scholarly journals High Accumulation and In Vivo Recycling of the New Antimalarial Albitiazolium Lead to Rapid Parasite Death

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Sharon Wein ◽  
Nicolas Taudon ◽  
Marjorie Maynadier ◽  
Christophe Tran Van Ba ◽  
Delphine Margout ◽  
...  
Keyword(s):  
Pharmacological Activity ◽  
Plasma Concentrations ◽  
Pharmacokinetic Studies ◽  
High Accumulation ◽  
Content Type ◽  
Viability Assay ◽  
Parasite Viability ◽  
Two Parameters

ABSTRACT Albitiazolium is the lead compound of bisthiazolium choline analogues and exerts powerful in vitro and in vivo antimalarial activities. Here we provide new insight into the fate of albitiazolium in vivo in mice and how it exerts its pharmacological activity. We show that the drug exhibits rapid and potent activity and has very favorable pharmacokinetic and pharmacodynamic properties. Pharmacokinetic studies in Plasmodium vinckei-infected mice indicated that albitiazolium rapidly and specifically accumulates to a great extent (cellular accumulation ratio, >150) in infected erythrocytes. Unexpectedly, plasma concentrations and the area under concentration-time curves increased by 15% and 69% when mice were infected at 0.9% and 8.9% parasitemia, respectively. Albitiazolium that had accumulated in infected erythrocytes and in the spleen was released into the plasma, where it was then available for another round of pharmacological activity. This recycling of the accumulated drug, after the rupture of the infected erythrocytes, likely extends its pharmacological effect. We also established a new viability assay in the P. vinckei-infected mouse model to discriminate between fast- and slow-acting antimalarials. We found that albitiazolium impaired parasite viability in less than 6 and 3 h at the ring and late stages, respectively, while parasite morphology was affected more belatedly. This highlights that viability and morphology are two parameters that can be differentially affected by a drug treatment, an element that should be taken into account when screening new antimalarial drugs.

Oestrogens in breast tumours and fat

1989 ◽  
Vol 95 ◽  
pp. 161-168
Author(s):  
J. H. H. Thijssen ◽  
M. A. Blankenstein
Keyword(s):  
Biological Effects ◽  
Plasma Concentrations ◽  
Normal Breast ◽  
Malignant Tumours ◽  
Breast Tumours ◽  
Two Parameters ◽  
Breast Tissues

SynopsisThe levels of endogenous steroids in the target tissues are thought to be more closely related to the biological effects than their concentrations in plasma. Therefore studies on oestrogen levels in malignant and non-malignant breast tissues (expressed per g wet weight) were conducted and the following conclusions were drawn:(1) malignant tumours contained higher oestradiol levels than normal or benign breast tissues, whereas oestrone levels were more comparable;(2) in contrast to the large decrease in plasma concentrations after menopause, the levels of oestradiol in tumours and in normal breast tissue did not change with advancing age;(3) the oestradiol levels in breast tissues were lower than in uterine tissues, particularly in women before menopause; oestrone levels were very similar in all tissues studied;(4) the mean oestradiol level was higher in oestrogen-receptor-positive tumours, but no correlation between the two parameters was found;(5) preliminary results indicated lower oestradiol levels in tumours obtained from countries with a lower incidence of breast cancer;(6) as far as available, oestrone levels were comparable and those of oestradiol were lower in fat tissues than in breast tumours;(7) neither in vitro studies with breast tumours, nor in vivo results using myometrial tissues support a prominent role of the metabolism of oestrogens at the 16α-position in the development of tumours;(8) the role of local factors in the production, retention and metabolism of oestradiol in the breast remains to be elucidated.

scholarly journals Structure-Activity Relationships of a Series of Echinocandins and the Discovery of CD101, a Highly Stable and Soluble Echinocandin with Distinctive Pharmacokinetic Properties

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Kenneth D. James ◽  
Christopher P. Laudeman ◽  
Navdeep B. Malkar ◽  
Radha Krishnan ◽  
Karen Polowy
Keyword(s):  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Activity Data ◽  
Content Type ◽  
Structure Activity Relationships ◽  
First Line Therapy ◽  
Structure Activity ◽  
Pharmacokinetic Properties

ABSTRACT Echinocandins are a first-line therapy for candidemia and invasive candidiasis. They are generally safe with few drug interactions, but the stability and pharmacokinetic properties of currently approved echinocandins are such that each was developed for daily intravenous infusion. We sought to discover a novel echinocandin with properties that would enable more flexible dosing regimens, alternate routes of delivery, and expanded utility. Derivatives of known echinocandin scaffolds were generated, and an iterative process of design and screening led to the discovery of CD101, a novel echinocandin that has since demonstrated improved chemical stability and pharmacokinetics. Here, we report the structure-activity relationships (including preclinical efficacy and pharmacokinetic data) for the series of echinocandin analogs from which CD101 was selected. In a mouse model of disseminated candidiasis, the test compounds displayed clear dose responses and were generally associated with lower fungal burdens than that of anidulafungin. Single-dose pharmacokinetic studies in beagle dogs revealed a wide disparity in the half-lives and volumes of distribution, with one compound (now known as CD101) displaying a half-life that is nearly 5-fold longer than that of anidulafungin (53.1 h versus 11.6 h, respectively). In vitro activity data against panels of Candida spp. and Aspergillus spp. demonstrated that CD101 behaved similarly to approved echinocandins in terms of potency and spectrum of activity, suggesting that the improved efficacy observed in vivo for CD101 is a result of features beyond the antifungal potency inherent to the molecule. Factors that potentially contribute to the improved in vivo efficacy of CD101 are discussed.

scholarly journals In VivoPharmacodynamics of Torezolid Phosphate (TR-701), a New Oxazolidinone Antibiotic, against Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus Strains in a Mouse Thigh Infection Model

2011 ◽  
Vol 55 (7) ◽  
pp. 3453-3460 ◽  
Author(s):  
Arnold Louie ◽  
Weiguo Liu ◽  
Robert Kulawy ◽  
G. L. Drusano
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Dose Fractionation ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTTorezolid phosphate (TR-701) is the phosphate monoester prodrug of the oxazolidinone TR-700 which demonstrates potentin vitroactivity against Gram-positive bacteria, including methicillin-susceptibleStaphylococcus aureus(MSSA) and methicillin-resistantS. aureus(MRSA). The pharmacodynamics of TR-701 or TR-700 (TR-701/700) againstS. aureusis incompletely defined. Single-dose pharmacokinetic studies were conducted in mice for TR-701/700. Forty-eight-hour dose range and 24-hour dose fractionation studies were conducted in a neutropenic mouse thigh model ofS. aureusinfection using MRSA ATCC 33591 to identify the dose and schedule of administration of TR-701/700 that was linked with optimized antimicrobial effect. Additional dose range studies compared the efficacies of TR-701/700 and linezolid for one MSSA strain and one community-associated MRSA strain. In dose range studies, TR-701/700 was equally bactericidal against MSSA and MRSA. Mean doses of 37.6 and 66.9 mg/kg of body weight/day of TR-701/700 resulted in stasis and 1 log CFU/g decreases in bacterial densities, respectively, at 24 h, and mean doses of 35.3, 46.6, and 71.1 mg/kg/day resulted in stasis and 1 and 2 log CFU/g reductions, respectively, at 48 h. Linezolid administered at doses as high as 150 mg/kg/day did not achieve stasis at either time point. Dose fractionation studies demonstrated that the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the pharmacodynamic index for TR-701/700 that was linked with efficacy. TR-701/700 was highly active against MSSA and MRSA,in vivo, and was substantially more efficacious than linezolid, although linezolid's top exposure has half the human exposure. Dose fractionation studies showed that AUC/MIC was the pharmacodynamic index linked with efficacy, indicating that once-daily dosing in humans is feasible.

scholarly journals Mode of Action,In VitroActivity, andIn VivoEfficacy of AFN-1252, a Selective Antistaphylococcal FabI Inhibitor

2012 ◽  
Vol 56 (11) ◽  
pp. 5865-5874 ◽  
Author(s):  
Nachum Kaplan ◽  
Monique Albert ◽  
Donald Awrey ◽  
Elias Bardouniotis ◽  
Judd Berman ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Fatty Acid Biosynthesis ◽  
Acyl Carrier Protein ◽  
Pharmacokinetic Studies ◽  
Coagulase Negative Staphylococci ◽  
Resistance Development ◽  
Content Type ◽  
Peritoneal Infection

ABSTRACTThe mechanism of action of AFN-1252, a selective inhibitor ofStaphylococcus aureusenoyl-acyl carrier protein reductase (FabI), which is involved in fatty acid biosynthesis, was confirmed by using biochemistry, macromolecular synthesis, genetics, and cocrystallization of an AFN-1252–FabI complex. AFN-1252 demonstrated a low propensity for spontaneous resistance development and a time-dependent reduction of the viability of both methicillin-susceptible and methicillin-resistantS. aureus, achieving a ≥2-log10reduction inS. aureuscounts over 24 h, and was extremely potent against clinical isolates ofS. aureus(MIC90, 0.015 μg/ml) and coagulase-negative staphylococci (MIC90, 0.12 μg/ml), regardless of their drug resistance, hospital- or community-associated origin, or other clinical subgroup. AFN-1252 was orally available in mouse pharmacokinetic studies, and a single oral dose of 1 mg/kg AFN-1252 was efficacious in a mouse model of septicemia, providing 100% protection from an otherwise lethal peritoneal infection ofS. aureusSmith. A median effective dose of 0.15 mg/kg indicated that AFN-1252 was 12 to 24 times more potent than linezolid in the model. These studies, demonstrating a selective mode of action, potentin vitroactivity, andin vivoefficacy, support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.

scholarly journals VT-1161 Dosed Once Daily or Once Weekly Exhibits Potent Efficacy in Treatment of Dermatophytosis in a Guinea Pig Model

2015 ◽  
Vol 59 (4) ◽  
pp. 1992-1997 ◽  
Author(s):  
E. P. Garvey ◽  
W. J. Hoekstra ◽  
W. R. Moore ◽  
R. J. Schotzinger ◽  
L. Long ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Pig Model ◽  
Pharmacokinetic Studies ◽  
Once Daily ◽  
Guinea Pig Model ◽  
Oral Doses

ABSTRACTCurrent therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potentin vitroantifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potentialin vivoefficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizingTrichophyton mentagrophytesand at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P< 0.001) and improvement in clinical scores (P< 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P< 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 μg/ml (or μg/g), at or above the MIC against the isolate used in the model (0.5 μg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.

scholarly journals Splenic Retention of Plasmodium falciparum Gametocytes To Block the Transmission of Malaria

2015 ◽  
Vol 59 (7) ◽  
pp. 4206-4214 ◽  
Author(s):  
Julien Duez ◽  
John P. Holleran ◽  
Papa Alioune Ndour ◽  
Sasdekumar Loganathan ◽  
Pascal Amireault ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Transmission ◽  
Microtiter Plate ◽  
Positive Control ◽  
Microfluidic Chips ◽  
Content Type ◽  
Microtiter Plates ◽  
Parasite Viability

ABSTRACTPlasmodium falciparumis transmitted from humans toAnophelesmosquito vectors via the sexual erythrocytic forms termed gametocytes. Erythrocyte filtration through microsphere layers (microsphiltration) had shown that circulating gametocytes are deformable. Compounds reducing gametocyte deformability would induce their splenic clearance, thus removing them from the blood circulation and blocking malaria transmission. The hand-made, single-sample prototype for microsphiltration was miniaturized to a 96-well microtiter plate format, and gametocyte retention in the microsphere filters was quantified by high-content imaging. The stiffening activity of 40 pharmacological compounds was assessed in microtiter plates, using a small molecule (calyculin) as a positive control. The stiffening activity of calyculin was assessed in spleen-mimetic microfluidic chips and in macrophage-depleted mice. Marked mechanical retention (80% to 90%) of mature gametocytes was obtained in microplates following exposure to calyculin at concentrations with no effect on parasite viability. Of the 40 compounds tested, including 20 antimalarials, only 5 endoperoxides significantly increased gametocyte retention (1.5- to 2.5-fold; 24 h of exposure at 1 μM). Mature gametocytes exposed to calyculin accumulated in microfluidic chips and were cleared from the circulation of macrophage-depleted mice as rapidly as heat-stiffened erythrocytes, thus confirming results obtained using the microsphiltration assay. An automated miniaturized approach to select compounds for their gametocyte-stiffening effect has been established. Stiffening induces gametocyte clearance bothin vitroandin vivo. Based on physiologically validated tools, this screening cascade can identify novel compounds and uncover new targets to block malaria transmission. Innovative applications in hematology are also envisioned.

scholarly journals In VivoPharmacokinetics and Pharmacodynamics of APX001 againstCandidaspp. in a Neutropenic Disseminated Candidiasis Mouse Model

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Brian VanScoy ◽  
Justin C. Bader ◽  
Karen Marchillo ◽  
...  
Keyword(s):  
Dose Fractionation ◽  
Coefficient Of Determination ◽  
Maximum Effect ◽  
Pharmacokinetic Studies ◽  
Maximum Plasma ◽  
Time Curve ◽  
Content Type ◽  
Disseminated Candidiasis

ABSTRACTAPX001 is the prodrug of APX001A, which is a first-in-class small molecule with a unique mechanism of action that inhibits the fungal enzyme Gwt1 in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model forCandida albicans(n= 5),C. glabrata(n= 5), andC. auris(n= 4). MIC values ranged from 0.002 to 0.03 mg/liter forC. albicans, from 0.008 to 0.06 mg/liter forC. glabrata, and from 0.004 to 0.03 mg/liter forC. auris. Plasma APX001A pharmacokinetic measurements were performed in mice after oral administration of 4, 16, 64, and 256 mg/kg of body weight APX001. Single-dose pharmacokinetic studies exhibited maximum plasma concentration (Cmax) values of 0.46 to 15.6 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC0–inf) values of 0.87 to 70.0 mg · h/liter, and half-lives of 1.40 to 2.75 h. A neutropenic murine disseminated candidiasis model was utilized for all treatment studies, and drug dosing was by the oral route. Dose fractionation was performed againstC. albicansK1, with total doses ranging from 4 to 1,024 mg/kg/day of APX001 fractionated into regimens of dosing every 3, 6, 8, and 12 h for a 24-h treatment duration. Nonlinear regression analysis was used to determine which PK/PD index best correlated with efficacy on the basis of the reduction in the number of CFU/kidney at 24 h. The 24-h free-drug AUC/MIC ratio (fAUC0–24/MIC) was the PK/PD index that best correlated with efficacy (coefficient of determination [R2] = 0.88). Treatment studies with the remaining strains utilized regimens of 1 to 256 mg/kg of APX001 administered every 6 h for a 24-h duration withC. albicansand a 96-h study duration withC. glabrataandC. auris. The dose required to achieve 50% of the maximum effect (ED50) and stasisfAUC/MIC targets were as follows: forC. albicans, 3.67 ± 3.19 and 20.60 ± 6.50, respectively; forC. glabrata, 0.38 ± 0.21 and 1.31 ± 0.27, respectively; and forC. auris, 7.14 ± 4.54 and 14.67 ± 8.30, respectively. The present studies demonstratedin vitroandin vivoAPX001A and APX001 potency, respectively, againstC. albicans,C. glabrata, andC. auris.These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC/MIC ratio target forC. glabratasuggests that species-specific susceptibility breakpoints should be explored.

Comparison of Specific Antibody, D-Phe-Pro-Arg-CH2Cl and Aprotinin for Prevention of In Vitro Effects of Recombinant Tissue-Type Plasminogen Activator on Haemostasis Parameters

1987 ◽  
Vol 58 (03) ◽  
pp. 921-926 ◽  
Author(s):  
E Seifried ◽  
P Tanswell
Keyword(s):  
Specific Antibody ◽  
Plasma Concentrations ◽  
Fibrinolytic Therapy ◽  
Tissue Type ◽  
Control Value ◽  
Type Plasminogen Activator ◽  
In Vitro Effects ◽  
Fibrinolytic Parameters

SummaryIn vitro, concentration-dependent effects of rt-PA on a range of coagulation and fibrinolytic assays in thawed plasma samples were investigated. In absence of a fibrinolytic inhibitor, 2 μg rt-PA/ml blood (3.4 μg/ml plasma) caused prolongation of clotting time assays and decreases of plasminogen (to 44% of the control value), fibrinogen (to 27%), α2-antiplasmin (to 5%), FV (to 67%), FVIII (to 41%) and FXIII (to 16%).Of three inhibitors tested, a specific polyclonal anti-rt-PA antibody prevented interferences in all fibrinolytic and most clotting assays. D-Phe-Pro-Arg-CH2Cl (PPACK) enabled correct assays of fibrinogen and fibrinolytic parameters but interfered with coagulometric assays dependent on endogenous thrombin generation. Aprotinin was suitable only for a restricted range of both assay types.Most in vitro effects were observed only with rt-PA plasma concentrations in excess of therapeutic values. Nevertheless it is concluded that for clinical application, collection of blood samples on either specific antibody or PPACK is essential for a correct assessment of in vivo effects of rt-PA on the haemostatic system in patients undergoing fibrinolytic therapy.

The Role of nitro (NO2-), chloro (Cl), and fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds

2020 ◽  
Vol 21 ◽  
Author(s):  
Boniface Pone ◽  
Ferreira Igne Elizabeth
Keyword(s):  
Chagas Disease ◽  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Pharmacokinetic Studies ◽  
Scientific Publications ◽  
Antitrypanosomal Activity ◽  
Chemical Groups

: Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas disease are among the most severe NTDs, and are caused by the Leishmania sp, and Trypanosoma cruzi, respectively. Glucantime, pentamidine and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance, and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, which chemical groups are known to improve the biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluoro-synthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth to mention that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro- and chloro-groups in the compound backbone. All in all, nitro and h0alogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts on in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies, and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

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