RESUMEN
AIM: Thiocolchicoside (THC) is a drug under the category of BCS III. Due to its high molecular weight, it has poor oral bioavailability and low skin permeability. This study aims to find an alternative delivery method for THC that enhances its bioavailability through nasal application approach. In situ gels containing plain or liposomal THC with different combinations of Pluronic® F127 and PEG 400 were prepared. METHOD: Liposome formulations were prepared using the thin film hydration method and tested for their characterization such as for drug content, particle size, and zeta potential. In vivo pharmacokinetic parameters of formulations such as Cmax, Tmax, and AUC were tested on the rabbit model. The formulations were also scrutinized for their cell viability properties. RESULT: Formulation composition with 2% soybean phosphatidylcholine and 10 mg THC exhibited â¼94% entrapment efficiency, minimum particle size 101.32 nm, low polydispersity index 0.225 and +0.355 zeta potential. In situ liposomal dispersion containing 15% Pluronic® F127 turned into gel at nasal temperature. Cell lines were unharmed for 48 h. In situ liposomal gels showed 1.5x higher blood concentration than the control formula. CONCLUSION: In situ gels of liposomal THC formulations offer advantages over traditional nasal solutions, demonstrating comparable bioavailability to parenteral medication while also preserving the health of nasal mucosa cells.
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Administración Intranasal , Disponibilidad Biológica , Colchicina , Geles , Liposomas , Tamaño de la Partícula , Poloxámero , Polietilenglicoles , Animales , Conejos , Poloxámero/química , Colchicina/administración & dosificación , Colchicina/análogos & derivados , Colchicina/farmacocinética , Polietilenglicoles/química , Temperatura , Humanos , Masculino , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacosRESUMEN
TCC is a semisynthetic molecule widely used in clinical settings as a pain killer and myorelaxant. Several neurological side effects have been reported in association with TCC treatment including somnolence, confusion and seizure, the latter in a lower percentage of patients. Some previous reports described seizure onset after TCC intake in adulthood. However, major epileptological complication, namely status epilepticus, has never been previously reported in association with TCC treatment. In our report, we describe a case of acute refractory non-convulsive status epilepticus (NCSE) in the context of a TCC-induced acute toxic encephalopathy (ATE) in a woman without any previous neurological or physical comorbidities.
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Estado Epiléptico , Adulto , Colchicina/efectos adversos , Colchicina/análogos & derivados , Electroencefalografía , Femenino , Humanos , Inyecciones Espinales/efectos adversos , Convulsiones/tratamiento farmacológico , Estado Epiléptico/inducido químicamente , Estado Epiléptico/complicaciones , Estado Epiléptico/tratamiento farmacológicoRESUMEN
To assess the stability and efficiency of liposomes carrying a phospholipase A2-sensitive phospholipid-allocolchicinoid conjugate (aC-PC) in the bilayer, egg phosphatidylcholine and 1-palmitoyl-2-oleoylphosphatidylglycerol-based formulations were tested in plasma protein binding, tubulin polymerization inhibition, and cytotoxicity assays. Liposomes L-aC-PC10 containing 10 mol. % aC-PC in the bilayer bound less plasma proteins and were more stable in 50% plasma within 4 h incubation, according to calcein release and FRET-based assays. Liposomes with 25 mol. % of the prodrug (L-aC-PC25) were characterized by higher storage stability judged by their hydrodynamic radius evolution yet enhanced deposition of blood plasma opsonins on their surface according to SDS-PAGE and immunoblotting. Notably, inhibition of tubulin polymerization was found to require that the prodrug should be hydrolyzed to the parent allocolchicinoid. The L-aC-PC10 and L-aC-PC25 formulations demonstrated similar tubulin polymerization inhibition and cytotoxic activities. The L-aC-PC10 formulation should be beneficial for applications requiring liposome accumulation at tumor or inflammation sites.
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Alcaloides/farmacología , Antineoplásicos/farmacología , Colchicina/análogos & derivados , Liposomas/química , Fosfolipasas A2/metabolismo , Fosfolípidos/química , Alcaloides/síntesis química , Alcaloides/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Estabilidad de Medicamentos , Transferencia Resonante de Energía de Fluorescencia , Humanos , Polimerizacion/efectos de los fármacos , Profármacos , Tubulina (Proteína)/metabolismoRESUMEN
Background and Aim: This study aimed to evaluate acute postoperative pain management and trismus in 35 patients undergoing extractions of the two mandibular third molars, in mesioangular positions, at two different visits who consumed nimesulide + thiocolchicoside or only nimesulide. Material and Methods: According to the medication given, the patients were divided into two groups. Following the first surgery of the impacted third molar patients were given nimesulide (100 mg) + thiocolchicoside (8 mg) together. The healing period was waited for 15 days and in the poursuite of the second surgery, only nimesulide (100 mg) was administered every 12 hours for 7 days. Visual analog scales (VAS) were used to assess the pain in the 6th, 8th, 12th, 24th, and 48th hours and on the 3rd, 5th, and 7th days postoperatively. Digital calipers were used to measure (in mm) the mouth opening capacity pre and postoperatively on the 2nd and 7th days, respectively. Results: Regarding pain alleviation, the nimesulide + thiocolchicoside group was more effective than the nimesulide group. The VAS levels of nimesulide + thiocolchicoside at the 6th, 8th, 12th, 24th, and 48th hours and on the 3rd and 5th days were significantly lower than the nimesulide group. The mouth opening was observed higher in the nimesulide + thiocolchicoside group than in the nimesulide group (P > 0.05). In the nimesulide group, at the end of the 7th day, the trismus measurements were less than the preoperative measurements. There was no statistically significant difference in the Nimesulide + Thiocolchicoside group in the preop-7th days. Conclusion: Nimesulide (100 mg) + thiocolchicoside (8 mg) combination has higher analgesic efficacy and better trismus outcomes compared to only nimesulide (100 mg) when orally administered following mandibular third molar surgeries.
Asunto(s)
Tercer Molar , Diente Impactado , Colchicina/análogos & derivados , Edema , Humanos , Tercer Molar/cirugía , Boca , Dolor Postoperatorio/tratamiento farmacológico , Sulfonamidas , Extracción Dental , Diente Impactado/cirugía , TrismoRESUMEN
A series of 22 amine analogs of thiocolchicine were synthesized using the reductive amination reaction. The antiproliferative activities of these compounds were tested against four tumor cell lines as well as one normal cell line. The tested analogs exhibited IC50 values in the nanomolar range accompanied by high selectivity indexes, and most importantly, they were able to break the drug resistance of the human colon adenocarcinoma resistant cell line (LoVo/DX). Also, a correlation between the antiproliferative activity and physicochemical properties of the novel compounds has been found.
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Aminas/farmacología , Antineoplásicos/farmacología , Colchicina/análogos & derivados , Células 3T3 , Aminas/síntesis química , Aminas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colchicina/síntesis química , Colchicina/química , Colchicina/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Colchicine is a plant alkaloid with a broad spectrum of biological and pharmacological properties. It has found application as an anti-inflammatory agent and also shows anticancer effects through its ability to destabilize microtubules by preventing tubulin dimers from polymerizing leading to mitotic death. However, adverse side effects have so far restricted its use in cancer therapy. This has led to renewed efforts to identify less toxic derivatives. In this article, we describe the synthesis of a set of novel double- and triple-modified colchicine derivatives. These derivatives were tested against primary acute lymphoblastic leukemia (ALL-5) cells and several established cancer cell lines including A549, MCF-7, LoVo and LoVo/DX. The novel derivatives were active in the low nanomolar range, with 7-deacetyl-10-thiocolchicine analogues more potent towards ALL-5 cells while 4-iodo-7-deacetyl-10-thiocolchicine analogues slightly more effective towards the LoVo cell line. Moreover, most of the synthesized compounds showed a favorable selectivity index (SI), particularly for ALL-5 and LoVo cell lines. Cell cycle analysis of the most potent molecules on ALL-5 and MCF-7 cell lines revealed contrasting effects, where M-phase arrest was observed in MCF-7 cells but not in ALL-5 cells. Molecular docking studies of all derivatives to the colchicine-binding site were performed and it was found that five of the derivatives showed strong ß-tubulin binding energies, lower than -8.70 kcal/mol, while the binding energy calculated for colchicine is -8.09 kcal/mol. The present results indicate that 7-deacetyl-10-thiocolchicine and 4-iodo-7-deacetyl-10-thiocolchicine analogues constitute promising lead compounds as chemotherapy agents against several types of cancer.
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Antineoplásicos Fitogénicos/farmacología , Colchicina/análogos & derivados , Simulación del Acoplamiento Molecular , Animales , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colchicina/síntesis química , Colchicina/química , Colchicina/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Colchicine (COL) shows strong anticancer activity but due to its toxicity towards normal cells its wider application is limited. To address this issue, a library of 17 novel COL derivatives, namely N-carbamates of N-deacetyl-4-(bromo/chloro/iodo)thiocolchicine, has been tested against two types of primary cancer cells. These included acute lymphoblastic leukemia (ALL) and human breast cancer (BC) derived from two different tumor subtypes, ER+ invasive ductal carcinoma grade III (IDCG3) and metastatic carcinoma (MC). Four novel COL derivatives showed higher anti-proliferative activity than COL (IC50 = 8.6 nM) towards primary ALL cells in cell viability assays (IC50 range of 1.1-6.4 nM), and several were more potent towards primary IDCG3 (IC50 range of 0.1 to 10.3 nM) or MC (IC50 range of 2.3-9.1 nM) compared to COL (IC50 of 11.1 and 11.7 nM, respectively). In addition, several derivatives were selectively active toward primary breast cancer cells compared to normal breast epithelial cells. The most promising derivatives were subsequently tested against the NCI panel of 60 human cancer cell lines and seven derivatives were more potent than COL against leukemia, non-small-cell lung, colon, CNS and prostate cancers. Finally, COL and two of the most active derivatives were shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants. The present findings indicate that the select COL derivatives constitute promising lead compounds targeting specific types of cancer.
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Antineoplásicos Fitogénicos/farmacología , Carbamatos/farmacología , Carcinoma Ductal de Mama/metabolismo , Colchicina/análogos & derivados , Extractos Vegetales/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Apoptosis/efectos de los fármacos , Carcinoma Ductal de Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colchicina/farmacología , Colchicum/química , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC50 values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different ß tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics.
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Antineoplásicos/química , Antineoplásicos/farmacología , Colchicina/análogos & derivados , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colchicina/síntesis química , Colchicina/química , Colchicina/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Halogenación , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
Hiccup is a condition caused by involuntary contraction of inspiratory muscles, especially the diaphragm. Although it is generally considered as a physiological. response, if hiccup persists for a long time, it can lead to many undesirable conditions such as depression, weight loss, insomnia, and fatigue. A 35-year-old male patient was admitted to our emergency department with hiccup lasting for 15 h. He had a history of several hiccup attacks. Classical non-pharmacological and pharmacological therapies were used to treat the condition without any response. As an alternative method, an intradermal injection was applied. A mixture of thiocolchicoside and lidocaine was administered intradermally to a depth of 1-3 mm at the epigastric region and adjacent to the sternocleidomastoid muscle. The patient's hiccup ended after the intradermal injection procedure. During 48 h of follow-up the hiccup attack did not develop again. No complications related to the process were detected. This is the first case in the literature demonstrating the use of intradermal injection to terminate hiccups. The intradermal injection approach can be administered in cases of hiccups that do not respond to medical treatment.
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Anestésicos Locales/administración & dosificación , Colchicina/análogos & derivados , Servicio de Urgencia en Hospital , Hipo/tratamiento farmacológico , Lidocaína/administración & dosificación , Adulto , Anestésicos Locales/uso terapéutico , Colchicina/administración & dosificación , Colchicina/uso terapéutico , Diafragma , Combinación de Medicamentos , Humanos , Inyecciones Intradérmicas , Lidocaína/uso terapéutico , Masculino , Resultado del TratamientoRESUMEN
INTRODUCTION: Musculoskeletal pain such as low back pain (LBP) are routinely encountered in the ED and contribute to ED overcrowding. The aim of our study was to compare the efficiency of mesotherapy with systemic therapy in pain control in patients with lumbar disk herniation. METHODS: We conducted this prospective parallel randomized controlled trial with the patients admitted to the emergency department with low back pain related to herniated lumbar disk. Mesotherapy was performed to one group, while intravenous dexketoprofen was administered to the control group. Changes in pain intensity at 15th minute, 30th minute, 60th minute and 24th hours after treatment using Visual Analogue Scale (VAS), need to use analgesic drug within 24 h after treatment, and adverse effect of the treatment methods were compared between groups. RESULTS: The decreases in pain intensity were statistically significantly higher in mesotherapy group for all time intervals. The need to use analgesics was statistically significantly three fold higher in the systemic therapy group. There was no statistically significant difference in having any adverse effect between study groups during one-week follow-up period. CONCLUSIONS: Changes in medical practices, from the systemic administration of NSAIDs to the minimally invasive techniques such as mesotherapy with potent efficacy and minimal side effects, may enhance the ability of EDs to meet the waiting time targets and improve patient's satisfaction.
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Anestésicos Locales/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Dolor de la Región Lumbar/terapia , Mesoterapia , Adulto , Colchicina/análogos & derivados , Colchicina/uso terapéutico , Servicio de Urgencia en Hospital , Femenino , Humanos , Desplazamiento del Disco Intervertebral/complicaciones , Cetoprofeno/uso terapéutico , Lidocaína/uso terapéutico , Dolor de la Región Lumbar/etiología , Masculino , Persona de Mediana Edad , Piroxicam/análogos & derivados , Piroxicam/uso terapéutico , Estudios Prospectivos , Escala Visual AnalógicaRESUMEN
Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) and 1-demethylthiocolchicine (3), a series of 12 colchicine derivatives including 5 novel esters (2b-c and 4b-d) and 4 carbonates (2e-f and 4e-f) were synthesized. The antiproliferative activity assay, together with in silico evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate 3, hemihydrate 4e and monohydrate 4a.
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Antimitóticos/química , Antimitóticos/farmacología , Técnicas de Química Sintética , Colchicina/análogos & derivados , Antimitóticos/síntesis química , Fenómenos Químicos , Colchicina/síntesis química , Colchicina/química , Colchicina/farmacología , Desmetilación , Relación Dosis-Respuesta a Droga , Conformación Molecular , Estructura Molecular , Análisis Espectral , Relación Estructura-ActividadRESUMEN
Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to ß-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin.
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Antineoplásicos/química , Antineoplásicos/farmacología , Técnicas de Química Sintética , Colchicina/análogos & derivados , Modelos Moleculares , Sulfonamidas/química , Sulfonamidas/farmacología , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colchicina/síntesis química , Colchicina/química , Colchicina/farmacología , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Electricidad Estática , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
Colchicine is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute lymphoblastic leukemia cells, specifically compounds: 5-9 against primary ALL-5 (IC50â¯=â¯5.3-14â¯nM), 5, 7-9 against A549 (IC50â¯=â¯10â¯nM), 5, 7-9 against MCF-7 (IC50â¯=â¯11â¯nM), 5-9 against LoVo (IC50â¯=â¯7-12â¯nM), and 5, 7-9 against LoVo/DX (IC50â¯=â¯48-87â¯nM). These IC50 values were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies revealed that colchicine and selected analogues induced characteristics of apoptotic cell death but manifested their effects in different phases of the cell cycle in MCF-7 versus ALL-5 cells. Specifically, while colchicine and the studied derivatives arrested MCF-7 cells in mitosis, very little mitotically arrested ALL-5 cells were observed, suggesting effects were manifest instead in interphase. We also developed an in silico model of the mode of binding of these compounds to their primary target, ß-tubulin. We conducted a correlation analysis (linear regression) between the calculated binding energies of colchicine derivatives and their anti-proliferative activity, and determined that the obtained correlation coefficients strongly depend on the type of cells used.
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Antineoplásicos/química , Antineoplásicos/farmacología , Colchicina/análogos & derivados , Neoplasias/tratamiento farmacológico , Células A549 , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Colchicina/síntesis química , Colchicina/química , Colchicina/farmacología , Diseño de Fármacos , Halogenación , Humanos , Células MCF-7 , Mitosis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Neoplasias/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
The reported characterization data for the allocolchicinoid alkaloid suhailamine, isolated from Colchicum decaisnei and known to have an erroneous structure, have been reanalyzed. This analysis has led to the current proposal that suhailamine has the same structure as N-acetylcolchinol methyl ether (NCME), an assertion that is supported by comparison with previously reported data for NCME. Suhailamine is therefore a phantom natural product, while NCME represents a naturally occurring allocolchicinoid rather than a purely synthetic entity.
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Productos Biológicos/química , Colchicina/análogos & derivados , Éteres Metílicos/química , Colchicina/química , Estructura MolecularRESUMEN
Seizure is the most common presentation of neurological disorder in the pediatric emergency care setting. In evaluating the child after a first seizure, the first consideration should be determining if the seizure was provoked or unprovoked. Investigation listing the causes of the first seizure is considerably long, and adverse drug reactions must be in mind. Epileptic seizures after using thiocolchicoside (TCC) have been reported in several adult patients with epilepsy and acute brain injury. We present a previously healthy 3-month-old female infant who was admitted to the emergency department with a generalized seizure after exposure to TCC. To the best of our knowledge, this is the first case of a child who had an epileptic seizure after TCC intake via breastfeeding in the literature.
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Colchicina/análogos & derivados , Convulsiones/inducido químicamente , Lactancia Materna , Colchicina/envenenamiento , Femenino , Humanos , LactanteRESUMEN
BACKGROUND: Postoperative pain is one of the most common complications. The aim of this study is to evaluate the analgesic efficacies of dexketoprofen trometamol and two different dosages of dexketoprofen trometamol + thiocolchicoside combination in the impacted third molar tooth operation. MATERIAL AND METHODS: This randomized, double-blind study included 75 patients who did not have any disease. Patients were assigned to 3 groups. Group 1 received 25 mg dexketoprofen trometamol + 4 mg thiocholchicoside, Group 2 received 25 mg dexketoprofen trometamol +8 mg thiocholchicoside, and Group 3 received 25 mg dexketoprofen trometamol. In each group, the analgesic medication was administered twice a day, starting 1 hour before the operation. The level of pain was assessed with VAS. RESULTS: Patient age varied from 18 to 36 years. Of all patients, 59.2% (n=42) were female and 40.8% (n=29) were male. Drug side effects were observed in 28.17% (n=20) of the patients. Mean 24th hour VAS score was lower in dexketoprofen trometamol + 8 mg thiocolchicoside group compared to dexketoprofen trometamol group (p<0.05). There was no statistically significant difference between the three groups regarding drug side effects (p>0.05). CONCLUSIONS: Dexketoprofen trometamol + 8 mg thiocolchicoside combination has higher analgesic efficacy compared to dexketoprofen trometamol. More studies are needed to interpret the analgesic and anti-inflammatory effects of thiocholchicoside + dexketoprofen trometamol combination.
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Analgesia , Antiinflamatorios no Esteroideos/administración & dosificación , Colchicina/análogos & derivados , Cetoprofeno/análogos & derivados , Tercer Molar/cirugía , Diente Impactado/cirugía , Trometamina/administración & dosificación , Adolescente , Adulto , Colchicina/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Cetoprofeno/administración & dosificación , Masculino , Adulto JovenRESUMEN
A number of naturally occurring compounds such as paclitaxel, vinblastine, combretastatin, and colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives, modified at ring-B, labelled here compounds 4-14. These compounds have been obtained in a simple reaction of 7-deacetyl-10-thiocolchicine 3 with eleven different alcohols in the presence of triphosgene. These novel agents have been checked for anti-proliferative activity against four human cancer cell lines and their mode of action has been confirmed as colchicine binding site inhibition (CBSI) using molecular docking. Molecular simulations provided rational tubulin binding models for the tested compounds. On the basis of in vitro tests, derivatives 4-8 and 14 demonstrated the highest potency against MCF-7, LoVo and A549 tumor cell lines (IC50 valuesâ¯=â¯0.009-0.014⯵M). They were more potent and characterized by a higher selectivity index than several standard chemotherapeutics including cisplatin and doxorubicin as well as unmodified colchicine. Further, studies revealed that colchicine and its several derivatives arrested MCF-7 cells in mitosis, while its selected derivatives caused microtubule depolymerization.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Colchicina/análogos & derivados , Uretano/análogos & derivados , Uretano/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Colchicina/síntesis química , Colchicina/química , Colchicina/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Mitosis/efectos de los fármacos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Uretano/síntesis químicaRESUMEN
This work reports the synthesis, radiolabeling, and biological studies of 99m Tc-diethylene triamine pentaacetic acid (DTPA)-colchicine dimer in tumor-bearing mice. The novel colchicine dimer was successfully synthesized by conjugation of DTPA to 2 colchicine biomolecules. The ligand could be labeled by 99m Tc in high yield to get 99m Tc-DTPA-colchicine dimer, which was hydrophilic and stable at room temperature. Biodistribution and imaging studies in tumor-bearing mice showed that 99m Tc-DTPA-colchicine dimer accumulated in the tumor with improved uptake and retention. The results indicate the need for synthetic modification of the parent colchicine derivative and the 99m Tc-chelate with a view to improve the tumor-targeting efficacy and in vivo kinetic profiles.
Asunto(s)
Colchicina/análogos & derivados , Neoplasias Experimentales/diagnóstico por imagen , Radiofármacos/síntesis química , Pentetato de Tecnecio Tc 99m/química , Animales , Ratones , Ratones Endogámicos ICR , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
OBJECTIVE: To evaluate the feasibility and effectiveness of mesotherapy in dogs compared with a positive control group. STUDY DESIGN: Experimental, randomized, blinded study. ANIMALS: Fifteen working police dogs with chronic back pain. METHODS: Animals were divided randomly into control (CG; n = 5) and treatment groups (TG; n = 10). A combination of 140 mg lidocaine, 15 mg dexamethasone and 20 mg thiocolchicoside was administered to group TG along with a 70-day course of a placebo, administered as if it was carprofen. Carprofen was administered to Group CG for 70 days, at a dose adjusted to their weight. On day 0, an intradermal injection of Ringer's lactate was also administered. Both groups were rested for 3 days and resumed normal activity over a 5-day period. Response to treatment, measured by the Canine Brief Pain Inventory (CBPI) and the Hudson Visual Analogue Scale (HVAS), was evaluated before treatment (T0), after 15 days (T1) and 1 (T2), 2 (T3), 3 (T4), 4 (T5) and 5 (T6) months. Results were compared using a Mann-Whitney test or a paired samples t test. RESULTS: When comparing CBPI results, no differences were found between groups TG and CG at T0 through T3 and in T6 and T7. Differences were observed in CBPI sections after the discontinuation of carprofen: at T4 [p = 0.02 for Pain Interference Score (PIS) and p = 0.03 for Pain Severity Score (PSS)] and T5 (p = 0.16 for PIS and p = 0.03 for PSS), with group TG having overall better results. Individual treatment results were considered successful in one dog of group CG (20%), whereas in group TG, success was higher (ranging from 78% at T1 to 22% at T7). No significant differences were registered with the HVAS. CONCLUSIONS AND CLINICAL RELEVANCE: Mesotherapy may be a promising treatment option for canine musculoskeletal-related pain. Further studies are required.
Asunto(s)
Dolor de Espalda/veterinaria , Enfermedades de los Perros/terapia , Mesoterapia/veterinaria , Analgésicos/administración & dosificación , Analgésicos/uso terapéutico , Animales , Dolor de Espalda/terapia , Carbazoles/administración & dosificación , Carbazoles/uso terapéutico , Colchicina/administración & dosificación , Colchicina/análogos & derivados , Colchicina/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Perros , Quimioterapia Combinada , Femenino , Lidocaína/administración & dosificación , Lidocaína/uso terapéutico , Masculino , Mesoterapia/métodos , Dimensión del Dolor/veterinaria , PoliciaRESUMEN
BACKGROUND: Gout is one of the common inflammatory arthritis which affects many people for inflicting unbearable pain. Macrophage-mediated inflammation plays an important role in gout. The uptake of monosodium urate (MSU) crystals by macrophages can lead to activation of NOD-like receptors containing a PYD 3 (NLRP3) inflammasome, thus accelerating interleukin (IL)-1ß production. Reactive oxygen species (ROS) promoted development of the inflammatory process through NLRP3 inflammasome. Our study aimed to find a food-derived compound to attenuate gout pain via the specific inhibition of the NLRP3 inflammasome in macrophages. METHODS: CD-1 mice were used to evaluate the degree of pain and the swelling dimension of joints after an intra-articular (IA) MSU injection in the ankle. The murine macrophage cell line Raw 264.7 was used to investigate the effects of procyanidins and the mechanism underlying such effects. Histological analysis was used to measure the infiltration of inflammatory cells. ROS produced from Raw 264.7 cells were evaluated by flow cytometry. Cell signaling was measured by Western blot assay and immunofluorescence. RESULTS: Procyanidins significantly attenuated gout pain and suppressed ankle swelling. Procyanidins also inhibited MSU-induced activation of the NLRP3 inflammasome and increase of IL-1ß. Furthermore, procyanidins decreased ROS levels in Raw 264.7 cells. CONCLUSIONS: Suppression of the NLRP3 inflammasome in macrophages contributes to the amelioration of gout pain by procyanidins.