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).

Pharmacological studies with a GABA uptake inhibitor in rats with kindled seizures in the amygdala.

The anticonvulsant effects of the inhibitor of the uptake of GABA, SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid), were investigated using the amygdala kindling seizure model in rats. The time course of activity of the racemic mixture, given orally, and the relative potencies of its d- and l-isomers, when given intraperitoneally, were tested. The drug SKF 89976-A was active, when given orally with anticonvulsant effects lasting 2-4 hr when given at 15 mg/kg, and 4-6 hr when given at 30 mg/kg. Peak inhibition of severity of seizures occurred at 1 hr after administration with an ED50 of 17.8 mg/kg. The d-isomer of SKF 89976-A was significantly more potent than the l-isomer and inhibited various parameters of kindled seizure activity in a dose-dependent manner. The l-isomer had significant effects on kindled seizures only at the largest dose (20 mg/kg). The ED50 of the d-isomer for inhibition of severity of seizures measured 0.5 hr after intraperitoneal injection, was 11.2 mg/kg and the antiseizure effects of the d-isomer lasted for 2-3 hr. Side effects of SKF 89976-A, such as sedation, abdominal muscle relaxation, rear limb splaying and ataxia, were seen at 30 mg/kg; there was a marked suppression of seizure activity with no side effects at smaller doses. The characterization of a biphasic kindled seizure allows for speculation regarding the role of GABAergic mechanisms in its pathogenesis and of the mechanism of action of SKF 89976-A.

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.

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.

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.

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.

Isoelectric focusing and capillary zone electrophoretic studies using luteinizing hormone releasing hormone and its analog.

Iontophoresis is the movement of charged compounds into and through the skin under an external electromotive force. A molecule's charge and size, as well as other factors, will determine its ability to be iontophoresed. One can gain insight into certain electrical aspects of a molecule by determining its isoelectric point as well as its electrophoretic mobility. In the present study, isoelectric focusing and capillary zone electrophoretic studies of luteinizing hormone releasing hormone, (LHRH) and one of its analogs are performed in order to predict their ability to be iontophoresed. The pI of LHRH is determined to be 9.6 while that of its free acid is 6.9. In addition, it is concluded that although the two compounds are chemically similar, the native compound is more mobile at pH > 2.5. These results suggest that the native compound might be better suited for iontophoretic delivery than is the free-acid analog.

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.

Transdermal iontophoretic peptide delivery: in vitro and in vivo studies with luteinizing hormone releasing hormone.

Protein and peptide drugs are not orally active. Their large molecular size and charged character make them poor candidates for passive transdermal delivery. With an applied electromotive force, these drugs can be forced through the skin to be absorbed by the systemic circulation. The present study investigates the transdermal iontophoretic delivery of a peptide hormone in an in vitro model system, the isolated perfused porcine skin flap, as well as in vivo. It is shown that with knowledge of the systemic disposition of the drug, transdermal fluxes can be utilized to accurately predict in vivo serum concentrations. It is also shown that the iontophoretically delivered hormone retains both its immunologic and biologic activity.

Electrothermal atomic-absorption spectrometric analysis of lake waters for Mn, Fe, Pb and Cd.

Analyses have been made for trace metals in surface waters from lakes known to be sensitive to inputs of acidic deposition. Electrothermal atomic-absorption spectrometry was used for direct measurement of the low metal concentrations. The studies revealed non-spectral interferences resulting from small amounts of inorganic material in the sample matrix that prevent accurate measurements of Mn and Pb. Several types of interferences were identified by means of a computer coupled to the atomic-absorption spectrometer and procedures to overcome them were evaluated. Matrix modification with nitric acid is required for the determination of Mn. Atomization from a platform inserted within the graphite tube is necessary for interference-free Pb determination.

The effects of dissecting tools on the trace element concentrations of fish and mussel tissues.

A comparison of the effects of dissecting tools composed of various materials on the trace element content of the muscle of the marine bluefish, Pomatomus saltatrix, and the soft tissues of freshwater mussels, Eliptio complanatus and Lampsilus radiata, is presented. The fish were dissected with blades made of stainless steel, Lexan plastic, titanium, and Teflon-coated stainless steel. The mussels were dissected with stainless and Teflon tools only. Elements measured included As, Cd, Cr, Cu, Hg, Ni, Pb, Se, Sn, Te, V, and Zn. Significant concentration differences (P = 0.01) were not found for any element in fish or mussel samples dissected by the different tools.

Radioactive fallout reconstruction from contemporary measurements of reservoir sediments.

The temporal history of atmospheric deposition to a watershed area can be preserved in the sediment of a lake or reservoir that is supplied by the watershed. The 137Cs and isotopic Pu concentrations with depth were determined in the sediments of two reservoirs, Enterprise and Deer Creek, which are located in widely separated regions of the state of Utah. Our data not only reconstruct the history of the total radioactive fallout in the area, but also permit estimating the contributions from global sources and from the Nevada Test Site detonations in the 1950s.

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.

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.

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.

Clinical correlates in patients not completing a voiding diary.

Our objective was to determine whether voiding diary non-compliance was an important clinical predictor for the absence of urinary symptoms. History questionnaires and voiding diaries are mailed to all patients before initial visits. The study included 349 patients capable of filling out the history questionnaire and voiding diary prior to their initial visit. The control group (n = 261) consisted of patients who filled out both forms. The study group (n = 88) consisted of patients who filled out their history questionnaire yet left their voiding diary blank. Study variables were extracted by chart review to determine the clinical significance of non-compliance with voiding diary completion. Non-Caucasian patients were less likely to complete their diary (P = 0.008). Patients presenting for treatment of pelvic organ prolapse (no urinary symptoms) were also less likely to complete their diary (P = 0.01, OR 0.41, 0.20-0.85). These patients should be counseled about the importance of the voiding diary in validating urinary symptoms. Urodynamic diagnosis were similar in patients considering surgical correction of pelvic organ prolapse, independent of diary non-compliance.

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.

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.