Phase II study of a fixed dose-rate infusion of gemcitabine associated with docetaxel in advanced non-small-cell lung carcinoma.

PURPOSE: To evaluate the efficacy and toxicity profile of the combination of docetaxel and prolonged gemcitabine infusion in front-line chemonaive patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 50 chemonaive patients diagnosed with advanced NSCLC according to the AJCC/TNM classification system were included in the present study. Treatment consisted of 1000 mg/m(2) gemcitabine given as a 100-min continuous infusion (10 mg/m(2) per min) on days 1 and 8 of each course and 75 mg/m(2) docetaxel as a 60-min infusion on day 8, repeating each course every 21 days. RESULTS: The ECOG performance status of the patients were as follows: 0 (10%), 1 (60%), and 2 (30%). All patients had two-dimensionally measurable disease. Their median age was 63 years (range 41-75 years). Of the 50 patients, 28 (56%) had squamous cell carcinoma, 14 adenocarcinoma (28%), and 8 (16%) large-cell carcinoma, and 40% and 60% of patients presented with stage IIIB and IV disease, respectively. Of those with stage IV disease, 33% had more than one metastatic site. A total of 220 courses were administered with a median of five courses per patient. Of 46 patients assessed for response, 12 (26%) had a partial remission (95% CI 13-39%). In 19 patients (41%) the disease remained stable, while disease progression was observed in 15 (33%). The median time to disease progression was 4 months, and median survival time was 7 months. At 1 year, 25% of patients remained alive, and the main grade 3/4 toxicity (according to the WHO scale) consisted of neutropenia ( n=6, 12%), asthenia ( n=4, 8%), peripheral edema ( n=3, 6%), dyspnea ( n=3, 6%), and diarrhea ( n=2, 4%). CONCLUSIONS: Prolonged gemcitabine infusion combined with docetaxel is well tolerated and its efficacy is similar to that of other chemotherapeutic schemes used for NSCLC treatment. However, the prolonged infusion of gemcitabine did not appear to result in any improvement in outcome or toxicity versus the standard dose rate.

Comparative effects of quinine and cinchonine in reversing multidrug resistance on human leukemic cell line K562/ADM.

We have previously suggested that quinine and cinchonine could be good candidates for clinical circumvention of multidrug resistance (MDR) in hematological malignancies because of their tolerance and their retained efficacy in serum. In the present study, we have used the well-characterized multidrug resistant human leukemic cell line K562/ADM to compare the effect in vitro of quinine and cinchonine on doxorubicin, mitoxantrone, and vincristine uptake and cytotoxicity. In serum-free medium, quinine induced a dose-dependent increase of doxorubicin uptake reaching about 200% at 40 microM, while it had a slight and no effect on mitoxantrone and vincristine uptake respectively. In the same conditions, cinchonine induced a rapid and significant increase in the accumulation of the three drugs, reaching a plateau phase between 5 and 10 microM. Quinine and cinchonine induced both potentiation of doxorubicin, vincristine and mitoxantrone cytotoxicity in K562/ADM cells. However, quinine reached a plateau phase at 10 microM, while cinchonine had a maximal effect at 5 microM and was significantly more potent at low concentrations. When diluted in plasma, cinchonine was less bound to proteins than quinine. The free fraction of alkaloids was 37-55% for cinchonine and 20-30% for quinine. Cinchonine-induced enhancement of vincristine cellular accumulation was little modified by plasma proteins. When incubated in whole blood, the fraction of cinchonine trapped in red blood cells was rapidly and completely exchangeable with plasma. We conclude that cinchonine is a stronger inhibitor of MDR than quinine.

Helpless behavior (escape deficits) in streptozotocin-diabetic rats: resistance to antidepressant drugs.

Using the learned helplessness model of depression in rats, the present study undertook to investigate the possibility of an impaired response to antidepressant drugs in diabetic animals. Experimental diabetes was induced by three intraperitoneal (IP) injections of streptozotocin (37.5, 37.5, 50 mg/kg, three days apart), four weeks before behavioral testing. Diabetic and non-diabetic rats were first exposed to 60 inescapable shocks. Forty-eight hours later and over three consecutive days, they were subjected to daily shuttle-box sessions for assessment of escape failures (helpless behavior). Twice daily (IP) injection of clomipramine (24 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg) or clenbuterol (0.75 mg/kg) prevented escape deficits in the non-diabetic but not in the diabetic rats. However, this prevention was made possible in the diabetic rats by increasing the duration of the antidepressant treatment. Moreover, one week of insulin therapy restored operant escape responding to both the tricyclics and a beta-agonist. The inefficacy of clenbuterol (a central beta-agonist) in reversing helpless behavior in diabetic rats, along with the observation that triiodothyronine (T3) supplementation also restored the response to imipramine in the diabetic rats, suggests that thyroid-mediated alterations of central noradrenergic function might be a critical factor in the resistance or delayed response to antidepressants in experimental diabetes. These animal findings raise the possibility of a similar resistance to conventional antidepressants in depressed diabetic patients.

Docetaxel and high-dose epirubicin as neoadjuvant chemotherapy in locally advanced breast cancer.

PURPOSE: Epirubicin and docetaxel are two of the most active drugs against breast carcinoma. As the achievement of a pathological complete response (pCR) is important for survival of patients with locally advanced disease, we used both drugs as neoadjuvant chemotherapy. PATIENTS AND METHODS: Women with locally advanced or inflammatory breast cancer received epirubicin 120 mg/m2 followed by docetaxel 75 mg/m2, both on day 1, every 21 days for four cycles. Lenograstim was administered for 10 days in all cycles. RESULTS: Of 51 patients included, 50 received a total of 188 cycles, with a median of 4 per patient. The median age was 47 years, tumour stage was IIIA in 14 patients and IIIB in 36. Oestrogen receptors were positive in 65% of tumours. There were 10 clinical complete responses (20%) and 29 partial responses (58%). Surgery consisted of mastectomy in 40 patients and tumorectomy in 6. After surgery, 9 pCR were recorded (18%). One patient progressed and died soon after the end of chemotherapy. After a median follow-up of 22 months, the median disease-free survival was 33.7 months. Grade 3/4 neutropenia was observed in 32% of patients, anaemia in 6%, and thrombocytopenia in 4%. Five patients had febrile neutropenia. There were no toxic deaths or grade 4 nonhaematological toxicities. CONCLUSIONS: Docetaxel plus high-dose epirubicin showed promising activity in patients with locally advanced and inflammatory breast cancer, at the cost of moderate toxicity.

Are antidepressant-like effects of triiodothyronine (T3) in rodents related to an hyperthyroid state?

1. The physiological and behavioral effects of T3 and corresponding plasma T3 levels were studied in mice. 2. On the tests performed (antagonism of apomorphine- and oxotremorine-induced hypothermia, potentiation of yohimbine toxicity, L-5-HTP-induced head twitches and the learned-helplessness paradigm), T3 was active after subchronic treatment (1 injection per day for 3 days, ending 24 hours before testing). 3. In these tests T3 exhibited the same profile as antidepressant drugs in rodents. 4. The similar activity of beta-agonists in these tests and the ability of T3 to potentiate the effect of clenbuterol agree with the hypothesis that T3 can induce beta-adrenergic hypersensitivity. 5. Under the present experimental conditions these effects were obtained with doses of T3 which did not induce hyper-triiodothyroninemia. Thus, the lowest doses significantly affecting apomorphine- and oxotremorine-induced hypothermia were respectively .008 and .032 mg/kg/day. 6. Doses as low as .032 mg/kg/day were active in the yohimbine test. 7. L-5-HTP-induced head twitches were potentiated by a dose of .25 mg/kg/day and in the learned-helpless paradigm, the lowest effective dose was .06 mg/kg/day. 8. Plasma T3 values obtained in the same conditions were not significantly different from control at doses less than .5 mg/kg/day, and increased dramatically with higher doses, suggesting an accumulation of the hormone in plasma. 9. The doses inducing an hyper-triiodothyroninemia coincided with physiological signs of hyperthyroidism in the animals (i.e. loss of weight and slight hyperthermia). Thus, the active dose range of T3 was below the lowest dose required to produce a significant hyperthyroid state. 10. This results suggest that a clinical benefit could be obtained with low doses of T3 that do not significantly induce an hyperthyroidism.

The UFT/leucovorin/etoposide regimen for the treatment of advanced gastric cancer. Oncopaz Cooperative Group.

Gastric cancer is the most chemosensitive adenocarcinoma among digestive neoplasms. A few years ago, we performed a phase II trial with the FLEP regimen, in which fluorouracil (5-FU) and leucovorin are combined with etoposide and cisplatin (Platinol). This regimen resulted in a 39% response rate and high toxicity. Then we used the combination UFT (tegafur and uracil)/leucovorin/etoposide: UFT 390 mg/m2/day orally on days 1 to 14; leucovorin 500 mg/m2 i.v. day 1, and 15 mg/12 h orally on days 2 to 14; and etoposide 100 mg/m2 i.v. on day 1 and then 200 mg/m2/day orally on days 2 and 3. Forty-six patients received a median of five courses. Five patients (11%) achieved a complete response and 12 (26%) a partial response, for an overall response rate of 37%. The response rate was 50% in patients with an Eastern Cooperative Oncology Group performance status of 0 to 1. Grades 3 to 4 toxicities appeared as follow: 17% of patients had diarrhea, 11% had nausea/vomiting, and 13% of patients had anemia. One patient died of neutropenia and sepsis. The median survival time was 9 months. In summary, UFT/leucovorin/etoposide is effective and moderately toxic in patients with advanced gastric cancer. A new trial with UFT/leucovorin/epirubicin is ongoing.

A prospective randomized trial of continuous infusion 5-fluorouracil (5-FU) versus 5-FU plus cisplatin in patients with advanced colorectal cancer. A trial of the Spanish Cooperative Group for Digestive Tract Tumor Therapy (T.T.D.).

One hundred sixty consecutive patients with histologically confirmed colorectal cancer (advanced disease) without prior chemotherapy were entered in a randomized trial comparing 5-fluorouracil (5-FU) 1,000 mg/m2 intravenously per day for 5 consecutive days in continuous infusion versus cisplatin (CP) 100 mg/m2 on day 1 plus 5-FU as described on days 2 to 6. In both arms, treatment was recycled every 4 weeks. Both groups were well balanced for age, sex, colon or rectal origin, median time between diagnosis to advanced disease, performance status at entry, and visceral involvement. The overall response rate in the combination and in the single arm were 18 and 23%, respectively. There were no differences in time to progression (a median of 17.8 and 14.9 weeks for CP-5-FU and 5-FU, respectively) and in overall survival (a median of 71.2 and 59.6 weeks, respectively). The incidence of grade 3-4 emesis was significantly higher in the CP-containing chemotherapy (p = .00001). Our study has failed to demonstrate any clinical benefit from adding cisplatin to 5-FU in patients with cancer of the colon and rectum.

Phase II study with iododoxorubicin in measurable advanced colorectal adenocarcinoma. Effective rescue using weekly high-dose 5-fluorouracil (WFU). Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD), Work Group of SEOM (Spanish Medical Oncology Society).

AIMS AND BACKGROUND: To evaluate a new anthracycline 4'-iodo-4'-deoxydoxorubicin (I-DOX) in patients with measurable advanced colorectal adenocarcinoma in a phase II study. METHODS: We investigated therapeutic activity and toxicities associated with repeated courses of I-DOX 80 mg/m2 administered every 3 weeks. Eighteen patients entered the trial, all of them evaluable for response and toxicity. RESULTS: A total of 47 courses were administered. The median cumulative I-DOX dose was 238 mg/m2 (80-320). Myelosuppression, particularly leukopenia, was the most frequent and serious side effect associated with I-DOX treatment; World Health Organization (WHO) grade 3-4 leukopenia occurred in 4 patients (22%). No thrombocytopenia was observed except in 1 patient who presented WHO grade 4. Only 1 patient developed febrile neutropenia but recovered uneventfully. Overall, the I-DOX treatment was well tolerated. Grade 3-4 nausea/vomiting was observed in 2% of the cycles and no other severe toxicities were recorded. Echocardiography or multiple gated scan was performed before treatment and during follow-up in 14 patients to measure left ventricular ejection fraction (LVEF), and a decrease > 15% was detected in 3, including 1 whose LVEF fell below normal values (48%) (normal range > 49%). There were no cases of congestive heart failure or treatment-related deaths. No complete or partial response (PR) was observed. Twelve patients received weekly high-dose 5-fluorouracil (WFU) as rescue. Four patients had PR, 5 no change and 3 progressive disease (PD). The median time to PD of the whole group from study entry to failure after WFU was 30 weeks and the overall median survival was 11 months. CONCLUSIONS: As reported for other anthracyclines, I-DOX showed no activity in colorectal adenocarcinoma; however, the use of an investigational agent as front-line chemotherapy for colorectal adenocarcinoma does not compromise further response to 5-FU.

Weekly first-line chemotherapy of metastatic breast cancer with cyclophosphamide and epirubicin.

Forty-six patients with metastatic breast cancer who had not received previous chemotherapy for advanced disease entered a phase II trial of weekly chemotherapy with cyclophosphamide (250 mg/m2) + epirubicin (25 mg/m2) for 16 weeks. The overall response rate was 61% (95% confidence limits, 47-75%), with 10 complete and 17 partial responses. Toxicity was mild and confined to nausea and vomiting and asymptomatic neutropenia (except in 2 cases). Sixty-three per cent of patients had no side effects. Weekly cyclophosphamide + epirubicin is an active and nontoxic regimen for patients with metastatic breast cancer who have had no prior anthracycline-containing adjuvant chemotherapy.

Effects of glipizide on beta-endorphin secretions in response to hyperglycaemia in obese cafeteria rats.

Regulation of blood glucose involves the integration of the central nervous system with both hormonal and neural mechanisms. Considerable evidence suggests that beta-endorphin is involved in the regulation of feeding in experimental animals and man. Previous studies have shown that beta-endorphin plays an important role during hyperglycaemia. Glipizide has been shown to increase glucose metabolism by both pancreatic and extrapancreatic actions. This study indicates that glipizide may exert its pharmacological action in obese cafeteria rats through a modification of beta-endorphin secretions via central and peripheral mechanisms.

Effects of glipizide on beta-endorphin concentration in the brain of genetically diabetic (db/db) mice.

Sulphonylurea drugs have been shown to augment glucose metabolism by both pancreatic and extrapancreatic actions. The regulation of glucose involves a modification of beta-endorphin secretions via central and peripheral mechanisms. beta-Endorphin participates in the regulation of feeding and is implicated both in obesity and diabetes mellitus. This study shows that glipizide could exert its pharmacological action in genetically diabetic (db/db) mice via beta-endorphin secretions by a central mechanism.

[Adenocarcinoma of the kidney in children]. / Adenocarcinoma renal en la infancia.

Renal adenocarcinoma in infancy is a rare tumour. The presence of a case in our service has encouraged us to submit it and to carry out a review of the literature available.

[The prescription in dispensary practice]. / La prescription en pratique officinale.

Although the medical prescription is a well-established process, prescribing in the pharmacy does not follow a well-defined set of rules as, in official terms, there is no such thing as a pharmaceutical prescription. Despite this fact, daily pharmacy practice involves giving professional advice and dispensing drugs not only in fulfillment of a medical practitioner's prescription but also by selling drugs the pharmacist personally advises use of. In this particular case, the pharmacist must assess the patients desire for a specific treatment and determine whether it is well founded. The pharmacist has to decide whether he/she can deal with the presenting symptom or whether the person should be referred to a practising physician. For example, often-recurring mouth disease such as mouth-ulcers and gingivitis can be handled within the pharmacy. The pharmacist may think of implementing a suitable treatment involving dietary and hygienic counselling and dispense carefully selected drugs. The situation is similar in many other clinical conditions. As the pharmacist has had professional training in drugs at the university and teaching hospital, he/she is the expert in drugs and can rightly claim entitled to prescribing drugs within reasonable limits.

[Testing of an ultraviolet Halothane Meter]. / Mise à l'essai d'un "Halothane Meter" à ultraviolets.

The object of Halothane Meter (HM) study is to estimate its reliability (accuracy and stability) and its possible effect on the degradation of the molecule by the action of the UV (254 nm). The zero instability of the apparatus, clinically evident, is due to the constructor who undertakes to modify it. The molecule analysis, treated in vivo (4 hours of anesthesia) and in vitro by irradiation respectively by the HM (cathodeon 254 nm) and a source of some wavelength UV is realised by UV spectrophotometry, IR spectrophotometry, RMN spectrometry. The results of all analysis allow to exclude the molecule degradation which could impede the recirculation of treated gas in a closed circle.

[Filter circuits and pollution]. / Circuits filtres et pollution.

The contamination of air of a 50 m3 operating room has been analyzed after three and half hours of halothane enaesthesia with a closed circle system and an opened system. The analysis has been made by gaz chromatography. Concentrations of Halothane found during the use of an opened system are 100 to 120 times the allowable norms in U.S.A. After using the closed circle system, the analysis of air does not reveale any trace of Halothane.

[Role of community pharmacist in the management of patients in ophthalmology]. / Place du pharmacien de ville dans la prise en charge des patients en ophtalmologie.

OBJECTIVES: To assess the role of community pharmacists in ophthalmology, to evaluate the frequency of giving patients advice, and to report their difficulties in daily practice. MATERIAL AND METHODS: An anonymous questionnaire consisting of 13 questions was sent to 620 community pharmacists of Burgundy (France). Pharmacists were asked about their ophthalmic products, their ophthalmic activity in giving patients advice on ocular symptoms, and patients' expectations. For analysis, community pharmacies were separated into three groups: pharmacies in rural areas (under 2000 inhabitants), pharmacies in an urban zone with fewer than 10,000 inhabitants, and pharmacies in an urban zone with more than 10,000 inhabitants. RESULTS: The response rate was 46.9%. Ophthalmic products were mainly glasses for presbyopia (84.5%), eye care hygiene products (76.0%), and contact lens solutions (55.3%). Ophthalmic vitamin supplements were sold by 36.8% of pharmacists, mainly in urban areas. On average, the pharmacist was consulted for ocular problems seven times a week. Acute benign symptoms were most frequent. Advice on prescriptions came next. Then, information on contact lenses and chronic ocular disease were given (cataract, glaucoma, visual acuity loss, age-related maculopathy). Finally, the pharmacist either sold the patient an ocular treatment or oriented the patient to an ophthalmologist when needed. DISCUSSION: The pharmacist and his staff are active players in providing advice on ocular diseases and taking care of patients. Moreover, pharmacists have to manage ocular therapeutics, urgent symptoms, and chronic diseases. However, in our study, 46.0% of pharmacists felt confident with their knowledge on ophthalmology, 36.4% did not give their opinion, and 7.0% were uncomfortable with some questions. Most community pharmacists mentioned a lack of continuing education from pharmaceutical companies and postgraduate education on ocular diseases and treatment, mainly for age-related maculopathy.