Efficacy of oclacitinib for the control of feline atopic skin syndrome: correlating plasma concentrations with clinical response

2021 ◽  
pp. 1098612X2110484
Author(s):  
Isaac Carrasco ◽  
Luis Ferrer ◽  
Anna Puigdemont
Keyword(s):  
Clinical Response ◽  
Analogue Scale ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Therapeutic Regimen ◽  
Clinical Effects ◽  
Plasma Drug ◽  
Drug Levels ◽  
Time Points ◽  
Atopic Skin

Objectives The aim of this study was to assess the efficacy of a new therapeutic regimen of oclacitinib for the control of feline atopic skin syndrome (FASS) and to correlate plasma levels of this drug with clinical effects. Methods Twenty-eight client-owned cats with a clinical diagnosis of FASS were recruited. Oclacitinib was administered at 1 mg/kg q12h for 2 weeks and then at 1 mg/kg q24h for a further 2 weeks. At the study outset (D0), and 7 (D7) and 28 (D28) days after starting treatment, clinical lesions were assessed using a validated scoring system (SCORing Feline Allergic Dermatitis [SCORFAD]) and pruritus was graded via an adapted visual analogue scale (PVAS). At the same time points, plasma oclacitinib levels and haematological variables were measured. Results Among 18 cats completing the study, PVAS and SCORFAD improved by ⩾50% in 61% and 88% of animals, respectively. Mean PVAS decreased significantly between D0 and D7 and between D0 and D28 (both P <0.001) but not between D7 and D28. Likewise, mean SCORFAD values decreased significantly between D0 and D7 and between D0 and D28 (both P <0.001) but not between D7 and D28. On D7 and D28, plasma oclacitinib concentrations varied widely from 0 to 1443.2 ng/ml and from from 0 to 1177.7 ng/ml, respectively. Oclacitinib concentrations showed no correlation with clinical effects (SCORFAD and PVAS). Conclusions and relevance Oclacitinib emerged as being safe and effective to control clinical signs of FASS. A mean dose of 1 mg/kg, even without extending twice-daily treatment beyond the first 2 weeks, could be a suitable therapeutic regimen. Plasma drug levels did not seem useful to predict clinical response during treatment.

scholarly journals Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 102
Author(s):  
Magda Babina ◽  
Zhao Wang ◽  
Kristin Franke ◽  
Torsten Zuberbier
Keyword(s):  
Mast Cells ◽  
Priming Effect ◽  
Skin Diseases ◽  
Thymic Stromal Lymphopoietin ◽  
Dependent Manner ◽  
Atopic Diseases ◽  
Time Points ◽  
Histamine Liberation ◽  
Atopic Skin ◽  
Th2 Immunity

Thymic stromal lymphopoietin (TSLP) is released by epithelial cells following disturbed homeostasis to act as “alarmin” and driver of Th2-immunity. Aberrant TSLP expression is a hallmark of atopic diseases, including atopic dermatitis (AD). Mast cells (MCs) are overabundant in AD lesions and show signs of degranulation, but it remains unknown whether TSLP contributes to granule discharge. Degranulation of skin MCs proceeds via two major routes, i.e., FcεRI-dependent (allergic) and MRGPRX2-mediated (pseudo-allergic/neurogenic). Evidence is accumulating that MRGPRX2 may be crucial in the context of skin diseases, including eczema. The current study reveals TSLP as a novel priming factor of human skin MCs. Interestingly, TSLP selectively cooperates with MRGPRX2 to support granule discharge, while it does not impact spontaneous or FcεRI-driven exocytosis. TSLP-assisted histamine liberation triggered by compound 48/80 or Substance P, two canonical MRGPRX2 agonists, was accompanied by an increase in CD107a+ cells (a MC activation marker). The latter process was less potent, however, and detectable only at the later of two time points, suggesting TSLP may prolong opening of the granules. Mechanistically, TSLP elicited phosphorylation of STAT5 and JNK in skin MCs and the reinforced degranulation critically depended on STAT5 activity, while JNK had a contributory role. Results from pharmacological inhibition were confirmed by RNA-interference, whereby silencing of STAT5 completely abolished the priming effect of TSLP on MRGPRX2-mediated degranulation. Collectively, TSLP is the first factor to favor MRGPRX2- over FcεRI-triggered MC activation. The relevance of TSLP, MCs and MRGPRX2 to pruritis and atopic skin pathology indicates broad repercussions of the identified connection.

scholarly journals Impact of weight loss achieved through a multidisciplinary intervention on appetite in patients with severe obesity

2018 ◽  
Vol 315 (1) ◽  
pp. E91-E98 ◽  
Author(s):  
S. R. Coutinho ◽  
J. F. Rehfeld ◽  
J. J. Holst ◽  
B. Kulseng ◽  
C. Martins
Keyword(s):  
Weight Loss ◽  
Severe Obesity ◽  
Peptide Yy ◽  
Plasma Concentrations ◽  
Cardiovascular Fitness ◽  
Ghrelin Concentration ◽  
Time Points ◽  
Diet And Exercise ◽  
The Impact

The impact of lifestyle-induced weight loss (WL) on appetite in patients with obesity remains controversial. This study aimed to assess the short- and long-term impact of WL achieved by diet and exercise on appetite in patients with obesity. Thirty-five (22 females) adults with severe obesity (body mass index: 42.5 ± 5.0 kg/m2) underwent a 2-yr WL program focusing on diet and exercise. Body weight (BW), cardiovascular fitness (V̇o2max), appetite feelings, and plasma concentrations of insulin, active ghrelin (AG), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK), in the fasting and postprandial states, were measured at baseline (B), week 4 (W4), and 1 and 2 yr (and average values for all fasting and postprandial time points computed). BW was significantly reduced and V̇o2max(ml·kg−1·min−1) increased at all time points compared with B (3.5, 8.1, and 8.4% WL and 7, 11, and 8% increase at W4 and 1 and 2 yr, respectively). Basal hunger and average hunger and desire to eat were significantly increased at 1 and 2 yr. Basal fullness was significantly increased at W4, and average ratings were reduced at 1 yr. Average AG and PYY were significantly increased, and insulin was reduced, at all time points compared with B. Average GLP-1 was reduced at W4, and CCK was increased at 2 yr. After lifestyle-induced WL, patients with severe obesity will, therefore, have to deal with increased hunger in the long term. In conclusion, sustained WL at 2 yr achieved with diet and exercise is associated with increased hunger feelings and ghrelin concentration but also increased postprandial concentrations of satiety hormones.

scholarly journals NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Patrick J. Mansky ◽  
Dawn B. Wallerstedt ◽  
Timothy S. Sannes ◽  
Jamie Stagl ◽  
Laura Lee Johnson ◽  
...  
Keyword(s):  
Clinical Response ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Stage Iv ◽  
Dosage Level ◽  
Maximum Tolerated Dose ◽  
Stage I ◽  
Fixed Dose ◽  
Mistletoe Lectin ◽  
Mistletoe Extract

Purpose.European Mistletoe (Viscum albumL.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM.Methods.Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery.Results.DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high.Conclusion.GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.

Influence of parasitism on plasma concentrations of growth hormone, somatomedin-C and somatomedin-binding proteins in calves

1988 ◽  
Vol 116 (2) ◽  
pp. 191-200 ◽  
Author(s):  
T. H. Elsasser ◽  
T. S. Rumsey ◽  
A. C. Hammond ◽  
R. Fayer
Keyword(s):  
Feed Intake ◽  
Binding Proteins ◽  
Binding Protein ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Nitrogen Retention ◽  
Protein Patterns ◽  
Somatomedin C ◽  
Treatment Groups ◽  
Ad Libitum

ABSTRACT A parasitic disease model (sarcocystosis) was used to study the effects of infection and associated plane of nutrition on GH and somatomedin-C (SM-C) patterns in plasma, and SM-C binding protein patterns in plasma from 4-month-old male Holstein calves. Calves, matched by age and rate of growth before the experiment, were divided into three treatment groups (n = 7). In the first (control), animals were uninfected and food was available ad libitum; in the second, animals were infected with Sarcocystis cruzi and food was available ad libitum. The third group consisted of uninfected animals pair-fed to the level of feed intake of the infected animals. Blood samples were obtained at various times after infection for analysis of the secretory patterns of GH (day 27 after infection, samples every 10 min for 6 h), SM-C (days 27, 35 and 58 after infection) or binding protein (day 42 after infection). Samples were analysed for GH and SM-C by radioimmunoassay. Relative molecular weights of binding proteins were assessed by elution patterns from gel permeation columns. Clinical signs of infection were manifest abruptly on day 26 after infection. Voluntary feed intakes of infected calves as a per cent of control calves were 18, 46 and 78 on days 27, 35 and 58 after infection respectively. Plasma GH concentrations were lower in infected and pair-fed than in control calves (P < 0·05). Plasma SM-C concentrations were reduced in calves with diminished feed intakes and lower still in infected calves (P < 0·05). Plasma SM-C was positively correlated with nitrogen retention across treatment groups (r = 0·81). Two classes of binding proteins differing in molecular weight were identified. The relative amounts of each binding protein in plasma were reduced during low feed intake with some differences in the endogenous saturation affected by infection. These data suggest that altered growth and metabolism in parasitized calves may arise in part from both nutritional and infection-mediated effects on the regulation of GH, SM-C and SM-C binding proteins. J. Endocr. (1988) 116, 191–200

Sulpiride and Haloperidol in Schizophrenia: A Double-blind Cross-over Study of Therapeutic Effect, Side Effects and Plasma Concentrations

1985 ◽  
Vol 147 (3) ◽  
pp. 283-288 ◽  
Author(s):  
Jes Gerlach ◽  
Kirsten Behnke ◽  
Jon Heltberg ◽  
Ebbe Munk-Andersen ◽  
Henrik Nielsen
Keyword(s):  
Side Effects ◽  
Plasma Concentrations ◽  
Clinical Effects ◽  
Median Dose ◽  
Double Blind ◽  
Day Range ◽  
Daily Dose ◽  
Schizophrenic Patients ◽  
High Doses ◽  
Therapeutic Profile

SummaryIn a double-blind cross-over trial, 20 chronic schizophrenic patients were treated with sulpiride and haloperidol in two 12-week periods. The final median dose of sulpiride was 2000 mg/day (range 800–3200) and of haloperidol 12 mg/day (range 6–24). Sulpiride had an antipsychotic effect and therapeutic profile not significantly different from that of haloperidol. In spite of the high doses of sulpiride, extrapyramidal side-effects were seen less frequently during the first four weeks of the sulpiride period than during the corresponding haloperidol period (P < 0.05), whereas autonomic side-effects were equally rare for both drugs. A positive correlation was found between daily dose and plasma concentration of both sulpiride (P < 0.001) and haloperidol (P < 0.05), but no correlation could be established between clinical effects and plasma levels of either neuroleptic.

Pharmacokinetic (PK) analyses in CSF and plasma from TBCRC049, an ongoing trial to assess the safety and efficacy of the combination of tucatinib, trastuzumab and capecitabine for the treatment of leptomeningeal metastasis (LM) in HER2 positive breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1044-1044
Author(s):  
Erica Michelle Stringer-Reasor ◽  
Barbara Jane O'Brien ◽  
Ariel Topletz-Erickson ◽  
Jason B White ◽  
Mina Lobbous ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Leptomeningeal Metastasis ◽  
Newly Diagnosed ◽  
Her2 Positive ◽  
Safety And Efficacy ◽  
Her2 Breast Cancer ◽  
Metastatic Setting

1044 Background: Tucatinib is a potent and highly selective HER2-targeted tyrosine kinase inhibitor approved for use in combination with trastuzumab and capecitabine for patients with metastatic HER2+ breast cancer (MBC) who have received ≥1 prior HER2-based regimen in the metastatic setting, including patients with brain metastases (BM). TBCRC049 (NCT03501979) is an investigator-initiated phase 2 single-arm study currently enrolling to evaluate the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ BC with newly diagnosed LM. Here, we report the pre-specified pharmacokinetic (PK) analysis for the first 15 patients to determine bioavailability of tucatinib and its predominant metabolite, ONT-993, in the CSF. Methods: Eligible patients included adults with HER2+ MBC, KPS > 50, and newly diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Patients with treated or concurrent/new BM were allowed. The primary endpoint is overall survival with an accrual goal of 30 pts. Parallel PK samples were collected in plasma and CSF via Ommaya reservoir on day 1 of cycles 1 and 2 at 0h (baseline), 2-3h, 5-7h and 24h (optional) following initiation of tucatinib 300 mg BID. Tucatinib and ONT-993 were quantified in plasma (n=15) and CSF (n=13) using validated liquid chromatography-mass spectrometry methods. Results: Tucatinib and ONT-993 plasma concentrations were consistent with previous studies and exhibited high interindividual variability. Tucatinib and ONT-993 were detectable in the CSF within 2 hours post tucatinib administration; concentrations ranged from 0.57 to 25 ng/mL for tucatinib (IC50 for tucatinib against HER2 is 3.3 ng/mL) and 0.28 to 4.7 ng/mL for ONT-993. Tucatinib concentrations in the CSF per timepoint were in a similar range to unbound plasma (plasmaub) tucatinib. CSF to plasmaub ratios were generally consistent over time; the steady-state (cycle 2) median tucatinib CSF to plasmaub ratio was 0.83 (0.19 to 2.1). ONT-993 CSF to plasmaub ratios were similar to tucatinib CSF to plasmaub ratios. Conclusions: In patients with LM from HER2+MBC who were treated with tucatinib, trastuzumab, and capecitabine, tucatinib and ONT-993 were detectable in the CSF of all patients at median levels similar to plasmaub tucatinib. This is the first documented evidence of tucatinib distributing into the CSF in patients with HER2+MBC. Efficacy and safety of tucatinib, trastuzumab, and capecitabine in patients with HER2+ LM will be reported upon completion of TBCRC 049 accrual. Clinical trial information: NCT03501979 .

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