A prospective randomised phase II trial of thalidomide with carboplatin compared with carboplatin alone as a first-line therapy in women with ovarian cancer, with evaluation of potential surrogate markers of angiogenesis.

OBJECTIVES: To compare the safety and efficacy of thalidomide in combination with carboplatin to carboplatin alone as a first-line therapy in women with ovarian cancer and to evaluate the anti-angiogenic effects of thalidomide by measurement of surrogate markers of angiogenesis. METHODS: Forty patients with Stage IC-IV ovarian cancer were randomly assigned to receive either carboplatin (AUC 7) intravenously every four weeks for up to six doses (n = 20) or carboplatin at the same dose and schedule, plus thalidomide 100 mg orally daily for six months (n = 20). RESULTS: After median follow-up of 1.95 years, there was no difference in the overall response rate (90% in carboplatin arm, 75% in combination arm; p = 0.41). Increased incidence of symptoms of constipation, dizziness, tiredness and peripheral neuropathy was observed in the combination arm. There was a significant fall in CA-125 and E-selectin in both arms after treatment and VCAM-1 in the carboplatin arm. No significant difference between the two arms was observed in any of the markers analysed. CONCLUSIONS: In our trial the addition of thalidomide to carboplatin was well tolerated with no increased efficacy. The fall in some of the angiogenic markers in both groups may reflect tumour response rather than any specific anti-angiogenic effect of thalidomide.

Phase I and pharmacological study of the oral matrix metalloproteinase inhibitor, MMI270 (CGS27023A), in patients with advanced solid cancer.

This Phase I study of MMI270, an p.o. administered matrix metalloproteinase inhibitor, assessed toxicity, pharmacokinetics, and tumor response data and investigated markers of biological activity to recommend a dose for Phase II studies. MMI270 was administered continuously at seven dose levels (50 mg once daily to 600 mg three times/day). Patients were evaluated for toxicity and tumor response, and blood and urine samples were taken for pharmacokinetics, bone resorption markers, direct targets of the inhibitor [matrix metalloproteinase-2 (MMP-2), MMP-8, and MMP-9], indirect targets [tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, basic fibroblast growth factor, vascular endothelial growth factor, vascular cell adhesion molecule-1, soluble urokinase plasminogen activator receptor, and cathepsins B and H] and for a tumor necrosis factor-alpha cytokine release assay. Ninety-two patients were entered. There was no myelotoxicity. Eighteen patients developed a widespread maculopapular rash, which increased in frequency and severity at doses > or = 300 mg bid. Thirty nine patients developed musculoskeletal side effects, which were related to duration of treatment, not to dose level. Pharmacokinetics were linear, and MMI270 was rapidly absorbed and eliminated with minimal accumulation on chronic dosing. Sustained plasma concentrations in excess of 4 x mean IC(50) for the target enzymes were observed at dose levels > or = 150 mg bid. There were no tumor regressions; however, 19 patients had stable disease for > or = 90 days. There was a dose-response increase of MMP-2 and TIMP-1 with MMI270. Transient effects on the bone resorption markers were detected. MMI270 was generally well tolerated, with adequate plasma levels for target enzyme inhibition. The two main toxicities were rash, resulting in a maximum tolerated dose of 300 mg bid and musculoskeletal side effects. Biological marker data indicate drug effects. The rise in TIMP-1 suggests that a reflex rise in inhibitors could modify the effects of MMI270. The recommended Phase II dose is 300 mg bid.

A phase II study of bryostatin 1 in metastatic malignant melanoma.

Bryostatin 1 is a protein kinase C partial agonist which has both antineoplastic and immune-stimulatory properties, including the induction of cytokine release and expansion of tumour-specific lymphocyte populations. In phase I studies, tumour responses have been observed in patients with malignant melanoma, lymphoma and ovarian carcinoma. The dose-limiting toxicity is myalgia. Sixteen patients (age 35-76 years, median 57 years) with malignant melanoma were treated. All had received prior chemotherapy. In each cycle of treatment, patients received bryostatin 25 degrees g m(-2) weekly for three courses followed by a rest week. The drug was given in PET diluent (10 microg bryostatin ml(-1) of 60% polyethylene glycol, 30% ethanol, 10% Tween 80) and infused in normal saline over 1 h. The principal toxicities were myalgia (grade 2, eight patients and grade 3, six patients) and grade 2 phlebitis (four patients), fatigue (three patients) and vomiting (one patient). Of 15 patients evaluable for tumour response, 14 developed progressive disease. One patient developed stable disease for 9 months after bryostatin treatment. In conclusion, single-agent bryostatin appears ineffective in the treatment of metastatic melanoma in patients previously treated with chemotherapy. It should, however, be investigated further in previously untreated patients.

Modulation of bryostatin 1 muscle toxicity by nifedipine: effects on muscle metabolism and oxygen supply.

Bryostatin 1, an anti-neoplastic agent and protein kinase C activator, has dose-limiting toxicity manifesting as myalgia. Studies in vivo have suggested that this myalgia may be caused by impairment of oxidative metabolism as mitochondrial capacity, muscle reoxygenation and proton washout from muscle are reduced by bryostatin, possibly as a result of vasoconstriction. To investigate these mechanisms further, and to enable use of bryostatin for prolonged periods, the effect of a vasodilator on the established effects of bryostatin on calf metabolism was studied using 31P magnetic resonance spectroscopy and near infrared spectroscopy. Six patients with disseminated melanoma were examined on four occasions: before and 1 week after initiation of long-term nifedipine (10 mg twice daily) treatment and then 4 and 48 h after bryostatin infusion (25 micrograms m(-2)). Nifedipine impaired muscle oxidative metabolism but had no effect on proton efflux or muscle reoxygenation rate. In the presence of nifedipine, two of the effects of bryostatin, impaired reoxygenation rate and reduced proton efflux, were abolished, but the impaired mitochondrial activity remained. These results show that nifedipine counteracted the vasoconstrictive effect of bryostatin 1. However, because nifedipine itself had an unexpected effect on mitochondrial metabolism, it was not possible to assess whether nifedipine modified bryostatin's effect on this variable. There was no additive detrimental effect of bryostatin on mitochondrial metabolism and nifedipine did not reduce the clinical toxicity of bryostatin 1, which cannot therefore be due to vasoconstriction.

Análise quantitativa da lidocaína e da bupivacaína de diversos laboratórios / Quantitative analysis of lidocaine and bupivacaine from several laboratories

Las quejas frecuentes de fallas de bloqueos anestésicos con relación a su instalación, distribuición y duración de acción, llevó a los autores a conseguir el análisis cuantitativa de la lidocaina y de la bupivacaina procedentes de varios laboratorios. Los resultados de las dosajes cuantitativas de siete muestras diferentes, provaron que todos los anestésicos examinados estaban adentro de los requisitos minimos acceptados, excluyendo la calidad del producto como causa de las fallas

Limitations of provider interventions in hypertension quality assurance.

In an institutional quality assurance program in hypertension, performance of tests, control of blood pressure, and follow-up were monitored through a computer program that was developed to audit records in an automated record system. Two types of feedback previously shown to be effective were provided quarterly for a period of one year to experimental providers. For all hypertensives considered together, there were no differences between scores of Experimental and Control providers based on percentage of patients meeting pre-set criteria in testing--87% vs 87%--, blood pressure control--58% vs 59%--, or follow-up--79% vs 77%. Only small but significant differences occurred in the subgroup of moderate to severe hypertensives. There appear to be limitations to what can be accomplished through hypertension quality assurance interventions directed at providers of care in this institutional setting. Interventions designed to deal directly with patients whose blood pressures are uncontrolled may be more effective.

Raquianestesia hiperbarica com bupivacaina a 0,55%. / Hyperbaric spinal anesthesia with bupivacaina 0,55%

Foram anestesiados 300 pacientes de ambos so sexos, previamente selecionados, de estado fisico entre I e III (ASA), para serem submetidos a procedimentos cirurgicos diversos. A tecnica anestesica constou da injecao de 2,7 ml de uma solucao composta por 15 mg de bupivacaina (2 ml de solucao de bupivacaina 0, 75%), 125 mg de glicose (0,5 ml de solucao de glicose a 25%) e 0,2 mg de adrenalina (0,2 ml de solucao de adrenalina a 10/00) ficando a bupivacaina a uma concentracao de 0,55% e a solucao con densidade de 1023 e pH 3,02 a 30 graus C. Pelo metodo de "pin-prick" avaliou-se o tempo de latencia para a instalacao do bloqueio sensitivo e o seu nivel. A intensidade do bloqueio motor foi avaliada pelo metodo proposto por Bromage.No decurso da anestesia foram registradas a incidencia e a intensidade das oscilacoes da pressao arterial e da frequencia cardiaca.Foi avaliaado tambem a incidencia pos-anestesica de cefaleia, nauseas, vomitos, parestesias e paralisias, bem como a duracao do bloqueio sensitivo

A study of lithium carbonate use in a health maintenance organization.

The Harvard Community Health Plan, a Boston-based health maintenance organization, evaluated the use of lithium carbonate in its mental health department. Criteria were developed for four categories of care: prerequisite workup, initialization of therapy, maintenance of therapy, and management of side effects. Patient records were evaluated for a retrospective control period, an experimental period in which educational interventions (education seminars and reminder notices) were provided to practitioners, and a postexperimental period in which interventions were discontinued. Practitioners' performance improved during the experimental period but declined to control-period levels during the postexperimental period.

The role of patient interventions in ambulatory quality assurance programs.

This paper highlights several studies conducted by a quality assurance research program in a health maintenance organization which provide tangible support for the need to integrate patient interventions with quality assurance activities. A model for quality assurance is described which proposes to include identification of the role of patient behavior in affecting health outcomes, and to develop intervention mechanisms directed towards patients. The experiences from this investigation suggest the need to add patient interventions to the traditional quality assurance efforts of affecting system and provider behaviors. Four of the ten projects conducted are described to illustrate these issues. Topics reviewed are maternity care, hypertension, management of breast disease, and pap smears for high-risk women. These recommendations are particularly appropriate for health maintenance organizations since both quality assurance and health education programs are mandated in the 1973 HMO Act. However, these findings are of relevance to other ambulatory care settings as well.

Anestesia venosa para mamaplastia. / Intravenous anesthesia for mammaplasty

Os autores estudaram 30 pacientes de sexo feminino que foram anestesiadas com alfatesin e fentanil para serem submetidas a mamaplastia redutora, em posicao sentada.A associacao destes agentes possibilitou uma anestesia de excelente qualidade e facil execucao, com boa cardioestabilidade, pequeno sangramento per-anestesico e despertar isento de excitacao, nauseas ou vomitos. Por estas vantagens e por ser uma tecnica venosa total, nao poluente e de baixo custo, os autores a consideram uma opcao segura para pacientes que tenham que ser operados na posicao sentada, desde que respeitadas as contra-indicacoes inerentes aos agentes utilizados

Urine culture after treatment of uncomplicated cystitis in women.

The follow-up urine culture for urinary tract infection (UTI) is widely recommended, but it is done relatively infrequently in everyday practice. We thought an investigation of its effectiveness was warranted. The study population consisted of 141 women with a culture-proven symptomatic lower UTI. Of these, 56.7% (80) had a follow-up culture and 43.3% (61) did not. The two groups were found to be comparable in important parameters of risk for urinary tract infection and its complications. The relative risk of a subsequent symptomatic UTI was 0.5 for women who did not obtain a follow-up urine culture (95% confidence interval = 0.2 to 1.5). The follow-up urine culture in asymptomatic, healthy women may be unjustified.