The pharmacokinetics and in vitro cyclooxygenase selectivity of deracoxib in horses.

The purpose of this study was to determine the pharmacokinetics of deracoxib following oral administration to horses. In addition, in vitro equine whole blood cyclooxygenase (COX) selectivity assays were performed. Six healthy adult horses were administered deracoxib (2 mg/kg) orally. Plasma samples were collected prior to drug administration (time 0), and 10, 20, 40 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after administration for analysis with high pressure liquid chromatography using ultraviolet detection. Following PO administration, deracoxib had a long elimination half-life (t(1/2) k(10) ) of 12.49 ± 1.84 h. The average maximum plasma concentration (C(max) ) was 0.54 µg/mL, and was reached at 6.33 ± 3.44 h. Bioavailability was not determined because of the lack of an IV formulation. Results of in vitro COX selectivity assays showed that deracoxib was selective for COX-2 with a COX-1/COX-2 ratio of 25.67 and 22.06 for the IC(50) and IC(80) , respectively. Dosing simulations showed that concentrations above the IC(80) for COX-2 would be maintained following 2 mg/kg PO q12h, and above the IC(50) following 2 mg/kg PO q24h. This study showed that deracoxib is absorbed in the horse after oral administration, and may offer a useful alternative for anti-inflammatory treatment of various conditions in the horse.

Efficacy and pharmacokinetics of pantoprazole in alpacas.

BACKGROUND: Despite frequent clinical use, information about the pharmacokinetics and efficacy of pantoprazole in camelids is not available. OBJECTIVES: To examine the pharmacokinetics of both IV and SC pantoprazole and to determine whether pantoprazole administration would increase 3rd compartment pH in alpacas. ANIMALS: Six healthy adult alpacas. METHODS: Alpacas were fitted with a 3rd compartment cannula for measuring gastric pH. After recovery, alpacas received 1 mg/kg pantoprazole IV, q24h for 3 days or 2 mg/kg SC q24h for 3 days. Alpacas received both IV and SC pantoprazole, with a minimum of 3 weeks between treatments. Third compartment pH was recorded and plasma samples were taken for pharmacokinetic analysis. RESULTS: Pantoprazole induced a slow but sustained increase in 3rd compartment pH when given by both the IV and SC routes. Third compartment pH was significantly increased as compared with baseline values (1.81+/-0.7; mean+/-SD) at 24 (2.47+/-0.8), 48 (3.53+/-1.0) and 72 hours (4.03+/-1.3) after daily IV administration of pantoprazole. Third compartment pH increased from 1.73+/-0.6 at baseline to 3.05+/-1.1, 4.02+/-1.4, and 3.61+/-1.6 at 24, 48, and 72 hours after SC administration, respectively. Pharmacokinetic analysis demonstrated that pantoprazole had a short elimination half-life (0.47+0.06 h) and a high clearance rate (12.2+/-2.9 mL/kg/min) after both IV and SC administration. CONCLUSIONS AND CLINICAL RELEVANCE: Based on the results of this study, pantoprazole represents a safe and effective drug for increasing 3rd compartment pH in camelids. Either IV or SC administration is likely to be an effective treatment for gastric ulcers.

Third-compartment cannulation in alpacas using a polyurethane gastrostomy tube.

OBJECTIVE: To develop a simple and effective surgical technique for third-compartment cannulation in alpacas. DESIGN: Prospective study using six adult male alpacas. METHODS: General anaesthesia was induced and a polyurethane gastrostomy tube was surgically implanted into the distal portion of the third compartment. RESULTS: Three of the alpacas retained their cannulas for a 100-day period; however, three cannulas were dislodged during the study. Two of the three dislodged cannulas were replaced during a second surgical procedure. Cannulas were well tolerated by the alpacas and all animals remained clinically healthy during the study period. Third compartment contents did not leak from the cannulation site. The tubes were manually removed following the completion of the study and the small defect in the body wall quickly healed over in all animals. CONCLUSION: Surgical placement of polyurethane tubes designed for percutaneous endoscopic gastrostomy is a useful method of cannulating the third compartment in camelids. This technique can be used for experimental studies and possibly could be used for nutritional support and fluid therapy in sick camelids that might need long-term care.

Attenuation of ischaemic injury in the equine jejunum by administration of systemic lidocaine.

REASONS FOR PERFORMING STUDY: Absorption of endotoxin across ischaemic-injured mucosa is a major cause of mortality after colic surgery. Recent studies have shown that flunixin meglumine retards mucosal repair. Systemic lidocaine has been used to treat post operative ileus, but it also has novel anti-inflammatory effects that could improve mucosal recovery after ischaemic injury. HYPOTHESIS: Systemic lidocaine ameliorates the deleterious negative effects of flunixin meglumine on recovery of mucosal barrier function. METHODS: Horses were treated i.v. immediately before anaesthesia with either 0.9% saline 1 ml/50 kg bwt, flunixin meglumine 1 mg/kg bwt every 12 h or lidocaine 1.3 mg/kg bwt loading dose followed by 0.05 mg/kg bwt/min constant rate infusion, or both flunixin meglumine and lidocaine, with 6 horses allocated randomly to each group. Two sections of jejunum were subjected to 2 h of ischaemia by temporary occlusion of the local blood supply, via a midline celiotomy. Horses were monitored with a behavioural pain score and were subjected to euthanasia 18 h after reversal of ischaemia. Ischaemic-injured and control jejunum was mounted in Ussing chambers for measurement of transepithelial electrical resistance (TER) and permeability to lipopolysaccharide (LPS). RESULTS: In ischaemic-injured jejunum TER was significantly higher in horses treated with saline, lidocaine or lidocaine and flunixin meglumine combined, compared to horses treated with flunixin meglumine. In ischaemic-injured jejunum LPS permeability was significantly increased in horses treated with flunixin meglumine alone. Behavioural pain scores did not increase significantly after surgery in horses treated with flunixin meglumine. CONCLUSIONS: Treatment with systemic lidocaine ameliorated the inhibitory effects of flunixin meglumine on recovery of the mucosal barrier from ischaemic injury, when the 2 treatments were combined. The mechanism of lidocaine in improving mucosal repair has not yet been elucidated.

Pharmacokinetics of etodolac in the horse following oral and intravenous administration.

The purpose of this study was to determine the pharmacokinetics of etodolac following oral and intravenous administration to six horses. Additionally, in vitro cyclooxygenase (COX) selectivity assays were performed using equine whole blood. Using a randomized two-way crossover design, horses were administered etodolac (20 mg/kg) orally or intravenously, with a minimum 3-week washout period. Plasma samples were collected after administration for analysis using high pressure liquid chromatography with ultraviolet detection. Following intravenous administration, etodolac had a mean plasma half-life (t(1/2)) of 2.67 h, volume of distribution (Vd) of 0.29 L/kg and clearance (Cl) of 234.87 mL/h kg. Following oral administration, the average maximum plasma concentration (Cmax)) was 32.57 mug/mL with a t(1/2) of 3.02 h. Bioavailability was approximately 77.02%. Results of in vitro COX selectivity assays showed that etodolac was only slightly selective for COX-2 with a COX-1/COX-2 selectivity ratio effective concentration (EC)50 of 4.32 and for EC80 of 4.77. This study showed that etodolac is well absorbed in the horse after oral administration, and may offer a useful alternative for anti-inflammatory treatment of various conditions in the horse.

The effects of cyclo-oxygenase inhibitors on bile-injured and normal equine colon.

A potential adverse effect of cyclo-oxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) in horses is colitis. In addition, we have previously shown an important role for COX-produced prostanoids in recovery of ischaemic-injured equine jejunum. It was hypothesised that the nonselective COX inhibitor flunixin would retard repair of bile-injured colon by preventing production of reparative prostaglandins, whereas the selective COX-2 inhibitor, etodolac would not inhibit repair as a result of continued COX-1 activity. Segments of the pelvic flexure were exposed to 1.5 mmol/l deoxycholate for 30 min, after which they were recovered for 4 h in Ussing chambers. Contrary to the proposed hypothesis, recovery of bile-injured colonic mucosa was not affected by flunixin or etodolac, despite significantly depressed prostanoid production. However, treatment of control tissue with flunixin led to increases in mucosal permeability, whereas treatment with etodolac had no significant effect. Therefore, although recovery from bile-induced colonic injury maybe independent of COX-elaborated prostanoids, treatment of control tissues with nonselective COX inhibitors may lead to marked increases in permeability. Alternatively, selective inhibition of COX-2 may reduce the incidence of adverse effects in horses requiring NSAID therapy.

Recovery of ischaemic injured porcine ileum: evidence for a contributory role of COX-1 and COX-2.

BACKGROUND: We have previously shown that the non-selective cyclooxygenase (COX) inhibitor indomethacin retards recovery of intestinal barrier function in ischaemic injured porcine ileum. However, the relative role of COX-1 and COX-2 elaborated prostaglandins in this process is unclear. AIMS: To assess the role of COX-1 and COX-2 elaborated prostaglandins in the recovery of intestinal barrier function by evaluating the effects of selective COX-1 and COX-2 inhibitors on mucosal recovery and eicosanoid production. METHODS: Porcine ileal mucosa subjected to 45 minutes of ischaemia was mounted in Ussing chambers, and transepithelial electrical resistance was used as an indicator of mucosal recovery. Prostaglandins E1 and E2 (PGE) and 6-keto-PGF1alpha (the stable metabolite of prostaglandin I2 (PGI2)) were measured using ELISA. Thromboxane B2 (TXB2, the stable metabolite of TXA2) was measured as a likely indicator of COX-1 activity. RESULTS: Ischaemic injured tissues recovered to control levels of resistance within three hours whereas tissues treated with indomethacin (5x10(-6) M) failed to fully recover, associated with inhibition of eicosanoid production. Injured tissues treated with the selective COX-1 inhibitor SC-560 (5x10(-6) M) or the COX-2 inhibitor NS-398 (5x10(-6) M) recovered to control levels of resistance within three hours, associated with significant elevations of PGE and 6-keto-PGF1alpha compared with untreated tissues. However, SC-560 significantly inhibited TXB2 production whereas NS-398 had no effect on this eicosanoid, indicating differential actions of these inhibitors related to their COX selectivity. CONCLUSIONS: The results suggest that recovery of resistance is triggered by PGE and PGI2, which may be elaborated by either COX-1 or COX-2.

Pharmacokinetics of fluconazole following intravenous and oral administration and body fluid concentrations of fluconazole following repeated oral dosing in horses.

OBJECTIVE: To determine the pharmacokinetics of fluconazole in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Fluconazole (10 mg/kg of body weight) was administered intravenously or orally with 2 weeks between treatments. Plasma fluconazole concentrations were determined prior to and 10, 20, 30, 40, and 60 minutes and 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after administration. A long-term oral dosing regimen was designed in which all horses received a loading dose of fluconazole (14 mg/kg) followed by 5 mg/kg every 24 hours for 10 days. Fluconazole concentrations were determined in aqueous humor, plasma, CSF, synovial fluid, and urine after administration of the final dose. RESULTS: Mean (+/- SD) apparent volume of distribution of fluconazole at steady state was 1.21+/-0.01 L/kg. Systemic availability and time to maximum plasma concentration following oral administration were 101.24+/-27.50% and 1.97+/-1.68 hours, respectively. Maximum plasma concentrations and terminal half-lives after IV and oral administration were similar. Plasma, CSF, synovial fluid, aqueous humor, and urine concentrations of fluconazole after long-term oral administration of fluconazole were 30.50+/-23.88, 14.99+/-1.86, 14.19+/-5.07, 11.39+/-2.83, and 56.99+/-32.87 microg/ml, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Bioavailability of fluconazole was high after oral administration to horses. Long-term oral administration maintained plasma and body fluid concentrations of fluconazole above the mean inhibitory concentration (8.0 mg/ml) reported for fungal pathogens in horses. Fluconazole may be an appropriate agent for treatment of fungal infections in horses.

The role of cyclooxygenase inhibitors in repair of ischaemic-injured jejunal mucosa in the horse.

Cyclooxygenase inhibitors are administered to horses to prevent endotoxin-induced elaboration of prostaglandins. However, PGE2 and PGI2 stimulate repair of injured intestine. There are 2 isoforms of cyclooxygenase: COX-1, which constitutively produces prostaglandins and COX-2, which is induced by inflammation. We hypothesised that the nonspecific cyclooxygenase inhibitor flunixin meglumine would retard repair of ischaemic intestinal injury by preventing production of reparative prostaglandins, whereas the selective COX-2 inhibitor, etodolac, would permit repair as a result of continued COX-1 prostaglandin production. Segments of equine jejunum were subjected to ischaemia for 1 h, and recovered for 4 h in Ussing chambers. In ischaemic tissue, treated with the nonspecific cyclooxygenase inhibitor, flunixin meglumine (2.7 x 10(-5) mol/l), production of PGE2 and PGI2 was inhibited, and there was no evidence of recovery based on measurements of transepithelial resistance. Conversely, untreated ischaemic tissues or tissues treated with the specific COX-2 inhibitor etodolac (2.7 x 10(-5) mol/l) had significant elevations in PGE2 and PGI2, and significant recovery of transepithelial resistance. These studies suggest that specific COX-2 inhibitors may provide an advantageous alternative to nonspecific cyclooxygenase inhibitors in horses with colic.

Preadolescent suicidal behavior: the role of cognitive functioning.

The recent suicidal behavior of fifty-three hospitalized preadolescents was assessed in interviews with children and their parents. Children described by their parents as more suicidal scored higher on measures of verbal intelligence and language production than their less suicidal counterparts, with unique variance predicted only by language production ability. The results suggest that parents of preadolescents with better language production skills may be more aware of their youngsters' suicidal thoughts than parents of children with poorer language production ability.

Unrecognized language and speech deficits in preadolescent psychiatric inpatients.

Of 55 psychiatrically hospitalized preadolescents with DSM-III-R diagnoses that are not commonly associated with language deficits, 60% were determined to have language or speech deficits, although only 38% had ever received speech or language therapy. The clinical implications of these findings are discussed and guidelines for practice outlined.

Rumination in adults: two case histories.

Rumination has been reported to be a relatively rare disorder of eating during infancy. Over the past decade, there appears to be a renewed interest in and recognition of adult rumination. Although some authors believe adult rumination is benign, others have begun to link it with both eating disorders and depressive symptoms. This paper presents two adult cases whose rumination was associated with anorexia and bulimia nervosa. More identification and study of adult rumination is needed to clarify its course and medical significance.

Suicide: a review of calls to an adolescent peer listening phone service.

Calls about suicide to a teen peer listening phone service over a period of 5 1/2 years are described. The majority of those calling about suicide were females. The phone contacts were of longer duration and later in the evening than calls about other concerns. Those concerned with suicide also discussed other serious issues such as self-esteem, family problems, substance use, and abuse and were less likely to be calling "just to talk."

The psychosocial climate of families with suicidal pre-adolescent children.

A structured interview measure of suicidal behavior and a questionnaire measure of family psychosocial climate were administered to 43 pre-adolescent psychiatric inpatients and their parents. Results showed that suicidal behavior tended to be associated with greater family conflict and with less family organization, cohesion, and achievement orientation.

Physician pregnancy: male and female colleagues' attitudes.

A survey questionnaire was mailed to residents and faculty at a midwestern medical school to assess male and female attitudes toward colleagues' pregnancies. A total of 67% (N = 97) of the 145 faculty and 48% (N = 103) of the 214 residents completed surveys, yielding an overall return rate of 56% (N = 200). Among faculty, responses on only 1 of the 15 items showed a significant difference by gender. Residents' responses, however, showed statistically significant gender differences on 8 of the 15 items. More female than male residents felt that pregnant physicians maintain job performance and interest in medicine. More male than female residents believed pregnancy was disruptive to relationships with colleagues and viewed women of childbearing age as a risk to the optimum functioning of a department. The authors discuss reasons for the gender differences in attitude found among the residents and suggest possible interventions.

The relationship of suicidality and psychiatric diagnosis in hospitalized pre-adolescent children.

Two structured interview measures of suicidal behavior were administered to 43 child psychiatric inpatients between the ages of 7 and 11 and their parents. DSM-III-R diagnoses were assigned to the children, with twenty-six Axis I and Axis II diagnostic categories represented. Generally, the interview measures of suicidal behavior were found to be unrelated to psychiatric diagnosis. The results suggest that to better understand pre-adolescent suicidal behaviors, it may be more useful to examine associations between these behaviors and the biopsychosocial dimensions that underlie the diagnostic categories.

Suicidal behavior among psychiatric inpatient children: an estimate of prevalence.

The prevalence of suicidal behavior among pre-adolescent child psychiatric inpatients has been estimated to range between 18 and 80 percent of the inpatient population. This study is a chart review of the documentation of suicidal behaviors displayed by 45 consecutive child psychiatric inpatient admissions. According to the Pfeffer Spectrum of Suicidal Behavior Scale, 31 percent of the sample had recently engaged in some form of suicidal behavior and 9 percent had made a life-threatening attempt.

Postabortion dysphoria and religion.

This study explores psychosocial factors, especially religion, in women identified as dysphoric 1 to 15 years after abortion. The Millon Clinical Multiaxial Inventory (MCMI) and a demographic questionnaire were mailed to patient-led support groups for women who had poorly assimilated a previous abortion experience. Of the 150 surveys mailed, 71 (47%) were returned. Thirty-three women (46%) stated they had changed to a Fundamentalist or Evangelical church. On the MCMI, members of these conservative denominations scored significantly lower on the subscales for passive-aggressive behavior, ethanol abuse, and avoidance. Religion was strongly perceived by the women as playing a healing role. These findings suggest that conservative personal values may be more critical in understanding attitudes toward abortion than other demographic characteristics. Previous follow-up studies that reported no change in postabortion religiosity may have been too short to detect changes in religion. Implications for treatment of postabortion dysphoria include sensitivity to patients' religious beliefs, with support for the healing aspects of their religion.