Review on Arakoda (Tafenoquine) and its approach as an Anti-Malarial Agent.

2021 ◽  
pp. 2336-2340
Author(s):  
Syeda Sana ◽  
Mohsina Abed
Keyword(s):  
Plasmodium Species ◽  
Pharmacokinetic Interaction ◽  
Volume Of Distribution ◽  
Molecular Formula ◽  
Liver Stage ◽  
Antimalarial Agents ◽  
Plasmodium Vivax Malaria ◽  
Long Acting ◽  
Cyp 2D6

Tafenoquine is an analogue of primaquine with an improved therapeutic and safety profile. It has a long half-life and activity against liver-stage malaria parasites, so may be useful for chemoprophylaxis. Antimalarial agents are drugs used for the treatment or prophylaxis of malaria. Malaria is caused by four species of Plasmodium, such as Plasmodium falciparum, P. malariae, P. ovale, and P. vivax. Arakoda contains tafenoquine succinate, an antimalarial agent for oral administration. The molecular formula of tafenoquine succinate is C24H28F3N3O3∙C4H6O4 and its molecular weight is 581.6 as the succinate salt. It is given in prophylaxis of malaria patient aged 18 years older. Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of Plasmodium species. G6PD test is performed before giving the drug. Analytical studies were on NMR, IR, MS, HPLC, Flourimetry analysis. In vitro studies have shown that tafenoquine presents an average 50% inhibitory concentration of 0.436mcg against blood stages of seven strains of P. falciparum. The long‐acting 8‐aminoquinoline tafenoquine (TQ) co-administered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Volume of distribution. The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. Routes of elimination are through feces.

THYROID STIMULATORS AND THYROID STIMULATION

1971 ◽  
Vol 66 (3) ◽  
pp. 558-576 ◽  
Author(s):  
Gerald Burke
Keyword(s):  
Regulatory System ◽  
Control Site ◽  
Thyroid Cell ◽  
Primary Control ◽  
Physico Chemical ◽  
Site Of Action ◽  
Long Acting

ABSTRACT A long-acting thyroid stimulator (LATS), distinct from pituitary thyrotrophin (TSH), is found in the serum of some patients with Graves' disease. Despite the marked physico-chemical and immunologic differences between the two stimulators, both in vivo and in vitro studies indicate that LATS and TSH act on the same thyroidal site(s) and that such stimulation does not require penetration of the thyroid cell. Although resorption of colloid and secretion of thyroid hormone are early responses to both TSH and LATS, available evidence reveals no basic metabolic pathway which must be activated by these hormones in order for iodination reactions to occur. Cyclic 3′, 5′-AMP appears to mediate TSH and LATS effects on iodination reactions but the role of this compound in activating thyroidal intermediary metabolism is less clear. Based on the evidence reviewed herein, it is suggested that the primary site of action of thyroid stimulators is at the cell membrane and that beyond the(se) primary control site(s), there exists a multifaceted regulatory system for thyroid hormonogenesis and cell growth.

Small Molecules Effective Against Liver and Blood Stage Malarial Infection

2019 ◽  
Vol 18 (23) ◽  
pp. 2008-2021 ◽  
Author(s):  
Snigdha Singh ◽  
Neha Sharma ◽  
Charu Upadhyay ◽  
Sumit Kumar ◽  
Brijesh Rathi ◽  
...  
Keyword(s):  
Drug Targets ◽  
Malaria Parasite ◽  
Blood Stage ◽  
Culture Methods ◽  
Liver Stage ◽  
Malarial Infection ◽  
Dual Stage ◽  
New Treatment ◽  
Global Threat

Malaria is a lethal disease causing devastating global impact by killing more than 8,00,000 individuals yearly. A noticeable decline in malaria related deaths can be attributed to the most reliable treatment, ACTs against P. falciparum. However, the cumulative resistance of the malaria parasite against ACTs is a global threat to control the disease and, therefore the new effective therapeutics are urgently needed, including new treatment approaches. Majority of the antimalarial drugs target BS malarial infection. Currently, scientists are eager to explore the drugs with potency against not only BS but other life stages such as sexual and asexual stages of the malaria parasite. Liver Stage is considered as one of the important drug targets as it always leads to BS and the infection can be cured at this stage before it enters into the Blood Stage. However, a limited number of compounds are reported effective against LS malaria infection probably due to scarcity of in vitro LS culture methods and clinical possibilities. This mini review covers a range of chemical compounds showing efficacy against BS and LS of the malaria parasite’s life cycle collectively (i.e. dual stage activity). These scaffolds targeting dual stages are essential for the eradication of malaria and to evade resistance.

Discovery of 3-Cinnamamido-N-Substituted Benzamides as Potential Antimalarial Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Haicheng Liu ◽  
Yushi Futamura ◽  
Honghai Wu ◽  
Aki Ishiyama ◽  
Taotao Zhang ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antimalarial Activity ◽  
In Vitro Assays ◽  
Compound Library ◽  
Antimalarial Agents ◽  
Phenotypic Screen ◽  
Ic50 Values ◽  
Substituted Benzamides

Background: Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear. Objective: This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3-cinnamamido-N-substituted benzamides. Method: In this study, a screening of our compound library was carried out against the multidrug-sensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters’ 4-day suppressive test. Results: The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC50 = 1.20 µM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC50 values of approximately 0.1 µM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective which might be ascribed to the poor solubility of these compounds. Conclusion: In this study, phenotypic screen of our compound library resulted in the first report of 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against P. falciparum 3D7 strain with IC50 values around 0.1 µM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.

Design and Evaluation of Long Acting Biodegradable PLGA Microspheres for Ocular Drug Delivery

2019 ◽  
Vol 10 ◽  
Author(s):  
Anjali Pandya ◽  
Rajani Athawale ◽  
Durga Puro ◽  
Geeta Bhagwat
Keyword(s):  
Particle Size ◽  
Drug Release ◽  
Degradation Products ◽  
Ex Vivo ◽  
Research Work ◽  
Entrapment Efficiency ◽  
Rational Approach ◽  
Plga Microspheres ◽  
Long Acting

Background: The research work involves development of PLGA biodegradable microspheres loaded with dexamethasome for intraocular delivery. Objective: To design and evaluate long acting PLGA microspheres for ocular delivery of dexamethasone. Method: Present formulation involves the development of long acting dexamethasone loaded microspheres composed of a biodegradable controlled release polymer, Poly(D, L- lactide-co-glycolide) (PLGA), for the treatment of posterior segment eye disorders intravitreally. PLGA with monomer ratio of 50:50 of lactic acid to glycolic acid was used to achieve a drug release up to 45 days. Quality by Design approach was utilized for designing the experiments. Single emulsion solvent evaporation technique along with high pressure homogenization was used to facilitate formation of microspheres. Results: Particle size evaluation, drug content and drug entrapment efficiency were determined for the microspheres. Particle size and morphology was observed using Field Emission Gun-Scanning Electron Microscopy (FEG-SEM) and microspheres were in the size range of 1-5 μm. Assessment of drug release was done using in vitro studies and transretinal permeation was observed by ex vivo studies using goat retinal tissues. Conclusion: Considering the dire need for prolonged therapeutic effect in diseases of the posterior eye, an intravitreal long acting formulation was designed. Use of biodegradable polymer with biocompatible degradation products was a rational approach to achieve this aim. Outcome from present research shows that developed microspheres would provide a long acting drug profile and reduce the frequency of administration thereby improving patient compliance.

scholarly journals Long-Acting Risperidone Dual Control System: Preparation, Characterization and Evaluation In Vitro and In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1210
Author(s):  
Xieguo Yan ◽  
Shiqiang Wang ◽  
Kaoxiang Sun
Keyword(s):  
Drug Loading ◽  
Entrapment Efficiency ◽  
In Vitro Dissolution ◽  
Dissolution Behavior ◽  
In Vivo Evaluation ◽  
Long Term Treatment ◽  
Long Acting

Schizophrenia, a psychiatric disorder, requires long-term treatment; however, large fluctuations in blood drug concentration increase the risk of adverse reactions. We prepared a long-term risperidone (RIS) implantation system that can stabilize RIS release and established in-vitro and in-vivo evaluation systems. Cumulative release, drug loading, and entrapment efficiency were used as evaluation indicators to evaluate the effects of different pore formers, polymer ratios, porogen concentrations, and oil–water ratios on a RIS implant (RIS-IM). We also built a mathematical model to identify the optimized formulation by stepwise regression. We also assessed the crystalline changes, residual solvents, solubility and stability after sterilization, in-vivo polymer degradation, pharmacokinetics, and tissue inflammation in the case of the optimized formulation. The surface of the optimized RIS microspheres was small and hollow with 134.4 ± 3.5 µm particle size, 1.60 SPAN, 46.7% ± 2.3% implant drug loading, and 93.4% entrapment efficiency. The in-vitro dissolution behavior of RIS-IM had zero-order kinetics and stable blood concentration; no lag time was released for over three months. Furthermore, the RIS-IM was not only non-irritating to tissues but also had good biocompatibility and product stability. Long-acting RIS-IMs with microspheres and film coatings can provide a new avenue for treating schizophrenia.

scholarly journals Development of In Situ Self-Assembly Nanoparticles to Encapsulate Lopinavir and Ritonavir for Long-Acting Subcutaneous Injection

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 904
Author(s):  
Irin Tanaudommongkon ◽  
Asama Tanaudommongkon ◽  
Xiaowei Dong
Keyword(s):  
Sustained Release ◽  
Trough Concentration ◽  
Self Assembly ◽  
Subcutaneous Injection ◽  
Drug Loading ◽  
Entrapment Efficiency ◽  
Long Acting

Most antiretroviral medications for human immunodeficiency virus treatment and prevention require high levels of patient adherence, such that medications need to be administered daily without missing doses. Here, a long-acting subcutaneous injection of lopinavir (LPV) in combination with ritonavir (RTV) using in situ self-assembly nanoparticles (ISNPs) was developed to potentially overcome adherence barriers. The ISNP approach can improve the pharmacokinetic profiles of the drugs. The ISNPs were characterized in terms of particle size, drug entrapment efficiency, drug loading, in vitro release study, and in vivo pharmacokinetic study. LPV/RTV ISNPs were 167.8 nm in size, with a polydispersity index of less than 0.35. The entrapment efficiency was over 98% for both LPV and RTV, with drug loadings of 25% LPV and 6.3% RTV. A slow release rate of LPV was observed at about 20% on day 5, followed by a sustained release beyond 14 days. RTV released faster than LPV in the first 5 days and slower than LPV thereafter. LPV trough concentration remained above 160 ng/mL and RTV trough concentration was above 50 ng/mL after 6 days with one subcutaneous injection. Overall, the ISNP-based LPV/RTV injection showed sustained release profiles in both in vitro and in vivo studies.

scholarly journals Ex vivo susceptibility to new antimalarial agents differs among human-infecting Plasmodium species

2021 ◽  
Vol 17 ◽  
pp. 5-11
Author(s):  
Donelly A. van Schalkwyk ◽  
Robert W. Moon ◽  
Maëlle Duffey ◽  
Didier Leroy ◽  
Colin J. Sutherland
Keyword(s):  
Ex Vivo ◽  
Plasmodium Species ◽  
Antimalarial Agents

scholarly journals Poly(l-Lactic Acid)-co-poly(Butylene Adipate) New Block Copolymers for the Preparation of Drug-Loaded Long Acting Injectable Microparticles

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 930
Author(s):  
Vasiliki Karava ◽  
Aggeliki Siamidi ◽  
Marilena Vlachou ◽  
Evi Christodoulou ◽  
Nikolaos D. Bikiaris ◽  
...  
Keyword(s):  
Lactic Acid ◽  
Block Copolymers ◽  
In Vitro Dissolution ◽  
Sem Images ◽  
Exterior Surface ◽  
Erosion Rates ◽  
Cytotoxicity Studies ◽  
Release Data ◽  
Long Acting

The present study evaluates the use of newly synthesized poly(l-lactic acid)-co-poly(butylene adipate) (PLA/PBAd) block copolymers as microcarriers for the preparation of aripiprazole (ARI)-loaded long acting injectable (LAI) formulations. The effect of various PLA to PBAd ratios (95/5, 90/10, 75/25 and 50/50 w/w) on the enzymatic hydrolysis of the copolymers showed increasing erosion rates by increasing the PBAd content, while cytotoxicity studies revealed non-toxicity for all prepared biomaterials. SEM images showed the formation of well-shaped, spherical MPs with a smooth exterior surface and no particle’s agglomeration, while DSC and pXRD data revealed that the presence of PBAd in the copolymers favors the amorphization of ARI. FTIR spectroscopy showed the formation of new ester bonds between the PLA and PBAd parts, while analysis of the MP formulations showed no molecular drug–polyester matrix interactions. In vitro dissolution studies suggested a highly tunable biphasic extended release, for up to 30 days, indicating the potential of the synthesized copolymers to act as promising LAI formulations, which will maintain a continuous therapeutic level for an extended time period. Lastly, several empirical and mechanistic models were also tested, with respect to their ability to fit the experimental release data.

Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4197-4205 ◽  
Author(s):  
J.M. Herbert ◽  
J.P. Hérault ◽  
A. Bernat ◽  
R.G.M. van Amsterdam ◽  
J.C. Lormeau ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Therapeutic Index ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
Treatment And Prevention ◽  
Long Acting

Abstract SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

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