The Rieske/cytochrome b complex of Heliobacteria.

Heliobacteria have a Rieske/cytochrome b complex composed of a Rieske protein, a cytochrome b(6,) a subunit IV and a di-heme cytochrome c. The overall structure of the complex seems close to the b(6)f complex from cyanobacteria and chloroplasts to the exception of the di-heme cytochrome. We show here by biochemical and biophysical studies that a heme c(i) is covalently attached to the Rieske/cytochrome b complex from Heliobacteria. We studied the EPR signature of this heme in two different species, Heliobacterium modesticaldum and Heliobacillus mobilis. In contrast to the case of b(6)f complex, a strong axial ligand to the heme is present, most probably a protonatable amino acid residue.

Oncostatic effects of Alangium vitiense extracts (ICIG-EORTC 1131, 1186 and 1207) on lymphoid murine tumors.

A total alkaloid and two purified alkaloid extracts of Alangium vitiense were found to be oncostatic for L1210 leukemia; the total alkaloid exerted a noticeable activity, and the purified extracts exerted a borderline activity. These two purified extracts are noticeably oncostatic for two other lymphoid neoplasias in mice, P388 leukemia and Gardner lymphosarcoma. These compounds are not active on Warner myelomonocytic leukemia WEH13 or on B16 melanoma.

Synthesis and evaluation of antileukemic activity of 5-thienyl- or 5-(2-furyl)-2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine bis(alkylcarbamates) and derivatives.

Treatment of N-(2-furoyl)proline or N-thenoylprolines and N-(2-thenoyl)thiazolidine-4-carboxylic acid with acetic anhydride and dimethyl acetylenedicarboxylate gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate and derivatives of dimethyl 5-(2-thienyl)pyrrolo[1,2-c]thiazole. Reduction of 2 with lithium aluminum hydride gave the diols 3a, 3b, 3c and 3d. These diols yielded the corresponding diacetates 4 by treatment with acetic anhydride. The bis(methylcarbamates) 5a, 5b, 5c, and 5d and bis(isopropylcarbamates) 6b and 6c are obtained with the appropriate isocyanates. The 1-substituted pyrrolizines were synthesized, the 1-acetoxy compounds 7b and 7c further transformed into 1-hydroxy and 1-oxo analogues. The action of hydrochloric acid on 1-acetoxy derivatives gave 3H-pyrrolizines. Evaluation of antileukemic activity was investigated on the leukemia L1210 in vivo, on several bis(alkylcarbamates). The compounds 5c and 5d show good antileukemic activity comparable with the mitomycin.

Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients.

BACKGROUND: The 20210 A allele variation in the 3' -untranslated region of the prothrombin gene was recently identified as a risk factor as regards deep venous thrombosis. AIM: To assess the frequency of the variation in unselected patients with a proven venous thromboembolism (VTE). METHODS: The presence of the prothrombin variation was determined in all consecutive patients referred from July 1994 to August 1997 for a clinical suspicion of VTE, and in whom the diagnosis was confirmed. A control group consisted of bone marrow volunteer donors. RESULTS: Of the 366 patients included, 17 (4.6%) were carriers of the 20210 A allele (95% CI, 2.4% to 6.7%). The mutation was present in 1.0% of the 400 controls. Odds ratio for having VTE in the presence of the 20210 A allele was 4.8 (95% CI, 1.5 to 19.8). Forty-six (12.5%) patients had the mutation of the factor V gene and five (1.4%) patients shared both mutations. After excluding the carriers of the factor V mutation, odds ratio for having VTE in the presence of the 20210 A allele was 3.7 (95% CI, 1.1 to 13.6). Mean age at admission as well as mean age of the first VTE episode were both significantly higher in patients free from the two mutations studied, as compared to carriers of the 20210 A allele (p = 0.04 and 0.01, respectively). CONCLUSION: Our findings in a large series of patients (1) confirm the 20210 A allele prothrombin gene as a risk factor for VTE. (2) suggest that its association with the factor V Leiden is not uncommon.

Cytostatic action of two nitrosoureas derived from cysteamine.

2-Chloroethyl nitrosocarbamoylcystamine or ICIG-1325 (CNCC) is a lipid-soluble isomeric mixture of nitrosoureas. Its dose-effect relationship on L1210 leukaemia is characterized by a large maximally efficient dose-range (MEDR), greater than that of other nitrosoureas. CNCC also demonstrated significant therapeutic activity on intracerebrally (i.c.) transplanted L1210 leukaemia and on six transplanted solid tumours, TM2 mammary carcinoma, M555 ovarian carcinoma, B16 melanoma, glioma 26, 3LL, Lewis lung carcinoma and colon 26 carcinoma. It was inactive on fibrosarcoma ICIG-Ci4. Its antitumour activity spectrum is wider than that of the related compounds 2-[3-(2-chloroethyl) 3-nitrosoureido]D-glucopyranose (CZT), (chloro-2-ethyl)-1(ribofuranosyl-isopropylidene-2'-3' paranitrobenzoate-5')-3 nitrosourea (RFCNU), and (chloro-2-ethyl)-1 (ribopyranosyl triacetate-2'-3'-4')-3 nitrosourea (RPCNU). A study of its metabolic disposition in animals has shown that CNCC undergoes extensive first-pass metabolism leading to the formation of four main plasma metabolites. These metabolites are water-soluble nitrosoureas that arose from the bioreduction of the disulphide bridge followed by the methylation and the oxidation of the thiol groups. Experimental screening was performed with these chemically synthesized metabolites. Both N'-(2-chloroethyl)-N-[2-(methylsulphinyl)ethyl]-N'-nitrosourea (CMSOEN2) and N'-(2-chloroethyl)-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea (CMSO2EN2) are very active on L1210 leukaemia grafted intraperitoneally (i.p.) and i.c., L40 leukaemia, B16 melanoma, glioma 26 and Lewis lung carcinoma. Their effectiveness is better than that of the parent compound CNCC. In addition,the percentage of mice cured after CMSOEN2 or CMSO2EN2 treatment is increased especially on B16 melanoma and glioma 26. 6 Haematological toxicity of both active metabolites is lower than that of CNCC, particularly on platelets which is the main toxicity location due to nitrosoureas.

Experimental antitumor activity of 5'-nor-anhydrovinblastine navelbine.

We have found that navelbine, a new semi-synthetic Vinca alkaloid analogue, is as active as vincristine on implanted murine tumors. It has a low cross-resistance with vincristine and vindesine.

Antitumor activity of l-OHP in mice.

The isomeric mixtures of platinum complexes of diaminocyclohexane (DACH) had been found active on several murine tumors. A recent separation of the oxalato-platinum complex of trans-l-DACH isomer allowed more precise screening studies and permitted the selection of one compound: l-OHP was submitted to our murine tumor screening system. The drug was given: (a) at doses of 1-12 mg/kg i.p. or i.v. on day 1, 5 and 9 compared to identical doses of cis-dichlorodiamine platinum II (CDDP) in L1210 bearing mice and (b) to AkR leukemia, LGC lymphoma, glioma 26, B16 melanoma, MA 16-C mammary carcinoma and Lewis lung carcinoma bearing mice at 2 dosages: 5 mg/kg (minimal effective dose on L1210), and 8 mg/kg (subtoxic dose in L1210). Acute LD10 and LD50 appeared similar to CDDP and l-OHP. l-OHP administered i.p. was more active on L1210 than CDDP. On L1210 grafted intracerebrally and on LGC lymphoma l-OHP increased significantly the lifespan while CDDP was inactive. On AkR leukemia, both drugs were active but l-OHP was less toxic. Both drugs were inactive on murine solid tumors. No renal toxicity was observed with l-OHP as compared to CDDP.

Experimental protection by a luteinizing hormone-releasing hormone agonist of a bone marrow nitrosourea aplasia. Preliminary observations.

D-Tryptophan-6-luteinizing hormone-releasing hormone (D-Trp6-LH-RH) applied from day -8 to day +15 before and after administration of the nitrosourea analog, N,N'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl]cysteamine (CNCC), favored bone marrow restoration, as independently evaluated by 3 observers in a double-blind fashion.

Experimental in vivo cross-resistance of vinca alkaloid drugs.

In human therapy, an absence of cross-resistance has been observed between vincristine and vindesine in patients receiving polychemotherapy whilst, in our experimental in vivo studies, such a cross-resistance has been found between Vinca alkaloids. Further studies are required to explain this discrepancy.

Virostatic in vivo effect of elliptinium on Friend's retrovirus (a model for HIV infection).

As we had discovered the virostatic effects of some analogues of acriflavine, a non-oncostatic intercalating agent, on HIV1 and on its best murine model, Friend's virus [7], we then studied other non- or poorly oncostatic intercalating agents, in particular ellipticins (whose negligible cytostatic effect with methoxy-9-ellipticin we first published. We report in this paper the in vivo virostatic effect of 2-methyl-9-hydroxy-ellipticinium (elliptinium) on Friend's virus.

Can virostatic chemotherapy and/or adoptive allogeneic immunotherapy eradicate in vivo Friend's virus infection?

While none of the three drugs which exert an in vitro anti-HIV effect, neither AZT nor the other two, acriflavine and elliptinium, which we have shown to be more efficient than AZT, is able to eradicate Friend's virus in vivo, the combination of the 3 drugs at much smaller doses than when given alone seems able to eradicate it in almost 30% of the infected animals. This possible eradicating effect of virostatics in combination is compared with the results we had previously obtained with lymphocytes of virus-immunized allogeneic donors.

The in vivo effect of ellipticine analogues on the blood concentration of Friend virus: a murine model for studying anti-HIV drugs.

The viremia of a mouse carrying a murine retrovirus, the Friend virus, was taken as a model for screening drugs which could be active on the human HIV retrovirus. Ellipticine and two of its analogues injected ip at appropriate doses drastically reduced the viremia of the Friend virus-injected mice, as measured by transfer of their serum on day 8 of the treatment to secondary recipients and numeration, in the spleens of the latter, of the foci the remaining virus had induced. Since phase I and II trials have already been published (for leukemia treatment), the efficacy of those drugs on HIV-1 positive AZT-resistant patients can be tested directly.

In vivo eradication of Friend virus as an experimental HIV-model, by combination of zidovudine, acriflavine and an ellipticine analogue. Possible application to the treatment of human pre-AIDS?

Simultaneous administration of zidovudine, acriflavine and celliptium to Friend virus-injected mice eradicates the virus, as evidenced by the impossibility of the treated-mouse serum, when injected to virgin recipients, to induce spleen foci formation. An adapted preliminary protocol given to patients in whose p 24 antigen was present in the blood, lead to a considerable reduction of that marker. The cures lasted 3 weeks, and were repeated after 3-week intervals. Since p 24 antigen returns to pre-treatment levels at the end of the interval, research should concentrate on the maintenance of the effect during the interval.

Effects of B16 melanoma transplantation on the respiration of grouped C57Bl female mice.

Two batches of 110 females C57Bl mice were grafted with B 16 melanoma, the first batch at the age of 67 days, the second at 82 days. The animals were divided into groups of 10, and kept under a LD 12 : 12 regimen. The growth of the tumors was more rapid in the second batch. This was accompanied in this batch, by a decrease in body growth, a diminution of heart rate and an increase in QRSII amplitude. Significant decreases in carbon dioxide emission (VCO2) level, mostly during the dark period of time, when the mice had their greatest activity, and decrease in respiratory photic variations at light transitions were obtained when the tumors were well developed. Harmonic analysis of the continuous recording of carbon dioxide shows slight changes in VCO2 ultradian (40 minutes less than tau less than 12 hours) rhythms. The effects on respiration were confirmed by different survival rates and rectal temperatures between tumor grafted and controls submitted to an acute nitrogen normobaric hypoxia.

Oxalato-platinum or 1-OHP, a third-generation platinum complex: an experimental and clinical appraisal and preliminary comparison with cis-platinum and carboplatinum.

A new platinum complex, oxalatoplatin or l-OHP, which, at the same metal dose in experimental tests is as efficient as cisplatin, and is more so at a lower metal dose than carboplatin; which is as efficient in human tumors of the testis and ovary as these other analogs, and more so in melanoma and breast cancer; which is not nephrotoxic, cardiotoxic or mutagenic, and hardly hematotoxic and neurotoxic, is described and compared with the above-mentioned platinum complexes. Combined with 5Fu, it induces a high number of remissions in colorectal cancer, and has brought about cures in inoperable gastric cancers. Combined with carboplatin, it has resulted in a high proportion of cures in L1210-carrying mice, which no other two-by-two combination of these complexes has achieved.

[What investigations should be done following the first episode of pulmonary embolism?]. / Quel bilan réaliser au décours d'un premier épisode d'embolie pulmonaire?

Thromboembolic venous disease is both common and potentially serious, thus the first episode of pulmonary embolus calls for careful assessment. This involves two stages: a search for a venous localization of the pulmonary embolus and a search for risk factors contributing to thromboembolic venous disease. The emergence of non-invasive echographic-Doppler techniques and echocardiography make possible the localization of any residual venous thrombus. The risk of post thrombotic disease is raised in symptomatic thrombotic venous disease which requires wearing elastic stockings for a least two years. On the other hand this risk has not been assessed in asymptomatic cases of venous thrombosis. A search for risk factors requires a detailed history, a rigorous clinical examination and a routine list of laboratory investigations. Some complex investigations for detecting the early stages of a neoplasm would not appear justified unless there is objective evidence to support his. At the same time thrombophilia studies are not currently performed routinely for a first episode but may be suggested in the following cases: family history of thromboembolic venous disease, age less than 45, including those in whom the episode occurs at the same time as pregnancy, or whilst taking hormone therapy, idiopathic thromboembolism, the association of arterial and venous thrombi and finally venous thromboses occurring in an unusual anatomical site. Prospective studies have shown the value of long term anticoagulation in patients suffering from constitutional hemostatic anomalies. Finally, if there is an after thought of occult cancer or constitutional thrombocytopenia a careful follow up should be performed particularly during the first year.

[Current trends in asthma management]. / Actualités de la prise en charge de la maladie asthmatique.

INHALED CORTICOSTEROIDS: There has been substantial improvement in asthma management over the last few years. Inhaled glucocorticoids (ICS) are the most effective therapy in the treatment of asthma. COMPLEMENTARY TREATMENTS: Additional treatments such as theophyllines, long-acting beta 2 agonists or more recently leukotriene antagonists allow in most cases the maintenance of ICS at safe dosages without substantial adverse effects. COMPLIANCE: Compliance is a major issue that can only be improved using global management strategies in which asthma education plays a prominent role.

[Hypersensitivity pneumonitis in a patient taking pravastatin]. / Une pneumopathie iatrogènique rapportée à la prise de pravastatine.

A 41-year-old man who had been taking pravastatin for two years developed hypersensitivity pneumonitis. The initial examination found intestinal pneumonitis and hypereosinophilia. The patient's syndromes gradually resolved with withdrawal of pravastatin. As HMG coenzyme A reductase inhibitors are commonly prescribed, any respiratory symptoms in this setting should be considered with special attention.

[Plastic bronchitis]. / La bronchite plastique.

We report a case of plastic bronchitis occurring in a 58 year-old man free from underlying pulmonary disease. Relief of symptoms was observed under steroid therapy (1 mg/kg), but relapse occurred as treatment being tapered. Such evolution is in accordance with recent published data.

Can neo-adjuvant chemotherapy prevent residual tumors?

MA 16/C is a spontaneous mouse mammary adenocarcinoma. It is hormone-dependent and was injected s.c. into C3H/He female mice on day 0. Tumors were excised on day 15. Neo-adjuvant treatments were applied from day 1 to day 21 for hormonotherapy and immunotherapy and on days 1, 5 and 9 for chemotherapy. Adjuvant treatments were applied from day 21 to day 42 for hormonotherapy and immunotherapy, and on days 21, 25 and 29 for chemotherapy. Mixed (neo-adjuvant and adjuvant) treatments combined the two patterns. Chemotherapy consisted of an oxalato-platinum complex of trans-l-dach (l-OHP) at a dose of 5 mg/kg i.p. Hormonotherapy consisted of the LH-RH agonist (D-Trp6) LH-RH, at a dose of 100 micrograms/kg i.p. Zinc gluconate (6mg/kg per os) and bestatin (6mg/kg per os) were administered as immunoregulators. Under present experimental conditions, surgery alone did not increase the life span. Both neo-adjuvant and adjuvant chemotherapy and neo-adjuvant hormonotherapy, however, when added to surgery, increased survival significantly (p less than 0.02-p less than 0.03).