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1.
Int J Biol Macromol ; : 132268, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38734336

RESUMEN

Paclitaxel (PTX) is a potent anticancer drug. However, PTX exhibits extremely poor solubility in aqueous solution along with severe side effects. Therefore, in this study, an inclusion complex was prepared between PTX and hydroxypropyl-ß-cyclodextrin (HPßCD) by solvent evaporation to enhance the drug's solubility. The HPßCD-PTX inclusion complex was then encapsulated in poly-3-hydroxybutyrate (PHB) to fabricate drug-loaded nanoparticles (HPßCD-PTX/PHB NPs) by nanoprecipitation. The HPßCD-PTX/PHB NPs depicted a higher release of PTX at pH 5.5 thus demonstrating a pH-dependent release profile. The cytotoxic properties of HPßCD-PTX/PHB NPs were tested against MCF-7, MDA-MB-231 and SW-620 cell lines. The cytotoxic potential of HPßCD-PTX/PHB NPs was 2.59-fold improved in MCF-7 cells in comparison to free PTX. Additionally, the HPßCD-PTX/PHB NPs improved the antimitotic (1.68-fold) and apoptotic (8.45-fold) effects of PTX in MCF-7 cells in comparison to PTX alone. In summary, these pH-responsive nanoparticles could be prospective carriers for enhancing the cytotoxic properties of PTX for the treatment of breast cancer.

2.
Pak J Pharm Sci ; 37(1): 17-23, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38741396

RESUMEN

As a major concern in the healthcare sector, polypharmacy is correlated with an increased risk of potential drug-drug interactions (pDDIs), treatment costs and adverse drug reactions (ADR). To assess the prevalence of polypharmacy and its associated factors among postoperative cardiac patients admitted to the National Institute of Cardiovascular Diseases (NICVD), a hospital-based cross-sectional study was conducted between November 2021 and April 2022. Medication charts of postoperative patients were reviewed for medication utilization and polypharmacy. Data was collected using a form approved by the Ethical Review Committee (ERC) regarding patient's clinical and demographic characteristics and medications administered. Statistical analysis was performed using the SPSS software version 25.0. Patients were taking an average of 10.3±1.7 medications. The minimum number of drugs taken per patient was 5, while the maximum was 15 drugs. Only 114 (29.7%) received polypharmacy (5-9 drugs) and hyper-polypharmacy (≥10 drugs) was 270 (70.3%). The mean±SD cardiovascular drugs used were 5.45±1.18 and the mean±SD non-cardiovascular drugs were 4.83±1.18. The prevalence of hyper-polypharmacy suggests a critical need for optimized medication management strategies in this population. Incorporating clinical pharmacists within public healthcare institutions can address polypharmacy-related challenges and enhance medication safety, adherence and patient outcomes.


Asunto(s)
Farmacéuticos , Polifarmacia , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Pakistán , Anciano , Adulto , Interacciones Farmacológicas , Servicio de Farmacia en Hospital , Cardiopatías/cirugía , Prevalencia
3.
J Coll Physicians Surg Pak ; 34(4): 456-460, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38576290

RESUMEN

OBJECTIVE: To assess the predictive ability of the laboratory risk indicator for necrotising fasciitis (LRINEC) score for lower extremity amputation in patients with moderate to severe diabetic foot infection (DFI). STUDY DESIGN: Observational study. Place and Duration of the Study: Department of General Surgery, Combined Military Hospital, Rawalpindi, Pakistan, from June to September 2023. METHODOLOGY: Patients admitted to the surgical ward with moderate to severe DFI were included by convenience sampling. Patients with severe sepsis, unstable haemodynamics, pressure injuries, and terminal illnesses were excluded. Demographic and clinical data of patients were noted down. LRINEC score was calculated on the day of admission. Final outcome (amputation or otherwise) was recorded on the 30th day the since the day of admission. RESULTS: Two hundred patients with moderate to severe DFI were included. The median age of patients was 56 years (IQR 49-66 years). The median duration of diabetes was 11 years (IQR 4 - 18.75 years). The median LRINEC score at admission was 6 (IQR 3-9). The majority of the patients (65.5%) had some other medical comorbid besides diabetes. Patients who had amputation due to DFI at 30 days post-admission had higher LRINEC scores on admission as compared to those patients who did not have amputation (Median 8 vs. 2, p <0.001). The cut-off point of LRINEC score ≥6.5 at admission had sensitivity of 74% and specificity of 94% in predicting amputation. CONCLUSION: The LRINEC score may be used as an objective scoring system to predict the risk of amputation in patients with moderate to severe DFI in indoor clinical settings. KEY WORDS: Diabetic foot, LRINEC score, Limb loss, Necrotising fasciitis.


Asunto(s)
Diabetes Mellitus , Pie Diabético , Fascitis Necrotizante , Enfermedades de la Piel , Humanos , Persona de Mediana Edad , Anciano , Fascitis Necrotizante/cirugía , Pie Diabético/cirugía , Estudios Retrospectivos , Factores de Riesgo , Amputación Quirúrgica , Extremidad Inferior/cirugía
4.
Pulm Circ ; 14(1): e12337, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38500737

RESUMEN

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.

5.
RSC Adv ; 14(13): 8905-8920, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38495980

RESUMEN

Alzheimer's disease (AD) is a multifactorial irreversible neurological disorder with multiple enzymes involved. In the treatment of AD, multifunctional agents targeting cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have shown promising results. Herein, a series of novel quinoline-sulfonamides (a1-18) were designed and synthesized as a dual inhibitor of MAOs and ChEs. The in vitro results showed that compounds a5, a12, a11, and a6 exhibited the most potent compounds against specific enzymes. They had IC50 value 0.59 ± 0.04 for MAO-A, 0.47 ± 0.03 for MAO-B, 0.58 ± 0.05 for BChE and 1.10 ± 0.77 for AChE µM respectively. Furthermore, kinetic studies revealed that these compounds are competitive. Molecular docking studies enhanced the understanding of the in silico component, unveiling critical interactions, specifically the hydrogen bonding interaction, π-π, π-alkyl, π-amid and π-sulfur interactions between the ligand and enzymes. These findings suggest that compounds a5, a6, a11, a12, a15, and a18 may be potent multifunctional candidates for AD treatment.

6.
Eur Respir J ; 63(3)2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38302154

RESUMEN

BACKGROUND: Diagnostic rates and risk factors for the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism (PE) are not well defined. METHODS: Over a 10-year period (2010-2020), consecutive patients attending a PE follow-up clinic in Sheffield, UK (population 554 600) and all patients diagnosed with CTEPH at a pulmonary hypertension (PH) referral centre in Sheffield (referral population estimated 15-20 million) were included. RESULTS: Of 1956 patients attending the Sheffield PE clinic 3 months following a diagnosis of acute PE, 41 were diagnosed with CTEPH with a cumulative incidence of 2.10%, with 1.89% diagnosed within 2 years. Of 809 patients presenting with pulmonary hypertension (PH) and diagnosed with CTEPH, 32 were Sheffield residents and 777 were non-Sheffield residents. Patients diagnosed with CTEPH at the PE follow-up clinic had shorter symptom duration (p<0.01), better exercise capacity (p<0.05) and less severe pulmonary haemodynamics (p<0.01) compared with patients referred with suspected PH. Patients with no major transient risk factors present at the time of acute PE had a significantly higher risk of CTEPH compared with patients with major transient risk factors (OR 3.6, 95% CI 1.11-11.91; p=0.03). The presence of three computed tomography (CT) features of PH in combination with two or more out of four features of chronic thromboembolic pulmonary disease at the index PE was found in 19% of patients who developed CTEPH and in 0% of patients who did not. Diagnostic rates and pulmonary endarterectomy (PEA) rates were higher at 13.2 and 3.6 per million per year, respectively, for Sheffield residents compared with 3.9-5.2 and 1.7-2.3 per million per year, respectively, for non-Sheffield residents. CONCLUSIONS: In the real-world setting a dedicated PE follow-up pathway identifies patients with less severe CTEPH and increases population-based CTEPH diagnostic and PEA rates. At the time of acute PE diagnosis the absence of major transient risk factors, CT features of PH and chronic thromboembolism are risk factors for a subsequent diagnosis of CTEPH.


Asunto(s)
Hipertensión Pulmonar , Embolia Pulmonar , Tromboembolia , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Estudios de Seguimiento , Embolia Pulmonar/complicaciones , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/epidemiología , Factores de Riesgo , Tromboembolia/complicaciones , Tromboembolia/diagnóstico , Sistema de Registros , Enfermedad Crónica
7.
J Photochem Photobiol B ; 251: 112841, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38194816

RESUMEN

The most prevalent solar ultraviolet radiation is ultraviolet-A (UVA) radiation. It is the inducer of reactive oxygen species (ROS), a potent mediator of inflammation and photocarcinogenesis. Regular application of sunscreens containing UVA filters is an effective preventive measure in mitigating the risk associated with the formation of dermal carcinoma. Therefore, the development of new photoprotective agents is of great need. The current work examined the in vitro photoprotection of the aryl-linked (thio)semicarbazone derivatives against UVA-mediated DNA damage, inflammation, reactive nitrogen species (RNS), and ROS. Except for the inflammatory cytokine assay, which was carried out on the human monocytic leukemia (THP-1) cell line, all tests were conducted on the human dermal fibroblast (BJ) cell line. In comparison to benzophenone (reference compound), the compound (2Z, 2'Z)-2,2'-(1,3-Phenylenebis (methanylylidene)) bis (hydrazine-1-carbothioamide) (DD-21) demonstrated considerable protection against UVA-induced damage. Compared to the UVA-irradiated control, DD-21 significantly decreased the levels of nitric oxide (NO) and ROS (p < 0.001). In the presence of DD-21, the release of UVA-induced pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), was also significantly reduced (p < 0.05). Moreover, it was observed that DD-21 protected the cells from UVA-mediated DNA strand breaks and also inhibited the formation of cyclobutane pyrimidine dimers (CPDs) upon comparison to the UVA-exposed control cells (p < 0.001). In conclusion, the findings of this study revealed that DD-21 exhibits remarkable photoprotective properties, thus demonstrating its potential as a candidate UVA filter.


Asunto(s)
Daño del ADN , Rayos Ultravioleta , Humanos , Especies Reactivas de Oxígeno , Dímeros de Pirimidina , Inflamación
8.
Trials ; 25(1): 9, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38167206

RESUMEN

BACKGROUND: Pakistan is one of most vulnerable low- and middle-income countries with 29 million adult active tobacco users. Smoking cessation services are lacking as the tobacco control initiatives have largely failed to address the smoking endemic. Over the last 5 years, Pakistan has witnessed the use of innovative tobacco harm reduction (THR) products such as e-cigarettes and nicotine pouches. However, their use remains limited. THR products are imported legally as consumer goods and are taxable. The lack of sufficient data for THR and its application is a challenge in gauging their effectiveness in assisting smokers quit combustible smoking. Evidence-based studies can help in measuring the effectiveness of e-cigarettes and nicotine pouches as smoking cessation aids. METHOD: Keeping in view the study objectives, a sample size of 600 participants will be sufficient to assess the effectiveness of e-cigarettes and nicotine pouches for smoking cessation in Pakistan. Of these, 200 participants each will receive e-cigarettes and nicotine pouches along with basic care counselling, while the remaining 200 participants will only receive basic care counselling for 48 weeks. The association of participants' characteristics with smoking and health status will be based on the bivariate and multivariate analysis. The simple t-test and variance analysis will assess the differences in intervention indicators between the control and treatment groups. For the inferential analysis, the average treatment impact will be based on the quasi-experimental techniques such as difference in difference (DID) or propensity score matching (PMS). DISCUSSION: The study will evaluate the participants at the baseline as they decide the quit date. After every 12 weeks, a follow-up survey with the participants will be conducted. Results are anticipated to inform the public, decision-makers, and researchers about the effects of using e-cigarettes and nicotine pouches in the short- and medium-term periods. Critically, the potential of e-cigarettes and other alternative nicotine delivery systems as smoking cessation aid will be assessed. TRIAL REGISTRATION: ClinicalTrials.gov NCT05715164 . Registered on February 6, 2023. PROTOCOL VERSION: Protocol version 1.0, 14-12-2022 Trial in progress and not yet recruiting participants. Estimated primary data collection date-April 2024.


Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Cese del Hábito de Fumar , Adulto , Humanos , Nicotina , Cese del Hábito de Fumar/métodos , Pakistán , Dispositivos para Dejar de Fumar Tabaco , Ensayos Clínicos Controlados Aleatorios como Asunto
9.
Expert Opin Ther Pat ; 33(12): 841-864, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38115554

RESUMEN

INTRODUCTION: Schiff bases are compounds with characteristic features of azomethine linkage (-C=N-). Schiff bases are capable of coordinating with metal ions via azomethine nitrogen. Schiff base derivatives and their metal complexes are known for intriguing novel therapeutic properties. In organic synthesis, the Schiff base reaction is prime in creating the C-N bond. Synthetic accessibility and structural diversity are the salient features for facile synthesis of Schiff base hybrids via a condensation reaction between an aldehyde/ketone and primary amines. AREA COVERED: This review aims to provide a comprehensive overview of the commendable medicinal applications of Schiff base derivatives and their metal complexes patented from 2016 to 2023. EXPERT OPINION: Schiff base derivatives are exceptional molecules for their assorted applications in medicinal chemistry. Several Schiff base products are marketed as drugs, and plenty of room is available for the purposive synthesis of new compounds in a diverse pool of disciplines. Expansion in the derivatization of Schiff bases in innumerable directions with multitudinous applications makes them 'magical molecules.' These compounds have proved extraordinary, from medicinal chemistry to other fields outside medicine. This review covers the therapeutic importance of Schiff base derivatives and aims to cover the patents published in recent years (2016-2023).


Asunto(s)
Compuestos Azo , Complejos de Coordinación , Tiosemicarbazonas , Humanos , Complejos de Coordinación/química , Química Farmacéutica , Bases de Schiff/química , Patentes como Asunto , Ligandos
10.
Eur Respir Rev ; 32(170)2023 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-38123231

RESUMEN

Pulmonary hypertension (PH) is defined by the presence of a mean pulmonary arterial pressure >20 mmHg. Current guidelines describe five groups of PH with shared pathophysiological and clinical features. In this paper, the first of a series covering all five PH classification groups, the clinical, radiological and pathological features of pulmonary arterial hypertension (PAH) will be reviewed. PAH may develop in the presence of associated medical conditions or a family history, following exposure to certain medications or drugs, or may be idiopathic in nature. Although all forms of PAH share common histopathological features, the presence of certain pulmonary arterial abnormalities, such as plexiform lesions, and extent of co-existing pulmonary venous involvement differs between the different subgroups. Radiological investigations are key to diagnosing the correct form of PH and a systematic approach to interpretation, especially of computed tomography, is essential.


Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar Primaria Familiar , Arteria Pulmonar/diagnóstico por imagen
11.
Cureus ; 15(9): e45216, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37842429

RESUMEN

BACKGROUND: Immunomodulatory drugs target the overall immune system, hence producing numerous toxic effects on the other organs with serious health manifestations. Due to these safety concerns, there is a need to introduce or repurpose a new drug with immunomodulatory effects with good safety, efficacy, and better tolerance. Metformin, a standard antidiabetic drug, was evaluated for its immunomodulatory effects in diabetic models in the current study. METHODOLOGY: The diabetic model was developed by intraperitoneal (IP) administration of streptozotocin (60 mg/kg). The experimental rats were divided into six groups (three diabetic and three non-diabetic) with six rats in each group. Metformin (50 mg/kg and 80 mg/kg) was given orally to both diabetic and non-diabetic groups, once a day, for 42 days. Immunomodulatory cytokines interleukin (IL)-2, IL-4, IL-5, tumor necrosis factor (TNF)-α, and interferon gamma (INF-É£) were analyzed from blood samples by BD FCAP flow cytometer. RESULTS: The results revealed a significant (p=0.002) decrease in IL-2 and TNF-α in diabetic groups in comparison to control rats. However, no significant changes were observed in IL-4, IL-5, and INF-É£ levels. Importantly, the treatment of metformin at both doses, i.e., 50 and 80 mg/kg, significantly reduced the elevated levels of IL-2 and TNF-α when compared to untreated diabetic groups. CONCLUSION: Metformin may be considered as an optimum drug candidate to reduce pro-inflammatory cytokines, IL-2 and TNF-α, that can lead to the reduction of long-term diabetic complications.

12.
PLoS One ; 18(8): e0269717, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37585472

RESUMEN

Carlsberg subtilisin from Bacillus licheniformis PB1 was investigated as a potential feed supplement, through immobilizing on bentonite for improving the growth rate of broilers. Initially, the pre-optimized and partially-purified protease was extracted and characterized using SDS-PAGE with MW 27.0 KDa. The MALDI-TOF-MS/MS spectrum confirmed a tryptic peptide peak with m/z 1108.496 referring to the Carlsberg subtilisin as a protein-digesting enzyme with alkaline nature. The highest free enzyme activity (30 U/mg) was observed at 50°C, 1 M potassium phosphate, and pH 8.0. the enhanced stability was observed when the enzyme was adsorbed to an inert solid support with 86.39 ± 4.36% activity retention under 20 optimized conditions. Additionally, the dried immobilized enzyme exhibited only a 5% activity loss after two-week storage at room temperature. Structural modeling (Docking) revealed that hydrophobic interactions between bentonite and amino acids surrounding the catalytic triad keep the enzyme structure intact upon drying at RT. The prominent hygroscopic nature of bentonite facilitated protein structure retention upon drying. During a 46-days study, supplementation of boilers' feed with the subtilisin-bentonite complex promoted significant weight gain i.e. 15.03% in contrast to positive control (p = 0.001).


Asunto(s)
Aves de Corral , Subtilisinas , Animales , Subtilisinas/metabolismo , Aves de Corral/metabolismo , Pollos/metabolismo , Bentonita , Espectrometría de Masas en Tándem , Subtilisina , Concentración de Iones de Hidrógeno
13.
J Biomol Struct Dyn ; : 1-15, 2023 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-37643014

RESUMEN

To explore the new mode of action and reduce side effects, making conjugates of existing drugs is becoming an attractive tool in the realm of medicinal chemistry. In this work, we exploited this approach and synthesized new conjugates to assess their activities against the enzymes involved in different pathological conditions. Specifically, we design and synthesized conjugates involving acetylsalicylic acid and sulfa drugs, validating the newly crafted conjugates using techniques like IR, 1HNMR, 13CNMR, and elemental analysis. These conjugates underwent assessment for their ability to inhibit cyclooxygenase-2 (COX-2), urease enzymes, and their anti-inflammatory potential. A competitive mode of urease inhibition was observed for acetylsalicylic acid conjugated with sulfanilamide, sulfacetamide, and sulfadiazine with IC50 of 2.49 ± 0.35 µM, 6.21 ± 0.28 µM, and 6.57 ± 0.44 µM, respectively. Remarkably, the acetylsalicylic acid-sulfamethoxazole conjugate exhibited exceptional anti-inflammatory activity, effectively curtailing induced edema by 83.7%, a result akin to the reference anti-inflammatory drug indomethacin's performance (86.8%). Additionally, it demonstrated comparable COX-2 inhibition (75.8%) to the reference selective COX-2 inhibitor celecoxib that exhibited 77.1% inhibition at 10 µM concentration. To deepen our understanding, we employed molecular docking techniques to predict the binding interactions of competitive inhibitors with COX-2 and urease receptors. Additionally, MD simulations were carried out, confirming the stability of inhibitor-target complexes throughout the simulation period, devoid of significant conformational changes. Collectively, our research underscores the potential of coupling approved medicinal compounds to usher in novel categories of pharmacological agents, holding promise for addressing a wide spectrum of pathological disorders involving COX-2 and urease enzymes.Communicated by Ramaswamy H. Sarma.

14.
Eur Respir J ; 62(2)2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37414419

RESUMEN

BACKGROUND: Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient "feels, functions or survives". METHODS: Consecutive treatment-naïve patients with pulmonary arterial hypertension (PAH) between 2010 and 2022 who had two CMR scans (at baseline prior to treatment and 12 months following treatment) were identified from the ASPIRE registry. All patients were followed up for 1 additional year after the second scan. For both scans, cardiac measurements were obtained from a validated fully automated segmentation tool. The MID in CMR metrics was determined using two distribution-based (0.5sd and minimal detectable change) and two anchor-based (change difference and generalised linear model regression) methods benchmarked to how a patient "feels" (emPHasis-10 quality of life questionnaire), "functions" (incremental shuttle walk test) or "survives" for 1-year mortality to changes in CMR measurements. RESULTS: 254 patients with PAH were included (mean±sd age 53±16 years, 79% female and 66% categorised as intermediate risk based on the 2022 European Society of Cardiology/European Respiratory Society risk score). We identified a 5% absolute increase in RV ejection fraction and a 17 mL decrease in RV end-diastolic or end-systolic volumes as the MIDs for improvement. Conversely, a 5% decrease in RV ejection fraction and a 10 mL increase in RV volumes were associated with worsening. CONCLUSIONS: This study establishes clinically relevant CMR MIDs for how a patient "feels, functions or survives" in response to PAH treatment. These findings provide further support for the use of CMR as a clinically relevant clinical outcome measure and will aid trial size calculations for studies using CMR.


Plain language summaryPulmonary arterial hypertension (PAH) is a disease of the vessels of the lung that causes their narrowing and stiffening. As a result, the heart pumping blood into these diseased lung vessels has to work harder and eventually gets worn out. PAH can affect patients' ability to function in daily activities and impact their quality of life. It also reduces their life expectancy dramatically. Patients are, therefore, often monitored and undergo several investigations to adapt treatment according to their situation. These investigations include a survey of how a patient feels (the emPHasis-10 questionnaire), functions (walking test) and how well the heart is coping with the disease (MRI of the heart). Until now, it is unclear how changes on MRI of the heart reflect changes in how a patient feels and functions. Our study identified patients that had the emPHasis-10 questionnaire, walking test and MRI of the heart at both the time of PAH diagnosis and one year later. This allowed us to compare how the changes in the different tests relate to each other. And because previous research identified thresholds for important changes in the emPHasis-10 questionnaire and the walking tests, we were able to use these tests as a benchmark for changes in the MRI of the heart. Our study identified thresholds for change on heart MRI that might indicate whether a patient has improved or worsened. This finding might have implications for how patients are monitored in clinical practice and future research on PAH treatments.


Asunto(s)
Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , Hipertensión Arterial Pulmonar/diagnóstico por imagen , Calidad de Vida , Imagen por Resonancia Magnética/métodos , Volumen Sistólico/fisiología , Hipertensión Pulmonar Primaria Familiar , Función Ventricular Derecha , Valor Predictivo de las Pruebas
15.
Crit Rev Eukaryot Gene Expr ; 33(6): 87-100, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37522547

RESUMEN

Choice of vector is the most critical step in gene therapy. Adeno-associated viruses (AAV); third generation vectors, are getting much attention of scientists to be used as vehicles due to their non-pathogenicity, excellent safety profile, low immune responses, great efficiency to transduce non-dividing cells, large capacity to transfer genetic material and long-term expression of genetic payload. AAVs have multiple serotypes and each serotype shows tropism for a specific cell. Different serotypes are used to target liver, lungs, muscles, retina, heart, CNS, kidneys, etc. Furthermore, AAV based gene therapies have tremendous marketing applications that can be perfectly incorporated in the anticipated sites of the host target genome resulting in life long expression of transgenes. Some therapeutic products use AAV vectors that are used to treat lipoprotein lipase deficiency (LPLD) and it is injected intramuscularly, to treat mutated retinal pigment epithelium RPE65 (RPE65) that is introduced to subretinal space, an intravenous infusion to treat spinal muscular atrophy and rAAV2-CFTR vector is introduced into nasal epithelial cells to treat cystic fibrosis. AAV therapies and other such interdisciplinary methodologies can create the miracles for the generation of precision gene therapies for the treatment of most serious and sometimes fatal disorders.


Asunto(s)
Dependovirus , Técnicas de Transferencia de Gen , Humanos , Dependovirus/genética , Dependovirus/metabolismo , Vectores Genéticos/genética , Terapia Genética/métodos , Retina/metabolismo
16.
Cureus ; 15(6): e41019, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37519491

RESUMEN

While the presence of metastatic melanocytoma in the central nervous system (CNS) is relatively common, primary spinal melanocytoma (PSM) is an extremely rare entity. Only 70 cases have been reported, and its usual position is the cervical region. We report a case of a 35-year-old male with primary spinal intramedullary melanocytoma with a dorsal exophytic component. The tumor was first opened in the periphery and was closed without being operated upon due to it being an uncommon pathology.

17.
Curr Heart Fail Rep ; 20(3): 194-207, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37271771

RESUMEN

PURPOSE OF REVIEW: The right ventricle (RV) has a complex geometry and physiology which is distinct from the left. RV dysfunction and failure can be the aftermath of volume- and/or pressure-loading conditions, as well as myocardial and pericardial diseases. RECENT FINDINGS: Echocardiography, magnetic resonance imaging and right heart catheterisation can assess RV function by using several qualitative and quantitative parameters. In pulmonary hypertension (PH) in particular, RV function can be impaired and is related to survival. An accurate assessment of RV function is crucial for the early diagnosis and management of these patients. This review focuses on the different modalities and indices used for the evaluation of RV function with an emphasis on PH.


Asunto(s)
Insuficiencia Cardíaca , Hipertensión Pulmonar , Disfunción Ventricular Derecha , Humanos , Función Ventricular Derecha/fisiología , Hipertensión Pulmonar/diagnóstico , Ecocardiografía/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Disfunción Ventricular Derecha/diagnóstico por imagen
18.
Front Cardiovasc Med ; 10: 1016994, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37139140

RESUMEN

Introduction: Severe pulmonary hypertension (mean pulmonary artery pressure ≥35 mmHg) in chronic lung disease (PH-CLD) is associated with high mortality and morbidity. Data suggesting potential response to vasodilator therapy in patients with PH-CLD is emerging. The current diagnostic strategy utilises transthoracic Echocardiography (TTE), which can be technically challenging in some patients with advanced CLD. The aim of this study was to evaluate the diagnostic role of MRI models to diagnose severe PH in CLD. Methods: 167 patients with CLD referred for suspected PH who underwent baseline cardiac MRI, pulmonary function tests and right heart catheterisation were identified. In a derivation cohort (n = 67) a bi-logistic regression model was developed to identify severe PH and compared to a previously published multiparameter model (Whitfield model), which is based on interventricular septal angle, ventricular mass index and diastolic pulmonary artery area. The model was evaluated in a test cohort. Results: The CLD-PH MRI model [= (-13.104) + (13.059 * VMI)-(0.237 * PA RAC) + (0.083 * Systolic Septal Angle)], had high accuracy in the test cohort (area under the ROC curve (0.91) (p < 0.0001), sensitivity 92.3%, specificity 70.2%, PPV 77.4%, and NPV 89.2%. The Whitfield model also had high accuracy in the test cohort (area under the ROC curve (0.92) (p < 0.0001), sensitivity 80.8%, specificity 87.2%, PPV 87.5%, and NPV 80.4%. Conclusion: The CLD-PH MRI model and Whitfield model have high accuracy to detect severe PH in CLD, and have strong prognostic value.

20.
Bioorg Chem ; 134: 106450, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36924652

RESUMEN

Ectonucleotidases, a well-known superfamily of plasma membrane located metalloenzymes plays a central role in mediating the process of purinergic cell signaling. Major functions performed by these enzymes include the hydrolysis of extracellular nucleosides and nucleotides which are considered as important cell-signaling molecules. Any (patho)-physiologically induced disruption in this purinergic cell signaling leads to several disorders, hence these enzymes are important drug targets for therapeutic purposes. Among the major challenges faced in the design of inhibitors of ectonucleotidases, an important one is the lack of selective inhibitors. Access to highly selective inhibitors via a facile synthetic route will not only be beneficial therapeutically, but will also lead to an increase in our understanding of intricate interplay between members of ectonucleotidase enzymes in relation to their selective activation and/or inhibition in different cells and tissues. Herein we describe synthesis of highly selective inhibitors of human intestinal alkaline phosphatase (h-IAP) and human tissue non-specific alkaline phosphatase (h-TNAP), containing chromone sulfonamide and sulfonylhydrazone scaffolds. Compound 1c exhibited highest (and most selective) h-IAP inhibition activity (h-IAP IC50 = 0.51 ± 0.20 µM; h-TNAP = 36.5%) and compound 3k showed highest activity and selective inhibition against h-TNAP (h-TNAP IC50 = 1.41 ± 0.10 µM; h-IAP = 43.1%). These compounds were also evaluated against another member of ectonucleotidase family, that is rat and human ecto-5'-nucleotidase (r-e5'NT and h-e5'NT). Some of the compounds exhibited excellent inhibitory activity against ecto-5'-nucleotidase. Compound 2 g exhibited highest inhibition against h-e5'NT (IC50 = 0.18 ± 0.02 µM). To rationalize the interactions with the binding site, molecular docking studies were carried out.


Asunto(s)
5'-Nucleotidasa , Fosfatasa Alcalina , Ratas , Humanos , Animales , Simulación del Acoplamiento Molecular , Inhibidores Enzimáticos/química , Sulfonamidas/farmacología , Sulfonamidas/química , Cromonas/farmacología
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