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OBJECTIVES: Endoxifen is a protein kinase C inhibitor. The objective of the present phase III study was to demonstrate the safety and efficacy of endoxifen in treating bipolar I disorder (BPD I) patients. METHODS: A multicenter, double-blind, active-controlled study was conducted using a daily dose of 8 mg endoxifen compared to 1000 mg divalproex, the current standard treatment, in patients with BPD I acute manic episodes with/without mixed features. The primary endpoint of our study was the mean change in total Young Mania Rating Scale (YMRS) score at day 21. RESULTS: Endoxifen (n = 116) significantly (p < 0.0001) reduced total YMRS score (from 33.1 to 17.8. A significant (p < 0.001) improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score was observed for endoxifen (4.8 to 2.5). Early time to remission of the disease was observed with endoxifen compared to divalproex. None of the patients required rescue medication and there was no drug-associated withdrawals. Changes in Clinical Global Impressions-Bipolar Disorder and Clinical Global Impression-Severity of Illness scores showed that treatment with endoxifen was well-tolerated. CONCLUSIONS: Endoxifen at a low daily dose of 8 mg was as efficacious and safe in patients with BPD I acute manic episodes with/without mixed features.
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Antipsicóticos , Trastorno Bipolar , Antipsicóticos/uso terapéutico , Trastorno Bipolar/complicaciones , Trastorno Bipolar/tratamiento farmacológico , Método Doble Ciego , Humanos , Manía , Proteína Quinasa C/uso terapéutico , Escalas de Valoración Psiquiátrica , Tamoxifeno/análogos & derivados , Resultado del TratamientoRESUMEN
Endoxifen, an active metabolite of tamoxifen, has been shown to be an effective anti-estrogenic agent in estrogen receptor-positive breast cancer patients. In melanoma, estrogen receptor expression is shown to be associated with disease progression. However, the therapeutic benefit of endoxifen in melanoma has not yet been evaluated. Here, we present the first demonstration of the anti-melanogenic activity of endoxifen in vitro and in vivo. The in vitro cytotoxic effect of endoxifen was tested using a cell viability assay. The in vivo anti-melanogenic activity was evaluated in B16F10 cell-bearing C57BL/6 mice, a mouse melanoma model. The general toxicity was tested in Swiss albino mice. Endoxifen exhibited greater activity against melanoma cell lines. Treatment of B16F10 mouse and SK-MEL-5 human melanoma cell lines with 10 µM of endoxifen for 48 h respectively resulted in 93.6 and 92.5% cell death. Orally administered endoxifen, at dose levels of 4 and 8 mg/kg body weight/day for 20 consecutive days, respectively reduced metastatic melanoma nodules in the lungs by 26.7 and 82.7%. Endoxifen was found to be a safe and effective anti-melanogenic agent in animal studies.
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Antineoplásicos/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Tamoxifeno/análogos & derivados , Administración Oral , Animales , Antineoplásicos/toxicidad , Línea Celular Tumoral , Femenino , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Tamoxifeno/administración & dosificación , Tamoxifeno/uso terapéutico , Tamoxifeno/toxicidadRESUMEN
Background: A novel nanosomal paclitaxel lipid suspension (NPLS), free from Cremophor EL (CrEL) and ethanol, was developed to address the solvent-related toxicities associated with conventional paclitaxel formulation. Objective: To evaluate the efficacy and safety of NPLS versus CrEL-based paclitaxel (conventional paclitaxel) in patients with metastatic breast cancer (MBC). Design: A prospective, open-label, randomized, multiple-dose, parallel, phase II/III study. Methods: Adult (18-65 years) female patients with MBC who had previously failed at least one line of chemotherapy were randomized (2:2:1) to NPLS 175 mg/m2 every 3 weeks (Q3W, n = 48, arm A), NPLS 80 mg/m2 every week (QW, n = 45, arm B) without premedication or conventional paclitaxel (Taxol®, manufactured by Bristol-Myers Squibb, Princeton, NJ, USA) 175 mg/m2 Q3W (n = 27, arm C) with premedication. In the extension study, an additional 54 patients were randomized (2:1) to arm A (n = 37) or arm C (n = 17). Results: Pooled data from the primary study and its extension phase included 174 patients. The primary endpoint was the overall response rate (ORR). As per intent-to-treat analysis, ORR was significantly better in the NPLS QW arm as compared to conventional paclitaxel [44.4% (20/45) versus 22.7% (10/44), (p = 0.04)]. An improvement in ORR with NPLS Q3W versus conventional paclitaxel arm [29.4% (25/85) versus 22.7% (10/44)] (p = 0.53) was observed. Disease control rates observed were improved with NPLS Q3W versus conventional paclitaxel Q3W (77.7% versus 72.7%, p = 0.66) and with NPLS QW versus conventional paclitaxel Q3W (84.4% versus 72.7%, p = 0.20), although not significant. A lower incidence of grade III/IV peripheral sensory neuropathy, vomiting, and dyspnea was reported with NPLS Q3W versus conventional paclitaxel Q3W arms. Conclusion: NPLS demonstrated an improved tumor response rate and a favorable safety profile versus conventional paclitaxel. NPLS 80 mg/m2 QW demonstrated a significantly better response versus conventional paclitaxel 175 mg/m2 Q3W. Trial registration: Clinical Trial Registry-India (CTRI), CTRI/2010/091/001344 Registered on: 18 October 2010 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MjEzNQ==&Enc=&userName=CTRI/2010/091/001344), CTRI/2015/07/006062 Registered on: 31 July 2015 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTE2Mjc=&Enc=&userName=CTRI/2015/07/006062).
Role of nanosomal paclitaxel lipid suspension (NPLS) in the treatment of patients with metastatic breast cancer (MBC) Why was the study done? Paclitaxel is a commonly used drug for the treatment of breast cancer. Conventional formulation of paclitaxel is known to cause side effects like injection site reactions. A newer formulation named NPLS was developed to overcome the limitations of the conventional paclitaxel. The current study was done to compare the safety and effectiveness of NPLS and conventional paclitaxel in patients with advanced breast cancer. What did the researchers do? The research team conducted a large study in multiple hospitals across India, involving women with advanced breast cancer who had experienced treatment failure with previous chemotherapy. A total of 174 patients were randomly assigned to receive either of the three treatment schedules: (1) NPLS every 3 weeks, (2) NPLS every week, (3) conventional paclitaxel every 3 weeks. What did the researchers find? The results showed that NPLS, in a weekly schedule, led to better tumor response rates compared to conventional paclitaxel given every 3 weeks. Additionally, NPLS demonstrated a favorable safety profile, as compared to conventional paclitaxel. What do the findings mean? These findings suggest that NPLS could be a promising alternative for women with advanced breast cancer. NPLS improved the response to treatment, with a better safety profile compared to conventional paclitaxel.
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Vaginal yeast infection is one of the most common diseases caused by vulvovaginal candidiasis (VVC). Effective therapy for VVC is needed. A lipid-based amphotericin B gel 0.1% (LAB) was developed and evaluated for the treatment of VVC patients and those who failed to azole therapy. LAB was applied topically twice daily for 7 days to 64 moderate patients and 14 days to 55 severely infected VVC patients. Additionally, 66 patients who failed to azole therapy were treated twice daily with LAB for 14 days. A 91.5% clinical response and 93.16% mycological response was observed in VVC patients. The patients treated with LAB who failed to azole therapy showed a 75% clinical, 95.3% mycological response and 83% remission was observed.Overall, the LAB was found to be efficacious and safe for the treatment of VVC patients. Clinical Trial Registration All the trials were registered at Clinical Trial Registry of India (CTRI/2013/02/003378, CTRI/2014/02/004409).
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Candidiasis Vulvovaginal , Femenino , Humanos , Anfotericina B/efectos adversos , Antifúngicos/efectos adversos , Azoles/uso terapéutico , Candidiasis Vulvovaginal/tratamiento farmacológico , LípidosRESUMEN
OBJECTIVE: Antihyperglycemic activity of Thymoquinone (TQ) was evaluated in diabetic mouse model and patients. METHODS: TQ (50 mg/kg) was orally administered daily for 21 days in combination with metformin in diabetic mice and a reduction on blood glucose level was monitored. In human, a 90-day randomized study was carried out in 60 Type 2 Diabetes mellitus patients to evaluate safety and efficacy of TQ administration with metformin in a 3-arm study. Patients in arm 1 (T1) received 1 tablet of metformin SR 1000 mg and 1 tablet of TQ 50 mg once daily. The second arm (T2) patients received 1 tablet of metformin SR 1000 mg and 2 tablets of TQ 50 mg once daily. Patients in arm 3 (R) received 1 tablet of metformin SR 1000 mg only. RESULTS: The diabetic mice treated with combination of TQ and metformin showed significant decrease in blood sugar compared to those treated with only metformin. In patients who completed the study, the glycated hemoglobin (HbA1c) values in T1, T2 and R decreased after 3 months from 7.2, 7.2 and 7.3 to 6.7, 6.8, and 7.1, respectively. A greater reduction in Fasting Blood Glucose and Post Prandial Blood Glucose was also observed in T1 and T2 arms compared to R. CONCLUSION: At dose levels of 50 and 100 mg of TQ combined with a daily dose of 1000 mg Metformin demonstrated a reduction in the levels of HbA1c and blood glucose compared to the standard treatment of diabetic patients with metformin alone.
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Benzoquinonas/administración & dosificación , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Administración Oral , Adulto , Animales , Glucemia/análisis , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/diagnóstico , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada/métodos , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Ratones , Persona de Mediana Edad , Estudios Prospectivos , Estreptozocina/administración & dosificación , Estreptozocina/toxicidadRESUMEN
Endoxifen is the key active metabolite of tamoxifen, a widely used breast cancer drug. Orally administered tamoxifen, is extensively metabolized by cytochrome P450 (CYP) enzymes, namely CYP3A4 and CYP2D6, into active metabolites, especially endoxifen. Due to genetic polymorphism of CYP2D6, significant numbers of women metabolize tamoxifen to varying degree and may not receive the optimal benefit from tamoxifen treatment. We show that oral administration of endoxifen achieved the optimally effective systemic levels reliably, which may eliminate variability associated with tamoxifen metabolism that leads to unpredictability in efficacy. Furthermore, use of endoxifen may avoid a potential serious drug interaction found between tamoxifen and commonly used selective serotonin reuptake inhibitors, antidepressants. Endoxifen was active in inhibiting the growth of various breast tumor cell lines in NCI 60-Cell Line Screen. Orally administered endoxifen is rapidly absorbed and systemically available when tested in female rats. The endoxifen-treated rats showed 787% higher exposure (AUC(0-infinity)) and 1,500% higher concentration (C (max)) levels of endoxifen when compared with tamoxifen. Oral endoxifen administration once a day for 28 consecutive days at dosages 2, 4, and 8 mg/kg proved safe and resulted in progressive inhibition of the growth of the human mammary tumor xenografts in female mice. This is the first ever in vivo report on endoxifen as a potentially new therapeutic agent for breast cancer.
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Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Tamoxifeno/análogos & derivados , Administración Oral , Animales , Antineoplásicos Hormonales/sangre , Antineoplásicos Hormonales/farmacocinética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Tamoxifeno/administración & dosificación , Tamoxifeno/sangre , Tamoxifeno/farmacocinética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Protein kinase C (PKC) plays a major role in regulation of both pre and postsynaptic neurotransmission. Excessive activation of PKC results in symptoms related to bipolar disorder. Tamoxifen, a widely used breast cancer drug is known to inhibit PKC and demonstrate antimanic properties in human. We describe herein the synthesis of endoxifen, a tamoxifen active metabolite and compared its PKC inhibitory activity with that of tamoxifen. Endoxifen exhibited fourfold higher potency compared to tamoxifen.
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Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Tamoxifeno/análogos & derivados , Animales , Espectroscopía de Resonancia Magnética , Ratones , Inhibidores de Proteínas Quinasas/química , Ratas , Tamoxifeno/química , Tamoxifeno/farmacologíaRESUMEN
Cationic liposomes have been successfully used as an alternative approach to viral systems to deliver nucleic acids. However, high toxicity and inconsistent transfection efficiency have been associated with the currently available liposomes. Therefore, a novel cationic liposome was developed based on a synthetic cationic cardiolipin analogue (CCLA) to test the DNA transfection efficiency. This CCLA-based liposome was also used to determine the therapeutic efficacy of c-raf small interfering RNA (siRNA) in mice. In this report, we showed that the CCLA-based liposome was less toxic and effectively transfected reporter genes in vitro and in vivo. The transfection efficiency in mice was seven-fold higher than the commercially available DOTAP-based liposome. In addition, c-raf siRNA in the presence of CCLA-based liposome induced up to 62% of growth inhibition in cancer cells. Treatment of c-raf siRNA/CCLA complex in SCID mice bearing human breast xenograft tumors resulted in 73% of tumor growth suppression as compared to free c-raf siRNA group. In conclusion, a novel CCLA-based liposome showed less toxicity and broad usage both in vitro and in vivo with DNA and siRNA.
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Cardiolipinas/uso terapéutico , ADN/administración & dosificación , Terapia Genética/métodos , Neoplasias/terapia , ARN Interferente Pequeño/administración & dosificación , Transfección/métodos , Animales , Peso Corporal/efectos de los fármacos , Cardiolipinas/química , Cardiolipinas/metabolismo , Cardiolipinas/toxicidad , Línea Celular Tumoral , ADN/genética , Humanos , Liposomas , Luciferasas , Masculino , Ratones , Ratones Endogámicos BALB C , Neoplasias/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/toxicidad , Rodaminas , Trasplante Heterólogo , beta-GalactosidasaRESUMEN
BACKGROUND: SN-38, 7-ethyl-10-hydroxycamptothecin, is a biologically active metabolite of irinotecan. Its poor solubility restricted its development as an anticancer agent. We have developed an easy-to-use liposome-entrapped SN-38 (LE-SN38) and evaluated its toxicology, pharmacokinetics and antitumor efficacy profile. MATERIALS AND METHODS: Toxicity and pharmacokinetics studies were conducted in CD2F1 mice and beagle dogs. Therapeutic efficacy studies were performed in murine leukemia (P388 and P388/ADR) and in a human pancreatic (Capan-1) tumor models. RESULTS: Multiple dose administration (i.v. x 5) of LE-SN38 indicated a maximum tolerated dose (MTD) of 5.0 and 7.5 mg/kg/day for male and female mice, respectively. The MTD of LE-SN38 in dogs was 1.2 mg/kg. The elimination half-life (t1/2) of SN-38 in mouse plasma was 6.38 h with volume of distribution (VdSS) 2.55 L/kg. In dogs, t1/2 and VdSS were 1.38-6.42 h and 1.69-5.01 L/kg; respectively. P388 tumor-bearing mice dosed with LE-SN38 at 5.5 mg/kg (i.v. x 5) showed 100% survival. LE-SN38 at 4 or 8 mg/kg (i. v. x 5) inhibited 65% and 98% tumor growth, respectively, in a human pancreatic tumor model. CONCLUSION: LE-SN38 showed a favorable pharmacokinetics profile and can be administered safely at therapeutically effective doses.
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Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Leucemia P388/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Irinotecán , Leucemia P388/metabolismo , Liposomas , Masculino , Ratones , Ratones SCID , Neoplasias Pancreáticas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new synthetic methodology for cationic glycolipids using p-aminophenyl-α-D-mannopyranoside (PAPM) and p-aminophenyl-α-D-galactopyranoside (PAPG) with spacer in between the quaternary nitrogen atom and the sugar unit is developed. In addition, a new class of neutral glycolipid conjugates, such as PAPM-lipids or PAPG-lipids conjugates was also synthesized for targeting drugs to receptors. The precipitation-inhibition assay showed that conjugate of PAPM inhibited the concanavalin A and invertase aggregation. This binding inhibition study of a synthesized compound suggests that conjugates of PAPM can be potentially used to target mannose receptors. In addition, a higher transfection was obtained by mixing PAPM with pSV-ß-gal reporter gene and incubating with mannose binding protein/receptor expressing A549 cells. The coexistence of both mannose group and a net positive charge may result in improved transfection efficiency in cells expressing mannose binding proteins/receptors.
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Sistemas de Liberación de Medicamentos , Glucolípidos/química , Liposomas/química , Línea Celular , Concanavalina A/metabolismo , Glucolípidos/síntesis química , Glucolípidos/metabolismo , Humanos , Liposomas/síntesis química , Liposomas/metabolismo , Manosa/metabolismo , beta-Fructofuranosidasa/metabolismoRESUMEN
A new synthetic methodology for cationic glycolipids using p-aminophenyl-α-d-mannopyranoside (PAPM), p-aminophenyl-α-d-galactopyranoside (PAPG) was developed. PAPM-lipids and PAPG-lipids conjugates were also synthesized for targeting drugs to receptors. A binding inhibition study of synthesized p-(dimethylamino butylamido) phenyl-α-d-mannopyranoside (1a) with Concanavalin A was performed using invertase enzyme. In addition, transfection of pSV-ß-gal reporter gene with was investigated in A549 cells.
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BACKGROUND: Nanosomal docetaxel lipid suspension formulation was developed to eliminate ethanol and polysorbate 80 from the currently used docetaxel (Taxotere) drug for treatment of cancer patients. NDLS clinical safety and efficacy was evaluated and compared with Taxotere at 75 mg/m(2) in metastatic breast cancer patients. PATIENTS AND METHODS: A total of 72 patients were randomized in a ratio of 2:1 (NDLS:Taxotere). Patients treated with NDLS were not premedicated with corticosteroids as required with solvent-based Taxotere. Disease status and tumor response was assessed after every 2 cycles of treatment using Response Evaluation Criteria in Solid Tumors 1.1 guidelines through cycle 6. RESULTS: Overall therapeutic response (complete + partial) rate in metastatic breast cancer patients treated with NDLS and Taxotere were 35.5% and 26.3%, respectively, indicating better response in patients treated with NDLS. Patients in the NDLS group were not premedicated but the safety results of NDLS were found to be comparable with Taxotere. CONCLUSION: NDLS formulation with no premedication provides an alternative treatment option for breast cancer patients.
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Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Taxoides/administración & dosificación , Adulto , Antineoplásicos/efectos adversos , Docetaxel , Femenino , Humanos , Liposomas , Persona de Mediana Edad , Nanotecnología , Taxoides/uso terapéutico , Adulto JovenRESUMEN
Two guggullipid derivatives, Z-guggulsulfate [4,17(20)-pregnadiene-3-one-16beta-sulfate] sodium salt and Z-guggullaurate [4,17(20)-pregnadiene-3-one-16beta-laurate], have been synthesized and evaluated for liposomal drug delivery system. Its precursor, Z-guggulsterol [4,17(20)-pregnadiene-3-one-16beta-ol], is also synthesized in gram scale starting from guggulsterone using the novel combination of known reactions in fewer steps and with higher yield than previously reported synthesis. These new synthetic guggullipid derivatives were also used in the preparation of liposomes. This new class of lipid molecules will be a useful tool in the development of nanosomal or liposomal drug delivery system.
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Portadores de Fármacos/química , Liposomas/química , Extractos Vegetales/síntesis química , Gomas de Plantas/síntesis química , Commiphora , Extractos Vegetales/análisis , Gomas de Plantas/análisisRESUMEN
OBJECTIVE: Develop Nanosomal formulation of Tacrolimus to provide safer alternative treatment for organ transplantation patients. Investigate safety, tolerability and pharmacokinetics of Nanosomal Tacrolimus formulation versus marketed Tacrolimus containing polyoxyl 60 hydrogenated castor oil (HCO-60) that causes side effects. METHODS: Nanosomal Tacrolimus was prepared in an aqueous system. The particle size was measured by Particle Sizing Systems and structure morphology was determined by freeze-fracture electron microscopy. Investigational safety studies were conducted in mice and rats. Safety and pharmacokinetics of Nanosomal Tacrolimus were also evaluated in healthy human subjects. RESULTS: The morphology of Nanosomal Tacrolimus showed a homogeneous population of nanosized particles with mean particle size of less than 100 nm. A 14 day consecutive administration of Nanosomal Tacrolimus up to 5 and 10mg/kg dose in rats and mice respectively, resulted in no mortality. Nanosomal Tacrolimus in human studies showed that it is safe and the pharmacokinetics profile is similar to the marketed HCO-60 based Tacrolimus. No significant change in peripheral blood lymphocyte percentage was noted in either mice or healthy human male subjects. CONCLUSIONS: Nanosomal Tacrolimus is well characterized product which provides a new treatment option. It contains no alcohol or surfactants like HCO-60. Thus, Nanosomal Tacrolimus presents a new and improved therapeutic approach for organ transplant patients compared to the marketed HCO-60 based Tacrolimus product.
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Aceite de Ricino/análogos & derivados , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacocinética , Tacrolimus/administración & dosificación , Tacrolimus/farmacocinética , Adolescente , Adulto , Animales , Área Bajo la Curva , Aceite de Ricino/química , Química Farmacéutica , Química Física , Cromatografía Líquida de Alta Presión , Excipientes , Femenino , Técnica de Fractura por Congelación , Semivida , Humanos , Inmunosupresores/efectos adversos , Indicadores y Reactivos , Recuento de Linfocitos , Masculino , Espectrometría de Masas , Ratones , Nanopartículas , Ratas , Ratas Sprague-Dawley , Tacrolimus/efectos adversos , Adulto JovenRESUMEN
Amphotericin B was formulated in lipids (Nanosomal Amphotericin B) without using any detergent or toxic organic solvents during the preparation. Electron microscopy and particle size determination of Nanosomal Amphotericin B showed a homogeneous population of nanosized particles below 100 nm. Hemolysis assay indicated that Nanosomal Amphotericin B causes significantly less lysis of red blood cells than Amphotericin B deoxycholate and was comparable to Ambisome. A maximum daily dose of Nanosomal Amphotericin B at 5 mg/kg in rabbits and 10 mg/kg in mice for 28 days showed no symptoms of toxicity, mortality or significant body weight reduction. Hematological and gross pathological analysis of tissues revealed no abnormalities attributable to the drug treatment. Nanosomal Amphotericin B and Ambisome were injected (iv) at 2 mg/kg consecutively for 5 days into mice infected with Aspergillus fumigatus. The treatment resulted in 90% survival with Nanosomal Amphotericin B and only 30% survival with Ambisome after 10 days of fungal infection. However, all of the 10 control mice which were not treated with Amphotericin B died within 5 days of fungal infection. Nanosomal Amphotericin B is safe, cost effective and provides an alternative option for treatment of fungal disease.
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Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Aspergilosis/tratamiento farmacológico , Anfotericina B/química , Anfotericina B/uso terapéutico , Anfotericina B/toxicidad , Animales , Antifúngicos/química , Antifúngicos/uso terapéutico , Antifúngicos/toxicidad , Aspergilosis/microbiología , Aspergillus fumigatus/efectos de los fármacos , Femenino , Liposomas , Masculino , Ratones , Ratones Mutantes , Nanopartículas , ConejosRESUMEN
Our objectives were to study the biological activity of a novel gemcitabine-cardiolipin conjugate (NEO6002) and compare that with gemcitabine. Cytotoxicity in vitro was determined against several gemcitabine-sensitive parental and gemcitabine-resistant cancer cell lines using the sulforhodamine B assay. The in vivo toxicity was examined by changes in body weight and hematologic indices of conventional mice. Immunodeficient SCID mice bearing P388 and BxPC-3 tumor xenografts were used to evaluate the in-vivo therapeutic efficacy. Both NEO6002 and gemcitabine showed pro-apoptotic and cytotoxic effects against all gemcitabine-sensitive cell lines tested. Unlike gemcitabine, the cytotoxicity of NEO6002 was independent of nucleoside transporter (NT) inhibitors, indicating a different internalization route of NEO6002. The conjugate demonstrated a favorable activity not only in ARAC-8C, a NT-deficient gemcitabine-resistant human leukemia cell line, but also in several other gemcitabine-resistant cell lines. At the in-vivo level, a comparative toxicity study showed a significant body weight loss and a decrease in white blood cell counts in gemcitabine-treated mice, whereas the influence of NEO6002 was mild. Treatment of NEO6002 at 27 micromol/kg increased the median survival of CD2F1 mice bearing P388 cells by up to 73%, while at the same doses and schedule of gemcitabine resulted in toxic deaths of all treated mice. At a dose of 18 micromol/kg, NEO6002 inhibited the growth of BxPC-3 xenografts by 52%, while only 32% of tumor inhibition was achieved with gemcitabine. We conclude that NEO6002 may be an effective chemotherapeutic agent with improved tolerability and can potentially circumvent NT-deficient, gemcitabine-resistant tumors.
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Antineoplásicos/farmacología , Cardiolipinas/farmacología , Desoxicitidina/análogos & derivados , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/metabolismo , Peso Corporal/efectos de los fármacos , Cardiolipinas/administración & dosificación , Cardiolipinas/metabolismo , Proliferación Celular/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/metabolismo , Desoxicitidina/farmacología , Dipiridamol/farmacología , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Células HT29 , Humanos , Leucemia P388/tratamiento farmacológico , Recuento de Leucocitos , Ratones , Ratones SCID , Neutropenia/inducido químicamente , Proteínas de Transporte de Nucleósidos/antagonistas & inhibidores , Proteínas de Transporte de Nucleósidos/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Tioinosina/análogos & derivados , Tioinosina/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
A novel gemcitabine-lipid conjugate 5 was synthesized and tested for its in vivo efficacy and toxicity. Compound 5 was tested in BxPC-3 human pancreatic tumor model in SCID mice and exhibited promising activity and lower toxicity when compared with Gemzar.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Lípidos/síntesis química , Lípidos/farmacología , Animales , Línea Celular Tumoral , Desoxicitidina/síntesis química , Desoxicitidina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones SCID , GemcitabinaRESUMEN
An approach was developed to synthesize a new class of cationic cardiolipin analogues containing two quaternary ammonium groups with tetra alkyl groups retaining "glycerol" moiety, the central core of the molecule. Cationic cardiolipin analogues were modified via introduction of either two or four oxyethylene groups to enhance the solubility in polar solvents. These newly synthesized cationic cardiolipin analogues can be applied to a broad range of drug delivery systems such as transfection reagents.
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Cardiolipinas/química , Cationes , Portadores de Fármacos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Fosfolípidos/síntesis química , Fosfolípidos/química , Relación Estructura-ActividadRESUMEN
SN-38 is an active metabolite of CPT-11. The poor solubility of SN-38 in any pharmaceutically acceptable solvent and pH-dependent activity has limited its clinical use. Our objective was to evaluate an easy-to-use liposome-based formulation of SN-38 (LE-SN38) and compare the antitumor activity with its pro-drug CPT-11 against cancer cell lines and human xenograft tumor models. The cytotoxicity of LE-SN38 and CPT-11 was determined in four human cancer cell lines using the sulforhodamine B assay. The therapeutic efficacy was tested against human colon (HT-29) and breast (MX-1) xenograft tumor models in SCID mice. LE-SN38 with greater than 95% drug entrapment was found to be highly cytotoxic against four different cell lines with GI50 values of less than 0.1 microM. In the HT-29 tumor model, LE-SN38 (q x d5) at 2, 4 or 8 mg/kg resulted in 33, 81 and 91% tumor growth inhibition, respectively, compared to the drug-free liposome group. In contrast, similar dose levels of CPT-11 treatment led to only 2, 36 and 46% growth inhibition. For the MX-1 model, LE-SN38 (q x d5) regressed tumor growth by 44 and 88% at 4 and 8 mg/kg dose, respectively, whereas no regression was observed in the CPT-11-treated group. We conclude that LE-SN38 is a novel liposome-based formulation with enhanced therapeutic efficacy against human tumor models.