A general and rapid LC-MS/MS method for simultaneous determination of voriconazole, posaconazole, fluconazole, itraconazole and hydroxyitraconazole in IFI patients

Article

作者: Wang, Zhipeng ; Tang, Mao ; Chen, Shun ; Xia, Wenwen ; Cui, Lili ; Hou, Juanjuan ; Tao, Xia ; Gao, Shouhong ; Shao, Rongzi ; Yun, Yunlei ; Bu, Chen

OBJECTIVE:

To establish a rapid and universal quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) method for measuring the exposure levels of five triazole antifungal drugs in human plasma, including voriconazole, fluconazole, posaconazole, itraconazole, and hydroxyitraconazole.

METHODS:

A triple quadrupole mass spectrometer operating in positive ionization mode was used to detect the analyte, and multiple reaction monitoring mode was employed to gather data. The mobile phase included 0.05 % formic acid in water (phase A) and acetonitrile (phase B). The analytes were separated on an Agilent EclipsePlusC₁₈ RRHD column (30 × 50 mm, 1.8 μm) using gradient elution. The flow rate was 0.3 mL/min with the column temperature set at 35 °C. The acetonitrile was used to pretreat the plasma sample, and the itraconazole-D5 and hydroxyitraconazole-D5 were utilized as the internal standards.

RESULTS:

The calibration range was from 100 to 10,000 ng/mL for posaconazole, itraconazole, and hydroxyitraconazole, from 200 to 20,000 ng/mL for fluconazole and from 50 to 5000 ng/mL for voriconazole, with linear correlation coefficients more than 0.99 for all regression curves. The intra- and inter-day accuracy and precision of the method were within ±15 %. The mean extraction recovery of all the analytes ranged from 74.32 % to 117.83 %, and the matrix effect was from 72.54 % to 111.2 %. The results of stability fell into the scope of ±15 % deviation.

CONCLUSION:

This newly developed method is sensitive, simple, and robust, and successfully applied in determining triazole antifungal drugs in plasma from 66 IFI patients to provide reference for safe and effective drug administration in clinical practice.

2024-11-01·JOURNAL OF CHROMATOGRAPHY A

Corrigendum to “Method optimization for a simultaneous determination of neonicotinoid, carbamate/thiocarbamate, triazole, organophosphate and pyrethroid pesticides and their metabolites in urine using UPLC-MS/MS” [Journal of Chromatography A 1730 (2024) 465054]

作者: Bustamante, Carolina M. ; Grimalt, Joan O ; Bustamante, Carolina M ; Ruiz, Paula ; Grimalt, Joan O. ; Bravo, Natalia ; Garí, Mercè

2024-11-01·ANALYTICA CHIMICA ACTA

Ultrasound assisted upper critical solution temperature type switchable deep eutectic solvent based liquid-liquid microextraction for the determination of triazole in water

Article

作者: Yan, Yuan ; Gong, Bincheng ; Chen, Kexian ; Li, Zuguang ; Zhu, Guohua ; Wang, Yu ; Shen, Lingqi

BACKGROUND:

The use of pesticides to protect crops has long been an important measure to provide healthy and safe agricultural products, but excess pesticides flow into fields and rivers, causing environmental pollution. Earlier methods utilizing organic solvent liquid-liquid microextraction for pesticide residue detection were not environmentally friendly. Therefore, it is significant to find a greener and more convenient detection method to determine pesticide residues.

RESULTS:

A new method was established to detect three triazole fungicides (TFs), including myclobutanil, epoxiconazole and tebuconazole, in environmental water samples. And the determination was conducted using a high-performance liquid chromatography with the ultraviolet detector (HPLC-UV). The switchable deep eutectic solvent (SDES) can be reversibly switched between hydrophilic and hydrophobic states through temperature modulation. Additionally, the method exhibited excellent linearity for all target analytes within the concentration range of 10-2000 μg L^-1, with satisfactory R² values (≥0.9975). The limits of detection (LODs) ranged from 2.3 to 2.6 μg L^-1, and the limits of quantification (LOQs) ranged from 7.8 to 8.7 μg L^-1. The accuracy of the method was assessed through intra-day and inter-day precision tests, yielding relative standard deviations (RSDs) in the ranges of 2.8%-6.7% and 2.2%-7.5%, respectively. Density functional theory (DFT) results indicated that hydrogen bonding is a significant factor affecting the binding of DES with triazoles. Three different green assessment tools were used to prove that the SDES-HLLME method had good greenness and broad applicability.

SIGNIFICANCE:

This is a homogeneous liquid-liquid microextraction (HLLME) method based on the upper critical solution temperature (UCST) type switchable deep eutectic solvent program, which can complete the extraction within a few minutes without dispersant. In terms of pesticide detection, the analytical method is simple and more conducive to environmental protection.

项与 PC-1244 相关的新闻（医药）

2024-03-11

·PRNewswire

FDA Grants Orphan Drug and Pediatric Exclusivities for CRESEMBA® (isavuconazonium sulfate) for Invasive Aspergillosis and Invasive Mucormycosis in Children

Designation follows December 2023 FDA approval for the treatment of these serious, potentially life-threatening fungal infections in children CRESEMBA receives seven years and six months of US market exclusivity for these pediatric indications NORTHBROOK, Ill., March 11, 2024 /PRNewswire/ -- Astellas Pharma US, Inc. (TSE: 4503, President: Mark Reisenauer, "Astellas") announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug and pediatric exclusivity to CRESEMBA® (isavuconazonium sulfate) for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM) in pediatric patients. On December 8, 2023, CRESEMBA for injection was approved for pediatric patients 1 year of age and older and capsules for pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater. The FDA grants orphan drug exclusivity to orphan drugs that receive FDA marketing approval. As the first company to obtain FDA approval for the treatment of IA and IM in patients as young as one for a triazole antifungal, Astellas has received orphan drug exclusivity, which provides seven years of exclusive marketing rights for CRESEMBA in those indications beginning from the date of approval of the supplemental New Drug Application on Dec. 8, 2023. Pediatric exclusivity extends that period by another six months. The FDA previously granted orphan drug exclusivity for CRESEMBA in 2015 for the treatment of IA and IM in adults. Laura Kovanda, PhD, Executive Director, Asset Lead, BioPharma Development, Astellas "Astellas recognizes the importance of addressing significant unmet medical needs, especially for pediatric patients with rare and potentially life-threatening IA and IM infections. I am incredibly proud of the Astellas team for advancing research, development and commercialization to offer CRESEMBA to pediatric patients who have limited treatment options." CRESEMBA is the only azole antifungal therapy FDA approved for the treatment of IA and IM in patients as young as one. About Invasive Aspergillosis and Invasive Mucormycosis Invasive aspergillosis can be a life-threatening fungal infection that is seen predominantly in immunocompromised patients, such as patients with leukemia.1 Invasive mucormycosis is a rare and often life-threatening fungal infection.2 IA and IM are a major cause of morbidity and death among immunocompromised and hospitalized pediatric patients.3 About CRESEMBA® (isavuconazonium sulfate) CRESEMBA® (isavuconazonium sulfate) is an azole antifungal indicated for the treatment of invasive aspergillosis and invasive mucormycosis as follows: CRESEMBA for injection: adults and pediatric patients 1 year of age and older CRESEMBA capsules: adults and pediatric patients 6 years of age and older who weigh 16 kg and greater Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy. Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly. Important Safety Information for CRESEMBA (isavuconazonium sulfate) Contraindications CRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole Coadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with CRESEMBA is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John's wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome Warnings and Precautions Hepatic Adverse Drug Reactions (e.g., elevations in ALT, AST, alkaline phosphatase, total bilirubin) have been reported in clinical trials and were generally reversible and did not require discontinuation of CRESEMBA. Cases of severe hepatic adverse drug reactions including hepatitis, cholestasis or hepatic failure including death have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with azole antifungal agents, including CRESEMBA. Evaluate liver tests at the start and during therapy. Monitor patients who develop liver abnormalities during CRESEMBA therapy for severe hepatic injury. Discontinue if clinical signs and symptoms consistent with liver disease develop that may be attributable to CRESEMBA. Infusion-Related Reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur. Hypersensitivity Reactions: Anaphylactic reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Serious skin reactions, such as Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if anaphylactic or serious skin reactions occur, and initiate supportive treatment as needed. Embryo-Fetal Toxicity: During pregnancy, CRESEMBA may cause fetal harm when administered, and CRESEMBA should only be used if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant while receiving CRESEMBA are encouraged to contact their physician. Drug Interactions: Coadministration of CRESEMBA with strong CYP3A4 inhibitors such as ketoconazole or high-dose ritonavir and strong CYP3A4 inducers such as rifampin, carbamazepine, St. John's Wort, or long acting barbiturates is contraindicated. Drug Particulates: Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter. Adverse Reactions In adult patients, the most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%). In adult patients, the adverse reactions which most often led to permanent discontinuation of CRESEMBA therapy during the clinical trials were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnea (0.5%), epilepsy (0.5%), respiratory failure (0.5%), and vomiting (0.5%). In pediatric patients, the most frequently reported adverse reactions were diarrhea (26%), abdominal pain (23%), vomiting (21%), elevated liver chemistry tests (18%), rash (14%), nausea (13%), pruritus (13%), and headache (12%). In general, adverse reactions in pediatric patients (including serious adverse reactions and adverse reactions leading to permanent discontinuation of CRESEMBA) were similar to those reported in adults. For Full Prescribing Information, please visit here. About Astellas Pharma US Astellas Pharma US, Inc. is a U.S. affiliate of Tokyo-based Astellas Pharma Inc., a pharmaceutical company conducting business in more than 70 countries around the world. Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. Keeping our focus on addressing unmet medical needs and conducting our business with ethics and integrity enables us to improve the health of people throughout the U.S. and around the world. CRESEMBA was licensed from and co-developed with Basilea Pharmaceutica International Ltd, Allschwil. For more information on Astellas, please visit: . You can also follow us on Twitter at @AstellasUS, Facebook at or LinkedIn at . About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at . Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. 1 Thornton CR. Detection of invasive aspergillosis. Adv Appl Microbiol. 2010;70:187-216. doi: 10.1016/S0065-2164(10)70006-X. Epub 2010 Mar 6. PMID: 20359458. 2 Zhang Y, Sung AH, Rubinstein E, Benigno M, Chambers R, Patino N, Aram JA. Characterizing patients with rare mucormycosis infections using real-world data. BMC Infect Dis. 2022;22(1):154. doi: 10.1186/s12879-022-07115-w. PMID: 35164701; PMCID: PMC8845356. 3 Pana ZD, Roilides E, Warris A, Groll AH, Zaoutis T. Epidemiology of Invasive Fungal Disease in Children. J Pediatric Infect Dis Soc. 2017;6(suppl_1):S3-S11. doi:10.1093/jpids/pix046 SOURCE Astellas Pharma US, Inc.

上市批准孤儿药

2023-10-11

·GlobeNewswire-Health Care

Patient with Candida krusei Infection in Matinas BioPharma’s Oral MAT2203 Expanded Access Program Achieves Complete Clinical Resolution

BEDMINSTER, N.J., Oct. 11, 2023 (GLOBE NEWSWIRE) -- Matinas BioPharma (NYSE American: MTNB), a clinical-stage biopharmaceutical company focused on delivering groundbreaking therapies using its lipid nanocrystal (LNC) platform delivery technology, announces complete clinical resolution of a patient’s recurrent hemorrhagic cystitis due to Candida krusei (C. krusei), a fluconazole inherited resistant fungal pathogen, following treatment with MAT2203, Matinas’ oral formulation of the potent antifungal amphotericin B. This patient was treated under Matinas’ Expanded Access/Compassionate Use Program by Marisa H. Miceli, MD, Professor of Medicine, Specializing in Fungal Infections and Transplant Diseases, Division of Infectious Diseases, Internal Medicine, at the University of Michigan. “We are thrilled with the positive clinical impact MAT2203 had on this extremely ill patient with limited treatment options,” said Dr. Miceli. “This 61-year-old male with a history of diabetes, kidney disease, chronic obstructive lung disease, and coronary heart disease with heart failure had developed recurrent hemorrhagic cystitis due to C. krusei. In this case, neither an echinocandin nor a second-generation triazole was an option due to their inability to deliver adequate drug levels in urine. Treatment with IV-amphotericin B deoxycholate was quickly discontinued due to renal toxicity and we transitioned this patient to MAT2203, which was well-tolerated with no adverse effects. Treatment with MAT2203 led to complete resolution of his symptoms and improvement of his kidney function to baseline. Ultimately, the patient’s urine culture was negative for C. krusei after just 14 days of treatment with MAT2203.” A total of 11 patients with no other treatment options are currently receiving or have completed treatment with MAT2203 under this program, and several additional cases are under consideration. In each instance, the patient was not responding to or was resistant to azole therapy or was unable to receive azole therapy due to drug/drug interactions. All patients who experienced serious renal toxicity while receiving IV-amphotericin B who were subsequently treated with MAT2203 saw their renal toxicity reversed and renal function return to normal. “It’s exciting to share the ongoing, consistent positive clinical impact of our broad-spectrum, fast-acting oral MAT2203, especially with a major infectious disease conference, IDWeek, kicking off today,” said Theresa Matkovits, PhD, Chief Development Officer at Matinas. “We look forward to advancing MAT2203 into a Phase 3 registration trial to evaluate its potential in patients suffering from invasive aspergillosis who have limited or no treatment options. We believe that oral, effective, and safe MAT2203, if approved, would represent a dramatic improvement to current clinical standard of care and become the treatment of choice for patients and physicians battling invasive fungal infections. We are grateful to the participants in our Expanded Access program and to their physicians for recognizing the clinical potential of MAT2203 in treating a broad spectrum of invasive fungal infections.” MAT2203 is not yet licensed or approved anywhere globally. About MAT2203Matinas BioPharma is developing MAT2203 as a potential oral broad-spectrum treatment for invasive deadly fungal infections. Although amphotericin B is a fungicidal agent, it is currently only available through an intravenous route of administration, which is known to be associated with a number of significant safety issues such as renal toxicity and anemia due to very high circulating levels of amphotericin B. MAT2203 has the potential to overcome the significant limitations of the currently available amphotericin B products due to its targeted oral delivery, combining comparable fungicidal activity with targeted delivery resulting in a lower risk of toxicity and potentially creating the ideal antifungal agent for the treatment of invasive fungal infections. MAT2203 was successfully evaluated in the completed Phase 2 EnACT study in cryptococcal meningitis, meeting its primary endpoint and achieving robust survival. MAT2203 will be further evaluated as an oral step-down monotherapy treatment following IV-amphotericin B in a single pivotal Phase 3 study in the treatment of aspergillosis in persons with limited treatment options who are unable to be treated with azoles for reasons related to drug-drug interactions, resistance or for whom these antifungal agents are unable to be used for other clinical reasons. About Matinas BioPharmaMatinas BioPharma is a biopharmaceutical company focused on delivering groundbreaking therapies using its lipid nanocrystal (LNC) platform delivery technology. Matinas’ lead LNC-based therapy is MAT2203, an oral formulation of the broad-spectrum antifungal drug amphotericin B. In addition to MAT2203, preclinical and clinical data have demonstrated that this novel technology can provide solutions to many of the challenges standing in the way of achieving safe and effective intracellular delivery of both small molecules and larger, more complex molecular cargos such as RNAi, antisense oligonucleotides, and vaccines. The combination of its unique mechanism of action and flexibility with routes of administration (including oral) positions Matinas’ LNC technology to potentially become a preferred next-generation orally available intracellular drug delivery platform. For more information, please visit www.matinasbiopharma.com. Forward-looking StatementsThis release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including those relating to our business activities, our strategy and plans, the future development of its product candidates, including MAT2203, the Company’s ability to identify and pursue development, licensing and partnership opportunities for its products, including MAT2203, or platform delivery technology on favorable terms, if at all, and the ability to obtain required regulatory approval and other statements that are predictive in nature, that depend upon or refer to future events or conditions. All statements other than statements of historical fact are statements that could be forward-looking statements. Forward-looking statements include words such as "expects," "anticipates," "intends," "plans," "could," "believes," "estimates" and similar expressions. These statements involve known and unknown risks, uncertainties and other factors which may cause actual results to be materially different from any future results expressed or implied by the forward-looking statements. Forward-looking statements are subject to a number of risks and uncertainties, including, but not limited to, our ability to continue as a going concern, our ability to obtain additional capital to meet our liquidity needs on acceptable terms, or at all, including the additional capital which will be necessary to complete the clinical trials of our product candidates; our ability to successfully complete research and further development and commercialization of our product candidates; the uncertainties inherent in clinical testing; the timing, cost and uncertainty of obtaining regulatory approvals; our ability to protect the Company’s intellectual property; the loss of any executive officers or key personnel or consultants; competition; changes in the regulatory landscape or the imposition of regulations that affect the Company’s products; and the other factors listed under "Risk Factors" in our filings with the SEC, including Forms 10-K, 10-Q and 8-K. Investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this release. Except as may be required by law, the Company does not undertake any obligation to release publicly any revisions to such forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. Matinas BioPharma’s product candidates are all in a development stage and are not available for sale or use. Investor Contact LHA Investor RelationsJody Cain Jcain@lhai.com310-691-7100

临床3期临床2期

2023-08-04

·Science Daily

Scientists develop novel method to synthesize azide compounds for wider industrial applications

Azides are chemical compounds widely used in synthetic organic chemistry, pharmaceutical sciences, and materials chemistry. However, conventional synthesis methods for azide compounds have severe limitations. To this end, a team of researchers has developed an efficient method to prepare chemical intermediates having protected 'azido' groups. The team successfully synthesized several azides by the Grignard reaction, paving the way for the synthesis of a broad range of organonitrogens (amines and triazoles) for industrial applications. Azide compounds play a pivotal role for subsequent synthesis of organonitrogens such as amines and triazoles that are essential compounds in organic and materials chemistry. Triazoles that can be synthesized by the 'click' reaction have attracted attention in the development of pharmaceuticals and other industries. However, the azido groups are electrophilic and are susceptible to various nucleophiles such as carbanions. This poses a significant challenge for the synthesis of carbanions having azido groups. To this end, a team of researchers from Japan, led by Associate Professor Suguru Yoshida from Tokyo University of Science (TUS), has now developed an innovative and efficient azide synthesis method. In their recent article published in the journal Frontiers in Chemistry, Dr. Yoshida and his colleagues Ms. Rina Namioka (TUS) and Ms. Minori Suzuki (Tokyo Medical and Dental University) have detailed an efficient method to prepare organomagnesium (organic compound containing a magnesium ion linked to a carbon) intermediates having a protected azido group. This paper was published in Volume 11 of the journal Frontiers in Chemistry. "We conducted this research because we believe that the range of azide compounds that can be easily synthesized can be expanded by developing a synthesis method based on the azide group protection method that we discovered," says Dr. Yoshida. The novelty of this synthesis method lies in protection of azido groups with di(tert-butyl)(4-(dimethylamino) phenylphosphine (Amphos) and following iodine-magnesium exchange realized the preparation of organomagnesium intermediates, which served in the synthesis of diverse azides by transformations with various electrophiles followed by deprotection with elemental sulfur. In this study, the authors found a new azide synthesis method utilizing the Grignard reaction and developed a new method for the synthesis of 1,2,3-triazoles. Specifically, the team found that the iodine-magnesium exchange reaction proceeds efficiently with aryl iodides having azido groups by using the 'azide group protection method' that they have recently developed. Speaking about the underlying mechanism that enabled the researchers to achieve this novel azide synthesis method, Dr. Yoshida recalls, "The Grignard reaction of organomagnesium compounds that were synthesized by this reaction succeeded in the synthesis of a wide range of azide compounds." As azide compounds play a central role in the synthesis of 1,2,3-triazoles in click chemistry, this method is expected to contribute to the efficient development of pharmaceuticals and other industrially important products. "Our lab is currently conducting research on the preparation and transformation of carbanions with phosphazide moieties to expand the toolbox of such compounds," notes an optimistic Dr. Yoshida. The seamless, efficient synthesis of azides facilitating subsequent synthesis of a broad range of organonitrogen compounds such as amines and triazoles will immensely benefit synthetic organic chemistry, pharmaceutical sciences, and materials chemistry communities.

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