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5-Aza-2'-deoxycytidine (5-AZA-CdR, Decitabine) is a nucleoside analog and an active drug for the therapy of acute leukemia. The incorporation of 5-AZA-CdR into DNA blocks DNA methylation and can result in the activation of specific genes, such as tumor suppressor genes. This novel mechanism of action of 5-AZA-CdR stimulated our interest in its potential for cancer therapy in patients with lung cancer. Using a colony assay we observed that 5-AZA-CdR showed a potent antineoplastic effect against two human lung carcinoma cell lines. The objective of this preliminary phase I-II study was to evaluate the toxicity and clinical efficacy of 5-AZA-CdR in patients with stage IV non-small cell lung carcinoma. There were 15 patients that entered the clinical study. For nine assessable patients that received 5-AZA-CdR by a single 8 h i.v. infusion of 200-660 mg/m2 for one or more cycles, the median survival duration was 6.7 months, with three patients surviving more than 15 months. The steady-state plasma concentration of 5-AZA-CdR during the infusion was estimated in some patients and was in the same range that produced activation of a tumor suppressor gene in human lung tumor cell lines as reported by other investigators. The major side effect of 5-AZA-CdR was hematopoietic toxicity which required a 5-6 week recovery period before the next cycle of therapy. This study suggests that 5-AZA-CdR may have some clinical activity against metastatic lung carcinoma using this type of dose schedule.

Continuous monitoring of cardiac output during liver transplantation is essential to evaluate the patient's haemodynamic tolerance to acute volume variations. The aim of this study was to compare the cardiac output values obtained with a transoesophageal echo-Doppler and those obtained with a continuous thermodilution cardiac output pulmonary artery catheter.Twenty adult patients were prospectively studied during a 5 min hepatic vascular exclusion test performed at the end of the dissection phase. Echo-Doppler and continuous thermodilution cardiac output, mean arterial pressure and end-tidal CO2 were measured before and at the end of the test.Before the test, echo-Doppler cardiac output was 7.0 +/- 2.7 L min(-1) and thermodilution was 9.4 +/- 3.1 L min(-1), (R = 0.85, P0.001). The end test values were, respectively, 3.5 +/- 2.7 and 7.8 +/- 3.5 L min(-1) (R = 0.23, P = 0.34). Bland and Altman analysis showed a bias of -2.2 before the test, which increased to -4.4 at the end of the test. Mean arterial pressure decreased from 85.5 +/- 15 to 66.8 +/- 16 mmHg, end-tidal CO2 from 31.4 +/- 2.3 to 23.8 +/- 2.7 mmHg.Echo-Doppler cardiac output values are different from those measured by thermodilution cardiac output in these patients. Echo-Doppler cardiac output monitoring seems to detect the output changes, which can occur during acute haemodynamic changes more rapidly than thermodilution cardiac output in the course of liver transplantation.

Background Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl™) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials. Methods The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired t test using GraphPad prism software. Results Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. In vivo testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine. Conclusion These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients.

Troxacitabine (BCH-4556, l-(-)-OddC, Troxatyl) is a novel beta- l-nucleoside analogue with potent antineoplastic activity both in vitro and in several tumor models in vivo, and is presently in phase II clinical trials. The combination of the cytosine analogues troxacitabine and araC (1-beta- d-arabinofuranosylcytosine, cytarabine) has shown promising activity in patients with acute myelogenous leukemia. To further examine the interactions between these two analogues, we investigated the in vitro and in vivo effects of their combination against a human leukemia cell line, CCRF-CEM.. The in vitro cytotoxic effect of the combination of troxacitabine and araC on the survival of CCRF-CEM cells was measured using a standard MTT assay and combination indices were generated with the CalcuSyn software. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on survival of CCRF-CEM tumor-bearing animals. Mechanistic studies addressed recovery of DNA synthesis, intracellular levels of araC metabolites, feedback inhibition by triphosphate species and pharmacokinetics of both drugs.The combination of troxacitabine and araC in vitro was synergistic with combination indices between 0.1 and 0.7. This appeared to be related to the impact of the combination on DNA synthesis recovery, which was significantly delayed following exposure to the combination of troxacitabine and araC compared to either agent alone. Analysis of the effect of troxacitabine on the intracellular metabolites of araC revealed that troxacitabine did not inhibit araC deamination and caused a slight decrease in the overall intracellular accumulation of araCTP. The lower accumulation of araCTP could not be attributed to feedback inhibition caused by troxacitabine triphosphate on dCK. Furthermore, our in vivo experiments demonstrated that the combination of araC and troxacitabine was better at slowing down the progression of leukemia in SCID mice than either agent used alone without additive toxicities. Injections of 10 mg/kg troxacitabine i.p. daily for 5 days in combination with araC at 10 mg/kg led to an increase in median survival time of 58 days compared to 49.5 and 53.5 days for araC and troxacitabine, respectively, given as single agents. This represents an increase in life span of 17%, respectively when compared to araC alone. A pharmacokinetic study revealed that troxacitabine did not influence the disposition of araC when coadministered.Overall, our results show that the antileukemic activity of troxacitabine and araC is complementary when the two nucleoside analogues are combined in vivo. These effects appear to be related to their interaction at the level of DNA repair rather than to pharmacokinetic interactions. These results encourage the use of troxacitabine and araC in combination in patients with acute leukemia.

Purpose. We have recently identified a deoxycytidine nucleoside analogue, troxacitabine (β-L-dioxolane cytidine, Troxatyl; Shire BioChem), which has potent antitumor activity against both leukemia and solid tumors. In contrast to the cytidine nucleoside analogues currently in clinical use (cytarabine and gemcitabine), troxacitabine is a poor substrate of nucleoside transporters and enters cells primarily by passive diffusion. This unusual property led us to evaluate the efficacy of troxacitabine in multidrug resistant (MDR) and multidrug resistance-associated protein (MRP) tumors. Methods. The in vitro antiproliferative activity of troxacitabine was investigated in the human nasopharyngeal epidermoid carcinoma cell line, KB, and its vincristine-resistant derivative (KBV), as well as in human leukemia cell lines of myeloid and lymphoblastoid origin, HL60 and CCRF-CEM, respectively, and their MDR (HL60/R10 and CCRF-CEM/VLB) and MRP (HL60/ADR) derivatives, using the thymidine incorporation assay. For in vivo studies, we compared the antitumor efficacy of troxacitabine with that of doxorubicin and vinblastine in xenograft models of these solid and hematological human anthracycline-resistant tumor xenografts. Results. Troxacitabine demonstrated potent antiproliferative activity against both P-glycoprotein-positive (KBV, HL60/R10, CCRF-CEM/VLB) and P-glycoprotein-negative (HL60/ADR) multidrug-resistant cell lines with IC50 values ranging from 7 to 171 nM. Tumor regression was observed in the KBV xenograft following a 5-day treatment with 20, 50 and 100 mg/kg of troxacitabine, with percent total growth inhibition (TGI) of 81, 96 and 97, respectively, and some cures at the two highest dose levels. In the HL60, HL60/R10, HL60/ADR and CCRF-CEM/VLB xenografts, the effect of troxacitabine was evaluated on survival time. In the HL60 promyelocytic human xenograft models, troxacitabine treatment (25, 50 and 100 mg/kg per day for 5 days) was initiated 10 days after tumor cell inoculation, once animals had developed disseminated tumors. In all three promyelocytic leukemia xenografts, troxacitabine was quite potent, producing T/C values of 162% to 315% as well as complete cures at the higher dose levels. In the CCRF-CEM/VLB T-lymphoblastoid leukemia xenograft, troxacitabine treatment (10, 30 or 250 mg/kg total doses using different schedules) was initiated 20 days after tumor cell inoculation. Troxacitabine was not as potent in this model but did result in significant antileukemic activity (T/C of 131%) when administered at 10 mg/kg on days 20, 27 and 34. Conclusions. These results indicate that troxacitabine has a potent in vivo antitumor activity associated with tumor regressions and complete cures in animals with tumors refractory to current chemotherapeutic agents.

Early somatosensory (SEP) and auditory (BAEP) evoked potentials, when recorded within the first seven days of the course of anoxic coma, appear to be reliable to evaluate anoxic ischemic cortical or under-cortical lesions. Prognosis depends especially on cortical SEP (N20-P25): the lack of SEP is a good outcome predictor of death (abnormal BAEP) or of vegetative status (normal BAEP); the presence of normal and bilateral cortical SEP (with normal BAEP) allows to predict awakening, without prejudging of neurologic sequelae, even if they are severe.

Forty-eight hours after a women was poisoned by ingesting Amanita phalloides mushrooms, she developed fulminant hepatic failure with collapse, pH 7.24, lactic acidosis 7.6 mmol/l, hypoglycaemia 3.5 mmol/l, anuria and stage IV coma requiring tracheal intubation and mechanical ventilation. Transaminase level was up to 8,000 UI/l. Prothrombin and factor V levels were below 10 percent, with an APT time of 86 s versus a 29 s control time. Twenty-four hours after her admission, the patient underwent orthotopic liver transplantation. The postoperative period was uneventful, with return to consciousness and rapid normalization of hepatic biochemistry values, without signs of acute rejection. This 10th published case of orthotopic liver transplantation for Amanita phalloides poisoning with acute hepatic necrosis confirms that this type of treatment must be systematically envisaged in all such cases.

We report a case with focal neurological deficits suggesting vertebro-basilar system ischemia, in the course of pre-eclampsia. An early CT scan showed a large hypodensity throughout the midbrain. Brainstem auditory evoked potentials initially showed an abolition of III and V pikes suggesting brainstem injury. Two days later both neurological examination and brain stem auditory evoked potentials returned to normal. A CT scan performed three weeks after the onset was normal. These findings suggest a vasospasm which may have been due to sympathomimetic agents given two weeks before the onset of toxemia for preterm labor.

Early somatosensory (ESEP) and auditory (EAEP) evoked potentials were recorded in 27 patients with severe coma (Glasgow score less than 5) following cardiorespiratory arrest, within the first 7 days of its course. Somatosensory responses were elicited by stimulation of the median nerve. ESEP were abolished in 17 patients due to a parietal thalamo-cortical lesion. Among these, 6 patients died within one month and 11 presented with a persistent vegetative state. In all patients EAEP were obtained, showing functional brainstem activity. Low-voltage EAEP, especially for peak V (inferior colliculus or upper part of the brainstem), was sometimes observed. One patient, in whom ESEP and EAEP were initially abolished, died rapidly. In 9 other patients scalp-recorded ESEP and EAEP were normal; all emerged from coma including 5 with good neurological recovery and 4 with neurological sequelae. Clinical, electroencephalographic and computerized tomographic data appeared to be devoid of predictive value at the same initial period. In view of their sensitivity to anoxia and to cerebral oedema, even with neurosedative drugs, ESEP seemed to be reliable in predicting outcomes and in evaluating central nervous system lesions at cortical and subcortical levels (basal ganglia and brainstem) after cardiorespiratory arrest.

The pharmacokinetics of alfentanil were studied in 11 patients with alcoholic cirrhosis and 10 control patients during general anesthesia. All patients received 50 micrograms . kg-1 alfentanil as an intravenous bolus injection. Plasma concentrations were measured at intervals up to 10 h, using a specific radioimmunoassay technique. Protein binding was measured by equilibrium dialysis. Patients with cirrhosis had a significantly lower (P less than 0.01) plasma clearance of alfentanil of 1.6 +/- 1.0 ml . min-1 . kg-1 (mean +/- SD) instead of 3.1 +/- 1.6 ml . min-1 . kg-1 in the controls. The total apparent volume of distribution was similar in the two groups. The elimination half-life was prolonged from 90 +/- 18 min in the controls to 219 +/- 128 min in the cirrhotics (P less than 0.01). Patients with cirrhosis had a higher (P less than 0.01) alfentanil plasma-free fraction (18.6 +/- 9.4%) compared with the control patients (11.5 +/- 3.9%). When kinetic parameters were corrected for protein binding, the unbound volume of distribution and the free drug clearance were decreased significantly in patients with cirrhosis. Since the concentration alpha 1-glycoprotein to which alfentanil mainly is bound in plasma did not differ in the two groups, it is suggested that the increase in the free fraction is caused by an alteration of binding sites of this protein in patients with cirrhosis. Owing to its delayed elimination and increased free fraction, alfentanil will exert a prolonged and pronounced effect in patients with cirrhosis.

Seven cases of acute ajmaline overdose admitted over a 3 year period to a polyvalent intensive care unit are reported. The severity of this condition is related to the membrane stabilising and depolarising effects of ajmaline on the myocardium. The dose ingested varied from 10 to 40 mg/kg. The delay between ingestion and hospital admission ranged from 3 to 6 1/2 hours. The first cardiac disturbances can appear one hour after ingestion. Three cardiac arrests and one hypovolemic shock occurred. Three atrioventricular blocks, six intraventricular blocks, three ventricular tachycardias, and six prolongations of the QT interval were observed. Serum ajmaline levels varied from 0,8 to 6 mg/l. Symptomatic therapy was mainly based on sodium, temporary cardiac pacing, external DC shock, sympathomimetics and external cardiac massage with assisted ventilation. Cardiac bypass should be a part of the therapeutic arsenal. Elimination of the drug is assisted by a complete digestive evacuation. Renal or extrarenal dialysis is not indicated. One of the seven patients died. Prophylaxis is based on the non-prescription of ajmaline for benign cardiac disturbances.

Between 1977 and 1982, fifty cases of post-traumatic fat embolism were treated in a general intensive care unit. Average age of patients was 25.5 +/- 13 years; there was no male majority. Mean free interval was 39 +/- 27 h. 12 cases (24%) had single fractures and 38 (76%) multiple fractures. Forty-four patients had a fractured femur. Thirty-two patients presented the complete clinical syndrome with general, respiratory, neurological and cutaneous signs. Thrombocytopaenia and hypocholesterolaemia were the biological signs most often seen. In forty-four patients, orthopaedic treatment consisted of immediate immobilization, usually with traction. Twenty-six patients were reoperated on: intramedullary nail for twenty patients, plate for the other six. Fat embolism appeared in spite of surgery in six cases; it worsened after surgery in six others. Seven patients had per- or postanaesthetic problems. Fourteen per cent of patients died. The decrease in mortality was mainly due to an improvement in mechanical ventilation techniques. Early surgical fixation remained the rule if there was no serious respiratory distress or haemodynamic instability, although it did not seem to change the mortality rate in this group of patients.

A case of postoperative myocardial infarction is reported. It occurred seven days after intra-abdominal surgery (left hemicolectomy), in a patient with coronary heart disease. Diagnosis was delayed because of lack of pain; it was suggested by cardiogenic shock occurring 48 h after the initial phase. The patient had been receiving postoperative epidural analgesia with an opioid (pethidine); this may explain the pain was missing, so delaying the diagnosis.

The neurological signs, the cerebral CAT scan aspects and the ocular problems seen in five cases of acute methanol poisoning are reported; these were, respectively, coma requiring assisted ventilation, convulsions, hypotonicity, hypodensity of the putamen, and amaurosis and papillary oedema. The simplified acute physiologic score varied from 11 to 26; the value of 26 was observed in the only death of the series. Pathogenesis of the metabolic acidosis, as well as the different parts played by formic acid, lactic acid and ketone bodies are discussed. A normal or lowered serum potassium in a case of unexplained metabolic acidosis associated with an osmotic gap should make one think of the diagnosis. Macrocytosis, an indirect sign of folic acid deficiency, was in favour of a poor prognosis. The treatment included early gastric lavage, alkalinization, blocking of the metabolism of methanol by ethanol and haemodialysis with a bicarbonate dialysate enriched in ethanol; this corrected the acidosis and permitted the elimination of the toxic metabolites (clearance of methanol: 159 ml X min-1; half-life of methanol during purification: 3.46 +/- 1.32 h; quantity extracted: 246 g). The possible advantages of 4-methyl-pyrazol and alkyldiol derivatives need further confirmation.

A 73 years old patient, treated with Amiodarone for ventricular tachycardia, ingested 6 000 mg of Amiodarone. This did not induce hemodynamic troubles or aggravation of ventricular arrhythmia. Treatment included a gastric lavage and purging at the third hour. Plasma assay revealed a concentration of 3.69 mg/l at the fourth hour. Their evolution can be described as the sum of two exponentials. The half-life of the first exponential is 4.9 hours ; the half-life of the second one is 544 hours. Amiodarone is an antiarrhythmic agent of high safety.

A new case of oxytocin-induced water intoxication is reported in a 30 year old gravid woman. The severe symptoms of this uncommon complication are principally neurological; biological signs are a hyponatraemia with low plasma osmolality. Usually, biological and clinical signs are rapidly cleared up by treatment, but maternal death or neonatal water intoxication may occur. Such accidents must be prevented by clinical monitoring, watching out for alarm signals (oliguria is always found, resulting from the effect of oxytocin on the kidney), minimum fluid and proportional salt intakes, careful monitoring of oxytocin infusion rates, facilitated by the use of a constant flow-rate pump.

Among the 94 tricyclic antidepressant intoxications received in 3 years in the intensive care unit of Edouard Herriot Hospital, 16 with cardio-vascular manifestations are studied. The criteria of selection is the presence on the electrocardiogram (ECG) of a ventricular trouble in conduction excitability or automaticity. Eight times, the ingested dose exceeds 20 mg/kg. 10 times several toxics are taken explaining the severity of coma and the rarity of convulsions. 2 collapses, 1 shock, 1 cardiac arrest occur. The most frequent ECG abnormalities are: T modifications, (90 p. 100), prolongation of QT interval (60 p. 100), right bundle branch block (50 p. 100) or left one (25 p. 100). Only one death occurs; (1 p. 100 of this series). Ventricular dysrythmia or myocardial failure represent the main criteria in the evaluation of severity of the tricyclic antidepressant intoxication. For the treatment, a complete digestive evacuation is needed, Hemodialysis, plasmapheresis, or hemoperfusion cannot be actually recommended. The treatment of cardiac troubles involves essentially sodium. and eventually intra-cardiac pace maker.

The case of a 58 year old woman who died after ingestion of 14.4 g of sotalol and 50 mg of triazolam is described. Despite medical treatment, intracardiac pacing and hemodialysis, cardiovascular failure persisted and became irreversible. High sotalol concentrations were observed in plasma (65 micrograms/ml) and in post mortem tissues samples. Tissue to plasma ratios ranged from 2.5 to 6. The high drug concentration found in heart tissue (104.4 micrograms/g) explains the difficulties experienced in the sotalol poisoning.

This clinical investigation examined deep venous thrombosis with clinical signs indicating superior vena caval involvement, secondary to installation of central venous catheters. Thrombophlebitis was rare, but very dangerous if of septic origin.