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https://www.readbyqxmd.com/read/28924630/role-of-in-vitro-release-methods-in-liposomal-formulation-development-challenges-and-regulatory-perspective
#1
Deepak Solomon, Nilesh Gupta, Nihal S Mulla, Snehal Shukla, Yadir A Guerrero, Vivek Gupta
In the past few years, measurement of drug release from pharmaceutical dosage forms has been a focus of extensive research because the release profile obtained in vitro can give an indication of the drug's performance in vivo. Currently, there are no compendial in vitro release methods designed for liposomes owing to a range of experimental challenges, which has created a major hurdle for both development and regulatory acceptance of liposome-based drug products. In this paper, we review the current techniques that are most often used to assess in vitro drug release from liposomal products; these include the membrane diffusion techniques (dialysis, reverse dialysis, fractional dialysis, and microdialysis), the sample-and-separate approach, the in situ method, the continuous flow, and the modified United States Pharmacopeia methods (USP I and USP IV)...
September 18, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28905273/early-to-long-term-alterations-of-cns-barriers-after-traumatic-brain-injury-considerations-for-drug-development
#2
Beatriz Rodriguez-Grande, Aleksandra Ichkova, Sighild Lemarchant, Jerome Badaut
Traumatic brain injury (TBI) is one of the leading causes of death and disability, particularly amongst the young and the elderly. The functions of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are strongly impaired after TBI, thus affecting brain homeostasis. Following the primary mechanical injury that characterizes TBI, a secondary injury develops over time, including events such as edema formation, oxidative stress, neuroinflammation, and alterations in paracelullar and transcellular transport...
September 13, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28895093/sirna-mediated-rna-interference-in-precision-cut-tissue-slices-prepared-from-mouse-lung-and-kidney
#3
Mitchel J R Ruigrok, Nalinie Maggan, Delphine Willaert, Henderik W Frijlink, Barbro N Melgert, Peter Olinga, Wouter L J Hinrichs
Small interfering RNA (siRNA)-mediated RNAi interference (RNAi) is a powerful post-transcriptional gene silencing mechanism which can be used to study the function of genes in vitro (cell cultures) and in vivo (animal models). However, there is a translational gap between these models. Hence, there is a need for novel experimental models that combine the advantages of in vitro and in vivo models (e.g., simplicity, flexibility, throughput, and representability) to study the effects of siRNA. This need may be addressed by precision-cut tissue slices (PCTS), which represent an ex vivo model that mimics the structural and functional characteristics of a whole organ...
September 11, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28895080/population-pharmacokinetic-and-pharmacodynamic-modeling-of-artemisinin-resistance-in-southeast-asia
#4
Jesmin Lohy Das, Arjen M Dondorp, Francois Nosten, Aung Pyae Phyo, Warunee Hanpithakpong, Pascal Ringwald, Pharath Lim, Nicholas J White, Mats O Karlsson, Martin Bergstrand, Joel Tarning
Orally administered artemisinin-based combination therapy is the first-line treatment against uncomplicated P. falciparum malaria worldwide. However, the increasing prevalence of artemisinin resistance is threatening efforts to treat and eliminate malaria in Southeast Asia. This study aimed to characterize the exposure-response relationship of artesunate in patients with artemisinin sensitive and resistant malaria infections. Patients were recruited in Pailin, Cambodia (n = 39), and Wang Pha, Thailand (n = 40), and received either 2 mg/kg/day of artesunate mono-therapy for 7 consecutive days or 4 mg/kg/day of artesunate monotherapy for 3 consecutive days followed by mefloquine 15 and 10 mg/kg for 2 consecutive days...
September 11, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28895076/new-botanical-anxiolytics-for-use-in-companion-animals-and-humans
#5
Rui Liu, Fida Ahmed, Christian Cayer, Martha Mullally, Ana Francis Carballo, Marco Otarola Rojas, Mario Garcia, John Baker, Aleksandar Masic, Pablo E Sanchez, Luis Poveda, Zul Merali, Tony Durst, John T Arnason
As part of our ongoing research into botanical therapies for anxiety disorders, the neotropical vine Souroubea sympetala was chosen for study as a phytochemical discovery strategy focusing on rare Central American plant families. When orally administered to male Sprague-Dawley rats, the crude plant extract, its ethyl acetate fraction, supercritical carbon dioxide fraction, or its isolated triterpenes reduced anxiety and/or fear-related behavior in standardized behavioral models. Pharmacological studies showed that the extracts acted at the benzodiazepine GABAA receptor and reduced corticosterone levels...
September 11, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28879628/in-vitro-approaches-to-support-bioequivalence-and-substitutability-of-generic-proton-pump-inhibitors-via-nasogastric-tube-administration
#6
Ping Ren, Minglei Cui, Om Anand, Li Xia, Zhuojun J Zhao, Dajun Sun, Trueman Sharp, Dale P Conner, John Peters, Wenlei Jiang, Ethan Stier, Xiaojian Jiang
Administration of proton pump inhibitors (PPIs) through nasogastric tubes may present risks. If the PPI drug products are not prepared properly, clogging or obstruction of nasogastric tubes can pose a safety concern. In addition, the integrity of the enteric coating of the drug product may be damaged resulting in reduced bioavailability of the active moiety. From the perspective of administration of generic PPIs when compared to the reference drug product, differences in formulation can potentially result in a greater relative risk for the generic drug product...
September 6, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28875479/development-of-an-enantioselective-and-biomarker-informed-translational-population-pharmacokinetic-pharmacodynamic-model-for-etodolac
#7
Carolina de Miranda Silva, Adriana Rocha, Eduardo Tozatto, Lucienir Maria da Silva, Eduardo Antônio Donadi, Teresa Dalla Costa, Vera Lucia Lanchote, Stephan Schmidt, Jürgen B Bulitta
Cyclooxygenase-2 (COX-2) isoform has a critical role in the development of pain. Inhibition of COX-2 in vitro serves as a biomarker for nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAID concentrations yielding 80% COX-2 inhibition (IC80) correlate with therapeutic doses to achieve analgesia across multiple COX-2 inhibitors. However, there are no time-course models relating COX-2 inhibition with decreased pain. This study aimed to characterize the relationship between NSAID concentrations, in vitro COX-2 inhibition, and acute pain decrease in humans over time by a translational approach using clinical pharmacokinetic and literature reported in vitro and clinical pharmacodynamic data...
September 5, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28875358/determination-of-critical-quality-attributes-for-a-biotherapeutic-in-the-qbd-paradigm-gcsf-as-a-case-study
#8
Sumit K Singh, Deepak Kumar, Anurag S Rathore
Estimating impact of the various product-related variants and impurities on a biotherapeutic's safety and efficacy is an essential requirement in the quality by design paradigm. In view of the limited role that clinical studies offer in this regard, we demonstrate a preclinical approach to achieve this for granulocyte colony-stimulating factor (GCSF). While our repeated-dose toxicity data suggest that these variants do not elicit any adverse effects or histopathological changes, aggregated GCSF impurity caused sluggishness in animal behavior manifested by a possible muscular injury...
September 5, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28853055/quantification-of-the-pharmacodynamic-interaction-of-morphine-and-gabapentin-using-a-response-surface-approach
#9
Theodoros Papathanasiou, Rasmus Vestergaard Juul, Charlotte Gabel-Jensen, Mads Kreilgaard, Anne-Marie Heegaard, Trine Meldgaard Lund
The combination of morphine and gabapentin has shown to be promising for managing postoperative pain but finding the right dose for the combination has proven to be a challenge. The purpose of this study was to quantitatively characterize the pharmacodynamic interaction between the two drugs and to identify the optimal concentration-effect relationship of the combination. Information regarding plasma concentrations and von Frey withdrawal thresholds following incisional surgery on Sprague Dawley rats, after administration of morphine, gabapentin, or their combination was available from published studies...
August 29, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28849396/investigation-of-the-influence-of-protein-losing-enteropathy-on-monoclonal-antibody-pharmacokinetics-in-mice
#10
Yujie Yang, Tommy R Li, Joseph P Balthasar
Protein losing enteropathy (PLE), which is characterized by substantial loss of plasma proteins into the gastrointestinal (GI) tract, is a complication of a variety of GI diseases, including inflammatory bowel disease. Clinical studies have found that the clearance of monoclonal antibodies (mAb) is often increased in subjects with diseases known to cause PLE; however, direct relationships between PLE and mAb pharmacokinetics have not been demonstrated. This study employed a murine model of colitis to examine the influence of PLE on mAb pharmacokinetics...
August 28, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28842850/a-flavonoid-glycoside-compound-from-murraya-paniculata-l-interrupts-metastatic-characteristics-of-a549-cells-by-regulating-stat3-nf-%C3%AE%C2%BAb-cox-2-and-egfr-signaling-pathways
#11
Qing Shi, Zhou Jiang, Jingyi Yang, Yunlong Cheng, Yaqiong Pang, Ning Zheng, Jiahang Chen, Wenge Chen, Lee Jia
Metastasis remains the leading cause of death from lung carcinoma. It is urgent to find safe and efficient pre-metastasis preventive agents for cancer survivors. We isolated a flavonoid glycoside, hexamethoxy flavanone-o-[rhamnopyranosyl-(1 → 4)-rhamnopyranoside (HMFRR), from the traditional Chinese medicine (TCM) Murraya paniculata (L.) that can effectively inhibit the adhesion, migration, and invasion of lung adenocarcinoma A549 cells in vitro. Molecular and cellular studies demonstrated that HMFRR significantly downregulated the expressions of cell adhesion-related and invasion-related molecules such as integrin β1, EGFR, COX-2, MMP-2, and MMP-9 proteins...
August 25, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28831727/approaches-for-establishing-clinically-relevant-dissolution-specifications-for-immediate-release-solid-oral-dosage-forms
#12
Andre Hermans, Andreas M Abend, Filippos Kesisoglou, Talia Flanagan, Michael J Cohen, Dorys A Diaz, Y Mao, Limin Zhang, Gregory K Webster, Yiqing Lin, David A Hahn, Carrie A Coutant, Haiyan Grady
This manuscript represents the perspective of the Dissolution Analytical Working Group of the IQ Consortium. The intent of this manuscript is to highlight the challenges of, and to provide a recommendation on, the development of clinically relevant dissolution specifications (CRS) for immediate release (IR) solid oral dosage forms. A roadmap toward the development of CRS for IR products containing active ingredients with a non-narrow therapeutic window is discussed, within the context of mechanistic dissolution understanding, supported by in-human pharmacokinetic (PK) data...
August 22, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28828752/dibenzoylmethane-protects-against-ccl4-induced-acute-liver-injury-by-activating-nrf2-via-jnk-ampk-and-calcium-signaling
#13
Mingnan Cao, Huixia Wang, Limei Guo, Simin Yang, Chun Liu, Tin Oo Khor, Siwang Yu, Ah-Ng Kong
Oxidative stress is an important pathogenic factor in various hepatic diseases. Nuclear factor-erythroid 2-related factor-2 (Nrf2), which coordinates the expression of an array of antioxidant and detoxifying genes, has been proposed as a potential target for prevention and treatment of liver disease. Dibenzoylmethane (DBM) is a minor ingredient in licorice that activates Nrf2 and prevents various cancers and oxidative damage. In the present study, the mechanisms by which DBM activates Nrf2 signaling were delineated, and its protective effect against carbon tetrachloride (CCl4)-induced liver injury was examined...
August 21, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28828691/pharmacokinetics-of-mephedrone-and-its-metabolites-in-human-by-lc-ms-ms
#14
Eulàlia Olesti, Magí Farré, Esther Papaseit, Aristotelis Krotonoulas, Mitona Pujadas, Rafael de la Torre, Óscar J Pozo
Mephedrone is a synthetic cathinone consumed as a recreational drug. Recently, it was identified several of its metabolites in vivo in humans but there is little information about its pharmacokinetics in plasma and urine. Although several analytical methods have been proposed for mephedrone quantification in different matrices, none are available for its metabolites. Therefore, the aim of the study was to develop and validate an analytical method using liquid chromatography-tandem mass spectrometry for the quantification of mephedrone, nor-mephedrone, N-succinyl-nor-mephedrone, 1'-dihydro-mephedrone, and 4'-carboxy-mephedrone...
August 21, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28808917/development-of-a-translational-physiologically-based-pharmacokinetic-model-for-antibody-drug-conjugates-a-case-study-with-t-dm1
#15
Antari Khot, Jay Tibbitts, Dan Rock, Dhaval K Shah
Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i...
August 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28795351/advancements-in-understanding-immunogenicity-of-biotherapeutics-in-the-intraocular-space
#16
Eric Wakshull, Valerie Quarmby, Hanns-Christian Mahler, Hongwen Rivers, Dhananjay Jere, Meg Ramos, Piotr Szczesny, Karoline Bechtold-Peters, Sharmila Masli, Swati Gupta
Therapeutic breakthroughs in a number of retinal degenerative diseases have come about through the development of biotherapeutics administered directly into the eye. As a consequence of their use, we have gained more insight into the immune privileged status of the eye and the various considerations that development, manufacturing, and use of these drugs require. It has been observed that therapeutic proteins injected into the vitreous can elicit an immune response resulting in the production of anti-drug antibodies (ADAs) which can have clinical consequences...
August 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28791599/comparison-of-nmr-and-dynamic-light-scattering-for-measuring-diffusion-coefficients-of-formulated-insulin-implications-for-particle-size-distribution%C3%A2-measurements-in-drug-products
#17
Sharadrao M Patil, David A Keire, Kang Chen
Particle size distribution, a measurable physicochemical quantity, is a critical quality attribute of drug products that needs to be controlled in drug manufacturing. The non-invasive methods of dynamic light scattering (DLS) and Diffusion Ordered SpectroscopY (DOSY) NMR can be used to measure diffusion coefficient and derive the corresponding hydrodynamic radius. However, little is known about their use and sensitivity as analytical tools for particle size measurement of formulated protein therapeutics. Here, DLS and DOSY-NMR methods are shown to be orthogonal and yield identical diffusion coefficient results for a homogenous monomeric protein standard, ribonuclease A...
August 8, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28779380/peripheral-nerve-nanoimaging-monitoring-treatment-and-regeneration
#18
Jelena M Janjic, Vijay S Gorantla
Accidental and iatrogenic trauma are major causes of peripheral nerve injury. Healing after nerve injury is complex and often incomplete, which can lead to acute or chronic pain and functional impairment. Current assessment methods for nerve regeneration lack sensitivity and objectivity. There is a need for reliable and reproducible, noninvasive strategies with adequate spatial and temporal resolution for longitudinal evaluation of degeneration or regeneration after injury/treatment. Methods for noninvasive monitoring of the efficacy and effectiveness of neurotherapeutics in nerve regeneration or of neuropathic pain are needed to ensure adequacy and responsiveness to management, especially given the large variability in the patient populations, etiologies, and complexity of nerve injuries...
August 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28779379/submicron-matrices-embedded-in-a-polymeric-caplet-for-extended-intravaginal-delivery-of-zidovudine
#19
Felix Mashingaidze, Yahya E Choonara, Pradeep Kumar, Lisa C du Toit, Vinesh Maharaj, Eckhart Buchmann, Viness Pillay
In this study, an intravaginal delivery system able to deliver an anti-HIV-1 agent for the purpose of potentially reducing HIV-1 transmission acting over an extended duration was successfully formulated. This delivery system was a composite polymeric caplet comprising zidovudine-loaded polyethylene glycol enclatherated pectin-mucin submicron matrices embedded within a poly (D,L-lactide), magnesium stearate, Kollidon® SR, and Carbopol® 974P NF-based polymeric caplet matrix. A three-factor and three-level Box-Behnken statistical design was utilized to optimize the polymeric caplet...
August 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28779378/blood-brain-barrier-driven-pharmacoresistance-in-amyotrophic-lateral-sclerosis-and-challenges-for-effective-drug-therapies
#20
Loqman A Mohamed, Shashirekha Markandaiah, Silvia Bonanno, Piera Pasinelli, Davide Trotti
The blood-brain barrier (BBB) is essential for proper neuronal function, homeostasis, and protection of the central nervous system (CNS) microenvironment from blood-borne pathogens and neurotoxins. The BBB is also an impediment for CNS penetration of drugs. In some neurologic conditions, such as epilepsy and brain tumors, overexpression of P-glycoprotein, an efflux transporter whose physiological function is to expel catabolites and xenobiotics from the CNS into the blood stream, has been reported. Recent studies reported that overexpression of P-glycoprotein and increase in its activity at the BBB drives a progressive resistance to CNS penetration and persistence of riluzole, the only drug approved thus far for treatment of amyotrophic lateral sclerosis (ALS), rapidly progressive and mostly fatal neurologic disease...
August 4, 2017: AAPS Journal
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