Piperazine-modified ketoconazole derivatives show increased activity against fungal and trypanosomatid pathogens
ChemMedChem. 2022 Sep 17. doi: 10.1002/cmdc.202200385. Online ahead of print.ABSTRACTKetoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ' efficacy and safety no longer justify its use as a first-line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we s...
Source: ChemMedChem - September 17, 2022 Category: Chemistry Authors: Ond řej Štěpánek Ad éla Čmoková Eli ška Procházková Val éria Grobárová Jan Černý Martina Sklapni čková Alena Panicucci Z íková Miroslav Kola řík Ondrej Baszczynski Source Type: research
Piperazine-modified ketoconazole derivatives show increased activity against fungal and trypanosomatid pathogens
ChemMedChem. 2022 Sep 17. doi: 10.1002/cmdc.202200385. Online ahead of print.ABSTRACTKetoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ' efficacy and safety no longer justify its use as a first-line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we s...
Source: ChemMedChem - September 17, 2022 Category: Chemistry Authors: Ond řej Štěpánek Ad éla Čmoková Eli ška Procházková Val éria Grobárová Jan Černý Martina Sklapni čková Alena Panicucci Z íková Miroslav Kola řík Ondrej Baszczynski Source Type: research
Piperazine-modified ketoconazole derivatives show increased activity against fungal and trypanosomatid pathogens
ChemMedChem. 2022 Sep 17. doi: 10.1002/cmdc.202200385. Online ahead of print.ABSTRACTKetoconazole (KTZ) is an imidazole drug applied topically to treat numerous skin infections. However, as a systemic antifungal, KTZ' efficacy and safety no longer justify its use as a first-line treatment. Azole conjugates often display higher solubility and better antifungal activities than their parent azoles. Accordingly, we aimed at developing suitable linkers for clickable azole conjugation with a second antifungal molecule, and targeted drug delivery towards improving antifungal activity. For its low price and high availability, we s...
Source: ChemMedChem - September 17, 2022 Category: Chemistry Authors: Ond řej Štěpánek Ad éla Čmoková Eli ška Procházková Val éria Grobárová Jan Černý Martina Sklapni čková Alena Panicucci Z íková Miroslav Kola řík Ondrej Baszczynski Source Type: research
Differential effects of ketoconazole, fluconazole, and itraconazole on the pharmacokinetics of pyrotinib in vitro and in vivo
It has been reported that drug-drug interactions (DDIs) can affect the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of azole antifungal drugs (ketoconazole, fluconazole, and itraconazole) on pyrotinib’s pharmacokinetics, DDIs between pyrotinib and three azoles were studied with Sprague-Dawley (SD) rat liver microsomes in vitro. Additionally, in vivo pyrotinib metabolic experiment was also performed. Twenty-four male SD rats were randomly divided into four groups: the ketoconazole (40 mg/kg), fluconazole (40 mg/kg), itraconazole (40 mg/kg), and the control group. UPLC-MS...
Source: Frontiers in Pharmacology - September 7, 2022 Category: Drugs & Pharmacology Source Type: research
PBPK Model Development, Validation, and Application for Prediction of Eliglustat Drug-Drug Interactions
The objectives of this study were: (1) to develop and validate an eliglustat physiologically based pharmacokinetic (PBPK) model with and without drug interactions, (2) to simulate untested DDI scenarios, and (3) to explore potential dosing flexibility using lower doses of eliglustat (commercially not available). PK data from healthy adults receiving eliglustat with or without interacting drugs were obtained from literature and used for the PBPK model development and validation. The model-predicted single dose and steady-state Cmax and AUC of eliglustat were within 50-150% of the observed values when eliglustat was administ...
Source: Clinical Pharmacology and Therapeutics - September 3, 2022 Category: Drugs & Pharmacology Authors: Siddhee A Sahasrabudhe Shen Cheng Mahmoud Al-Kofahi Jeanine R Jarnes Neal J Weinreb Reena V Kartha Source Type: research
PBPK Model Development, Validation, and Application for Prediction of Eliglustat Drug-Drug Interactions
The objectives of this study were: (1) to develop and validate an eliglustat physiologically based pharmacokinetic (PBPK) model with and without drug interactions, (2) to simulate untested DDI scenarios, and (3) to explore potential dosing flexibility using lower doses of eliglustat (commercially not available). PK data from healthy adults receiving eliglustat with or without interacting drugs were obtained from literature and used for the PBPK model development and validation. The model-predicted single dose and steady-state Cmax and AUC of eliglustat were within 50-150% of the observed values when eliglustat was administ...
Source: Clinical Pharmacology and Therapeutics - September 3, 2022 Category: Drugs & Pharmacology Authors: Siddhee A Sahasrabudhe Shen Cheng Mahmoud Al-Kofahi Jeanine R Jarnes Neal J Weinreb Reena V Kartha Source Type: research
Familial male-limited precocious puberty (testotoxicosis): Usefulness of treatment with ketoconazole and triptorelin
Med Clin (Barc). 2022 Aug 29:S0025-7753(22)00430-4. doi: 10.1016/j.medcli.2022.08.007. Online ahead of print.NO ABSTRACTPMID:36049976 | DOI:10.1016/j.medcli.2022.08.007 (Source: Medicina Clinica)
Source: Medicina Clinica - September 1, 2022 Category: General Medicine Authors: Emilio Garc ía García Concepci ón Álvarez Del Vayo Luis Casta ño Source Type: research
Cancers, Vol. 14, Pages 4256: An FDA-Approved Antifungal, Ketoconazole, and Its Novel Derivative Suppress tGLI1-Mediated Breast Cancer Brain Metastasis by Inhibiting the DNA-Binding Activity of Brain Metastasis-Promoting Transcription Factor tGLI1
as
Roy Strowd
Hui-Wen Lo
The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-p...
Source: Cancers - August 31, 2022 Category: Cancer & Oncology Authors: Daniel Doheny Sara Manore Sherona R. Sirkisoon Dongqin Zhu Noah R. Aguayo Alexandria Harrison Mariana Najjar Marlyn Anguelov Anderson O ’Brien Cox Cristina M. Furdui Kounosuke Watabe Thomas Hollis Alexandra Thomas Roy Strowd Hui-Wen Lo Tags: Article Source Type: research
Cushing ’s disease: adrenal steroidogenesis inhibitors
AbstractCushing ’s disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, is the most common form of Cushing’s syndrome (CS), accounting for approximately 70% of cases. CD requires a prompt diagnosis, an adequate treatment selection, and long-term management to limit hypercorti solism duration and long-term complications and improve patient outcomes. Pituitary surgery is the first-line option, which is non-curative in one third of patients, therefore requiring additional treatments. Medical therapy has recently acquired an emerging role, with the availability of several d rugs with di...
Source: Pituitary - August 29, 2022 Category: Endocrinology Source Type: research
Physiologically based pharmacokinetic modeling of ponatinib to describe drug –drug interactions in patients with cancer
ConclusionsThe PBPK model predicted a significant drug interaction when ponatinib was combined with a strong CYP3A4 inducer. Conversely, the combination with weak-to-strong CYP3A4 inhibitors did not suggest a drug interaction with ponatinib. (Source: Cancer Chemotherapy and Pharmacology)
Source: Cancer Chemotherapy and Pharmacology - August 23, 2022 Category: Cancer & Oncology Source Type: research
Evidence for Metabolic Activation of Omeprazole In Vitro and In Vivo
This study aimed to identify reactive metabolites of OPZ, determine the pathways of the metabolic activation, and define the correlation of the bioactivation with OPZ cytotoxicity. Quinone imine-derived glutathione (GSH), N-acetylcysteine (NAC), and cysteine (Cys) conjugates were detected in OPZ-fortified rat and human liver microsomal incubations captured with GSH, NAC, or Cys. The same GSH conjugates were detected in bile of rats and cultured liver primary cells after exposure to OPZ. Similarly, the same NAC conjugates were detected in urine of OPZ-treated rats. The resulting quinone imine was found to react with Cys res...
Source: Cell Research - August 22, 2022 Category: Cytology Authors: Yanjia Zhao Chen Sun Mengdie Su Junzu Shi Zixia Hu Ying Peng Jiang Zheng Source Type: research
Simulation of Intraluminal Performance of Lipophilic Weak Bases in Fasted Healthy Adults Using DDDPlusTM
AbstractThe majority of drug candidates exhibit weakly basic characteristics with high lipophilicity. The risk of intraluminal compound precipitation has been studiedin vivo and extensivelyin vitro using advanced dissolution transfer setups mimicking drug transfer from the stomach to the small intestine. The present investigation aims to evaluate the usefulness of the recently introduced Artificial Stomach-Duodenumin silico tool in the DDDPlusTM platform (ASD-D+) to simulate intraluminal drug behavior. The weakly basic drugs ketoconazole and dipyridamole were used as model drugs within the ASD-D+ model at two dose levels. ...
Source: The AAPS Journal - August 16, 2022 Category: Drugs & Pharmacology Source Type: research
An Overview of the Diagnosis and Management of Seborrheic Dermatitis
Clin Cosmet Investig Dermatol. 2022 Aug 6;15:1537-1548. doi: 10.2147/CCID.S284671. eCollection 2022.ABSTRACTSeborrheic dermatitis (SD) is a common chronic inflammatory skin disorder that mostly affects young adults in areas rich in sebaceous glands (scalp, face, and trunk). In adolescents and adults, SD clinical presentation may range from mild patches to diffuse scalp scaling. In infants, it mainly occurs on the scalp as yellowish, scaly patches ("cradle cap"). In adults, several environmental triggers are likely to promote SD development, along with fungal colonization by Malassezia spp., sebaceous gland activity, as wel...
Source: Clinical, Cosmetic and Investigational Dermatology - August 15, 2022 Category: Dermatology Authors: Federica Dall'Oglio Maria Rita Nasca Carlo Gerbino Giuseppe Micali Source Type: research
Global Consumption Trend of Antifungal Agents in Humans From 2008 to 2018: Data From 65 Middle- and High-Income Countries
CONCLUSION: Global consumption of triazoles and terbinafine has gradually increased in middle- and high-income countries. Life-saving antifungal agents, including echinocandins and polyenes, are available only parenterally and may be underutilized, mainly in middle-income countries. Future research on country-specific epidemiology is warranted to guide health policy coordination to ensure equitable access to appropriate use of antifungal agents.PMID:35960433 | DOI:10.1007/s40265-022-01751-x (Source: Cancer Control)
Source: Cancer Control - August 12, 2022 Category: Cancer & Oncology Authors: Swathi Pathadka Vincent K C Yan Chin Fen Neoh Daoud Al-Badriyeh David C M Kong Monica A Slavin Benjamin J Cowling Ivan F N Hung Ian C K Wong Esther W Chan Source Type: research
