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1.
Mol Pharm ; 21(5): 2065-2080, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38600804

RESUMEN

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence "safe space" industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.


Asunto(s)
Biofarmacia , Industria Farmacéutica , Humanos , Biofarmacia/métodos , Industria Farmacéutica/métodos , Modelos Biológicos , Equivalencia Terapéutica , Preparaciones Farmacéuticas/química , Estados Unidos
2.
Mol Pharm ; 21(8): 3697-3731, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-38946085

RESUMEN

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.


Asunto(s)
Biofarmacia , Modelos Biológicos , Biofarmacia/métodos , Humanos , Solubilidad , Preparaciones Farmacéuticas/química , Excipientes/química , Química Farmacéutica/métodos
3.
Mol Pharm ; 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39348508

RESUMEN

The proceedings from the 30th August 2023 (Day 2) of the workshop "Physiologically Based Biopharmaceutics Models (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives" are provided herein. Day 2 covered PBBM case studies from six regulatory authorities which provided considerations for model verification, validation, and application based on the context of use (COU) of the model. PBBM case studies to define critical material attribute (CMA) specification settings, such as active pharmaceutical ingredient (API) particle size distributions (PSDs) were shared. PBBM case studies to define critical quality attributes (CQAs) such as the dissolution specification setting or to define the bioequivalence safe space were also discussed. Examples of PBBM using the credibility assessment framework, COU and model risk assessment, as well as scientific learnings from PBBM case studies are provided. Breakout session discussions highlighted current trends and barriers to application of PBBMs including: (a) PBBM credibility assessment framework and level of validation, (b) use of disposition parameters in PBBM and points to consider when iv data are not available, (c) conducting virtual bioequivalence trials and dealing with variability, (d) model acceptance criteria, and (e) application of PBBMs for establishing safe space and failure edges.

4.
Br J Clin Pharmacol ; 90(6): 1428-1449, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38450818

RESUMEN

AIMS: The current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations. METHODS: Vaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel. Due to lack of data, the vaginal absorption parameters were calculated based on assumptions or optimized. The model uses release rate/in vitro release profiles with formulation characteristics to predict drug mass transfer across vaginal tissue into the systemic circulation. RESULTS: For lidocaine and tenofovir vaginal gel, the predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits. The average fold error (AFE) and absolute AFE indicating bias and precision of predictions range from 0.62 to 1.61. For dapivirine, the pharmacokinetic parameters are under and overpredicted in some studies due to lack of formulation composition details and relevance of release rate used in ring model. The predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits for etonogestrel and ethinylestradiol vaginal ring (AFEs and absolute AFEs from 0.84 to 1.83). CONCLUSION: The current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future.


Asunto(s)
Simulación por Computador , Dispositivos Anticonceptivos Femeninos , Modelos Biológicos , Tenofovir , Vagina , Absorción Vaginal , Cremas, Espumas y Geles Vaginales , Femenino , Humanos , Cremas, Espumas y Geles Vaginales/administración & dosificación , Cremas, Espumas y Geles Vaginales/farmacocinética , Tenofovir/farmacocinética , Tenofovir/administración & dosificación , Vagina/metabolismo , Vagina/efectos de los fármacos , Administración Intravaginal , Etinilestradiol/farmacocinética , Etinilestradiol/administración & dosificación , Desogestrel/administración & dosificación , Desogestrel/farmacocinética , Pirimidinas/farmacocinética , Pirimidinas/administración & dosificación , Adulto , Área Bajo la Curva , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación
5.
J Food Sci Technol ; 61(5): 870-878, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38487282

RESUMEN

Sorbitol has been the new and emerging adulterant in dairy industry. The main aim of the study was to develop a method to detect sorbitol in milk, which is not affected by other sugars, polyols and formalin. Hence, a thin layer chromatographic (TLC) method was standardized to detect the sorbitol in milk. In the study 90 s duration for the impregnation of Silica gel 60F TLC plates with Cu- ions was found suitable to resolve sorbitol as a distinct spot. The standardized conditions were (1) developing solvent system consisting of n-propanol: ethyl acetate: water (7:1:2), (2) 0.5% of potassium permanganate in 0.1 M NaOH as color developing reagent. (3) Drying temperature (65°C/ 10 min.) after spraying the color developing reagent. The limit of detection was 0.2% of added sorbitol in milk. The standardized method could also detect the sorbitol in the presence of sucrose, glucose and polyols like mannitol and maltitol. In both cow and buffalo milk samples the standardized methodology performed well in detection of sorbitol. The method also performed well in sorbitol spiked formalin preserved milk samples. This method can be an alternative to the other methods involving costly equipment in detecting adulteration of milk with sorbitol.

6.
Arch Orthop Trauma Surg ; 143(1): 453-468, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35780426

RESUMEN

BACKGROUND: There are various classification systems described in the literature for managing bone defects in revision knee arthroplasty (RTKA). We analysed the reliability and usefulness of these classification systems. QUESTIONS/PURPOSES: (1) To review and critique the various classification systems proposed for bone loss in RTKA. (2) Among all the proposed classifications which one is the most commonly used by surgeons to report their results. (3) What is the reliability of various bone defect classification systems for RTKA. In this review, we have assessed the studies validating those classifications with a detailed description of the limitations and the proposed modifications. METHODS: This systematic review was conducted following PRISMA guidelines. Pubmed/Medline, CINAHL, EMBASE, Scopus, Cochrane databases and Web of Science databases were searched using multiple search terms and MeSH terms where possible. Studies meeting inclusion criteria were assessed for statistical parameters of reliability of a classification system. RESULTS: We found 16 classification systems for bone defects in RTKA. Six studies were found evaluating a classification system with reporting their reliability parameters. Fifty-four studies were found which classified bone loss using AORI classification in their series. AORI classification is most commonly reported for classifying bone defects. Type T2B and F2B are the most common bone defects in RTKA. The average kappa value for AORI classification for femoral bone loss was 0.38 (0.27-0.50) and 0.76 (0.63-1) for tibial bone loss assessment. CONCLUSION: None of the available classification systems is reliably established in determining the bone loss and treatment plans in RTKA. Among all, AORI classification is the most widely used system in clinical practice. The reliability of AORI Classification is fair for femoral bone loss and substantial for tibial bone loss.


Asunto(s)
Artroplastia de Reemplazo de Rodilla , Prótesis de la Rodilla , Humanos , Artroplastia de Reemplazo de Rodilla/métodos , Reproducibilidad de los Resultados , Reoperación , Tibia/cirugía , Articulación de la Rodilla/cirugía
7.
Arch Orthop Trauma Surg ; 143(3): 1371-1378, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35039914

RESUMEN

The results of conventional corrective procedures remain suboptimal for severe cubitus varus deformities (> 30°) in children. We present the results of shortening dome osteotomy for the correction of such deformities. PATIENTS AND METHODS: We present retrospective review of prospectively collected data of 18 patients (11 boys and 7 girls) who underwent shortening dome osteotomy between January 2011 and December 2019 for severe cubitus varus deformities (> 30°) secondary to malunited supracondylar fracture. The procedure involved the removal of convexo-concave bone (5-8 mm wide) between the two domes. Humero-ulnar angles, lateral condylar prominence index (LCPI), and elbow range of movements were recorded preoperatively and postoperatively. RESULTS: Mean age was 7.5 years (range 5 years-11 years). Indication for surgery was poor cosmesis in all the patients and tardy ulnar nerve symptoms in three patients. Mean preoperative humero-ulnar angle was 26.1° varus (range 22°-34°), while it was 7.1° valgus (range 0°-12°) for contralateral normal elbow. They were followed for a mean duration of 2.2 years (range 12 months-5.8 years). The mean postoperative valgus angle achieved was 7.3° (range 2°-12°) as total angular correction achieved was 34.4° (range 30°-44°) (p < 0.001). Radiological healing was observed in all the patients at mean duration of 7.1 weeks (range 5 weeks-9 weeks). Mean preoperative and postoperative LCPI were - 2.4 (range +4.7 to - 10.5) and - 1.7 (range +4.5 to - 5.1), respectively (p = 0.595). Three patients had pin tract infections and two of them responded to aseptic dressings and oral antibiotics, while another required early pin removal and additional protection in splint. All patients regained preoperative arc of motion within 6 months after the procedure. CONCLUSION: Shortening dome osteotomy is a safe and effective method for correcting severe cubitus varus deformities (> 30°) secondary to malunited supracondylar fracture in children.


Asunto(s)
Articulación del Codo , Fracturas Mal Unidas , Fracturas del Húmero , Deformidades Adquiridas de la Articulación , Masculino , Femenino , Humanos , Niño , Preescolar , Fracturas del Húmero/cirugía , Resultado del Tratamiento , Deformidades Adquiridas de la Articulación/complicaciones , Deformidades Adquiridas de la Articulación/cirugía , Rango del Movimiento Articular/fisiología , Articulación del Codo/cirugía , Osteotomía/métodos , Fracturas Mal Unidas/diagnóstico
8.
J Food Sci Technol ; 60(12): 3014-3023, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37786594

RESUMEN

Ghee is a premium product in Southeast Asia and is prone to adulteration with vegetable oils/ fats. The main aim of the study was to develop an easy-to-use paper-based sensor to detect this adulteration. Hence, a protocol involving hexane and acetonitrile for the extraction of synthetic antioxidants from adulterated ghee and its rapid detection using DPPH was standardized. Paper-based discs impregnated with 4 mM DPPH were developed. The developed paper-based disc sensors worked well and their response time was indirectly proportional to the antioxidant concentration (0.0025-0.02%). Using the developed disc sensors, the palm oil, and sunflower oil added to cow ghee @2.5% or more, and 1% or more, respectively could be detected. The shelf life of the developed sensors was 30 and 90 days at 30 °C and 4-6 °C, respectively. In stored cow ghee samples, the response time of the sensors increased as the storage period of ghee samples increased. The cutoff limit to declare the sample of cow ghee as unadulterated was fixed to 60 min. Based on the response time of the sensor, the level of detection of vegetable oils in stored cow ghee was found to be 2.5%.

9.
Mol Pharm ; 19(7): 2542-2548, 2022 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-35729720

RESUMEN

The first aim of this study was to evaluate the usefulness of optimized human fecal material in simulating sulforeductase activity in the lower intestine by assessing bacterial degradation of sulindac and sulfinpyrazone, two sulforeductase substrates. The second aim was to evaluate the usefulness of drug degradation half-life generated in simulated colonic bacteria (SCoB) in informing PBPK models. Degradation experiments of sulfinpyrazone and of sulindac in SCoB were performed under anaerobic conditions using recently described methods. For sulfinpyrazone, the abundance of clinical data allowed for construction of a physiologically based pharmacokinetic (PBPK) model and evaluation of luminal degradation clearance determined from SCoB data. For sulindac, the availability of sulindac sulfide and sulindac sulfone standards allowed for evaluating the formation of the main metabolite, sulindac sulfide, during the experiments in SCoB. Both model compounds degraded substantially in SCoB. The PBPK model was able to adequately capture exposure of sulfinpyrazone and its sulfide metabolite in healthy subjects, in ileostomy and/or colectomy subjects, and in healthy subjects pretreated with metoclopramide by implementing degradation half-lives in SCoB to calculate intrinsic colon clearance. Degradation rates of sulindac and formation rates of sulindac sulfide in SCoB were almost identical, in line with in vivo data suggesting the sulindac sulfide is the primary metabolite in the lower intestine. Experiments in SCoB were useful in simulating sulforeductase related bacterial degradation activity in the lower intestine. Degradation half-life calculated from experiments in SCoB is proven useful for informing a predictive PBPK model for sulfinpyrazone.


Asunto(s)
Sulfinpirazona , Sulindac , Bacterias , Humanos , Intestinos , Cinética , Sulfinpirazona/metabolismo , Sulindac/metabolismo
10.
Mol Pharm ; 19(9): 3139-3152, 2022 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-35969125

RESUMEN

Physiologically based pharmacokinetic (PBPK) modeling has increasingly been employed in dermal drug development and regulatory assessment, providing a framework to integrate relevant information including drug and drug product attributes, skin physiology parameters, and population variability. The current study aimed to develop a stepwise modeling workflow with knowledge gained from modeling in vitro skin permeation testing (IVPT) to describe in vivo exposure of metronidazole locally in the stratum corneum following topical application of complex semisolid drug products. The initial PBPK model of metronidazole in vitro skin permeation was developed using infinite and finite dose aqueous metronidazole solution. Parameters such as stratum corneum lipid-water partition coefficient (Ksclip/water) and stratum corneum lipid diffusion coefficient (Dsclip) of metronidazole were optimized using IVPT data from simple aqueous solutions (infinite) and MetroGel (10 mg/cm2 dose application), respectively. The optimized model, when parameterized with physical and structural characteristics of the drug products, was able to accurately predict the mean cumulative amount permeated (cm2/h) and flux (µg/cm2/h) profiles of metronidazole following application of different doses of MetroGel and MetroCream. Thus, the model was able to capture the impact of differences in drug product microstructure and metamorphosis of the dosage form on in vitro metronidazole permeation. The PBPK model informed by IVPT study data was able to predict the metronidazole amount in the stratum corneum as reported in clinical studies. In summary, the proposed model provides an enhanced understanding of the potential impact of drug product attributes in influencing in vitro skin permeation of metronidazole. Key kinetic parameters derived from modeling the metronidazole IVPT data improved the predictions of the developed PBPK model of in vivo local metronidazole concentrations in the stratum corneum. Overall, this work improves our confidence in the proposed workflow that accounts for drug product attributes and utilizes IVPT data toward improving predictions from advanced modeling and simulation tools.


Asunto(s)
Metronidazol , Piel , Administración Cutánea , Lípidos , Agua
11.
Chin J Traumatol ; 25(4): 224-231, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34330596

RESUMEN

PURPOSE: Common peroneal nerve palsy is quite disabling and every effort should be made to prevent its injury during the treatment. METHODS: We retrospectively reviewed the prospectively collected data of 7 cases of tibial plateau fractures in association with proximal fibula fracture from January 2019 to September 2019 who presented to emergency room of our hospital. RESULTS: In addition to fibular neck fracture, the first case had type 6 tibial plateau displaced fracture and the second case had displaced acetabular fracture with instability of knee with tibial tuberosity avulsion. common peroneal nerve palsy developed following application of distal tibial skeletal traction in both the cases. Other 6 such cases remained neurologically intact as traction was not applied to them. CONCLUSION: Such iatrogenic complication could have been prevented if the injury pattern of "concomitant medial and lateral columns" of the proximal leg is kept in mind by the treating surgeon before applying skeletal traction.


Asunto(s)
Traumatismos de la Rodilla , Fracturas de la Tibia , Peroné/lesiones , Humanos , Enfermedad Iatrogénica/prevención & control , Parálisis , Estudios Retrospectivos , Fracturas de la Tibia/complicaciones , Fracturas de la Tibia/cirugía
12.
J Food Sci Technol ; 59(8): 3231-3236, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35872712

RESUMEN

Ghee production form one of the largest segments of the milk consumption and utilization pattern in India. Recently, cow ghee has become more popular and fetching premium over buffalo ghee as there are innumerable health benefits credit to cow ghee since they contain an important array of nutrients and therapeutic principles. Therefore, the present investigation was conducted to differentiate and characterize cow ghee from buffalo ghee using physico-chemical parameters viz. BR reading, RM value, Polenske value, Kirschner value and different color values. Pure cow and buffalo ghee samples were prepared using creamery butter method. Pure ghee samples (cow and buffalo) and cow ghee samples admixed with buffalo ghee @ 5%, 10%, 15% and 20% were analyzed for above mentioned physico-chemical parameters and different color parameters. The results revealed that BR reading, RM value, Polenske value and Kirschner value of pure cow ghee ranged from 41.87-43.62, 27.5-31.13, 1.30-1.90 and 20.74-24.14 and in buffalo ghee these values ranged from 40.01-43.23, 31.91-39.99, 1.10-1.50 and 26.84-33.96, respectively. The color values i.e. lightness (L), redness(a), yellowness (b), yellowness index (Y) and whiteness index (W) of pure cow ghee ranged from 70.17-81.56, - 14.04 to - 28.96, 59.68-79.31, 74.25-88.92 and 16.07-28.85 and of buffalo ghee ranged from 71.89-83.71, - 1.07 to - 11.92, 1.39-9.61, 5.21-22.46 and 68.74-84.61. BR reading, RM value, Polenske value and L, a, b and Y of cow ghee adulterated with buffalo ghee up to 20% falls within the range of different pure cow ghee samples but whiteness index (W) and Kirschner value of admixed cow ghee (23.91 and 34.86) were having significantly higher values than the pure cow ghee (21.07 and 25.45, respectively). Kirschner Value and whiteness index (W) can be used to distinguish cow ghee from buffalo ghee.

13.
J Food Sci Technol ; 59(3): 956-967, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35185202

RESUMEN

Ultrafiltration (UF) of buffalo skim milk (BSM) induces changes in its delicate protein-mineral equilibrium. Appling UF causes alteration in chemical composition of UF retentates as a function of protein concentration that adversely affect their physical and rheological properties. Hence, present investigation was targeted to evaluate the changes taking place in heat stability, ζ-potential, particle size, apparent viscosity, pH, turbidity and crossover temperature of storage (G') and loss (G″) modulus of high-protein BSM based UF retentates as a function of homogenization and sodium hydrogen phosphate (SHP) addition. The UF of BSM (heat treated at 85 ± 1 °C for 5 min), significantly increased (P < 0.05) the concentration of protein, fat and minerals, however, it decreased the concentration of lactose and water soluble minerals in UF retentates over BSM. The SHP addition significantly increased (P < 0.05) pH, crossover temperature of G' and G″, ζ-potential, while significantly decreased (P < 0.05) turbidity and particle size in most non-homogenized retentates. Heat coagulation time (HCT) of control and treated UF retentates were at par (P > 0.05) with each other, however, variations were observed in their viscosity values. Rheological behaviour of most of these UF retentates was efficiently described by Bingham model. The correlation among ζ-potential, particle size, apparent viscosity, pH, turbidity, HCT and crossover temperatures G' and G″ of evaluated samples was also established. Overall, this study concluded that 0.5-6% SHP addition in non-homogenized UF retentates, markedly improved their milk protein stability as advocated by higher ζ-potential, G' and G″ crossover temperature values. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-021-05097-2.

14.
J Biol Chem ; 295(25): 8413-8424, 2020 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-32358063

RESUMEN

Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C-X-C motif chemokine receptor 4 (CXCR4) and hedgehog pathways cooperate in PC chemoresistance via bidirectional tumor-stromal crosstalk. We show that when PC cells are co-cultured with pancreatic stellate cells (PSCs) they are significantly more resistant to gemcitabine toxicity than those grown in monoculture. We also demonstrate that this co-culture-induced chemoresistance is abrogated by inhibition of the CXCR4 and hedgehog pathways. Similarly, the co-culture-induced altered expression of genes in PC cells associated with gemcitabine metabolism, antioxidant defense, and cancer stemness is also reversed upon CXCR4 and hedgehog inhibition. We have confirmed the functional impact of these genetic alterations by measuring gemcitabine metabolites, reactive oxygen species production, and sphere formation in vehicle- or gemcitabine-treated monocultures and co-cultured PC cells. Treatment of orthotopic pancreatic tumor-bearing mice with gemcitabine alone or in combination with a CXCR4 antagonist (AMD3100) or hedgehog inhibitor (GDC-0449) displays reduced tumor growth. Notably, we show that the triple combination treatment is the most effective, resulting in nearly complete suppression of tumor growth. Immunohistochemical analysis of Ki67 and cleaved caspase-3 confirm these findings from in vivo imaging and tumor measurements. Our findings provide preclinical and mechanistic evidence that a combination of gemcitabine treatment with targeted inhibition of both the CXCR4 and hedgehog pathways improves outcomes in a PC mouse model.


Asunto(s)
Proteínas Hedgehog/metabolismo , Receptores CXCR4/metabolismo , Anilidas/farmacología , Anilidas/uso terapéutico , Animales , Antimetabolitos Antineoplásicos/metabolismo , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Bencilaminas , Comunicación Celular , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Ciclamas , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Resistencia a Antineoplásicos/genética , Proteínas Hedgehog/antagonistas & inhibidores , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/uso terapéutico , Humanos , Ratones , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Células Estrelladas Pancreáticas/citología , Células Estrelladas Pancreáticas/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Transducción de Señal/efectos de los fármacos , Gemcitabina
15.
Int J Vitam Nutr Res ; 91(1-2): 133-142, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31699013

RESUMEN

The objective of this investigation was to evaluate the stability of vitamin A in fortified milk which was exposed to different processing conditions viz. heat treatments (pasteurization, boiling and sterilization), light exposure treatments (1485, 2970 and 4455 lux for 2, 4, 8, 16 and 32 h) and different packaging materials (polyethylene pouches and glass bottles) and also to evaluate the effect of fortified iron (ferric pyrophosphate soluble (FPP) and ferrous gluconate hydrate (FG) on vitamin A stability during processing and storage. Toned milk was fortified with 25 ppm iron and vitamin A acetate 2500 IU/L, singly and also in combination. The vitamin A analysis method was optimized and accuracy and precision were below ± 5%. The results indicated that vitamin A was heat-labile and its degradation increased with the increase in the intensity of heat treatments. Pasteurized milk (318.11 IU/L) showed non-significant (p > 0.05) decrease, however, boiling (250.21 IU/L) and sterilization (205.65 IU/L) showed a significant difference (p < 0.05) in vitamin A content in comparison to control (324.71 IU/L). Similarly, vitamin A was light sensitive and its degradation significantly increased (p < 0.05) with an increase in the intensity of light exposure (34.82 to 92.53%). Loss of vitamin A (%) was significantly greater (p < 0.05) in iron-fortified milk suggesting that iron might have played a role in accelerating the degradation of vitamin A. Extent of losses were significantly higher (p < 0.05) in FG compared to FPP fortified milk. Vitamin A (microencapsulated form) which was added externally was more stable than the inherent vitamin A present in milk.


Asunto(s)
Leche , Vitamina A , Animales , Suplementos Dietéticos , Diterpenos , Alimentos Fortificados , Ésteres de Retinilo
16.
Int Orthop ; 45(7): 1783-1792, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34028572

RESUMEN

BACKGROUND: Leprous neuropathy is treatable but still a source of disability worldwide. Multidrug therapy (MDT) and oral steroids are the main stay of treatment. Ulnar nerve, at the elbow, is commonly involved. Nerve decompression may be required in selected cases by an epineurotomy (internal neurolysis). The preferred surface of ulnar nerve for performing this procedure to minimize iatrogenic vascular compromise is a matter of debate. QUESTIONS/PURPOSES: We describe the epineural vessel arrangement on the medial and lateral surface of ulnar nerve around the medial epicondyle while performing epineurotomy for leprous neuropathy. METHODS: We enrolled patients of symptomatic leprous ulnar neuropathy of less than one year duration on MDT that did not respond to steroids, for surgical decompression. Ten patients underwent epineurotomy of ulnar nerves (N = 11) around medial epicondyle. The epineural vessels were classified as per Sunderland's classification of arteriae nervorum. The number of epineural vessels was assessed on the medial and lateral surface of the ulnar nerve adjoining the medial epicondyle. The epineurotomy incision was placed over the surface of ulnar nerve having relatively less vessels. RESULTS: The mean number of epineural vessels on the medial surface was 9.72 (range; 7-14) and on the lateral surface were 4.72 (range; 3-6). The average number of vessels per cm2 of the medial and lateral surface of the nerve was 0.94 and 0.48, respectively. The most common type of epineural vessel was type 3 on both medial and lateral surface of the nerve. Lateral epineurotomy was performed in all 11 cases. All the patients had relief from neuropathic pain. The mean VAS score improved from 3.20 ± 0.89 to 0.50 ± 0.34 at 2 years follow-up (p = 0.02). The mean motor score improved from 9.31 ± 4.12 to 15.42 ± 3.10 and sensory score improved from 40.0 ± 30.70 to 85 ± 9.90 at two years follow-up (p < 0.01). CONCLUSION: Lateral surface (facing the medial epicondyle) of ulnar nerve has a lesser density of epineural vessels in comparison to its medial (subcutaneous) surface. CLINICAL RELEVANCE: This anatomical understanding may be helpful in minimizing the iatrogenic vascular compromise of ulnar nerve while performing its epineurotomy around the medial epicondyle for leprous neuropathy. The findings may be extrapolated to other clinical indications of epineurotomy of ulnar nerve, for example, in cubital tunnel syndrome, traumatic ulnar neuroma in continuity, and benign ulnar nerve tumors.


Asunto(s)
Síndrome del Túnel Cubital , Leprostáticos , Síndrome del Túnel Cubital/cirugía , Descompresión Quirúrgica , Quimioterapia Combinada , Codo/cirugía , Humanos , Nervio Cubital/cirugía
17.
Acta Orthop Belg ; 87(1): 25-34, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34129754

RESUMEN

Spontaneous subcapital fracture (SSF) of femoral neck in pre-existent osteonecrosis of femoral head (ONFH) is a rare presentation. Only a few cases have been reported so far and majority of them have been reported to have unilateral hip involvement. We retrospectively reviewed clinical-radiological data of 10 patients (12 hips) with SSF complicating ONFH. All of them underwent uncemented total hip arthroplasty. All the available publications in the English language based medical literature were critically reviewed and results were summarized. The median age of presentation was 32 years (range : 24 years to 61 years). They were followed up for a mean duration of 25 months (range : 12 months to 59 months). The most common risk factor was corticosteroid consumption (7 out of 10 patients). All except one (modified Ficat and Arlet stage II) belonged to advanced stage of ONFH {stage III 3 patients (3 hips), stage IV 6 patients (8 hips)}. The mean time lag of ONFH to presentation was 22.3 months (range : 5 months to 60 months), and SSF to presentation was 13.8 days (range : 1 day to 28 days). Mean pre- operative Harris Hip Score was 10.8 (range : 8 to 14), which improved to 93 (range : 91 to 96) after total hip arthroplasty when last followed up (p<0.05). Corticosteroids induced ONFH has a propensity to develop SSF. This entity should find a place in existing classification system.


Asunto(s)
Artroplastia de Reemplazo de Cadera , Fracturas del Cuello Femoral , Necrosis de la Cabeza Femoral , Adulto , Artroplastia de Reemplazo de Cadera/efectos adversos , Fracturas del Cuello Femoral/complicaciones , Fracturas del Cuello Femoral/diagnóstico por imagen , Fracturas del Cuello Femoral/cirugía , Cabeza Femoral/cirugía , Necrosis de la Cabeza Femoral/complicaciones , Necrosis de la Cabeza Femoral/diagnóstico por imagen , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
18.
J Food Sci Technol ; 58(10): 3953-3962, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34471319

RESUMEN

Among the natural pigments anthocyanins have potential to be applied as natural colourants besides exhibiting wide range of bioactivity. Colouring potential and storage stability of black carrot concentrate (BCC) containing anthocyanins in yoghurt was determined in present investigation. The instrumental colour (CIELAB) values were altered by the addition of BCC in yoghurt in which the L* and b* values decreased, while a* value increased with increasing levels of BCC. Maximum sensory scores were observed for yoghurt with 1.5% BCC, as it was similar to strawberry in colour and appearance. Enhancement in the total anthocyanin, total phenolics and DPPH antioxidant activity was observed with increasing levels of BCC in yoghurt. L* value remained same during storage in both yoghurts, but a* value increased slightly. Similar trend was also noticed in BCC yoghurt for anthocyanins and antioxidant activity. The total phenolic content got enhanced in control, but decreased significantly in BCC yoghurt. Sensory evaluation revealed that scores decreased during storage but the product was acceptable up to 15 days. Our study further confirmed that higher stability and better colouring properties of black carrot concentrate in fermented milk system was due to higher degree of acylation.

19.
Mol Pharm ; 17(7): 2329-2344, 2020 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-32427480

RESUMEN

Ritonavir is a well-known CYP3A4 and CYP2D6 enzyme inhibitor, frequently used to assess the drug-drug interaction (DDI) liability of susceptible drugs. It is also used as a pharmacokinetic booster to increase exposure to CYP3A4 substrates. This study aimed to develop a mechanistic absorption and disposition model to describe exposure to ritonavir following oral dosing of the commercial amorphous solid dispersion tablet, Norvir, under fasted and fed conditions. A mechanistic description of ritonavir absorption from Norvir tablets may help to improve the design of DDI studies. Key parameters of amorphous ritonavir including free base solubility (solubility of the unbound, un-ionized species), bile micelle partition coefficients, formulation wetting/disintegration, and in vivo precipitation parameters were either obtained from the literature or estimated by modeling in vitro biopharmaceutic experiments. Based on variety of in vitro evidence, a main assumption of the model is that ritonavir does not form a crystalline precipitate while resident in the gastrointestinal tract. In the model, if simulated luminal concentration exceeds the amorphous solubility limit, then precipitation to an amorphous form is immediate. Simulated and observed Cmax and AUC0-t parameters were well captured (within 1.5-fold) for both fasted and fed states in healthy volunteers. By accounting for luminal fluid viscosity differences in the different prandial states (affecting drug diffusivity) as well as the effect of drug free fraction on gut wall permeation rates, it was possible to explain the negative food effect observed for Norvir tablets in humans. In summary, a biopharmaceutic in vitro in vivo extrapolation approach provides confidence in (verification of) key input parameters of the physiologically-based pharmacokinetic ritonavir model which resulted in successful simulation of observed plasma profiles.


Asunto(s)
Productos Biológicos/farmacocinética , Ingestión de Alimentos , Ayuno , Absorción Intestinal/efectos de los fármacos , Ritonavir/farmacocinética , Administración Oral , Productos Biológicos/administración & dosificación , Productos Biológicos/química , Biofarmacia , Simulación por Computador , Dieta Alta en Grasa , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Concentración de Iones de Hidrógeno , Modelos Biológicos , Permeabilidad , Ritonavir/administración & dosificación , Ritonavir/química , Solubilidad , Comprimidos , Viscosidad , Agua/química
20.
Int J Vitam Nutr Res ; 90(5-6): 448-458, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30932789

RESUMEN

The study was aimed to assess vitamin A bioavailability and allergenicity of pearl millet (Pennisetum glaucum) based weaning food (PMWF) fortified with iron and retinyl acetate in male Wistar albino rats. Animals (n = 64) were divided into Normal (NG) and Anemic (AG) groups; further sub-divided into 4 sub-groups having 8 animals each receiving synthetic diet, commercial diet, iron fortified PMWF diet and iron (150.00 ± 0.73 ppm) plus retinyl acetate (393.00 ± 3.07 µg/100 g) fortified PMWF diet (Final diet). Results revealed that anemic sub-groups showed apparent digestibility coefficient (ADC) in the range of 69.5 ± 0.40-93.2 ± 0.79%, which was significantly (P < 0.01) higher than normal sub-groups (65.5 ± 0.62-84.6 ± 0.33%). In both groups, rats fed final diet presented significantly (P < 0.01) higher ADC (84.6 ± 0.33-93.2 ± 0.79%) than that of animals received iron fortified diet (69.0 ± 0.59-76.1 ± 1.02%), indicating higher bioavailability of vitamin A in final diet. Moreover, hepatic vitamin A replenished rapidly in anemic groups (1.79-27.8) when compared to normal rats (1.11-19.4 µg/g liver). Immunoglobulins IgG, IgE in blood serum and IgA in intestinal fluid ranged from 574 ± 6.48 to 603 ± 9.76 µg/ml, 287 ± 4.46 to 309 ± 5.70 ng/ml and 204 ± 10.33 to 255 ± 13.22 µg/ml, respectively. However, no significant (P > 0.05) difference was observed between the groups and/or subgroups, suggesting no allergic response of final diet. Stimulation index triggered by lipopolysaccharide (LPS) ranged from 1.22 ± 0.06 to 1.45 ± 0.09 µg ml-1 in normal sub-groups and 1.16 ± 0.02 to 1.33 ± 0.03 µg ml-1 in anemic sub-groups with no significant (P > 0.05) difference among them. Overall, it can be concluded that retinyl acetate could be an effective fortificant to improve the status of vitamin A in anemic models.


Asunto(s)
Pennisetum , Vitamina A , Animales , Disponibilidad Biológica , Hierro/metabolismo , Masculino , Ratas , Ratas Wistar , Destete
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