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1.
Cancer Res ; 43(11): 5293-7, 1983 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-6225515

RESUMO

Adriamycin and menogarol are anthracyclines which cause more than 100% increase in life span of mice bearing P388 leukemia and B16 melanoma. Unlike Adriamycin, menogarol does not bind strongly to DNA, and it minimally inhibits DNA and RNA synthesis at lethal doses. Adriamycin is a clinically active drug, and menogarol is undergoing preclinical toxicology at National Cancer Institute. In view of the reported mutagenicity of Adriamycin, we have compared the genotoxicity of the two drugs. Our results show that, although Adriamycin and menogarol differ significantly in their bacterial mutagenicity (Ames assay), they have similar genotoxic activity in several mammalian systems. Adriamycin is strongly mutagenic in the Ames assay with TA98 and TA100. Menogarol is nonmutagenic to TA98 and TA100. For the mammalian cell culture systems, V79 (Chinese hamster) cells are exposed for 2 hr to drug, following which cell survival, induction of sister chromatid exchanges, chromosome damage, and production of mutants resistant to 6-thioguanine are measured. The percentage of survival obtained with the two drugs ranges between 25 and 50% at 0.15 microgram/ml and 5 to 15% at 0.3 microgram/ml. At 0.15 microgram/ml, Adriamycin and menogarol increase the percentage of cells with chromosome damage from a background level of 8.8 to 30 and 22.5%, respectively. The same drug concentration causes a small but significant increase in sister chromatid exchange rate. Both drugs are equally active (increase mutation frequency about 3- to 6-fold above background) in producing 6-thioguanine-resistant mutants. The induction of micronuclei in polychromatic erythrocytes of rats is the most sensitive assay system. Both drugs cause 10- to 15-fold increase in micronuclei at nontoxic doses.


Assuntos
Antineoplásicos/toxicidade , Daunorrubicina/análogos & derivados , Doxorrubicina/toxicidade , Mutagênicos , Mutação , Nogalamicina/toxicidade , Animais , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Cricetinae , Pulmão , Menogaril , Mesocricetus , Microssomos Hepáticos/metabolismo , Testes de Mutagenicidade , Nogalamicina/análogos & derivados , Salmonella typhimurium/efeitos dos fármacos , Relação Estrutura-Atividade
2.
Hypertension ; 9(2 Pt 2): II90-6, 1987 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-3542820

RESUMO

Abnormalities in left ventricular (LV) wall thickness and mass have been demonstrated in patients with mild hypertension utilizing M-mode echocardiography. In addition, studies using radionuclide angiography have demonstrated abnormalities in early diastolic LV filling in asymptomatic hypertensive patients with normal ejection fraction and cardiac output. Recently, Doppler recordings of flow velocity in the ascending aorta and through the mitral valve have been shown to provide useful information about LV function. To determine whether flow abnormalities could be detected in patients with mild hypertension, we recorded Doppler aortic and mitral valve flow velocities in 21 men with mild hypertension. Casual systolic blood pressure was 147 +/- 18 mm Hg (mean +/- SD) and diastolic blood pressure was 96 +/- 9 mm Hg. LV mass (310 +/- 75 g) was elevated (i.e., above the 95% normal prediction interval) in 8 of 19 patients who underwent M-mode echocardiography; LV ejection fraction was normal in all patients (mean, 80%). As in previous studies in normal subjects, we found in these hypertensive patients an inverse correlation between age and both aortic peak flow velocity (r = -0.51, p less than 0.05) and transmitral early diastolic peak flow velocity (r = -0.44, p less than 0.05) and a positive relationship between age and mitral valve late diastolic peak flow velocity (r = 0.73, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Ecocardiografia/métodos , Hipertensão/diagnóstico , Adulto , Idoso , Diástole , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia
3.
Arch Neurol ; 55(1): 56-62, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9443711

RESUMO

OBJECTIVE: To determine the efficacy and tolerability of tiagabine, a new antiepileptic drug (AED) that inhibits gamma-aminobutyric acid (GABA) uptake, at 3 dose levels vs placebo as adjunctive therapy in patients with intractable complex partial seizures (CPS). DESIGN: Randomized, double-blind, placebo-controlled study with a parallel-group, add-on design, starting with a 12-week unblinded baseline phase followed by a 20-week double-blind treatment phase. SETTING: Twenty-one US medical centers. PATIENTS: Patients (N = 297) aged 12 to 77 years, previously diagnosed as having CPS and receiving stable regimens of 1 to 3 hepatic enzyme-inducing AEDs; divalproex sodium or valproic acid was allowed in combination with any of these drugs. INTERVENTIONS: Placebo or tiagabine 4 times a day at 16, 32, or 56 mg daily. MAIN OUTCOME MEASURES: Median change in 4-week CPS frequency and adverse events. RESULTS: Median decreases in 4-week CPS frequency for the 32-mg (-2.2) and 56-mg (-2.8) tiagabine groups were significantly greater than for the placebo (-0.7) group (P = .03 and P < .03, respectively); 20% and 29% of patients in the 32- and 56-mg groups had a 50% or greater reduction in the frequency of CPS vs 4% in the placebo group (P = .002 and P < .001, respectively). Adverse effects were similar for placebo and tiagabine except for a significantly greater incidence of dizziness in the 32-mg tiagabine group, tremor in the 32- and 56-mg groups, abnormal thinking (usually mental lethargy or difficulty concentrating) in the 56-mg group, and depressed mood in the 16- and 56-mg groups. CONCLUSIONS: Tiagabine is efficacious and well tolerated as adjunctive therapy for CPS; there is a clear dose-response relationship.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsias Parciais/tratamento farmacológico , Ácidos Nipecóticos/administração & dosagem , Adolescente , Adulto , Idoso , Anticonvulsivantes/farmacologia , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Nipecóticos/farmacologia , Tiagabina , Resultado do Tratamento
4.
Arch Neurol ; 54(5): 595-601, 1997 May.
Artigo em Inglês | MEDLINE | ID: mdl-9152116

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of 2 regimens of tiagabine as add-on therapy for patients with complex partial seizures (CPSs) that are refractory to other treatment. DESIGN: Randomized, double-blind, placebo-controlled, add-on, parallel-group trial with an 8-week baseline period, 12-week experimental period (4 weeks of dose titration and 8 weeks of fixed-dose therapy), and 4-week termination period. SETTING: Twenty-six centers throughout the United States. PATIENTS: Three hundred fifty-one patients were enrolled, 318 were entered in the double-blind period, and 271 completed the study. INTERVENTIONS: Tiagabine, 16 mg 2 times per day (106 patients); tiagabine, 8 mg 4 times daily (105 patients); and placebo (107 patients). The doses of tiagabine were titrated in 3 steps to the fixed dose. MAIN OUTCOME MEASURE: The median change in the 4-week rate of CPSs from baseline to experimental period. RESULTS: The median change from baseline was -1.6 CPSs per 4 weeks in the group of patients who were given tiagabine 2 times per day, and it was -1.2 CPSs in the group of patients who were given tiagabine 4 time per day (P = .06 and P = .02, respectively, compared with placebo). The 4-week seizure frequency was reduced by 50% or more in 31% of the patients who were given tiagabine 2 times per day and in 27% of the patients who were given tiagabine 4 times per day vs 10% of the placebo-treated patients (P < or = .001 for each tiagabine-treated group compared with the placebo group). The most frequent adverse events involved the central nervous system and occurred in comparable proportions in the 3 treatment groups. Similar proportions of patients discontinued the study prematurely for adverse events. CONCLUSIONS: Tiagabine administered 2 and 4 times daily as add-on pharmacotherapy was effective in reducing CPSs in patients with epilepsy whose conditions were refractory to treatment with other antiepileptic agents, and it was well tolerated.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Parcial Complexa/tratamento farmacológico , Ácidos Nipecóticos/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Nipecóticos/administração & dosagem , Ácidos Nipecóticos/efeitos adversos , Retratamento , Tiagabina , Resultado do Tratamento
5.
Neurology ; 48(1): 182-8, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9008516

RESUMO

This is the first randomized, double-blind, parallel-group, multicenter trial that evaluated the efficacy of divalproex sodium monotherapy by comparing seizure frequency in 143 patients with poorly controlled partial epilepsy randomly assigned to high (80 to 150 micrograms/mL; 555 to 1,040 mumol/L) or low (25 to 50 micrograms/mL; 175 to 345 mumol/L) plasma valproate groups. There was a statistically significant reduction from baseline in the 8-week frequency of complex partial (p = 0.001) and secondarily generalized tonic-clonic seizures (p = 0.018) for patients in the high, compared with the low, plasma valproate group. Compared with baseline, there was a 30% median reduction in complex partial seizures for patients in the high group and a 19% increase for those in the low group. The median reduction for secondarily generalized tonic-clonic seizures was 70% for patients in the high group compared with a 22% increase in the low group. Adverse events that occurred significantly more frequently in the high group included tremors, thrombocytopenia, alopecia, asthenia, diarrhea, vomiting, and anorexia. This study demonstrates the efficacy of divalproex sodium as monotherapy for the treatment of partial-onset seizures and supports its role as one of the first-line antiepileptic drug treatments for patients with partial epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Ácido Valproico/uso terapêutico , Adolescente , Adulto , Idoso , Anticonvulsivantes/efeitos adversos , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Epilepsias Parciais/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Resultado do Tratamento , Ácido Valproico/efeitos adversos , Ácido Valproico/sangue
6.
Neurology ; 46(1): 49-53, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8559420

RESUMO

We studied the efficacy of divalproex sodium in patients with complex partial seizures taking concomitant carbamazepine or phenytoin as monotherapy. Patients were selected because of inadequate seizure control by current therapy. The primary efficacy measure was median reduction of seizure frequency during add-on treatment compared with baseline. A secondary measure was the percentage of patients achieving > or = 50% reduction in seizure frequency. In the intent-to-treat analysis (137 patients), divalproex-treated patients experienced a median reduction of 7.9 complex partial seizures per 8 weeks compared with 2.5 in the placebo group (p = 0.001). Also, 38% of divalproex-treated patients completed the study with a seizure reduction of > or = 50% compared with 19% receiving placebo (p = 0.011). Six divalproex- and one placebo-treated patient became free of complex partial seizures. We conclude that divalproex sodium is an effective drug for treating patients with complex partial seizures.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Parcial Complexa/tratamento farmacológico , Ácido Valproico/uso terapêutico , Método Duplo-Cego , Eletroencefalografia , Epilepsia Parcial Complexa/fisiopatologia , Humanos , Estudos Multicêntricos como Assunto , Ácido Valproico/efeitos adversos
7.
Neurology ; 48(4): 1025-31, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9109894

RESUMO

Tiagabine blocks the uptake by neurons or glia of synaptically released GABA resulting in prolonged GABAergic activity and decreased likelihood of epileptic seizures. We evaluated the cognitive and quality of life effects of tiagabine in a double-blind, add-on, placebo-controlled, parallel, multicenter, dose-response efficacy study in patients with focal epilepsy whose complex partial seizures were difficult to control. One hundred sixty-two patients provided cognitive and quality of life data for the analyses and received the following treatments: placebo (n = 57), 16 mg/d tiagabine (n = 34), 32 mg/d tiagabine (n = 45), or 56 mg/d tiagabine (n = 26) at a fixed-dose for 12 weeks after a 4-week dose titration period. Eight cognitive tests and three measures of mood and adjustment were administered during the baseline period and again during the double-blind period near the end of treatment (or at the time of dropout). The patient groups were similar at entry into the study. Results showed no clinically important changes with the addition of tiagabine on the test battery. Although this is an encouraging finding, it remains for future investigations to determine the cognitive and behavioral effects of tiagabine either as monotherapy or in relation to other antiepileptic drugs.


Assuntos
Anticonvulsivantes/administração & dosagem , Cognição , Epilepsia Parcial Complexa/tratamento farmacológico , Epilepsia Parcial Complexa/psicologia , Ácidos Nipecóticos/administração & dosagem , Qualidade de Vida , Adolescente , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Epilepsia Parcial Complexa/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Nipecóticos/uso terapêutico , Tiagabina , Resultado do Tratamento
8.
Am J Med ; 88(3A): 6S-11S, 1990 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-1968721

RESUMO

The hypnotic efficacy of estazolam, a triazolobenzodiazepine, has been established in well-controlled sleep laboratory and outpatient clinical trials. Estazolam 1.0 mg and 2.0 mg significantly improves sleep latency, total sleep time, number of nocturnal awakenings, depth of sleep, and sleep quality in adults with chronic insomnia. Long-term studies indicate that estazolam 2.0 mg remains an effective hypnotic for at least six weeks of continuous nightly administration with no evidence of clinically significant tolerance. Estazolam is an effective treatment for situational insomnia and significantly improves sleep in patients with insomnia associated with moderately severe anxiety or depression.


Assuntos
Ansiolíticos/uso terapêutico , Estazolam/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos de Ansiedade/tratamento farmacológico , Doença Crônica , Ensaios Clínicos como Assunto , Transtorno Depressivo/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Estazolam/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Placebos , Sono/efeitos dos fármacos , Fatores de Tempo , Estados Unidos
9.
Am J Med ; 88(3A): 12S-17S, 1990 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-1968713

RESUMO

The safety profile of estazolam, a new triazolobenzodiazepine hypnotic medication, has been developed in 1,320 normal volunteers and patients with insomnia. No clinically significant effects of estazolam on vital signs or laboratory values were detected. Drug-specific adverse effects such as somnolence, dizziness, hypokinesia, and abnormal coordination occurred, but these are expected extensions of benzodiazepine pharmacologic activity. No consistent effects on psychomotor performance, including memory, were seen at the recommended hypnotic doses in insomniac subjects. These data, combined with the evidence for hypnotic activity, indicate that estazolam is a safe and effective treatment for insomnia.


Assuntos
Ansiolíticos/uso terapêutico , Estazolam/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Método Duplo-Cego , Estazolam/administração & dosagem , Estazolam/efeitos adversos , Feminino , Coração/efeitos dos fármacos , Humanos , Masculino , Memória/efeitos dos fármacos , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Placebos , Distribuição Aleatória , Respiração/efeitos dos fármacos , Segurança , Sono/efeitos dos fármacos , Síndrome de Abstinência a Substâncias , Estados Unidos
10.
J Med Chem ; 25(12): 1482-8, 1982 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-6218302

RESUMO

A series of novel hexahydrothiopyrano[4,3-c]pyrazoles and related analogues were prepared and tested for antiinflammatory activity by using the mouse active Arthus reaction and the delayed hypersensitivity skin reaction in guinea pigs as primary screens. The compounds of most interest, 18 and 28, were further tested in a model of adjuvant-induced arthritis; in this system, both compounds were active when dosed intraperitoneally but failed to produce significant activity when dosed orally at subtoxic doses.


Assuntos
Anti-Inflamatórios/síntese química , Pirazóis/síntese química , Animais , Anti-Inflamatórios/toxicidade , Artrite Experimental/tratamento farmacológico , Reação de Arthus/tratamento farmacológico , Fenômenos Químicos , Química , Edema/tratamento farmacológico , Cobaias , Hipersensibilidade Tardia/tratamento farmacológico , Masculino , Camundongos , Pirazóis/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos
11.
Chest ; 94(5): 994-7, 1988 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-3053063

RESUMO

Doppler measurements of pulmonary artery (PA) acceleration time (AT) have been used clinically to estimate PA pressure. However, these studies have been performed primarily in patients without tachycardia. To determine the effect of acute changes in heart rate on PA AT, atrial pacing studies were performed in seven closed-chest pigs. Pulsed Doppler PA flow velocity recordings were obtained from a parasternal position at pacing rates from 100 to 140 beats/min. PA pressure remained constant (mean +/- SD = 14 +/- 5 mm Hg) over the entire range of paced rates. When PA Doppler measurements were compared at heart rates of 100 and 140 beats/min, there were decreases at the higher heart rate in both acceleration time (110 +/- 12 vs 83 +/- 11 ms, p less than 0.01) and ejection time (ET) (315 +/- 23 vs 237 +/- 21 ms, p less than 0.01). In contrast, there was no change in either PA peak flow velocity (69 +/- 15 vs 62 +/- 18 cm/s) or the ratio of AT/ET (0.35 +/- .02 vs. .36 +/- .03). Consequently, when estimating PA pressure in states of tachycardia, the PA AT/ET ratio may be a more useful measurement than PA acceleration time.


Assuntos
Frequência Cardíaca , Artéria Pulmonar/fisiologia , Suínos/fisiologia , Animais , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Estimulação Cardíaca Artificial , Taquicardia/fisiopatologia , Ultrassonografia
12.
Artigo em Inglês | MEDLINE | ID: mdl-6131489

RESUMO

1. Evaluation of the side effects of psychoactive drugs presents a special statistical situation because many of the symptoms of psychiatric disorders are also potential side effects. 2. Reported incidences of adverse events can be viewed as being a combination of psychoactive drug effects, disease state effects and other concomitant effects. 3. An intriguing statistical problem is to develop methodology to separate these effects. 4. This paper discussed four methodologies for estimating incidence of side effects assessed with a symptom and side effect check list.


Assuntos
Psicotrópicos/efeitos adversos , Alprazolam , Ansiolíticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Ensaios Clínicos como Assunto , Diazepam/efeitos adversos , Método Duplo-Cego , Humanos , Imipramina/efeitos adversos , Estatística como Assunto
13.
Epilepsy Res ; 21(1): 37-42, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-7641674

RESUMO

Tiagabine is a new antiepileptic drug which acts by a novel mechanism, inhibiting the reuptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into neurons and glia. A double-blind, placebo-controlled, crossover trial was undertaken, based upon a response-dependent design. Ninety-four patients with complex partial seizures with or without secondary generalised tonic-clonic seizures were recruited into an open screening phase and tiagabine was added to their existing drug therapy in doses titrated to reduce seizure frequency by > or = 25% or to the limit of tolerance. Forty-six responders were subsequently randomised to a double-blind crossover trial in which tiagabine was compared with placebo. Forty-two patients completed the trial. A significant reduction in the frequency of complex partial and secondary generalised tonic clonic seizures was seen. Twenty-six percent had a reduction of > or = 50% in the frequency of their complex partial seizures, and of the 27 patients who also had secondary generalised tonic clonic seizures, 63% experienced a reduction of > or = 50%. No interactions with baseline antiepileptic drugs were detected and no serious adverse reactions occurred. The commonest adverse events were tiredness, dizziness and headache. We conclude that tiagabine has promising antiepileptic effects. Further trials are underway.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Ácidos Nipecóticos/uso terapêutico , Adolescente , Adulto , Idoso , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Placebos , Tiagabina , Resultado do Tratamento
14.
Antimicrob Agents Chemother ; 30(5): 689-93, 1986 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-3800345

RESUMO

By using high-performance liquid chromatography, the metabolism and pharmacokinetics of difloxacin were characterized in humans after single oral doses of 200, 400, and 600 mg. Group mean peak levels in plasma were obtained 4 h after administration. The means of the individual peak levels for the 200-, 400-, and 600-mg groups were 2.17, 4.09, and 6.12 micrograms/ml, respectively. The mean respective terminal-phase half-lives were 20.6, 27.1, and 28.8 h; the mean half-life for all subjects was 25.7 h. Within the dose range studied, the behavior of difloxacin could be well described by a set of linear pharmacokinetic parameters with a one-compartment open model. Levels of unconjugated metabolites in plasma were negligible. The major urinary components were difloxacin and its glucuronide, each accounting for roughly 10% of the dose. Also present were the N-desmethyl and N-oxide metabolites, accounting for 2 to 4%. Trace levels of other metabolites were observed. Group mean renal clearances ranged from 4.1 to 5.6 ml/min, indicating extensive reabsorption from the glomerular filtrate. As a result, the terminal phase half-life and the dose-normalized area under the curve were substantially greater than those of other members of the class.


Assuntos
Anti-Infecciosos/metabolismo , Ciprofloxacina/análogos & derivados , Fluoroquinolonas , Administração Oral , Ciprofloxacina/metabolismo , Meia-Vida , Humanos , Rim/metabolismo , Cinética , Taxa de Depuração Metabólica
15.
Am Heart J ; 120(1): 87-95, 1990 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-1972862

RESUMO

Intravenous medroxalol, an alpha- and beta-adrenergic blocking agent, causes an immediate hypotensive effect. In 14 subjects with mild-to-moderate hypertension, cardiac output (CO) and cardiac index (CI) were significantly decreased without significant changes in stroke volume, reflecting the fact that a reduced CO and CI were related to decreases in heart rate. The vasodilator effect of intravenous medroxalol was not apparent with the dosages used in this study. Transient changes noted in two Doppler diastolic velocity indexes--mitral early diastolic peak flow velocity (PFVE) and the ratio of mitral late-to-early diastolic peak flow velocity (PFVA/E)--are suggestive of an improvement in left ventricular (LV) diastolic filling during medroxalol infusion, possibly related to changes in loading conditions. Systolic and diastolic blood pressure did not correlate with any of the Doppler diastolic and systolic indexes in our patient population. Reduced aortic peak flow velocity, rate of aortic flow acceleration, and the rate of mitral early diastolic deceleration were noted with increasing LV mass index, independent of age or blood pressure. Doppler echocardiography may be a useful tool in the assessment and follow-up of LV systolic and diastolic function in patients undergoing pharmacologic interventions.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Etanolaminas/farmacologia , Coração/efeitos dos fármacos , Hipertensão/fisiopatologia , Antagonistas Adrenérgicos alfa/administração & dosagem , Antagonistas Adrenérgicos alfa/uso terapêutico , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Ecocardiografia Doppler , Etanolaminas/administração & dosagem , Etanolaminas/uso terapêutico , Coração/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade
16.
Epilepsia ; 39(1): 33-42, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9578010

RESUMO

PURPOSE: We evaluated the dose-related impacts of tiagabine (TGB) on cognition and mood in a monotherapy study. METHODS: Patients were 123 adults with uncontrolled partial seizures, each treated with a single currently available antiepileptic drug (AED) for management of clinical epilepsy. They completed a battery of neuropsychological tests during an 8-week prospective baseline period and once again at the end of the 12-week fixed-dose period (or earlier if they dropped out of the study). Sixty-six patients were randomized to 6 mg/day TGB and 57 were randomized to 36 mg/day TGB. RESULTS: Few changes in either abilities or adjustment and mood were noted when all patients were considered as a single group. However, analysis of both dose and attainment of TGB monotherapy showed that patients receiving TGB monotherapy did best, improving particularly in the areas of adjustment and mood with low-dose TGB and in the area of abilities with high-dose TGB. Patients who did not attain monotherapy showed no change except that the high-dose group did not perform as well on measures of mood and adjustment. Baseline AED and changes in seizure control did not affect the results. CONCLUSIONS: Patients' attainment of TGB monotherapy was associated with their achievement of positive changes of varying degree on psychological tests. Failure to attain TGB monotherapy was associated with no changes on the tests except in patients receiving high-dose TGB where it appeared that some alterations in mood might have been avoided if a slower titration schedule had been used.


Assuntos
Afeto/efeitos dos fármacos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Cognição/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Ácidos Nipecóticos/farmacologia , Ácidos Nipecóticos/uso terapêutico , Adolescente , Adulto , Anticonvulsivantes/administração & dosagem , Escalas de Graduação Psiquiátrica Breve , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Ácidos Nipecóticos/administração & dosagem , Inventário de Personalidade , Desempenho Psicomotor/efeitos dos fármacos , Qualidade de Vida , Ajustamento Social , Tiagabina , Resultado do Tratamento
17.
J Clin Psychopharmacol ; 11(4): 249-53, 1991 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1918423

RESUMO

Estazolam, a triazolobenzodiazepine with an intermediate elimination half-life, has been shown previously to be an effective and safe hypnotic in insomniacs without concomitant psychiatric illness. Our study of the efficacy of estazolam in patients with insomnia associated with generalized anxiety disorder began when 108 patients meeting criteria for generalized anxiety disorder (mean total score of Hamilton Rating Scale for Anxiety [HAM-A] = 22.0 +/- 3.1 [SD]) and insomnia were given single-blind placebo for 7 nights. Nine patients whose anxiety and/or insomnia improved were dropped as placebo responders. The remaining 99 patients were randomly allocated (1:1) to double-blind treatment with either estazolam 2.0 mg or matching placebo for 7 nights. Hypnotic efficacy, as determined by patient-completed sleep questionnaires, was statistically significant for estazolam 2.0 mg versus placebo for all sleep indices (p less than 0.01). Patients treated with estazolam 2.0 mg showed significantly greater improvement in anxiety than those receiving placebo on the mean total score of HAM-A ([placebo, -3.4; estazolam, -7.1; p less than 0.001] and without the insomnia item [placebo, -2.7; estazolam, -5.5; p less than 0.001]). Anxiety scores on the State-Trait Anxiety Inventory showed greater improvement in the estazolam group, but without statistical significance (p = 0.237). Estazolam 2.0 mg is an effective hypnotic in patients with generalized anxiety disorder and appears to have a favorable anxiolytic action.


Assuntos
Transtornos de Ansiedade/complicações , Estazolam/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adulto , Idoso , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/psicologia , Análise por Conglomerados , Método Duplo-Cego , Estazolam/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Distúrbios do Início e da Manutenção do Sono/etiologia
18.
Crit Care Med ; 29(11): 2081-9, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11700399

RESUMO

OBJECTIVE: To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis. DESIGN: Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial. SETTING: Thirty-eight intensive care units in the United States and Europe. PATIENTS: Two hundred and ten subjects with severe sepsis who received standard supportive care and antimicrobial therapy. INTERVENTIONS: Subjects received a continuous intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs). MEASUREMENTS AND MAIN RESULTS: There were no significant imbalances in demographics, severity of illness, or source of infection in patients randomized to placebo or either dose of rTFPI. A 20% relative reduction in 28-day all-cause mortality was observed when all rTFPI-treated patients were compared with all placebo patients. An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the rTFPI-treated patients. Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p =.037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log10 interleukin 6 were adjusted for (p =.026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial rTFPI effect. There was no increase in mortality in subjects treated with either dose of rTFPI compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all rTFPI-treated patients compared with those receiving placebo. There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and severe adverse events (SAEs) was similar among the treatment groups, with a slight increase in SAEs and SAEs involving bleeding in the 0.05 mg/kg/hr rTFPI group. The overall incidence of AEs involving bleeding was 28% of patients in the all placebo group and 23% of patients in the all rTFPI-treated group; a slight but statistically insignificant increase in incidence of SAEs involving bleeding was observed in the all rTFPI group (9%) as compared with the all placebo group (6%; p =.39). CONCLUSIONS: Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.


Assuntos
Lipoproteínas/uso terapêutico , Sepse/tratamento farmacológico , APACHE , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Unidades de Terapia Intensiva , Coeficiente Internacional Normatizado , Lipoproteínas/administração & dosagem , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Sepse/classificação , Sepse/mortalidade , Taxa de Sobrevida
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