for references relevant to your research.

Request your ALZET bibliography search!

 

Order the ALZET SurgicalImplantation Video

What researchers are saying...

“Insofar as multiple dosing is concerned, we propose that only administration by pump (or administration more than four times a day) can provide clinical-like occupancies for haloperidol, olanzapine, and risperidone.” Kapur et al., The Journal of Pharmacology and Experimental Therapeutics 2003;305:625-631.