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1.
Acta Crystallogr C Struct Chem ; 76(Pt 10): 982-991, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33016269

RESUMO

The present work utilizes density functional theory (DFT) calculations to study the influence of cation-π interactions on the electronic properties of the complexes formed by Altretamine [2,4,6-tris(dimethylamino)-1,3,5-triazine], an anticancer drug, with mono- and divalent (Li+, Na+, K+, Be2+, Mg2+ and Ca2+) metal cations. The structures were optimized with the M06-2X method and the 6-311++G(d,p) basis set in the gas phase and in solution. The theory of `Atoms in Molecules' (AIM) was applied to study the nature of the interactions by calculating the electron density ρ(r) and its Laplacian at the bond critical points. The charge-transfer process during complexation was evaluated using natural bond orbital (NBO) analysis. The results of DFT calculations demonstrate that the strongest/weakest interactions belong to Be2+/K+ complexes. There are good correlations between the achieved densities and the amounts of charge transfer with the interaction energies. Finally, the stability and reactivity of the cation-π interactions can be determined by quantum chemical computation based on the molecular orbital (MO) theory.


Assuntos
Altretamine/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Cátions/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Eletrônica , Ligação de Hidrogênio , Lítio/química , Metais/química , Teoria Quântica , Sódio/química
2.
Int J Biol Macromol ; 138: 359-369, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323265

RESUMO

Binding of anticancer drug altretamine with bovine serum albumin (BSA) and its inhibitory effect on fibrillation of the protein has been studied by using a combination of spectroscopic and calorimetric methods. Altretamine is observed to bind with BSA with a moderate binding affinity of the order of 105, which is weakly temperature dependent. Circular dichroism, fluorescence spectroscopic and dynamic light scattering methods have been employed to monitor the conformational change in the protein. Time correlated single photon counting measurements have confirmed ground state complexation of the drug with the protein. Docking studies have led to identification of binding sites on BSA at site III in domain IB. Thioflavin T (ThT) fluorescence emission has been used as a tool to monitor the formation of fibrils/aggregates in BSA. It is observed that anticancer drug altretamine can also act as an inhibitor of fibrillation in BSA and hence can be useful in the treatment of neuro-degenerative diseases. Differential scanning calorimetry has been employed to study the thermal transitions of BSA at different stages of the fibrillation process with and without altretamine to obtain insights into the extent of stabilisation provided by the drug to the protein in native, nucleation/elongation and matured state in the fibrillation process.


Assuntos
Altretamine/metabolismo , Altretamine/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Multimerização Proteica/efeitos dos fármacos , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Animais , Bovinos , Simulação de Acoplamento Molecular , Conformação Proteica , Temperatura
3.
Elife ; 82019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31184303

RESUMO

Microbes are nature's chemists, capable of producing and metabolizing a diverse array of compounds. In the human gut, microbial biochemistry can be beneficial, for example vitamin production and complex carbohydrate breakdown; or detrimental, such as the reactivation of an inactive drug metabolite leading to patient toxicity. Identifying clinically relevant microbiome metabolism requires linking microbial biochemistry and ecology with patient outcomes. Here we present MicrobeFDT, a resource which clusters chemically similar drug and food compounds and links these compounds to microbial enzymes and known toxicities. We demonstrate that compound structural similarity can serve as a proxy for toxicity, enzyme sharing, and coarse-grained functional similarity. MicrobeFDT allows users to flexibly interrogate microbial metabolism, compounds of interest, and toxicity profiles to generate novel hypotheses of microbe-diet-drug-phenotype interactions that influence patient outcomes. We validate one such hypothesis experimentally, using MicrobeFDT to reveal unrecognized gut microbiome metabolism of the ovarian cancer drug altretamine.


Assuntos
Alimentos , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/química , Trato Gastrointestinal/microbiologia , Preparações Farmacêuticas/metabolismo , Altretamine/química , Altretamine/metabolismo , Bactérias/metabolismo , Biotransformação , Metabolismo dos Carboidratos , Dieta , Interações entre Hospedeiro e Microrganismos , Humanos , Estrutura Molecular
4.
Int J Biol Macromol ; 101: 24-31, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28315435

RESUMO

Altretamine is a synthetic drug approved for treatment of ovarian cancer. The only drawback with its formulation is poor aqueous solubility and low oral bioavailability. In the present work an attempt has been made to prepare inclusion complex of altretamine with epichlorohydrin beta cyclodextrin. The complexes were prepared by kneading, co-evaporation and freeze-drying method and were confirmed by FTIR, XRD, DSC, drug content and dissolution study. Kneaded complex possess maximum solubilizing efficiency of 82.63 in 25mM Epi-ß-CD solution. SLNs of pure altretamine and ALT complexed with Epi-ß-CD were prepared by modified emulsification-ultrasonication method. The particle size and zeta potential was found to be 151.5nm and -21.3mV. The drug release pattern of SLNs was bi-phasic in nature; with an initial burst release followed by sustained drug release. Pharmacokinetic study showed that the average Cmax was found to be 0.94µg/ml, which was 2.47 times higher as compared to the pure drug. The AUCt for SLNs was 150minµgh/ml and 54minµgh/ml for pure ALT suspension which proved that the SLNs exhibited greater absorption compared to the pure drug. Thus, smaller particle size, higher entrapment efficiency and enhanced aqueous solubility led to improvement in oral bioavailability of ALT.


Assuntos
Altretamine/química , Altretamine/farmacocinética , Portadores de Fármacos/química , Epicloroidrina/química , Lipídeos/química , Nanopartículas/química , beta-Ciclodextrinas/química , Administração Oral , Altretamine/administração & dosagem , Animais , Disponibilidade Biológica , Ratos , Ratos Wistar , Solubilidade
5.
Artif Cells Nanomed Biotechnol ; 44(2): 571-80, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25363752

RESUMO

The objective of the present study was to prepare solid lipid nanoparticles (SLNs) of altretamine (ALT) by the hot homogenization and ultrasonication method. The study was conducted using the Box-Behnken design (BBD), with a 3(3) design and a total of 17 experimental runs, performed in combination with response surface methodology (RSM). The SLNs were evaluated for mean particle size, entrapment efficiency, and drug-loading. The optimized formulation, with a desirability factor of 0.92, was selected and characterized. In vitro release studies showed a biphasic release pattern from the SLNs for up to 24 h. The results of % EE (93.21 ± 1.5), %DL (1.15 ± 0.6), and mean diameter of (100.6 ± 2.1) nm, were very close to the predicted values.


Assuntos
Altretamine/química , Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Tamanho da Partícula , Tensoativos/química , Ondas Ultrassônicas
6.
Drug Deliv ; 17(3): 164-70, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20196698

RESUMO

Liposomes incorporating sodium deoxycholate (NaDC) were prepared by the method of reverse phase evaporation and used for drug delivery by the oral route. Hexamethylmelamine (HMM), an anti-tumor agent, was chosen as a model drug and encapsulated into liposomes incorporating NaDC (NaDC-Lip). Several properties of NaDC-Lip containing HMM (HMM NaDC-Lip), such as particle size, entrapment efficiency, pinacyanol chloride (PIN) spectral characteristics with various molar ratio of NaDC/PC, as well as the vesicle stability measurements with calcein were evaluated. In vivo, the area under the plasma concentration-time curve obtained from the pharmacokinetics study of HMM NaDC-Lip was found to be approximately 9.76- and 1.21-fold higher than that of HMM solution and HMM Lip, respectively, indicating that NaDC-Lip can be used as a potential carrier for oral drug administration.


Assuntos
Altretamine/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Ácido Desoxicólico/química , Lipossomos/química , Administração Oral , Altretamine/farmacocinética , Animais , Antineoplásicos Alquilantes/farmacocinética , Carbocianinas/química , Colesterol/química , Cromatografia Líquida de Alta Pressão , Portadores de Fármacos , Composição de Medicamentos , Estabilidade de Medicamentos , Feminino , Fluoresceínas/química , Lipídeos/química , Tamanho da Partícula , Ratos , Ratos Wistar , Espectrofotometria Ultravioleta
7.
J Korean Med Sci ; 24(4): 679-83, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19654952

RESUMO

The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC). Patients treated at our hospital between January 1997 and November 2006 and in documented clinical complete response from advanced ovarian cancer following front-line platinum-based therapy were retrospectively analyzed. The patients treated with HMM were compared to the patients of matched counterpart without consolidation therapy. Of 102 patients enrolled, 49 were treated with HMM and 53 received no consolidation treatment. For patients with HMM and observed patients, the mean age were 54.6 and 55.6 yr; the distribution of stage was similar (P=0.977); the optimal surgery was performed in 36 (73.5%) and 44 (83%) (P=0.336); the recurrence rate were 27 (55.1%) and 33 (62.3%) (P=0.463); and the median progression-free survival were 38 months and 21 months for patients with HMM and observed patients (P=0.235). No treatment-related adverse events were reported during the follow-up period. Although this study failed to show the significant survival benefit of consolidation therapy with HMM in patients with advanced EOC, we consider that our study can contribute data to investigate the effectiveness of consolidation therapy in epithelial ovarian cancer.


Assuntos
Altretamine/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos
8.
J Am Geriatr Soc ; 56(10): 1845-52, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18811611

RESUMO

OBJECTIVES: To examine the association between frailty status and change in cognitive function over time in older Mexican Americans. DESIGN: Data used were from the Hispanic Established Population for the Epidemiological Study of the Elderly. SETTING: Five southwestern states: Texas, New Mexico, Colorado, Arizona, and California. PARTICIPANTS: One thousand three hundred seventy noninstitutionalized Mexican-American men and women aged 65 and older with a Mini-Mental State Examination (MMSE) score of 21 or higher at baseline (1995/96). MEASUREMENTS: Frailty, defined as three or more of the following components: unintentional weight loss of more than 10 pounds, weakness (lowest 20% in grip strength), self-reported exhaustion, slow walking speed (lowest 20% in 16-foot walk time in seconds), and low physical activity level (lowest 20% on Physical Activity Scale for the Elderly score). Information about sociodemographic factors, MMSE score, medical conditions (stroke, heart attack, diabetes mellitus, arthritis, cancer, and hypertension), depressive symptoms, and visual impairment was obtained. RESULTS: Of the 1,370 subjects, 684 (49.9%) were not frail, 626 (45.7%) were prefrail (1-2 components), and 60 (4.4%) were frail (>/=3 components) in 1995/96. Using general linear mixed models, it was found that frail subjects had greater cognitive decline over 10 years than not frail subjects (estimate=-0.67, standard error=0.13; P<.001). This association remained statistically significant after controlling for potential confounding factors. CONCLUSION: Frail status in older Mexican Americans with MMSE scores of 21 or higher at baseline is an independent predictor of MMSE score decline over a 10-year period. Future research is needed to establish pathophysiological components that can clarify the relationship between frailty and cognitive decline.


Assuntos
Transtornos Cognitivos/etnologia , Idoso Fragilizado/psicologia , Americanos Mexicanos/psicologia , Idoso , Altretamine , Transtornos Cognitivos/complicações , Comorbidade , Feminino , Avaliação Geriátrica , Força da Mão , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Atividade Motora , Força Muscular , Sudoeste dos Estados Unidos , Transtornos da Visão/complicações , Caminhada
10.
Chem Commun (Camb) ; (31): 3645-7, 2008 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-18665286

RESUMO

A novel method for the cyclotrimerization of dimethylcyanamide to form hexamethylmelamine has been developed using an aluminium amide catalyst; detailed DFT modelling of the catalytic cycle supports a triple insertion, nucleophilic ring closure, deinsertion mechanism.


Assuntos
Alumínio/química , Cianamida/síntese química , Altretamine/química , Catálise , Cristalografia por Raios X , Cianamida/química , Ciclização , Conformação Molecular , Termodinâmica
11.
Cancer Chemother Pharmacol ; 63(1): 19-26, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18305940

RESUMO

PURPOSE: Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O'Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)(2) system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway. METHODS: The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with different DNA damaging agents. RESULTS: Two main classes of DNA damaging agents, platinum-derived agents, and select bifunctional alkylating agents, demonstrated in vivo synergistic or super-additive interaction with irofulven. DNA helicase inhibiting agents also demonstrated synergy in vitro, but an enhanced interaction with irofulven could not be demonstrated in vivo. There was no detectable synergistic activity between irofulven and agents capable of inducing DNA cleavage or intercalating into DNA. CONCLUSION: These results indicate that the antitumor activity of irofulven is enhanced when combined with platinum-derived agents, altretamine, and select alkylating agents such as melphalan or chlorambucil. A common factor between these agents appears to be the production of intrastrand DNA crosslinks. The synergistic interaction between irofulven and other agents may stem from the nucleotide excision repair system being selectively overwhelmed at two distinct points in the pathway, resulting in prolonged stalling of transcription forks, and subsequent initiation of apoptosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Altretamine/administração & dosagem , Altretamine/farmacologia , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma/genética , Sinergismo Farmacológico , Feminino , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacologia , Distribuição Aleatória , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacologia , Transcrição Genética/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Clin Oncol ; 24(9): 1454-8, 2006 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-16549840

RESUMO

PURPOSE: A previous report suggested the nadir serum CA-125 level within the group of patients with ovarian cancer who achieved normalization of CA-125 accurately defined the risk of relapse. Using similar CA-125 subgroups, we sought to determine if the baseline CA-125 level before initiation of maintenance chemotherapy in women achieving a clinically-defined complete response to primary chemotherapy would be of prognostic value. PATIENTS AND METHODS: Patients included in this retrospective analysis had been treated on one of two previously reported trials of maintenance chemotherapy (three v 12-monthly cycles of paclitaxel; oral altretamine), with a baseline CA-125 level of < or = 35 u/mL. Progression-free survival (PFS) from study entry was analyzed by the Cox regression model. RESULTS: The distribution of premaintenance baseline CA-125 levels for the 384 patients was 58%, 34%, and 8% for values of (A) < or = 10 u/mL, (B) 11 to 20 u/mL, and (C) 21 to 35 u/mL, respectively. The baseline CA-125 was highly statistically significant, either as a categoric variable (P < .001) or as a continuous variable (P < .0001). Median PFS was 24 months, 17 months, and 7 months for groups (A), (B), and (C), respectively. There was no evidence the CA-125 effect differed by trial or treatment in an interaction analysis (P = .70). CONCLUSION: The baseline CA-125 level before initiation of maintenance chemotherapy strongly predicts the risk of subsequent relapse. Patients with premaintenance baseline CA-125 values < or = 10 u/mL have a superior PFS compared with higher levels in the normal CA-125 range.


Assuntos
Antígeno Ca-125/sangue , Recidiva Local de Neoplasia , Neoplasias Ovarianas/patologia , Idoso , Altretamine/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Valor Preditivo dos Testes , Estudos Retrospectivos , Análise de Sobrevida
14.
Clin Cancer Res ; 10(22): 7439-49, 2004 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-15569973

RESUMO

Ovarian cancer is increasingly recognized as a chronic disease whose treatment is often characterized by administration of multiple, sequential active agents, each of which may or may not be accompanied by a tumor response. Despite the large proportion of patients who relapse and undergo longer-term treatment, the question of optimal treatment duration has not been fully addressed to date. For patients who progress on therapy, the answer is straightforward: they are switched to another active agent, presumably having a different mechanism of action from previous therapies with, ideally, limited overlapping toxicities. However, for patients who remain in partial response or who have stable disease, the answer is less apparent and less clear. The majority of oncologists believe that treatment beyond 6 cycles of a given therapy does not provide any additional benefit to patients. There are some data to support that treatment strategy. However, with the advent of new, less toxic agents, treatment to progression should be further explored. Agents that are potentially well suited for extended treatment intervals may include such properties as absence of cumulative toxicity, non-cross-resistance, positive benefit on quality of life, and convenient schedule. A number of active agents in ovarian cancer (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) will be reviewed in the context of what is known about cumulative toxicity, potential adverse effects on patients' quality of life, and evidence addressing the potential benefits of longer-term treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Recidiva , Altretamine/administração & dosagem , Antineoplásicos/uso terapêutico , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Progressão da Doença , Docetaxel , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Paclitaxel/administração & dosagem , Risco , Taxoides/administração & dosagem , Fatores de Tempo , Topotecan/administração & dosagem
15.
Int J Gynecol Cancer ; 14(2): 224-8, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15086720

RESUMO

OBJECTIVE: This report provides follow-up progression-free survival (PFS) and median survival data for women who achieved clinical complete remission (cCR) from stage III ovarian cancer after first-line therapy and were treated with altretamine consolidation therapy. METHODS: Patients who enrolled in the SWOG 9326 study from September 1993 to July 1997 were required to have documented cCR from stage III ovarian cancer following front-line platinum-based therapy. Treatment consisted of 6 months of oral altretamine at 260 mg/m(2)/day for 14 consecutive days of a 28-day cycle. RESULTS: Ninety-seven of 112 enrolled patients were evaluable for efficacy. This report presents median 6.2-year follow-up, dating from study registration. Median PFS was 28 (95% CI: 19-43) months. Median PFS for patients with optimal disease was 45 (95% CI: 27-48) months and for patients with suboptimal disease was 17 (95% CI: 12-26) months. Twenty-six of 61 (43%) patients with optimally debulked lesions and 5 of 36 (14%) patients with suboptimally debulked lesions remained disease free. Median survival of patients with optimally debulked disease has not been reached; median survival of patients with suboptimally debulked disease was 39 (95% CI: 19-51) months. No treatment-related adverse events were reported during the follow-up period. CONCLUSIONS: Consolidation therapy with oral altretamine was generally well tolerated and associated with prolonged progression-free and overall survival in the Phase II setting.


Assuntos
Altretamine/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase II como Assunto , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Terapia de Salvação , Sudoeste dos Estados Unidos , Análise de Sobrevida
16.
Gynecol Oncol ; 92(1): 368-71, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14751188

RESUMO

BACKGROUND: Altretamine has reported efficacy in the treatment of recurrent ovarian cancer following platinum-based therapy. This report presents the cases of two long-term survivors with recurrent ovarian cancer given oral altretamine. CASES: Two patients diagnosed with stage IIIC ovarian cancer underwent optimal cytoreductive surgery. Both women were subsequently treated with platinum-based chemotherapy. One had persistent cancer documented 2 months post therapy, while the other was disease-free for 22 months before recurring. Both received altretamine in a salvage setting. Each of these women achieved a prolonged response to third-line altretamine therapy, and one of whom was disease-free for 4 years and the other remains disease-free over 7 years following initiation of salvage therapy. CONCLUSION: Outpatient-administered oral altretamine can provide a prolonged disease-free interval with minimal toxicity.


Assuntos
Altretamine/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Administração Oral , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Salvação
17.
Gynecol Oncol ; 88(2): 118-22, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12586589

RESUMO

OBJECTIVE: To evaluate the activity of oral Altretamine in women with epithelial ovarian carcinoma who responded (PR or CR) to first line chemotherapy but relapsed within 6 months. The protocol was later amended to include patients with relapse within 12 months. METHODS: A multicentric phase II trial. The patients had to have measurable disease. No more than one prior chemotherapy regiment was allowed. The patients were treated with 260 mg/m(2)/day of Altretamine in four divided doses for 2 weeks, repeated every 4 weeks. The response was evaluated after every two courses. RESULTS: Thirty-one eligible patients were treated with a median of 3 courses of Altretamine (range 1-12). Hematological toxicity was minimal. Gastrointestinal toxicity was common. Response evaluation was possible for 26 patients. Three patients (9.7% intent-to-treat) achieved a partial response. Eight patients had stable disease, and 15 patients had progressive disease after two treatment courses. The median time to progression was 10 weeks (range, 5-51 weeks). Medial survival was 34 weeks (range, 7-112+). CONCLUSION: Altretamine should not be chosen as standard treatment in patients with platinum-resistant recurrent ovarian cancer. However, Altretamine represents a useful alternative in patients who prefer oral treatment or when socioeconomic considerations are an important issue.


Assuntos
Altretamine/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Administração Oral , Idoso , Altretamine/efeitos adversos , Antineoplásicos Alquilantes/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico
19.
J Microencapsul ; 19(1): 95-109, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11811763

RESUMO

Biodegradable poly(D,L-lactic acid) (PLA) microspheres containing hexamethylmelamine (HMM) were developed for potential use in chemoembolization and intraperitoneal implantation. The emulsion-solvent-evaporation/extraction method was used to prepare 15 formulations with different drug/polymer ratios, solvent compositions and emulsifer concentrations in the continuous aqueous phase. A central composite experimental design was used, with five levels of the three different factors. All formulations resulted in the formation of discrete matrix microspheres containing crystalline drug. The mean particle sizes of the microsphere formulations ranged from 62-348 microm and the effect of the independent variables on microsphere size was satisfactorily predicted using response surface methodology. For theoretical drug loads of 5-40%, efficiency of entrapment ranged from 75-107% and porosities of the microspheres were between 0-6.5%. The rate of drug release from the microspheres depended on drug loading and particle size. Microspheres with 22.5% or greater theoretical drug content released drug rapidly, with almost complete release occurring in 70 h or less. Formulations with drug loading of 5% and 9.57%, however, released drug very slowly, with less than 50% released in 40 days. Release kinetics of narrow sieve cuts of microspheres with high drug load (35.4%) followed square root of time profiles.


Assuntos
Altretamine/administração & dosagem , Altretamine/química , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/química , Ácido Láctico/química , Polímeros/química , Varredura Diferencial de Calorimetria , Fenômenos Químicos , Físico-Química , Densitometria , Emulsões , Excipientes , Cinética , Microscopia Eletrônica de Varredura , Microesferas , Tamanho da Partícula , Poliésteres , Solubilidade , Solventes
20.
Gynecol Oncol ; 82(2): 317-22, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11531286

RESUMO

OBJECTIVE: The aim of this study was to evaluate the 2-year survival rate in a group of women in complete clinical remission (cCR) from Stage III ovarian cancer following front-line therapy who were then treated with a 6-month course of altretamine. METHODS: Patients were documented to be in cCR by physical examination, computed tomography or magnetic resonance imaging scan, and serum CA-125. Treatment consisted of altretamine (Hexalen) 260 mg/m(2)/day po divided into four doses taken after meals and at bedtime for 14 of 28 days for six cycles. Based on previous experience in the Southwest Oncology Group, the treatment would be considered promising if the 2-year survival rate was > or = 65% as measured from study registration. RESULTS: From 9/1/93 and 7/1/97, 112 patients were registered and 97 were fully evaluable. The majority of patients had optimally debulked (< or = 1 cm: 63%), high-grade (Grade 3: 82%) tumors. The 2-year survival rate in this study was 75% (95% CI: 66-84%). For those patients with optimal disease, the 2-year survival rate was 82% (95% CI: 72-92%) and for those with suboptimal disease it was 64% (95% CI: 48-79%). Four patients (4%) experienced Grade 4 and 21 patients (22%) experienced Grade 3 toxicities consisting primarily of nausea/vomiting, neutropenia, fatigue, anxiety, and paresthesias. CONCLUSIONS: The 2-year survival rate in this study warrants further evaluation of consolidation therapy for women in clinical complete remission following front-line chemotherapy for Stage III ovarian cancer. Caution is advised in the interpretation of these data, however, because of the nonrandomized nature of the trial and the unknown contribution of front-line use of paclitaxel to the durability of clinical complete response.


Assuntos
Altretamine/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Altretamine/efeitos adversos , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Antígeno Ca-125/sangue , Esquema de Medicação , Células Epiteliais/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Paclitaxel/uso terapêutico , Indução de Remissão , Taxa de Sobrevida
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