RESUMO
BACKGROUND: Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). RESULTS: One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms. CONCLUSION(S): The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials. CLINICAL TRIAL NUMBER: NCT00294996.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/análogos & derivados , Paclitaxel/uso terapêutico , Receptor ErbB-2/metabolismo , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Metástase Neoplásica/tratamento farmacológico , Paclitaxel/efeitos adversos , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos , Trastuzumab , Resultado do TratamentoRESUMO
Previous retrospective analyses have suggested a very positive correlation in toxic doses of antineoplastic agents between mice and humans. Additional toxicological information has now been accumulated and reveals a noticeable variability in the existing data base. Nevertheless, it is likely that mouse toxicological studies will become a principal determinant for estimating initial doses to be used in humans. Recognition of the factors responsible for differences in determinations of toxic dose levels in mice will enhance the proper utilization of this approach.
Assuntos
Antineoplásicos/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação de Medicamentos/métodos , Animais , Antineoplásicos/administração & dosagem , Humanos , Dose Letal Mediana , Camundongos , Projetos de Pesquisa , Especificidade da EspécieRESUMO
Twenty-six adult patients were entered in a phase I trial of carboplatin, a new cisplatin derivative with reduced potential for nephrotoxicity. All patients had solid tumors and the median World Health Organization performance score was 2 (0-3). Twelve patients had not received prior chemotherapy. The drug was administered as a 15-minute IV infusion, without pre- or posthydration, at daily doses of 40-125 mg/m2 for five consecutive days. Antiemetics were given only if needed. Thrombocytopenia and neutropenia were dose related and dose limiting. One patient died from septic shock at the highest dose level. Nonhemolytic anemia was also encountered. Nausea and vomiting were experienced by most patients but gastrointestinal intolerance was severe in only two patients. One patient had hypercreatininemia, which was minor and rapidly reversible. Other toxic effects consisted of negligible fatigue, paresthesia, pruritus, local pain, stomatitis, headache, and alopecia. Although none of the patients achieved a partial or complete response, antitumor effect was strongly suggested in two patients with thyroid and cervix cancer, respectively. Carboplatin is an attractive candidate for phase II trials. In good-risk patients, such trials could be initiated at a daily dose of 100 mg/m2 for five consecutive days every five to six weeks.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carboplatina , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Parenterais , Nefropatias/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêuticoRESUMO
Sixty-three evaluable patients with advanced breast cancer were randomly allocated to receive three-week intravenous courses of carminomycin (18 mg/m2) or 4'-epidoxorubicin (90 mg/m2). The former yielded one (3%) partial response for nine weeks among 29 patients whereas, in the other arm, nine (27%) of 34 patients achieved partial response for a median of 28 weeks (range, nine to 36 weeks; p less than 0.02). The major toxic effect of these anthracyclines was leukopenia with median white blood cell nadirs of 1,600/microL (range, 300-4,000/microL) versus 1,800/microL (range, 500-4,300/microL), respectively. Acute nonhematologic toxic effects were qualitatively similar but carminomycin produced significantly less gastrointestinal intolerance and alopecia. Patients whose disease failed to respond to first-line anthracycline received doxorubicin (60 mg/m2) every three weeks. Four partial responses were obtained among 19 patients previously treated with carminomycin. Following 4'-epidoxorubicin therapy, one of 12 evaluable patients also attained partial response. Survival curves were not affected by the initial treatment option. Carminomycin has marginal activity against breast cancer whereas 4'-epidoxorubicin deserves further evaluation of its therapeutic index relative to doxorubicin. The design used in this trial appears attractive for prompt phase II evaluation of anthracycline analogs.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carrubicina/administração & dosagem , Daunorrubicina/análogos & derivados , Doxorrubicina/administração & dosagem , Adulto , Idoso , Alopecia/induzido quimicamente , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carrubicina/efeitos adversos , Doxorrubicina/efeitos adversos , Avaliação de Medicamentos , Epirubicina , Feminino , Seguimentos , Cardiopatias/induzido quimicamente , Humanos , Leucopenia/induzido quimicamente , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Metástase Neoplásica , Distribuição Aleatória , Vômito/induzido quimicamenteRESUMO
The existing literature data base on carboplatin updated to June, 1985 has been reviewed. The compound seems to retain the same spectrum of activity as cisplatin, and a definite set of efficacy data is available for ovarian cancer of epithelial origin, small cell carcinoma of the lung and epidermoid carcinoma of the head and neck. A yet unpublished toxicity data base on carboplatin suggests that the compound has an improved therapeutic index over the parent compound, cisplatin, and that it does not seem inferior to another platinum coordination compound currently in clinical trials, iproplatin.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Medula Óssea/efeitos dos fármacos , Carboplatina , Carcinoma de Células Pequenas/tratamento farmacológico , Cisplatino/efeitos adversos , Ensaios Clínicos como Assunto , Avaliação de Medicamentos , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Rim/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
PIP: The use of megestrol acetate in treatment of malignancy (endometrial carcinoma, ovarian cancer, prostate cancer, breast cancer, renal cell carcinoma, malignant melanoma), endometrial hyperplasia, benign prostatic hypertrophy, contraception, anorexia, cachexia and weight loss is reviewed, concluding with a toxicity profile. Megestrol acetate was introduced in 1971 for treatment of endometrial carcinoma. Megestrol acetate is probably effective in proportion to the number of cytoplasmic progesterone receptors, but it has not been tested in a Phase III trial. For ovarian cancer it has been reported to be effective in 1 trail at doses of 800 mg/day. Prostate cancer, although difficult to assess, responds to megestrol acetate at doses of 120 mg/day because of its suppression of gonadotropins, its inhibition of 5alpha-reductase and its binding to the dihydrotestosterone receptor. Megestrol acetate permits a lower dose of diethylstilbestrol, and thus lower toxicity. There is apparently a dose-response between megestrol acetate and breast cancer, along with a response dependent on the number and type of estrogen and progestin receptors. Responses are better in postmenopausal women, and additive with other agents such as tamoxifen and mitomycin C. The medium duration of effect is 6-8 months. It has no effect on renal cancer or malignant melanoma. Megestrol acetate can be considered as an effective medical alternative to surgery for endometrial hyperplasia or benign prostatic hypertrophy. As a contraceptive in inhibits sperm transport rather than ovulation, but also causes irregular bleeding. Megestrol acetate has few side effects, and has the advantage of stimulating appetite and weight gain, a benefit in cancer patients.^ieng
Assuntos
Megestrol/análogos & derivados , Síndrome da Imunodeficiência Adquirida/complicações , Adulto , Animais , Anorexia/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Caquexia/tratamento farmacológico , Caquexia/etiologia , Carcinoma de Células Renais/tratamento farmacológico , Anticoncepcionais Masculinos/administração & dosagem , Anticoncepcionais Orais/administração & dosagem , Hiperplasia Endometrial/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Megestrol/administração & dosagem , Megestrol/efeitos adversos , Megestrol/uso terapêutico , Acetato de Megestrol , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Hiperplasia Prostática/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Coelhos , Tamoxifeno/administração & dosagem , Tamoxifeno/uso terapêutico , Neoplasias Uterinas/tratamento farmacológicoRESUMO
The safety profile of Taxol administered intravenously as a single agent has been established based on the experience of 655 patients. Of these patients, 253 were treated in nine phase I studies, and 402 were treated in eight disease-oriented phase II studies. Myelosuppression, specifically neutropenia, was the dose-limiting toxicity in all studies conducted in patients with solid tumors. Neutropenia was schedule dependent and was less severe when Taxol was administered via a 3-hour infusion. Severe hypersensitivity reactions were controlled in the phase II program with a premedication regimen consisting of dexamethasone, an antihistamine, and an H2 blocker. Cardiovascular toxicities were minimal and do not indicate constant electrocardiographic monitoring during Taxol infusions. Peripheral neuropathy was usually mild to moderate and dose related; however, it rarely caused treatment discontinuation. Additional adverse events associated with Taxol include arthralgia/myalgia, mucositis, nausea and vomiting, and alopecia.
Assuntos
Paclitaxel/efeitos adversos , Medula Óssea/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Hipersensibilidade a Drogas , Humanos , Doenças do Sistema Nervoso/induzido quimicamenteRESUMO
Single equimolar oral doses of bacampicillin and ampicillin were given to 9 healthy subjects on a crossover randomized basis. Data were interpreted in terms of a 3-compartment pharmacokinetic open model. Intestinal absorption of bacampicillin was found to be faster and more complete than that of ampicillin, yielding an increase in bioavailability of 30% to 40% as measured by the area under serum levels curve, the urinary excretion and absorption rate constants. After the administration of bacampicillin, much higher and sharper peaks were achieved in the serum and in the "tissue" water than after the administration of ampicillin. The maximum bactericidal dilution (MBD) of the serum samples taken 1 hr after the administration of the antibiotics against 10 strains of Diplococcus pneumoniae was higher following bacampicillin (p less than 0.01), as was the MBD of the 0 to 2 hr urine specimens against 10 strains of Escherichia coli. Further clinical trials are required to accurately assess the possible greater therapeutic effectiveness of bacampicillin than of ampicillin.
Assuntos
Ampicilina/análogos & derivados , Ampicilina/farmacologia , Ampicilina/metabolismo , Bacillus subtilis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Rim/metabolismo , Cinética , Streptococcus pneumoniae/efeitos dos fármacos , Fatores de TempoRESUMO
It is clear from this review that a number of the antineoplastics cause or are associated with cardiotoxicity. Cardiotoxicity is not uncommon with the anthracyclines, but is rare for most of the other antineoplastics. With the use of anthracyclines earlier in patients' illnesses and in particular in adjuvant situations the clinical investigator must be constantly aware of the possible cardiotoxicity of those agents. Improved methods to detect cardiotoxicity before it is clinically apparent are sorely needed, particularly for this adjuvant group. The possibility of a chemotherapy induced cardiac disorder should always be entertained in the patient with cancer who develops a cardiac problem.
Assuntos
Antineoplásicos/efeitos adversos , Cardiopatias/induzido quimicamente , Cardiomiopatias/induzido quimicamente , Daunorrubicina/efeitos adversos , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Eletrocardiografia , Coração/efeitos dos fármacos , Cardiopatias/complicações , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/prevenção & controle , Humanos , Neoplasias/complicaçõesRESUMO
Hormonal therapy of breast cancer is widely used and effective. Although never curative in advanced disease, significant palliation and durable remissions can be obtained with a wide variety of hormonal manipulations. Historically, surgical ablation was used to reduce endogenous hormone levels, but this invasive procedure has been largely supplanted by drugs that reduce hormone secretion or block steroid hormone activity. A number of such antagonists are available, with tamoxifen probably the most widely used. Response can also be achieved with hormone agonists. Estrogens and androgens or their congeners have about the same level of activity as surgical ablation or drug antagonists (20% to 30% overall response rate). The progestins, another class of agonists, are also effective in the palliation of advanced breast cancer. Megestrol acetate, in part because of its oral formulation, is probably the most commonly used progestational drug for the treatment of breast cancer. Reports of 16 trials involving 1,342 patients show a response rate of 26% in patients with advanced breast cancer treated with megestrol acetate. The drug has proved active in a small number of male patients and, in randomized trials, it has been shown to be comparable with tamoxifen in efficacy (30% response for megestrol acetate v 35% for tamoxifen). Studies are currently under way to evaluate the possibility that high doses of megestrol acetate may increase response rates, and to determine whether weight gain, a well-described effect of this drug, may prove beneficial in cancer treatment.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Megestrol/análogos & derivados , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Megestrol/uso terapêutico , Acetato de Megestrol , Metanálise como Assunto , Tamoxifeno/uso terapêuticoRESUMO
The discovery and development of new anticancer drugs is a complex and largely empirical process. New compounds can be discovered by screening, modification of existing compounds, rational drug design, and serendipitous basic research observations. Selection of compounds for clinical trials depends on assays of uncertain predictive value. In the pharmaceutical industry, priorities for development of potentially active entities are set and available resources allocated based on the availability and cost of supplies, patent status, potential spectrum of activity, ability to meet regulatory requirements, and market assessments. Competition for resources also occurs from noncancer drugs, eg, cardiovascular agents. Clinical development (testing and approval for commercial distribution) requires close attention to the requirements of national regulatory agencies such as the United States Food and Drug Administration. The arbitrary nature by which compounds with antitumor potential are chosen for development means that some that would be useful never reach clinical trial and others are never made generally available. This article reviews the decision making process in the pharmaceutical industry by which compounds are identified and selected for clinical trial, the regulations in the United States that govern such trials, and what is required to have the drug approved for commercial distribution.
Assuntos
Indústria Farmacêutica , Drogas em Investigação , Animais , Antineoplásicos , Ensaios Clínicos como Assunto , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Estados UnidosRESUMO
Daunomycin, like its anthracycline analog adriamycin, is a cardiotoxic antitumor antibiotic. Reports on 5,613 patients receiving daunomycin were reviewed for cardiotoxicity. Two distinct patterns of cardiotoxicity were defined, congestive heart failure (cardiomyopathy) and electrocardiographic changes. Dose-response curves were constructed using the percent incidence of cardiomyopathy versus the total dose of daunomycin in mg/m2. There was a dose-response relationship between the total dose of daunomycin and the development of cardiomyopathy, both in children and adults. The children seem more susceptible to the drug-induced cardiomyopathy. The electrocardiographic changes in the children and adults did not show a dose-dependent relationship, were present consistently even at the lowest dosage levels, and did not predict for subsequent development of cardiomyopathy. The dose-response curves constructed enable the clinician to judge the relative risk of developing cardiomyopathy at a given total dosage level and allows comparison of the human experience with the experimental animal model data.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Daunorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Eletrocardiografia , Humanos , Maryland , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de TempoRESUMO
The endocrine response to prolonged dexamethasone treatment was investigated in six postmenopausal women with generalized mammary carcinoma. Plasma cortisol levels decreased rapidly and became undetectable whereas significant concentrations of plasma dehydroepiandrosterone and androstenedione persisted throughout the study, even in two ovariectomized patients, indicating a certain degree of autonomy or a greater resistance of adrenal 'androgens' to the inhibition of ACTH secretion. Except in the ovariectomized patients, plasma testosterone did not fall significantly whereas the plasma oestrogens tended progressively towards undetectable concentrations. A similar response was found in six normal postmenopausal women although the disappearance of their oestrogens was relatively rapid. This indicates that much of the testosterone present after the menopause could still be produced by the ovaries whereas the ovarian production of oestrogens becomes negligible. The delayed disappearance of oestrogens in the patients with mammary carcinoma indicates that the persisting adrenal 'androgens' remained efficient precursors of oestrogen synthesis within the peripheral tissues and presumably within the mammary tumour itself. Plasma dihydrotestosterone behaved like the plasma oestrogens. Despite the fall in plasma oestrogens, plasma gonadotrophins did not increase further but plasma prolactin rose progressively. The persistance of steroid sex hormones and the rise of plasma prolactin might explain the poor response to dexamethasone treatment in mammary carcinoma.
PIP: A prolonged suppression of the adrenal cortex was produced by giving dexamethasone to 6 postmenopausal women with generalized mammary carcinoma. Plasma cortisol levels decreased rapidly while plasma dehydroepiandrosterone and androstenedione persisted. Plasma testosterone did not fall, except in ovariectomized patients. Plasma estrogens gradually decreased. This slow disappearance of estrogen indicated that persisting adrenal androgens continued to be precursors of estrogen synthesis in peripheral tissues, and possibly within the tumor tissue also. Plasma dihydrotestosterone estimations were similar to those of plasma estrogens. Plasma gonadotropins remained the same. Prolactin increased gradually. Since the growth of mammary carcinoma in postmenopausal women may be partially under endocrine control and the hormones involved are the sex hormones, and possibly prolactin, the persistence of sex hormones and rise of plasma prolactin may be why dexamethasone produces only a minimal response.
Assuntos
Androgênios/sangue , Neoplasias da Mama/sangue , Dexametasona/uso terapêutico , Estrogênios/sangue , Menopausa , Prolactina/sangue , Idoso , Androstenodiona/sangue , Neoplasias da Mama/tratamento farmacológico , Castração , Desidroepiandrosterona/sangue , Feminino , Gonadotropinas Hipofisárias/sangue , Humanos , Hidrocortisona/sangue , Pessoa de Meia-Idade , Testosterona/sangueRESUMO
A modified double-layer Hamburger and Salmon cloning assay was used to test cisplatin and its analogs (spiroplatin, carboplatin and iproplatin) on fresh tumor samples from 63 patients with a variety of non-hematological malignancies. Among them were 18 breast cancers, 17 ovarian cancers and 7 of unknown primaries. Half the patients received prior chemotherapy. Cisplatin regimens were given in 16 cases. When possible, cells were exposed for 1 h to each drug in concentrations of 0.1 microgram/ml and 1.0 microgram/ml for cisplatin and spiroplatin, 1.0 microgram/ml and 10 micrograms/ml for carboplatin and iproplatin. A greater than or equal to 50% cell kill with at least one drug was found in 20 samples including 8 ovarian cancers, 3 breast cancers and 1 unknown primary. A greater than or equal to 70% cell kill was seen in 2 samples with cisplatin, 3 with spiroplatin and carboplatin, and 6 with iproplatin. There was only partial cross-resistance between cisplatin and its analogs. Among 57 paired comparisons of cisplatin with spiroplatin, 2 showed drug sensitivity to cisplatin alone, 6 to spiroplatin alone, and 6 to both. The same sort of observation was made with carboplatin. The lack of cross-resistance between cisplatin and iproplatin was particularly striking: among 53 pairs, 6 were sensitive to cisplatin alone, 8 to iproplatin alone, and 2 to both. About 20% of the samples that were resistant to cisplatin were sensitive to iproplatin. Our data show hints of activity in breast and ovarian cancers with all analogs and suggest that they will achieve clinical antitumor activity similar to that they will achieve clinical antitumor activity similar to that of cisplatin. The in vitro evidence of incomplete cross-resistance between cisplatin and its analogs should be investigated further.
Assuntos
Cisplatino/uso terapêutico , Compostos Organoplatínicos/uso terapêutico , Carboplatina , Ensaios de Seleção de Medicamentos Antitumorais/métodos , HumanosRESUMO
BRL-4664, a THC analog, has been administered to 23 patients at a dose of 10 or 15 mg repeated twice. All patients were on cisplatin therapy, and 16 of them had experienced severe vomiting during the previous course of cisplatin. There was a statistically significant difference between the group with prior cisplatin therapy and without prior therapy in terms of number of vomiting episodes, emphasizing the role of conditioned reflexes. The dose of 15 mg administered before and twice after the infusion of cisplatin was well tolerated. Only minor side effects were observed.
Assuntos
Antieméticos/uso terapêutico , Benzopiranos/uso terapêutico , Cisplatino/efeitos adversos , Vômito/prevenção & controle , Antieméticos/efeitos adversos , Benzopiranos/efeitos adversos , Avaliação de Medicamentos , Humanos , Vômito/induzido quimicamenteRESUMO
The potency of 5 migrogram moxestrol (R 2858). 11beta-methoxy-17alpha-ethinyl-estra-1,3,5-[10]-triene-3,17-diol, administered orally, was compared to that of 25 microgram ethinyl estradiol in a double-blind crossover clinical pharmacology study of six postmenopausal women. At these doses, both compounds increased the eosinophilic index and decreased serum LH and FSH levels. A marked effect on circulating prolactin was observed only during ethinyl estradiol treatment.
Assuntos
Etinilestradiol/análogos & derivados , Etinilestradiol/farmacologia , Menopausa/efeitos dos fármacos , Idoso , Ensaios Clínicos como Assunto , Método Duplo-Cego , Eosinófilos/efeitos dos fármacos , Etinilestradiol/uso terapêutico , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Pessoa de Meia-Idade , Prolactina/sangueRESUMO
Alizapride is a methoxy-2-benzamide derivative three times more potent than its parent compound, metoclopramide, as an antagonist of apomorphine-induced emesis in dogs. The antiemetic activity of alizapride plus dexamethasone (DXM) was compared with that of placebo plus DXM in a randomized, double-blind, crossover study in cancer patients receiving cisplatin (DDP). Alizapride, given at the maximally tolerated dose of 4 mg/kg x 5, or placebo was given in a sequence determined by randomization during two successive, identical courses of antitumor chemotherapy. The antiemetic treatment was given 30 min before and 1.5, 3.5, 5.5, and 7.5 h after starting. DXM, in a dose of 12 mg, was given IV with the first administration of alizapride or placebo. A total of 39 patients completed the two courses of chemotherapy. The severity of gastrointestinal symptoms was influenced by previous treatment but not by the treatment sequence. Although our overall results suggest that alizapride does not add to the activity of DXM against DDP-induced amesis, a statistically significant difference favoring alizapride plus DXM was found among patients with the lowest gastrointestinal tolerance to DDP: women, patients under 50 years of age, and patients pretreated with chemotherapy including DDP and non-DDP agents. Side effects consisted of orthostatic hypotension, which was symptomatic in two patients, and a single occurrence of severe extrapyramidal syndrome. We conclude that alizapride is more active than placebo when combined with DXM for DDP-induced emesis in patients at high risk of severe nausea and vomiting. The severity of the side effects in this study indicates that a dose reduction of alizapride might be appropriate for further studies.
Assuntos
Antieméticos/uso terapêutico , Pirrolidinas/uso terapêutico , Adolescente , Adulto , Idoso , Ensaios Clínicos como Assunto , Dexametasona/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição AleatóriaRESUMO
The antitumor antibiotics have thus made a major impact on oncologic practice. The continued search for productive strains of these organisms should be encouraged; in addition, the activity and toxicity spectrum suggests the need for vigorous analogue development. An active anthracycline devoid of cardiotoxicity, a bleomycin with no effect on pulmonary tissue, an analogue of streptozoticin devoid of nephrotoxicity -- these would be advances of inestimable benefit to the cancer patient of the future.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Doença Aguda , Adenoma de Células das Ilhotas Pancreáticas/tratamento farmacológico , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Hipercalcemia/tratamento farmacológico , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Masculino , Osteossarcoma/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Gravidez , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Trofoblásticas/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológicoRESUMO
4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) and N-(phosphonacetyl)-L-aspartate (PALA) are two new anticancer agents that have been recently introduced into clinical investigation. This review summarizes the preclinical information that has accumulated with these compounds as well as the very preliminary data presently available from early clinical trials. This information indicates the promising potential of m-AMSA and PALA in the treatment of cancer.