Table 1. Selected animal models induced by chronic administration with ALZET pumps Animal Model Alzheimer’s Alzheimer’s Amnesia Breast cancer Cardiac injury Hormone replacement Hypertension Immune suppression In vivo cell labeling Osteoporosis Parkinson’s Parkinson’s Psychosis Renal fibrosis Sepsis Infused Agent/Drug p-Amyloid protein Okadaic acid Scopolamine Estrogens Isoproterenol Testosterone, estrogen, others Angiotensin II Immunosuppressants BrdU Desmopressin MPTP Rotenone Amphetamines Angiotensin II LPS (endotoxin) Chronic administration of several months or longer may be necessary to evaluate the long-term effects of test compounds in vivo, or to establish a stable animal model of disease. In these cases, it is essential to maintain steady-state levels of the test substance in tissues or plasma during the duration of the study to ensure reliable results. Injections are commonly used in research, but repeated injections over prolonged periods are inadequate for some compounds (i.e., those with short half-lives), stressful to the animals, and inconvenient for the researcher. For studies requiring chronic dosing, ALZET® Osmotic Pumps offer a reliable and convenient alternative to injections and other repetitive dosing methods. With ALZET pumps, drug administration continues, around the clock, for up to 6 weeks with a single pump, and the duration can be extended for multiple months through serial implantation. For instance, Ravindranath et al. used ALZET pumps for chronic administration of buserelin acetate to bonnet macaque monkeys for a period of 3 years, with pumps replaced every 3 weeks and up to 52 serial implantations. (Table 4 contains a list of the longest ALZET pump studies by species.) Listed below is a summary of recent research publications Smoke inhalation Nicotine describing the use of ALZET pumps in chronic duration studies. Additional references are available from ALZET Technical Services at 800.692.2990 or [email protected]. • Alzheimer’s disease • Cancer • Cardiomyopathy • Depression • Diabetes • Drug abuse and addition • Dysrhythmia (irregular heartbeat) • Epilepsy • Hemophilia • Hyperlipidemia (high cholesterol) • Hypertension (high blood pressure) • Hypothyroidism • Obesity • Pain management • Parkinson's disease • Rheumatoid arthritis dzef OSMOTIC PUMPS DURECT Corporation | 10260 Bubb Road | Cupertino CA, 95014 T: 408.367.4036 F: 408.865.1406 Toll Free 800.692.2990 WWW.ALZET.COM | ALZE

ALZET Research Application Chronic Delivery Table 3. Recent research describing the use of ALZET pumps in chronic duration studies Duration Pump ALZET Pump Use (Citation) 16 weeks Model 2006 (replaced after 8 weeks) Chronic administration of various doses of INFa and/or INFX to evaluate the effect of interferon-accelerated disease in a mouse model of systemic lupus erythematosus. Yuan et al. Molecular Immunology 2012;52(2):61-70 Model 2004 (replaced every month) ALZET pumps were used to supply a continuous dose of NPY to investigate the peptide's long-term effect on baroreflex sensitivity in...