Characterization of osteoarthritis in cats and meloxicam efficacy using objective chronic pain evaluation tools.

This study aimed to characterize osteoarthritis (OA)-related chronic pain and disability in experimental cats with naturally occurring OA. Peak vertical ground reaction force (PVF), accelerometer-based motor activity (MA) and the von Frey anesthesiometer-induced paw withdrawal threshold were used to define OA and to test the efficacy of meloxicam. A diagnosis of OA was based on radiographic and orthopedic examinations. Cats with OA (n=39) and classified as non-OA (n=6) were used to assess the reliability and sensitivity of the parameters to assess OA over 3weeks while being administered placebo medication. A randomised parallel design study was then used to investigate the effects on OA of daily oral meloxicam treatment for 4weeks at different dose rates (0.025mg/kg, n=10mg/kg; 0.04mg/kg, n=10; 0.05mg/kg, n=9), compared to cats administered a placebo (n=10). The test-retest repeatability for each tool was good (intra-class correlation coefficient ⩾0.6). The PVF and the von Frey anesthesiometer-induced paw withdrawal threshold discriminated OA (P<0.05). Meloxicam did not add to the PVF improvement observed in placebo-treated cats during the treatment period (adj-P⩽0.01). The 0.025 and the 0.05mg/kg meloxicam-treated cats experienced a higher night-time (17:00-06:58h) MA intensity during the treatment period compared to the placebo period (adj-P=0.04, and 0.02, respectively) and this effect was not observed in the placebo group. The high allodynia rate observed in the 0.04mg/kg meloxicam-treated group may explain the lower responsiveness to the drug. The von Frey anesthesiometer-induced paw withdrawal threshold demonstrated no responsiveness to meloxicam. The results from this study indicated that daily oral meloxicam administration for 4weeks provided pain relief according to night-time MA.

Pharmacokinetics and pharmacodynamics of protamine zinc recombinant human insulin in healthy dogs.

Protamine zinc insulins are generally considered to be long acting, with slow absorption from subcutaneous tissue. Protamine zinc recombinant human insulin (PZIR) may be useful to treat diabetic dogs. The purpose of this study was to describe the pharmacokinetics and pharmacodynamics of PZIR in dogs. PZIR was administered subcutaneously to 10 healthy Beagles using an incomplete crossover design, at doses of 0.3 or 0.5 U/kg (each n=5), 0.8 U/kg (n=10), or 0.8 U/kg at three separate sites (n=6). Insulin and glucose concentrations were measured over 24 h. The shapes of insulin and glucose curves were variable among dogs, and the relationship between insulin dose, concentration, and glucose-lowering effect was nonlinear. For single-site 0.8 U/kg, median (range) onset of action was 3.5 h (0.5-10 h), time to glucose nadir was 14 h (5 to >24 h), and duration of action was >24 h (16 to >24 h). Mathematical model predictions of times to 50% and 90% insulin absorption, and fraction of insulin absorbed in 24 h, were not significantly different among protocols. Results confirm the tendency toward a late onset and long duration of action for PZIR in dogs. This insulin may be an alternative treatment option for diabetic dogs.

Considerations for extrapolating in vivo bioequivalence data across species and routes.

The purpose of this article is to discuss the numerous species-specific and route-specific factors that can influence the peak and extent of exposure of an active pharmaceutical ingredient as they relate to the demonstration of bioequivalence between veterinary drug products (test and reference formulations). Evaluation of potential circumstances when species-to-species or route-to-route extrapolations of bioequivalence data could be considered is provided, together with suggestions for alternative statistical analysis. It is concluded that further research is much needed in this area to establish an appropriate scientific basis for across-species and across-route comparisons.

The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan at clinical and supraclinical doses.

This study aimed to determine the pharmacokinetic parameters and pharmacodynamics of alfaxalone in a 2-hydroxypropyl-beta-cyclodextrin alfaxalone formulation (Alfaxan), Jurox Pty Ltd, Rutherford, NSW, Australia) in cats after single administration at clinical and supraclinical dose rates and as multiple maintenance doses. First, a prospective two-period cross-over study was conducted at single clinical and supraclinical doses. Second, a single group multiple dose study evaluated the effect of maintenance doses. Eight (five female and three male) domestic cats completed the cross-over experiment and six female cats completed the multiple dose study. In the first experiment, alfaxalone was administered intravenously (IV) at 5 or 25 mg/kg with a washout period of 14 days. In the second experiment, alfaxalone was administered IV at 5 mg/kg followed by four doses each of 2 mg/kg, administered at onset of responsiveness to a noxious stimulus. Blood was collected at prescribed intervals and analysed by LCMS for plasma alfaxalone concentration. Noncompartmental pharmacokinetics were used to analyse the plasma alfaxalone data. The plasma clearance of alfaxalone at 5 and 25 mg/kg differed statistically at 25.1 and 14.8 mL/kg/min respectively. The elimination half lives were 45.2 and 76.6 min respectively. Alfaxalone has nonlinear pharmacokinetics in the cat. Nevertheless, for cats dosed with sequential maintenance doses, a regression line through their peak plasma concentrations indicated that there was no clinically relevant pharmacokinetic accumulation. The duration of nonresponsiveness after each maintenance dose was similar at approximately 6 min, indicating a lack of accumulation of pharmacodynamic effect. The cardiovascular and respiratory parameters measured in cats after administration of the labelled doses of Alfaxan were stable. In conclusion, the pharmacokinetics of alfaxalone in cats are nonlinear. At clinical dose rates, however, neither alfaxalone nor its effects accumulated to a clinically relevant extent. Further, in the un-premedicated cat the induction and maintenance of surgical anaesthesia was free of untoward events after a dose of 5 mg alfaxalone/kg body weight followed by four sequential doses of 2 mg/kg as needed (i.e., approximately 7 to 8 mg/kg/h).

Effect of anesthesia on voiding function after tension-free vaginal tape procedure.

OBJECTIVE: To determine whether the mode of anesthesia used during the tension-free vaginal tape procedure affects postoperative voiding function. METHODS: A retrospective cohort study was performed using cases in which tension-free vaginal tape placement was the sole procedure performed. Of the 173 cases reviewed, we were able to use the data from 163. Hierarchal linear regression was used to identify independent predictors of our dependent variable: days to complete voiding. In the first block, established predictors of postoperative voiding dysfunction were entered into the model. In the second block, potential confounders of the relationship between anesthesia type and days to complete voiding identified during univariate analysis (P <.15) were entered into the model. In the third block, anesthesia type was entered into the model to determine whether it added any unique variance after controlling for previously established predictors of postoperative voiding dysfunction. RESULTS: The mean days to complete voiding was similar in our local or regional anesthesia (n = 90) and general anesthesia groups (n = 73) (2.3 [0-21] versus 2.3 [0-14], P =.95). Our final regression model (F = 2.74, P =.011) included age, prior pelvic organ prolapse surgery, and preoperative urge symptoms and explained 22.2% of the variance in days to complete voiding. Anesthesia type did not add any predictive improvement after controlling for these variables. CONCLUSION: General anesthesia, and therefore lack of a cough-stress test, does not increase the chance of postoperative voiding dysfunction associated with tension-free vaginal tape.

Release of tension-free vaginal tape for the treatment of refractory postoperative voiding dysfunction.

OBJECTIVE: To report our experience with surgical release of tension-free vaginal tape (TVT) for the treatment of persistent post-TVT voiding dysfunction. METHODS: A total of 1175 women underwent TVT placement for treatment of genuine stress urinary incontinence and/or intrinsic sphincter deficiency over a 2-year period. Additional procedures and vaginal repairs were performed as indicated. Among these patients, 23 women (1.9%) had persistent voiding dysfunction (urinary retention, incomplete bladder emptying, or severe urgency or urge incontinence) refractory to conservative management. This cohort underwent a simple vaginal TVT release procedure, performed on an outpatient basis. Preoperative characteristics, intraoperative, and postoperative details were assessed by review of operative notes, medical records, and office notes. Continence status was assessed using subjective and objective information. RESULTS: Mean age was 67 years (range 46-86 years), and the mean interval between TVT placement and release was 17.3 weeks (range 2-69 weeks; median 8.6 weeks). For the release procedure, there were no intraoperative complications, and all patients were discharged on the day of surgery. All cases of impaired emptying were completely resolved, and all cases of irritative symptoms were resolved (30%) or improved (70%) by 6 weeks. Fourteen (61%) patients remained continent 6 weeks after the release procedure, six (26%) were improved over baseline, and three patients (13%) had recurrence of stress incontinence. CONCLUSION: Refractory voiding dysfunction after TVT is a relatively uncommon situation and can be successfully managed with a simple midline release procedure. In most cases, the release procedure does not compromise overall improvement in symptoms of stress incontinence.

The safety of reusing injectable collagen: a multicenter microbiological study.

We have previously reported pilot data regarding the safety of saving partially used syringes of a glutaraldehyde cross-linked collagen for use in subsequent treatment sessions with the same individual. That single institution study involved 56 partially used syringes cultured for aerobic bacteria. Only one weakly positive culture was detected among these 56 samples, which prompted us to carry out this expanded study involving multiple centers and different injection techniques. Samples were collected from four centers. Following periurethral injection in an office setting, 166 partially used syringes of glutaraldehyde cross-linked collagen were refrigerated for between 1 and 104 weeks (average 58). Material from all 166 syringes was then cultured qualitatively and quantitatively for both aerobic and anaerobic organisms. Collagen from one syringe grew >100,000 colonies of Escherichia coli. All other cultures were negative. In the pilot study, one culture of 56 syringes was weakly positive for coagulase-negative staphylococcus. When the results from both studies were considered together, only two of 222 partially used syringes (0.9%) were contaminated. The background risk of local infection associated with periurethral collagen injection is approximately 0.29%. Using the statistical equation 'number needed to harm', we found that a clinician would have to reuse 111 syringes at a saving of $34,965 before he or she would cause a single local injection by so doing. Therefore, we feel that it may be cost-effective and safe to reinject material from a partially used syringe of glutaraldehyde cross-linked collagen during a subsequent treatment session on an individual.

Poor surgical outcomes after fascia lata allograft slings.

The objective of this retrospective case control study was to determine whether our poor surgical outcomes were associated with the material used to construct our pubovaginal slings. Autologous rectus fascia was used in 33 patients and cadaveric fascia lata was used in 12 patients who underwent pubovaginal sling placement for intrinsic urethral sphincter deficiency (ISD). Treatment was successful in 78.8% and 33.3% of patients who underwent rectus fascia and fascia lata allograft slings, respectively (P=0.006). Based on regression analysis, the sling material was found to be strongly associated with surgical outcome after controlling for all confounding variables (beta coefficient = 1,204.6, P<0.00005). We conclude that fascia lata allografts are a poor choice for pubovaginal slings.

The clinical utility of a vaginal template designed to standardize suture placement during retropubic colposuspensions.

Suture placement and bite size utilizing a vaginal template are compared to a traditional surgical approach during modified retropubic colposuspension on four fresh-frozen human female cadavers. Overall, a larger suture bite was obtained utilizing the template (71.5 +/- 4.6 vs 46.7 +/- 25.3 mm2, P = 0.001). However, with increased surgical experience the suture bites obtained with the traditional approach and template technique were similar. Inconsistent suture placement relative to the urethrovesical junction and urethra was observed with both techniques. Differences in pelvic floor anatomy make consistent suture placement with respect to the urethrovesical junction and urethra neither possible nor entirely preferable with either technique. There seems to be little clinical value in the use of this vaginal template during modified retropubic colposuspensions.

Prevention of childbirth injuries to the pelvic floor.

The majority of childbirth injuries to the pelvic floor occur after the first vaginal delivery. Cesarean sections performed after the onset of labor may not protect the pelvic floor. Elective cesarean section is the only true primary prevention strategy for childbirth injuries to the pelvic floor. Alternative primary prevention strategies include elective cesarean section for women with nonmodifiable risks for childbirth injuries to the pelvic floor, antepartum pelvic floor exercises, or intrapartum pudendal nerve monitoring. Secondary prevention strategies must focus on modifying obstetric practices that predispose women to pelvic floor injury. These factors are best delineated for anal incontinence and include restrictive use of episiotomy, mediolateral episiotomy when necessary, spontaneous over forceps-assisted vaginal delivery, vacuum extraction over forceps delivery, and antepartum perineal massage. Finally, tertiary prevention strategies should address the mode of delivery made for women with childbirth injuries to the pelvic floor who desire future fertility.

Urinary incontinence in women: evaluation and management.

Because the prevalence of urinary incontinence increases with age, a working knowledge of the diagnosis and treatment of the various types of urinary incontinence is fundamental to the care of women. As the population of the United States ages, primary care physicians can expect to see an increasing number of patients with urinary incontinence. By obtaining a careful medical history and performing a comprehensive physical examination, the primary care physician can initiate successful treatment for the majority of patients without the need for invasive testing. This article offers a comprehensive approach to the evaluation and management of urinary incontinence in women.

Intraurethral ultrasonography: correlation of urethral anatomy with functional urodynamic parameters in stress incontinent women.

To determine whether differences in functional urodynamic parameters can be explained by changes in urethral anatomy, 39 patients underwent intraurethral ultrasonography to obtain a 360 degree view of the urethra. The point of maximal rhabdosphincter thickness was identified in all patients. The thickness, circumference and area of the urethral smooth and skeletal muscle layers were calculated. Data from patient histories and urodynamic evaluations were compared with this anatomical survey. The urodynamic diagnoses were as follows: 10 patients were normal, 24 had genuine stress incontinence and 5 had intrinsic sphincter deficiency. These patients had decreasing rhabdosphincter thicknesses of 3.91, 3.35 and 2.70 mm (P = 0.048). A weak linear relationship was found between maximal urethral closure pressure and rhabdosphincter (r = 0.40, P = 0.013) and longitudinal smooth muscle (r = 0.35, P=0.027) thickness. It was concluded that a loss of urethral resistance as measured by maximal urethral closure pressure is associated with changes in urethral anatomy identified by intraurethral ultrasonography.

Correlation of intraurethral ultrasonography and needle electromyography of the urethra.

OBJECTIVE: To correlate structural intraurethral ultrasound findings with needle electromyography of striated urethral sphincters in young continent nulliparas. METHODS: Twenty-three nulliparas, each less than 35 years old and without pelvic floor disorders, were recruited at Methodist Hospital in Indianapolis, Indiana, and the University of Louisville in Louisville, Kentucky. Each had concentric needle electromyography of their urethra to localize their striated urethral sphincter. Intraurethral ultrasound was used to identify the needle tip and layer in which it was found, examine the sonographic appearance of periurethral anatomy, and measure the thickness of hypoechoic and outer hyperechoic layers. RESULTS: Three layers were seen on intraurethral ultrasound: a mildly hyperechoic inner layer, a hypoechoic middle layer, and a hyperechoic outer layer. The concentric needle tip was seen in all subjects and showed motor unit action potentials when located in the outer hyperechoic layer. The mean thickness of the hypoechoic layer was 2.5 mm, and the mean thickness of the outer hyperechoic layer was 2.6 mm. CONCLUSION: Motor unit action potentials showed that striated muscle was present in the outer hyperechoic layer on intraurethral ultrasound, implying that it contains the striated urethral sphincter.

The urinary bladder of a woman is a novel site of luteinizing hormone-human chorionic gonadotropin receptor gene expression.

OBJECTIVE: The female reproductive tract contains functional luteinizing hormone-human gonadotropin receptors; therefore our objective was to test the hypothesis that bladder trigone, which is derived from intermediate mesoderm along the urogenital ridge during embryonic development of the female reproductive tract, may also contain these receptors. STUDY DESIGN: Bladder trigones or domes were biopsied from 15 premenopausal and 19 postmenopausal women undergoing surgical correction of genital prolapse, incontinence, or both. The biopsy specimens were submitted for luteinizing hormone-human chorionic gonadotropin receptor analysis by in situ hybridization and immunocytochemical examination. The receptor immunostaining was visually scored by 3 investigators without knowing the identity of the menopausal status. RESULTS: In situ hybridization demonstrated the presence of receptor transcripts, and immunocytochemical examination revealed the presence of receptor protein in bladder trigone. The bladder trigones from postmenopausal women contained lower levels compared with those from premenopausal women, implying that luteinizing hormone might down-regulate its own receptors. Transitional epithelium contained the highest receptor levels followed by smooth muscle and blood vessels. The bladder dome contained receptor levels similar to those in trigone, which suggests that a common embryologic origin is not the only reason for bladder trigone containing the luteinizing hormone-human chorionic gonadotropin receptors. Rather, they are present because luteinizing hormone-human chorionic gonadotropin may regulate bladder functions in women. CONCLUSIONS: A woman's urinary bladder, which has never been thought of as a gonadotropin target, has now been demonstrated to contain luteinizing hormone-human chorionic gonadotropin receptors. These findings suggest for the first time that gonadotropins directly regulate bladder functions in women.

Site-specific drug delivery in the dog using flexible fiberoptic endoscopy.

The development of a nonsurgical repeatable method of site-specific delivery to the gastrointestinal tract in the canine is described. Studies to characterize and validate this method were performed utilizing propranolol and etodolac due to their well-known pharmacokinetic properties. Using a catheter placed through the auxiliary port of a flexible fiberoptic endoscope, liquid dosage formulations were consistently delivered to the canine stomach, duodenum, ileum, and colon. It was shown that differences in site-specific delivery could be demonstrated with this model. Propranolol tended to have the highest exposure following dosing to the ileum as compared to other sites. The anesthetic regimen used to perform endoscopy affected certain pharmacokinetic parameters of the compounds being tested including decreasing the intrinsic clearance of propranolol. However, since decreased intrinsic clearance should similarly affect AUCo regardless of the site of delivery, this does not preclude site-specific comparisons to be made. Further, no evidence has been reported for the effect of anesthesia on one GI segment but not another. Thus for other compounds, assuming there are either no anesthetic effects on intestinal pharmacokinetic parameters (absorption, intestinal metabolism, etc.) or that they are consistent and uniform throughout the intestinal tract, this model allows comparisons of the exposure following delivery to differing intestinal sites.

Fluconazole in cats: pharmacokinetics following intravenous and oral administration and penetration into cerebrospinal fluid, aqueous humour and pulmonary epithelial lining fluid.

The pharmacokinetics of fluconazole following intravenous (i.v.) and oral (p.o.) administration and the penetration of fluconazole into cerebrospinal fluid, aqueous humour and epithelial lining fluid (ELF) of the lungs were evaluated in adult male cats. Pharmacokinetic parameters were calculated from serum concentration-time data obtained following i.v. and p.o. administration of 50 mg per cat using a cross-over study design. Fluconazole concentrations were measured using a high-performance liquid chromatography assay. Mean total body clearance of fluconazole was 37.7 mL/h.kg, mean volume of distribution at steady state was 1.14 L/kg, mean residence time was 31.0 h and mean half-life of elimination was 25 h as derived by non-compartmental analysis of data. Absorption was complete. Mean ratios of fluid:serum fluconazole concentrations following administration of 50 mg fluconazole per day for 8 days were as follows: cerebrospinal fluid, 0.88; aqueous humour 0.79; ELF, 1.20. Fluconazole concentrations in cerebrospinal fluid, aqueous humour and ELF exceeded reported minimum inhibitory concentrations of fluconazole for pathogenic fungi. Results of this study suggest fluconazole can effectively be administered to cats at 50 mg per cat per day.

Electrically-assisted transdermal drug delivery.

Electrically-assisted transdermal delivery (EATDD) is the facilitated transport of compounds across the skin using an electromotive force. It has been extensively explored as a potential means for delivering peptides and other hydrophilic, acid-labile or orally unstable products of biotechnology. The predominant mechanism for delivery is iontophoresis, although electroosmosis and electroporation have also been investigated. The focus of this review is to put these different mechanisms in perspective and relate them to the drug and skin model system being investigated.

Infectious peritonitis complicating suprapubic catheter removal.

Peritonitis following suprapubic catheter placement may result from inadvertent placement of the drain through the large and small bowel and bladder base. The author describes a case of infectious peritonitis which developed after suprapubic catheter removal. The patient, underwent suprapubic catheter placement after Burch Colposuspension for genuine stress incontinence. The catheter was removed with a full bladder after an uneventful postoperative course, but the patient subsequently developed acute infectious peritonitis due to extravasated urine from the cystostomy site. It was concluded that suprapubic catheters should be removed after the bladder is emptied, to prevent this complication. This may be most important in patients who void without residual prior to epithelialization of the cystostomy site.

An alternative statistical approach for predicting prolonged catheterization after Burch colposuspension during reconstructive pelvic surgery.

Our objective was to use an alternative statistical approach to identify clinical and urodynamic predictors of prolonged catheterization following Burch colposuspension. Seventy women with genuine stress incontinence underwent Burch colposuspension with suprapubic catheter placement at Rush Presbyterian-St. Luke's Medical Center from 1 July 1992 to 1 October 1993. Patient charts were retrospectively reviewed to extract pertinent variables from their history, examination and preoperative urodynamic evaluation. The day of suprapubic catheter removal was considered the end-point 'event' for the purposes of survival analysis. This statistical model allowed us to identify preoperative clinical parameters important in determining the percentage of patients requiring catheters as a function of time. The need for defining prolonged postoperative catheterization was eliminated. Aging (P=0.01), increasing maximal urethral pressures (P=0.02) and menopausal status (P=0.02) were important in determining the percentage of patients requiring catheters as a function of time. Data from our preoperative voiding studies were not predictive of prolonged catheterization following Burch colposuspension.

Prolonged urinary retention after collagen periurethral injections: a sequela of humoral immunity.

BACKGROUND: Approximately 3% of candidates for collagen periurethral injections are ineligible because of an immediate hypersensitivity reaction to skin testing. After a negative skin test, physicians believe patients should be free of any adverse clinical events from hypersensitivity reactions. We present a patient who developed prolonged urinary retention from a delayed hypersensitivity reaction after negative skin testing. CASE: After a negative skin test, a 51-year-old woman underwent collagen periurethral injections for recurrent genuine stress incontinence associated with a fixed bladder neck. After reporting complete resolution of symptoms, she developed complete urinary retention associated with a delayed hypersensitivity reaction at both the skin test and injection sites. Her retention resolved after a year of intermittent catheterization and antibiotics for persistent urinary tract infection. CONCLUSION: Delayed hypersensitivity reactions may be associated with an adverse clinical event in up to 2.5% of patients despite a negative skin test. After skin testing, physicians should counsel their patients accordingly.