scholarly journals Drugs Shown to Inhibit SARS-CoV-2 in COVID-19 Disease: Comparative Basic and Clinical Pharmacology of Molnupiravir and Ivermectin

2021 ◽  
Vol 9 (5) ◽  
Author(s):  
Ajayi AAL ◽  
Keyword(s):  
Viral Replication ◽  
Oral Absorption ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
The Body ◽  
Randomized Controlled Clinical Trials ◽  
Cytokine Inhibition ◽  
Viral Mutagenesis ◽  
Viral Cell Entry

The pharmacology of anti-SARS-CoV-2 drugs, Molnupiravir (M) and repurposed Ivermectin (IV) were compared. The IC50 for the inhibition of viral replication were 0.3μM for M and 2.8μM for IV. Both drugs have good oral absorption, with M achieving peak plasma concentrations by 2 hours and IV by 5 hours. The plasma half life were 7 hours for M and 81-91 hours for IV. M inhibits viral replication inducing viral mutagenesis in RdRp, causing viral error catastrophe and viral extinction. IV affects viral cell entry, nuclear transport and inhibits replication via RdRp. IV has additional effect to suppress cytokine production through STAT-3 inhibition. M is a more potent antiviral drug and IV has a longer residence in the body. Their effects on RdRp and cytokine inhibition are potentially complimentary for anti-COVID-19 activity. Both IV and M should be compared in randomized controlled clinical trials, and the possibility of their combination for anti-SARS-CoV-2 antiviral actions, explored further.

scholarly journals Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro

2021 ◽  
Vol 22 (6) ◽  
pp. 3163
Author(s):  
Hirofumi Ohashi ◽  
Feng Wang ◽  
Frank Stappenbeck ◽  
Kana Tsuchimoto ◽  
Chisa Kobayashi ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Cultured Cells ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Membrane Vesicles ◽  
Drug Candidates ◽  
Increased Risk ◽  
Derivatives Of

The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19.

scholarly journals Epidural Block for Abdominal Surgery: Aspects of Clinical Pharmacology of Etidocaine

1978 ◽  
Vol 6 (2) ◽  
pp. 105-115 ◽  
Author(s):  
M. J. Cousins ◽  
J. A. Augustus ◽  
M. Gleason ◽  
D. J. Morgan ◽  
J. Thomas
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Onset Time ◽  
Sensory Block ◽  
Epidural Block ◽  
The Body ◽  
Sensory Loss ◽  
Controlled Study ◽  
Motor Blockade ◽  
Initial Onset

A randomized, prospective, controlled study has compared 1% etidocaine (E) in nineteen patients and 0.5% bupivacaine (B) in 22 patients when used with 1/200,000 adrenaline for epidural blockade. There were unexpected similarities in onset profiles for the two agents, however etidocaine produced a superior intensity of sensory and motor blockade without increased toxicity. Onset times for sympathetic blockade (E = 6.9 ± 1.2, B = 6.8 ±1.2 minutes) were similar for both agents as were times to maximum change in blood pressure (E = 19.4 ± 9.7, B = 18.9 ± 3.7 minutes). Initial onset time for sensory loss to pin prick (partial sensory block) was surprisingly similar for the two drugs (E = 5.6 ± 0.6, B = 6.4 ± 0.7 minutes). However, onset of loss of touch sensation (complete sensory block) was much more rapid for etidocaine (E = 17.7 ± 1.7 minutes, B = 36.8 ± 3.5 minutes). Readiness for surgery, as assessed by spread of complete sensory block into four segments above and below the injection site, was rapid for etidocaine (23.1 ± 2.3 minutes) but this degree of blockade was only achieved in two patients following bupivacaine. Complete blockade on both sides of the body was achieved for two segments on either side of the infection site in 100% of patients following etidocaine, compared to only 30–50% following bupivacaine. A similar example of superior neural penetration was seen in onset of blockade of the large S1 root (E = 8.3 ± 1.4, B = 16.2 ± 4.6 minutes) Complete spread of motor blockade was much more rapid for etidocaine (14.7 ± 2.8, B = 28.9 ± 2.8 minutes). Degree of motor blockade was also significantly greater for etidocaine from ten minutes post blockade onwards (P < 0.001). Peak plasma concentrations were in keeping with ctox/cmax ratios of 1.9 for bupivacaine and 2.7 for etidocaine. Etidocaine was shown to be extensively and rapidly metabolized and to have a high degree of plasma protein binding.

scholarly journals Metabolism and Pharmacokinetics of SP-8356, a Novel (1S)-(−)-Verbenone Derivative, in Rats and Dogs and Its Implications in Humans

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1775
Author(s):  
Yuanyuan Zhou ◽  
Mun Hwan Oh ◽  
Yeon Joon Kim ◽  
Eun-yeong Kim ◽  
Jinhong Kang ◽  
...  
Keyword(s):  
Oral Absorption ◽  
Plasma Concentrations ◽  
The Body ◽  
Human Pharmacokinetics ◽  
Preclinical Development ◽  
Rapid Phase ◽  
Safety Risks ◽  
Potential Safety ◽  
Metabolic Reactions

(1S,5R)-4-((E)-3,4-dihydroxy-5-methoxystryryl)-6,6-dimethylbicylco[3.1.1]hept-3-en-2-one (SP-8356) is a novel (1S)-(−)-verbenone derivative that is currently in preclinical development for the treatment of ischemic stroke and atherosclerosis. This report aimed at characterization of the metabolism and pharmacokinetic properties of SP-8356. Following intravenous dose in rats and dogs, plasma concentrations of SP-8356 declined rapidly with high clearance (CL) and short half-life; after oral administration in both species, its plasma levels were below the quantitation limit. Fourteen circulating metabolites, formed by mono-oxygenation, demethylation, glucuronidation, catechol O-methylation, sulfation and oxidation (bioactivation) followed by glutathione (GSH) conjugation, were tentatively identified in both species. Urinary excretion of SP-8356 appeared to be minimal in rats, compared to its metabolites. GSH conjugate of SP-8356 was also formed during incubation with rat liver S9 fraction consistent with oxidative bioactivation; this bioactivation was almost completely inhibited by the cofactors for glucuronidation, sulfation and methylation, indicating that it may be abolished by competing metabolic reactions in the body. The human pharmacokinetics of SP-8356 was predicted to be similar to that of the animals based on the current in vitro metabolic stability results. In summary, rapid phase II metabolism appears to be mainly responsible for its suboptimal pharmacokinetics, such as high CL and low oral absorption. Because of competing metabolic reactions, potential safety risks related to SP-8356 bioactivation may be low.

Comparative Plasma Heparin Levels after Subcutaneous Sodium and Calcium Heparin

1978 ◽  
Vol 40 (02) ◽  
pp. 397-406 ◽  
Author(s):  
Joyce Low ◽  
J C Biggs
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Normal Subjects ◽  
Sodium Salts ◽  
Sodium Heparin ◽  
Significant Difference ◽  
Heparin Plasma ◽  
Calcium Heparin ◽  
Plasma Heparin

SummaryComparative plasma heparin levels were measured in normal subjects injected subcutaneously with 5,000 units of the sodium and calcium salts of heparin. Plasma heparin levels were measured up to 7 hr post-injection by an anti-factor Xa assay (Denson and Bonnar 1973). Preliminary studies indicated that heparin levels were reproducible in subjects who received two injections of the same heparin. Peak plasma concentrations (Cmax) and the time at which peak concentration was reached (Tmax) varied greatly from subject to subject. In one group of subjects (15) two commonly used heparins, a sodium heparin (Evans) and a calcium heparin (Choay) were compared. Peak heparin concentrations were not significantly different. However the Tmax for the sodium heparin (1.5 hr) was significantly earlier than the Tmax for the calcium heparin (3 hr) and this was not due to a difference in the volume of the two heparin injections. No significant difference could be detected in the plasma clearance rate and the molecular weight distribution of the two heparins.In two other groups of subjects, sodium and calcium preparations from two manufacturers were compared. In general, the sodium salts gave rise to significantly higher plasma concentrations, which could be interpreted as a greater bioavailability of sodium salts. These results indicate that the salt of the heparin can influence the plasma concentration achieved after subcutaneous injection.

Bioavailability in Rats of Human Recombinant Tissue Plasminogen Activator After Subcutaneous and Intramuscular Injection

1986 ◽  
Vol 56 (03) ◽  
pp. 299-301 ◽  
Author(s):  
L J Garcia Frade ◽  
S Poole ◽  
S Hanley ◽  
L J Creighton ◽  
A D Curtis ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Fibrinolytic Activity ◽  
Inferior Vena ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Vena Cava ◽  
Recombinant Tissue Plasminogen Activator ◽  
Fibrin Plate ◽  
Tissue Plasminogen

SummaryThe bioavailability of human recombinant tissue plasminogen activator (rt-PA) in rats was measured after subcutaneous (s.c.) and intramuscular (i.m.) injection. Rt-PA was absorbed after both i.m. and s.c. injection, giving peak plasma concentrations within 30 min and 1 h, respectively, with detectable concentrations up to 6 h. These peak values of bioavailable t-PA were obtained in a functional fibrin plate assay of euglobulin precipitates and expressed as +88% and +243% (for s.c. and i.m. routes respectively) above basal rat fibrinolytic activity. Prior injection of rt-PA, s.c. or i.m., significantly reduced the weights of thrombi induced in the inferior vena cava after injection.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Ileal transposition helps to regulate plasma hepatokine levels in obese Zucker (Crl:ZUC(ORL)-Leprfa) rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dominika Stygar ◽  
Tomasz Sawczyn ◽  
Agnieszka Dulska ◽  
Elżbieta Chełmecka ◽  
Łukasz Mielańczyk ◽  
...  
Keyword(s):  
Body Weight ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
The Body ◽  
Retinol Binding Protein ◽  
Fibroblast Growth Factor 21 ◽  
Adult Males ◽  
Total Lipids ◽  
Ileal Transposition ◽  
Sham Surgery

AbstractWe studied the long-term effect of ileal transposition (IT) metabolic surgery on the hepatokines: retinol-binding protein-4 (RBP4), α-2-HS-glycoprotein (aHSG/fetuin-A), and fibroblast growth factor 21 (FGF21), C-reactive protein (CRP) plasma levels, glucose metabolism, body weight, liver histology, as well as total lipids concentration in muscle, liver, and fat tissue of obese Zucker (Crl:ZUC(ORL)-Leprfa) rats. 14 adult males were randomly submitted either to IT or SHAM (control) surgery. Pre-operative hepatokines plasma levels were not significantly different in rats submitted to IT or SHAM protocol. Three months after the procedures the plasma levels of RBP4, aHSG, FGF21, and CRP were significantly lower in IT-operated animals when compared to SHAM-operated group. Three and 12 weeks after the IT and SHAM surgery, the AUCOGTT were significantly lower than AUCOGTT before the surgery. HOMA-IR was lower in rats after IT surgery in comparison to the SHAM-operated rats. Muscle and liver total lipids concentration was reduced after the IT procedure when compared to pre-IT conditions. IT had a significant reductive impact on the body weight in comparison to SHAM surgery in the 4th, 6th, 8th, and 10th week after the surgery. We conclude that IT reduces hepatokines’ plasma concentrations, muscle and liver total lipids concentration but not the inflammatory processes in the liver of Zucker (Crl:ZUC(ORL)-Leprfa) rats.

scholarly journals Oral absorption and drug interaction kinetics of moxifloxacin in an animal model of weightlessness

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dong Liang ◽  
Jing Ma ◽  
Bo Wei
Keyword(s):  
Oral Dose ◽  
Oral Absorption ◽  
Jugular Vein ◽  
Plasma Concentrations ◽  
Pharmacokinetic Data ◽  
Simulated Weightlessness ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Interaction Kinetics ◽  
Kinetics Of

AbstractTo investigate the effect of simulated weightlessness on the pharmacokinetics of orally administered moxifloxacin and the antacid Maalox or the antidiarrheal Pepto-Bismol using a tail-suspended (TS) rat model of microgravity. Fasted control and TS, jugular-vein-cannulated, male Sprague-Dawley rats received either a single 5 mg/kg intravenous dose or a single 10 mg/kg oral dose of moxifloxacin alone or with a 0.625 mL/kg oral dose of Maalox or a 1.43 mL/kg oral dose of Pepto-Bismol. Plasma concentrations of moxifloxacin were measured by HPLC. Pharmacokinetic data were analyzed using WinNonlin. Simulated weightlessness had no effect on moxifloxacin disposition after intravenous administration but significantly decreased the extent of moxifloxacin oral absorption. The coadministration of moxifloxacin with Maalox to either control or TS rats caused significant reductions in the rate and extent of moxifloxacin absorption. In contrast, the coadministration of moxifloxacin with Pepto-Bismol to TS rats had no significant effect on either the rate or the extent of moxifloxacin absorption. These interactions showed dose staggering when oral administrations of Pepto-Bismol and moxifloxacin were separated by 60 min in control rats but not in TS rats. Dose staggering was more apparent after the coadministration of Maalox and moxifloxacin in TS rats.

scholarly journals Human Endotoxemia Induces Down-Regulation of Monocyte CC Chemokine Receptor 2

2006 ◽  
Vol 13 (1) ◽  
pp. 156-159 ◽  
Author(s):  
Michael Heesen ◽  
Rosemarijn Renckens ◽  
Alex F. de Vos ◽  
Dagmar Kunz ◽  
Tom van der Poll
Keyword(s):  
Chemokine Receptor ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Necrosis Factor Alpha ◽  
Human Endotoxemia ◽  
Cc Chemokine ◽  
Chemotactic Protein ◽  
Human Volunteers ◽  
Cc Chemokine Receptor 2 ◽  
Factor Alpha

ABSTRACT Upon injection of Escherichia coli lipopolysaccharide into human volunteers, the monocyte density of CC chemokine receptor 2 (CCR2) decreased. Minimal CCR2 density was observed 4 h after injection. Peak plasma concentrations of the CCR2 ligand monocyte chemotactic protein 1 and of tumor necrosis factor alpha were reached after 4 h and 2 h, respectively.

Single-dose pharmacokinetics of orally administered terbinafine in bearded dragons (Pogona vitticeps) and the antifungal susceptibility patterns of Nannizziopsis guarroi

2021 ◽  
pp. 1-8
Author(s):  
Michael S. McEntire ◽  
Jennifer M. Reinhart ◽  
Sherry K. Cox ◽  
Krista A. Keller
Keyword(s):  
Single Dose ◽  
High Performance ◽  
Clinical Decision Making ◽  
Peak Plasma ◽  
Antifungal Susceptibility ◽  
Plasma Concentrations ◽  
Clinical Decision ◽  
Oral Solution ◽  
Susceptibility Data ◽  
Pogona Vitticeps

Abstract OBJECTIVE To identify the antifungal susceptibility of Nanniziopsis guarroi isolates and to evaluate the single-dose pharmacokinetics of orally administered terbinafine in bearded dragons. ANIMALS 8 healthy adult bearded dragons. PROCEDURES 4 isolates of N guarroi were tested for antifungal susceptibility. A compounded oral solution of terbinafine (25 mg/mL [20 mg/kg]) was given before blood (0.2 mL) was drawn from the ventral tail vein at 0, 4, 8, 12, 24, 48, 72, and 96 hours after administration. Plasma terbinafine concentrations were measured with high-performance liquid chromatography. RESULTS The antifungal minimum inhibitory concentrations against N guarroi isolates ranged from 4,000 to > 64,000 ng/mL for fluconazole, 125 to 2,000 ng/mL for itraconazole, 125 to 2,000 ng/mL for ketoconazole, 125 to 1,000 ng/mL for posaconazole, 60 to 250 ng/mL for voriconazole, and 15 to 30 ng/mL for terbinafine. The mean ± SD peak plasma terbinafine concentration in bearded dragons was 435 ± 338 ng/mL at 13 ± 4.66 hours after administration. Plasma concentrations remained > 30 ng/mL for > 24 hours in all bearded dragons and for > 48 hours in 6 of 8 bearded dragons. Mean ± SD terminal half-life following oral administration was 21.2 ± 12.40 hours. CLINICAL RELEVANCE Antifungal susceptibility data are available for use in clinical decision making. Results indicated that administration of terbinafine (20 mg/kg, PO, q 24 to 48 h) in bearded dragons may be appropriate for the treatment of dermatomycoses caused by N guarroi. Clinical studies are needed to determine the efficacy of such treatment.

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