Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams,fetuses, and neonates with physiologically based pharmacokinetic modeling

Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans.     

Microvascular volume in symptomatic Achilles tendons is associated with VISA-A score

Objectives

The role of neovascularisation in tendinopathy is still poorly understood, potentially due to technical limitations of conventional power Doppler ultrasound. This study aimed to investigate the association between contrast-enhanced ultrasound (CEUS) microvascular volume (MV), Victorian Institute of Sports Assessment-Achilles (VISA-A) scores and intrinsic Achilles tendon tenderness, as well as two different Power Doppler modes.

Acute and sub-chronic toxicity of a lyophilised aqueous extract of Centaurium erythraea in rodents

Ethnopharmacological relevance

An aqueous concoction made from centaury (Centaurium erythraea (L.) Rafn., (Gentianaceae) whole plant is used in the Moroccan traditional medicine for the treatment of diabetes, as well as a number of other diseases. No systematic study of the potential toxicity of the plant has been described.

Aim of the study

The present investigation was carried out to evaluate the safety of an aqueous extract of Centaurium erythraea whole plant (CE-extract) by determining its potential toxicity after acute and sub-chronic administration in rats and mice.

Materials and methods

For the acute study, the lyophilised CE-extract was administered to adult IOPS OFA mice in single oral doses of 1-15 g/kg given by gavage, and single intraperitoneal (i.p.) doses of 1-14 g/kg. General behavioral adverse effects, mortality, and latency of mortality were determined for up to 14 days. In the sub-chronic dose study, the CE-extract was administered orally at doses of 100, 600 and 1200 mg/kg daily for 90 days to Wistar rats. Body weight and selected biochemical and hematological parameters were determined every 30 days and at the end of 90 days of daily administration; sections of liver and kidney were examined histologically for any signs of organ damage at the end of the treatment.

Results

In the acute study in mice, there were no deaths or any signs of toxicity observed after oral administration of single doses of the CE-extract at any dose level up to the highest dose tested (15 g/kg), which was the no-observed-adverse-effect level (NOAEL). However, the mortality rate as well as the acute toxicity of the i.p. administered CE-extract increased progressively with increasing dose. The NOAEL for the i.p. dose was 6 g/kg while the lowest-observed-adverse-effect level (LOAEL) was 8 g/kg; the calculated acute toxicity (LD₅₀) of i.p. administered CE-extract in mice was 12.13 g/kg.In sub-chronic studies in rats, the CE-extract (administered orally at daily doses of 100, 600 and 1200 mg/kg for 90 days), did not cause any changes in hematological and biochemical parameters, except a small reduction of mean corpuscular volume, and a decrease in serum glucose and triglyceride levels at the higher doses. Histopathological examination of the liver and kidneys at the end of the study showed normal architecture suggesting no morphological disturbances.

Conclusions

Because of the lack of toxicity of the CE-extract given by the oral route, and relatively high NOAEL values for the i.p. dose in the acute study in mice, as well as lack of mortality or clinically significant adverse changes in the biological and hematological parameters, and the morphology of liver and kidneys in rats after 90 days of daily dosing, it may be concluded that the CE-extract is relatively non-toxic. Also, in view of the doses consumed empirically in traditional medicine in Morocco, there is a wide margin of safety for the therapeutic use of Centaurium erythraea.     

Transcranial US of preterm neonates: High risk gestational age and birth weight for perinatal asphyxia

Objective

The study aims to determine the high risk gestational week (GW) and/or birth weight (BW) of the preterm neonate, below which perinatal hypoxic cerebral injuries are expected to occur.

Material and methods

Eighty preterm neonates, born at or before 37 GW, were included. Twenty-three of them were <32 GW and 57 >32 GW. Also, 28 of them were <1500 g and 52 >1500 g. Imaging was done by transcranial ultrasound with 4–9 MHz curvilinear probe. CT scan was additionally performed for only 18 candidates. The study protocol was approved by the ethics committee in Al-Mana General Hospital (AGH).

Results

Intraventricular hemorrhage (IVH) was diagnosed in six preterm neonates <32 GW and two >32 GW. Three <32 GW and one >32 GW presented with hypoxic ischemic encephalopathy (HIE) with no hemorrhage. Two preterm neonates <32 GW had both IVH & HIE. All positive cases were below 1500 g BW.

Conclusion

Preterm neonates <32 GW and/or <1500 g are highly susceptible for HIE and/or IVH. Thus, special medical care, including post-labor hospitalization in well equipped special baby care units (SCBU) and routine transcranial ultrasound (TCUS) screening is recommended for those preterm neonates.     

Comparison of intermittent- and continuous-flow cell separators for the collection of autologous peripheral blood progenitor cells in patients with hematologic malignancies

BACKGROUND: The transplantation of autologous peripheral blood progenitor cells (PBPCs) after high-dose chemotherapy is a valuable therapy for patients with hematologic and solid malignancies. Several methods are used for harvesting PBPCs. The efficiency of intermittent- and continuous-flow blood cell separators in collecting progenitor cells from the blood of patients undergoing myeloablative treatment for cancer was compared. STUDY DESIGN AND METHODS: PBPC components (n = 133) were obtained from 72 patients by leukapheresis with continuous-flow machines (Spectra, COBE; CS 3000 Plus, Baxter) and with an intermittent-flow machine (MCS 3P, Haemonetics). The data were analyzed retrospectively. Blood samples obtained from the patients before leukapheresis and samples of the leukapheresis components themselves were analyzed for their content of RBCs, WBCs, platelets, and CD34+ cells. RESULTS: The Spectra processed more than twice the blood volume in the shortest time (15 L in 178 min), whereas the Baxter CS 3000 Plus (10 L in 185 min) and the MCS 3P (4.8 L in 239 min) processed significantly smaller volumes in a longer time. The mean ACD consumption was 403 mL with the MCS 3P, 900 mL with the CS 3000 Plus, and 1000 mL with the Spectra. The product volumes were 50 mL (CS 3000 Plus), 69 mL (MCS 3P), and 166 mL (Spectra). In all groups, differences in the preapheresis hemograms were not significant, but the Spectra group had fewer CD34+ cells than the other groups. Despite this, the differences in the number of CD34+ cells in the leukapheresis components of all groups were without statistical significance. In the Spectra group, the collection of MNCs of 104 percent and CD34+ cells of 154 percent was significantly more efficient than that in the MCS 3P group (42.2% and 56%, respectively) or the CS 3000 Plus group (50.8% and 47.15%) as related to the patients' blood volume. CONCLUSION: PBPC collection can be performed successfully with continuous-flow and intermittent-flow blood cell separators. The Spectra had the best recovery of CD34+ cells within the shortest time. Leukapheresis with the MCS 3P is indicated if only a single venous access is available.     

Subchronic (13-week) oral toxicity study of dihomo-γ-linolenic acid (DGLA) oil in rats

Dihomo-γ-linolenic acid (DGLA) is one of the essential fatty acids, and has anti-inflammatory and anti-allergic effects. To assess the toxicity of a novel DGLA oil produced by the fungus Mortierella alpina, we examined it in the Ames test and in acute and subchronic oral toxicity tests in rats. In the Ames test, no mutagenicity was found up to 5000 μg/plate. The acute toxicity test revealed no toxicity related to DGLA oil at 10 g/kg. In the subchronic toxicity test, DGLA oil (500, 1000, and 2000 mg/kg) was orally administered. Water and soybean oil (2000 mg/kg) were used for the no-oil control and soybean oil control groups, respectively. There was no death in either sex. Because of administration of large amounts of oil, food consumption was low in the soybean oil control and the three test groups, which appeared to mildly decrease urinary excretion of Na, K, and Cl, as well as total serum protein, albumin, and blood urea nitrogen levels. There were no toxicological changes in body weight, food consumption, ophthalmological examination, urinalysis, hematological examination, blood biochemical examination, necropsy, organ weight, or histopathological examination. These findings show that the no-observed-adverse-effect level of the DGLA oil was 2000 mg/kg.     

Comparison of the anti-inflammatory effects of dexamethasone,indomethacin and BW755C on carrageenin-induced pleurisy in rats

In rat carrageenin pleurisy, dexamethasone (0.25 mg/kg p.o.) inhibited exudate accumulation in the pleural cavity throughout the period of testing while the non-steroidal anti-inflammatory drugs indomethacin (10 mg/kg p.o.) and BW755C (100 mg/kg p.o.) inhibited it for 6 and 9 h respectively after the intrapleural injection of carrageenin but not thereafter. These observations were confirmed by the finding that, of the treatments 6 h after carrageenin, only that with dexamethasone reduced exudate volume at 15 h after carrageenin. The anti-exudative action of dexamethasone at 15 h after carrageenin may be at least in part mediated by endogenous substance(s) formed through gene expression, because it was prevented by actinomycin D. Dexamethasone and BW755C markedly inhibited cell accumulation in the pleural exudate throughout the period tested, while indomethacin inhibited it significantly between 9–24 h after carrageenin.     

A preliminary study of the pharmacodynamics and pharmacokinetics of a novel enkephalin analogue [Tyr-D.Arg-Gly-Phe(4NO2)·Pro·NH2 (BW443C)] in healthy volunteers

Summary We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 µg·kg^–1 for 60 min and increasing to a maximum of 2.0 µg·kg^–1·min^–1 for 180 min. Subsequently 12 different subjects received single i.v. infusions of 10 µg·kg^–1·min^–1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN.Dry mouth and some nasal stuffiness were reported and postural hypotension occurred in 5/16 subjects at plasma concentrations >0.8 µg·ml^–1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60–90 min of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accomodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations.The disposition of the peptide was adequately described by a 2-compartment model with a mean ± SD plasma clearance of 123±18 ml·min^–1 and a half-life of 2.0±0.4 h.