Efficacy of Fumonisin Esterase in Piglets as Animal Model for Fumonisin Detoxification in Humans: Pilot Study Comparing Intraoral to Intragastric Administration.

Fumonisins, a group of highly prevalent and toxic mycotoxins, are suspected to be causal agents of several diseases in animals and humans. In the animal feed industry, fumonisin esterase is used as feed additive to prevent mycotoxicosis caused by fumonisins. In humans, a popular dosage form for dietary supplements, with high patient acceptance for oral intake, is capsule ingestion. Thus, fumonisin esterase provided in a capsule could be an effective strategy against fumonisin intoxication in humans. To determine the efficacy of fumonisin esterase through capsule ingestion, two modes of application were compared using piglets in a small-scale preliminary study. The enzyme was administered intraorally (in-feed analogue) or intragastrically (capsule analogue), in combination with fumonisin B1 (FB1). Biomarkers for FB1 exposure; namely FB1, hydrolysed FB1 (HFB1) and partially hydrolysed forms (pHFB1a and pHFB1b), were measured both in serum and faeces using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and toxicokinetic parameters were calculated. Additionally, the serum sphinganine/sphingosine (Sa/So) ratio, a biomarker of effect, was determined using LC-MS/MS. A significantly higher Sa/So ratio was shown in the placebo group compared to both esterase treatments, demonstrating the efficacy of the esterase. Moreover, a significant decrease in serum FB1 area under the concentration-time curve (AUC) and an increase of faecal HFB1 AUC were observed after intraoral esterase administration. However, these effects were not observed with statistical significance after intragastric esterase administration with the current sample size.

Esterase-Mediated Sustained Release of Peptide-Based Therapeutics from a Self-Assembled Injectable Hydrogel.

A synthetic strategy for conjugating small molecules and peptide-based therapeutics, via a cleavable ester bond, to a lipidated ß3-tripeptide is presented. The drug-loaded ß3-peptide was successfully co-assembled with a functionally inert lipidated ß3-tripeptide to form a hydrogel. Quantitative release of lactose from the hydrogel, by the action of serum esterases, is demonstrated over 28 days. The esterase-mediated sustained release of the bioactive brain-derived neurotrophic factor (BDNF) peptide mimics from the hydrogel resulted in increased neuronal survival and normal neuronal function of peripheral neurons. These studies define a versatile strategy for the facile synthesis and co-assembly of self-assembling ß3-peptide-based hydrogels with the ability to control drug release using endogenous esterases with potential in vivo applications for sustained localized drug delivery.

Concentrations of canine prostate specific esterase, CPSE, at baseline are associated with the relative size of the prostate at three-year follow-up.

BACKGROUND: Enlargement of the prostate is associated with prostatic diseases in dogs, and an estimation of prostatic size is a central part in the diagnostic workup. Ultrasonography is often the method of choice, but biomarkers constitute an alternative. Canine prostate specific esterase (CPSE) shares many characteristics with human prostate specific antigen (PSA) and is related to prostate size. In men with clinical symptoms of prostatic disease, PSA concentrations are related to prostate growth. The aims of the present follow-up study were to evaluate if the concentration of CPSE is associated with future growth of the prostate, and if analysis of a panel of 16 steroids gives further information on prostatic growth. Owners of dogs included in a previous study were 3 years later contacted for a follow-up study that included an interview and a clinical examination. The prostate was examined by ultrasonography. Serum concentrations of CPSE were measured, as was a panel of steroids. RESULTS: Of the 79 dogs included at baseline, owners of 77 dogs (97%) were reached for an interview, and 22 were available for a follow-up examination. Six of the 79 dogs had clinical signs of prostatic disease at baseline, and eight of the remaining 73 dogs (11%) developed clinical signs between baseline and follow-up, information was lacking for two dogs. Development of clinical signs was significantly more common in dogs with a relative prostate size of ≥2.5 at baseline (n = 20) than in dogs with smaller prostates (n = 51). Serum concentrations of CPSE at baseline were not associated with the change in prostatic size between baseline and follow-up. Serum concentrations of CPSE at baseline and at follow-up were positively associated with the relative prostatic size (Srel) at follow-up. Concentrations of corticosterone (P = 0.024), and the class corticosteroids (P = 0.0035) were positively associated with the difference in Srel between baseline and follow-up. CONCLUSIONS: The results support the use of CPSE for estimating present and future prostatic size in dogs ≥4 years, and the clinical usefulness of prostatic size for predicting development of clinical signs of prostatic disease in the dog. The association between corticosteroids and prostate growth warrants further investigation.

Echotexture Analysis of Prostate Parenchyma for Detection of Benign Prostatic Hyperplasia in Dogs.

Ultrasonography is one of the most common methods for the diagnosis of prostate disorders, such as benign prostatic hyperplasia (BPH), in dogs. Changes in the echotexture are one of the indicators used to diagnose prostate disorders. The purpose of this study was to investigate the changes occurred in the dogs' prostate echotexture during the induction of BPH using image analysis. Twenty sexually mature male intact mixed-breed dogs were selected and divided randomly into control and BPH-induced groups. BPH was induced using testosterone and estrogen injections for 63 days. The ultrasound imaging of the dogs' prostate was performed during the induction of BPH on days 0, 21, 42, and 63. The echotexture of the prostate parenchyma was analyzed using the Image J software. Then, the changes in the echotexture and its correlation and linear regression with the prostate volume and canine prostate specific esterase (CPSE) concentration were evaluated by statistical tests. The prostate parenchyma echotexture did not show any significant changes during the induction of BPH and in comparison with that of the control group. While prostate volume and CPSE concentration increased significantly, indicating that BPH was induced in the dogs. There was no significant correlation and linear regression between the prostate echotexture and prostate volume or between the CPSE concentration and prostate echotexture. According to the results, the alteration in the prostate parenchymal echotexture did not occur in the early stages of induced BPH, but significant changes occurred in the prostate volume and CPSE concentration during those early stages.

Vitamin E and Selenium Treatment Alleviates Saline Environment-Induced Oxidative Stress through Enhanced Antioxidants and Growth Performance in Suckling Kids of Beetal Goats.

Salinity is a worldwide, threatening problem affecting socioeconomic status globally. Saline land comprises salt content in soil, plants, and drinking water. Livestock farming is the worthy option for proper utilization of saline land in a cost-effective approach. Animals reared on this land experience a variety of stresses. Such stresses promote oxidative stress and reduced animal performance. The purpose of this study was to investigate the antioxidative function of vitamin E and selenium (Se) on pregnant/nonpregnant animals reared on the saline environment. A total of 36 multiparous pregnant (n = 18) and nonpregnant (n = 18) goats weighing about 38-45 (average 41.5) kg were equally divided into control and supplemented groups. The experiment lasted from 120 days of gestation to 15 days after parturition for pregnant goats and 0 to 45 days for nonpregnant cyclic goats (>50 days post-kidding). The supplemented group was administered vitamin E (1000 mg/kg BW) and selenium (3 mg/50 kg BW), while the control group was kept on normal saline (0.9% NaCl) with the same route 15 days apart. The blood samples were collected with 15 days apart during the entire experimental period of 45 days and subjected to assessment of enzymatic/nonenzymatic antioxidants, hydrolytic enzymes, oxidants, stress metabolic biomarkers, Se, and progesterone concentration of (pregnant) animals. Results revealed that vitamin E and Se supplementation significantly enhanced the activity of enzymatic (catalase and peroxidase) and nonenzymatic antioxidants such as total phenolic/flavonoid content and vitamin C and increased blood plasma level of Se concentration in comparison with the control group (P < 0.01). Exposure to antioxidant supplementation mitigated lipid peroxidation and enhanced progesterone level and total antioxidant capacity (P < 0.01) as compared to the control group in pregnant goats. Administration of vitamin E and selenium promoted kid survival rate (100%) along with increased initial birth weight, daily average weight gain, and total weight gain in comparison with the control group. Besides, the twinning rate and sex ratio were also recorded in pregnant animals. It is concluded that vitamin E and Se supplementation ameliorated salinity-induced oxidative stress, improved antioxidant status, and enhanced reproductive and growth performance of suckling kids reared on saline land.

Changes in the Serum Prostatic Biomarkers During the Treatment of Benign Prostatic Hyperplasia with a 5alpha-reductase Inhibitor: Finasteride.

The monitoring of serum prostatic biomarkers during the treatment will help clinicians to know the statement of the response to finasteride in dogs affected by benign prostatic hyperplasia (BPH). The present study was aimed to assess changes in the serum canine prostate-specific esterase (CPSE), prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), testosterone, dihydrotestosterone (DHT) and prostate volume evaluation using ultrasonographic examination during the treatment with finasteride in BPH-induced dogs. Twenty dogs were divided into 4 groups (n = 5): BPH + finasteride group, dogs which were induced for BPH and received oral finasteride once daily for 1 month; BPH group, dogs which were induced for BPH and received placebo; finasteride group, normal dogs which received finasteride; and normal group, normal intact dogs which did not receive treatment. Blood sampling and ultrasonography examination were performed on days 0, 14, and 28. The administration of finasteride led to a significant decrease in the concentration of the prostate-specific biomarkers (PSA, CPSE), DHT, testosterone, and the volume of the prostate in BPH + finasteride group compared with the BPH group during 1 month. Interestingly, the PAP concentration did not change in the BPH-induced dogs and in dogs treated with finasteride. It seems that the monitoring of serum PSA and CPSE levels and ultrasonographic examination of the prostate are useful methods for following up the response to finasteride treatment in dogs affected by BPH.

Changes in specific serum biomarkers during the induction of prostatic hyperplasia in dogs.

BACKGROUND: Prostatic hyperplasia (PH) is one of the most important disorders in intact dogs. In this study, we aimed to induce PH experimentally using the combination of testosterone and estrogen and evaluate important factors associated with this disease. RESULTS: The results showed that in the induction group, prostate volume and prostate specific antigen (PSA) concentration increased significantly on day 21 onwards compared to those of the control group. Canine prostatic specific esterase (CPSE) and dihydrotestosterone (DHT) concentrations increased significantly on day 42 onwards while the testosterone levels increased on day 63. In addition, prostatic acid phosphatase (PAP) concentration did not change significantly in the control and induction groups. Biochemistry profiles and hematologic factors were measured for monitoring the function of liver and kidney, and there were no adverse effects following the induction of PH. CONCLUSIONS: It seems that testosterone and estrogen administration led to prostatic hyperplasia during 2 months. Investigating the size of the prostate, accompanied by prostate markers including CPSE, PSA, DHT, and testosterone, is helpful for the PH diagnosis. However, further studies should be carried out on PAP.

Characterization of aspirin esterase activity in health and disease: In vitro and ex vivo studies.

Due to its ability to irreversibly inactivate platelet cyclooxygenase, low-dose aspirin (ASA) is the most widely used antithrombotic agent. Although, studies in specific types of patients with cardiovascular disease (CVD) have shown an incomplete inhibition of platelet's cyclooxygenase, which may increase the variability in drug response. Some aspects of ASA pharmacokinetics (PK) still need further investigation. In this study, we aimed to characterise the contribution of esterase enzymes to ASA hydrolysis in the peripheral blood and to assess their activity in 36 healthy subjects (Ctrl) and 77 CVD patients. To this aim, an in vitro assay testing esterase activity in parallel to a liquid chromatography-tandem mass spectrometry method simultaneously detecting ASA and its main metabolites salicylic (SA) and gentisic acids, have been developed. Michaelis-Menten constant (Km) calculation, ASA esterase isoforms characterisation, and ASA PK study were then achieved. The calculated Km identified plasma esterases as the enzymes with the higher affinity for the substrate compared to the RBC ones. Both rivastigmine and 4-bis-nitrophenyl phosphate inhibited plasma esterase activities, suggesting that acetylcholinesterase and carboxylesterase largely contribute to ASA hydrolysis. The feasibility of the method here developed has been explored in Ctrl and CVD patients. The effect of ASA treatment on enzyme activity was further evaluated on an age, sex and BMI matched subgroup of patients and Ctrl (n = 10 for each subgroup, on and off ASA). No overall variations were evidenced in both CVD and Ctrl groups, even when the effect of ASA treatment was tested. This result suggests the absence of any influence of disease state, drug treatments, and comorbidities on plasma esterase and the inability of ASA intake to induce esterase function. In conclusion, the method here developed allows a better characterisation of ASA esterase activity and could be helpful to define the PK-related determinants of ASA responsiveness in order to personalise regimen in specific pathological conditions.

Advances in Prostatic Diagnostics in Dogs: The Role of Canine Prostatic Specific Esterase in the Early Diagnosis of Prostatic Disorders.

In last years, following the increased canine life expectancy and the rising attention pet-owners devote to their animals, several authors have carried on investigations concerning new techniques to early identify canine prostatic disorders that might affect the dog's quality of life. Prostatic disorders often have an asymptomatic onset and their early diagnosis is difficult: hence, they are usually identified at an advanced stage, only. Traditionally, the diagnosis of prostatic disorders is based on noninvasive tools, such as transrectal and abdominal palpation, seminal or prostatic fluid evaluation, and urinalysis and imaging. On the other hand, a definite diagnosis of prostatic abnormalities could be achieved through prostatic parenchyma Fine Needle Aspiration (FNA) or biopsy. However, these investigations are performed rarely because of their invasiveness. Thus, several authors investigated canine serum biomarkers in order to achieve an earlier diagnostic timing and to apply therapeutic strategies for better outcomes. The Canine Prostatic Specific Esterase (CPSE) has been identified as a suitable biomarker to be included in a prostate health screening program, following the model of prostate-specific antigen (PSA) in human medicine. A higher CPSE in dogs suffering from several prostatic diseases, such as benign prostatic hyperplasia, bacterial prostatitis, or prostatic carcinoma, was reported in literature. Thanks to the potential usefulness in clinical practice, further studies should investigate the potential role of CPSE in monitoring the medical treatment success in the male reproductive system. Moreover, the spreading availability of serum biomarkers, easily carried out on blood samples in clinical practice, could assure a more accurate evaluation of the actual prevalence of prostatic disorders. The CPSE is actually recognized as a promising diagnostic tool for the detection of prostatic disorders in a "prostate health screening program," in order to properly select those patients requiring further more accurate and expensive diagnostic investigations.

Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1.

The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.

Isavuconazole: A new broad-spectrum azole. Part 2: pharmacokinetics and clinical activity.

Isavuconazole, the active moiety of its prodrug isavuconazonium, is a new extended-spectrum triazole whose activity against yeasts, molds, including Aspergillus and mucorales, and dimorphic fungi has been shown in vitro and in preclinical models. The most relevant pharmacokinetics features are water-solubility of the prodrug, rapid cleavage of the prodrug into active moiety and cleavage product by plasmatic esterases, high oral bioavailability of isavuconazole with an extensive penetration into most tissues and a good safety profile even in case of renal impairment. The results of two main clinical studies have led to an approval by FDA and EMA in the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazole is non-inferior to voriconazole in terms of response and survival in invasive aspergillosis and has shown improved safety and tolerability. Importantly, less hepatobiliary, skin and eye disorders have been reported in isavuconazole-treated patients. Isavuconazole has therefore been granted a grade A-I recommendation by the European Conference on Infections in Leukemia (ECIL) for the treatment of invasive aspergillosis. Efficacy has also been demonstrated in mucormycosis in an open-label study. Survival was similar to the survival of matched patients from the international Fungiscope registry and treated with an amphotericin B formulation. Isavuconazole failed to show non-inferiority to caspofungin in a large double-blind candidemia trial. The aim of this review is to give the reader an overview of the data available so far to support inclusion of isavuconazole in the anti-mold therapeutic arsenal.

p-Nitrophenyl Acetate Esterase Activity and Cortisol as Biomarkers of Metal Pollution in Blood of Olive Ridley Turtles (Lepidochelys olivacea).

This study was designed to determine the concentrations of p-nitrophenyl acetate esterase activity (EA) and cortisol in serum of marine Olive Ridley turtles (Lepidochelys olivacea) from a Mexican Pacific population ("La Escobilla" beach) and to evaluate the possible relationship of inorganic elements with these biomarkers. EA, cortisol, and selected chemical elements (Cd, Pb, Ti, Sr, Se, Al, As, and Zn) were measured in the blood of 44 sea turtles from the Eastern Pacific (Southeast Mexico). Serum EA ranged from 0.4 to 3.9 UI mL-1, and cortisol concentrations ranged from 0.07 to 2.5 µL dL-1. A strong negative correlation between EA and cortisol was observed (r = - 0.59, p < 0.01), and significant correlations also were found between EA and important metals, such as Cd (r = - 0.31, p < 0.05) and Pb (r = - 0.27, p < 0.05), and elements of growing concern like Ti (r = - 0.37, p < 0.01) or Al (r = - 0.34, p < 0.05) and between cortisol and Sr (r = 0.29, p < 0.05), Se (r = - 0.38, p < 0.01), and As (r = - 0.26, p < 0.05). These results suggest that turtles chronically exposed to different inorganic elements (such as Pb and Cd), driving to a highly consume of esterase and to a prolonged cortisol elevation. The obtained results indicate the usefulness of these biomarkers in the assessment of inorganic elements pollution in this species.

Canine prostate specific esterase (CPSE) as an useful biomarker in preventive screening programme of canine prostate: CPSE threshold value assessment and its correlation with ultrasonographic prostatic abnormalities in asymptomatic dogs.

Due to the increased attention that pet-owners devote to their animals and to the improved veterinary care, investigations regarding methods to early detect prostatic disorders that might affect canine life quality have been performed. Canine prostate specific esterase (CPSE) concentration was reported to be higher in dogs suffering from prostatic diseases. This study aimed to estimate the CPSE threshold as a biomarker to early identify prostatic diseases in asymptomatic dogs. The ultrasonographic examination of the prostate was performed in 19 dogs (6-40 kg; 1-5 years) with no symptoms of prostatic diseases. Dogs were grouped according to the presence (Group A) or absence (Group B) of prostatic disorders at the ultrasound (altered appearance, the presence of cysts or irregular borders). For each dog, a venous blood sample was collected to measure serum CPSE and the ratio between calculated and normal expected prostatic volume was assessed for each dog. The CPSE data were statistically analysed (t test, p < .05), and the CPSE threshold in blood serum between groups was calculated by ROC. In 11 dogs, ultrasonography showed signs of prostatic abnormalities (Group A, 2-5 years), while no signs were detected in eight dogs (Group B, 1-3 years). The calculated/estimated volume ratio resulted greater than 1.5 in Group A dogs. The CPSE was statistically different between groups (p < .0001): higher in Group A (mean = 184.9, SD = 126 ng/ml) than in Group B (38.9 ± 22.1 ng/ml). The cut-off CPSE threshold was 52.3 ng/ml (ROC, AUC = 0.974, SE 95.6%, SP 89.2%). This study suggests that CPSE serum concentration higher than 50 ng/ml in asymptomatic dogs is associated with ultrasonographic alterations and increased the prostatic size (volume by 1.5 times greater than the normal size). As the onset of prostatic disorders often remains asymptomatic, the rapid assessment of CPSE could be suitable for selecting preventively those animals that would require further accurate evaluation.

The association between the serum concentration of canine prostate specific esterase (CPSE) and the size of the canine prostate.

Benign prostatic hyperplasia (BPH) is an age-related disorder in the intact male dog that is associated with an increase in the prostatic size. Ultrasonography gives a reliable estimate of the prostatic size, but a method for screening the prostate size using a serum sample has advantages, such as requiring less expensive equipment. The primary aim of the study was to study the association between the concentration of the circulating biomarker canine prostate specific esterase (CPSE) and prostatic size. Seventy-nine dogs that were four years old or older were included in the study. Ultrasonography was used for calculating the volume of the prostate. The calculated volume was divided by an estimate of the normal prostatic volume in dogs aged one to four years, to determine the relative prostatic size: the size of the prostate in relation to the normal size in dogs 1-4 years old (Srel). CPSE was analyzed from serum samples. Multiple linear regression analysis was used for studying associations between variables. Prediction intervals for the relative prostatic size based on CPSE concentrations were calculated, as were receiver operating curves for CPSE concentrations predicting Srel. The concentration of CPSE was associated with the relative size and contour of the prostate (P < 0.001). All dogs with clinical signs of BPH had an Srel ≥ 2.5. A CPSE concentration of 200 ng/mL predicted Srel to 2.5 (95% P.I: 1.2-4.8). Based on ROC analysis, the optimal discrimination threshold for CPSE concentration for Srel ≥ 2.5 was estimated as 90 ng/mL (95% confidence interval: 50-140), with a sensitivity of 85% and a specificity of 72%. Screening for CPSE is of potential value in the aging intact male dogs. Although many dogs with an Srel ≥ 2.5 show no clinical signs, the insidious nature of BPH supports further investigations of the prostate in these dogs, corresponding to a CPSE concentration of approximately 90 ng/mL or higher.

Esterase profiles of organophosphorus compounds in vitro predict their behavior in vivo.

We studied 4 serine esterases (EOHs) that are associated with the following consequences from their inhibition by organophosphorus compounds (OPCs): acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE; inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity, OPIDN). The relative degree of inhibition of these EOHs constitutes the "esterase profile" of an OPC, which we hypothesize can serve as a predictor of its overall physiological effects. To test this hypothesis, we selected 3 OPCs known from previous work on reference enzymes to span a wide range of esterase profiles, neuropathic potential, and acute cholinergic toxicity. For each compound, we determined in vitro IC50 and in vivo ED50 values for inhibition of AChE, BChE, CaE, and NTE in mouse brain and blood. The results showed good correlations between in vitro and in vivo measures of potency and selectivity except for brain CaE, a tissue-specific isoform of the enzyme that was less sensitive to the test compounds than expected. Thus, this synthesis of new and previously published results indicates that the concept of the esterase profile of OPCs is useful for the prediction of therapeutic and toxic effects in vivo.

[The enzyme activity of neutrophils of blood in patients with chronic viral hepatitis C depending on gender characteristics].

The study was carried out to analyze dynamics of diaphorase and esterase activity ofneutrophils of blood in patients with chronic viral hepatitis C of lower degree of activity depending on gender characteristics in dynamics of treatment. The examination and treatment were organized concerning sampling of 113 patients with chronic viral hepatitis C of lower degree of activity. The diaphorase and esterase activity of neutrophils in dynamics of treatment was detected The analysis of diaphorases was carried out according R.P. Nartsissov technique. The content of esterase was estimated by V.M. Wachstein-FG. Wolf technique. The count of results was implemented using Kaplow semiquantitative technique. In patients with chronic viral hepatitis C of lower degree of activity prior to treatment the activity of NAD-diaphorase was lowered both in males and females. The activity of NADF-diaphorase prior to treatment significantly exceeded standard in males and matched standard in females. The application of basic therapy resulted in qualitative redistribution of cellular composition of reacting cells. All of them reacted following medium degree of activity (b). At that, average cytochemical indicator of reaction was normal in males and in females increasing of activity was observed. The activity og both diaphorases after application of complex therapy (basic therapy and cycloferon) totally returned to normality both in males and females. The esterase activity prior to treatment was decreased in males and increased in females (alpha-naphthylacetate esterase) and vice versa (alpha-naphthylbutyrate esterase) was increased in males and decreased infemales. After application of basic therapy in males increasing of esterase activity was registered and total redistribution of qualitative composition of reacting neutrophils (from degree "a" to degree "b"). In females after treatment the activity of alpha-naphthylacetate esterase was decreased and alpha-naphthylbutyrate esterase was increased. The redistribution of qualitative composition of cells was absent. The application of cycloferon brings to normality the activity of alpha-naphthylbutyrate esterase in males and activity of diaforaselpha- naphthylacetate esterase in females. In patients with chronic viral hepatitis C of lower degree of activity the differences in diaphorase and esterase activity ofneutrophils depending on gender characteristics in dynamics of treatment are observed.

Neurologic dysfunction and genotoxicity induced by low levels of chlorpyrifos.

Chlorpyrifos (CPF) is an organophosphorus cholinesterase inhibitor widely used as an insecticide. Neuro and genotoxicity of this agent were evaluated following daily subcutaneous injections at 0.1, 1 and 10mg/kg or its vehicle to laboratory rats during one week, at the end of which somatosensory evoked potentials (SEP) and power spectrum of the electroencephalogram (EEGp) were recorded under urethane anesthesia. In another group of conscious animals, auditory startle reflex (ASR) was evaluated followed, after euthanasia, with measurements of plasma B-esterases, and genotoxicity with the alkaline comet assay (ACA) at the same CPF doses. The results indicated a CPF dose related inhibition of B-esterases. Enhanced inhibition of the ASR by a subthreshold pre-pulse was observed at all doses and ACA showed a significant higher DNA damage than vehicle controls in animals exposed to 10mg/kg CPF. A trend to higher frequencies of EEGp and an increase in amplitude of the first negative wave of the SEP were found at all doses. The first positive wave of the SEP decreased at the CPF dose of 10mg/kg. In summary, a shift to higher EEG frequencies and alterations of somatosensory and auditory input to the central nervous system were sensitive manifestations of CPF toxicity, associated with depression of B-esterases. The changes in electrical activity of the cerebral cortex and DNA damage observed at doses that do not elicit overt toxicity may be useful in the detection of CPF exposure before clinical signs appear.

Experimental measurements for the effect of dilution procedure in blood esterases as animals biomarker for exposure to OP compounds.

Organophosphate compounds can bind to carboxylesterase, which may lower the concentration of organophosphate pesticides at the target site enzyme, cholinesterase. It is unclear from the literature whether it is the carboxylesterase affinity for the organophosphate and/or the number of carboxylesterase molecules that is the dominant factor in determining the protective potential of carboxylesterase. The fundamental dilutions and kinetic effects of esterase enzyme are still poorly understood. This study aims to confirm and extend our current knowledge about the effects of dilutions on esterases activities in the blood for birds with respect to protecting the enzyme from organophosphate inhibition. There was significantly higher esterases activities in dilution 1 : 10 in the all blood samples from quail, duck, and chick compared to other dilutions (1 : 5, 1 : 15, 1 : 20, and 1 : 25) in all cases. Furthermore, our results also pointed to the importance of estimating different dilutions effects prior to using in birds as biomarker tools of environmental exposure. Concentration-inhibition curves were determined for the inhibitor in the presence of dilutions 1 : 5, 1 : 10, plus 1 : 15 (to stimulate carboxylesterase). Point estimates (concentrations calculated to produce 20, 50, and 80% inhibition) were compared across conditions and served as a measure of esterase-mediated detoxification. Results with well-known inhibitors (malathion) were in agreement with the literature, serving to support the use of this assay. Among the thiol-esters dilution 1 : 5 was observed to have the highest specificity constant (k(cat)/K(m)), and the K m and k cat values were 176 µM and 16,765 s(-1), respectively, for S-phenyl thioacetate ester, while detected in dilution 1: 15 was the lowest specificity constant (k(cat)/K(m)), and the Km and k cat values were 943 µM and 1154 s(-1), respectively, for acetylthiocholine iodide ester.

Multiple myeloma: relationship to antioxidant esterases.

OBJECTIVE: To investigate the status of the oxidant/antioxidant balance in patients with multiple myeloma compared to healthy controls. MATERIALS AND METHODS: This study was conducted on 40 multiple myeloma patients and 40 healthy controls of matched age and sex. Serum total thiol, oxidative stress index (OSI), total oxidant status (TOS), and total antioxidant status (TAS) were measured using colourimetric methods; paraoxonase-1 and arylesterase enzyme activities were also quantified. RESULTS: Serum paraoxonase-1 and arylesterase activities and total thiol levels were significantly lower (p = 0.0001, p = 0.036 and p < 0.0001, respectively), whereas TOS and OSI levels were significantly higher (p < 0.0001 for both parameters) in multiple myeloma patients compared to controls. However, no significant differences in TAS were identified when the two groups were compared. CONCLUSIONS: Our findings indicate an impaired oxidative/antioxidative balance in multiple myeloma. We recommend further studies with larger groups to investigate the possible relationship between oxidative stress and the aetiopathogenesis of multiple myeloma.

A population pharmacokinetic model of remifentanil in pediatric patients using body-weight-dependent allometric exponents.

BACKGROUND: Allometric exponents in population pharmacokinetic analysis are regularly used but the issue of fixing or estimating an allometric exponent remains controversial. The objective of the current analysis is to evaluate the performance of a body-weight-dependent allometric exponent (BDE) model of remifentanil. METHODS: The study was conducted in 34 patients (neonates to 17 years and 2.5 to 97 kg body weight) following a single intravenous (IV) infusion of remifentanil (5 µg/kg). A population pharmacokinetic approach was taken to describe drug clearance by the following BDE equation: CL=CLpop(BW/14.6 kg)L×BW(-M). Three allometric models were used to explore the impact of allometric exponents on the total clearance of remifentanil. RESULTS: All model-fitted structural, covariate, and statistical parameters were estimated with good to excellent precision (%RSE). However, on the basis of calculated Akaike weights (0.000 for model 1, 0.004 for model 2, and 0.996 for model 3), model 3 is the most robust model to describe individual clearance estimates. CONCLUSIONS: The BDE model performed best for the estimation of remifentanil clearance and is realistic and of practical value. Further investigation should be conducted for such models.