Anti-Drug Antibodies in Pigtailed Macaques Receiving HIV Broadly Neutralising Antibody PGT121

Broadly neutralising antibodies (bNAbs) may play an important role in future strategies for HIV control. The development of anti-drug antibody (ADA) responses can reduce the efficacy of passively transferred bNAbs but the impact of ADA is imperfectly understood. We previously showed that therapeutic administration of the anti-HIV bNAb PGT121 (either WT or LALA version) controlled viraemia in pigtailed macaques with ongoing SHIV infection. We now report on 23 macaques that had multiple treatments with PGT121. We found that an increasing number of intravenous doses of PGT121 or human IgG1 isotype control antibodies (2-4 doses) results in anti-PGT121 ADA induction and low plasma concentrations of PGT121. ADA was associated with poor or absent suppression of SHIV viremia. Notably, ADA within macaque plasma recognised another human bNAb 10E8 but did not bind to the variable domains of PGT121, suggesting that ADA were primarily directed against the constant regions of the human antibodies. These findings have implications for the development of preclinical studies examining multiple infusions of human bNAbs.

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Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

10.31234/osf.io/su2kw ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Ex Vivo ◽

Oral Treatment ◽

Plasma Concentrations ◽

Vaginal Ring ◽

Vaginal Fluid ◽

Cervical Tissue ◽

Double Blind ◽

Group A ◽

Group B ◽

Anti Hiv

Objectives: Self-administered vaginal rings are a promising method for delivery of topical anti-HIV microbicidesand might offer an adherence advantage over daily or coitally-dependent dosage forms such as gels. This trialassessed the safety and pharmacokinetic aspects of the Dapivirine Vaginal Ring-004 when worn as multiple rings oversequential periods of ring use by healthy, sexually-active, HIV-negative women.Methods: This double-blind trial was conducted among 48 women (18-40 years). Participants were randomlyassigned to two groups (A or B) and received (3:1) either the dapivirine or a placebo vaginal ring. Group A used tworings over a 56-day period and Group B used three rings over a 57-day period. Safety evaluations were conductedthroughout the trial. Dapivirine concentrations were measured in plasma, vaginal fluid and cervical tissue samplescollected during and after the 56 days (Group A) or 57 days (Group B) of vaginal ring use.Results: Ring-004 was safe and well tolerated in all participants. The pharmacokinetic profile demonstrated arapid increase in plasma and vaginal fluid concentrations and achieved concentrations in vaginal fluids and cervicaltissue well above the in vitro IC99 in cervical tissue (3.3 ng/mL) that were sustained for a 28 to 35-day ring use period(approximately 3000 times higher in vaginal fluids and 14 -1000 times higher in cervical tissue). Drug levels wereassociated with significant inhibitory activity of genital secretions against HIV ex vivo, a biomarker of pharmacodynamics.Individual plasma dapivirine concentrations did not exceed 553 pg/mL and were well below plasma concentrations atthe maximum tolerated dose for oral treatment (mean Cmax 2286 ng/mL).Conclusions: The consecutive use of several rings over a period of up to 57 days was safe and well tolerated, andPK data indicate that a single Ring-004 is likely to be protective for at least 35 days.

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Vitamin D and Blood Parameters

Biomolecules ◽

10.3390/biom11071017 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1017

Author(s):

Thomas Müller ◽

Lutz Lohse ◽

Andreas Blodau ◽

Katja Frommholz

Keyword(s):

Vitamin D ◽

Mean Corpuscular Volume ◽

Plasma Concentrations ◽

Blood Parameters ◽

Vitamin D Supplementation ◽

Mean Corpuscular Hemoglobin ◽

Corpuscular Volume ◽

Corpuscular Haemoglobin ◽

Mean Corpuscular Haemoglobin ◽

The Impact

Background: Vitamin D has a steroid- and an anabolic-resembling chemical structure. Vitamin D is essential for many processes in the human body after hydroxylation. Aims of the Study: To investigate the impact of 25-hydroxy-vitamin D plasma concentrations on the blood parameters number of erythrocytes, hematocrit, mean corpuscular hemoglobin and mean corpuscular volume. Methods: Serial assessments were done in 290 patients with multiple sclerosis and repeated after a mean interval of 245 days. A recommendation for vitamin D supplementation was given in case of a concentration lower than 20 ng/mL combined with a prescription of a formulation containing vitamin D but not vitamin K. Results: There was a fall of vitamin D in 119 subjects and a rise in 164, while no change appeared in 7 participants. When vitamin D values went down between both assessments moments, the computed increase of mean corpuscular haemoglobin was significantly lower compared with the rise of mean corpuscular haemoglobin associated with a vitamin D elevation. When vitamin D declined, the computed fall of mean corpuscular volume fall was significantly lower compared with the decrease of mean corpuscular volume, when vitamin D rose. Positive correlations were found between differences of vitamin D and mean corpuscular haemoglobin, respectively mean corpuscular volume. Inverse relations appeared between disparities of vitamin D and erythrocytes, respectively haematocrit. Conclusions: The elevation of vitamin D plasma levels provides enhanced preconditions for a better tissue oxygenation on a cellular level.

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Viscoelastometry for detecting oral anticoagulants

Thrombosis Journal ◽

10.1186/s12959-021-00267-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Philipp Groene ◽

Daniela Wagner ◽

Tobias Kammerer ◽

Lars Kellert ◽

Andreas Giebl ◽

...

Keyword(s):

Healthy Volunteers ◽

Prospective Observational Study ◽

Oral Anticoagulants ◽

Plasma Concentrations ◽

Factor Xa ◽

Clotting Time ◽

Emergency Situations ◽

Tissue Plasminogen ◽

The Impact

Abstract Background Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device. Methods This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17–525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel’s viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test). Results 70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTEX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CTECA-test compared to controls (median 307 vs 73 s; p < 0.0001). CTECA-test correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CTRVV-test (r = 0.7998; p < 0.0001), and CTRVV-test provided 83% sensitivity and 64% specificity for detecting FXa inhibitors. Conclusions In emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking. Trial registration German clinical trials database ID: DRKS00015302.

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Antioxidants Promote Intestinal Tumor Progression in Mice

Antioxidants ◽

10.3390/antiox10020241 ◽

2021 ◽

Vol 10 (2) ◽

pp. 241

Author(s):

Zhiyuan V. Zou ◽

Kristell Le Gal ◽

Ahmed E. El Zowalaty ◽

Lara E. Pehlivanoglu ◽

Viktor Garellick ◽

...

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Tumor Progression ◽

Human Subjects ◽

Plasma Concentrations ◽

Intestinal Tumor ◽

Adenomatous Polyposis ◽

Intestinal Tumors ◽

The Impact

Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.

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Role of the Pharmacist in Managing Treatment-Resistant Depression: A Focus on Ketamine

Pharmacy ◽

10.3390/pharmacy9030118 ◽

2021 ◽

Vol 9 (3) ◽

pp. 118

Author(s):

Linda Xing Yu Liu ◽

Marina Golts ◽

Virginia Fernandes

Keyword(s):

Current Practice ◽

Quality Care ◽

Treatment Options ◽

Critical Role ◽

Transitions Of Care ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resistant Depression ◽

Multiple Treatments ◽

The Impact

The impact of depression is well described in the literature, and it is most prominent in patients who have trialed multiple treatments. Treatment-resistant depression (TRD) is particularly debilitating, and it is associated with significant morbidity and mortality. Despite this, there seems to be therapeutic inertia in adopting novel therapies in current practice. Ketamine is an N-methyl-D-aspartate receptor antagonist and anesthetic agent which has recently been shown to be effective in the management of TRD when administered intravenously or intranasally. The treatments, however, are not easily accessible due to restrictions in prescribing and dispensing, high costs, and the slow uptake of evidence-based practice involving ketamine within the Canadian healthcare system. Given the limited treatment options for TRD, novel approaches should be considered and adopted into practice, and facilitated by a multi-disciplinary approach. Pharmacists play a critical role in ensuring access to quality care. This includes dissemination of evidence supporting pharmacological treatments and facilitating translation into current practice. Pharmacists are uniquely positioned to collaborate with prescribers and assess novel treatment options, such as ketamine, address modifiable barriers to treatment, and triage access to medications during transitions of care. Extending the reach of these novel psychiatric treatments in both tertiary and primary care settings creates an emerging role for pharmacists in the collaborative effort to better manage treatment-resistant depression.

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An In Vivo Predictive Dissolution Methodology (iPD Methodology) with a BCS Class IIb Drug Can Predict the In Vivo Bioequivalence Results: Etoricoxib Products

Pharmaceutics ◽

10.3390/pharmaceutics13040507 ◽

2021 ◽

Vol 13 (4) ◽

pp. 507

Author(s):

Isabel Gonzalez-Alvarez ◽

Marival Bermejo ◽

Yasuhiro Tsume ◽

Alejandro Ruiz-Picazo ◽

Marta Gonzalez-Alvarez ◽

...

Keyword(s):

Plasma Concentrations ◽

In Vitro Dissolution ◽

Case Examples ◽

Dissolution Studies ◽

Weak Bases ◽

Transit Times ◽

Class Iib ◽

The Impact

The purpose of this study was to predict in vivo performance of three oral products of Etoricoxib (Arcoxia® as reference and two generic formulations in development) by conducting in vivo predictive dissolution with GIS (Gastro Intestinal Simulator) and computational analysis. Those predictions were compared with the results from previous bioequivalence (BE) human studies. Product dissolution studies were performed using a computer-controlled multicompartmental dissolution device (GIS) equipped with three dissolution chambers, representing stomach, duodenum, and jejunum, with integrated transit times and secretion rates. The measured dissolved amounts were modelled in each compartment with a set of differential equations representing transit, dissolution, and precipitation processes. The observed drug concentration by in vitro dissolution studies were directly convoluted with permeability and disposition parameters from literature to generate the predicted plasma concentrations. The GIS was able to detect the dissolution differences among reference and generic formulations in the gastric chamber where the drug solubility is high (pH 2) while the USP 2 standard dissolution test at pH 2 did not show any difference. Therefore, the current study confirms the importance of multicompartmental dissolution testing for weak bases as observed for other case examples but also the impact of excipients on duodenal and jejunal in vivo behavior.

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Impact of weight loss achieved through a multidisciplinary intervention on appetite in patients with severe obesity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00322.2017 ◽

2018 ◽

Vol 315 (1) ◽

pp. E91-E98 ◽

Cited By ~ 11

Author(s):

S. R. Coutinho ◽

J. F. Rehfeld ◽

J. J. Holst ◽

B. Kulseng ◽

C. Martins

Keyword(s):

Weight Loss ◽

Severe Obesity ◽

Peptide Yy ◽

Plasma Concentrations ◽

Cardiovascular Fitness ◽

Ghrelin Concentration ◽

Time Points ◽

Diet And Exercise ◽

The Impact

The impact of lifestyle-induced weight loss (WL) on appetite in patients with obesity remains controversial. This study aimed to assess the short- and long-term impact of WL achieved by diet and exercise on appetite in patients with obesity. Thirty-five (22 females) adults with severe obesity (body mass index: 42.5 ± 5.0 kg/m2) underwent a 2-yr WL program focusing on diet and exercise. Body weight (BW), cardiovascular fitness (V̇o2max), appetite feelings, and plasma concentrations of insulin, active ghrelin (AG), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK), in the fasting and postprandial states, were measured at baseline (B), week 4 (W4), and 1 and 2 yr (and average values for all fasting and postprandial time points computed). BW was significantly reduced and V̇o2max(ml·kg−1·min−1) increased at all time points compared with B (3.5, 8.1, and 8.4% WL and 7, 11, and 8% increase at W4 and 1 and 2 yr, respectively). Basal hunger and average hunger and desire to eat were significantly increased at 1 and 2 yr. Basal fullness was significantly increased at W4, and average ratings were reduced at 1 yr. Average AG and PYY were significantly increased, and insulin was reduced, at all time points compared with B. Average GLP-1 was reduced at W4, and CCK was increased at 2 yr. After lifestyle-induced WL, patients with severe obesity will, therefore, have to deal with increased hunger in the long term. In conclusion, sustained WL at 2 yr achieved with diet and exercise is associated with increased hunger feelings and ghrelin concentration but also increased postprandial concentrations of satiety hormones.

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Management of Oral Anti-Coagulation in Patients with Heart Failure—Insights from the ThrombEVAL Study

Thrombosis and Haemostasis ◽

10.1055/s-0038-1673380 ◽

2018 ◽

Vol 118 (11) ◽

pp. 1930-1939

Author(s):

Sebastian Göbel ◽

Jürgen Prochaska ◽

Lisa Eggebrecht ◽

Ronja Schmitz ◽

Claus Jünger ◽

...

Keyword(s):

Heart Failure ◽

Adverse Events ◽

Vitamin K Antagonists ◽

Plasma Concentrations ◽

Regular Care ◽

Increased Risk ◽

Patients With Heart Failure ◽

Specialized Care ◽

The Impact

AbstractPatients with heart failure (HF) are frequently anti-coagulated with vitamin K-antagonists (VKAs). The use of long-acting VKA may be preferable for HF patients due to higher stability of plasma concentrations. However, evidence on phenprocoumon-based oral anti-coagulation (OAC) therapy in HF is scarce. The aim of this study was to assess the impact of the presence of HF on quality of phenprocoumon-based OAC and the subsequent clinical outcome. Quality of OAC therapy and the incidence of adverse events were analysed in a cohort of regular care (n = 2,011) from the multi-centre thrombEVAL study program (NCT01809015) stratified by the presence of HF. To assess the modifiability of outcome, results were compared with data from individuals receiving specialized care for anti-coagulation (n = 760). Overall, the sample comprised of 813 individuals with HF and 1,160 subjects without HF in the regular care cohort. Quality of OAC assessed by time in therapeutic range (TTR) was 66.1% (47.8%/82.8%) for patients with HF and 70.6% (52.1%/85.9%) for those without HF (p = 0.0046). Stratification for New York Heart Classification (NYHA)-class demonstrated a lower TTR with higher NYHA classes: TTRNYHA-I 69.6% (49.4%/85.6%), TTRNYHA-II 66.5% (50.1%/82.9%) and TTRNYHA-≥III 61.8% (43.1%/79.9%). This translated into a worse net clinical benefit outcome for HF (hazard ratio [HR] 1.63 [1.31/2.02]; p < 0.0001) and an increased risk of bleeding (HR 1.40 [1.04/1.89]; p = 0.028). Management in a specialized coagulation service resulted in an improvement of all, TTR (∆+12.5% points), anti-coagulation-specific and non-specific outcome of HF individuals. In conclusion, HF is an independent risk factor for low quality of OAC therapy translating into an increased risk for adverse events, which can be mitigated by specialized care.

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Update on the drug-food interactions

Batna Journal of Medical Sciences (BJMS) ◽

10.48087/bjmstf.2014.1211 ◽

2014 ◽

Vol 1 (2) ◽

pp. 100-106

Author(s):

Hafid Bahri ◽

◽

Abdelkader Douaoui ◽

Moufida Gharbi ◽

Djamila Amroun

Keyword(s):

Drug Interactions ◽

Renal Clearance ◽

Enzyme Inhibitor ◽

Plasma Concentrations ◽

Public Health Problem ◽

Therapeutic Index ◽

Major Public Health Problem ◽

Urine Ph ◽

Pharmacodynamic Interaction ◽

The Impact

Drug interactions are a major public health problem, which partly attributed to some 10,000 deaths/year in Canada. Besides the interactions between two drugs, drug interactions are also due to the effect of other substances such as foods or nutrients. The drug-food interaction will be pharmacokinetic (affecting the absorption, distribution, metabolism, and elimination) or pharmacodynamic interaction. It is in the intestine that food may have the greatest impact with mainly a change in the amount of drugs absorbed that may be clinically significant for some drugs with narrow therapeutic index (cyclosporine, phenytoin, theophylline, etc.). The absorption of the drug in the presence of food will be determined by the particular physicochemical properties of the drug but also by the impact of food on one of the parameters determining the absorption such as: modified gastric acidity and emptying, the fat content of the food, the use of common transport between the drug and nutrients, chemical reactions between elements and drugs. Fasting situations or malnutrition can affect the distribution of drugs by increasing the free drug fraction, involving sometimes the risk of overdose. Diet affects drug metabolism by changing the activity of cytochrome P450. Most often is described the increase by grapefruit juice (enzyme inhibitor) of plasma concentrations of some drugs (cyclosporine, some statins, and calcium antagonists). Other foods (garlic, smoked meats and fish, caffeine) may increase metabolism. Diet can influence two stages of renal clearance (glomerular filtration - tubular reabsorption) by modifying urine pH or renal clearance. Pharmacodynamic interactions are also monitored, especially foods rich in vitamin k or tyramine with antivitamins K or MAOIs. Finally, health professionals must mobilize against these interactions, including through patient information.

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Clopidogrel Pharmacokinetics in Malaysian Population Groups: The Impact of Inter-Ethnic Variability

Pharmaceuticals ◽

10.3390/ph11030074 ◽

2018 ◽

Vol 11 (3) ◽

pp. 74 ◽

Cited By ~ 2

Author(s):

Zaril Zakaria ◽

Alan Fong ◽

Raj Badhan

Keyword(s):

Plasma Concentration ◽

Plasma Concentrations ◽

High Dose ◽

Population Groups ◽

Adjunct Treatment ◽

Malaysian Population ◽

Significant Difference ◽

Target Plasma Concentration ◽

Ethnic Variability ◽

The Impact

Malaysia is a multi-ethnic society whereby the impact of pharmacogenetic differences between ethnic groups may contribute significantly to variability in clinical therapy. One of the leading causes of mortality in Malaysia is cardiovascular disease (CVD), which accounts for up to 26% of all hospital deaths annually. Clopidogrel is used as an adjunct treatment in the secondary prevention of cardiovascular events. CYP2C19 plays an integral part in the metabolism of clopidogrel to the active metabolite clopi-H4. However, CYP2C19 genetic polymorphism, prominent in Malaysians, could influence target clopi-H4 plasma concentrations for clinical efficacy. This study addresses how inter-ethnicity variability within the Malaysian population impacts the attainment of clopi-H4 target plasma concentration under different CYP2C19 polymorphisms through pharmacokinetic (PK) modelling. We illustrated a statistically significant difference (P < 0.001) in the clopi-H4 Cmax between the extensive metabolisers (EM) and poor metabolisers (PM) phenotypes with either Malay or Malaysian Chinese population groups. Furthermore, the number of PM individuals with peak clopi-H4 concentrations below the minimum therapeutic level was partially recovered using a high-dose strategy (600 mg loading dose followed by a 150 mg maintenance dose), which resulted in an approximate 50% increase in subjects attaining the minimum clopi-H4 plasma concentration for a therapeutic effect.

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