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2022 ◽  
Vol 9 (3) ◽  
pp. 3-7
Author(s):  
Uma Advani ◽  
Ravi Prakash ◽  
Parmanand Swami ◽  
Neha Sharma ◽  
Charu Jain ◽  
...  

Abstract Objective: To review the literature on equianalgesic efficacy and better safety(less respiratory depression and gastrointestinal dysfunction) of oliceridine versus opioid analgesic in moderate to severe postoperative pain. Methodology: A comprehensive literature search was conducted in PubMed (January 2021 to March 2021) using keywords as ‘oliceridine’, ‘ligand biased mu receptor agonist’, ‘acute postoperative pain’, ‘conventional opioids’ and ‘morphine’. All English language full text pre-clinical and clinical research articles were searched. In addition, other data source was from ClinicalTrial. Gov. Data Synthesis: Oliceridine is a novel selective µ (mu)-receptor G-protein pathway modulator. G protein biased mu receptor agonists are a new class of opioids exhibiting analgesic properties at par to morphine with less respiratory depressant properties. Oliceridine a first-in-class intravenous (IV) analgesic has received the US FDA approval in August 2020, for management of moderate to severe acute pain in adults. The drug can be administered in cases where the pain is severe enough to require an intravenous opioid and when alternative treatments become inadequate. Oliceridine is an opioid agonist with a rapid onset of action within two to five minutes, was administered via clinician-administered bolus dosing, patient-controlled analgesia (PCA), or a combination of the two. Bolus dosing was initiated at 1 to 2 mg, with supplemental doses of 1 to 3 mg every one to three hours, as needed, based on individual patient need and previous response to oliceridine in management of acute post-operative pain. If oliceridine was administered via PCA, the loading dose was 1.5 mg, the demand dose was 0.5 mg, and the lockout interval (repeat dose)was six minutes. The clinically relevant concentration range of 0 to 35 ng/ml. It is indicated for short-term use only & limited to hospitals or other controlled clinical settings. Oliceridine requires no dosage adjustments in patients with renal impairment as well as in patient with significant medical complications. Therefore, opioids that bias towards G-protein and away from β arrestin signaling should produce analgesia with reduced side effects.


PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261900
Author(s):  
Margitta Dziwenka ◽  
Laurie Dolan ◽  
Jason Mitchell

VOHO Hemp Oil (Verdant Nature LLC (in collaboration with HempFusion)) is an extract of the aerial parts of hemp (Cannabis sativa L) manufactured using a supercritical CO2 extraction process. The results of four safety studies are reported here including a bacterial reverse mutation assay, an in vivo mammalian micronucleus study, a maximum tolerated dose study in rats and a 90-day repeat dose subchronic toxicity study in rats. VOHO Hemp oil can contain up to 30% phytocannabinoids and less than 0.2% is tetrahydrocannabinol (THC). VOHO Hemp Oil was found to be non-mutagenic in the bacterial reverse mutation assay and was negative for inducing micronuclei in the rat bone marrow micronucleus assay. The maximum tolerated dose in male and female Wistar rats was 2250 mg/kg bw/day. A 90-day repeat dose study was conducted in male and female Wistar rats according to OECD Guideline 408 and included a 21-day recovery period. The doses used in the study were 0, 25, 90 and 324 mg/kg bw per day in the main study, and in the recovery phase a control and 324 mg/kg bw/day group were included. One mortality was reported during the study, a high dose female, and test substance-related adverse clinical signs were reported in the high dose group. Other test substance-related changes noted in the high dose group included changes in body weights, activated partial thromboplastin time (APTT) values, and in absolute and relative organ weights. Based on the results of the study, the no observed adverse effect level (NOAEL) for VOHO Hemp Oil was determined to be 90 mg/kg bw/day in both male and female Wistar rats.


2021 ◽  
Vol 90 (1) ◽  
pp. 1
Author(s):  
Naseem Ahmad Charoo ◽  
Syeed Untoo ◽  
Ziyaur Rahman

Many specified impurities in vildagliptin's finished product have been disclosed in the literature that are above their qualification threshold. We used the impurity B (amide impurity) as a case example to explore whether existing literature can be leveraged to determine the safe level of impurity and thereby develop a patient-centric specification (PCS) for impurities. No-observed-adverse-effect level (NOAEL) was derived from rate metabolism information and converted to human equivalent dose (HED). The HED was estimated as 6.5 mg/day. The high qualification levels are supported by repeat dose toxicity studies performed in rats, mice and dogs. Maximum theoretical amount (MTA) was correlated with the maximum observed amount (MOA) to verify whether the exposure was due to impurity and/or metabolite. MOA/MTA was found ≥1 suggesting that metabolism contributed to the amount excreted in feces and therefore could be used to further justify a higher specification limit than the usual one of ≤0.5%. Quite often the drug metabolism and degradation pathways overlap, resulting in the formation of identical constituents. Therefore, metabolism data can be leveraged for deriving safe levels of degradation impurities and develop PCS for impurities.


Author(s):  
Toshko Jelev Lissitchkov ◽  
Annemieke Willemze ◽  
Suresh Katragadda ◽  
Kara Rice ◽  
Stacey Poloskey ◽  
...  

Efanesoctocog alfa (rFVIIIFc-VWF-XTEN, BIVV001) is a new class of factor VIII (FVIII) replacement that breaks the von Willebrand factor-imposed FVIII half-life ceiling. In a Phase 1/2a study, single-dose efanesoctocog alfa was well tolerated and no safety concerns were identified. We evaluated the safety, tolerability, and pharmacokinetics of repeat-dose efanesoctocog alfa in a Phase 1 study in previously treated adults (≥150 exposure days) with severe hemophilia A. Participants received four once-weekly efanesoctocog alfa doses (Cohort 1, 50 IU/kg; Cohort 2, 65 IU/kg). All enrolled participants (Cohort 1, n=10; Cohort 2, n=14) completed the study. Inhibitor development to FVIII was not detected. After the last efanesoctocog alfa dose, geometric mean (range) FVIII activity half-life, area under the activity-time curve, and steady state maximum concentration for Cohort 1 and Cohort 2 were 41.3 (34.2-50.1) hours and 37.3 (28.9-43.8) hours, 8290 (5810-10,300) h × IU/dL and 11,200 (7040-15,800) h × IU/dL, and 131 (96-191) IU/dL and 171 (118-211) IU/dL, respectively. There was minimal accumulation after 4 doses. Mean FVIII activity on Day 3 post dose was 46% and 69% and on Day 7 was 10% and 12% for Cohorts 1 and 2, respectively. Overall, four once-weekly doses of efanesoctocog alfa were well tolerated, no safety concerns identified, and no bleeds reported during the treatment period. Once-weekly efanesoctocog alfa provided high sustained FVIII activity within the normal to near-normal range for 3-4 days post-dose and may improve protection against bleeds in patients with hemophilia A. (EU Clinical Trials Register study 2018-001535-51)


2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A748-A748
Author(s):  
Ekta Patel ◽  
Natalia Malkova ◽  
Sallyann Vu ◽  
Rebekah O'Donnell ◽  
Manoussa Fanny ◽  
...  

BackgroundInterleukin-12 (IL-12) is a proinflammatory cytokine which bridges innate and adaptive immunity via induction of T helper 1 differentiation and promoting cytolytic activity of natural killer and T cells. IL-12 has demonstrated potent antitumor activity in syngeneic mouse models and promising anti-tumor efficacy in humans. However, development of IL-12 has been limited by severe systemic toxicities. To overcome toxicity and improve the therapeutic index of IL-12, we employed protein engineering to generate XTX301, a highly potent, half-life extended and masked IL-12. The masking domain of XTX301 is designed to pharmacologically inactivate IL-12 systemically and render an active IL-12 moiety upon cleavage by proteases that are enriched in the tumor microenvironment.MethodsWe conducted experiments to assess the binding, bioactivity, safety, and anti-tumor efficacy of XTX301. Binding interactions were measured via SPR, bioactivity was measured using STAT-4 phosphorylation in a reporter cell line, and IFN-g production was assessed in human PBMCs via ELISA. Anti-tumor efficacy and pharmacodynamics were assessed in MC38 and B16F10 syngeneic tumor mouse models using a XTX301 murine surrogate, mXTX301. Safety and pharmacokinetics of XTX301 were evaluated in non-human primates (NHP).ResultsXTX301 showed no detectable binding to the high affinity IL12RB2 demonstrating that the masking domain indeed prevents interaction with the receptor. Upon cleavage of the masking domain by relevant proteases, binding was observed and was comparable to XTX300 unmasked control. Likewise, restoration of activity upon proteolytic cleavage was observed in an IL-12-dependent reporter gene assay and in primary human PBMCs. Human IL-12 does not cross react with mouse IL-12 receptors; hence a murine surrogate (mXTX301) was created for in vivo anti-tumor efficacy evaluation. A single dose of mXTX301 demonstrated up to 90% tumor growth inhibition in an inflamed MC38 and non-inflamed B16F10 syngeneic mouse models. mXTX301 induced a ~3 fold increase in IFN-g in tumors compared to vehicle control and ~150 fold less peripheral IFN-g compared to mXTX300. XTX301 exhibits minimal elevation in liver enzymes and a 50-fold improvement in tolerability compared to XTX300, in a repeat dose NHP safety study.ConclusionsOur data demonstrates that both XTX301 and mXTX301 are inactive when in masked form and become activated upon proteolytic cleavage to exert bioactivity comparable to recombinant IL-12. For efficacy, mXTX301 demonstrated tumor selective activity in syngeneic mouse models. XTX301 was well tolerated in repeat dose NHP safety study. In conclusion, XTX301 has potential for exerting potent anti-tumor activity with a favorable tolerability profile.


2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A888-A888
Author(s):  
Michelle Kuhne ◽  
Hamlet Chu ◽  
Christopher Clarke ◽  
Brian Carr ◽  
Manuel Baca ◽  
...  

BackgroundThe ligand for the receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3) plays an importantrole in hematopoiesis. FLT3 signaling is required for the differentiation andexpansion of dendritic cells. In the context of cancer immunity, the conventional dendritic cellsubtype 1 (cDC1) are required for the generation of tumor-specific T cell responses in mousepreclinical models. In human tumors cDC1 are often underrepresented in thetumor microenvironment, supporting the hypothesis that therapeutically increasing their number via FLT3 pathway stimulation has the potential to promote T cell-mediated anti-tumor activity.MethodsGS-3583 is a fusion protein composed of the extracellular domain of human FLT3 ligand(FLT3L) combined with a modified fragment crystallizable (Fc) region of human IgG4. GS-3583was designed to induce cDC1 expansion and subsequently promote tumor-reactive T cell priming, activation and recruitment into the tumor microenvironment. The pharmacokinetics (PK) and pharmacodynamics (PD) of GS-3583 has been characterized in a 4-week repeat dose GLP study in cynomolgus monkeys at doses ranging from 0.3 to 10mg/kg GS-3583 was given as an intravenous injection.ResultsImmunophenotyping analysis of peripheral blood cells from GS-3583 treated monkeys demonstrated a non-dose-dependent expansion of cDC1 and cDC2 populations. The peak expansion for cDC1 and cDC2 occurred at Day 8 to Day 15. At peak, there was a 160-fold relative increase in cDC1 and 150-fold increase in cDC2 at the highest dose tested. There were dose-dependent increases in the exposure (AUC and Cmax) of GS-3583. GS-3583 was well-tolerated with no mortality or adverse clinical signs.ConclusionsThe administration of GS-3583 leads to increases in cDC1 and cDC2 populations. It was well tolerated at the maximal dose tested with no adverse clinical signs. Further clinical development of GS-3583 is warranted.


Author(s):  
Rita Lala ◽  
Nikita Nandvikar

Background: Acne vulgarise is an inflammatory disease involving the pathological alteration of the sebaceous glands of the body. It is not a life-threatening disease but has a great influence on lifestyle. Topical combination therapy of vitamin A and antibacterial drugs is an effective treatment for acne. Materials and Methods: The current work investigates the nanostructure lipid colloidal carrier system of Tretinoin and Clindamycin phosphate. Nanostructured lipid carriers (NLCs) were prepared by highspeed homogenization-sonication technique and characterized for physicochemical properties, permeation, in vivo anti-acne and toxicity (acute 2000 mg/Kg, repeat 1000 mg/kg) in Wistar rats.  Results: The prepared system was found to be stable, homogenous with more site retention of drugs having non-irritation and toxicity potential. The formulation showed a size of 283 nm, polydispersity index (PDI) 0.43 and Zeta potential (ZP) -37.9 mV with drug entrapment 92.0% and 66.15% for tretinoin and clindamycin respectively. Observed permeation was 18 % and 45% for Tretinoin and Clindamycin less than marketed formulation which is more focused on dermal retention of drug. No significant abnormalities and toxicological symptoms were observed for acute and repeat dose toxicity study for histopathology and haematological examinations of organs. Conclusion: Prepared NLC formulation was aimed at epidermal targeting. Based on obtained results it is concluded that developed lipid-based nanocarrier system of selected drugs showed the targeting potential for effective acne treatment. 


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Krzysztof Pyrć ◽  
Aleksandra Milewska ◽  
Emilia Barreto Duran ◽  
Paweł Botwina ◽  
Agnieszka Dabrowska ◽  
...  

AbstractThere are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549ACE2+ and Vero E6 cells with a log removal value of − 3 to − 4 at a concentration of 10–100 μg/ mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 μg/ mL (p < 0.05 compared to untreated controls). In vivo studies using transgenic mice expressing the ACE-2 receptor, dosed nasally with SARS-COV-2 (426,000 TCID50/mL) showed a trend for nasal GCPQ (20 mg/kg) to inhibit viral load in the respiratory tract and brain, although the study was not powered to detect statistical significance. GCPQ’s electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 h after nasal dosing. With a no observed adverse effect level of 18 mg/kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted.


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