RESUMEN
The introduction of innovative therapies has changed the scenario of complications. The delay in the recognition of kidney adverse effects is partly due to the timing of the development of the kidney damage which occurs later than the observation period of registration studies, and partly to the exclusion of patients with known kidney impairment from registration trials. Renal disease has a significant impact on the management of cancer patients and often leads to discontinuation of therapy. Histological evaluations of kidney disorders induced by targeted/immunotherapy are very limited. Renal biopsy is critical for the management of renal toxicities and should be especially encouraged for patients showing adverse renal effects to novel cancer agents. We recently examined the histological features of patients treated with new cancer agents who underwent renal biopsy for new onset renal failure and/or urinary abnormalities. The cohort included 42 patients. The most frequently administered therapies were immunotherapy (54.8%) and anti-angiogenic treatments (45.2%). The most common adverse effect was tubular interstitial nephritis in the first group and thrombotic microangiopathy in the second one. Based on histological findings, definitive discontinuation of treatment could be restricted to a very limited number of patients. All of them had anti-VEGF-related TMA. Treatment discontinuation was unneeded in patients treated with ICIs. In patients treated with multidrug therapy, the histological findings made it possible to identify the weight of drug-related specific injury. Based on this data, renal biopsy should be considered in every cancer patient who develops urinary abnormalities or shows a worsening of renal function during treatment with immunotherapy or targeted therapy.
Asunto(s)
Antineoplásicos , Enfermedades Renales , Neoplasias , Humanos , Quimioterapia Combinada , Terapia Molecular Dirigida/efectos adversos , Leprostáticos/efectos adversos , Riñón/patología , Antineoplásicos/efectos adversos , Enfermedades Renales/tratamiento farmacológico , Neoplasias/tratamiento farmacológicoRESUMEN
Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL (N-2-hydroxypropylmethacrylamide-polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA-HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ-HP-PCL PMCs, while CFA-HP-PCL PMCs significantly (p < 0.001) scavenged the ROS generated in 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ-HP-PCL PMCs (p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ-HP-PCL PMCs than BTZ+CFA-HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs (p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.
Asunto(s)
Antineoplásicos , Inhibidores de Proteasoma , Femenino , Ratones , Animales , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Micelas , Especies Reactivas de Oxígeno , Distribución Tisular , Quimioterapia Combinada , Leprostáticos/uso terapéutico , Bortezomib/farmacología , Bortezomib/química , Polímeros/química , Línea Celular Tumoral , Antineoplásicos/químicaRESUMEN
OBJECTIVE: This study reports new solubility and physicochemical data for ribociclib (RCB) in water and ten organic solvents including "methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), n-butanol (n-BuOH), propylene glycol (PG), polyethylene glycol-400 (PEG-400), acetone, ethyl acetate (EA), Transcutol-HP (THP), and dimethyl sulfoxide (DMSO)" at 293.2-313.2 K and 101.1 kPa. SIGNIFICANCE: The obtained data are useful for the industrial applications of RCB. METHODS: The solubility of RCB was measured and regressed using "van't Hoff, Buchowski-Ksiazczak λh, the modified Apelblat, and Jouyban models." RESULTS: The overall deviations of <4.0% were recorded for all four models. The maximum mole fraction solubility of RCB was 2.66 × 10-2 in PEG-400 at 313.2 K, however, the lowest one was in the water. The RCB solubility increased with temperature and the order followed in the water and ten different organic solvents was PEG-400 (2.66 × 10-2) > THP (1.00 × 10-2) > PG (5.39 × 10-3) > DMSO (5.00 × 10-3) > n-BuOH (3.23 × 10-3) > acetone (3.11 × 10-3) > IPA (1.58 × 10-3) > EA (1.41 × 10-3) > EtOH (1.37 × 10-3) > MeOH (8.10 × 10-4) > water (2.38 × 10-5) at 313.2 K. The maximum solute-solvent interactions were found in RCB-PEG-400 in comparison with other combination of RCB and solvents. "Apparent thermodynamic analysis" indicated an "endothermic and entropy-driven dissolution" of RCB in water and ten organic solvents. CONCLUSIONS: Based on all these data and observations, PEG-400 can be used as the best co-solvent for RCB solubilization.
Asunto(s)
Antineoplásicos , Agua , 2-Propanol , Acetona , Aminopiridinas , Dimetilsulfóxido , Metanol , Purinas , Solubilidad , Solventes , Temperatura , TermodinámicaAsunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Antineoplásicos/efectos adversos , Enfermedades del Colágeno/inducido químicamente , Clorhidrato de Erlotinib/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Enfermedades de la Piel/inducido químicamente , Enfermedades del Colágeno/diagnóstico , Enfermedades del Colágeno/terapia , Femenino , Humanos , Persona de Mediana Edad , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/terapiaRESUMEN
Small molecule-chemotherapeutic drug conjugate nanoparticles (SMCDC NPs) has a great advantage in improving drug loading. However, the factors which influence these conjugates forming stable nanoparticles (NPs) are currently unclear. In our previous studies, we synthesized a series of fatty acid-paclitaxel conjugates and suggested that the changes in the hydrophobic parameters (XlogP), solubility parameters and crystallinity of these fatty acid-paclitaxel conjugates were the key factors for affecting these small molecule-chemotherapeutic drug conjugates (SMCDCs) forming stable NPs in water. Here, we selected clinically widely used chemotherapeutic drug (docetaxel (DTX), doxorubicin (DOX) and irinotecan (Ir)) as model drug, and chose three straight-chain fatty acids (acetic acid (Ac), hexanoic acid (HA) and stearic acid (SA)) and one branched small molecule (N-(tert-butoxycarbonyl) glycine (B-G)) to synthesize 12 SMCDCs. Our results indicated that our prediction criterions obtained from paclitaxel conjugates were also appropriated for these synthesized SMCDCs. We suggested that the present studies expanded the scope of application of the above-mentioned influencing factors, provided research ideas for the rational design of SMCDC forming NPs and a basis for screening NPs with good anticancer activity.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Portadores de Fármacos/química , Ácidos Grasos/química , Nanopartículas/química , Ácido Acético/química , Caproatos/química , Supervivencia Celular , Química Farmacéutica , Docetaxel/administración & dosificación , Docetaxel/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Liberación de Fármacos , Estabilidad de Medicamentos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Irinotecán/administración & dosificación , Irinotecán/farmacología , Células MCF-7 , Tamaño de la Partícula , Solubilidad , Ácidos Esteáricos/químicaAsunto(s)
Antineoplásicos/efectos adversos , Mesilato de Imatinib/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piodermia Gangrenosa/inducido químicamente , Piodermia Gangrenosa/patología , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Persona de Mediana EdadAsunto(s)
Antineoplásicos/uso terapéutico , Enfermedades de los Párpados/diagnóstico , Enfermedades del Cabello/diagnóstico , Imiquimod/uso terapéutico , Queratosis/diagnóstico , Queratosis/tratamiento farmacológico , Anciano , Dermoscopía , Enfermedades de los Párpados/tratamiento farmacológico , Enfermedades del Cabello/tratamiento farmacológico , Folículo Piloso , Humanos , MasculinoAsunto(s)
Antineoplásicos/administración & dosificación , Carcinoma Basocelular/terapia , Pabellón Auricular , Neoplasias del Oído/terapia , Imiquimod/administración & dosificación , Neoplasias Cutáneas/terapia , Administración Tópica , Carcinoma Basocelular/patología , Quimioterapia Adyuvante , Cartílago Auricular , Neoplasias del Oído/patología , Humanos , Terapia Neoadyuvante , Neoplasias Cutáneas/patologíaRESUMEN
Xeroderma pigmentosum is a rare hereditary autosomal recessive genodermatosis. At present, there are many treatment options for xeroderma pigmentosum, covering medical/procedural, surgical and combined modalities. However, the quality of these interventions has not been assessed. Our study aimed to perform a systematic review of the literature regarding the treatment of xeroderma pigmentosum. Multiple medical databases were accessed with the Medical Subject Headings terms; "xeroderma pigmentosum," "therapeutics" and "surgical procedures, operative" from January 2000 to April 2019, including articles published in Portuguese, Spanish and English (PROSPERO-CRD42018114858). Two hundred and ninety-eight studies were found in the databases researched, of which, after applying the inclusion criteria, only 33 studies remained. The 33 complete articles were read by three of the authors, having been found: 16 reported medical/procedural and 17 reported surgical treatments. Only one clinical study presented a good level of evidence (EL: 2): a randomized clinical trial using a T4 endonuclease V (T4N5) liposome lotion which reduced the development of skin lesions in patients with xeroderma pigmentosum. Amongst surgical modalities, all studies presented low evidence level (EL: 4). Three illustrative cases are also presented, to emphasize the multiple number of times that surgical modalities may be required in these patients. The therapeutic modalities, both clinical and surgical, for xeroderma pigmentosum presented a low level of scientific evidence which did not allow meta-analysis. More therapeutic studies, both clinical and surgical, with better scientific evidence are needed.
Asunto(s)
Neoplasias Cutáneas/terapia , Xerodermia Pigmentosa/terapia , Antineoplásicos/uso terapéutico , Procedimientos Quirúrgicos Dermatologicos , Fluorouracilo/uso terapéutico , Humanos , Imiquimod/uso terapéutico , Pomadas , FotoquimioterapiaRESUMEN
BACKGROUND: There are few studies on basal cell carcinoma (BCC) from India. Long-term follow-up is available in only one study and the aesthetic outcome of treatment has not been evaluated in Indian patients. AIMS: In this retrospective study on BCC, we compared treatment failure, recurrence rates and aesthetic outcomes on long-term follow-up between surgical excision and repair, and nonsurgical and ablative treatments. METHODS: Records of patients with BCC treated in the dermatologic surgery clinic over the past 10 years were analyzed. Patients with histopathologically confirmed BCC who could be contacted were evaluated for recurrence, treatment failure, overall satisfaction and aesthetic outcomes by global aesthetic improvement scale. RESULTS: Out of 98 patients, 72 were contactable. Four patients received both nonsurgical and ablative treatments and surgical excision and repair sequentially and were excluded. The mean age of patients was 57.9 ± 15.8 years (24-90 years) and the male: female ratio was 1.6:1. The most common site involved was the face (72.1%) followed by trunk and scalp, and the most common type of BCC was the pigmented superficial type (33.8%), followed by the pigmented noduloulcerative type (16.2%). There was no significant difference between the groups in the number of high-risk cases. The mean follow-up period was 37.1 ± 31.4 (range, 4-120) months. Fifty one patients were treated with surgical excision and repair, and 17 with nonsurgical and ablative treatments (9-imiquimod, 5-cryotherapy, 4-radiotherapy). Treatment failure was seen in 5 (7.4%) patients, all in the nonsurgical and ablative treatments group (P = 0.0006). Recurrence was seen in 2 (2.9%) patients, both in the surgical excision and repair group (P > 0.05). Mean patient satisfaction was significantly higher with surgical excision and repair, though there was no significant difference in the Global Aesthetic Improvement Scale between the groups. LIMITATIONS: The sample size was low. Only telephonic and pictorial assessments were done where the patient could not come for follow-up. CONCLUSIONS: Surgical excision and repair was associated with better outcomes than nonsurgical and ablative treatments. Treatment failures and adverse events were high with nonsurgical and ablative treatments. The recurrence rate was low.
Asunto(s)
Carcinoma Basocelular/terapia , Neoplasias Cutáneas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Crioterapia , Femenino , Humanos , Imiquimod/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Satisfacción del Paciente , Ablación por Radiofrecuencia , Estudios Retrospectivos , Adulto JovenAsunto(s)
Antineoplásicos/uso terapéutico , Neoplasias del Ano/terapia , Tumor de Buschke-Lowenstein/terapia , Neoplasias del Ano/patología , Tumor de Buschke-Lowenstein/patología , Terapia Combinada , Electrocirugia , Femenino , Humanos , Imiquimod/uso terapéutico , Fotoquimioterapia , Adulto JovenAsunto(s)
Antineoplásicos/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Dermatosis Facial/inducido químicamente , Síndrome Mano-Pie/etiología , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/efectos adversos , Resultado Fatal , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The solubility and thermodynamic analysis of baricitinib (BNB) in various dimethyl sulfoxide (DMSO) + water mixtures were performed. The "mole fraction solubilities (xe)" of BNB in DMSO and water mixtures were determined at "T = 298.2-323.2 K" and "p = 0.1 MPa" using an isothermal saturation technique. "Hansen solubility parameters (HSPs)" of BNB, pure DMSO, pure water and "DMSO + water" mixtures free of BNB were also estimated. The xe data of BNB was regressed well by five different thermodynamics-based co-solvency models, which included "Apelblat, Van't Hoff, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-Van't Hoff models" with overall deviations of <5.0%. The highest and lowest xe value of BNB was computed in pure DMSO (1.69 × 10-1 at T = 323.2 K) and pure water (2.23 × 10-5 at T = 298.2 K), respectively. The HSP of BNB was found to be closer to that of pure DMSO. Based on activity coefficient data, maximum solute-solvent molecular interactions were observed in BNB-DMSO compared to BNB-water. The results of "apparent thermodynamic analysis" indicated endothermic and entropy-drive dissolution of BNB in all "DMSO + water" combinations including mono-solvents (water and DMSO). "Enthalpy-entropy compensation analysis" showed enthalpy-driven to be the main mechanism of solvation of BNB.
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Antineoplásicos/química , Azetidinas/química , Inhibidores de las Cinasas Janus/química , Modelos Moleculares , Purinas/química , Pirazoles/química , Sulfonamidas/química , Dimetilsulfóxido/química , Estructura Molecular , Solubilidad , Solventes/química , Termodinámica , Agua/químicaAsunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Granuloma Piogénico/inducido químicamente , Granuloma Piogénico/diagnóstico , Hemangioma/inducido químicamente , Hemangioma/diagnóstico , Paclitaxel/efectos adversos , Adulto , Antineoplásicos/efectos adversos , Humanos , Masculino , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/diagnóstico , RamucirumabAsunto(s)
Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Basoescamoso/tratamiento farmacológico , Neoplasias Faciales/tratamiento farmacológico , Piridinas/uso terapéutico , Cuero Cabelludo , Neoplasias Cutáneas/tratamiento farmacológico , Carcinoma Basoescamoso/patología , Neoplasias Faciales/patología , Femenino , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Cutáneas/patologíaRESUMEN
A neutral polysaccharide (DIP-1) from Duchesnea indica (Andr.) Focke was obtained by hot water extraction, ethanol precipitation and chromatographic separation (DEAE-52 cellulose anion-exchange column and Sephadex G-100 gel column). The physicochemical properties of DIP-1 were elucidated by gel permeation chromatography, monosaccharide composition, Fourier transform infrared spectrometry, UV-visible spectrophotometry, scanning electron microscope and Congo red test. The results indicated that DIP-1 was consisted of mannose, glucosamine, glucose, galactose and arabinose in a ratio of 1.00:0.42:18.36:14.17:0.81, and its molecular weight was 218.3 kDa. Meanwhile, DIP-1 presented a straight hexahedron structure, but no triple-helical conformation. In antioxidant activity tests, DIP-1 exhibited powerful scavenging activities on hydroxyl, DPPH, ABTS radicals and reducing power in a dose-dependent manner. Especially, DIP-1 demonstrated high inhibitory activities against SKOV-3 and Hep-G2 cells in vitro, with IC50 values of 1.42 and 1.23 mg/ml, respectively. PRACTICAL APPLICATIONS: D. indica has been used for a long time as a Chinese medicine for therapy of many diseases, including cancer, inflammation, leprosy, fever, bleeding and so on. At present, polysaccharides have attracted comprehensive attention because of a large range of pharmacological and biological properties, including antitumor, antidiabetic, antioxidant and immunomodulatory activity. In the present study, we purified and characterized a neutral polysaccharide from D. indica for the first time. Moreover, the neutral polysaccharide exhibits significant antioxidant and antitumor activities. Therefore, the present study laid a foundation for the high-value application of D. indica polysaccharides in functional food and pharmaceutical industries.