Plasma concentration and safety of lopinavir/ritonavir in patients with Covid-19: a short communication

ABSTRACTBackgroundLopinavir/ritonavir has been proposed as off-label treatment for Covid-19, although efficacy have not been proven. It has previously been shown that lopinavir plasma concentration is dramatically increased in inflammatory settings. As Covid-19 may be associated with major inflammation, assessing lopinavir plasma concentration and its safety in Covid-19 patients is essential.MethodsReal-world Covid-19 experience based on a retrospective study.ResultsOf 31 patients treated by lopinavir/ritonavir for Covid-19, we observed very high lopinavir plasma concentrations, increased of 4.6-fold (IQR, 3.6-6.2) with regards to average plasma concentrations in HIV. All except one patient were above the upper limit of the concentration ranges of HIV treatment. About one over four to five patients prematurely stopped treatment mainly secondary an adverse drug reaction related to hepatic or gastrointestinal disorders.ConclusionLopinavir plasma concentrations in patients with moderate to severe Covid-19 were higher than expected, associated with the occurrence of hepatic or gastrointestinal adverse drug reactions. However, owing that high plasma concentration may be required for in vivo antiviral activity against SARS-CoV-2 as suggested by previous studies, it appears that, in the absence of adverse drug reaction, lopinavir dosage should not be reduced. Cautious is necessary as off-label use can be associated with a new drug safety profile.

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Intoxication with Phenprocoumon (Marcoumar) Pharmacokinetics and Side Effects

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653541 ◽

1969 ◽

Vol 21 (02) ◽

pp. 320-324 ◽

Cited By ~ 3

Author(s):

K Seiler ◽

F Duckert

Keyword(s):

Plasma Concentration ◽

Side Effects ◽

Half Life ◽

Plasma Proteins ◽

Repeated Administration ◽

High Plasma ◽

Vitamin K1 ◽

Clotting Factors ◽

Therapeutic Concentration ◽

High Plasma Concentration

SummaryA case of severe Marcoumar intoxication is described. Eleven hours after the intake a plasma concentration of 15.75 µg/ml was found which corresponds approximately to the 5-fold therapeutic concentration. Repeated administration of vitamin K1 made it possible to avoid extreme lowering of the activity of the clotting factors II, VII and X and to prevent bleeding. Side effects were not observed. The biologic half-life of Phenprocoumon has been found to be shortened at high plasma concentration (3.7 instead of 5.9 days). It is probable that in extreme concentration the drug is less strongly bound to the plasma proteins.

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

Medicinal Chemistry ◽

10.2174/1573406416666201120102905 ◽

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.

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Propranolol in Children: Safety-Toxicity

PEDIATRICS ◽

10.1542/peds.70.1.30 ◽

1982 ◽

Vol 70 (1) ◽

pp. 30-31

Author(s):

Michael Artman ◽

Mitch Grayson ◽

Robert C. Boerth

Keyword(s):

Heart Rate Response ◽

Plasma Concentrations ◽

Caloric Intake ◽

High Plasma ◽

Intravenous Glucose ◽

First Case ◽

Acute Ingestion ◽

Pharmacologic Effect ◽

Propranolol Therapy ◽

Very High

Four hours after acute ingestion of 400 to 1,200 mg of propranolol by a healthy, 3-year-old boy, his plasma concentration of propranolol was 2,289 ng/ml. The only pharmacologic effect observed was a diminished heart rate response to crying and activity. In a second case, a 4-year-old boy on chronic propranolol therapy for renovascular hypertension had a hypoglycemic seizure when solid food was refused for three days because of an oral wound. The hypoglycemia was easily managed with intravenous glucose, and there were no sequelae. The first case alludes to the safety of propranolol in a healthy child even with very high plasma concentrations. The second case suggests the necessity of anticipating and avoiding hypoglycemia that can develop in children on chronic propranolol therapy when caloric intake is impaired.

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High plasma concentration of beta-D-glucan after administration of sizofiran for cervical cancer

International Journal of General Medicine ◽

10.2147/ijgm.s12319 ◽

2010 ◽

pp. 273

Author(s):

Tokuyasu Hirokazu

Keyword(s):

Cervical Cancer ◽

Plasma Concentration ◽

High Plasma ◽

High Plasma Concentration

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Glucose regulates lipid metabolism in fasting king penguins

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00094.2003 ◽

2003 ◽

Vol 285 (2) ◽

pp. R313-R320 ◽

Cited By ~ 9

Author(s):

Servane F. Bernard ◽

Jord Orvoine ◽

René Groscolas

Keyword(s):

Lipid Metabolism ◽

Plasma Concentration ◽

Energy Production ◽

Important Determinant ◽

Plasma Concentrations ◽

Glucose Infusion ◽

Nonesterified Fatty Acids ◽

Fat Stores

This study aims to determine whether glucose intervenes in the regulation of lipid metabolism in long-term fasting birds, using the king penguin as an animal model. Changes in the plasma concentration of various metabolites and hormones, and in lipolytic fluxes as determined by continuous infusion of [2-3H]glycerol and [1-14C]palmitate, were examined in vivo before, during, and after a 2-h glucose infusion under field conditions. All the birds were in the phase II fasting status (large fat stores, protein sparing) but differed by their metabolic and hormonal statuses, being either nonstressed (NSB; n = 5) or stressed (SB; n = 5). In both groups, glucose infusion at 5 mg·kg-1·min-1 induced a twofold increase in glycemia. In NSB, glucose had no effect on lipolysis (maintenance of plasma concentrations and rates of appearance of glycerol and nonesterified fatty acids) and no effect on the plasma concentrations of triacylglycerols (TAG), glucagon, insulin, or corticosterone. However, it limited fatty acid (FA) oxidation, as indicated by a 25% decrease in the plasma level of β-hydroxybutyrate (β-OHB). In SB, glucose infusion induced an ∼2.5-fold decrease in lipolytic fluxes and a large decrease in FA oxidation, as reflected by a 64% decrease in the plasma concentration of β-OHB. There were also a 35% decrease in plasma TAG, a 6.5- and 2.8-fold decrease in plasma glucagon and corticosterone, respectively, and a threefold increase in insulinemia. These data show that in fasting king penguins, glucose regulates lipid metabolism (inhibition of lipolysis and/or of FA oxidation) and affects hormonal status differently in stressed vs. nonstressed individuals. The results also suggest that in birds, as in humans, the availability of glucose, not of FA, is an important determinant of the substrate mix (glucose vs. FA) that is oxidized for energy production.

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Renin dynamics in adipose tissue: adipose tissue control of local renin concentrations

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90693.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. E343-E350 ◽

Cited By ~ 15

Author(s):

Jason D. Fowler ◽

Stacy B. Krueth ◽

David A. Bernlohr ◽

Stephen A. Katz

Keyword(s):

Adipose Tissue ◽

Cardiac Tissue ◽

Plasma Concentrations ◽

Renin Angiotensin System ◽

Plasma Renin ◽

Treated Group ◽

Rat Plasma ◽

High Plasma ◽

Tissue Growth

The renin-angiotensin system (RAS) has been implicated in a variety of adipose tissue functions, including tissue growth, differentiation, metabolism, and inflammation. Although expression of all components necessary for a locally derived adipose tissue RAS has been demonstrated within adipose tissue, independence of local adipose RAS component concentrations from corresponding plasma RAS fluctuations has not been addressed. To analyze this, we varied in vivo rat plasma concentrations of two RAS components, renin and angiotensinogen (AGT), to determine the influence of their plasma concentrations on adipose and cardiac tissue levels in both perfused (plasma removed) and nonperfused samples. Variation of plasma RAS components was accomplished by four treatment groups: normal, DOCA salt, bilateral nephrectomy, and losartan. Adipose and cardiac tissue AGT concentrations correlated positively with plasma values. Perfusion of adipose tissue decreased AGT concentrations by 11.1%, indicating that adipose tissue AGT was in equilibrium with plasma. Cardiac tissue renin levels positively correlated with plasma renin concentration for all treatments. In contrast, adipose tissue renin levels did not correlate with plasma renin, with the exception of extremely high plasma renin concentrations achieved in the losartan-treated group. These results suggest that adipose tissue may control its own local renin concentration independently of plasma renin as a potential mechanism for maintaining a functional local adipose RAS.

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Changes in the hypothalamic contents of LHRH-I and -II and in pituitary responsiveness to synthetic chicken LHRH-I and -II during the progesterone-induced surge of LH in the laying hen

Journal of Endocrinology ◽

10.1677/joe.0.1270487 ◽

1990 ◽

Vol 127 (3) ◽

pp. 487-496 ◽

Cited By ~ 9

Author(s):

S. C. Wilson ◽

R. A. Chairil ◽

F. J. Cunningham ◽

R. T. Gladwell

Keyword(s):

Plasma Concentration ◽

Pituitary Gland ◽

Laying Hens ◽

Plasma Concentrations ◽

Posterior Hypothalamus ◽

Anterior Hypothalamus ◽

Significant Fall ◽

Basal Plasma

ABSTRACT The contents of LHRH-I and -II in the anterior hypothalamus and posterior hypothalamus (including the mediobasal hypothalamus and median eminence) were measured at 90, 180 and 360 min after the i.m. injection of laying hens with progesterone. Whilst no changes were observed in the content of LHRH-I in the anterior hypothalamus, LHRH-I in the posterior hypothalamus tended to fall at 90 and 180 min after injection of progesterone in hens maintained on 16 h light:8 h darkness (16L:8D) and 8L:16D respectively. Pretreatment of laying hens with tamoxifen significantly increased the hypothalamic contents of LHRH-I and -II, raised the basal plasma concentration of LH and modified the LH response to progesterone injection. In hens in which tamoxifen prevented an increase in the plasma concentration of LH after progesterone injection, the content of LHRH-I in the posterior hypothalamus remained unchanged. In contrast, in hens in which progesterone stimulated a steep increase in LH within 90 min, there was a pronounced and significant fall in LHRH-I content of the posterior hypothalamus. No change in the hypothalamic content of LHRH-II was observed during the progesterone-induced surge of LH until plasma concentrations had attained maximal values or started to decline. Then, in hens maintained on 16L:8D, a significant fall in the content of LHRH-II in the anterior hypothalamus was found at both 180 and 360 min after injection with progesterone. Tests in vitro and in vivo of the responsiveness of the pituitary gland to synthetic LHRH-I and -II revealed no change at 90 min after injection of laying hens with progesterone, when plasma concentrations of LH were increasing, but a pronounced reduction when plasma LH concentrations were maximal or falling. These results suggest that LHRH-I mediates in the progesterone-induced increase in the plasma concentration of LH. Although the subsequent decline in plasma LH was associated with a reduced responsiveness of the pituitary gland to LHRH, a significant correlation between the contents of LHRH-I and -II in the anterior hypothalamus and a fall in the hypothalamic content of LHRH-II when plasma LH was maximal or declining allows the possibility of an involvement of this peptide in the neuroendocrine events preceding ovulation. Journal of Endocrinology (1990) 127, 487–496

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Plasma Inorganic Fluoride Concentrations after Sevoflurane Anesthesia in Children

Anesthesiology ◽

10.1097/00000542-199602000-00012 ◽

1996 ◽

Vol 84 (2) ◽

pp. 348-353. ◽

Cited By ~ 25

Author(s):

M. F. Levine ◽

J. Sarner ◽

J. Lerman ◽

P. Davis ◽

N. Sikich ◽

...

Keyword(s):

Plasma Concentration ◽

Elective Surgery ◽

Plasma Concentrations ◽

Sevoflurane Anesthesia ◽

Inorganic Fluoride ◽

Time Curve ◽

Plasma Urea ◽

The Mean ◽

Group 2

Background Sevoflurane is degraded in vivo in adults yielding plasma concentrations of inorganic fluoride [F-] that, in some patients, approach or exceed the 50- micron theoretical threshold for nephrotoxicity. To determine whether the plasma concentration of inorganic fluoride [F-] after 1-5 MAC x h sevoflurane approaches a similar concentration in children, the following study in 120 children scheduled for elective surgery was undertaken. Methods Children were randomly assigned to one of three treatment groups before induction of anesthesia: group 1 received sevoflurane in air/oxygen 30% (n = 40), group 2 received sevoflurane in 70% N2O/30% O2 (n = 40), and group 3 received halothane in 70% N2O/30% O2 (n = 40). Mapleson D or F circuits with fresh gas flows between 3 and 61/min were used Whole blood was collected at induction and termination of anesthesia and at 1, 4, 6, 12, and 18 or 24 h postoperatively for determination of the [F-]. Plasma urea and creatinine concentrations were determined at induction of anesthesia and 18 or 24 h postoperatively. Results The mean (+/- SD) duration of sevoflurane anesthesia, 2.7 +/- 1.6 MAC x h (range 1.1-8.9 MAC x h), was similar to that of halothane, 2.5 +/- 1.1 MAC x h. The peak [F-] after sevoflurane was recorded at 1 h after termination of the anesthetic in all but three children (whose peak values were recorded between 4 and 6 h postanesthesia). The mean peak [F-] after sevoflurane was 15.8 +/- 4.6 microns. The [F-] decreased to <6.2 microns b 24 h postanesthesia. Both the peak [F-] (r2 = 0.50) and the area under the plasma concentration of inorganic fluoride-time curve (r2 = 0.57) increased in parallel with the MAC x h of sevoflurane. The peak [F-] after halothane, 2.0 +/- 1.2 microns, was significantly less than that after sevoflurane (P<0.00012) and did not correlate with the duration of halothane anesthesia (MAC x h; r2 = 0.007). Plasma urea concentrations decreased 24 h after surgery compared with preoperative values for both anesthetics (P<0.01), whereas plasma creatinine concentrations did not change significantly with either anesthetic. Conclusions It was concluded that, during the 24 h after 2.7 +/- 1.6 MAC x h sevoflurane, the peak recorded [F-] is low (15.8 microns), F- is eliminated rapidly, and children are unlikely to be at risk of nephrotoxicity from high [F-].

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