scholarly journals Clinical Population Pharmacokinetics/Pharmacodynamics Protocol of Alkaloids from Leaf of Alstonia scholaris on Acute Bronchitis Patients

2019 ◽  
Author(s):  
Rui Li ◽  
Wan-Tong Zhang ◽  
Yun-Li Zhao ◽  
Ming-Yue Sun ◽  
Mao-Rong Fan ◽  
...  

Abstract Background Acute tracheobronchitis is the acute tracheobronchial mucosal inflammation caused by biological, physical, chemical stimulation, and accompanied by symptoms of cough and expectoration. The capsule of alkaloids from leaf of Alstonia scholaris (CALAS), an effective part riches in alkaloids, has the antiviral, antibacterial, anti-inflammatory, expectorant, anti-tussive, anti-asthmatic, immunoregulation effects. However, whether the clinical indexes could be improved by the same ingredients and pathways after oral administration, and the changes in the relationship between ingredients and pharmacodynamics indexes, still need further clinical verification.Methods/design This is a prospectively planned, blinded, placebo-controlled, parallel-grouped clinical trial with aggregated population pharmacokinetics/pharmacodynamics (PPK/PD) data. 55 subjects will be randomly allocated into four arms, specifically, 10 of the 55 subjects were selected randomly for the placebo arm who will be orally administered with placebo (Tid), and 45 subjects were randomly assigned to CALAS treatment group (20 mg, 40 mg, 80 mg Tid, 15 subjects per group). The medication, cough and phlegm, body temperature of every subject should be recorded daily during treatment. Each subject will be collected 3-4 blood samples at the following points for PPK/PPD parameters analysis. Blood samples will be acquired pre-dose (0 h) and post-dose at 15 min, 40 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 30 h, 48 h after last dosing. All subjects will receive a laboratory examination and efficacy evaluation on day 8.Discussion A new integrating strategy to explore relationship among drug ingredients, action pathway and clinical efficacy will be established through this study. We aim to explore the mechanism of CALAS in treatment of acute bronchitis on the premise of definite active ingredients and reliable clinical efficacy. It is difficult to be accepted by patients since classical pharmacokinetics (PK) research adopts intensive sampling method, meanwhile, it cannot quantify the variability of PK parameters (Intra-individual variation, interindividual variation and weekly variation). Moreover, extrapolation and prediction of dosage regimen between different species and populations cannot be realized. Therefore, PPK/PPD method, usually taking advantage of sparse data (3-5 time points sampling per patient), which be selected to find out the measurable factors of pathology and physiology that lead to the change of dose-concentration, and guide reasonable dose adjustment to achieve the optimal clinical effects.

2019 ◽  
Author(s):  
Rui Li ◽  
Wan-Tong Zhang ◽  
Yun-Li Zhao ◽  
Ming-Yue Sun ◽  
Mao-Rong Fan ◽  
...  

Abstract Background Acute tracheobronchitis is the acute tracheobronchial mucosal inflammation caused by biological, physical, chemical stimulation, and accompanied by symptoms of cough and expectoration. The capsule of alkaloids from leaf of Alstonia scholaris (CALAS), an effective part riches in alkaloids, has the antiviral, antibacterial, anti-inflammatory, expectorant, anti-tussive, anti-asthmatic, immunoregulation effects. However, whether the clinical indexes could be improved by the same ingredients and pathways after oral administration, and the changes in the relationship between ingredients and pharmacodynamics indexes, still need further clinical verification.Methods/design This is a prospectively planned, blinded, placebo-controlled, parallel-grouped clinical trial with aggregated population pharmacokinetics/pharmacodynamics (PPK/PD) data. 55 subjects will be randomly allocated into four arms, specifically, 10 of the 55 subjects were selected randomly for the placebo arm who will be orally administered with placebo (Tid), and 45 subjects were randomly assigned to CALAS treatment group (20 mg, 40 mg, 80 mg Tid, 15 subjects per group). The medication, cough and phlegm, body temperature of every subject should be recorded daily during treatment. Each subject will be collected 3-4 blood samples at the following points for PPK/PPD parameters analysis. Blood samples will be acquired pre-dose (0 h) and post-dose at 15 min, 40 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 30 h, 48 h after last dosing. All subjects will receive a laboratory examination and efficacy evaluation on day 8.Discussion A new integrating strategy to explore relationship among drug ingredients, action pathway and clinical efficacy will be established through this study. We aim to explore the mechanism of CALAS in treatment of acute bronchitis on the premise of definite active ingredients and reliable clinical efficacy. It is difficult to be accepted by patients since classical pharmacokinetics (PK) research adopts intensive sampling method, meanwhile, it cannot quantify the variability of PK parameters (Intra-individual variation, interindividual variation and weekly variation). Moreover, extrapolation and prediction of dosage regimen between different species and populations cannot be realized. Therefore, PPK/PPD method, usually taking advantage of sparse data (3-5 time points sampling per patient), which be selected to find out the measurable factors of pathology and physiology that lead to the change of dose-concentration, and guide reasonable dose adjustment to achieve the optimal clinical effects.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1845-1845
Author(s):  
Suzanne Trudel ◽  
Susan Lee ◽  
Christopher J. Kirk ◽  
Nashat Gabrail ◽  
Sagar Lonial ◽  
...  

Abstract Abstract 1845 Poster Board I-871 Background: Proteasome inhibition is an effective strategy for the treatment of multiple myeloma. In patients, proteasome inhibition has primarily been measured in peripheral blood samples (whole blood or mononuclear cells). However, it is unknown whether myeloma cells in the bone marrow (BM) are equally sensitive to proteasome inhibitors such as bortezomib (BTZ) and carfilzomib (CFZ). Aim: To measure proteasome inhibition in purified tumor cells from BM samples taken from patients enrolled in two ongoing Phase 2 trials of single agent CFZ in relapsed or refractory myeloma: PX-171-003 (003) and PX-171-004 (004). Methods: CFZ was administered as an IV bolus of 20 mg/m2 on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle on both trials. Bone marrow samples, from an optional sub-study of both trials, were taken during screening and Day 2 (post-treatment) and sorted into CD138+ and CD138− cells. Proteasome activity was measured by an enzymatic assay using a fluorogenic substrate (LLVY-AMC) for the chymotrypsin-like (CT-L) activity and an active site ELISA (ProCISE) to quantitate levels of the CT-L subunits of the constitutive proteasome (Beta5) and immunoproteasome (LMP7) and the immunoproteasome subunit MECL1. Results: Whole blood samples from patients treated with CFZ showed inhibition of CT-L activity of ∼80+, similar to values obtained in Phase 1 studies. A total of 10 CD138+ screening samples, 6 from 004 and 4 from 003, and 9 post-dose samples, 5 from 004 and 4 from 003, were analyzed for proteasome levels and activity. In addition, 15 CD138−screening samples, 7 from 004 and 8 from 003, and 9 post-dose samples, 5 from 004 and 4 from 003, were analyzed. When compared to the average base-line activity, CFZ treatment resulted in 88% CT-L inhibition in CD-138+tumor cells from 004 patients (P = 0.0212 by unpaired t-test) and 59% CT-L inhibition in CD-138+ tumor cells from 003 patients (P = 0.25). Baseline CT-L activity in CD138+ tumor cells was 3-fold higher in 004 than 003, which includes a more heavily pre-treated patient population with greater prior exposure to BTZ. Higher specific enzymatic activity was due to increased levels of both constitutive and immunoproteasomes in tumor cells, where immunoproteasomes account for >75% of total cellular proteasomes. No differences between trials were seen in baseline CT-L activity from non-tumor (CD138−) cells. Inhibition in CD138− cells was 84% (P = 0.0380 and 42% (P = 0.38) in 004 and 003, respectively. Using ProCISE, we measured inhibition of LMP7 (66%), beta5 (48%) and MECL1 (64%) in CD138+ tumor cells from 004 patients. Three patients from 004 and one from 003 had both a screening and post-dose tumor cell samples available for analysis. Inhibition of CT-L activity was >80% in two of the 3 patients on 004; the third patient showed no proteasome inhibition by ProCISE and was unavailable for analysis by CT-L. CT-L activity in the CD138+ tumor cells in the 003 patient was not inhibited, however, inhibition was seen in non-tumor cells. Conclusions: CFZ inhibits the proteasome activity of myeloma cells in the bone marrow of relapsed and refractory myeloma patients. The levels of inhibition were similar to those measured in whole blood samples, supporting the use of the blood-based assay as a surrogate marker for proteasome inhibition in tumor cells. CFZ treatment resulted in inhibition of both CT-L subunits as well as additional subunits of the immunoproteasome in tumor cells. Reduced baseline activity in the more heavily pretreated 003 patients may reflect reduced tumor-dependency on the proteasome and may be related to prior treatment with BTZ in these patients. More samples are needed in order to make correlations between levels of proteasome inhibition in bone marrow tumor cells and prior therapies or response. These observations support further evaluation of proteasome activity and the effects of this promising new agent in primary tumors cells from myeloma patients. Disclosures: Trudel: Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Lee:Proteolix, Inc.: Employment. Kirk:Proteolix, Inc.: Employment. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Wang:Proteolix, Inc.: Research Funding. Kukreti:Celgene: Honoraria. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. McDonagh:Proteolix: Research Funding. Zonder:Celgene: Speakers Bureau; Pfizer: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen: Consultancy; Millennium: Research Funding. Bennett:Proteolix: Employment.


2013 ◽  
Vol 16 (7) ◽  
pp. 1577-1586 ◽  
Author(s):  
Magdalena Nord ◽  
Sjoerd J. Finnema ◽  
Christer Halldin ◽  
Lars Farde

AbstractSelective serotonin reuptake inhibitors (SSRIs) are widely prescribed for treatment of psychiatric disorders. The exact mechanism underlying the clinical effects of SSRIs remains unclear, although increased synaptic serotonin concentrations have been hypothesized to be an initial step. [11C]AZ10419369 is a novel 5-HT1B receptor selective radioligand, which is sensitive to changes in endogenous serotonin concentrations. To assess whether a single dose of the SSRI escitalopram affects endogenous serotonin concentrations in serotonergic projection areas and in the raphe nuclei (RN), three cynomolgus monkeys and nine human subjects underwent PET examinations with [11C]AZ10419369 at baseline conditions and after escitalopram administration. In monkeys, the binding potential (BPND) was significantly lower post dose compared to baseline in dorsolateral prefrontal cortex, occipital cortex, thalamus, midbrain and RN (p < 0.05). In humans, the BPND tended to decrease in RN post dose (p = 0.08). In all serotonergic projection areas, the BPND was conversely higher post dose compared to baseline. The increase was significant in a combined region of all projection areas (p = 0.01) and in occipital and temporal cortex (p < 0.05). SSRIs are generally assumed to elevate endogenous serotonin concentrations in projection areas, evoking the antidepressant effect. In the present study, a single, clinically relevant, dose of escitalopram was found to decrease serotonin concentrations in serotonergic projection areas in humans. Hypothetically, desensitization of inhibitory serotonergic autoreceptors will cause the serotonin concentration in projection areas to increase over time with chronic administration. Thus, the findings in the present study might aid in understanding the mechanism of SSRIs' delayed onset of clinical effect.


2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Yan Jin ◽  
Yanzheng Wang ◽  
Sai Wang ◽  
Qiongqiong Zhao ◽  
Donghua Zhang ◽  
...  

Objective. This study aimed to explore the clinical efficacy and relevant mechanism of Tripterygium glycosides combined with low molecular weight heparin calcium (LMWH) in the treatment of Henoch–Schönlein purpura nephritis (HSPN) in children. Methods. 64 cases of children patients with HSPN treated at Qilu Hospital (Qingdao) from January 2015 to May 2020 were selected and randomly divided into the control group and the observation group and 32 cases in each group. Conventional medical treatment was applied in the two groups, besides which the control group was given LMWH while the observation group was given Tripterygium glycosides based on the control group. The clinical efficacy and the indexes of clinical symptoms of the two groups were compared. Immune globulin level, fibrinogen content (FIB), prothrombin time (PT), platelet level (PLT), and activated partial thromboplastin time (APTT) level of the two groups were compared before and after the treatment. Results. The total effective rate in the observation group was significantly higher than that of the control group, and the recurrence rate in the observation group was lower than that in the control group. After treatment, urine red blood cell count and 24 h urine protein were obviously better than those of the control group. There was no statistically significant difference in PT between the two groups of children before and after treatment. The levels of PLT and FIB in the two groups of patients after treatment were significantly lower than before treatment, and the PLT levels in the observation group were lower than those in the control group. Conclusion. The combination of Tripterygium glycosides and LMWH had good clinical effects in the treatment of children with HSPN, and it could improve the clinical symptoms, the mechanism of which might be related to the increase of PT, a decrease of PLT, and the improvement of coagulation function.


Author(s):  
Hussein Al-Hakeim ◽  
Ahmed Jasim Twayej ◽  
Arafat Hussein Al-Dujaili ◽  
Michael Maes

Major Depression Disorder (MDD) is accompanied by an immune response characterized by increased levels of pro-inflammatory and immune-regulatory cytokines and cytokine-induced stimulation of indoleamine-2,3-dioxygenase (IDO). There is also some evidence that anti-inflammatory drugs may have a clinical efficacy in MDD.The aim of this study is to examine the clinical effects of an eight-week combinatorial treatment of ketoprofen (a nonsteroidal anti-inflammatory drug) combined or not with sertraline, on serum levels of IDO, interferon (IFN)-&gamma;, interleukin (IL)-4 and transforming growth factor (TGF)-&beta;1 in association with changes in the Beck-Depression Inventory-II (BDI-II). The study included 140 MDD patients and 40 normal controls. The pre-treatment serum levels of IDO, IFN-&gamma;, TGF-&beta;1 and IL-4 were significantly higher in MDD patients compared with the control group. Treatment with sertraline with or without ketoprofen significantly reduced the increased baseline production of all 4 biomarkers to levels which were similar as those of normal controls. Ketoprofen add-on had a significantly greater effect on IDO and BDI-II as compared with placebo. The reductions in IDO, IL-4 and TGF-&beta;1 during treatment were significantly associated with those in the BDI-II.In conclusion, the clinical efficacy of both sertraline + ketoprofen may be ascribed at least in part to attenuated IDO levels and immune-inflammatory responses in MDD. Moreover, add-on treatment with ketoprofen may augment the efficacy of sertraline by attenuating IDO. However, these treatments may also significantly reduce the more beneficial properties of T helper-2 and T regulatory (Treg) immune subsets. Future research should develop immune treatments that target the immune-inflammatory response in MDD, while enhancing the compensatory immune-regulatory system (CIRS).


2018 ◽  
Vol 78 (2) ◽  
pp. 209-217 ◽  
Author(s):  
Michelle Rosenzwajg ◽  
Roberta Lorenzon ◽  
Patrice Cacoub ◽  
Hang Phuong Pham ◽  
Fabien Pitoiset ◽  
...  

ObjectiveRegulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential.AimWe aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases.MethodsWe performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation.Resultsld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed.ConclusionThe dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.Trial registration numberNCT01988506.


2011 ◽  
Vol 107 (8) ◽  
pp. 1128-1137 ◽  
Author(s):  
Kerry S. Jones ◽  
Inez Schoenmakers ◽  
Les J. C. Bluck ◽  
Shujing Ding ◽  
Ann Prentice

25-Hydroxyvitamin D (25(OH)D) half-life is a potential biomarker for investigating vitamin D metabolism and requirements. We performed a pilot study to assess the approach and practical feasibility of measuring 25(OH)D half-life after an oral dose. A total of twelve healthy Gambian men aged 18–23 years were divided into two groups to investigate the rate and timing of (1) absorption and (2) plasma disappearance after an 80 nmol oral dose of 25(OH)D2. Fasting blood samples were collected at baseline and, in the first group, every 2 h post-dose for 12 h, at 24 h, 48 h and on day 15. In the second group, fasting blood samples were collected on days 3, 4, 5, 6, 9, 12, 15, 18 and 21. Urine was collected for 2 h after the first morning void at baseline and on day 15. 25(OH)D2plasma concentration was measured by ultra-performance liquid chromatography-tandem MS/MS and corrected for baseline. Biomarkers of vitamin D, Ca and P metabolism were measured at baseline and on day 15. The peak plasma concentration of 25(OH)D2was 9·6 (sd0·9) nmol/l at 4·4 (sd1·8) h. The terminal slope of 25(OH)D2disappearance was identified to commence from day 6. The terminal half-life of plasma 25(OH)D2was 13·4 (sd2·7) d. There were no significant differences in plasma 25(OH)D3, total 1,25(OH)2D, parathyroid hormone, P, Ca and ionised Ca and urinary Ca and P between baseline and day 15 and between the two groups. The present study provides data on the plasma response to oral 25(OH)D2that will underpin and contribute to the further development of studies to investigate 25(OH)D half-life.


Author(s):  
H.A. Holm ◽  
U. Abildgaard ◽  
Chr. Bjerkelund

280 patients with phlebographically proven DVT have been treated with heparin infusion for 5 days followed by control phlebography. Daily blood samples were analyzed for heparin activity by 3 different assays (amidolytic assay, APTT, thrombin cl. time) to see if there exists a correlation between the clinical effects (on the local thrombotic process, on embolization, and on bleeding complications) and the results of laboratory tests.Four patients suffered from major bleedings, and one was fatal. Compared to mean results, heparin activity was clearly exessive in three of these patients, particularly with the amidolytic assay. About ten per cent of the patients had minor bleedings.A transient drop in the antithrombin concentration was observed in most patients, but sustained subnormal concentration (<70 %) was seen in ten patients. One patient developed thrombocytopenia and DIC. The influence of heparin dosage on heparin activity / concentration and on the thrombotic process will be evaluated.


Animals ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 585
Author(s):  
Beatrice Battaglia ◽  
Mario Angelone ◽  
Elena Vera ◽  
Giuseppina Basini ◽  
Simona Bussolati ◽  
...  

The extract of the seeds from Indian celery, Apium greaveolens (CSE), tested in experimental animals (rodents), and in humans affected by chronic osteoarthritic diseases, exhibits anti-inflammatory effects that can be compared, to some degree, to those of non-steroid anti-inflammatory drugs (NSAID). In view of a potential use of CSE in the equine species, it was tested on horses affected by chronic articular pathologies. The trial was performed on 20 horses divided into three different groups, orally treated with 0 (controls), 7.0 or 30 g of CSE BID. Basic orthopedic examinations were conducted, vital signs were observed, and blood samples collected. Improvement was observed at the highest dosage tested (30 g of CSE BID), as reflected in the score values of three clinical parameters, (i) amplitude and (ii) sensitivity to passive flexion and (iii) flexion test. Since the improvement of these parameters can be correlated with a lower perception of the pain, the present data suggest that the CSE treatment can have an analgesic effect in horses affected by chronic osteoarthritic diseases.


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