Pharmacoelectroencephalographic profile of befloxatone, a new reversible MAO-A inhibitor, in healthy subjects.

The pharmaco-EEG profile and the effects on P300 and CNV of befloxatone, a new selective and reversible MAO-A inhibitor, were assessed in a randomized, double-blind, placebo-controlled, 4-way crossover study. Twelve healthy young male volunteers were administered single doses of 2.5, 10 and 20 mg befloxatone and placebo separated by a 1-week washout. The EEG data were recorded before and at least 6 h after drug administration, by means of 28 leads allowing topographical analysis of the results. MAO inhibition, subjective effects and safety variables were also investigated. Statistical analysis was performed by means of the SDT method. Befloxatone induced dose-related EEG changes which occurred rapidly, peaked between 0.5 and 2 h and lasted at least until 6 h after drug administration. The EEG changes were characterized by an increase in absolute and/or relative alpha power, mainly alpha 1, after the 3 doses and a theta power increase after 10 and 20 mg only. These changes occurred mainly over the centroparietotemporal areas. Concerning the event-related potential, P300 latency of the auditory evoked potentials did not change. The P300 and CNV mean topographic amplitudes were decreased, between 0.5 and 2 h, after the two lowest doses for the P300 and the 3 doses for the CNV. After administration of 2.5, 10 and 20 mg, MAO inhibitions was shown by respectively 38, 76 and 81% reduction in plasma free 3, 4-dihydroxyphenylglycol reached after 2-4 h. Such a pharmaco-EEG profile, occurring at doses inducing MAO-A inhibition, is similar to those already described with nonsedative antidepressants.

Pressor effect of oral tyramine during treatment with befloxatone, a new reversible monoamine oxidase-A inhibitor, in healthy subjects.

The interaction between tyramine and befloxatone, a new selective, reversible monoamine oxidase-A (MAO-A) inhibitor, was studied in a single-blind, parallel-group study in 30 healthy male volunteers whose fasting tyramine 30 dose (Tyr30) was 400 or 600 mg. Each subject completed a placebo run-in period followed by a befloxatone period. Befloxatone was given in repeated doses according to one of three regimens: befloxatone 20 mg once daily at the end of a meal rich in tyramine or befloxatone 10 or 20 mg twice daily 2 hours before a meal rich in tyramine. Subjects were given increasing daily doses of tyramine mixed with the meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (Tyr30). The mean Tyr30 decreased from 1220 mg (range, 600-1800 mg) during placebo to 290 mg (range, 150-500 mg) during befloxatone 20 mg once daily, 250 mg (range, 100-300) during befloxatone 10 mg twice daily, and 155 mg (range, 100-250 mg) during befloxatone 20 mg twice daily; corresponding to a potentiation factor of 5.2-, 6.5-, and 7.9-fold, respectively. The extent and the duration of the systolic blood pressure increase did not significantly differ between the placebo and the befloxatone regimens, except for a longer duration with the 20-mg twice daily regimen. These results are similar to those reported with the therapeutic dosage of other selective MAO-A inhibitors. They suggest that there would be little risk of hypertensive crisis in patients treated in clinical studies with befloxatone, and thus dietary restrictions appear to be unnecessary when the drug is given in a regimen of up to 20-mg once daily after meals.

[Metastases from cancers of unknown primary site. Data from 302 autopsies]. / Métastases de cancers à point de départ inconnu. Enseignement de 302 autopsies.

The autopsies of 302 patients who had metastases from cancers of unknown primary site were studied. In two-thirds of the cases the metastases were located in the lymph nodes, the lungs and the bones. The primary tumour was found in 82 patients when still alive (27 percent) and in 173 patients (57 percent) at autopsy. It could not be identified in 16 percent of the cases. The primary tumours most often discovered were in the pancreas (26.5 percent), the lungs (17.2 percent), the kidneys (4.6 percent) and the colorectal bowel (3.6 percent). On the whole, the paraclinical examinations performed for diagnostic purposes had been disappointing. The survival rate was the same whether or not the primary tumour had been identified. The number of inaugural metastases seems to be a major prognostic factor. These highly progressive tumours must represent a very distinct clinical and biological neoplastic entity. A simple approach and a unicist practical management are suggested.

[Factorial validation of the HARD scale in 2 groups of depressive patients]. / Validation factorielle de l'échelle HARD dans deux groupes de déprimés.

A factor analysis performed in two groups of depressed patients first pointed out the validity of the total score of the scale, then pointed out four factors which are very similar to those used in the HARD diagram and clinically constructed by the authors.

Early metastatic cancer of unknown primary origin at presentation. A clinical study of 302 consecutive autopsied patients.

We studied 302 consecutive autopsied patients who presented with carcinoma of unknown primary origin. The most frequent metastatic sites were the nodes, lung, and bone. The primary site was identified while patients were alive in 27% and at autopsy in 57%; the site remained unidentified in 16%. The pancreas (26.5%), lung (17.2%), kidney (4.6%), and colorectum (3.6%) were the most frequent primary sites, but the reliability of diagnostic tests used in the search for this site was disappointing. Survival was identical in patients whose primary site was discovered while alive, at autopsy, or remained unknown. The number of metastases at presentation was the major prognostic factor. Analysis of autopsy data demonstrated that patients with carcinoma of unknown primary origin pursue a different course than expected when the primary site is the first manifestation of the disease. On the basis of these results and the results of other modern series, we suggest an approach consisting of a limited initial workup but with greater emphasis on modern histochemistry studies and immunohistopathologic and other kinetic and morphologic parameters to understand the patient tumor characteristics better and base the clinical management on an individual basis.

Preliminary phase I clinical study and pharmacokinetics of (1,2-diaminocyclohexane) (isocitrato) platinum (II) or PHIC.

PHIC [NSC-350602; (1,2-diaminocyclohexane) (isocitrato) platinum (II)] is a new highly water-soluble platinum derivative. Preclinical studies showed antitumor activity on a wide range of tumors, no cross-resistance with cisplatin and little or no nephrotoxicity in mice and baboons. A phase I clinical trial was then initiated at doses of 300 mg/m2 infused intravenously over one hour without induced diuresis or hydration. Dosages were escalated up to 1500 mg/m2. A total of 29 patients received 52 courses of treatment. The most important side-effect is thrombocytopenia which is rapidly reversible. Nausea and/or vomiting were mild or moderate with onset 1 hr after the end of the infusion and seldom persisted beyond 24 hrs. Measurements of biological parameters did not reveal significant evidence of nephrotoxicity except in one patient who developed urinary tract infection and for whom hemodialysis became necessary. No change in the audiogram could be demonstrated. Peripheral neuropathy was documented in one patient, and in two other patients to whom morphine was given confusional episodes were observed. Although no antitumor effect was observed, there was apparent stabilization of disease. Pharmacokinetic parameters were calculated in twelve out of these 29 patients. Based upon total platinum plasma concentrations, the elimination half-life is 58.3 hrs and the plasma clearance is 21.2 ml/min with an apparent volume of distribution of 7.6 liters. However, considering both plasma concentrations and urinary excretion, we could estimate the half-life of free filterable species (60 min), the plasma clearance (125 ml/min) and the renal clearance (86 ml/min). Mean urinary excretion is 64.4% of the dose after 6 days and 53.1% at 24 hrs. Other administration protocols are suggested, based upon these pharmacokinetic parameters.

Sites of primary malignancies in patients presenting with cerebral metastases. A review of 120 cases.

A retrospective study is reported of 120 consecutive cases of patients presenting with brain metastases as the primary sign of their malignancy. Primary site was found in 62 patients (53 while alive and 9 at postmortem examination) and remained unknown in 58. Lung was the most frequent primary site (45% of known sites), and digestive malignancies were surprisingly the second most frequent primary site (19% of known sites), whereas breast was found in less than 5%. When primary site was disclosed, in 85% it was after history, clinical exam, chest x-ray, and pathologic findings. Survival was almost identical in both known and unknown primary sites: 54% versus 44% at 6 months, 20% versus 16% at 1 year, and 6% versus 5% at 2 years. It was concluded that extensive evaluations to identify primary sites do not appear to be rational in patients presenting with brain metastases.

Phase II trial of elliptinium in advanced renal cell carcinoma.

Forty patients with advanced renal cell carcinoma were treated with elliptinium by a weekly infusion of 100 mg/m2. Of 38 evaluable patients, five had an objective response (13.2%). Average response duration was 8 months (range, 5-11). The major dose-limiting toxic effect was induction of antielliptinium antibodies, with the risk of intravascular hemolysis. Elliptinium has modest activity in advanced renal cell cancer and does not produce myelosuppression.

Phase II study of elliptinium in advanced breast cancer.

A group of 74 patients with advanced breast cancer received elliptinium as second- or third-line treatment (100 mg/m2/week). The objective response rate was 19% (30% in soft tissue metastases), lasting from 3 to 12 months. This drug appears to have no marrow toxicity. Mild to moderate nausea and mouth dryness were the most frequently encountered side effects. Hemolysis occurred in five patients who had an IgM antibody and represents the dose-limiting toxicity. Cumulative renal toxicity (World Health Organization, grade 2) was observed in one of ten patients who had received greater than 2000 mg of elliptinium.

Drug-induced antibodies during 2-N-methyl-9-hydroxyellipticinium acetate (NSC-264137) treatment: schedule dependency and relationship to hemolysis.

Drug-dependent antibodies were investigated in patients treated with elliptinium acetate, a cytostatic drug with activity in advanced breast cancer. Retrospective analysis of 83 patients, receiving weekly intravenous elliptinium, showed a high incidence of anti-elliptinium antibodies (20%). Hemolysis occurred among antibody-positive patients, apparently related to the antibody titer. The predictability of anti-elliptinium antibodies for hemolysis and the schedule dependency of antibody development was examined prospectively. Among 42 patients treated weekly for at least three courses, 40% developed antibodies. Of 30 patients receiving elliptinium daily for three days every three weeks, none developed either antibodies or hemolysis. Only antibody positive patients, with titers greater than or equal to 32 were at risk for hemolysis. The possible mechanisms are discussed.

A phase I clinical tolerance study of polyadenylic-polyuridylic acid in cancer patients.

Polyadenylic-polyuridylic acid [poly(A) X poly(U)], an immunomodulator, has been shown to have antitumor effects in rodents and in a randomized clinical trial as an adjuvant to surgery in patients with operable breast cancer. The purpose of the present study was to determine the following: (a) clinical tolerance and safety of poly(A) X poly(U) in 13 patients with advanced cancer receiving a single dose of this duplex, using increasing amounts per intravenous injection of 90, 180, 300, and 450 mg; (b) if such high doses increased the level of interferon-mediated protein kinase and enhanced natural killer (NK) cell activity as observed previously with lower doses; and (c) if circulating interferon could be detected. No toxicity was observed in the 13 patients by close observation of clinical parameters, hemogram, and renal and liver functions. Increases of interferon-mediated protein kinase and of NK cell activity were observed, but there was no correlation between the magnitude of the responses and the dose of poly(A) X poly(U). No circulating interferon was detected. We conclude that poly(A) X poly(U) is not toxic in humans, at least up to a dose of 450 mg.

[Combination vindesine, cyclophosphamide, cis-platinum and CCNU in esophageal epidermoid cancer. Preliminary analysis of 64 cases]. / Association vindésine, cyclophosphamide, cis-platinum et CCNU dans les cancers epidermoïdes de l'oesophage. Analyse préliminaire de 64 cas.

We have treated 64 patients with esophageal squamous cell carcinoma using a combination of Vindesine 1.4 mg/m2 on day 1-2, Cyclophosphamide 200 mg/m2 on day 2-3-4, Cis-Platin 100 mg/m2 on day 3 and CCNU. 28 of the 37 patients considered to be inoperable were evaluable. We observed three complete responses and three partial responses in this group (overall response rate 21,5%). Twenty seven patients considered to be operable received the same chemotherapy without CCNU, owing to the risk of thrombopenia. 23 of these patients were evaluable in whom we observed 35% partial responses and no complete responses. No severe toxicity related to the chemotherapy protocol was observed. The mediocre results among the group of inoperable patients suggest that other chemotherapy protocols need to be tested. On the other hand, in the group of operable patients, the preliminary results encourage us to continue this study.

[Treatment of metastatic renal cancer in adults with elliptinium acetate]. / Traitement des cancers du rein métastasés de l'adulte par l'acétate d'elliptinium.

The results obtained with N-methyl-hydroxy-elliptinium acetate (NMHE) in the treatment of 22 assessable adult patients with metastatic renal cancer are reported. According to the WHO criteria, there were 10 responses, including 7 stabilizations, 2 partial remissions (greater than 50%) and one complete and durable remission. Since there is no other effective medical treatment for this type of tumour, and since the protocol used so far appears to have low toxicity and makes it possible to evaluate the value of the drug within 4 to 6 weeks, the trial will be extended in order to determine more precisely (+/- 5%) the degree of effectiveness of NMHE.

[Manifestations of cerebral metastases: diagnostic and therapeutic importance of research on their primary sites in 120 cases]. / Les métastases cérébrales révélatrices: intérêt diagnostique et thérapeutique de la recherche de leur point de départ à propos de 120 observations.

Among 120 cases of cerebral metastases, 62 primary sites were found. The diagnosis of the primary site was confirmed: --after the first investigations in 48 cases (in 90% of cases by anamnestic inquiry, clinical examination or chest X ray); --by the evolution of the disease in 5 cases; --by autopsy in 9 cases. The most frequent primary sites were lung (45%), digestive tract (17.7%), melanoma (8%) and ovary (6.5%). Among the identified cases, 25 received treatment for their primary cancer, but only 4 had a surgical resection. There was no significant difference in mean survival between the 2 groups (defined as primary site known or unknown); over all mean survival was 8 months. The early discovery of cerebral metastases suggests the advanced state of the disease. Therefore, investigations which cause the patient to suffer do not seem justified merely for research purposes.

A systems theory approach to a case of anorexia nervosa.

Systems theory views mental and psychosomatic illness as the natural consequences of a dysfunctional human interactional group. The symptom chosen is affected by the symptom carrier's age, sex, and unique individual characteristics. However, the reason the symptom develops and is maintained is to be found in the system(s) of which the symptom carrier is a part. A human system consist of two or more individuals who have an ongoing, often goal-directed, relationship with each other. The most important human system today is undoubtedly the family. The welfare of the individual is usually related to membership in a vital, well-adjusted family. A dysfunctional family easily becomes dependent on mental or behavioral deviations in one of its members as a means of preventing disintegration. We hope this article's description of a typical treatment situation will demonstrate how a systems theory approach differs from other forms of family therapy in its evaluations and techniques.