Chronic Delivery Research

ALZET Research Alert - June 2013

Chronic administration of several months or longer can be necessary to maintain steady-state levels of experimental agents, either for establishing a stable animal model of disease, or investigating the long-term therapeutic potential of novel compounds. ALZET® Osmotic Pumps offer a reliable and convenient alternative to multiple injections for the long-term dosing of laboratory animals. Continuous delivery for up to 6 weeks is feasible with a single pump, and duration can be extended for multiple months through serial implantation. Read on for new research describing the use of ALZET pumps in chronic duration studies.

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

Chronic androgen therapy improves muscle atrophy after SCI
Spinal cord injury (SCI) results in severe atrophy of skeletal muscle. Wu et al. evaluated the effect of chronic androgen treatment in spinal cord transected rats. ALZET mini-pumps (Model 2004) were used to administer testosterone alone, or in combination with nandrolone, for 8 weeks. The study showed that androgen treatment suppresses the activin receptor and Smad2/3 signaling pathway that leads to muscular atrophy following SCI. Furthermore, combined treatment with testosterone and nandrolone, but not testosterone alone, increased muscle mass. The study suggests that androgen therapy can help reduce certain adverse effects of paralysis due to SCI..
Journal of Neurotrauma 2012;29(8):1663-1675

Leptin effects on bone growth
Stunes et al. studied the long-term skeletal effects of peripheral leptin administration at supraphysiological doses in female rats. Leptin (low and high dose) was administered continuously for 9 weeks using ALZET pumps. The study showed that bone mineral density, microarchitechture, and biomechanical strength can be maintained at high, but not low, leptin doses. The effects of leptin on bone seem to be dependent on a balance between concentrations achieved in plasma, the brain and in the bones. The authors suggest that this balance is dependent on the method of leptin administration and on endogenous production.
Endocrinology 2012:153(5):2245-2253

Antipsychotic treatment affects brain structure
Researchers at King’s College London examined the effect of chronic antipsychotic treatment on brain morphology in rats. Animals were treated with haloperidol (HAL) or lithium (Li) for 8 weeks, followed by 8 weeks of drug withdrawal. ALZET pumps (Model 2ML4) were used to avoid multiple daily injections and maintain clinically relevant drug levels throughout the treatment period. MRI data revealed contrasting effects for both drugs: HAL-treatment resulted in a dose-dependent whole brain volume (WBV) reduction, while Li-treatment led to a significant WBV increase. Moreover, the effects of HAL were reversible, whereas some effects of Li remained following drug withdrawal.
Biological Psychiatry 2012;71(10):855-863

Exendin-4 neuroprotective action
Exendin-4 (Ex-4) is neuroprotective in rodent models of neurodegenerative diseases, including stroke, Parkinson’s and Alzheimer’s disease. Researchers at the NIH and Indiana University School of Medicine investigated the neuroprotective action of Ex-4 in SOD1 (G93A) mice, a rodent model of amyotropic lateral sclerosis (ALS). ALZET pumps (Model 1004) were used to provide steady-state delivery of Ex-4; pumps were replaced every 3 weeks to extend treatment over 12 weeks. ALS mice treated with Ex-4 showed improved glucose tolerance, normalization of running behavior, and neuroprotection of lumbar spinal cord neurons. The authors propose further evaluation to determine if the neuroprotective action of Ex-4 is clinically relevant in the treatment of ALS.
PLoS One;7(2):U436-U448

Elevated miR-15a levels in lupus
Researchers at the New Jersey Medical School investigated the effect of interferon (INF)-accelerated disease in a mouse model of systemic lupus erythematosus (SLE). B/W mice were treated with various doses of INF alpha and/or INF lambda for up to 16 weeks using serially implanted ALZET pumps (Model 2006). INF treatment was associated with accelerated proteinuria, reduced levels of immunosuppressive B cells and increased levels of microRNAs (miR-15a) and autoantibodies. Data suggests that INF triggers miR-15a overexpression and accelerates the onset of autoimmunity. Thus therapeutic strategies to decrease miR-15a levels might be beneficial in the treatment of SLE.
Molecular Immunology 2012;52(2):61-70

Aliskiren supplements valsartan therapy for diabetes
Lei et al. showed that supplemental aliskiren treatment is required to produce a stronger renoprotective effect, compared to single therapy with valsartan (an AT1-receptor antagonist). Type 2 diabetic KKAy mice were treated with various doses of valsartan and aliskiren, alone or in combination. Aliskiren was infused for 10 weeks using serially implanted ALZET minipumps (Models 1002 and 1004). Valsartan-treated mice supplemented with aliskiren showed a stronger anti-albuminuric effect, which was also accompanied by podocyte-protective and anti-senescence effects, compared to single valsartan treatment - even at high doses. Lei et al. suggest aliskiren supplementation as alternative therapy for type 2 diabetic patients with kidney disease who are unresponsive to AT1-receptor antagonists.
Journal of Pharmacological Sciences 2012;119(2):131-138

Chronic neuropeptide Y induces abnormal baroreflex sensitivity
Researchers at Harbin Medical University and Ministry of Education of China investigated the impact of long-term neuropeptide Y (NPY) treatment on baroreflex sensitivity in Wistar rats. ALZET pumps (Model 2004) were used to supply a continuous, chronic dose of NPY for 4 months (with monthly replacements). The researchers found that chronic NPY treatment resulted in abdominal obesity and hyperlipidemia. They also found new evidence that long-term, elevated NPY plasma concentrations lead to significant impairment of baroreflex sensitivity, potentially attributed to imbalanced neuronal function in the brainstem.
Cellular Physiology and Biochemistry 2012;29(1-2):111-120

Epoxyeicosanoids stimulate metastasis in mice
Drugs that stimulate epoxyeicosatrienoic acid (EET) production are in clinical trials for treating hypertension and are being considered for long-term use in other diseases. Since little is known about the role of EETs in cancer, Panigrahy et al. evaluated their long-term effect in various mouse cancer models. ALZET pumps were used to establish elevated, steady-state plasma concentrations of EET in mice for up to 4 months (with pump replacements every 2 or 4 weeks). The study showed that elevated EETs have a stimulatory effect on primary tumor growth and tumor angiogenesis. Exogenous administration of EETs enhanced metastatic spread and escape from tumor dormancy in several low-metastasizing tumor models. These effects were reversed with EET antagonists. The study suggests that EET antagonists may be used for cancer treatment, and raises concerns about the chronic use EET stimulating drugs in cancer patients.
J Clin Invest. 2012;122(1):178-191

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What researchers are saying...

“...opioid and nonopioid analgesics were continuously infused from subcutaneously implanted osmotic mini-pumps, a convenient modality of drug delivery that allows for drug delivery at constant rate for prolonged periods of time without experimenter intervention.” Bruins Slot et al., Pharmacology, Biochemistry and Behavior 2002;72:943-951.