Pulsatile Administration of Agents Using ALZET^® Osmotic Pumps

Although ALZET pumps operate at constant rates, they can be adapted to deliver drugs at a time-varying schedule, such as a diurnal cycle of high-low delivery rates.

In this application, an ALZET pump filled with saline is attached to a length of catheter tubing which has been loaded with a predetermined series of drug infusions separated by an inert, spacer substance. The spacer substance can be any liquid in which the drug solution is not miscible (such as oil), or it can be sterile air (see P0639, below). Because the spacer substance and the drug solution are not miscible, in the loaded catheter the series of infusions appear as discrete segments along the length of the catheter.

When it begins pumping, the constant action of the ALZET pump pushes saline into one end of the catheter tubing, sequentially displacing the series of drug infusion and spacer substances from the opposite end. For more details about this technique, refer to the procedure on the following page, reference P0065, and the references listed below.

A more complete review of the injection-infusion comparison protocol can be found in the following references:

P0639 Mick, C.C.W. and Nicoll, C.S. Prolactin directly stimulates the liver in vivo to secrete a factor
(synlactin) which acts synergistically with the hormone. Endocrinology 116(5), 2049§]2053, 1985. Prolactin, ovine; Growth hormone, ovine IV (HEPATIC); IV (JUGULAR) PIGEON Combination: Glycerol; Citric acid; Control* 2001; 1 week comparison of agents effects; citric acid added to solvent for bacteriostatic effects; pulsed delivery of hormone or solvent (intermittent w/ air); peptides

P0065 Lynch, H.J., Rivest, R.W., and Wurtman, R.J. Artificial induction of melatonin rhythms by programmed microinfusion. Neuroendocrinology 31, 106§]111, 1980. Melatonin SC RAT Phenolsulfonphthalein; Saline* replacement therapy (pinealectomy); pulsed delivery of agent (intermittent w/vehicle)

 

PREPARING THE LYNCH COIL FOR USE WITH THE ALZET ® OSMOTIC PUMP

The Lynch coil method may be used for several purposes:

• Create a time-patterned delivery of an agent
• Deliver compounds and/or vehicles which are incompatible with the reservoir of the ALZET ® Osmotic Pump
• Provide an initial period of no drug for surgical recovery
• Adapt a longer duration pump to a shorter period of drug infusion

Polyethylene tubing should be used because it is thermoformal, and can be formed into a permanent coil. The length of the tubing depends upon the size and duration of pump being used, and the duration of infusion desired from the solution in the coil. The pump itself is filled with saline, which is separated from the drug solution by a drop of mineral oil * or bubble of air placed in the polyethylene tubing at the end between the coil and the pump.

 

I. Fabricating a coil of polyethylene tubing:

1. Using closely spaced turns, wind the appropriate length of PE-60 tubing around a glass rod or syringe of the same outside diameter as the ALZET pump which will be used.
2. Submerge the rod and the tubing in boiling water for one minute.
3. Immediately immerse the tubing into cold water.
4. Basic reference on the pump and coil technique:P0065 Lynch et al,   Neuroendocrinology 31, 106-111, 1980.

The heat thermoforms the tubing into a tidy, permanent coil which provides a space-efficient auxiliary reservoir whose contents are pumped by the pump via displacement.

 

II. Catheter volumes:

To determine the appropriate length of catheter tubing, use the following length-volume conversion:

1 cm of PE-60 tubing contains 4.566 µl of solution

1 cm of PE-50 tubing contains 2.679 µl of solution

Following are nominal tubing lengths for coils which will last the entire duration of an ALZET pump. ALZET pumps vary in reservoir volume and release rate from one lot to the next, and therefore the duration will also vary slightly. To determine the length of time a specific pump lot will release, subtract 5% from the mean reservoir volume and divide by the mean release rate. (These means are given on the instruction sheet within each box of ALZET pumps.)   The resulting number will be the number of hours over which a pump will release its contents.

Pump Volume	PE-60 Tubing Length	PE-50 Tubing Length
100 µl	22 cm	37.3 cm
200 µl	43.8 cm	74.7 cm
2000 µl (2 ml)	438 cm	746.5 cm

•  Or some fluid immiscible with the fluid in the pump and the fluid in the tubing.

These conversions are calculated using the formula for a volume of a cylinder:

R 2 x length = tubing volume

In this equation, R is the radius of a cross-section of the tubing, or half of the inner diameter given above. The length is equal to the length of tubing being considered. Be sure to use the same units of measure throughout, and to convert the volume to ?l to relate the final volume to the flow rate of the pumps, which is in ?l/hr.

P8053 Bruno,M.A., Cuello,A.C. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2006; 103(-17-):6735-6740. >>> Neuroserpin; GM6001; CSF, artificial, PBS; CSF/CNS (parietal cortex); Rat; 2001; 72 hours; Controls received mp w/ vehicle into contralateral side; enzyme inhibitor (tpa, metalloproteinase); multiple pumps per animal (2); animal info (Fischer 344, 6 month old); Lynch coil with air-oil spacer at mp end of tubing; bilateral infusion cannulae.

P7835 Vann,R.E., Balster,R.L., Beardsley,P.M. Dose, duration, and pattern of nicotine administration as determinants of behavioral dependence in rats. Psychopharmacology 2006; 184(-3-4-):482-493. >>> Nicotine hydrogen tartrate; Saline, physiological; SC; Rat; 2ML2; 7, 12, 14, 15 days; Controls received mp w/ vehicle; dose-response (fig. 2); dependence; animal info (male, Sprague-Dawley); catheter tubing Lynch coil used to deliver 3 days nicotine, followed by 1 day saline, followed by remaining contents of mp (nicotine); compared with continuous nicotine administration.

P7582 Cardoso,A., Paula-Barbosa,M.M., Lukoyanov,N.V. Reduced density of neuropeptide Y neurons in the somatosensory cortex of old male and female rats: Relation to cholinergic depletion and recovery after nerve growth factor treatment. Neuroscience 2006; 137(-3-):937-948. >>> Dye, methylene blue; nerve growth factor; CSF, artificial; BSA; CSF/CNS; Rat; 2002; 14 days; Controls received mp w/ vehicle or sham surgery; functionality of mp verified by pretesting; Alzet brain infusion kit used; post op. care (antiseptic); animal info (male, female, Wistar 6 month old, 24 month old); Lynch coil filled with NGF, air-oil spacer between mp and catheter, mp filled with dye.

P7289 Pereira,P.A., Cardoso,A., Paula-Barbosa,M.M. Nerve growth factor restores the expression of vasopressin and vasoactive intestinal polypeptide in the suprachiasmatic nucleus of aged rats. Brain Research 2005; 1048(-1-2-):123-130. >>> Nerve growth factor; dye, methylene blue; CSF/CNS; Rat; 2002; 14 days; Functionality of mp verified by pretesting delivery rate; ALZET brain infusion kit used; peptides; post op. care (SC saline, local antiseptic); mp filled with Methylene blue, air-oil spacer at tubing connection, tubing filled with NGF; Lynch coil; "Because there is evidence that the surgical procedure does not interfere with the structure of SCN, vehicle - treated rats were not included in this study." (p. 124).

P6922 Chen,J.R., Wang,Y.J., Tseng,G.F. The effects of decompression and exogenous NGF on compressed cerebral cortex. Journal of Neurotrauma 2004; 21(-11-):1640-1651. >>> Nerve growth factor; CSF, artificial; CSF/CNS; Rat; 2ML2; 14 days; Used coiled PE tubing (Lynch coil).

P6916 Zhang,M., Li,J., Chakrabarty,P., Bu,B.T., Vincent,I. Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick type C mice. American Journal of Pathology 2004; 165(-3-):843-853. >>> Roscovitine; olomoucine; iso-olomoucine; DMSO; CSF/CNS; Mice; 1002; 2, 4 weeks; Pumps replaced every 2 weeks for 4 week infusions; enzyme inhibitor (CDK); neurodegenerative (Alzheimer's disease, Amyotrophic Lateral Sclerosis, Niemann-Pick Type C disease); lynch coil used to accomodate 75% DMSO.

P7701 Callaerts-Vegh,Z., Evans,K.L., Shipley,G.L., Davies,P.J., Cuba,D.L., Gurji,H.A., Giles,H., Bond,R.A. Effects of different beta adrenoceptor ligands in mice with permanent occlusion of the left anterior descending coronary artery. Br.J.Pharmacol. 2003/4; 138(-8-):1505-1516. >>> ICI-118,551; Saline; DMSO; SC; Mice; 2004; 36 days; Controls received mp w/ vehicle or no treatment; half-life (p. 1507) "short half-life;" cardiovascular; ischemia (cardiac); animal info (male, C57BL/6, 12-15 weeks old); Lynch Coil; mp filled with saline, agent in catheter coil with 3 different concentrations; separated by air bubbles to give an increasing drug regimen; tygon tubing used.

P5973 Radu,R.A., Mata,N.L., Nusinowitz,S., Liu,X.R., Sieving,P.A., Travis,G.H. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2003; 100(-8-):4742-4747. >>> Isotretinoin; DMSO; SC; Mice (knockout); 2004; 1 month; Controls received mp w/ vehicle; comparison of IP injections vs chronic mp; Isotretinoin (accutane) is a retinoid&was dissolved in DMSO; Lynch coil used; solution was placed in catheter since 100% DMSO is not compatible with the pumps' reservoir.

P5965 Cadete-Leite,A., Pereira,P.A., Madeira,M.D., Paula-Barbosa,M.M. Nerve growth factor prevents cell death and induces hypertrophy of basil forebrain cholinergic neurons in rats withdrawn from prolonged ethanol intake. Neuroscience 2003; 119(-4-):1055-1069. >>> Nerve growth factor; dye, methylene blue; CSF; BSA; CSF/CNS; Rat; 2004; 28 days; good methods p. 1057; ALZET brain infusion kit 1 used; peptides; post op. care (sc injection of saline and cortrimoxazol); lynch coil used; air bubble used to separate vehicle and agent/vehicle; pump contained dye.

P5488 Ellinwood,E.H., Davidson,C., Yu,G.Z., King,G.R., Lee,T.H. Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens. European Neuropsychopharmacology 2002; 12(-5-):407-415. >>> Cocaine; pramipexole; Saline; SC; Rat; 2ML2; 14 days; Functionality of mp verified by measuring residual volume; pulsed delivery - drugs administered either continuously or for 16 or 20 hrs per day (p. 409); study included behavioral testing; pramipexole is a direct dopamine agonist; microdialysis fiber attached to pump via catheter to minimize tissue necrosis caused by the cocaine (p. 408); intermittent delivery made possible by disconnecting and reconnecting an externalized catheter.

P5451 Chutkow,W.A., Pu,J.L., Wheeler,M.T., Wada,T., Makielski,J.C., Burant,C.F., McNally,E.M. Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K-ATP channels. Journal of Clinical Investigation 2002; 110(-2-):203-208. >>> Epidermal growth factor; Fibroblast growth factor 2; Albumin, rat serum; Gentamicin sulfate; CSF, artificial; CSF/CNS (intrathecal); Rat; 2002; ; Controls received mp w/ vehicle; good methods (p. 224); lynch coil used; pump filled w/ saline; mineral oil spacer used to separate saline in pump from agent solution in catheter; agents infused separatedly or concomittantly in the same pump;.

P5125 Sayer,F.T., Oudega,M., Hagg,T. Neurotrophins reduce degeneration of injured ascending sensory and corticospinal motor axons in adult rat spinal cord. Experimental Neurology 2002; 175(--):282-296. >>> NT-3; PBS; Dye, toluidine blue; CSF/CNS (intrathecal); rat; 2002; 7 days; controls received mp w/ vehicle; comparison of IT injections vs. mp; pulsed delivery; peptides; pump partially coated w/ paraffin to reduce release rate to 0.2 ul/hr; Lynch coil used to separate agent from dye for verifying cannula patency (p. 285); diagram of pump, catheter and infusion location (p. 284); pump filled with dye vehicle, tubing filled with vehicle or NT-3, mineral oil spacer separated solution in pump from solution in catheter.

P4828 Buffelli,M., Busetto,G., Cangiano,A. The use of in vivo direct drug application to assess neural regulation of muscle properties.. Journal of Neuroscience Methods 2001; 106(--):113-120. >>> Tetrodotoxin; Potassium Chloride; Calcitonin gene-related peptide;; Saline; Dye, methylene blue;; IM (soleus); rat;; 2001; 2002;; 3 - 8 days;; Controls received mp w/ vehicle; tissue perfusion (soleus muscle); detailed methods for catheter construction and surgical procedures (p. 114 - 115); Lynch coil technique used; pump filled w/ saline and agents loaded in modified PE-100 tubing; solutions separated by oil drop; pumps w/ various flow rates were tested but model 2002 was chosed because its small flow rate permits to avoid excessive fluid accumulation on muscle surface; diagram of pump-catheter assembly and location (p. 114);.

P6184 Neumann,I.D. Antisense oligodeoxynucleotide effects on the hypothalamic-neurohypophysial system and the hypothalamic-pituitary-adrenal axis. METHODS 2000/11; 22(-3-):227-237. >>> Oligodeoxynucleotide, antisense; Ringer's solution; CSF/CNS; Rat (lactating); 1007D; 4 days; Tissue perfusion (various brain regions); comparison of ICV injections vs. mp; pulsed delivery (various ODN's, air bubble spacer); antisense; ODN's infused were antisense, mixed base, or 21-mer end capped phosphorothioated; the mp was filled with ringer's solution and PE tubing was filled w/ 50 ul of each agent solution. An air bubble was inserted between solutions; 25-g guide cannula and 27-g infusion cannula used together to allow concomitant icv injections.

P5538 Oudega,M., Rosano,C., Sadi,D., Wood,P.M., Schwab,M.E., Hagg,T. Neutralizing antibodies against neurite growth inhibitor NI-35/250 do not promote regeneration of sensory axons in the adult rat spinal cord. Neuroscience 2000; 100(-4-):873-883. >>> Nerve growth factor-beta; PBS; albumin, rat serum; gentamycin; CSF/CNS (intrathecal); Rat; 2002; 2 weeks; Lynch coil technique; solution loaded into coil reservoir and separated from a blue colored fluid in pump by mineral oil; flow rate reduced by half by partial coating of pump w/ paraffin; cannula patency confirmed by movement of blue-colored fluid into the coiled tubing.

P5103 Oudega,M, Rosano,C, Sadi,D, Wood,P.M., Schwab,M.E., Hagg,T. Neutralizing antibodies against neurite growh inhibitor NI-35/250 do not promote regeneration of sensory axons in the adult rat spinal cord. Neuroscience 2000; 100(-4-):873-883. >>> Dantrolene; Nerve growth factor, B-; PBS; Albumin, rat serum; Gentamicin; CSF/CNS (dorsal spinal cord, intrathecal); rat; 2002; 2 weeks; controls received mp w/ vehicle; functionality of mp verified by noting advance of colored fluid in catheter (p. 875); peptides; pumps coated with paraffin to reduce flow rate to 0.2 ul/hr; Lynch coil used; infusion solutions and blue-colored pump fluid separated by oil spacer; patency of device confirmed by passage of blue fluid into coils.

P4764 Larsen,P.J, Vrang,N, Petersen,P.C, Kristensen,P  Obesity Research 2000; 8(-8-):590-596. >>> CART (42-89);; PBS;; CSF/CNS;; rat;; 2001; 2002;; 7, 10 days;; Controls received mp w/ vehicle; dose-response (graph p. 592); pulsed delivery 24 hr. delay for recovery; stability verified by aspire 5 mL of pump contents, inject ICV into naive animals to verify biological activity; peptides; ALZET brain infusion kit used; recombinant CART (42-89) is a hypothalamic neuropeptide; CART (42-89) stands for cocaine-amphetamine-regulated transcript; low dose was 4.8 mg/day for 7 days, high dose was 12 mg/day for 10 days..

P4578 Sun,Y-N, Lee,H.J, Almon,R.R, Jusko,W.J  The Journal of Pharmacology and Experimental Therapeutics. 1999; 289(-3-):1523-1532. >>> Growth hormone, recomb. human; SC;; monkey;; 30 days;; comparison of SC injections vs. mp vs. microspheres; peptides; "Continuous rhGH input delivered by ProLease and osmotic pump is more effective than pulsatile injections in induction of IGF-I, especially when the delivery systems can maintain growth hormone concentration above the SC50" (p. 1531)..

P5232 Hagg,T. Neurotrophins prevent death and differentially affect tyrosine hydroxylase of adult rat nigrostriatal neurons in vivo. Exp.Neurol. 1998/1; 149(-1-):183-192. >>> Brain-derived neurotrophic factor; Nerve growth factor; NT-3; NT-4; PBS; Albumin, rat serum; Buffer, sodium acetate; CSF/CNS (nigrostriatal complex); Rat; 2002; 14 days; Controls received mp w/ vehicle; peptides: stability (p.184); "at 1 mg/ml these factors retain more than 70% of their activity after 14 days at 37 C in ALZET pumps"; pumps partially coated with paraffin to reduce flow rate to 0.25 ul/hr; lynch coil used; neuronal survival; neurodegenerative (Parkinson's disease).

P4421 Turner,R.T., Evans,G.L, Cavolina,J.M, Halloran,B, Morey-Holton,E. Programmed administration of parathyroid hormone increases bone formation and reduces bone loss in hindlimb-unloaded ovariectomized rats.. Endocrinology 1998; 139(--):4086-4091. >>> Parathyroid hormone, human 1-34; NaCl; HCl; Serum, rat;; SC;; rat;; 7 days;; controls received mp w/vehicle; replacement therapy (overiectomized); peptides; pulsed delivery; PTH during a daily 1-hour infusion for 7 days.

P4407 Grzywacz,F.W., Chen,H., Allegretti,J., Zirkin,B.R. Does age-associated reduced leydig cell testosterone production in brown Norway rats result from under-stimulation by luteinizing hormone?. Journal of Andrology 1998/10; 19(-5-):625-630. >>> Luteinizing hormone, ovine;; Buffer, borate;; SC;; rat;; 5 days;; controls received mp with peanut oil; pulsed delivery-LH was alternated with peanut oil;.

P4217 Donahey,J.C.K., van Dijk,G., Woods,S.C., Seeley,R.J. Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats. Brain Research 1998; 779(--):75-83. >>> Glucagon-like peptide-1(7-36) amide; Saline; CSF/CNS (third ventricle); rat; 2002; 4 days; controls received mp w/saline; functionality of mp verified by movement of air bubble along tubing; one week recovery after cannula placement; cannula placement confirmed by administration of angiotensin II; pump filled with saline and agent and loaded in catheter tubing; air bubble used to separate solutions; Lynch coil technique; peptides.

P3958 Dunbar,S.A., Pulai,I.J. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to n-methyl-d-aspartate receptor blockade in the rat. J.Pharmacol.Exp.Ther. 1998; 284(-2-):678-686. >>> Morphine sulfate; MK-801; Saline, sterile; CSF/CNS (intrathecal); rat; 2002; 8 days; controls received mp w/ saline; functionality of mp verified by in vivo and in vitro assays; pulsed delivery (air used as spacer in Lynch coil); no stress (see pg. 681); good methods (pg. 679); tolerance.

R0125 Vyas,S.P., Sood,A., Venugopalan,P., Mysore,N. Circadian rhythm and drug delivery design. Pharmazie 1997; 52(-11-):815-820. >>> ; no duration posted; review on the advantages of providing drugs in a pulsed delivery fashion; mentions mp briefly, pg. 818.

P4366 Day-Lollini,P.A., Stewart,G.R., Taylor,M.J., Johnson,R.M., Chellman,G.J. Hyperplastic changes within the leptomeninges of the rat and monkey in response to chronic intracerebroventricular infusion of nerve growth factor. Exp.Neurol. 1997/5; 145(-1-):24-37. >>> Nerve growth factor;; Saline; Citric acid; Albumin, rat; Albumin, human;; CSF/CNS;; rat; monkey;; 2002; 2ML4;; 6 months;; controls received mp with vehicle; functionality of mp verified by residual volume; dose-response; long-term study, pumps replaced every 28 days; stability of NGF verified at 37ºfor 1 month by RP-HPLC, bioassay, and/or ELISA; good methods; peptides; recomb. human NGF used; half the mp was coated with paraffin to reduce flow rate; NGF solutions were placed in Lynch coiled tubing rather than pumps, due to adsorptive loss of rhNGF to the pump reservoir; in monkeys, ventricular cannula placement was confirmed by rapid drop in fluid level in PE tubing;.

P3802 Dobnig,H., Turner,R.T. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997; 138(-11-):4607-4612. >>> Parathyroid hormone, human 1-34; NaCl; HCI; Serum, rat; rat; 2001; 6 days; controls received mp w/vehicle; comparison of sc injections vs mp; pulsed delivery, sesame oil used in lynch coil; no stress (see pg. 4609); stress/adverse reaction: high PTH dose lethal for 3/7 rats in first group; good methods (pg. 4608).

P4403 Ernfors,P., Duan,M.L., ElShamy,W.M., Canlon,B. Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3. Nature Medicine 1996/4; 2(-4-):463-467. >>> Amikacin; NT-3;; Perilymph, artificial;; Ear (cochlea);; guinea-pig;; 2ML2;; 2 weeks;; Antibiotic; controls received mp with vehicle; tissue perfusion (scala tympani); peptides; Lynch coil used, agents or vehicle given in different sequential combinations;.

P4162 Chekanov,V.S., Tchekanov,G.V., Rieder,M.A., Silverstein,E.L., Cheng,Q., Smith,L.M., Zander,F.L., Jacobs,G.B., McConchie,S., Christensen,C.W., Schmidt,D.H. Force enhancement of skeletal muscle used for dynamic cardiomyoplasty and as a skeletal muscle ventricle. ASAIO Journal 1995; 41(--):M499-M507. >>> Nandrolone decanoate; Sesame oil; IM; sheep; 2ML4; 8 weeks; functionality of pump verified by residual volume; pumps replaced after 4 weeks; pump filled with saline, while agent diluted in sesame oil was loaded in coiled catheter 100 cm long; Lynch coil technique; cardiovascular; tissue perfusion (latissimus dorsi).

P4101 Schindler,R.A., Gladstone,H.B., Scott,N., Hradek,G.T., Williams,H., Shah,S.B. Enhanced preservation of the auditory nerve following cochlear perfusion with nerve growth factor. Am.J.Otology 1995; 16(-3-):304-309. >>> Nerve growth factor; Neomycin; Saline; ear (cochlea); guinea-pig; 2 weeks; controls received mp w/vehicle; tissue perfusion (scala tympani); pulsed delivery; cannula/catheter filled with neomycin which was infused for the first 24 h; pump was filled with NGF; peptides.

R0105 Goldsworthy,T.L., Butterworth,B.E., Maronpot,R.R. Concepts, labeling procedures, and design of cell proliferation studies relating to carcinogenesis. Environ.Health Perspect. 1993; 101(-5-):59-66. >>> Uridine, bromodeoxy-;; rat;; no duration posted;; pump mentioned briefly on pg. 61-62 as method for continuous administration for cell proliferation labeling; some guidelines for using pumps in studies given, as well as how to decide between pump or pulsatile delivery; cancer;.

P7953 Hagg,T., Varon,S. Ciliary Neurotrophic Factor Prevents Degeneration of Adult Rat Substantia Nigra Dopaminergic Neurons in vivo. Proceedings of the National Academy of Sciences 1993; 90(-13-):6315-6319. >>> Ciliary neurotrophic factor, recomb. human; CSF, artificial; albumin, rat serum; CSF/CNS (substantia nigra); Rat; 2002; 14 days; Controls received mp w/ vehicle; peptides; neurodegenerative (Parkinson's disease); animal info (female, Sprague-Dawley, 200 grams); lynch coil filled with vehicle or agent, mp filled with vehicle; mp partly coated with paraffin.

P2944 Schlechter,N.L., Katz,L.S., Russell,S.M., Nicoll,C.S. Physiological evaluation of the role of the liver as a mediator of the growth-promoting action of somatotrophin. Zoological Science 1993; 10(--):235-244. >>> Growth hormone, human; Growth hormone, bovine; Growth hormone, rat; IV (jugular); IV (portal); rat; 2001; 7 Days; controls received mp with solvent or sham operation; replacement therapy (hypophysectomy); pulsed delivery; catheter contained heparin.

P2456 Katz,L.S., Nicoll,C.S. Evidence for a role of the liver in the luteotropic action of prolactin in rats. Biol.Reprod. 1993; 48(--):512-514. >>> Prolactin, ovine; Sodium azide; Sodium phosphate; Saline; Glycerol; IV (jugular); IV (hepatic portal); rat; 2002; no duration posted; pulsed delivery; peptides; air used in lynch coil.

P2312 Hebert,N.J., Kim,J.H., Lin,R.J., Nicoll,C.S. Restoration of lactation in bromocriptine-treated rats by prolactin replacement: comparison of constant versus pulsatile infusion and intrahepatic versus intrajugular routes of delivery. J.Endocrinol.Invest. 1993; 16(--):29-35. >>> Prolactin, ovine; IV (jugular); IV (hepatic portal); rat; 2001; 5 days; controls received mp w/ solvent; functionality of mp verified by in vitro dye testing of pulsatile release; comparison of pulsed delivery w/ mp vs. continuous infusion w/ mp; pulsed delivery; "Constant infusion of oPRL. . . was, overall, more effective at restoring lactation. . . than was giving pulses, regardless of the site of delivery." (pg. 29).

P1978 Lerman,S., Megaw,J. Miniosmotic pumps for liposomal drug delivery. Liposome Technol. 1993; 1(--):429-438. >>> Liposomes; Eye (lens); rabbit; 2ML1; no duration posted; pulsed delivery described; detailed surgical methods.

P2542 Torring,O., Turner,R.T., Carter,W.B., Firek,A.F., Jacobs,C.A., Heath III,H. Inhibition by human interleukin-1a of parathyroid hormone-related peptide effects on renal calcium and phosphorus metabolism in the rat. Endocrinology 1992; 131(-1-):5-13. >>> Parathyroid hormone-related peptide; Interleukin-1, alpha; Albumin, mouse serum; Cysteine HCl; SC; rat; 2001; 14 days; controls received mp w/ vehicle; comparison of injections vs. mp; pulsed delivery (pg. 10); pumps replaced after 7 days; no stress (see pg. 11); stability of IL-1a verified by ELISA (see pg. 6); peptides; agents given concomitantly in some cases; cysteine prevented degradation of PTHrP..

P2396 Hollt,V., Horn,G. Effect of nicotine on mRNA levels encoding opioid peptides, vasopressin and a-3 nicotinic receptor subunit in the rat. Clin.Investig. 1992; 70(--):224-231. >>> ; 4, 7, 14 days; controls received mp w/ saline; pulsed delivery of nicotine w/ sesame oil; sesame oil superior to air.

R0130 Theeuwes,F., Yum,S.I., Haak,R., Wong,P. Systems for triggered, pulsed, and programmed drug delivery. Ann.N.Y.Acad.Sci. 1991; 618(--):428-440. >>> Melatonin; rat; 7 days; review of programmed drug delivery systems; pulsed delivery.

R0092 Lee,V.H.L. Problems and solutions in peptide and protein drug delivery. Pharmacokinetics and Pharmacodynamics 1991; 3(--):80-92. >>> ; no duration posted; pulsed delivery, brief mention.

P2092 Billington,C.J., Briggs,J.E., Link,J.G., Levine,A.S. Glucagon in physiological concentrations stimulates brown fat thermogenesis in vivo. Am.J.Physiol. 1991; 261(--):R501-R507. >>> Glucagon; Ringer's solution, lactated; Saline; IP; rat; 5,7 days; comparison of multiple injections vs. mp; coiled tubing (Lynch coil) used to delay drug infusion for surgical recovery; constant infusion produced drug effect whereas intermittent delivery did not.

P2032 Petitte,J.N., Etches,R.J. Daily infusion of corticosterone and reproductive function in the domestic hen (Gallus domesticus). Gen.Comp.Endocrinol. 1991; 83(-3-):397-405. >>> Corticosterone; PEG 400; SC; bird (chicken); 2ML2; 2ML4; 14 days; dose-response; pulsed delivery achieved by externalizing PE-60 catheter from pump. Catheter could be disconnected at will for intermittent delivery: 10 hr on/14 hr off, 4 hr on/20 hr off, 24 hr on/0 hr off (pg 398-399).

P2029 Pampori,N.A., Agrawal,A.K., Shapiro,B.H. Renaturalizing the sexually dimorphic profiles of circulating growth hormone in hypophysectomized rats. Acta Endocrinol.(Copenh) 1991; 124(-3-):283-289. >>> Growth hormone; Albumin; Bicarbonate; Glycerol; IP; rat; 7 days; functionality of mp verified by serum GH RIA; replacement therapy (hypophysectomy); comparison of sc injections and intermittent external pump vs mp; pulsed delivery attempted; peptides.

P4166 Sun,Y., Xue,H., Janes,S., Sherman,S.E., Song,D.L. The use of an ALZET osmotic pump as a "carryable" external infusion pump for small animal studies. Proceed.Intern.Symp.Control.Rel.Bioact.Mater. 1990; 17(--):371-372. >>> Insulin; IV (jugular); Rat; 2ML1; 2ML2; no duration posted; pump used extracorporeally in external drug delivery device; the pumping rate was adjusted by greatly varying the osmolality of the medium in the fluid chamber in which the pump was placed; pulsed delivery: air used as spacer in Lynch coil; peptides; manufacturer's note: pumps need to be primed at 37 degrees rather than 23 degrees C, and the pumps cannot be reused.

P1832 English,D.E., Russell,S.M., Katz,L.S., Nicoll,C.S. Evidence for a role of the liver in the mammotrophic action of prolactin. Endocrinology 1990; 126(-5-):2252-2256. >>> Prolactin, ovine; Glycerol; Sodium azide; IV (jugular); IV (hepatic portal); rat; 2 weeks; pulse delivery; peptides.

P1557 Martin-Iverson,M.T., Stahl,S.M., Iversen,S.D. Chronic administration of a selective dopamine D-2 agonist: factors determining behavioral tolerance and sensitization. Psychopharmacology 1988; 95(--):534-539. >>> Hydroxynaphthoxacine, 4-propyl-9-; SC; rat; 2002; 11-15 days; 12 hours (intermittently); comparison of injections vs. mp infusion; functionality of mp verified in vitro; pulsed delivery using coiled tubing, intermittent inert placebo, 12h 'on' and 12h 'off'; PHNO is dopamine D-2 receptor agonist.

P1253 Rayner,V.C., Robinson,I.C.A.F., Russell,J.A. Chronic intracerebroventricular morphine and lactation in rats: dependence and tolerance in relation to oxytocin neurones. J.Physiol. 1988; 396(--):319-348. >>> Morphine sulfate; Radio-isotopes; 3H tracer; Water; CSF/CNS; rat; 2001; 5, 6, 7 days; controls received mp w/ water; mp connected to cannula in ICV; mp primed overnight in saline; mp used in 4 of 5 exp.; labeled morphine used in only 1 exp.; functionality of mp verified by compression of mp to obtain contents; pulsed delivery (increasing dose).

P1218 Bicknell,R.J., Leng,G., Lincoln,D.W., Russell,J.A. Naloxone excites oxytocin neurones in the supraoptic nucleus of lactating rats after chronic morphine treatment. J.Physiol. 1988; 396(--):297-317. >>> Morphine sulfate; Water; CSF/CNS; rat; 2001; 168 days; controls received mp w/ water; pulsed delivery (cannula and tubing filled w/ increasing doses of morphine separated by 1.0 ul of air); mp connected to cannula.

R0077 Ray,N., Theeuwes,F. Implantable osmotically powered drug delivery systems. In 'Drug Delivery Systems: Fundamentals and Techniques,' P.Johnson and J.G.Lloyd-Jones (eds.), Ellis Horwood Ltd., Chichester, England and VCH Verlasgesellschaft mbH, Weinheim, Federal Republic of Germany 1987; (-Ch. 7-):120-138. >>> Antipyrine; bleomycin; dopamine HCl; melatonin; methotrexate, sodium; nicotine; prednisolone; radio-isotopes; valproic acid; 14C tracer; 3H tracer; IA; IP; SC; Mice, rabbit, rat; no duration posted; ALZA-authored; synoptic review of mp; post op. care (antibiotic); comparison of sc injections vs. mp infusion; pulsed delivery.

R0075 Amkraut,A.A., Fara,J.W., Nichols,K.C., Ray,N.P. Delivery of therapeutic agents by osmotic pumps. In 'The Pharmacology and Toxicology of Proteins,' UCLA Symposia on Molecular and Cellular Biology, New Series, Alan R.Liss, Inc., New York 1987; (--):131-148. >>> ; no duration posted; ALZA-authored; general description of mp and its uses; comparison of routes of administration; replacement therapy; stability; pulsed delivery; peptides.

P1399 Phillips,J.A., Lasley,B.L. Modification of reproductive rhythm in lizards via GnRH therapy. Ann.N.Y.Acad.Sci. 1987; 519(--):128-136. >>> Luteinizing HRH analog, chicken; Peanut oil; IP; iguana; 2ML2; 10 days; coiled catheter; continuous versus pulsed delivery both by mp; pulsed delivery; peptides.

P1048 Phillips,J.A., Frye,F., Bercovitz,A., Calle,P., Millar,R., Rivier,J., Lasley,B.L. Exogenous GnRH overrides the endogenous annual reproductive rhythm in green iguanas, iguana iguana. J.Exp.Zool. 1987; 241(--):227-236. >>> Luteinizing HRH; Peanut oil; IP; iguana; 2ML2; 14 days; controls received mp w/vehicle; peptides; pumps primed in saline before implantation; pulsed delivery; chicken&mammal LHRH used.

P0902 Ruiz de Elvira,M.C., Abbott,D.H. A backpack system for long-term osmotic minipump infusions into unrestrained marmoset monkeys. Lab.Anim. 1986; 20(--):329-334. >>> Luteinizing HRH; SC; monkey; 2001; up to 22 days; mp conn. to cannula attached to backpack; pumps replaced every 10 days; mp cont. in saline filled vial attached to backpack; sys. used for long-term inf. up to 3 mths; pulsed delivery of LHRH using backpack system; peptides.

P0819 Fish,R.E., Lang,C.H., Spitzer,J.A. Regional blood flow during continuous low-dose endotoxin infusion. Circ.Shock 1986; 18(-4-):267-276. >>> Endotoxin, E. coli; Saline; IV (jugular); rat; 2ML1; 6 and 30 hours; Lynch coil; mp connected to coiled 100 cm length of PE-60 tubing terminating in jugular vein; tubing provided 42 hour surgical recovery period.

P0788 Spitzer,J.A., Fish,R.E. Lipolytic patterns in isolated adipocytes of continuously endotoxemic rats. Circ.Shock 1986; 18(-1-):21-29. >>> Endotoxin, E. coli; Saline; IV (jugular); rat; 2ML1; 6 and 30 hours; controls received mp w/ saline; mp connected to coiled polyethylene tubing in jugular vein; coil filled w/ saline to provide 42 hr. surgical recovery period; Lynch coil; dose-response.

P0771 Schlechter,N.L., Russell,S.M., Greenberg,S., Spencer,E.M., Nicoll,C.S. A direct growth effect of growth hormone in rat hindlimb shown by arterial infusion. Am.J.Physiol. 1986; 250(--):E231-E235. >>> Growth hormone, rat; Prolactin, ovine; Glycerol; Sodium azide; IA (superior vesicle); rat; 2001; 7 days; replacement therapy (hypophysectomy); mp connected to catheter in superior vesicle artery; detailed description and diagram of catheter apparatus; constant and pulsed delivery of GH; peptides.

R0064 Urquhart,J., Nichols,K. Delivery systems and pharmacodynamics in new drug research and development. In 'The Lastest Developments in Drug Delivery Systems: Conference Proceedings.' (Robert S.First Conference), October 7-8, 1985, Philadelphia, Aster Publishing Co., Springfield, OR 1985; (--):13-16. >>> ; no duration posted; ALZA-authored; lynch coil; injection-infusion comparison; drug free interval.

P0843 Lindburg,D., Millard,S., Lasley,B. Induced estrus in the cheetah. Ann.Proc.AAZPA 1985; (--):560-563. >>> Luteinizing HRH; SC; cat (cheetah); 10 days; mp model not stated; pulsed delivery of GnRH to induce estrus; peptides.

P0729 Zaharko,D.S., Covey,J.M. Arabinosyl-5-azacytosine: plasma kinetics and therapeutic response (L1210) in vitro and in vivo in mice. Invest.New Drugs 1985; 3(--):323-329. >>> Ara-AC; DMSO; SC; mice; 2001; 24, 48, 72, 96, and 144 hours; comparison of injection vs. mp infusion; cancer chemotherapy; Lynch coil; polyethylene tubing filled w/Ara-AC connected to mp; mp filled w/ PBS and primed at room temp.; air space in tubing to sep. drug from PBS; function.

P0724 Fish,R.E., Burns,A.H., Lang,C.H., Spitzer,J.A. Myocardial dysfunction in a nonlethal, nonshock model of chronic endotoxemia. Circ.Shock 1985; 16(--):241-252. >>> Endotoxin, E. coli; Saline; IV (jugular); rat; 2ML1; 6 and 30 hours; mp connected to saline filled tubing placed in jugular vein; coiled saline filled tubing provided 42 hr. surgical recovery period prior to endotoxin infusion; Lynch coil; controls received mp w/ saline.

P0701 Phillips,J.A., Alexander,N., Karesh,W.B., Millar,R., Lasley,B.L. Stimulating male sexual behavior with repetitive pulses of GnRH in female green iguanas, Iguana iguana. J.Exp.Zool. 1985; 234(-3-):481-484. >>> Luteinizing HRH; Acetic acid; IP; iguana; 2ML2; 4 weeks; no stress (see pg. 483); pulsed delivery of LHRH (intermittent w/peanut oil); mp primed in saline prior to implant; peptides; chicken LHRH used.

P0661 Cronan,T., Conrad,J., Bryson,R. Effects of chronically administered nicotine and saline on motor activity in rats. Pharmacol.Biochem.Behav. 1985; 22(-5-):897-899. >>> Nicotine; Saline; SC; rat; 2002; 8 days; pulsed delivery of nicotine and saline (intermittent w/air, 16 hrs. on, 8 hrs. off); pumps primed in saline; stress/adverse reaction (tissue growth over mp, preventing release of drug).

P0639 Mick,C.C.W., Nicoll,C.S. Prolactin directly stimulates the liver in vivo to secrete a factor (synlactin) which acts synergistically with the hormone. Endocrinology 1985; 116(-5-):2049-2053. >>> Growth hormone, ovine; Prolactin, ovine; Citric acid; Glycerol; IV (hepatic portal); IV (jugular); bird (pigeon); 2001; 1 week; comparison of agents effects; citric acid added to solvent for bacteriostatic effects; pulsed delivery of hormone or solvent (intermittent w/ air); peptides; tissue perfusion.

P0761 Lasley,B.L., Wing,A. Stimulating ovarian function in exotic carnivores with pulses of GnRH. Presented at the Annual Meeting of the American Association of Zoo Veterinarians, Oct.24-27, Tampa, FL 1983; (--):14-15. >>> Luteinizing HRH; SC; cat (cheetah); cat (golden cat); cat (leopard); 2ML2; 2ML4; 9-11 days; pulsed delivery of LHRH and peanut oil; mp primed in saline for 8 hrs. prior to implant; peptides; stress/adverse reaction (fibrous tissue adhering to silastic coils connected to mp in the golden cat).

P0322 Ewing,L.L., Wing,T.-Y., Cochran,R.C., Kromann,N., Zirkin,B.R. Effect of luteinizing hormone on Leydig cell structure and testosterone secretion. Endocrinology 1983; 112(-5-):1763-1769. >>> Follicle stimulating hormone; Growth hormone, ovine; Luteinizing hormone; Prolactin, ovine; Thyroid-stimulating hormone; Borate; Peanut oil; SC; rat; 5 days; replacement therapy (hypophysectomy); simultaneous infusion of testosterone&estradiol implants w/ mp infusion of polypeptides; pulsed delivery of agents (intermittent w/ vehicle); peptides; ovine LH used.

P0065 Lynch,H.J., Rivest,R.W., Wurtman,R.J. Artificial induction of melatonin rhythms by programmed microinfusion. Neuroendocrinology 1980; 31(--):106-111. >>> Melatonin; Phenolsulfonphthalein; Saline; SC; rat; no duration posted; replacement therapy (pinealectomy); pulsed delivery of agent (intermittent w/vehicle).

P0067 Lynch,H.J., Wurtman,R.J. Control of rhythms in the secretion of pineal hormones in humans and experimental animals. In 'Biological Rhythms and their Central Mechanism,' M.Suda, O.Hayaishi, and H.Nakagawa (eds.), Elsevier/N.Holland, Biomedical Press 1979; (--):117-131. >>> Melatonin; Phenolsulfonphthalein; Saline; SC; rat; no duration posted; replacement therapy (pinealectomy); pulsed delivery of agent (intermittent w/vehicle); comparison of human vs. animal data.

top of page