scholarly journals Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Seth C. Hopkins ◽  
Nina Dedic ◽  
Kenneth S. Koblan
Keyword(s):  
Clinical Trials ◽  
Rem Sleep ◽  
Therapeutic Potential ◽  
Brain Activity ◽  
Plasma Concentrations ◽  
Dose Selection ◽  
Double Blind ◽  
Drug Concentrations ◽  
Sleep Parameters

AbstractSEP-363856 is a trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) agonist, currently in Phase 3 clinical trials for the treatment of schizophrenia. Although SEP-363856 activates TAAR1 and 5-HT1A receptors in vitro, an accessible marker of time- and concentration-dependent effects of SEP-363856 in humans is lacking. In rodents, SEP-363856 has been shown to suppress rapid eye movement (REM) sleep. The aim of the current study was to translate the REM sleep effects to humans and determine pharmacokinetic/pharmacodynamic (PK/PD) relationships of SEP-363856 on a measure of brain activity. The effects of SEP-363856 were evaluated in a randomized, double-blind, placebo-controlled, 2-way crossover study of single oral doses (50 and 10 mg) on REM sleep in healthy male subjects (N = 12 at each dose level). Drug concentrations were sampled during sleep to interpolate individual subject’s pharmacokinetic trajectories. SEP-363856 suppressed REM sleep parameters with very large effect sizes (>3) following single doses of 50 mg and plasma concentrations ≥100 ng/mL. Below that effective concentration, the 10 mg dose elicited much smaller effects, increasing only the latency to REM sleep (effect size = 1). The PK/PD relationships demonstrated that REM sleep probability increased as drug concentrations declined below 100 ng/mL over the course of the night. SEP-363856 was generally safe and well tolerated at both doses. The REM sleep-suppressing effects of SEP-363856 provide an accessible marker of brain activity, which can aid in dose selection and help elucidate its therapeutic potential in further clinical trials.

scholarly journals Modelling of Systemic versus Pulmonary Chloroquine Exposure in Man for COVID-19 Dose Selection

2020 ◽  
Author(s):  
Ghaith Aljayyoussi ◽  
Rajith KR Rajoli ◽  
Henry Pertinez ◽  
Shaun H Pennington ◽  
W. David Hong ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Systemic Circulation ◽  
Dose Effect ◽  
Dose Selection ◽  
Pulmonary Exposure ◽  
Drug Concentrations ◽  
Treatment Dose ◽  
Relationship Of

ABSTRACTChloroquine has attracted intense attention as a potential clinical candidate for prevention and treatment of COVID-19 based on reports of in-vitro efficacy against SARS-CoV-2. While the pharmacokinetic-pharmacodynamic (PK-PD) relationship of chloroquine is well established for malaria, there is sparse information regarding its dose-effect relationship in the context of COVID-19.Here, we explore the PK-PD relationship of chloroquine for COVID-19 by modelling both achievable systemic and pulmonary drug concentrations. Our data indicate that the standard anti-malarial treatment dose of 25mg/kg over three days does not deliver sufficient systemic drug exposures for the inhibition of viral replication. In contrast, PK predictions of chloroquine in the lungs using in-vivo data or human physiologically-based PK models, suggest that doses as low as 3mg/kg/day for 3 days could deliver exposures that are significantly higher than reported antiviral-EC90s for up to a week. Moreover, if pulmonary exposure is a driver for prevention, simulations show that chronic daily dosing of chloroquine may be unnecessary for prophylaxis purposes. Instead, once weekly doses of 5mg/kg would be sufficient to achieve a continuous cover of therapeutically active pulmonary exposures.These findings reveal a highly compartmentalised distribution of chloroquine in man that may significantly affect its therapeutic potential against COVID-19. The systemic circulation is shown as one site where chloroquine exposure is insufficient to inhibit SARS-CoV-2 replication. However, if therapeutic activity is driven by pulmonary exposure, it should be possible to reduce the chloroquine dose to safe levels. Carefully designed randomized controlled trials are urgently required to address these outstanding issues.

A review on Remdesivir: A broad-spectrum antiviral molecule for possible COVID-19 treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Jabeena Khazir ◽  
Tariq Maqbool ◽  
Bilal Ahmad Mir
Keyword(s):  
Clinical Trials ◽  
Broad Spectrum ◽  
Ebola Virus ◽  
Controlled Trial ◽  
In Vivo Studies ◽  
Therapeutic Drug ◽  
Viral Agent ◽  
Double Blind

: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus strain and the causative agent of COVID-19 was identified to have emerged in Wuhan, China, in December 2019 [1]. This pandemic situation and magnitude of suffering has led to global effort to find out effective measures for discovery of new specific drugs and vaccines to combat this deadly disease. In addition to many initiatives to develop vaccines for protective immunity against SARS-CoV-2, some of which are at various stages of clinical trials researchers worldwide are currently using available conventional therapeutic drugs with potential to combat the disease effectively in other viral infections and it is believed that these antiviral drugs could act as a promising immediate alternative. Remdesivir (RDV), a broad-spectrum anti-viral agent, initially developed for the treatment of Ebola virus (EBOV) and known to show promising efficiency in in vitro and in vivo studies against SARS and MERS coronaviruses, is now being investigated against SARS-CoV-2. On May 1, 2020, The U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for RDV to treat COVID-19 patients [2]. A number of multicentre clinical trials are on-going to check the safety and efficacy of RDV for the treatment of COVID-19. Results of published double blind, and placebo-controlled trial on RDV against SARS-CoV-2, showed that RDV administration led to faster clinical improvement in severe COVID-19 patients compared to placebo. This review highlights the available knowledge about RDV as a therapeutic drug for coronaviruses and its preclinical and clinical trials against COVID-19.

scholarly journals Population Pharmacokinetic Modeling of VL-2397, a Novel Systemic Antifungal Agent: Analysis of a Single- and Multiple-Ascending-Dose Study in Healthy Subjects

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Laura L. Kovanda ◽  
Sean M. Sullivan ◽  
Larry R. Smith ◽  
Amit V. Desai ◽  
Pete L. Bonate ◽  
...  
Keyword(s):  
Antifungal Agent ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Binding Model ◽  
Saturable Binding ◽  
Drug Concentrations ◽  
Over Time

ABSTRACT VL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus species. Plasma concentrations from a phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397. Healthy subjects aged 18 to 55 years received single doses of VL-2397, ranging from 3 to 1,200 mg, multiple daily doses of 300, 600, or 1,200 mg for 7 days, or 300 mg three times/day for 7 days followed by 600 mg daily for 21 days. Plasma samples were collected throughout the dosing intervals. Sixty-six subjects provided 1,908 concentrations. Drug concentrations over time were increased less than dose proportionally for doses above 30 mg. Dose-normalized concentrations plotted over time did not overlap. A 3-compartment nonlinear saturable binding model fit the data well. Clearance increased with dose, and mean values ranged from 0.4 liters/h at 3 mg to 8.5 liters/h at 1,200 mg. Mean volume in the central compartment ranged from 4.8 to 6.9 liters across doses. In the first 24 h, once-daily dosing results in a rapid decrease in concentrations by hour 16 to approximately 1 mg/liter, regardless of dose, with slow clearance over time. Administration of 300 mg every 8 h achieved concentrations above 1 mg/liter over an entire 24-h period. There was a significant relationship between body surface area and clearance. The data suggest that VL-2397 has nonlinear saturable binding kinetics. Protein binding is the likely primary source of the nonlinearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets.

Pseudoephedrine is without ergogenic effects during prolonged exercise

1996 ◽  
Vol 81 (6) ◽  
pp. 2611-2617 ◽  
Author(s):  
Hunter Gillies ◽  
Wayne E. Derman ◽  
Timothy D. Noakes ◽  
Peter Smith ◽  
Alicia Evans ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
High Intensity ◽  
Muscle Function ◽  
Prolonged Exercise ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
High Intensity Exercise ◽  
Double Blind ◽  
Drug Concentrations ◽  
Ergogenic Effects

Gillies, Hunter, Wayne E. Derman, Timothy D. Noakes, Peter Smith, Alicia Evans, and Gary Gabriels.Pseudoephedrine is without ergogenic effects during prolonged exercise. J. Appl. Physiol. 81(6): 2611–2617, 1996.—This study was designed to measure whether a single dose of 120 mg pseudoephedrine ingested 120 min before exercise influences performance during 1 h of high-intensity exercise. The effects of exercise on urinary excretion of the drug were also studied. Ten healthy male cyclists were tested on two occasions, separated by at least 7 days, by using a randomly assigned, double-blind, placebo-controlled, crossover design. Exercise performance was tested during a 40-km trial on a laboratory cycle ergometer, and skeletal muscle function was measured during isometric contractions. On a third occasion, subjects ingested 120 mg pseudoephedrine but did not exercise [control (C)]. Pseudoephedrine did not influence either time trial performance [drug (D) vs. placebo: 58.1 ± 1.4 (SE) vs. 58.7 ± 1.5 min] or isometric muscle function. Urinary pseudoephedrine concentrations were significantly increased 1 h after exercise (D vs. C: 114.3 ± 27.2 vs. 35.4 ± 13.1 μg/ml; P < 0.05). Peak plasma pseudoephedrine concentrations ( P < 0.05) but not time taken to reach peak plasma concentrations or the area under the plasma pseudoephedrine concentration vs. time curve was significantly increased in the total group with exercise (D vs. C). In three subjects, plasma pseudoephedrine concentrations were not influenced by exercise. Only these subjects showed increased urinary pseudoephedrine excretion during exercise. We conclude that a single therapeutic dose of pseudoephedrine did not have a measurable ergogenic effect during high-intensity exercise of 1-h duration, but plasma drug concentrations and urinary excretion were altered by exercise. These findings have practical relevance to doping control regulations in international sporting competitions.

Combining galiximab with the chemotherapeutic agents fludarabine or doxorubicin improves efficacy in animal models of lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3040-3040 ◽  
Author(s):  
H. K. Hariharan ◽  
T. Murphy ◽  
D. Clanton ◽  
L. Berquist ◽  
P. Chu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Clinical Benefit ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Chemotherapeutic Agents ◽  
Model Systems ◽  
Anti Cd20

3040 Background: Galiximab, a primatized monoclonal antibody that binds with high affinity to CD80 and mediates antibody- dependent, cell-mediated cytotoxicity in vitro, is currently under investigation for the treatment of follicular non-Hodgkin’s lymphoma (NHL). In a phase I/II monotherapy study, galiximab produced an overall response rate of 11%, and tumor reductions were observed in 46% of patients. Initial clinical trials also demonstrate that galiximab is well tolerated and suggest that combining galiximab with rituximab (anti-CD20) provides clinical benefit. These results are consistent with preclinical studies in murine lymphoma xenograft model systems, which demonstrate the superiority of combination therapy. Methods: To further define the therapeutic potential of galiximab, the Raji subcutaneous and the SKW disseminated lymphoma murine xenograft models were used to define the in vivo efficacy of galiximab alone or in combination with fludarabine or doxorubicin. Similar studies were performed with rituximab. Results: In the Raji model, both galiximab and rituximab exhibited maximal inhibition of the growth of preestablished (150-mg) tumors at a dose of 3 mg/kg/wk. Interestingly, higher doses of galiximab (but not rituximab) showed reduced inhibition. Galiximab (3 mg/kg/wk) inhibited tumor growth alone (P<0.0001 vs. control) and showed significantly enhanced activity when combined with fludarabine (50 or 100 mg/kg daily for 5 days; P<0.0002 vs. galiximab alone and P<0.003 vs. fludarabine alone). Similar results were observed with rituximab. In the SKW model, treatment with galiximab (5 mg/kg/wk for 6 doses) significantly enhanced survival compared with a control (P<0.0001) or doxorubicin (2.5 mg/kg/day for 3 doses; P<0.0001). Studies combining fludarabine or doxorubicin with both galiximab and rituximab are ongoing. Conclusions: Studies in animal models of lymphoma indicate that galiximab may provide clinical benefit when used in combination with chemotherapeutic agents such as fludarabine and doxorubicin, and provide a rationale for the investigation of these novel chemoimmunotherapy combinations in clinical trials. No significant financial relationships to disclose.

The effect of Intravenous Sodium Cromoglycate on the Bronchoconstriction Induced by Sulphur Dioxide Inhalation in Man

1985 ◽  
Vol 68 (2) ◽  
pp. 227-232 ◽  
Author(s):  
Anne Allistone ◽  
J. G. Collier ◽  
R. N. Davidson ◽  
R. W. Fuller ◽  
P. S. Richardson
Keyword(s):  
Mast Cells ◽  
Sodium Cromoglycate ◽  
Sulphur Dioxide ◽  
Plasma Concentrations ◽  
Drug Infusion ◽  
Double Blind ◽  
Solution Saline ◽  
The Subject ◽  
Airway Conductance

1. Ten healthy subjects received, on separate occasions, intravenous infusions of 0.9% NaCl solution (saline) and of sodium cromoglycate given in a double-blind cross-over fashion. 2. After 20 min of infusion the specific airway conductance (sGaw) of each subject was measured in a body plethysmograph. The subject then breathed first a low (1-20 p.p.m.) and then a higher (4-40 p.p.m.) concentration of sulphur dioxide (SO2) for 2 min while the infusion continued. Measurements of sGaw were repeated after each inhalation of SO2. 3. Sodium cromoglycate infusion did not affect the sGaw measured before challenge with SO2. 4. During the infusion of sodium cromoglycate, the falls in sGaw in response to both concentrations of SO2 were significantly less than those which occurred during saline infusion. 5. Plasma concentrations of sodium cromoglycate were found to be 209 ± 22 nmol/l at the end of the drug infusion. This is about one-hundredth of lowest dose required to stabilize mast cells in vitro. 6. We conclude that sodium cromoglycate acted by a mechanism which did not involve mast cells. Other possible modes of action are discussed.

scholarly journals Pharmacological effects of saffron and its constituents in ocular disorders from in vitro studies to clinical trials; a systematic review

2020 ◽  
Vol 18 ◽  
Author(s):  
Samaneh Sepahi ◽  
Adel Ghorani-Azam ◽  
Seyedeh Maryam Hossieni ◽  
Seyed Ahmad Mohajeri ◽  
Elham Khodavrdi
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
Therapeutic Potential ◽  
In Vitro Studies ◽  
Therapeutic Effects ◽  
Potential Candidate ◽  
Retinal Cells ◽  
Age Related ◽  
Eye Disorders

Introduction: Some medicinal plants have shown promising therapeutic potential for management of the diseases. We aimed to systematically review the literature wherein the therapeutic effects of saffron have been studied on eye disorders. Methods: A systematic literature search was performed in PubMed, Scopus, Web of Science, Google scholar and other databases using eye disorders, and saffron as key terms. No strict inclusion criteria were defined, and almost all clinical studies, as well as in vivo and in vitro studies were included. The reported data in each study were extracted and then qualitatively described. Results: Finally, 78 articles were found but only 29 relevant articles were included. Nine articles are clinical trials and 20 articles were done on cellular and molecular aspects of saffron on eye disorders. According to the included studies, crocin prevented the pro-inflammatory response in retinal cells and decreased glucose level in diabetic mice. Also, crocetin prevented retinal degeneration and saffron protected photoreceptors from light-induced damage in retinal cells. Saffron also improved visual function in age-related macular edema and decreased intraocular pressure in patients with glaucoma. In addition, it was shown that crocin can improve best corrected visual acuity and decreased central macular thickness in patients with diabetic maculopathy. Conclusion: The results of this review indicated that saffron and its main ingredients such as crocin could be a potential candidate for the treatment of ocular disease especially eye inflammation; however, further clinical studies are needed to confirm such efficiency.

scholarly journals Orally Bioavailable Endochin-like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts

2020 ◽  
Author(s):  
J. Stone Doggett ◽  
Tracey Schultz ◽  
Alyssa J. Miller ◽  
Igor Bruzual ◽  
Sovitj Pou ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Oral Bioavailability ◽  
Oral Absorption ◽  
Therapeutic Potential ◽  
Plasma Concentrations ◽  
Intraperitoneal Administration ◽  
Maximum Plasma ◽  
Acute Toxoplasmosis ◽  
Ester Prodrug

AbstractToxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for the T. gondii cytochrome b over the human cytochrome b. Despite oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a six-fold increase in both Cmax (maximum plasma concentration) and AUC (area under the curve) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in greater efficacy than the equivalent dose of ELQ-316 against acute toxoplasmosis and had similar efficacy against latent toxoplasmosis compared to intraperitoneal administration of ELQ-316. Carbonate ester prodrugs are a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis.

Sensitivity of primary hematopoietic tumors and tumor lines to the novel HDAC inhibitor PCI-24781

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14062-14062
Author(s):  
S. Balasubramanian ◽  
J. Ramos ◽  
M. Sirisawad ◽  
J. J. Buggy ◽  
R. A. Miller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Cell Lines ◽  
Hdac Inhibitor ◽  
Primary Tumor ◽  
The Novel ◽  
Hdac Inhibition ◽  
Hematopoietic Malignancies ◽  
Drug Concentrations

14062 PCI-24781 (formerly CRA-024781) is a novel HDAC inhibitor that is in phase I clinical trials in patients with solid and hematopoietic malignancies. PCI-24781 has favorable pharmacokinetic and pharmacodynamic profiles in animal models and in humans. In the present study we show that PCI-24781 potently induces cell death in a variety of hematopoietic cell lines derived from B-cell, T-cell and myeloid malignancies, and in primary acute leukemic blasts from bone marrow aspirates. In tumor cell lines, growth inhibition and apoptosis were noted at drug concentrations ≡ 0.125 μM and were accompanied by known biochemical markers of HDAC inhibition including histone and tubulin hyperacetylation. To demonstrate the potential clinical utility of PCI-24781 in hematologic tumors, primary leukemia samples were isolated from patients and screened for resistance to PCI-24781-induced growth arrest in vitro. Of these 25 primary samples (10 acute myelogenous leukemia (AML), 6 multiple myeloma (MM) and 9 acute lymphocytic leukemia (ALL)), some of which were derived from patients who had failed standard therapy, none was resistant to PCI-24781 at 0.5 μM and only 4 (1 AML, 2 MM, and 1 ALL) were considered resistant at 50 nM. Gene expression analysis using DNA microarrays on these primary tumor samples revealed alterations of gene expression consistent with HDAC inhibition and defined potential pathways of activity for this compound in these tumors. These results demonstrate that hematopoietic tumors and tumor-derived cell lines are highly sensitive in vitro to the novel HDAC inhibitor PCI-24781. The high sensitivity of primary tumor cells to treatment with PCI-24781 in vitro coupled with the favorable pharmacokinetics of this compound in humans suggests that patients with hematopoietic malignancies would be responsive to treatment with PCI-24781 in clinical trials. No significant financial relationships to disclose.

Effect of everolimus on angiogenic biomarkers in patients with tuberous sclerosis complex (TSC): Results from EXIST-1 and EXIST-2.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10619-10619
Author(s):  
David Neal Franz ◽  
Christopher Kingswood ◽  
Sergiusz Jozwiak ◽  
Klemens Budde ◽  
Elena Belousova ◽  
...  
Keyword(s):  
Growth Factor ◽  
Collagen Type ◽  
Plasma Concentrations ◽  
Collagen Type Iv ◽  
Subependymal Giant Cell Astrocytoma ◽  
Renal Angiomyolipoma ◽  
Vegf Receptor ◽  
Double Blind ◽  
Type Iv

10619 Background: The efficacy and safety of everolimus, an oral mTOR inhibitor, was assessed in two randomized, double-blind, placebo-controlled, phase 3 trials: EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400). EXIST-1 examined everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) associated with TSC and EXIST-2 for the treatment of renal angiomyolipoma (AML) associated with either TSC or sporadic lymphangioleiomyomatosis. In each instance, everolimus was superior to placebo for the primary endpoints, SEGA and renal AML response rates. Inhibitors of mTOR have antiangiogenic effects on tumor growth in vitro and in vivo. Methods: Patients were randomized to receive everolimus (n=78) starting at 4.5 mg/m2/day (target trough, 5-15 ng/mL) or placebo (n=39) in EXIST-1 and 10 mg/day everolimus (n=79) or placebo (n=39) in EXIST-2. Plasma samples were taken at baseline and pre-dosing on day 1 of weeks 4, 12, 24, 36, and 48 of treatment. Angiogenic markers of interest were vascular endothelial growth factor (VEGF)-A and -D, placental growth factor (PlGF), soluble VEGF receptor-1 (sVEGFR1), soluble VEGF receptor 2 (sVEGFR2), c-Kit, and collagen type IV. Results: Compared with placebo, a sustained ~30% and ~60% increase in VEGF-A was observed in the everolimus arm of EXIST-1 and EXIST-2, respectively. A concomitant decrease in collagen type IV (~25% EXIST-1; ~45% EXIST-2) and sVEGFR2 (~25% both trials) was also observed in the everolimus arm. A sustained decrease (~60%) in VEGF-D was observed in the everolimus arm of EXIST-2, but not EXIST-1. In both studies, no change was observed in PlGF, sVEGFR1, or c-Kit plasma concentrations in the everolimus arm or any biomarkers evaluated in the placebo arm. Baseline sVEGFR2 and VEGF-D were ~40% and ~4-fold higher, respectively, while VEGF-A was ~50% lower in EXIST-2 compared with EXIST-1. A similar baseline plasma concentration for the other biomarkers was noted in both studies. Conclusions: Patients presenting with SEGA or renal AML associated with TSC had a reduction in plasma concentrations of sVEGFR2, collagen type IV, and VEGF-D (AML only) and an increase in VEGF-A. Everolimus may have antiangiogenic properties in TSC patients.

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