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1.
Glob Reg Health Technol Assess ; 11(Suppl 1): 8-10, 2024.
Article in English | MEDLINE | ID: mdl-39070243

ABSTRACT

In this article the pivotal role of hospital pharmacists in the multidisciplinary management of epilepsy is discussed. Hospital pharmacists are members of national and local ethics committees, oversee clinical trials, and ensure adherence to regulations for patient access to novel therapeutic treatments. They actively contribute to regulatory processes and the definition of prescribing centers. In the post-launch phase, hospital pharmacists are a key member in the multidisciplinary team, they are involved in decisions relating to the local introduction of drugs, in the management of the drug within the hospital structure and with the direct distribution, and to ensure proper and timely treatment. The pharmacovigilance network, including hospital and community pharmacists, monitors and prevents adverse effects related to epilepsy medications and enhances a collaborative approach with specialists to promote prescription appropriateness, targeting therapy for better patient outcomes. Finally, the potential benefits of deprescribing are briefly discussed, underscoring the importance of a multidisciplinary approach involving doctors and clinical pharmacists to gather comprehensive data and enhance patient care in epilepsy management.

2.
Eur J Pharm Biopharm ; 202: 114413, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39029878

ABSTRACT

In-situ API crystallization in carrier matrices has attracted extensive attention in recent years for its advantages over traditional preparation processes. However, due to the lack of systemic research on molecular self-assembly behaviors, the products obtained by in-situ crystallization suffer from the problems of polymorphic transformation and drug expulsion during storage, limiting its industrial application. This paper investigates the in-situ sequential crystallization behavior of tristearin (SSS) and fenofibrate (FEN), utilizing SSS as the carrier and FEN as the API. It was found that the behavior of mixed crystallization significantly differs from single-component crystallization, including direct formation of stable form of SSS and the rapid crystallization of FEN. During the crystallization process, the melting FEN promotes the movement of SSS molecules, while the sliding of SSS lamellae, in turn, provides a mechanical stimulus to enhance the nucleation of FEN. Based on the observed synergistic crystallization behavior, the distribution and stability of the API within FEN solid lipid microparticles (SLMs) during storage were evaluated, while also examining the stability variations in SLMs formulated at different cooling rates and drug loading concentrations. The findings indicate that the initial nucleated FEN results in a decrease in the surrounding molten FEN and the irregularity of the SSS lamellas, thereby preventing the remaining molten FEN from achieving complete crystallization within a brief period. Due to the compatibility between FEN and SSS, some SSS may blend with the molten FEN, potentially resulting in further crystallization during storage and consequently increasing the risk of drug expulsion.


Subject(s)
Crystallization , Drug Stability , Fenofibrate , Fenofibrate/chemistry , Lipids/chemistry , Triglycerides/chemistry , Particle Size , Drug Carriers/chemistry , Hypolipidemic Agents/chemistry , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Drug Storage
3.
Am J Health Syst Pharm ; 81(16): 684-705, 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-38780002

ABSTRACT

PURPOSE: Results of the 2023 ASHP National Survey of Pharmacy Practice in Hospital Settings are presented. METHODS: Pharmacy directors at 1,497 general and children's medical-surgical hospitals in the United States were surveyed using a mixed-mode method of contact by email and mail. Survey completion was online using Qualtrics. IQVIA supplied data on hospital characteristics; the survey sample was drawn from IQVIA's hospital database. RESULTS: The response rate was 21.6%. Inpatient pharmacists independently prescribe medications in 26.7% of hospitals. Advanced analytics are used in 5.7% of hospitals. Basic analytics are used in 87.3% of hospitals. Pharmacists work in ambulatory or primary care clinics in 54.2% of hospitals operating outpatient clinics. Most hospitals (86.1%) use automated dispensing cabinets as the primary method of maintenance dose distribution. Machine-readable coding is used in 73.6% of hospitals to verify doses during dispensing in the pharmacy. Autoverification functionality in the electronic health record system is used in 73.4% of hospitals. Most hospitals report some integration of pharmacy services to optimize patient care transitions (60.0%), while 24.9% report no integration. Traditional technician activities still predominate, but more advanced roles are emerging. Technologies to assist sterile product preparation are used in 62.8% of hospitals. CONCLUSION: Drug distribution continues to trend toward decentralized models with medications available closer to patients. Technologies are enabling this transition to occur without a significant negative impact on patient safety. The pharmacy workforce is stable, and more advanced responsibilities are being assigned to pharmacy technicians, enabling pharmacists to increase their clinical role.


Subject(s)
Pharmacists , Pharmacy Service, Hospital , Pharmacy Service, Hospital/organization & administration , Pharmacy Service, Hospital/trends , Humans , United States , Pharmacists/organization & administration , Pharmacists/trends , Surveys and Questionnaires , Societies, Pharmaceutical , Professional Role , Electronic Health Records , Medication Systems, Hospital/organization & administration
4.
Acta Pharmacol Sin ; 45(8): 1727-1739, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38605180

ABSTRACT

Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. Bispecific targeting could enhance the efficacy and safety of ADC by improving its specificity, affinity and internalization. In this study we constructed a HER2/HER3-targeting bispecific ADC (BsADC) and characterized its physiochemical properties, target specificity and internalization in vitro, and assessed its anti-tumor activities in breast cancer cell lines and in animal models. The HER2/HER3-targeting BsADC had a drug to antibody ratio (DAR) of 2.89, displayed a high selectivity against the target JIMT-1 breast cancer cells in vitro, as well as a slightly higher level of internalization than HER2- or HER3-monospecific ADCs. More importantly, the bispecific ADC potently inhibited the viability of MCF7, JIMT-1, BT474, BxPC-3 and SKOV-3 cancer cells in vitro. In JIMT-1 breast cancer xenograft mice, a single injection of bispecific ADC (3 mg/kg, i.v.) significantly inhibited the tumor growth with an efficacy comparable to that caused by combined injection of HER2 and HER3-monospecific ADCs (3 mg/kg for each). Our study demonstrates that the bispecific ADC concept can be applied to development of more potent new cancer therapeutics than the monospecific ADCs.


Subject(s)
Antibodies, Bispecific , Breast Neoplasms , Immunoconjugates , Receptor, ErbB-2 , Receptor, ErbB-3 , Humans , Animals , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/therapeutic use , Female , Receptor, ErbB-3/antagonists & inhibitors , Receptor, ErbB-3/metabolism , Immunoconjugates/therapeutic use , Immunoconjugates/pharmacology , Immunoconjugates/chemistry , Breast Neoplasms/drug therapy , Receptor, ErbB-2/antagonists & inhibitors , Cell Line, Tumor , Mice , Mice, Inbred BALB C , Mice, Nude , Xenograft Model Antitumor Assays , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects
5.
J Multidiscip Healthc ; 17: 1137-1145, 2024.
Article in English | MEDLINE | ID: mdl-38500480

ABSTRACT

Purpose: The shortage of nursing staff as well as the slow progress in the German health care system's digitalisation has gained much attention due to COVID-19. Patient-specific medication management using the unit-dose dispensing system (UDDS) has the potential for a lasting and positive influence on both digitalisation and the relief of nursing staff. Methods: Nursing staff UDDS-acceptance was determined via a validated online survey. For the evaluation of stock keeping on the wards, the delivery quantities were determined for a comparative period before and after the introduction of the UDDS. The time required for on-ward medication-related processes on ward before and after the introduction of UDDS was recorded based on a survey form and the nursing relief in full-time equivalent (FTE) was calculated using the data obtained. Results: We show that nurses appreciate the UDDS and confirm a significant reduction in drug stocks on the wards. The UDDS reduces the time needed to dispense medications from 4.52 ± 0.35 min to 1.67 ± 0.15 min/day/patient. In relation to the entire medication process, this corresponds to a reduction of 50% per day and per patient. Based on 40,000 patients/year and a supply of 1,125 beds with unit-dose blisters, 7.36 FTE nursing staff can be relieved per year. In contrast, 6.5 FTE in the hospital pharmacy are required for supplying the hospitals. Conclusion: UDDS is well accepted by nurses, reduces stock levels on ward, and fulfils criteria as a nursing-relief measure.

6.
Biomed Pharmacother ; 171: 116105, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38171245

ABSTRACT

Breast cancer prevention only requires local exposure of the breast to active drug. However, oral preventive agents entail systemic exposure, causing adverse effects that limit acceptance by high-risk women. Drug-delivery through the breast skin is an attractive option, but requires demonstration of dermal safety and drug distribution throughout the breast. We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. The primary endpoint was dermal toxicity. Thirty-two women planning mastectomy were randomized (2:1) to endoxifen-gel or placebo-gel applied to both breasts for 3-5 weeks. Both doses of endoxifen-gel incurred no dermal or systemic toxicity compared to placebo. All endoxifen-treated breasts contained the drug at each of five sampling locations; the median per-person tissue concentration in the treated participants was 0.6 ng/g (IQR 0.4-1.6), significantly higher (p < 0.001) than the median plasma concentration (0.2 ng/mL, IQR 0.2-0.2). The median ratio of the more potent (Z)-isomer to (E)-isomer at each breast location was 1.50 (IQR 0.96-2.54, p < 0.05). No discernible effects of breast size or adiposity on tissue concentrations were observed. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.


Subject(s)
Biological Products , Breast Neoplasms , Female , Humans , Breast Neoplasms/drug therapy , Mastectomy , Tamoxifen/pharmacology , Antineoplastic Agents, Hormonal
7.
Acta Pharm Sin B ; 14(1): 392-404, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38261815

ABSTRACT

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal cavity. However, no reliable method is currently available to assess its impact on delivery performance. In this study, a biomimetic nasal model based on three-dimensional (3D) reconstruction and three-dimensional printing (3DP) technology was developed for visualizing the deposition of drug powders in the nasal cavity. The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females. The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test. The experimental device produced the most satisfactory results with five spray times. Furthermore, particle sizes and spray angles were found to significantly affect the experimental device's performance and alter drug distribution, respectively. Additionally, mometasone furoate (MF) nasal spray (NS) distribution patterns were investigated in a goat nasal cavity model and three male goat noses, confirming the in vitro and in vivo correlation. In conclusion, the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.

8.
J Pharm Biomed Anal ; 241: 115984, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38266453

ABSTRACT

Flonoltinib Maleate (FM) is a dual-target inhibitor that selectively suppresses Janus kinase 2/FMS-like tyrosine kinase 3 (JAK2/FLT3), which is currently in phase I/IIa clinical trial in China for the treatment of myeloproliferative neoplasms (MPNs). In this research, we used [14C]-labeled FM (14C-FM) to investigate the distribution, metabolism, and excretion of FM in rats using High-Performance Liquid Chromatography coupled with High-Resolution Mass Spectrometry/Radioactivity Monitoring (HPLC-HRMS/RAM) and liquid scintillation counter. The results revealed that FM displayed widespread distribution in rats. Furthermore, FM demonstrated rapid clearance without any observed risk of organ toxicity attributed to accumulation. Profiling of FM metabolites in rat plasma, feces, urine, and bile identified a total of 17 distinct metabolites, comprising 7 phase I metabolites and 10 phase II metabolites. The major metabolic reactions involved oxygenation, dealkylation, methylation, sulfation, glucuronidation and glutathione conjugation. Based on these findings, a putative metabolic pathway of FM in rats was proposed. The overall recovery rate in the excretion experiment ranged from 93.04 % to 94.74 %. The results indicated that FM undergoes extensive hepatic metabolism in SD rats, with the majority being excreted through bile as metabolites and ultimately eliminated via feces. A minor fraction of FM (<10 %) was excreted through renal excretion in the form of urine. Integration of the current results with previous pharmacokinetic investigations of FM in rats and dogs enables a comprehensive elucidation of the in vivo ADME processes and characteristics of FM, thereby establishing a solid foundation for subsequent clinical investigations of FM.


Subject(s)
Bile , Maleates , Rats , Animals , Dogs , Rats, Sprague-Dawley , Tissue Distribution , Bile/metabolism , Feces/chemistry , Maleates/analysis , Maleates/metabolism , Chromatography, High Pressure Liquid/methods , Administration, Oral
9.
Acta Pharmaceutica Sinica B ; (6): 392-404, 2024.
Article in English | WPRIM (Western Pacific) | ID: wpr-1011240

ABSTRACT

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal cavity. However, no reliable method is currently available to assess its impact on delivery performance. In this study, a biomimetic nasal model based on three-dimensional (3D) reconstruction and three-dimensional printing (3DP) technology was developed for visualizing the deposition of drug powders in the nasal cavity. The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females. The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test. The experimental device produced the most satisfactory results with five spray times. Furthermore, particle sizes and spray angles were found to significantly affect the experimental device's performance and alter drug distribution, respectively. Additionally, mometasone furoate (MF) nasal spray (NS) distribution patterns were investigated in a goat nasal cavity model and three male goat noses, confirming the in vitro and in vivo correlation. In conclusion, the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.

10.
Ann Pharm Fr ; 82(2): 342-350, 2024 Mar.
Article in French | MEDLINE | ID: mdl-38101512

ABSTRACT

Since the healthcare system reform in prisons by the law of 18 January 1994, health care for prisoners has depended on the public hospital service. Since the application of this law, hospital pharmacists have been responsible for the health product circuit in the prison. In order to reassess the overall health care of detainees in prison in 2022, a study is being carried out. This study also aims to carry out an inventory of the organization of the drug circuit in prisons in France. In June 2022, a questionnaire was sent by email to pharmacists in charge of supplying health products to one or more prison health units in France. The response rate to the questionnaire is 34 %. The average number of full-time equivalent (FTE) somatic doctors is 1.25. The average FTE pharmacist and pharmacy technician are respectively 0.4 and 0.96. Prescriptions are computerized in 84 % of cases. Therapeutic education and pharmaceutical interviews are carried out in 24 % and 20 % respectively. This study showed an overall improvement in the care of prisoners and the organization of the medication circuit in France compared to the last study. Pharmacists are more present in prisons. However, clinical pharmacy and health promotion actions are insufficiently deployed.


Subject(s)
Pharmacy Service, Hospital , Prisoners , Humans , Prisons , Delivery of Health Care , Health Promotion , France
11.
Drug Metab Dispos ; 2023 Oct 26.
Article in English | MEDLINE | ID: mdl-37884391

ABSTRACT

A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. MALDI imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure, but also drug metabolism and elimination in a single suite of experiments. Significance Statement An integrated imaging approach utilizing MALDI IMS, immunohistochemistry (IHC), and histology was used to measure MALDI IMS complemented with other imaging techniques such as immunohistochemistry addressed the question of target exposure at the cellular level. Localized quantification of the parent drug in the target organ and identificaitonidentification of potential metabolites in the context of tissue histology were also achieved in one experimental suite to support characterization of pharmacokinetic properties of the drug in the early discovery stage.

12.
Cancer Manag Res ; 15: 851-862, 2023.
Article in English | MEDLINE | ID: mdl-37636030

ABSTRACT

Considerable progress has been made in cancer drug development in recent decades. However, for people in low- and middle-income countries, including Malaysia, many of these drugs are not readily available. During the 2nd Malaysian Association for Cancer Research (MACR) International Scientific Conference, a forum discussion was held to address these challenges and explore strategies to improve access to cancer medicines in the country. This paper presents the results of the said forum discussion. A few challenges to cancer drug access were highlighted, including lengthy approval and regulatory practices, cost of medicines, and manufacturing barriers. Besides, a few strategies for mitigating some of these challenges were proposed, such as mechanisms for cost reduction, uptake of biosimilars and generics, local manufacturing, public-private partnerships, strengthening the role of insurance companies, funding and regulation, and advocacy for fair pricing, by drawing examples from cancer medicines access initiatives in Malaysia and initiatives for different disease groups. Overall, this paper provides a comprehensive overview of the challenges and strategies for improving access to cancer medicines in Malaysia and provides valuable insights for policymakers, healthcare providers, the pharmaceutical industry, cancer patients, cancer support groups, and other stakeholders working on this important issue.

13.
AAPS PharmSciTech ; 24(6): 166, 2023 Aug 08.
Article in English | MEDLINE | ID: mdl-37552397

ABSTRACT

Exosomes are biological nanovesicles that are intrinsically loaded with thousands of biomacromolecules and are principally responsible for cell-to-cell communication. Inspired by the natural payload, they have been extensively investigated as drug delivery vehicles; however, the drug distribution, whether into or onto exosomes, is still debatable. In the present work, we have tried to investigate it systemically by selecting 5-fluorouracil (5-FU) (hydrophilic) and paclitaxel (PAC) (hydrophobic), drugs with very different physicochemical characteristics, for the loading to the exosomes. Exosomes were obtained from bovine milk, and the drugs were loaded using three different methods: incubation, sonication, and triton x-100. The particle size was found to be approximately 100 nm in all the cases; however, the highest drug loading was found in the sonication method. Fluorescence spectrophotometer, EDX analysis, EDX mapping, XPS, and XRD analysis indicated the possible presence of more drugs over the surface in the case of the incubation method. Drugs loaded by the sonication method had more controlled release than simple incubation and triton x-100. The method of drug loading had an insignificant effect on the cytotoxicity while in line with our previous observation, the combination (PAC and 5-FU) exhibited synergism as evidenced by ROS assay, colony formation assay, and mitochondrial membrane potential assay.


Subject(s)
Exosomes , Pharmaceutical Preparations/analysis , Cell Line, Tumor , Exosomes/chemistry , Octoxynol , Drug Delivery Systems , Paclitaxel/pharmacology , Fluorouracil
14.
J Int AIDS Soc ; 26 Suppl 1: e26113, 2023 07.
Article in English | MEDLINE | ID: mdl-37408477

ABSTRACT

INTRODUCTION: Non-communicable diseases (NCDs) are highly prevalent in people living with HIV above 50 years of age and account for increasing mortality. There is little published evidence supporting person-centred, integrated models of HIV care, hypertension and diabetes treatment in southern Africa, and no data demonstrating mortality reduction. Where clinical visits for NCDs and HIV cannot be combined, integrated medication delivery presents an opportunity to streamline care and reduce patient costs. We present experiences of integrated HIV and NCD medication delivery in Eswatini and South Africa, focusing on programme successes and implementation challenges. Programmatic data from Eswatini's Community Health Commodities Distribution (CHCD) from April 2020 to December 2021 and South Africa's Central Chronic Medicines Dispensing and Distribution (CCMDD) from January 2016 to December 2021 were provided by programme managers and are summarized here. DISCUSSION: Launched in 2020, Eswatini's CHCD provides over 28,000 people with and without HIV with integrated services, including HIV testing, CD4 cell count testing, antiretroviral therapy refills, viral load monitoring and pre-exposure prophylaxis alongside NCD services, including blood pressure and glucose monitoring and hypertension and diabetes medication refills.  Communities designate neighbourhood care points and central gathering places for person-centred medication dispensing.  This programme reported fewer missed medication refill appointments among clients in community settings compared to facility-based settings. South Africa's CCMDD utilizes decentralized drug distribution to provide medications for over 2.9 million people, including those living with HIV, hypertension and diabetes.  CCMDD incorporates community-based pickup points, facility "fast lanes" and adherence clubs with public sector health facilities and private sector medication collection units.  There are no out-of-pocket payments for medications or testing commodities.  Wait-times for medication refills are lower at CCMDD sites than facility-based sites.  Innovations to reduce stigma include uniformly labelled medication packages for NCD and HIV medications. CONCLUSIONS: Eswatini and South Africa demonstrate person-centred models for HIV and NCD integration through decentralized drug distribution. This approach adapts medication delivery to serve individual needs and decongest centralized health facilities while efficiently delivering NCD care.  To bolster programme uptake, additional reporting of integrated decentralized drug distribution models should include HIV and NCD outcomes and mortality trends.


Subject(s)
Diabetes Mellitus , HIV Infections , Hypertension , Noncommunicable Diseases , Humans , Noncommunicable Diseases/drug therapy , HIV Infections/drug therapy , HIV Infections/prevention & control , South Africa , Eswatini , Blood Glucose Self-Monitoring , Blood Glucose , Hypertension/drug therapy
15.
Int J Mol Sci ; 24(12)2023 Jun 13.
Article in English | MEDLINE | ID: mdl-37373226

ABSTRACT

Zebrafish (ZF; Danio rerio) larvae have emerged as a promising in vivo model in drug metabolism studies. Here, we set out to ready this model for integrated mass spectrometry imaging (MSI) to comprehensively study the spatial distribution of drugs and their metabolites inside ZF larvae. In our pilot study with the overall goal to improve MSI protocols for ZF larvae, we investigated the metabolism of the opioid antagonist naloxone. We confirmed that the metabolic modification of naloxone is in high accordance with metabolites detected in HepaRG cells, human biosamples, and other in vivo models. In particular, all three major human metabolites were detected at high abundance in the ZF larvae model. Next, the in vivo distribution of naloxone was investigated in three body sections of ZF larvae using LC-HRMS/MS showing that the opioid antagonist is mainly present in the head and body sections, as suspected from published human pharmacological data. Having optimized sample preparation procedures for MSI (i.e., embedding layer composition, cryosectioning, and matrix composition and spraying), we were able to record MS images of naloxone and its metabolites in ZF larvae, providing highly informative distributional images. In conclusion, we demonstrate that all major ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters, as part of in vivo pharmacokinetic studies, can be assessed in a simple and cost-effective ZF larvae model. Our established protocols for ZF larvae using naloxone are broadly applicable, particularly for MSI sample preparation, to various types of compounds, and they will help to predict and understand human metabolism and pharmacokinetics.


Subject(s)
Narcotic Antagonists , Zebrafish , Animals , Humans , Narcotic Antagonists/pharmacology , Naloxone/pharmacology , Larva , Pilot Projects , Mass Spectrometry
16.
Biomolecules ; 13(6)2023 06 14.
Article in English | MEDLINE | ID: mdl-37371566

ABSTRACT

Fungal-derived drugs include some of the most important medicines ever discovered, and have proved pivotal in treating chronic diseases. Not only have they saved millions of lives, but they have in some cases changed perceptions of what is medically possible. However, now the low-hanging fruit have been discovered it has become much harder to make the kind of discoveries that have characterised past eras of fungal drug discovery. This may be about to change with new commercial players entering the market aiming to apply novel genomic tools to streamline the discovery process. This review examines the discovery history of approved fungal-derived drugs, and those currently in clinical trials for chronic diseases. For key molecules, we discuss their possible ecological functions in nature and how this relates to their use in human medicine. We show how the conservation of drug receptors between fungi and humans means that metabolites intended to inhibit competitor fungi often interact with human drug receptors, sometimes with unintended benefits. We also plot the distribution of drugs, antimicrobial compounds and psychoactive mushrooms onto a fungal tree and compare their distribution to those of all fungal metabolites. Finally, we examine the phenomenon of self-resistance and how this can be used to help predict metabolite mechanism of action and aid the drug discovery process.


Subject(s)
Agaricales , Anti-Infective Agents , Humans , Fungi/metabolism , Anti-Infective Agents/metabolism , Drug Discovery , Genomics
17.
Best Pract Res Clin Anaesthesiol ; 37(2): 243-265, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37321769

ABSTRACT

Activation of neuraxial nociceptive linkages leads to a high level of encoding of the message that is transmitted to the brain and that can initiate a pain state with its attendant emotive covariates. As we review here, the encoding of this message is subject to a profound regulation by pharmacological targeting of dorsal root ganglion and dorsal horn systems. Though first shown with the robust and selective modulation by spinal opiates, subsequent work has revealed the pharmacological and biological complexity of these neuraxial systems and points to several regulatory targets. Novel therapeutic delivery platforms, such as viral transfection, antisense and targeted neurotoxins, point to disease-modifying approaches that can selectively address the acute and chronic pain phenotype. Further developments are called for in delivery devices to enhance local distribution and to minimize concentration gradients, as frequently occurs with the poorly mixed intrathecal space. The field has advanced remarkably since the mid-1970s, but these advances must always address the issues of safety and tolerability of neuraxial therapy.


Subject(s)
Drug Delivery Systems , Pain , Humans , Spinal Nerve Roots
18.
Br J Clin Pharmacol ; 89(11): 3364-3374, 2023 11.
Article in English | MEDLINE | ID: mdl-37272312

ABSTRACT

AIMS: Pleural mesothelioma (PM) is a highly aggressive thoracic tumour with poor prognosis. Although reduced tissue drug accumulation is one of the key features of platinum (Pt) resistance, little is known about Pt distribution in human PM. METHODS: We assessed Pt levels of blood samples and surgically resected specimens from 25 PM patients who had received neoadjuvant Pt-based chemotherapy (CHT). Pt levels and tissue distributions were measured by laser ablation-inductively coupled plasma-mass spectrometry and correlated with clinicopathological features. RESULTS: In surgically resected PM specimens, mean Pt levels of nontumourous (fibrotic) areas were significantly higher (vs tumourous regions, P = 0.0031). No major heterogeneity of Pt distribution was seen within the tumourous areas. Pt levels correlated neither with the microvessel area nor with apoptosis rate in the tumourous or nontumourous regions. A significant positive correlation was found between serum and both full tissue section and tumourous area mean Pt levels (r = 0.532, P = 0.006, 95% confidence interval [95% CI] 0.161-0.771 and r = 0.415, P = 0.039, 95% CI 0.011-0.702, respectively). Furthermore, a significant negative correlation was detected between serum Pt concentrations and elapsed time from the last cycle of CHT (r = -0.474, P = 0.017, 95% CI -0.738--0.084). Serum Pt levels correlated negatively with overall survival (OS) (P = 0.029). CONCLUSIONS: There are major differences in drug distribution between tumourous and nontumourous areas of PM specimens. Serum Pt levels significantly correlate with full section and tumourous area average Pt levels, elapsed time from the last CHT cycle, and OS. Further studies investigating clinicopathological factors that modulate tissue Pt concentration and distribution are warranted.


Subject(s)
Laser Therapy , Mesothelioma , Humans , Mesothelioma/surgery , Mesothelioma/drug therapy , Platinum/therapeutic use , Platinum/analysis , Mass Spectrometry/methods
19.
Molecules ; 28(10)2023 May 19.
Article in English | MEDLINE | ID: mdl-37241927

ABSTRACT

Electrospun fibers containing levocetirizine, a BCS III drug, were prepared from three water-soluble polymers, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA). Fiber-spinning technology was optimized for each polymer separately. The polymers contained 10 wt% of the active component. An amorphous drug was homogeneously distributed within the fibers. The solubility of the drug in the polymers used was limited, with a maximum of 2.0 wt%, but it was very large in most of the solvents used for fiber spinning and in the dissolution media. The thickness of the fibers was uniform and the presence of the drug basically did not influence it at all. The fiber diameters were in the same range, although somewhat thinner fibers could be prepared from PVA than from the other two polymers. The results showed that the drug was amorphous in the fibers. Most of the drug was located within the fibers, probably as a separate phase; the encapsulation efficiency proved to be 80-90%. The kinetics of the drug release were evaluated quantitatively by the Noyes-Whitney model. The released drug was approximately the same for all the polymers under all conditions (pH), and it changed somewhere between 80 and 100%. The release rate depended both on the type of polymer and pH and varied between 0.1 and 0.9 min-1. Consequently, the selection of the carrier polymer allowed for the adjustment of the release rate according to the requirements, thus justifying the use of electrospun fibers as carrier materials for levocetirizine.


Subject(s)
Polymers , Water , Polymers/metabolism , Drug Liberation , Cetirizine , Solubility , Polyvinyl Alcohol , Drug Carriers
20.
Res Social Adm Pharm ; 19(8): 1218-1227, 2023 08.
Article in English | MEDLINE | ID: mdl-37225602

ABSTRACT

BACKGROUND: Drug shortages impact multiple stakeholders and are detrimental to patient safety. Additionally, drug shortages are an extensive financial burden. In Germany, drug shortages, according to data from the federal ministry for drug and medical products (BfArM), have been increasing by 18% between 2018 and 2021. Studies show that shortages are most frequently supply side driven and that often reasons remain unknown. OBJECTIVE: The aim is to develop a holistic understanding of supply side causes for drug shortages in Germany from marketing authorization holders' perspectives and to derive implications for shortage mitigation. METHODS: A mixed-methods research design, with a grounded theory approach based on a structured literature review, BfArM data analysis, and semi-structured interviews, was used. RESULTS: Input factor supply issues, manufacturing issues, logistics issues, product recalls, and product discontinuations were identified as first-level causes. Furthermore, a theory on their connection to higher-level causes related to business decision-making, as well as root causes linked to regulations, company values, internal processes, market dynamics, external shocks, and macroeconomic factors, was developed. CONCLUSION: Actions to mitigate drug shortages in Germany (e.g., improving business processes, diversifying tender criteria) were derived. These may thus increase patient safety and decrease the financial burden on the healthcare system.


Subject(s)
Delivery of Health Care , Drug Industry , Humans , Patient Safety , Germany , Marketing
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