Subchronic Toxicity of Cupric Sulfate Administered in Drinking Water and Feed to Rats and Mice

Subchronic Toxicity of Cupric Sulfate Administered in DrinkingWater and Feed to Rats and Mice. HÉBERT, C. D., ELWELL,M. R., TRAVLOS, G. S., FITZ, C. J., AND BUCHER, J. R. (1993).Fundam. Appl. Toxicol. 21, 461–475. The effects of acute poisoning by cupric sulfate in a numberof species are well known; however, the effects of chronic low-levelingestion of cupric sulfate are less well characterized. Becauseexposure of humans to cupric sulfate may occur through drinkingwater, food, soil, or ambient air, subchronic toxicity studieswere conducted in male and female F344/N rats and B6C3F₁ miceby the drinking water (2-week exposure) and dosed feed (2-and13-week exposure) routes. Animals were evaluated for histopathology,clinical pathology, reproductive toxicity, and tissue metalaccumulation, and target organs were examined by a variety ofspecial stains and by electron microscopy to characterize theobserved lesions. In drinking water, cupric sulfate concentrationsof 300 to 100 ppm produced no ill effects, whereas concentrationsof 3000 to 30,000 ppm were lethal to rats and mice within 2weeks. In feed, cupric sulfate concentrations of 4000 to 16,000ppm caused significant reductions in body weight gain in bothspecies in the 2- and 13-week studies. Hyperplasia and hyperkeratosisof the limiting ridge of the forestomach were present in bothspecies in the 2- and 13-week studies. Rats in the dosed feedstudies had a dose-related increase in inflammation in the liverand changes in clinical chemistry parameters which were indicativeof hepatocellular damage and cholestasis. Histologic changesin the kidneys of rats consisted of a dose-related increasein the number and size of eosinophilic protein droplets in theepithelial cytoplasm and the lumina of the proximal convolutedtubules. Droplets were larger and more numerous in males thanin females. Urinalysis results were suggestive of renal tubularepithelial damage. Iron staining of spleens from treated animalsindicated a marked depletion of iron stores in both male andfemale rats, but not in mice, while hematologic and clinicalchemistry alterations in rats in the 13-week study, along withhistologic changes in bone in the 2-week dosed feed study, wereindicative of a microcytic anemia. Cupric sulfate produced noadverse effects on any of the reproductive parameters measuredin rats or mice of either sex. These results indicate that cupricsulfate at high exposure levels is a hepatic and renal toxicant,as well as an inducer of anemia in rodents, with rats more sensitivethan mice following subchronic exposure.     

Stroke Risk Stratification in a “Real‐World” Elderly Anticoagulated Atrial Fibrillation Population

Stroke Risk Stratification . Introduction: Appropriate stroke risk stratification is essential to ensure suitable tailoring of antithrombotic therapy. The objective of this study was to assess the predictive value of stroke risk classification schemes and to identify patients with atrial fibrillation (AF) who are at substantial risk of stroke despite optimal anticoagulant therapy, in a “real world” consecutive elderly AF cohort. Methods: Six hundred and sixty‐two consecutive AF patients (mean [SD] age 74 [7.7] years; 36.1% female) referred to the Anticoagulation Clinic of the Azienda Ospedaliera Careggi of Florence, Italy, were included and followed‐up for a mean 3.6 ± 2.7 years for the incidence of thromboembolic (TE) events. The ability of the new CHA₂DS₂‐VASc schema to predict TE was compared with other contemporary stroke risk schema (including CHADS₂, NICE 2006, ACC/AHA/ESC 2006, and ACCP 2008), by determining the c‐statistic. Results: Univariate predictors of TE events were female gender (odds ratio 1.9; 95%CI [confidence intervals] 1.01–3.70) and previous stroke/transient ischemic attack (TIA)/TE (OR 5.6; 95%CI 2.70–11.45), although after adjustment only previous stroke/TIA/TE was an independent predictor of TE (OR 5.5; 95%CI 2.68–11.31; P = 0.0001). All stroke risk schema had modest discriminating ability, with c‐statistics ranging from 0.54 (atrial fibrillation investigators [AFI]) to 0.72 (CHA₂DS₂‐VASc). The CHADS₂ and CHA₂DS₂‐VASc schemes having the best c‐statistics (0.717 and 0.724, respectively) with significant discriminating value between risk strata (both P < 0.001). The proportion of patients assigned to individual risk categories varied widely across the schema, with those categorized as “moderate‐risk” ranging from 5.3% (CHA₂DS₂‐VASc) to 49.2% (CHADS₂‐classical). Conclusion: In this “real world” cohort, current published risk schemas have modest predictive ability, with the CHADS₂ and CHA₂DS₂‐VASc schemes having the best predictive value for thromboembolism. Future trials could assess the value of alternative strategies for thromboprophylaxis in high‐risk anticoagulated patients identified by these schemes. (J Cardiovasc Electrophysiol, Vol. 22, pp. 25‐30, January 2011)     

Pharmacokinetic–pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty

Objectives:  Although remifentanil has been used to induce hypotension during surgery in infants, no pharmacokinetic–pharmacodynamic (PKPD) model exists for its quantitative analysis. Our aim was to determine the quantitative relationship between whole blood remifentanil concentration and its hypotensive effect during surgery in infants.
Methods/materials:  We studied seven infants (age 0.3–1 year) who underwent cranioplasty surgery and received remifentanil delivered by a computer-controlled infusion pump during the maintenance of anesthesia. Arterial blood samples to determine remifentanil concentration and mean arterial blood pressure (MAP) measurements were collected. A simultaneous PKPD mixed-effects model was built in NONMEM.
Results:  A total of 77 remifentanil concentrations and 185 MAP measurements were collected. Remifentanil pharmacokinetics was described with a two-compartment model, parameter estimates were 2.99 l·min⁻¹·70 kg⁻¹ for clearance and 16.23 l·70 kg⁻¹ for steady state volume of distribution. Mean baseline MAP was 69.7 mmHg and was decreased as per clinical requirements. A sigmoidal E _max model driven by an effect compartment described the decrease in MAP, with an estimated concentration to decrease MAP by half (EC₅₀) being 17.1 ng·ml⁻¹.
Conclusions:  Remifentanil is effective in causing hypotension. The final model predicts that a steady state remifentanil concentration of 14 ng·ml⁻¹ would typically achieve a 30% decrease in MAP.     

Determinants of Lesion Dimensions during Transcatheter Microwave Ablation

Background: Transcatheter microwave ablation is a novel technique for treating cardiac arrhythmias. Methods: We investigated the effects of catheter temperature, application duration, and antenna length on lesion dimensions during catheter‐based microwave ablation. In a swine thigh muscle preparation, microwave was delivered at targeted temperatures of 60°C (n = 18), 70°C (n = 27), 80°C (n = 43), or 90°C (n = 18) for 120 seconds with 10‐mm antenna; and at targeted temperatures of 80°C for 120 seconds (n = 22), 150 seconds (n = 18), 180 seconds (n = 18), 210 seconds (n = 18), and 240 seconds (n = 17) with 20‐mm antenna using 10 F catheter (MedWaves, San Diego, CA, USA) during parallel orientation. Conventional radiofrequency ablation (RF) using a 4‐mm tip electrode was performed as control. Results: With 120‐second energy applications, lesion length and depth were significantly larger with targeted temperatures of 80°C and 90°C than 60°C (P< 0.05). Furthermore, lesion depth and width, but not length, were significantly increased by prolonging energy application duration from 120 to 240 seconds at targeted temperature of 80°C (P< 0.05). Compared to RF, microwave lesions were significantly longer but had comparable depth and width. A 20‐mm microwave antenna produced longer lesions than either a 10‐mm antenna or RF ablation catheter. Multivariate analysis demonstrated that targeted temperature ≥80°C, application duration ≥150 seconds, and use of 20‐mm antenna were independent predictors for lesion depth and width (P< 0.05). Surface dessication was observed in 4/18 (22%) lesions at 90°C, as compared with 1/136 (0.7%) at 80°C targeted tip temperature (P < 0.05). Conclusions: This study demonstrated that lesions size with transcatheter microwave ablation can be controlled by adjusting targeted temperature, energy application duration, and antenna length. A targeted temperature of 80°C for more than 150 seconds should provide optimal lesion dimensions and lower risk of surface dessication or charring.     

ACCURACY OF PREDICTING LONG-TERM PROSTATE SPECIFIC ANTIGEN OUTCOME BASED ON EARLY PROSTATE SPECIFIC ANTIGEN RECURRENCE RESULTS AFTER RADICAL PROSTATECTOMY

PURPOSE: We determined how prostate specific antigen (PSA) doubling time changed with time and whether an early measure of doubling time would accurately predict long-term PSA values and clinical outcome in a cohort of patients followed expectantly after radical prostatectomy. MATERIALS AND METHODS: We analyzed data on 121 patients with PSA recurrence after radical retropubic prostatectomy. Group and individual analyses were performed on 60 patients who met study inclusion criteria. PSA doubling time was calculated and a curve was plotted using logarithmic transformation with linear regression and least squares analysis. In analysis 1 patients were placed into 3 subgroups according to doubling time. Doubling time was calculated per subgroup and the slopes of the aggregate curves were compared to determine how doubling time changed with time. In analysis 2 we calculated early doubling time per patient using only the initial 2 detectable PSA values and compared it with eventual doubling time in each using all PSA values. In addition, we analyzed how doubling time correlated with the clinical course. RESULTS: Using the group methodology there was no statistically significant acceleration or deceleration with time in doubling time slope in any of the 3 subgroups. On individual analysis we noted a weak correlation of early with eventual doubling time (correlation coefficient 0.69, p = 0.01). In 88% of patients eventual doubling time was not within 10% of early doubling time. Metastasis developed in 60% of patients with an eventual DT of 0 to 6 months, while 80% with an eventual doubling time of 6 to 12 months had no evidence of local or metastatic disease. No patients with an eventual doubling time of greater than 12 months have had metastatic disease and only 4 (16%) had local recurrence, which was treated with radiation therapy. In 8 of the 14 patients (23%) with local recurrence or metastatic disease early doubling time predicted eventual doubling time. Early doubling time was more rapid and slower than eventual doubling time in 5 and 1, respectively, of the remaining cases, which would have placed them in a different subgroup. CONCLUSIONS: On group analysis PSA doubling time appeared to be constant with time and there was no evidence that it accelerated with time in our dataset of PSA recurrence after radical prostatectomy. On individual analysis early doubling time showed a weak but statistically significant correlation with eventual doubling time. However, there was significant inaccuracy when predicting PSA doubling time based on early PSA values in individuals. Generally early projections of doubling time tend to over predict tumor biological aggressiveness, that is local recurrence or metastasis. A need remains for more accurate predictors of the rate of disease progression at initial PSA recurrence to determine accurately early in the clinical course the patients who may benefit from additional therapy. Currently no patient in our study has died of prostate cancer.     

Special Antigens on Sperm From Autoimmune Infertile Men

ABSTRACT: Sera from three fertile men and four infertile men without sperm antibodies, 17 infertile men with sperm antibodies in serum and seminal plasma (S.P.), and 25 infertile men with sperm antibodies in S.P. were tested by Western Blot analysis against sperm membrane extracts and S.P. from fertile nonautoimmune men and infertile autoimmune men. Sera from fertile men reacted against common antigens with molecular weights (MW) of 28, 38, 48, 60, and 68 kD present on sperm from autoimmune and nonautoimmune men and special antigen of MW 76 kD on the sperm of fertile men. Sera from 15 of 17 (88%) autoimmune infertile men with sperm antibodies in serum and S.P. detected special antigens with MW of 58 kD (sera reactivity in 47% of these men), 43kD (in 29%), 30 kD (in 24%), 35 kD (in 18%), 52 kD (in 12%), 41 kD (in 6%), and 71 kD (in 6%) on the sperm of autoimmune men in addition to the common antigens. Sera from 15 of 25 (60%) men with sperm antibodies in their S.P. showed reactivity to special antigens with MW 52 kD (in 20%), 35 kD (in 16%), 41 kD (in 16%), 58 kD (in 8%), 70/71 kD (in 8%), 30 kD (in 8%), and 56 kD (in 4%). Sera from 18 of 42 (43%) infertile men with sperm antibodies also detected special antigens of MW 26, 46, and 76 kD present only in fertile men's sperm. Sera from only 15 of 42 (36%) autoimmune infertile men reacted against special antigens with MW 17, 20, 23, 30, 43, and 58 kD in the seminal plasma of autoimmune infertile men. Cross-absorption studies using sera from autoimmune infertile men further supported the presence of unique antigens on their sperm. It is proposed that the special antigens present on the sperm from infertile autoimmune men may be responsible for the enhanced humoral and cell-mediated immune responses observed in these men.     

Taurine Failed to Protect against the Embryotoxic Effects of Isotretinoin in the Rat

Taurine Failed to Protect against the Embryotoxic Effects ofIsotretinoin in the Rat AGNISH, N. D., RUSIN, G., AND DINARDO,B. (1990). Fundam. Appl. To.xicol. 15, 249–257. Experimentalevidence exists to indicate that retinoids may act as detergentsto disrupt biological membranes. Taurine, an amino sulfonicacid, has been shown to possess membrane-stabilizing and cytoprotectiveproperties. This study was undertaken to test whether taurinecoadministered with isotretinoin might be able to protect againstthe teratogenic effects of the retinoid. Our study failed tofind any support for this speculation. Whether challenged againsta 75 (mildly teratogenic) or 150 (very teratogenic) mg/kg/daydose of isotretinoin, taurine for the most part worsened theretinoid embryotoxicity. While in a few combinations taurinedecreased the re-sorption or malformation rate associated withisotretinoin, the decrease was, at best, marginal. In no casewas taurine able to decrease these rates to those noted in thecontrols.     

EFFECTS OF PIPECURONIUM AND PANCURONIUM ON THE ISOLATED RABBIT HEART

We have studied the effects of pipecuronium and pancuroniumon myocardial contractility and heart rate in two differentanimal preparations. Pipecuronium and pancuronium produced nochange in isometric contraction of rabbit atria. The chronotropiceffects of pipecuronium, pancuronium and vecuronium were investigatedusing acetylcholine as an agonist in isolated perfused rabbitheart. Pancuronium but not pipecuronium or vecuronium, produceda significant degree of antagonism to the bradycardia producedby acetylcholine.