Method for Use of Catheter Tubing to Delay Drug Infusion Into the CNS Via ALZET Osmotic Pumps

 

Although ALZET pumps begin operating immediately upon contact with fluids, they can be adapted to allow for a period of recovery following surgery, such as following implantation of a brain cannula. In this application, the ALZET pump is filled with drug solution and attached to a length of catheter tubing, which has been loaded with a control solution (no drug). If the control solution is such that mixing could occur between it and the drug solution, then a spacer substance should be placed between the control and drug solutions. The spacer substance can be any liquid in which the drug solution is not miscible (such as oil), or it can be sterile air.

 

Upon implantation, the ALZET pump begins releasing the drug solution from the pump reservoir into the catheter tubing. This displaces the control solution from the catheter tubing into the animal. As the last of the control solution is being released into the animal, the drug solution reaches the end of the catheter tube and is then released into the animal at the pump's constant rate.

 

•  Catheter length:

 

For CNS infusion, the tubing length should be 25% longer than the distance between the pump (placed subcutaneously over the scapulae) and the site of cannula placement. As an example, if this distance is 8 cm, use a 10 cm length of tubing. If the 10 cm tubing is filled with control solution, the length of time for delivery of the control solution depends upon the total volume contained in the tubing and the pump model being used.

 

•  Catheter volume:

 

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

 

Tubing Type	Size	Volume per Centimeter
Vinyl	V3/A*	3.739 µl
Polyethylene (PE)	PE-60*	4.566 µl
PE	PE-50	2.679 µl

 

 

*V3/A & PE-60 tubing is available from DURECT Corporation.

V/3A comes either separately or as part of the ALZET Brain Infusion Kits

 

•  Example :

 

A researcher desires a one-week delay following implantation of a brain cannula. Drug infusion should begin after this delay and last three weeks. The researcher is using ALZET Model 2004 with the ALZET Brain Infusion Kit, in an adult rat.

 

Model 2004 releases at 0.25 µl/hr** and therefore delivers 42 µl over one week. This amount of control solution, such as artificial CSF, will be loaded into the tubing.

 

The vinyl tubing in the brain infusion kit contains 3.739 µl per cm, so 42 µl will fill 11.2 cm. The researcher measures a distance of 8 cm between the pump and cannula implantation sites. The minimum tube length would be 25% longer than this distance or 10 cm. The 11.2 cm needed to provide the one-week delay will work well. The tubing is filled with aCSF; a small air bubble is introduced to prevent mixing with the drug solution once attached to the primed and filled pump.

 

Note : When using a catheter, the entire contents of the pump reservoir will not be released in the animal. (Some solution will remain in the catheter tubing at the end of the infusion period.) Despite this, the pump must be filled completely in order to operate properly.

 

**Nominal pumping rate for Model 2004. (Refer to the instructions inside each box for lot-specific data.)

 

References

P7776 Stoyanovitch,A.G., Johnson,M.A., Clifton,D.K., Steiner,R.A., Fraley,G.S. Galanin-like peptide rescues reproductive function in the diabetic rat. Diabetes 2005; 54(-8-):2471-2476. >>> Galanin-like peptide; antibody, anti-GALP; immunoglobulin G, goat; CSF, artificaial; CSF/CNS; Rat; 2002; 11 days; Controls received mp w/ vehicle, or IgG; functionality of mp verified; AlZET brain infusion kit 2 used; peptides; animal info (adult, male, Sprague-Dawley, 280-320g.); catheter filled with vehicle to allow 6.5 days delay treatment before agent; cannula placement confirmed.

P7577 Zizzari,P., Halem,H., Taylor,J., Dong,J.Z., Datta,R., Culler,M.D., Epelbaum,J., Bluet-Pajot,M.T. Endogenous ghrelin regulates episodic growth hormone (GH) secretion by amplifying GH pulse amplitude: Evidence from antagonism of the GH secretagogue-R1a receptor. Endocrinology 2005; 146(-9-):3836-3842. >>> BIM-28163; Saline; SC; CSF/CNS; Rat; 2002; 7, 8 days; Controls received mp w/ vehicle; comparison of acute IV injection vs. mp; Alzet brain infusion kit 2 used; animal info (male Sprague-Dawley, 250 g); mp connected to catheter with saline to delay agent delivery start by 6 days, air bubble used to seperate agent from saline; GHS-R1a receptor antagonist; ghrelin analog.

P7353 Snodgrass-Belt,P., Gilbert,J.L., Davis,F.C. Central administration of transforming growth factor-alpha and neuregulin-1 suppress active behaviors and cause weight loss in hamsters. Brain Research 2005; 1038(-2-):171-182. >>> Transforming growth factor-alpha; BSA; acetic acid; CSF, artificial; CSF/CNS (third ventricle); Hamster; 2002; 16-20 days; Circadian; plastics one cannula; cannula/tubing were filled with aCSF to allow for a 48 delay; behavioral study.

P6887 Porter,J.P., Potratz,K.R. Effect of intracerebroventricular angiotensin II on body weight and food intake in adult rats. American Journal of Physiology-Regulatory Integrative and Comparative Physiology 2004; 287(-2-):R422-R428. >>> Angiotensin II; CSF/CNS; Rat; 2002; 2,5,11 days; Controls received mp w/ sterile saline; ALZET brain infusion kit 2 used; peptides; cyanoacrylate adhesive; ICV infusion of ANG II was delayed 2 days after surgery by prefilling the catheter between the mp and the cannula with saline instead of ANG II.

P5827 Kas,M.J.H., van Dijk,G., Scheurink,A.J.W., Adan,R.A.H. Agouti-related protein prevents self-starvation. Molecular Psychiatry 2003; 8(-2-):235-240. >>> Agouti-related protein; Saline; CSF/CNS; Rat; 1007D; 4-5 days; Controls received mp w/ vehicle; ALZET brain infusion kit used; peptides; catheter tubing filled w/ saline to allow 2-3 day delayed infusion; Agouti-related protein is a suppressor of melanocortin receptor activity.

P5244 Lanneau,C., Bluet-Pajot,M.T., Zizzari,P., Csaba,Z., Dournaud,P., Helboe,L., Hoyer,D., Pellegrini,E., Tannenbaum,G.S., Epelbaum,J., Gardette,R. Involvement of the Sst1 somatostatin receptor subtype in the intrahypothalamic neuronal network regulating growth hormone secretion: an in vitro and in vivo antisense study. Endocrinology 2000/3; 141(-3-):967-979. >>> Oligonucleotide, antisense; Saline; CSF/CNS; Rat; 2002; ; Controls received mp w/ vehicle; ALZET brain infusion kit used; antisense infusion was delayed for 4 days by vehicle infusion to allow recovery period from surgery; air bubble used as spacer to separate vehicle from antisense solution.

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..

P4659 Bradbury,M.J, McBurnie,M.I., Denton,D.A., Lee,K.-F, Vale,W.W. Modulation of urocortin-induced hypophagia and weight loss by corticotropin-releasing factor receptor 1 deficiency in mice.. Endocrinology 2000; 141(-8-):2715-2724. >>> Urocortin;; CSF, artificial;; CSF/CNS (third ventricle);; mice;; 2001; 2002;; 4 weeks;; Comparison of ICV injections vs mp; pumps replaced 2 times; peptides; delayed delivery; 2002 aCSF pumps were replaced with 2001 hormone pumps; then, these were replaced for 2001 aCSF pumps;.

P4478 Redgate,E.S., Grudziak,A.G., Deutsch,M., Boggs,S.S. Enhanced uptake of [3H] spermidine by 9L rat brain tumors after direct intratumoral infusion of inhibitors of enzymes of the polyamine biosynthetic pathway.. Journal of Neuro-oncology 1999; 42(--):123-130. >>> Spermidine; Putrescine; Ornithine, difluoromethyl-;; Radio-isotopes; 3H tracer; CSF;; CSF/CNS;; rat;; 14 days;; Controls received mp w/vehicle; tissue perfusion (intratumoral); cancer; polyamines; delayed delivery for 3 days.

P3927 Buwalda,B., de Boer,S.F., Van Kalkeren,A.A., Koolhaas,J.M. Physiological and behavioral effects of chronic intracerebroventricular infusion of corticotropin-releasing factor in the rat. Psychoneuroendocrinology 1997; 22(-5-):297-309. >>> Corticotropin-rel. factor, ovine; Saline; BSA; Ascorbic acid; CSF/CNS; rat; 2002; 10 days; controls received mp w/ vehicle; peptides; ALZET brain infusion kit used; catheter filled w/ saline to delay agent delivery.

P3780 Redgate,E.S., Grudziak,A.G., Deutsch,M., Boggs,S.S. Difluoromethylornithine enhanced uptake of tritiated putrescine in 9L rat brain tumors. Int.J.Radiat.Oncol.Biol.Phys. 1997; 38(-1-):169-174. >>> Ornithine, difluoromethyl-; Putrescine; CSF, artificial;; IP; CSF/CNS (corpus striatum); rat; 2001; 2002; no duration posted; tissue perfusion (tumor); functionality of mp verified by tumor radioactivity during infusion; stability verified (pg. 173); good methods (pp. 170-171); cancer; catheter used to delay drug infusion for 1 or 3 days after surgery.

P4324 Pellegrini,E., Bluet-Pajot,M.T., Mounier,F., Bennett,P., Kordon,C., Epelbaum,J. Central administration of a growth hormone (GH) receptor mRNA antisense increases GH pulsatility and decreases hypothalamic somatostatin expression in rats. Journal of Neuroscience 1996; 16(-24-):8140-8148. >>> Oligodeoxynucleotide, antisense;; Saline;; CSF/CNS;; rat;; 2002;; 60 hours; controls received anesthesia only or ICV saline; ALZET brain infusion kit used; antisense; 85 ml of saline in catheter tubing delayed antisense infusion for 7 days;.

P4103 Ren,K., Thomas,D.A., Dubner,R. Nerve growth factor alleviates a painful peripheral neuropathy in rats. Brain Research 1995; 699(--):286-292. >>> Nerve growth factor; Antiserum, anti-nerve growth factor; Saline; CSF/CNS (sciatic nerve); rat; 2001; 7 days; controls received mp w/saline; tissue perfusion (nerve cuff); perforated catheter attached to nerve cuff; delayed infusion; peptides.

P2887 Malmberg,A.B., Yaksh,T.L. Effect of continuous intrathecal infusion of w-conopeptides, N-type calcium-channel blockers, on behavior and antinociception in the formalin and hot-plate tests in rats. Pain 1995; 60(--):83-90. >>> SNX-III; SNX-239; Morphine sulfate; Saline, physiological; CSF/CNS (spinal cord, intrathecal); rat; 2001; 2 or 7 days; controls received mp with saline; peptides; tolerance; PE-10 tubing into spinal cord fused with PE-60 tubing on pump; catheter filled with saline to delay drug infusion 18 hours; SNX-III and SNX-239 are w-conopeptides and calcium channel blockers.

P1866 Swann,A.C. Brain Na+,K+-ATPase regulation in vivo: reduction in activity and response to sodium by intracerebroventricular tetrodotoxin. Brain Research 1991; 543(--):251-255. >>> Tetrodotoxin; CSF, artificial; CSF/CNS; rat; 2001; 2, 4, 7 days; infusion delayed by loading tubing with citrate buffer.

P1731 Rivest,S., Deshaies,Y., Richard,D. Effects of corticotropin-releasing factor on energy balance in rats are sex dependent. Am.J.Physiol. 1989; 257(--):R1417-R1422. >>> Corticotropin-rel. factor, human; Corticotropin-rel. factor, rat; Ascorbic acid; Albumin, bovine serum; Saline; CSF/CNS; rat; 2002; 14 days; infusion delayed about 4 days by 10.6 cm saline-filled catheter.

P0607 Jeffries,W.B., Orzechowski,R.F. Withdrawal syndrome follows abrupt cessation of intracerebroventricular infusion of epinephrine in spontaneously hypertensive rats. Life Sci. 1985; 36(-14-):1331-1337. >>> Epinephrine bitartrate; Ascorbic acid; Saline; CSF/CNS; rat; 2001; 5 days; 2 day delay of mp Epi achieved by filling connecting tubing with vehicle; some tubing externalized to allow immediate cutoff of infusion; dose-response data.

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