[Ultra Peanut]

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25–29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.

Background: Multiple idiopathic root resorption (MIRR) is a rare condition in man characterized by cervical resorption leading to significant tooth loss. A similar condition, feline osteoclastic resorptive lesions (FORL), affects up to 70% of domestic cats and thus provides a valuable model for investigating the etiopathogenesis of MIRR. The aim of the present study was to establish changes in the surface microanatomy of the tooth in late stage FORL and to identify whether its location has a surface bias.

Methods: Scanning electron microscopy (SEM) was used to analyze the surface features of enamel and cementum of feline teeth affected with advanced FORL.

Results: Resorption involved the coronal root at the cementoenamel junction (CEJ) in 95% of teeth and focal resorption of intact enamel was observed in 14% of teeth. In 55% of teeth, the main lesion was on the buccal surface and a distinct circumferential resorption "front" was present at the apical margin of resorption. The root surfaces of most affected teeth either lacked extrinsic fibers or cellular lacunae or featured evidence of cementum remodeling. Woven bone-like tissue was found within lesions, on resorbed dentin, or on the root surface in 27% of teeth.

Conclusions: This study demonstrates that most FORL involve the CEJ, and the presence of focal lesions at this site suggests that this is where resorption is initiated. This implies that local factors in the oral microenvironment play a role in the etiopathogenesis of this condition. The study also shows that FORL are more likely to occur on buccal surfaces and are associated with changes in the microarchitecture of the root surface consistent with destruction of the normal periodontal attachment and stimulation of a reparative response. These findings may be relevant to understanding the etiopathogenesis of multiple idiopathic resorption areas in man. J Periodontol 2005;76:1106-1112.

What is claimed is:

1. A compound of the formula (I):

wherein:

Y is NR,
wherein R is hydrogen or (C1–C6) lower alkyl;

represents (1) a phenyl ring optionally substituted with one or two substituents selected, independently, from the group comprising hydrogen, (C1–C6) lower alkyl, halogen, cyano, CF3, hydroxy, (C1–C6) lower alkoxy, or (C1–C6) lower alkoxy carbonyl, carboxy, —CONH2, —CONH[(C1–C6) lower alkyl], —CON[(C1–C6) lower alkyl]2; or (2) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C1–C6) lower alkyl, halogen or (C1–C6) lower alkoxy;

represents (1) a phenyl ring optionally substituted with one or two substituents selected, independently, from the group comprising hydrogen, (C1–C6) lower alkyl, halogen, cyano, CF3, hydroxy, (C1–C6) lower alkoxy, or (C1–C6) lower alkoxy carbonyl, carboxy, —CONH2, —CONH[(C1–C6) lower alkyl], —CON[(C1–C6) lower alkyl]2; (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C1–C6,) lower alkyl, (C1–C6) lower alkoxy, or halogen; or (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, optionally substituted by (C1–C6) lower alkyl, halogen, or (C1–C6) lower alkoxy;

or a pharmaceutically acceptable salt.

2. A (4-cyclohexyl-phenyl)-(5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone, or a pharmaceutically acceptable salt form thereof.

3. A (4-cyclohexyl-phenyl)-(5,11-dihydro-11-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone, or a pharmaceutically acceptable salt form thereof.

4. A (4-cyclohexyl-phenyl)-(5,11-dihydro-11-ethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone, or a pharmaceutically acceptable salt thereof.

5. A (4-cyclohexyl-phenyl)-(5,11-dihydro-10H-dibenzo[b,c][1,4]diazepin-10-yl)methanone, or a pharmaceutically acceptable salt form thereof.

6. A (4-cyclohexyl-phenyl)-(5,11-dihydro-5-methyl-10H-dibenzo[b,e][1,4]diazepin-10-yl)-methanone, or a pharmaceutically acceptable salt form thereof.

7. A method for treating diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, or bleeding and coagulation, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. A method of inducing temporary delay of urination in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt.

9. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.