References on the Administration of Benzodiazepines Using ALZET® Osmotic Pumps

1. Adinazolam

433 Turmel, A., de Montigny, C. Sensitization of rat forebrain neurons to serotonin by adinazolam, an antidepressant triazolobenzodiazepine. Eur. J. Pharmacol 1984; 99(--):241-244. >>> Adinazolam; Diazepam; Benzyl alcohol; Ethanol; Propylene glycol; Sodium benzoate; Water; IP; rat; 2002; comparison of adinazolam. iv injec vs. mp infusion; comparison of agents effects; adinazolam. used with water vehicle, Diaz. with combination vehicle.

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2. Alprazolam

16030 Ito, N., Ito, K., Koshimichi, H., Hisaka, A., Honma, M., Igarashi, T., Suzuki, H. Contribution of protein binding, lipid partitioning, and asymmetrical transport to drug transfer into milk in mouse versus human. Pharm Res 2013; 30(-9-):2410-22. >>> acetaminophen, cephalothin sodium salt, clindamycin hydrochloride, disopyramide phosphate salt, labetalol hydrochloride, nitrofurantoin +-propranolol hydrochloride, terbutaline hemisulfate salt, verapamil hydrochloride, Acyclovir, alprazolam, atenolol, anhydrous caffeine, cefotaxime sodium salt, cephapirin sodium salt, diltiazem hydrochloride, metronidazole, nitrazepam, prednisolone, 6-propyl-2-thiouracil, trazadone hydrochloride, chloramphenicol, cimetidine, theophylline, fluconazole, metoprolol, mirtazapine, praziquantel, quetiapine fumarate, triprolidine hydrochloride, metformin, moclobemide.; DMSO; water; IP; mice; 1003D; animal info: lactating mice, postnatal age of 14 days; functionality of mp verified by measurement of drug concentration in milk and plasma; mp were used to infuse study lactational drug transfer..

3775 Byrnes, J.J., Miller, L.G., Greenblatt, D.J., Shader, R.I. Chronic benzodiazepine administration. Psychopharmacology 1993; 111(--):91-95. >>> Alprazolam; Lorazepam; PEG 400; SC; mice; 2001; 2002; controls received vehicle; tolerance.

3606 Tanay, V.A.-M.I., Glencorse, T.A., Greenshaw, A.J., Baker, G.B., Bateson, A.N. Chronic administration of antipanic drugs alters rat brainstem GABA-A receptor subunit mRNA levels. Neuropharmacology 1996; 35(-9/10-):1475-1482. >>> Phenelzine; alprazolam; imipramine; buspirone; Water, sterile; DMSO; propylene glycol; SC; rat; Antidepressant; controls received mp w/ vehicle; pumps were turned in subcutaneous pocket to avoid fibrous tissue outgrowth.

3141 Moreau, J.-L., Jenck, F., Pieri, L., Schoch, P., Martin, J.R., Haefely, W.E. Physical dependence induced in DBA/2J mice by benzodiazepine receptor full agonists, but not by the partial agonist Ro 16-6028. Eur. J. Pharmacol 1990; 190(--):269-273. >>> Triazolam; Alprazolam; Diazepam; Propylene glycol; SC; mice; 2001; controls received mp with vehicle; functionality of mp verified by receptor binding study; comparison of oral alprozolam vs. mp;". . .the use of implantable minipumps. . .permitted. . .development of behavioral tolerance associated with downregulation of benzodiazepine receptor binding and GABA receptor function. . ."; dependence.

2293 Kaplan, G.B., Cotreau, M.M., Greenblatt, D.J. Effects of benzodiazepine administration on A1 adenosine receptor binding in-vivo and ex-vivo. J. Pharm. Pharmacol 1992; 44(--):700-703. >>> Alprazolam; Lorazepam; PEG 400; IP; mice; 2001; controls received mp w/ vehicle.

1776 Miller, L.G., Woolverton, S., Greenblatt, D.J., Lopez, F., Roy, R.B., Shader, R.I. Chronic benzodiazepine administration. IV. Rapid development of tolerance and receptor downregulation associated with alprazolam administration. Biochem. Pharmacol 1989; 38(-21-):3773-3777. >>> Alprazolam; PEG 400; SC; mice; 2001; 2002; functionality of mp verified by measuring plasma levels; tolerance.

1396 Bell, J., Bickford-Wimer, P.C., de la Garza, R., Egan, M., Freedman, R. Increased central nonadrenergic activity during benzodiazepine withdrawal: an electrophysiological study. Neuropharmacology 1988; 27(-11-):1187-1190. >>> Alprazolam; Lorazepam; Ethanol; Propylene glycol; Saline; SC; rat; 2ML2; no comment posted.

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3. Chlordiazepoxide

12215 de Mooij-van Malsen, AJG, Vinkers, C.H., Peterse, D.P., Olivier, B., Kas, M.J.H. Cross-species behavioural genetics: A starting point for unravelling the neurobiology of human psychiatric disorders. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY&BIOLOGICAL PSYCHIATRY 2011; 35(-6-):1383-1390. >>> Chlordiazepoxide; SC; Mice; Animal info (C57BL/6J).

12827 Sevoz-Couche, C., Brouillard, C., Camus, F., Laude, D., de Boer, S.F., Becker, C., Benoliel, J.J. Involvement of the dorsomedial hypothalamus and the nucleus tractus solitarii in chronic cardiovascular changes associated with anxiety in rats. JOURNAL OF PHYSIOLOGY-LONDON 2013; 591(-7-):1871-1887. >>> Chlordiazepoxide; SC; Rat; 2ML1; Control animals received mp w/ vehicle; animal info (Sprague Dawley, male, 250-300 g).

10670 Rivat, C., Becker, C., Blugeot, A., Zeau, B., Mauborgne, A., Pohl, M., Benoliel, J.J. Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia. Pain 2010; 150(-2-):358-368. >>> CI-988; chlordiazepoxide; aspirin; DMSO; saline; SC; CSF/CNS (intrathecal); Rat; 2ML1; 2001; 2002; Controls received mp w/ vehicle; animal info (Male, Sprague-Dawley, 300-325 g, 8 wks old; ALZET intrathecal catheter used (0007740); behavioral testing (elevated plus-maze).

10324 Vinkers, C.H., Korte-Bouws, G.A.H., Torano, J.S., Mirza, N.R., Nielsen, E.O., Ahring, P.K., de Jong, G.J., Olivier, B. The rapid hydrolysis of chlordiazepoxide to demoxepam may affect the outcome of chronic osmotic minipump studies. Psychopharmacology 2010; 208(-4-):555-562. >>> Chlordiazepoxide; In vitro; "When the cumulative CDP concentration over time was corrected for its hydrolysis, drug release from the minipumps followed the theoretical release profile over time (white symbols), suggesting that CDP hydrolysis completely accounted for the declined CDP release over time."pg 558;"In general, the use of osmotic minipumps presents a valid and attractive alternative to the labor-intensive daily injections. However, the issue of drug stability and release should always be carefully investigated before initiating chronic minipump experiments."pg 562.

9815 West, C.H.K., Ritchie, J.C., Boss-Williams, K.A., Weiss, J.M. Antidepressant drugs with differing pharmacological actions decrease activity of locus coeruleus neurons. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY 2009; 12(-5-):627-641. >>> Desipramine; mirtazapine; chlorpheniramine; Paroxetine; scopolamine; amphetamine; escitalopram; chlordiazepoxide; SC; IP; Rat; 2ML2; Controls received mp w/vehicle; dose-response (Fig 2-5); pumps replaced on day 14; good methods pg 629; animal info (male, Sprague Dawley, 5-7 mo old, 550-700g);"Importantly, use of minipumps also eliminates the need for repeated handling and injection of animals to administer the drug chronically."pg. 628; IP catheter used.

9296 Kas, M.J.H., Malsen, A.D., Olivier, B., Spruijt, B.M., van Ree, J.M. Differential genetic regulation of motor activity and anxiety-related behaviors in mice using an automated home cage task. Behavioral Neuroscience 2008; 122(-4-):769-776. >>> Chlordiazepoxide; Saline; SC; Mice; 1007D; Controls received mp w/ saline; animal info (C57BL/6J, male); chlordiazepoxide is an anxiolytic.

7528 Andre, J., Zeau, B., Pohl, M., Cesselin, F., Benoliel, J.J., Becker, C. Involvement of cholecystokininergic systems in anxiety-induced hyperalgesia in male rats: Behavioral and biochemical studies. Journal of Neuroscience 2005; 25(-35-):7896-7904. >>> Chlordiazepoxide; Water, distilled; SC; Rat; 2ML1; Controls received mp w/ saline.

4480 Cash, D.J., Serfozo, P., Allan, A.M. Desensitization of a g-aminobutyric acid type A receptor in rat is increased by chronic treatment with chlordiazepoxide: a molecular mechanism of dependence.. Journal of Pharmacology and Experimental Therapeutics 1997; 283(-2-):704-711. >>> Chlordiazepoxide;; SC;; rat;; controls received mp with vehicle; tolerance; dependence; chlordiazepoxide is a tranquilizer; rats were 6-8 weeks old;.

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4. Clonazepam

3664 Arnot, M.I., Bateson, A.N., Martin, I.L. Dimethyl sulfoxide/propylene glycol is a suitable solvent for the delivery of diazepam from osmotic minipumps. J. Pharm.&Tox. Meth 1996; 36(--):29-31. >>> Diazepam; Clonazepam; flumazenil; DMSO; Propylene glycol; Tetraglycol; 3H tracer; Radio-isotopes; in vitro; 2ML4; no comment posted.

3413 Lima, L., Trejo, E., Urbina, M. Serotonin turnover rate, [3H] paroxetine binding sites, and 5-HT1A receptors in the hippocampus of rats subchronically treated with clonazepam. Neuropharmacology 1995; 34(-10-):1327-1333. >>> Clonazepam; PEG; CSF/CNS (dorsal raphe nucleus); rat; comparison of IP injections vs. mp.

2740 Brodin, K., Ogren, S.-O., Brodin, E. Clomipramine and clonazepam increase cholecystokinin levels in rat ventral tegmental area and limbic regions. Eur. J. Pharmacol 1994; 263(--):175-180. >>> Nortriptyline; Amitriptyline; Clomipramine; Alaproclate; Clonazepam; Alcohol; Saline; SC; rat; 2ML2; antidepressant; controls received mp w/ vehicle; functionality of mp verified by plasma levels; dose-response (Table 1; pg. 177); enzyme inhibitor; clonazepam is a benzodiazepene; the others are monoamine uptake inhibitors.

1647 Miller, L.G., Galpern, W.R., Greenblatt, D.J., Lumpkin, M., Shader, R.I. Chronic benzodiazepine administration. VI. a partial agonist produces behavioral effects without tolerance or receptor alterations. J. Pharmacol. Exp. Ther 1990; 254(-1-):33-36. >>> Clonazepam; RO-16-6028; PEG 400; SC; mice; functionality of mp verified by tissue levels; dose-response (graph); tolerance/dependence.

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5. Diazepam

12426 Vinkers, C.H., van Oorschot, R., Nielsen, E.O., Cook, J.M., Hansen, H.H., Groenink, L., Olivier, B., Mirza, N.R. GABA-A Receptor alpha Subunits Differentially Contribute to Diazepam Tolerance after Chronic Treatment. PLoS One 2012; 7(-8-):U614-U624. >>> Diazepam; zolpidem; TPA023; bretazenil; PEG 400; alcohol; water, distilled; SC; Mice; 2004; Controls received mp w/ vehicle; animal info (129 Sv/Ev Tac, 10-12 wks old); 95% PEG 400 used; 2.5% alcohol used; stress/adverse effects"severe hypothermia likely explains the death of seven animal's postsurgically..."pg 9; TPA023 is an alpha 2/3 selective GABAa receptor positive allosteric modulator.

12252 Spolidoro, M., Baroncelli, L., Putignano, E., Maya-Vetencourt, J.F., Viegi, A., Maffei, L. Food restriction enhances visual cortex plasticity in adulthood. Nature Communications 2011; 2(-;-):U210-U217. >>> Diazepam; mercaptopropionic acid; Propylene glycol; CSF/CNS (visual cortex); Rat; 2002; Animal info (Long Evans hooded, P60-P90, male, female); 50% propylene glycol used.

9691 Stone, E.A., Lin, Y., Quartermain, D. Evaluation of the repeated open-space swim model of depression in the mouse. Pharmacology Biochemistry and Behavior 2008; 91(-1-):190-195. >>> Imipramine HCl, desmethyl; diazepam; fluoxetine; haloperidol; Saline; DMSO; water; SC; Mice; 1002; Controls received mp w/ vehicle; half-life (p. 191); animal info (male, Swiss Webster, 8-10 wks old); 25% ,50%, or 100% DMSO used; behavioral testing (swimming behavior, tail-suspension test, sucrose suspension test);"since drugs have relatively short half-lives in mice, to more closely mimic the human condition in which blood levels are maintained for prolonged periods, all agents were administered by osmotic minipump."(p. 191).

9047 Depino, A.M., Tsetsenis, T., Gross, C. GABA homeostasis contributes to the developmental programming of anxiety-related behavior. Brain Research 2008; 1210(--):189-199. >>> Diazepam; DMSO; propylene glycol; SC; Mice; mice (neonate); 1002; 2002; Controls received mp w/ vehicle; dose-response (Fig. 1); no stress (see pg. 193); post op. care (flumazenil); animal info (C57BL/6 x 129/SvJ, male, 14 days old, 60 days old); 50% DMSO used; behavioral testing (maze); wound clips used; 50% propylene glycol used.

8177 Hensch, T.K., Fagiolini, M., Mataga, N., Stryker, M.P., Baekkeskov, S., Kash, S.F. Local GABA Circuit Control of Experience-Dependent Plasticity in Developing Visual Cortex. Dynamics 1997; 210(--):53. >>> Tetrodotoxin; diazepam; Propylene glycol; CSF/CNS (visual cortex); Mice; 1007D; Controls received mp w/ vehicle; half-life (p. 1508), rapid breakdown (diazepam); monocular deprivation, localization of cannula delivery confirmed with dye.

6119 Hensch, T.K., Stryker, M.P. Columnar architecture sculpted by GABA circuits in developing cat visual cortex. Science 2004; 303(-5664-):1678-1681. >>> Diazepam; Propylene Glycol; CSF/CNS (visual cortex); Cat (kitten); 2004; 2ML4; Diazepam is a benzodiazepine agonist.

5407 Fagiolini, M., Hensch, T.K. Inhibitory threshold for critical-period activation in primary visual cortex. Nature 2000; 404(-6774-):183-186. >>> Diazepam; Propylene glycol; CSF/CNS (visual cortex); Mice; 1007D; Controls received mp w/ vehicle; comparison of icv injections vs. mp; 50% propylene glycol used.

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6. Lorazepam

8400 Fahey, J.M., Pritchard, G.A., Reddi, J.M., Pratt, J.S., Grassi, J.M., Shader, R.I., Greenblatt, D.J. The effect of chronic lorazepam administration in aging mice. Brain Research 2006; 1118(--):13-24. >>> Lorazepam; PEG 400; SC; Mice; Controls received mp w/ vehicle; functionality of mp verified by lorazepam plasma concentrations; tolerance; animal info (male, CD-1, 2-3 months old, 10-12 months old, 22-24 months old).

5025 Fahey, J.M., Pritchard, G.A., Grassi, J.M., Pratt, J.S., Shader, R.I., Greenblatt, D.J. Pharmacodynamic and receptor binding changes during chronic lorazepam administration. Pharmacology Biochemistry and Behavior 2001; 69(--):1-8. >>> Lorazepam; PEG 400; SC; mice; controls received mp w/ vehicle; plasma lorazepam levels; brains examined postmortem for membrane binding; lorazepam is a benzodiazepine with anxiolytic and anti-insomnia properties;.

4697 Tehrani, M.H.J, Barnes, E.M. Sequestration of g-Aminobutyric acidA receptors on clathrin-coated vesicles during chronic benzodiazepine administration in vivo;. The Journal of Pharmacology and Experimental Therapeutics 1997; 283(-1-):384-390. >>> Lorazepam;; PEG 400;; SC;; mice;; 2001;; controls received mp w/vehicle; tolerance;.

3775 Byrnes, J.J., Miller, L.G., Greenblatt, D.J., Shader, R.I. Chronic benzodiazepine administration. Psychopharmacology 1993; 111(--):91-95. >>> Alprazolam; Lorazepam; PEG 400; SC; mice; 2001; 2002; controls received vehicle; tolerance.

3436 Mortensen, M., Suzdak, P.D., Thomsen, C. The effect of lorazepam tolerance and withdrawal on metabotropic glutamate receptor function. J. Pharmacol. Exp. Ther 1995; 274(-1-):155-163. >>> Lorazepam; PEG 400; SC; mice; 2001; tolerance.

2698 Allan, A.M., Baier, L.D., Zhang, X. Effects of lorazepam tolerance and withdrawal on GABA receptor operated chloride channels in mice selected for differences in ethanol withdrawal severity. Life Sci 1992; 51(-12-):931-943. >>> Lorazepam; PEG 400; SC; mice; controls received mp w/ vehicle; tolerance.

2588 Miller, L.G., Galpern, W.R., Byrnes, J.J., Greenblatt, D.J., Shader, R.I. Chronic benzodiazepine administration. x. concurrent administration of the peripheral-type benzodiazepine ligand PK11195 attenuates chronic effects of lorazepam. J. Pharmacol. Exp. Ther 1992; 261(-1-):285-289. >>> Lorazepam; PK 11195; SC; mice; controls received mp w/ vehicle; tolerance; Lorazepam and PK11195 infused separately and together; PK11195 is a peripheral-type site ligand; pumps chosen because they produce"constant plasma and brain concentrations"..

2423 Miller, LG., Chesley, S., Galpern, W.R., Greenblatt, D.J., Shader, R.I. Prenatal benzodiazepine administration, II. lorazepam exposure is associated with decreases in [35S]TBPS binding but not benzodiazepine binding. Pharmacol. Biochem. Behav 1991; 40(--):429-432. >>> Lorazepam; PEG 400; SC; mice (pregnant); 2001; teratology.

2293 Kaplan, G.B., Cotreau, M.M., Greenblatt, D.J. Effects of benzodiazepine administration on A1 adenosine receptor binding in-vivo and ex-vivo. J. Pharm. Pharmacol 1992; 44(--):700-703. >>> Alprazolam; Lorazepam; PEG 400; IP; mice; 2001; controls received mp w/ vehicle.

2076 Allan, A.M., Baier, L.D., Zhang, X. Effects of lorazepam tolerance and withdrawal on GABA-A receptor-operated chloride channels. J. Pharmacol. Exp. Ther 1992; 261(-2-):395-402. >>> Lorazepam; PEG 400; SC; mice; tolerance.

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7. Triazolam

3141 Moreau, J.-L., Jenck, F., Pieri, L., Schoch, P., Martin, J.R., Haefely, W.E. Physical dependence induced in DBA/2J mice by benzodiazepine receptor full agonists, but not by the partial agonist Ro 16-6028. Eur. J. Pharmacol 1990; 190(--):269-273. >>> Triazolam; Alprazolam; Diazepam; Propylene glycol; SC; mice; 2001; controls received mp with vehicle; functionality of mp verified by receptor binding study; comparison of oral alprozolam vs. mp;". . .the use of implantable minipumps. . .permitted. . .development of behavioral tolerance associated with downregulation of benzodiazepine receptor binding and GABA receptor function. . ."; dependence.

2742 Cohen, C., Sanger, D.J. Tolerance, cross-tolerance and dependence measured by operant responding in rats treated with triazolam via osmotic pumps. Psychopharmacology 1994; 115(--):86-94. >>> Triazolam; Propylene glycol; SC; rat; 2ML2; controls received mp w/ vehicle; tolerance; dependence.

2109 Zhou, L.-W., Zhang, S.-P., Welsh, S., Connell, T.A., Weiss, B. Triazolam blocks the initial rotational effects of quinpirole but permits the later developing reduction of dopamine D2-mediated rotational behavior and dopamine D2 receptors. Eur. J. Pharmacol 1992; 218(--):219-227. >>> Quinpirole HCl; Sulpiride; Triazolam; Ascorbic acid; DMSO; SC; mice; 2001; Quinpirole is a dopamine agonist; antidepressant; stability verified in vitro for 7 days.

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What researchers are saying ...

“The infusion treatment using implanted ALZET-type osmotic mini-pumps proved to be superior to both S.C. and I.V. infusion applied twice a day for 2 weeks.” (p. 586) Szende et al., Anti-Cancer Drugs 2003;14:585-588.