The pharmacokinetics of oclacitinib maleate, a Janus kinase inhibitor, in the dog.

The pharmacokinetics of oclacitinib maleate was evaluated in four separate studies. The absolute bioavailability study used a crossover design with 10 dogs. The effect of food on bioavailability was investigated in a crossover study with 18 dogs. The breed effect on pharmacokinetics was assessed in a crossover study in beagles and mongrels dogs. Dose proportionality and multiple dose pharmacokinetics were evaluated in a parallel design study with eight dogs per group. In all four studies, serial blood samples for plasma were collected. Oclacitinib maleate was rapidly and well absorbed following oral administration, with a time to peak plasma concentration of <1 h and an absolute bioavailability of 89%. The prandial state of dogs did not significantly affect the rate or extent of absorption of oclacitinib maleate when dosed orally, as demonstrated by the lack of significant differences in pharmacokinetic parameters between the oral fasted and oral fed treatment groups. The pharmacokinetics of oclacitinib in laboratory populations of beagles and mixed breed dogs also appeared similar. Following oral administration, the exposure of oclacitinib maleate increased dose proportionally from 0.6 to 3.0 mg/kg. Additionally, across the pharmacokinetic studies, there were no apparent differences in oclacitinib pharmacokinetics attributable to sex.

Comparative analysis of antibody responses to outer surface protein (Osp)A and OspC in dogs vaccinated with Lyme disease vaccines.

Lyme disease (LD), the most common tick-borne disease of canines and humans in N. America, is caused by the spirochete Borreliella burgdorferi. Subunit and bacterin vaccines are available for the prevention of LD in dogs. LD bacterin vaccines, which are comprised of cell lysates of two strains of B. burgdorferi, contain over 1000 different proteins and cellular constituents. In contrast, subunit vaccines are defined in composition and consist of either outer surface protein (Osp)A or OspA and an OspC chimeritope. In this study, we comparatively assessed antibody responses to OspA and OspC induced by vaccination with all canine bacterin and subunit LD vaccines that are commercially available in North America. Dogs were administered a two-dose series of the vaccine to which they were assigned (3 weeks apart): Subunit-AC, Subunit-A, Bacterin-1, and Bacterin-2. Antibody titers to OspA and OspC were determined by ELISA and the ability of each vaccine to elicit antibodies that recognize diverse OspC proteins (referred to as OspC types) assessed by immunoblot. While all of the vaccines elicited similar OspA antibody responses, only Subunit-AC triggered a robust and broadly cross-reactive antibody response to divergent OspC proteins. The data presented within provide new information regarding vaccination-induced antibody responses to key tick and mammalian phase antigens by both subunit and bacterin LD canine vaccine formulations.

Metabolism of lipoprotein acylglycerols by liver parenchymal cells.

We investigated the metabolism by hepatocyte suspensions of the acylglycerols in lipoprotein remnants as well as those associated with albumin and low or high density lipoproteins. Remnants, albumin and plasma lipoproteins, rich in monoacylglycerol were prepared by short-term incubations of radio-labeled chylomicra or very low density lipoproteins with extrahepatic lipoprotein lipase in the presence of albumin and low and high density lipoproteins. We demonstrated that liver parenchymal cells contain an active monoacylglycerol acyltransferase that is located on the extracellular surface of the cell plasma membrane. Further, the enzyme is capable of degrading the monoacylglycerol in all the above forms. Triacylglycerol in intact chylomicra and very low density lipoproteins were not metabolized by the cells to any appreciable degree. The degradation of the remnant triacylglycerol appeared to depend solely on the activity of the lipoprotein lipase bound to the lipoprotein remnants. Little uptake of intact lipoprotein acylglycerols by the hepatocytes was observed; instead, hydrolysis of the substrates in the medium always preceded the uptake of the products. The products were then utilized for the synthesis of triacylglycerol and phospholipid within the cells.

Psychiatric and substance use comorbidity among treatment-seeking opioid abusers.

BACKGROUND: Major studies of psychiatric comorbidity in opioid abusers reported rates of comorbidity that far exceeded general population estimates. These studies were published more than a decade ago and reported on few women and few substance use diagnoses. METHODS: Psychiatric and substance use comorbidity was assessed in 716 opioid abusers seeking methadone maintenance. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition diagnostic assessment was conducted 1 month after admission. Rates of psychiatric and substance use disorder were compared by gender, and associations were assessed between psychiatric comorbidity and dimensional indexes of substance use severity, psychosocial impairment, and personality traits. RESULTS: Psychiatric comorbidity was documented in 47% of the sample (47% women and 48% men). Antisocial personality disorder (25.1%) and major depression (15.8%) were the most common diagnoses. Patients had at least 2 substance use diagnoses, most often opioid and cocaine dependence. Demographics, substance use history, and personality variables discriminated between patients with vs without comorbidity. Psychiatric comorbidity also was associated with a more severe substance use disorder. CONCLUSIONS: Psychiatric comorbidity, especially personality and mood disorder, was common in men and women. The positive associations between psychiatric comorbidity and severity of substance use and other psychosocial problems were most consistent among those with antisocial personality.

Gray-scale sonographic characterization of aminoglycoside-induced nephrotoxicosis in a canine model.

RATIONALE AND OBJECTIVES: The diagnostic usefulness of gray-scale sonography was evaluated in a canine model of aminoglycoside-induced nephrotoxicosis. METHODS: Sonography was performed before and during the onset and progression of nephrotoxicosis induced by administration of a toxic dosage of gentamicin. Subjective visualization of increased renal cortex echogenicity (IRCE) was objectified with digital image analysis methods. Results of both subjective and objective evaluation were correlated with clinicopathologic tests and renal cortex biopsy obtained concurrently. RESULTS: Subjective visualization of IRCE was associated with significant nephrotoxicosis and was superior to serum creatinine elevation in nephrotoxicity detection. Objective detection of IRCE improved nephrotoxicity detection sensitivity to that of increased urine enzymuria. CONCLUSIONS: Based on the above results, subjective visualization of IRCE in patients with aminoglycoside-induced nephrotoxicity may occur before azotemia and is suggestive of significant renal dysfunction; application of digital image analysis methods may lead to earlier sonographic recognition of nephrotoxicity.

Predictive validity of cocaine, sedative, and alcohol dependence diagnoses.

This study examined the predictive validity of Structured Clinical Interview for DSM-III-R (Spitzer, Williams, Gibbon, & First, 1990) based substance dependence diagnoses (i.e., cocaine, sedative, and alcohol) for 518 opioid-dependent outpatients entering methadone maintenance. Patients were followed over 1 year of treatment, which involved daily methadone substitution supplemented by individual and group counseling. Urine specimens were tested randomly 1-4 times per month. Patients diagnosed with current cocaine, sedative, or alcohol dependence were more likely to use these drugs than were patients with past only or no dependence syndrome. Current cocaine dependence predicted early treatment dropout. The results demonstrate the predictive and discriminant validity of several substance dependence diagnoses common among patients in substance abuse or other psychiatric treatment settings.

Increasing employment of opioid dependent outpatients: an intensive behavioral intervention.

The impact of a new, mandatory employment requirement in a community-based methadone treatment program was evaluated. All patients who had been in the methadone substitution program for at least 1 year but who were not currently employed (n = 36) were required to enhance their treatment with 20 h of employment (paid or volunteer). Patients with significant psychiatric or medical disabilities were excluded from the routine treatment requirement. Patients were informed by counseling staff that they had 2 months to secure employment. Those who did not accomplish the goal within that time period were transferred to more intensive weekly counseling (i.e. up to 8 h/week) for 10 weeks, with the enhanced counseling focusing primarily on resistance to the employment goal. Patients who remained resistant to the treatment plan were eventually started on a 21 day methadone taper until employment was verified. Seventy-five percent of the patients secured employment and maintained the position for at least 1 month. Positions were found in an average of 60 days. Most patients (78%) continued working throughout the 6-month follow-up. Those who failed to find work or maintain employment engaged in more illicit drug use. These results demonstrate that behavioral contingencies can motivate many methadone maintenance patients to obtain verified employment in the community.

Preliminary evidence of good treatment response in antisocial drug abusers.

Antisocial personality disorder (APD) is a chronic debilitating condition strongly associated with the development and maintenance of severe drug and alcohol use disorder. The overlap of these problems is associated with high rates of personal and social suffering. Available literature consistently point to this as a population in need of effective clinical services. The present study reports preliminary data from a controlled clinical trial aimed at improving the treatment outcomes of antisocial drug abusers using an intensive behavioral approach relying upon a highly structured contingency management intervention. Drug abusers in methadone substitution therapy (n = 40) were assessed for APD and other psychiatric and substance use problems. Patients were randomly assigned to an experimental (n = 20) or control (n = 20) condition following stratification on demographic and selected clinical variables (baseline drug use, evidence of other non-substance use psychiatric diagnoses). Treatment outcome data are presented for the first 17 weeks of participation in the study (4 weeks baseline and 13 weeks randomized treatment), including results of weekly urine drug testing and monthly self-reports of drug use and other psychosocial problems. Patients in both study conditions attained generally good outcomes. These early results suggest that antisocial drug abusers can respond positively to drug abuse treatments with a behavioral focus, but fail to support superior effectiveness for the more intensive intervention used in the experimental condition.

Concurrent validity of cocaine and sedative dependence diagnoses in opioid-dependent outpatients.

The present study evaluated the relationship between diagnoses of cocaine and sedative dependence and drug use early in treatment among opioid-dependent patients in methadone substitution therapy. New admissions (n = 138) were assessed via the Structured Clinical Interview for the DSM III-R (SCID) for presence of Axis I and Axis II disorders and followed for five weeks on standard methadone maintenance. Patients submitted urines three times per week tested for opioids, cocaine, and benzodiazepines. Patients diagnosed with current cocaine dependence (n = 90) submitted a higher proportion of cocaine-positive urines (M = 0.84) than patients diagnosed with past cocaine dependence (n = 32; M = 0.28) and those diagnosed with no cocaine use disorder (n = 14; M = 0.12), P < 0.001. Current cocaine dependence diagnosis accounted for 52% of the cocaine use variance. Patients exhibiting current sedative dependence (n = 25) submitted a higher proportion of benzodiazepine-positive urines (M = 0.60) than patients with past sedative dependence (n = 44; M = 0.20) and those with no sedative use disorder (n = 60; M = 0.05), P < 0.001. Current sedative dependence diagnosis accounted for 37% of the benzodiazepine use variance. Lifetime major depression (12%) and antisocial personality disorder (39%) were the most common nonsubstance use comorbid diagnoses. Axis I nonsubstance use disorder was associated with benzodiazepine use, while Axis II disorder was associated with both benzodiazepine and cocaine use early in treatment (P < 0.05). These data demonstrate the concurrent validity of DSM-III-R cocaine and benzodiazepine use diagnoses, and support the potentially important relationship between drug use and other psychiatric disorders.

Condom use rates for specific sexual behaviors among opioid abusers entering treatment.

A structured interview was used to determine the details of high risk sexual behaviors, including number of sexual partners, frequency of condom use, and involvement in commercial sexual activity in 165 opioid abusers (mean age 34 years, 36% minority, 47% female) entering out-patient methadone substitution therapy. The median number of sexual partners in the sample was one, and 95% were sexually active in the past year. Most patients (84%) denied any commercial sexual activity and reported rates of monogamy and sexual abstinence (81%), and rates of condom use (15%), that were comparable with reports from general population surveys. However, intravenous drug abusers (IVDAs) remain at higher risk for exposure to HIV-1 because they are likelier to have sexual contact with other IVDAs and former IVDAs. Continuing efforts are needed to improve the safe sex practices of IVDAs, but it may be a significant challenge to reduce their high risk sexual behavior considerably below that of the general population. Concomitant drug abuse treatment may help in efforts to accomplish sexual behavior change.

Uptake and metabolism of free fatty acids by the Morris 7777 hepatoma and host rat liver.

The relative capacity of Morris 7777 hepatomas and livers of tumor-bearing rats to take up and subsequently metabolize intravenously injected radiolabeled free fatty acids was investigated. The objective was to determine differences in lipid metabolism which may affect the lipid composition previously observed in this tumor. Both tissues demonstrated comparable selectivity in the uptake of palmitate, linoleate and arachidonate from blood, although the hepatoma took up one-tenth as much free fatty acid per g wet wt as liver. A much greater percentage of fatty acid taken up by the hepatoma was converted to aqueous soluble radioactivity, perhaps the result of oxidation. In the hepatoma, palmitate was incorporated into phospholipid molecular species in a pattern similar to that observed for diglyceride, which suggested that phospholipid synthesis occurred predominantly de novo. On the other hand, in liver, a large percentage of palmitate was incorporated into polyunsaturated phospholipid molecular species that were not present in the diglyceride pool, which suggested significant incorporation by the acylation of monoacyl phosphoglycerides. These studies indicate that the specificity for the uptake of fatty acids was not different in the two tissues; however, the subsequent metabolic processes are markedly different.

Motivating methadone patients to include drug-free significant others in treatment: a behavioral intervention.

The present study introduced a novel behavioral approach for encouraging methadone-treated patients to bring drug-free significant other support into treatment. Seventy-five patients referred to high-intensity psychosocial treatment due to chronic drug use were given 3 weeks to identify a drug-free significant other. Patients noncompliant with this intervention were started on a methadone dose taper that was stopped when significant other support was identified. Patients and their significant others were required to attend a significant other group one time per week for a minimum of 6 weeks. Eighty-five percent of the patients brought a drug-free significant other into treatment. Significant others included family members, partners, and friends. Patients who identified significant other support complied with 77% of their scheduled sessions. The results demonstrated that most methadone patients have drug-free support people who are willing to participate in their treatment. These individuals can be utilized to help patients initiate the process of building new drug-free social support networks.

Short-term stability of NEO-PI-R personality trait scores in opioid-dependent outpatients.

The present study examined the short-term stability of personality trait scores from the Revised NEO Personality Inventory (NEO-PI-R) among 230 opioid-dependent outpatients. The NEO-PI-R is a 240-item empirically developed measure of the five-factor model of personality (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). Participants completed the NEO-PI-R at admission and again approximately 19 weeks later. Results indicated fair to good stability for all NEO-PI-R factor domain scores, with coefficients ranging from .68 to .74. Stability of NEO-PI-R scores was decreased among potentially invalid response patterns but was not significantly affected by drug-positive versus drug-negative status at follow-up.

Preventing transmission of Sarcoptes scabiei var. suis from infested sows to nursing piglets by a prefarrowing treatment with doramectin injectable solution.

Studies were conducted at swine facilities in Illinois and North Carolina to evaluate the effect of treatment with doramectin injectable solution on transmission prevention of Sarcoptes scabiei var. suis from sows to nursing piglets. Approximately 42 days prefarrowing, 58 mange-free sows were experimentally infested with 200 S. scabiei in each ear. Seven to fourteen days prior to farrowing, 22 sows were given doramectin injectable intramuscularly at a dose of 300 microg/kg of body weight. A total of 21 sows served as untreated controls. Skin scrapings for mite counts and lesion scoring were performed on sows before treatment on day 21, and on either day 35 or 42. Each sow was observed on days 0, 7, 14, 21, 28, and 35 or 42 for the incidence of scratching/rubbing. Skin scrapings, lesion scoring, and observation of scratching/rubbing were performed on the piglets after weaning and at the end of the nursery stage. Geometric mean mite counts of the untreated sows were 0.70 and 0.26 on days 21 and 35 or 42, respectively, and 0.00 for doramectin-treated sows over the same time periods (P<0.05). Lesions scores and the incidence of scratching/rubbing were both higher in the untreated sows as compared to the doramectin-treated sows during the same time periods (P<0.05). Geometric mean mite counts of piglets farrowed by untreated sows were 0.50 and 0.60 after weaning and at the end of the nursery stage, respectively, and 0.00 for piglets from doramectin-treated sows over the same time periods (P>0.05). Lesion scores and the incidence of scratching/rubbing were both higher in piglets from untreated sows as compared to those piglets from doramectin-treated sows (P<0.05). Treating S. scabiei-infested sows with doramectin injectable solution before farrowing eliminated mite infestation and prevented the transmission of S. scabiei to piglets.

Production responses following strategic parasite control in a beef cow/calf herd.

Strategic parasite control has been reported to improve performance in a beef cow/calf herd that does not demonstrate clinical parasitism. This study was conducted to determine if strategic anthelmintic treatment at turnout and at midsummer would improve growth and reproduction. Two cow/calf groups of similar composition were grazed on separate, but equivalent pastures in the spring, and at midsummer, they were moved to new pastures. The treated group was given fenbendazole at tumout (cows) and at midsummer (cows and calves). The control group was not treated. The study was repeated in the following year. Across both years of the study, parasite egg counts were substantially reduced in both the treated cows (P < 0.005) and treated calves (P < 0.0001). The calves in the treated group significantly (P < 0.0001) outgained the control calves in both years of the study by 19.3 kg and 13.2 kg, respectively. Average daily gain (ADG) after adjusting for birth weight and birth date for treated calves was 0.13 kg greater than for control calves (0.83 vs 0.70) for the 2-year study (P < 0.0001) There was also a significant (P = 0.0357) increase in the reproductive performance of the cows. The pregnancy rate averaged across years was 94% for the treated cows compared to 82% for the control animals.

Management factors associated with swine breeding-herd productivity in the United States.

A database containing 24 key production measurements was created by abstracting data files of 673 U.S. farms which participated in the PigCHAMP data-share program in 1995. Summary statistics for breeding-herd performance data were presented for the Cornbelt and the South or Eastern regions. Eight models were built to assess the association between production system, operation management factors and productivity outcomes. Lactation length, percentage of multiple matings, parity of culled sows, percent gilts in the breeding-female inventory, and female culling rate were the management factors identified as having important associations with productivity outcomes. For example, shorter lactation length, higher percentage of multiple matings, and lower culling rate were associated with more pigs weaned per mated female per year. In addition, a lower percentage of gilts in the breeding-female inventory and a higher percentage of multiple matings were associated with fewer average non-productive female days. We recommend that producers change their management systems to decrease lactation length, the percentage of gilts in the breeding-female inventory, and female culling rate, and increase percentage of multiple matings in order to improve breeding-herd productivity on swine farms.

Influence of psychiatric comorbidity on HIV risk behaviors: changes during drug abuse treatment.

This study evaluated whether psychiatric comorbidity is related to change in HIV high risk behaviors during outpatient drug abuse treatment. Participants were opioid abusers entering methadone treatment. Psychiatric and substance use diagnoses were determined at intake. Information on HIV high risk drug use and sexual behaviors, psychosocial functioning, and urine toxicology was assessed at intake and at month six. Subjects were divided into those with versus without a lifetime comorbid non-substance use psychiatric disorder. The comorbid group reported more injection equipment sharing, lower rates of condom use, and higher rates of alcohol use at intake and follow-up. Overall injection drug use behavior decreased over the follow-up period for both groups, however. Methadone treatment had a beneficial effect on HIV risk behaviors, and though some risk behaviors improved signiticantly for both groups, comorbid subjects continued to have higher rates of HIV risk factors than noncomorbid subjects.

Returns to service after mating and removal of sows for reproductive reasons from commercial swine farms.

We studied the records of 30 herds with an average inventory of 11,705 sows, 25,719 farrowings and 25,040 daily feed intake logs. Production events were recorded by producers using the PigCHAMP production information system. Of 21,505 matings, 7.2% of sows subsequently returned to estrus after service. The proportionate rates of intervals from service to the subsequent post service event were 0 to 17 d, 2.1%; 18 to 25 d, 27.9%; 26 to 37 d, 13.8%; 38 to 46 d, 15.8%; 47 to 108 d, 30.4%; and >108 d, 10.0%. Sows returned to service after mating were categorized into groups that either regularly or irregularly returned to service after mating. Of a total inventory of 19,076 sows, 10.0% were removed following weaning for reproductive reasons. The reasons for removal included those of anestrus (25.2%), failure to conceive (37.0%), failure to farrow (15.0%), not pregnant (1.4%), negative pregnancy check (14.0%), and abortion (7.4%). The last 5 types of post weaning reproductive failure were grouped into the category of did not farrow. Categorical additive models and comparisons using contrasts were used to analyze the influence of risk factors on reproductive failure. Parity 1 sows had a higher proportion (P < 0.01) of returns to service and a greater proportion of sows remaining anestrous post weaning relative to Parity 3 sows. The proportion of sows that did not farrow was higher (P < 0.01) in Parities 9 and 10 than in Parity 3. More sows were removed for anestrus during the spring (P < 0.01) and summer (P = 0.06) than during the winter. All categories of lactation length had similar rates of reproductive failure except for the lactation length 1 to 7 d, which had a higher (P < 0.05) proportion of reproductive failure. Lower lactational feed intake was associated with an increased risk of occurrence of each reproductive failure category. The odds ratios of lactation feed intake in logistic regression analyses were 0.84, 0.89, 0.82 and 0.88 for regularly and irregularly returned to service, anestrus, and did not farrow groups, respectively. This means, for example, that a sow was 0.88 times less likely to have an occurrence of not farrowing for each 1 kg increase in average daily feed intake during lactation. Our results indicate that lower and higher parities, spring and summer seasons, a lactation length of less than 8 d and lower feed intake during lactation affect the occurrence of return to service after mating and of herd removal for reproductive reasons.

Ultrasonographic evaluation of the equine placenta by transrectal and transabdominal approach in the normal pregnant mare.

The objective of this study was to determine normal variations in the utero placental thickness during mid- and late gestation in the mare. Normal, healthy pregnant mares (n = 9) were examined monthly from 4 mo of gestation until parturition by transrectal and transabdominal ultrasonography. At each examination, the combined thickness of the uterus and the placenta (CTUP) was measured at the placento-cervical junction (transrectally) and at the uterine body or the uterine horns (transabdominally). In addition, the echogenicity of the amniotic and allantoic fluids was evaluated by transrectal ultrasonography. Following parturition and expulsion of the fetal membranes, the allantochorion was measured and visually examined for abnormalities. At all examinations, both transrectal and transabdominal, the chorioallantois and the uterus were indistinguishable from each other on the ultrasound image. The CTUP, measured by transrectal ultrasonography did not change between 4 and 8 mo of gestation, but increased significantly for each month between 10 and 12 mo of gestation (P < 0.001). A change in the CTUP was detected between months when measured by transabdominal ultrasonography, but no distinct pattern in these changes was observed. No correlation was found between transabdominal and transrectal measurements of the CTUP. The echogenicity of the amniotic and allantoic fluids did not consistently change over time during mid- and late gestation. The amniotic fluid was more echogenic than the allantoic fluid at most examinations from 6 mo of pregnancy and throughout gestation (P < 0.05). It was concluded that transrectal ultrasonographic examination to assess the CTUP and the echogenicity of the fetal fluids is superior to the transabdominal approach. We suggest that transrectal ultrasonographic examination should be added to current diagnostic tools during late gestation and that it be part of the biophysical profile of high risk equine pregnancies.

Duplex doppler estimation of intrarenal pourcelot resistive index in dogs and cats with renal disease.

In human beings, intrarenal blood flow impedance, expressed as the resistive index (RI) and obtained by duplex Doppler ultrasonography, has been used to aid in diagnosis and prognosis of renal failure. Higher than normal values for RI were obtained in 3 of 4 dogs with acute tubular necrosis (ATN) and in 5 of 10 dogs with glomerulonephrosis (GN). Normalization of RI was observed in 2 dogs with ATN evaluated serially during treatment. Increased RI values were obtained in 9 of 10 cats with nonobstructive renal disease and in 2 of 5 cats with obstructive renal disease. Normalization of RI was observed in 3 cats with renal failure in which treatment was effective (1 with obstruction; 2 with nonobstructive disease). The magnitude of increase in RI did not correlate with the magnitude of concurrent renal dysfunction. These results suggest that duplex Doppler evaluation of intrarenal RI is more useful as an ancillary diagnostic technique in azotemic dogs with ATN than in those with GN and in azotemic dogs with nonobstructive than in those with obstructive disease.