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There are more than 170 known species of non-tuberculous mycobacteria, and some are responsible for serious diseases in people infected with them. One of these is Buruli ulcers, a neglected tropical disease endemic in more than 33 countries and caused by Mycobacterium ulcerans, which infects skin tissue. Treatment consists of a long-term regimen combining the use of oral rifampin with another anti-tuberculosis drug (e.g., clarithromycin). Patients in these countries face difficulties in accessing and adhering to this therapy. This study investigates the feasibility of formulating stable, optimized clarithromycin as a topical cutaneous cream. The cream was formulated, and its stability was evaluated under different storage temperature conditions and using a stability indicator method. The results showed that the clarithromycin cream was stable for at least 60 days, even at extreme temperatures (40 °C). In conclusion, the data presented here demonstrate the stability of a new form of topical cutaneous clarithromycin, which may offer a new approach to the treatment of Buruli ulcers and clarithromycin-sensitive infections.
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Cytobacteriological urine examinations (CBEU) are frequently ordered for the older adults, sometimes without straightforward indication and with the risk of prescribing empirical antibiotics. The aim of this study was to evaluate the relevance of the CBEU prescription and empiric antibiotic therapy in our geriatric hospital. Among 129 patients (mean age 84 years, sex ratio 0.69), 229 CBEU were collected with 20.9% of inappropriate indication. Cultures were sterile in 43% (n = 99) of cases and positive in 57% (n = 130) cases. Gram-negative bacilli dominated the isolated bacteria (76.9%) followed by gram-positive cocci (17.6%). In 113 patients, probabilistic antibiotic therapy was prescribed of which 68 treatments were initiated before the CBEU. Ceftriaxone and amoxicillin plus clavulanic acid were the main therapeutic option used representing 70.8% of cases. Antibiotic therapy was re-evaluated after 3 days in 74.3% of patients. Efforts to reduce the number of useless ECBUs by training doctors to follow official guidelines are a priority.
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Antibacterianos , Urinálise , Humanos , Feminino , Masculino , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Idoso , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Infecções Urinárias/urina , Infecções Urinárias/diagnóstico , Estudos RetrospectivosRESUMO
This Special Issue, entitled "Recent Advances in Oral Drug Delivery Development", aims to demonstrate new advances and future trends in the field of oral drug delivery [...].
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Necrotizing fasciitis (NF) is a rare soft-tissue infection generally treated by emergency surgical intervention. We report a case of successfully drug treatment for NF in older patient with comorbidities thus avoiding surgical intervention.
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BACKGROUND: Lipin-1 deficiency is a life-threatening disease that causes severe rhabdomyolysis (RM) and chronic symptoms associated with oxidative stress. In the absence of treatment, Hydroxychloroquine sulfate (HCQ) was administered to patients off label use on a compassionate basis in order to improve their physical conditions. METHODS: Eleven patients with LPIN1 mutations were treated with HCQ. Clinical and biological efficacy and tolerance were assessed, including pain and quality of life, physical capacities, cardiopulmonary parameters, creatine kinase levels and plasma proinflammatory cytokines. To explore a dose-dependent effect of HCQ, primary myoblasts from 4 patients were incubated with various HCQ concentrations in growth medium (GM) or during starvation (EBSS medium) to investigate autophagy and oxidative stress. FINDINGS: Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM. We hypothesized that HCQ exerts deleterious effects at high concentrations by blocking autophagy, and beneficial effects on oxidative stress at low concentrations. We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation. INTERPRETATION: HCQ improves the condition of patients with lipin-1 deficiency, but at low concentrations. In vitro, 1 µM HCQ decreases oxidative stress in myoblasts whereas higher concentrations have a deleterious effect by blocking autophagy.
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Hidroxicloroquina , Qualidade de Vida , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Citocinas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fosfatidato Fosfatase/genéticaRESUMO
Polypharmacy increases the risk of unbearable side effects, drug-drug interactions, and hospitalizations in geriatric patients. The iatrogenic risk of inadequate management of antidepressants is very important in this population. Therefore, primary care physicians and geriatricians have the responsibility of the optimization of antidepressants prescriptions. Our work is a literature review of the European and the international guidelines regarding the management of antidepressants. We reviewed the PubMed database and Google scholar for articles and reviews from 2015. We also screened relevant articles for more references and searched the web for available European guidelines relevant to our topic. We divided our findings into four main inquiries that are Indication, effectiveness, tolerability, and iatrogenic risks. Poor or absence of effectiveness should lead to a readjustment of the treatment plan. In case of unbearable side effects, antidepressants should be stopped, and alternative non-pharmacological therapies should be proposed. Doctors should look out for drug-drug interaction risks in this population and constantly adjust the prescription. Prescription of antidepressants is not always evidence based which leads to heavy iatrogenic consequences. We suggest a simple 4-questions-algorithm that aims to remind doctors of the basics of good practice and helps in the process of deprescribing an antidepressant in older adults.
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L-Methionine (Met) is an essential alpha-amino acid playing a key role in several metabolic pathways. Rare inherited metabolic diseases such as mutations affecting the MARS1 gene encoding methionine tRNA synthetase (MetRS) can cause severe lung and liver disease before the age of two years. Oral Met therapy has been shown to restore MetRS activity and improve clinical health in children. As a sulfur-containing compound, Met has a strongly unpleasant odor and taste. The objective of this study was to develop an optimized pediatric pharmaceutical formulation of Met powder, to be reconstituted with water, to obtain a stable oral suspension. Organoleptic characteristics and physicochemical stability of the powdered Met formulation and suspension were evaluated at three storage temperatures. Met quantification was assessed by a stability-indicating chromatographic method as well as microbial stability. The use of a specific fruit flavor (e.g., strawberry) with sweeteners (e.g., sucralose) was considered acceptable. No drug loss, pH changes, microbiological growth, or visual changes were observed at 23 ± 2 °C and 4 ± 2 °C with the powder formulation for 92 days, and the reconstituted suspension for at least 45 days. The developed formulation facilitates the preparation, administration, the dose adjustment and palatability of Met treatment in children.
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The risks of iatrogenic medication related adverse events are high among older patients. Assessing prescriptions is critical to prevent overusing, underusing, or misusing medications. The aim of this study is to evaluate the prescription reassessment in older patients hospitalized in long-term care unit. Among the 30 patients (M age = 83 years, woman 66%), polymedication was present, patients taking 5 to 18 drugs (mean 11 drugs). The length of stay varied from 92 days to 4.5 years (mean 564 ± 430 days). The prescription reassessment of the patients hospitalized in our long-term care unit varied from 1 to 125 days with a mean of 16 days. Plan the prescription reassessment could reduce the iatrogenic medication in weakened patients.
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Dominant negative (DN) mutations in signal transducer and activator of transcription 3 (STAT3) are known to cause hyper-IgE syndrome, a rare primary immunodeficiency. STAT3 DN patients are prone to develop fungal infections, including chronic mucocutaneous candidiasis due to impaired IL-17-mediated immunity, and pulmonary aspergillosis. Despite having preserved phagocyte functions, STAT3 DN patients present connective tissue abnormalities and a defect in the immunological skin barrier. Fusarium species are ubiquitous molds, whose potential to infect humans depends on the host's innate and cellular immune status. Our aim was to describe four STAT3 DN patients with fusariosis confined to the skin. Medical records were reviewed and summarized. Four patients, aged 4, 11, 30, and 33 years, presented with chronic skin lesions which started in the extremities. Two patients had remote lesions, and none had systemic involvement. Skin biopsies showed mycelial threads with deep inflammatory-occasionally granulomatous-infiltrates, reaching the dermis; cultures grew Fusarium solani. Response to treatment was heterogeneous, often requiring multimodal therapies, including topical antifungal preparations. In this work, we describe primary invasive cutaneous fusariosis as a syndromic entity in four STAT3 DN patients.
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Fusariose , Síndrome de Job , Humanos , Fusariose/tratamento farmacológico , Fusariose/microbiologia , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Pele/microbiologia , Antifúngicos/uso terapêuticoRESUMO
PURPOSE: We evaluated the use of the PPI treatment by physicians in older adults hospitalized in a long-term care unit. METHODS: We included 40 patients aged 65 years or older with a lansoprazole prescription hospitalized in long-term care unit from January 2018 to January 2022. Patient characteristics, gastroduodenal history, dose of lansoprazole, indication, days of prescription, and number of medications were collected from electronic patient records. RESULTS: The mean age of patients was 84.2 ± 9.3. Patients were taking between 5 and 24 (mean = 12.7, SD = 4.4) medications overall with 15 patients taking low dose of aspirin (75 mg daily) and 8 patients taking an antiplatelet. Most patients (82.5%) received once-daily lansoprazole treatment, 55% of whom took a dose of 15 mg. Five patients were treated with the maximum dose of lansoprazole 30 mg twice daily. Only seven patients had an appropriate indication. The minimum of treatment time was 3 days and the maximum was 1198 days; moreover, 24 patients (60%) were still in treatment. CONCLUSION: Few PPI prescriptions had an indication in the patient's electronic record. Prescriptions were ongoing with no date of discontinuation or re-evaluation.
AIM: To evaluate the lansoprazole prescription in older adults hospitalized in long-term care unit. FINDINGS: In our study population of 65 years or more, the prevalence of appropriate prescription was 17.5% with mean of medications at 12.7 (SD = 4.4). The treatment time was ranging from 3 to 1198 days with 24 patients (60%) still in treatment. MESSAGE: Regular reassessment and the implementation of PPI prescription recommendations were still not routinely used in clinical practice.
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Assistência de Longa Duração , Inibidores da Bomba de Prótons , Humanos , Idoso , Inibidores da Bomba de Prótons/uso terapêutico , Lansoprazol/uso terapêutico , Prescrição Inadequada , AspirinaRESUMO
Objective: The main purpose of this study was to carry out a global risk analysis (GRA) on the subcontracting circuit to determine and evaluate the risks linked to the future subcontracting process and to propose corrective actions for the most critical risks to ensure safety. This study must allow to conclude in an objective way to the feasibility or not of this project. Methods: A GRA was performed, conducted by a multidisciplinary working group that met in 20 meetings, corresponding to about 50 h of work. Results: We identified 92 scenarios: 13% of scenarios had an initial criticality C1, 40% C2, and 47% C3. The GRA shows that the riskiest scenarios concern the management, material, and equipment with IT system and logistics with transport. The working group identified 25 corrective actions. After implementing those actions, 85% of scenarios had residual criticality C1, 8.5% C2, and 6.5% had residual criticality C3. The working group chose that it was impossible to subcontract part of the activity. Conclusion: The GRA conducted in this study highlighted the risks related to outsourcing this activity, evaluated and prioritized them, and recommended corrective actions. Therefore, we conclude that subcontracting the totality of sterile preparations would be harmful to patient care quality and reactivity for vital medical emergencies, such as macrophage activation syndrome, preparation of clinical trials, graft rejection therapies, preparation of very short stability chemotherapy, and the pediatric graft conditioning chemotherapy.
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Ruxolitinib, used in children with steroid-refractory acute graft-versus-host (GVH) disease, is currently commercially available only as a tablet adult dosage. For the paediatric population, an oral liquid would be an adapted dosage formulation. The aim of this study was to develop ruxolitinib compounded oral suspensions at 2 mg/mL by using commercial tablets in available aqueous vehicle (Inorpha) and to measure its stability at both room temperature and under refrigeration. Chemical stability of suspensions containing ruxolitinib was evaluated for 60 days based on pH, degradation, and drug content. Physical stability of the drug suspension was evaluated by visual aspect and odour. The remaining ruxolitinib concentration of the suspension was at least 95% of the initial concentration after 60 days at both temperatures. The pH, colour, and odour of the suspensions throughout the study remained unchanged with respect to the initial time point.
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Doença Enxerto-Hospedeiro , Administração Oral , Criança , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Nitrilas , Pirazóis , Pirimidinas , Esteroides , Suspensões , ComprimidosRESUMO
Pachyonychia congenita (PC) is a genodermatosis associated with severe painful palmoplantar keratoderma (PPK) and thickened dystrophic nails caused by autosomal dominant-negative mutations in five genes encoding keratins 6A-B-C, 16, and 17. The mechanical, surgical, or medical options for painful PC are inefficient. Given ErbB/Her family members' role in epidermal homeostasis, this study sought to investigate the possibility of treating PC patients with PPK by blocking signaling either with EGFR (Her1) inhibitor erlotinib or lapatinib, a dual EGFR(Her1)/Her2. After 1 month of therapy with oral erlotinib treatment at 75 mg/day, the pain disappeared for patient #1, with partially reduced hyperkeratosis, while increasing the dose to 100 mg/day resulted in painful skin fissures. Therapy replacement with erlotinib cream at 0.2% was inconclusive, and substitution with oral lapatinib at alternating doses of 500 and 750 mg/day achieved a good compromise between pain reduction, symptom improvements, and side effects. Patient #2's treatment with erlotinib cream failed to display significant improvements. Oral erlotinib started at 75 mg/day then reduced to 25 mg/day because of the formation of an acneiform rash. Treatment considerably improved the patient's condition, with an almost complete disappearance of pain. Oral Her1 or 1/2 inhibitors reduced pain, improved two PC patients' quality of life, and offered promising therapeutic perspectives.
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The new coronavirus disease 2019 (COVID-19) could be associated with elevated inflammatory cytokine levels, suggesting the involvement of cytokine release syndrome. This syndrome is characterized by release of interleukin 6 correlated with COVID-19 severity and mortality. Targeting IL-6 with Tocilizumab treatment could be a potential therapeutic option for old patients. We report the case of an 88-year-old man with COVID-19 disease who presented at the admission with anemia, fever, oxygen desaturation (92%), and inflammatory syndrome (C-reactive protein (CRP) at 182.5 mg/L; reference range <5.0 mg/L). After remaining CRP level increase (206.6 mg/L), Tocilizumab administration led to rapid clinical outcome and resolution of his inflammatory syndrome. This case report represents a supplementary data confirming the efficacy and safety of Tocilizumab for COVID-19 in elderly patients.
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Recent studies have highlighted the benefit of repurposing oral erlotinib (ERL) treatment in some rare skin diseases such as Olmsted syndrome. The use of a topical ERL skin treatment instead of the currently available ERL tablets may be appealing to treat skin disorders while reducing adverse systemic effects and exposure. A method to prepare 0.2% ERL cream, without resorting to a pure active pharmaceutical ingredient, was developed and the formulation was optimized to improve ERL stability over time. Erlotinib extraction from tablets was incomplete with Transcutol, whereas dimethyl sulfoxide (DMSO) allowed 100% erlotinib recovery. During preliminary studies, ERL was shown to be sensitive to oxidation and acidic pH in solution and when added to selected creams (i.e., Excipial, Nourivan Antiox, Pentravan, and Versatile). The results also showed that use of DMSO (5% v/w), neutral pH, as well as a topical agent containing antioxidant substances (Nourivan Antiox) were key factors to maintain the initial erlotinib concentration. The proposed ERL cream formulation at neutral pH contains a homogeneous amount of ERL and is stable for at least 42 days at room temperature in Nourivan cream with antioxidant properties.
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Antioxidantes/química , Cloridrato de Erlotinib/síntese química , Creme para a Pele/síntese química , Cromatografia Líquida de Alta Pressão , Dimetil Sulfóxido/química , Composição de Medicamentos , Estabilidade de Medicamentos , Cloridrato de Erlotinib/química , Etilenoglicóis/química , Concentração de Íons de Hidrogênio , Creme para a Pele/química , ComprimidosRESUMO
OBJECTIVES: To determine the physicochemical stability of pemetrexed diarginine in original vials, and after dilution in two commonly used infusion fluids (0.9% sodium chloride, 5% dextrose) in polyolefin bags, stored under refrigeration (2-8°C) or at ambient temperature (22-25°C) exposed to light. METHODS: Stability of pemetrexed diarginine injection concentrate was determined in the original glass vials with closed-system transfer device. Diluted pemetrexed diarginine infusion solutions were aseptically prepared by dilution of pemetrexed diarginine concentrate with either 0.9% sodium chloride or dextrose 5% in polyolefin bags, in amounts yielding pemetrexed diarginine concentrations of 4, 9 and 12 mg/mL. Test solutions were stored under refrigeration (2-8°C) or at ambient temperature (22-25°C) exposed to light. Pemetrexed diarginine concentrations were determined throughout a 14-day storage period using a stability-indicating HPLC assay. In addition, test solutions were visually examined for colour change and precipitation. RESULTS: Pemetrexed diarginine injection concentrate with closed-system transfer device is shown to be physicochemically stable for up to 4 days when stored under refrigeration and for 1 day at room temperature. A browning of the pemetrexed diarginine concentrate solutions appeared 0n day 2 when stored at ambient temperature and on day 5 under refrigeration. Pemetrexed diarginine diluted in dextrose 5% and 0.9% sodium chloride was physicochemically stable for up to 4 days when stored under refrigeration and for 1 day at room temperature. A browning of the diluted solutions appeared on day 2 when stored at room temperature and on day 5 when stored under refrigeration. CONCLUSIONS: Pemetrexed diarginine concentrate for solution stored under refrigeration with closed-system transfer device can be retained as a residual to reduce product losses. The analytical stability of pemetrexed diarginine in dextrose 5% and 0.9% sodium chloride under refrigeration enables our centralised unit to prepare this drug in advance.
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Embalagem de Medicamentos , Cloreto de Sódio , Pemetrexede , Armazenamento de Medicamentos , Estabilidade de Medicamentos , Soluções Farmacêuticas , GlucoseRESUMO
BACKGROUND: Imatinib is a protein-tyrosine kinase inhibitor which is currently only commercially available as a tablet dosage form in the strength of 100mg and 400mg. The elaboration of new oral liquid formulations is suitable in pediatrics and for patients who have difficulties to swallow, notably in the absence of commercial forms. This enables the adaptation of dosage and secure the administration. OBJECTIVES: The formulation of an oral pediatric solution of imatinib at a concentration of 30 mg/mL and the evaluation of its stability for the treatment of pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia. METHODS: The physicochemical stability parameters: appearance, pH, osmolality, and drug content of formulation were evaluated for 30 days when stored at 2-8°C. Concentration of solution was measured with a validated method using high performance liquid chromatography (HPLC) coupled with an absorbance UV detector. Equally, microbiological stability was performed. RESULTS: The remaining imatinib concentration was at least 95% of the initial concentration after 30 days stored in fridge temperature. No changes were observed regarding the physical properties of the formulation during the study period. CONCLUSIONS: The stability study showed that the imatinib oral solution at a concentration of 30 mg/mL provides an alternative option at the commercial tablet dosage forms for pediatric patients and patients who have difficulties to swallow.