Acceptance of Oclacitinib Maleate (Apoquel®) Chewable Tablets In Client-Owned Dogs With Allergic And Atopic Dermatitis.

Background: The oral acceptance of oclacitinib maleate (Apoquel®) chewable tablets administered twice daily for 7 days at the labeled dose range of 0.4-0.6 mg/kg was evaluated in 121 dogs treated at ten general practice veterinary clinics in the United States. Results: Dogs that were enrolled in the study ranged were client-owned, from 1 to 14 years of age, weighed 3.7 to 60.7 kg, and required twice daily treatment with oclacitinib for allergic or atopic dermatitis. One hundred and twenty-one (121) dogs with 1,673 total dose administrations successfully completed the study and were included in the data summary. Out of a total number of 1673 administrations, 1533 (91.6%) were accepted voluntarily within 5 minutes, 134 (8%) were consumed with assistance (with food treats or by pilling) outside of the 5 minutes offering time and 6 (0.4%) doses were not consumed. The per dose percent acceptance rate for the 14 offered doses showed minimal variation ranging from 89.9% to 93.3%. Conclusions: Client-owned dogs from the general veterinary patient population that required treatment with oclacitinib found the Chewable tablets to be very palatable and no aversion occurred with repeated dosing. Oclacitinib chewable tablets were well tolerated and is a palatable alternative to the film-coated tablet.

Plague and Plague Vaccines

Plague is a zoonosis caused by the Gram-negative bacillus, Yersinia pestis, a member of the Enterobacteriaceae family. Madagascar, the Democratic Republic of Congo and Peru are still considered highly endemic for plague; however, the bacterium also exists in some regions in Asia and the USA. First symptoms occur 1 to 7 days after exposure. There are three clinical forms of plague: bubonic, pneumonic, and septicemic plague. Transmitted as an aerosol, Y. pestis has been developed as a biological weapon. There are adjuvanted whole-cell vaccines which need repeated dosing, and which are highly reactogenic; subunit vaccines are in development.

Cell-based treatment of cerebral palsy: still a long way ahead

Background: Cerebral palsy (CP) is a permanent neurodevelopmental disorder with considerable global disability. Various rehabilitation strategies are currently available. However, none represents a convincing curative result. Cellular therapy recently holds much promise as an alternative strategy to repair neurologic defects. Method: In this narrative review, a comprehensive search of the MEDLINE and ClinicalTrials.gov was made, using the terms: "cell therapy" and "cerebral palsy", including published and registered clinical studies, respectively. Results: The early effects of these studies demonstrated that using cell therapy in CP patients is safe and improves the deficits for a variable duration. Despite such hopeful early bird results, the long-term outcomes are not conclusive. Conclusions: Due to the heterogeneous nature of CP, personal factors seem essential to consider. Cell dosage, routes of administration, and repeated dosing are pivotal to establish optimal personalized treatments. Future clinical trials should consider employing other cell types, specific cell modifications before administration, and cell-free platforms. Method: In this narrative review, a comprehensive search of the MEDLINE and ClinicalTrials.gov was made, using the terms: "cell therapy" and "cerebral palsy", including published and registered clinical studies, respectively. Results: The early effects of these studies demonstrated that using cell therapy in CP patients is safe and improves the deficits for a variable duration. Despite such hopeful early bird results, the long-term outcomes are not conclusive. Conclusions: Due to the heterogeneous nature of CP, personal factors seem essential to consider. Cell dosage, routes of administration, and repeated dosing are pivotal to establish optimal personalized treatments. Future clinical trials should consider employing other cell types, specific cell modifications before administration, and cell-free platforms.

471 Pharmacokinetics of first and repeated dosing of non-irAE-inducing anti-CTLA-4 monoclonal antibody ONC-392 in advanced cancer patients

BackgroundONC-392 preserves CTLA-4 recycling and thereby maintains its physiological immune tolerance checkpoint function while allowing more efficient and selective elimination of tumor-infiltrating regulatory T cells. The safety data in the first-in-human trial showed that ONC-392 is safe and well tolerated with no observed immunotherapy-related adverse events (irAE). Serum samples were used to determine pharmacokinetic parameters of ONC-392 to establish systemic drug exposure.MethodsSamples from the first and third dosing cycles were collected at predose and 0.5, 6, 24, 48, 192, 360, and 504 hours postdose. For other dosing cycles, predose and 0.5 hour postdose samples were collected. Serum ONC-392 concentrations were measured by ELISA and the PK parameters were analyzed under noncompartmental condition using linear trapezoidal method.ResultsSystemic exposure of ONC-392 is positively correlated to dosing concentration and number of doses. Mean Cmax and AUC 0–504hr values increase proportionately to dosing concentrations from 0.1mg/kg to 10mg/kg. Dose ratio in cycle 1 is 1:3:30:100. The mean cycle 1 Cmax and AUC 0–504hr ratios are 1:3.34:31.32:106.28 and 1:3.13:28.46:100.63 respectively. The Cmax in patients receiving one or more doses of ONC-392 at 3mg/kg is 89±16µg/mL. The Cmax in patients receiving one or more doses of ONC-392 at 10mg/kg is 259±55µg/mL. Inclusive of all dosing concentrations (0.1, 0.3, 1, 3, 10mg/kg) and cycles, Tmax is between 1.5–6 hours with one outlier observed at 24-hour postdose. The t½ range from 201 to 478 hours (8 - 20 days). The cycle 1 mean of t½ for 0.1, 0.3, 3, 10mg/kg dosing concentrations are 411.02, 359.25, 246.22, 355.01 hours respectively. A direct comparison between first and third cycle in the 3mg/kg dosing group confirms ONC-392 accumulation in repeated dosing. The trough levels (Cmin) in patients receiving one or multiple doses of ONC-392 at 3mg/kg and 10mg/kg are between 12–51µg/mL and 49–71µg/mL respectively. Lastly, inclusive of all dosing concentrations (0.1, 0.3, 1, 3, 10mg/kg) and cycles, MRT range from 307.91–655.04 hours, Vz range from 0.0305–0.0726 mg/(µg/mL), and Cl range from 0.000052–0.00019 mg/(µg/mL)/h.ConclusionsIntravenous infusion of ONC-392 provide adequate and dose-dependent exposure over extended period. Overall exposure is comparable or higher than those reported by others using different anti-CTLA-4 antibodies. The apparent lack of irAE in ONC-392 recipients despite the high exposure indicates intrinsic safety and tolerability of ONC-392.

Pharmacokinetics and Toxicokinetics of Artemisinin-Hydroxychloroquine Sulfate Tablets in Rats and Dogs

Artemisinin-hydroxychloroquine sulfate tablets (AH) are relatively inexpensive and a novel combination therapy for the treatment of all forms of malaria, especially aminoquinine drug-resistant strains of P. falciparum. Our aim was to assess the pharmacokinetics (PK) and toxicokinetics (TK) of AH following oral administration in Sprague Dawley rats and Beagle dogs by using the liquid chromatography tandem mass spectrometry methods (LC-MS/MS). The PK studies were carried out in eighteen rats at three doses and six dogs at three rounds of three doses after a single oral administration of AH. The TK studies in rats and dogs were accompanied by the 14-day repeated dosing studies. The PK results revealed that artemisinin was absorbed and cleared rapidly in rats with obvious gender difference and interindividual variability, and the systemic exposure with regard to AUC was positively correlated with the dosage in female rats. However, the kinetics parameters of artemisinin in dogs were not obtained because the plasma concentration was undetectable. The absorption and elimination of hydroxychloroquine in dogs and rats were relatively slow, and no gender difference was observed. The AUC of hydroxychloroquine showed a linear correlation with the dosage, but Cmax varied significantly among individuals. After 14-day repeated oral administration of AH, hydroxychloroquine shows an increase in systemic exposure and accumulation in rats and dogs, whereas the AUC and Cmax of artemisinin remarkably decreased in female rats due to its autoinduction metabolism. The TK results were basically consistent with the dose- and time-dependent toxic reaction in 14-day repeated dosing studies of AH in rats and dogs. The information from our studies could be helpful for further pharmacological and toxicological research and clinical application of AH.

Comparative Effects of Metamizole (Dipyrone) and Naproxen on Renal Function and Prostacyclin Synthesis in Salt-Depleted Healthy Subjects - A Randomized Controlled Parallel Group Study

Aim: The objective was to investigate the effect of metamizole on renal function in healthy, salt-depleted volunteers. In addition, the pharmacokinetics of the four major metamizole metabolites were assessed and correlated with the pharmacodynamic effect using urinary excretion of the prostacyclin metabolite 6-keto-prostaglandin F1α.Methods: Fifteen healthy male volunteers were studied in an open-label randomized controlled parallel group study. Eight subjects received oral metamizole 1,000 mg three times daily and seven subjects naproxen 500 mg twice daily for 7 days. All subjects were on a low sodium diet (50 mmol sodium/day) starting 1 week prior to dosing until the end of the study. Glomerular filtration rate was measured using inulin clearance. Urinary excretion of sodium, potassium, creatinine, 6-keto-prostaglandin F1α, and pharmacokinetic parameters of naproxen and metamizole metabolites were assessed after the first and after repeated dosing.Results: In moderately sodium-depleted healthy subjects, single or multiple dose metamizole or naproxen did not significantly affect inulin and creatinine clearance or sodium excretion. Both drugs reduced renal 6-keto-prostaglandin F1α excretion after single and repeated dosing. The effect started 2 h after intake, persisted for the entire dosing period and correlated with the concentration-profile of naproxen and the active metamizole metabolite 4-methylaminoantipyrine (4-MAA). PKPD modelling indicated less potent COX-inhibition by 4-MAA (EC50 0.69 ± 0.27 µM) compared with naproxen (EC50 0.034 ± 0.033 µM).Conclusions: Short term treatment with metamizole or naproxen has no significant effect on renal function in moderately sodium depleted healthy subjects. At clinically relevant doses, 4-MAA and naproxen both inhibit COX-mediated renal prostacyclin synthesis.

First-Line Administration of Fibrinogen Concentrate in the Bleeding Trauma Patient: Searching for Effective Dosages and Optimal Post-Treatment Levels Limiting Massive Transfusion—Further Results of the RETIC Study

Fibrinogen supplementation is recommended for treatment of severe trauma hemorrhage. However, required dosages and aimed for post-treatment fibrinogen levels remain a matter of discussion. Within the published RETIC study, adult patients suffering trauma-induced coagulopathy were randomly assigned to receive fibrinogen concentrate (FC) as first-line (n = 50) or crossover rescue (n = 20) therapy. Depending on bodyweight, a single dose of 3, 4, 5, or 6 g FC was administered and repeated if necessary (FibA10 < 9 mm). The dose-dependent response (changes in plasma fibrinogen and FibA10) was analyzed. Receiver operating characteristics (ROC) analysis regarding the need for massive transfusion and correlation analyses regarding fibrinogen concentrations and polymerization were performed. Median FC single doses amounted to 62.5 (57 to 66.66) mg.kg−1. One FC single-dose sufficiently corrected fibrinogen and FibA10 (median fibrinogen 213 mg.dL−1, median FibA10 11 mm) only in patients with baseline fibrinogen above 100 mg.dL−1 and FibA10 above 5 mm, repeated dosing was required in patients with lower baseline fibrinogen/FibA10. Fibrinogen increased by 83 or 107 mg.dL−1 and FibA10 by 4 or 4.5 mm after single or double dose of FC, respectively. ROC curve analysis revealed post-treatment fibrinogen levels under 204.5 mg.dL−1 to predict the need for massive transfusion (AUC 0.652; specificity: 0.667; sensitivity: 0.688). Baseline fibrinogen/FibA10 levels should be considered for FC dosing as only sufficiently corrected post-treatment levels limit transfusion requirements.

Probing the peripheral immune response in mouse models of oxaliplatin-induced peripheral neuropathy highlights their limited translatability

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of various chemotherapeutic agents, including oxaliplatin. It is highly prevalent amongst cancer patients, causing sensory abnormalities and pain. Unfortunately, as the underlying mechanisms remain poorly understood, effective therapeutics are lacking. Neuro-immune interactions have been highlighted as potential contributors to the development and maintenance of CIPN, however, whether this is the case in oxaliplatin-induced peripheral neuropathy (OIPN) is yet to be fully established. Methods: In this study we used flow cytometry to examine the peripheral immune response of male C57BL/6 mice following both single and repeated oxaliplatin administration. In animals exposed to repeated dosing, we also undertook mechanical and thermal behavioural assays to investigate how oxaliplatin alters phenotype, and conducted RT-qPCR experiments on bone marrow derived macrophages in order to further inspect the effects of oxaliplatin on immune cells. Results: In contrast to other reports, we failed to observe substantial changes in overall leukocyte, lymphocyte or myeloid cell numbers in dorsal root ganglia, sciatic nerves or inguinal lymph nodes. We did however note subtle, tissue-dependant alterations in several myeloid subpopulations following repeated dosing. These included a significant reduction in MHCII antigen presenting cells in the sciatic nerve and an increase in infiltrating cell types into the inguinal lymph nodes. Though repeated oxaliplatin administration had a systemic effect, we were unable to detect a pain-like behavioural phenotype in response to either cold or mechanical stimuli. Consequently, we cannot comment on whether the observed myeloid changes are associated with OIPN. Conclusions: Our discussion puts these results into the wider context of the field, advocating for greater transparency in reporting, alignment in experimental design and the introduction of more clinically relevant models. Only through joint concerted effort can we hope to increase our understanding of the underlying mechanisms of CIPN, including any immune contributions.

Comprehensive Review on Hydrogels

: The conventional drug delivery systems have a long list of issues of repeated dosing and toxicity arising due to it. The hydrogels are the answer to them and offer a result that minimizes such activities and optimizes therapeutic benefits. The hydrogels proffer tunable properties that can withstand degradation, metabolism, and controlled release moieties. Some of the areas of applications of hydrogels involve wound healing, ocular systems, vaginal gels, scaffolds for tissue, bone engineering, etc. They consist of about 90% of the water that makes them suitable bio-mimic moiety. Here, we present a birds-eye view of various perspectives of hydrogels, along with their applications.