SAFETY AND PHARMACOKINETICS OF PRAZIQUANTEL IN EUROPEAN POND TURTLES (EMYS ORBICULARIS).

Spirorchiidosis, caused by blood flukes of the genus Spirorchis, is a disease of great concern for the critically endangered European pond turtle (EPT; Emys orbicularis) in Switzerland. The endogenous life cycle of the parasite often leads to systemic inflammatory reactions, thrombosis, and death. Praziquantel (PZQ) is the treatment of choice against adult Spirorchis spp. in green (Chelonia mydas) and in loggerhead (Caretta caretta) sea turtles and is therefore considered for the treatment of EPT. This study aimed to establish a safe, easily applicable PZQ treatment for EPT, based on pharmacokinetics and tolerability. Three application methods were tested in a total of 12 adult EPT. Each turtle received a total of 75 mg/kg PZQ (three doses of 25 mg/kg in 3-h intervals [q3h × 3]) via IM (n = 3 turtles), SC (n = 3 turtles), or PO (n = 6 turtles) administration. Blood was collected 3, 6, 24, and 48 h after the first administration to determine the plasma concentration of PZQ using high-performance liquid chromatography coupled to mass spectrometry. Maximum measured R-PZQ concentrations (Cmax) were reached after 6 h. The mean Cmax of the total PZQ (sum of R- and S-PZQ) in the PO-treated EPT group was 1,929 ng/ml. Significantly higher concentrations were measured after IM and SC injection (mean Cmax of total PZQ = 12,715 ng/ml and 10,114 ng/ml, respectively). Transient side effects were evident after IM administration (local swelling and lameness), whereas no adverse drug effects were observed after PO and SC administration. Based on these results and the ease of administration to EPT, SC injection of PZQ at 25 mg/kg q3h times 3 serves as promising treatment application for the future.

Pharmacokinetics of Ascending Doses of Praziquantel in Adults Infected with Opisthorchis felineus in Western Siberia, Russian Federation.

Opisthorchiasis due to the liver fluke Opisthorchis felineus is highly prevalent in rural regions of Western Siberia, causing severe liver and bile duct maladies. Praziquantel administered as a three-dose regimen is the only drug used to treat O. felineus-infected individuals. A simpler single-dose treatment might serve as an alternative. The aim of this study was to compare the pharmacokinetic (PK) properties of single, ascending doses of praziquantel compared to multiple dosing in patients infected with O. felineus to contribute to updated treatment guidelines. Dried blood spots (DBSs) of 110 adults were collected at 11 time points post-drug administration at single oral doses of 20, 40, and 60 mg/kg, as well as 3× 20 mg/kg (4 h dosing interval). DBS samples were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and PK parameters were obtained for R-, S-, and R-trans-4-OH-praziquantel employing noncompartmental analysis. We observed the highest drug exposure for all analytes when the triple-dose scheme was used; area under the concentration-time curve from 0 to 24 h (AUC0-24) values of 8.04, 27.75, and 36.38 µg/mL·h were obtained, respectively. Maximal plasma concentrations (Cmax) values of 1.72, 4.89, and 2.69 µg/mL were calculated for R-, S-, and R-trans-4-OH-praziquantel, respectively, when patients were given a single 60-mg/kg dose, and they peaked at 1.5 and 2 h for the enantiomers and at 3 h for the metabolite. The herein-generated PK data, together with results that will be obtained from the integrated efficacy study, lay the groundwork for a possibly optimized treatment scheme for O. felineus-infected patients.

Improving translational power in antischistosomal drug discovery.

Schistosomiasis is a poverty-associated tropical disease caused by blood dwelling trematodes that threaten approximately 10% of the world population. Praziquantel, the sole drug currently available for treatment, is insufficient to eliminate the disease and the clinical drug development pipeline is empty. Here, we review the characteristics of the patent Schistosoma mansoni mouse model used for in vivo antischistosomal drug discovery, highlighting differences in the experimental set-up across research groups and their potential influence on experimental results. We explore the pharmacokinetic/pharmacodynamic relationship of selected drug candidates, showcasing opportunities to improve the drug profile to accelerate the transition from the early drug discovery phase to new clinical candidates.

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

ABSTRACT In the search for new anti-schistosomal agents, a series of fifteen ortho-nitrobenzyl derivatives was assayed in vitro against both the schistosomulum (somule) and adult forms of Schistosoma mansoni. Compounds 8 and 12 showed significant activity against somules at low micromolar concentrations, but none was active against adults. The SAR demonstrated that the compounds most active against the parasite were mutagenic to the human cell line RKO-AS45-1 only at concentrations 10- to 40-fold higher than the worm-killing dose. Given their electrophilicity, compounds were also screened as inhibitors of the S. mansoni cysteine protease (cathepsin B1) in vitro. Amides 5 and 15 exhibited a modest inhibition activity with values of 55.7 and 50.6 % at 100 µM, respectively. The nitrobenzyl compounds evaluated in this work can be regarded as hits in the search for more active and safe anti-schistosomal agents.

Chronic leukemia.

The chronic leukemias include chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). CML is a clonal myeloproliferative hematopoietic stem-cell disorder, and CLL is a monoclonal B-cell disorder. CML is Philadelphia chromosome positive. There are 3 phases of CML: the chronic phase, the accelerated phase, and the blast phase. The primary treatment of CML consists of tyrosine kinase inhibitors. CLL can present as indolent or fulminant disease. Early disease is managed with observation. Fulminant disease is currently treated with alkylating agents, purine analogues, and monoclonal antibodies, but new biotarged therapies are being developed.

The postoperative patella height: a comparison of additive and subtractive high tibial osteotomy in correcting the genu varum.

INTRODUCTION: Intraligamentary correctional operations like a high tibial osteotomy were performed in genua valga to prevent later medial gonarthrosis especially in younger patients. An unwanted effect of this method seems to be the inferiorization of the patella. This is feared because of the complications in case of subsequent alloarthroplasty. Besides the classical Coventry method as a subtractive osteotomy the hemicallotasis has been established as a sustainable additive procedure. This means a gradual open wedge correction using an external fixateur. OBJECTIVE: The aim of this study was to determine the position of the patella pre- and postoperatively and in follow-ups with subtractive versus additive intraligamentary high tibial osteotomies on the basis of five radiological parameters. It was expected that an additive osteotomy leads to an inferiorized patella position whereas a subtractive osteotomy leads postoperative to a higher position of the tibia. METHOD: Between 1990 and 2001, 54 patients (61 legs) had undergone an operation due to a genu varum either by the subtractive osteotomy (n = 30) according to Coventry's method or the additive gradually hemicallotasis (n = 31) with an external fixator. RESULTS: In coherence with the Coventry's osteotomy a significant inferiorization of the postoperative patella position with all five radiological parameters was observed, the hemicallotasis showed no operation-related significant alteration of the patella height. Instancing the Insall-Salvati Index there were four (12.9%) preoperative and three (9.7%) postoperative patella baja positions detected. Along with the subtractive osteotomy there were 5 preoperative patellae baja (16.7%) and 11 postoperative patellae baja (36.7%) positions. Furthermore a significant interrelation was noticed between the extent of the correctional angle and the postoperative alteration of the patella. CONCLUSION: The results are surprising, contrary was expected. First this can be explained by its gradual, additive correctional property in contrast to the spontaneous correction by the conventional method according to Coventry, second by the postoperative treatment, which allows an early mobilization and active remedial gymnastics, provided an impact resistant osteosynthesis by a fixateur externe is given. In the case of the additive hemicallotasis an intraligamentary osteotomy is recommended. Technically expensive step cuts in order to osteotomize below the tuberositas tibiae are not necessary. Due to the low quota of complications and the small operative expense the continuous distraction is preferential to ad hoc correction. A postoperative patella baja position has not to be afraid in hemicallotasis.