Biomedical subjects
Publications and source records attributed to D Lacoste.
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The authors report two cases of hematophagic histiocytosis in HIV positive patients. In the first case, a patient with Kaposi sarcoma and Mycobacterium avium infection had a rapidly deteriorating course with progressive pancytopenia and death, as generally described in the literature. In the second case, hematophagic histiocytosis appeared during HIV primo infection and reversed spontaneously. Although few cases of hemophagocytic syndrome have been reported in HIV positive patient, it could represent an underestimated cause of pancytopenia. Both opportunistic microorganisms and HIV are able to cause hematophagic histiocytosis.
The characteristics of 34 HIV-associated non Hodgkin's lymphomas diagnosed and treated at Bordeaux hospitals are described. The patients represented 7% of the AIDS cases observed in the Bordeaux area. HIV-lymphomas were almost always high-grade malignancies, usually disseminated (70%) with extranodal disease at presentation (91%) primarily in the bone marrow, meninges, gastrointestinal tract and liver. Twenty-eight patients were treated with different chemotherapy protocols or radiation therapy alone. Complete remission was achieved in 11 patients and partial remission in 3. The median survival was 3.9 months. Despite utilization of low-intensity chemotherapy regimens, opportunistic infections were not prevented. The only factor that accurately predicted complete remission was the WHO performance index. The total number of CD4-positive lymphocytes, the Ann Arbor stage and the WHO performance index were prognostic factors influencing survival. These results justify the use of high-intensity regimens, but only for patients without opportunistic infection and with a WHO performance index below 3.
OBJECTIVES: To study the epidemiological trends, clinical patterns, evolution and prognosis of HIV infection in women. DESIGN: Cohort study of 1816 HIV-infected patients. RESULTS: Up to 1 January 1991, 483 (26.6%) of the patients reported to the Groupe d'Epidemiologie Clinique du SIDA en Aquitaine surveillance system were women. The male-to-female ratio has decreased progressively (3.4:1 in 1985; 2.7:1 in 1990) over time. Fifty per cent of HIV-infected women are or have been intravenous drug users (IVDU). The proportion of heterosexually acquired HIV infection increased from 11.6 to 34.6% over the last 5 years; 46.9% of the women infected through heterosexual intercourse reported sexual contacts with male IVDU. Excluding Kaposi's sarcoma, no significant difference was observed between men and women in the overall distribution of AIDS-defining events. The observed trend of a slower progression to AIDS in women, compared with men, disappeared when controlling for prognostic variables. However, female sex significantly enhanced survival after AIDS diagnosis in multivariate analysis (relative risk, 2.7; 95% confidence interval, 1.1-6.2). CONCLUSION: Early diagnosis of HIV infection in female patients and prevention of HIV infection among women is now a priority for public health interventions, both in industrialized and in developing countries.
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We studied the relationship between circulating androsterone glucuronide, androstane-3 alpha, 17 beta-diol glucuronide and androstane-3 beta, 17 beta-diol glucuronide concentrations and adrenal as well as testicular C-19 steroids in men. Among the three 5 alpha-reduced steroid glucuronides, androsterone glucuronide is the predominant C-19 steroid glucuronide measured in plasma and its levels are markedly elevated compared to those of the non-conjugated steroid. The marked rise in testosterone during puberty was strongly correlated with the increase in both androsterone glucuronide and androstane-3 alpha, 17 beta-diol glucuronide, thus suggesting that testicular C-19 steroids are the main precursors of the steroid glucuronides. We also found that the presence of testicular androgen in plasma contributes to approx. 70% of plasma androsterone glucuronide and androstane-3 alpha, 17 beta-diol glucuronide. Our data suggest that the adrenal C-19 steroids remaining in circulation after castration in men are converted into potent androgen which are then glucuronidated by UDP-glucuronyltransferase. We also demonstrated that the human prostate cell line LNCaP is capable of converting to a large extent androstenedione into androsterone glucuronide. Our data further confirm that glucuronidation is a major pathway of steroid metabolism in steroid target tissues.
A hospital-based surveillance of HIV infection was implemented in the Bordeaux Regional University Hospital (France). This reporting system, initiated by the Groupe d'Epidemiologie Clinique du SIDA en Aquitaine, identified and followed-up 89 adult patients with transfusion-associated HIV-1 infection (7.2% of all reported cases). Contamination occurred between August 1981 and June 1985 and diagnosis was made between 1985 and 1989. By 30 June 1990, 43 patients (48.3%) had full-blown AIDS, and 28 of them had died. The mean follow-up period was 66 months (s.d. 16 months). The mean incubation period, i.e. The time interval between the contaminating transfusion and the development of full-blown AIDS, was 62 months [median 73 months; 95% confidence interval (CI) 66-82 months]. Five years after contamination, the cumulative probability of reaching the AIDS stage was 34.2% (95% CI 20.3-49.3%), and the probability of survival was 81.7% (95% CI 72.5-90.0%). From this surveillance system we estimate that in south-western France at the end of 1989 the cumulative incidence of transfusion-associated HIV-1 infection was at least 126 cases (45.6 per million inhabitants). Although we anticipate an increase in transfusion-associated AIDS cases over the next 5 years, there have been no reports of contamination after 1 August 1985, when systematic screening of HIV antibodies was implemented in French blood banks. This confirms the efficacy of screening in countries like France where the risk of contamination through blood products is now minimal.
The plasma kinetics of [D-Trp6, des-Gly-NH2(10)]gonadotropin-releasing hormone (GnRH) ethylamide was assessed in eight dogs over a period of 8 h after rapid intravenous or subcutaneous injection. Each animal received doses of 0.2, 2, and 20 micrograms/kg body wt iv and 1 and 10 micrograms/kg body wt sc. A two-compartment structure, to which a source compartment was added to represent the subcutaneous route, adequately fits the five kinetics when the apparent volume of distribution follows a plasma concentration-dependent sigmoid function. Despite the nonlinearity, the apparent volume of distribution can be approximated by a constant value of 280 ml/kg body wt for the dynamics corresponding to the three lowest and more physiological doses. The metabolic clearance rate is 4.63 ml.min-1.kg body wt-1. The two exponential components that characterize the two-compartment structure are equal to 0.0348 +/- 0.0053 and 0.00470 +/- 0.00060 min-1, respectively. The agonist injected subcutaneously diffuses to plasma at a fractional rate of 0.0265 +/- 0.0029 min-1. Disposal occurs at a maximal rate of 0.017 and 0.0055 min-1 of the amount of agonist present in the central and peripheral compartments, respectively. The highest fractional exchange rate between compartments reaches 0.01 min-1. As simulated with the model, a continuous infusion of 4.63 ng.min-1.kg body wt-1 leads to a steady state of 1 ng/ml plasma; 90% of that level is reached 7 h after the onset of the subcutaneous input signal. The kinetics of plasma [D-Trp6, des-Gly-NH2(10)]GnRH ethylamide is many times slower than that of the native hormone and of the other GnRH agonists.
The kinetics of plasma immunoreactive [D-Trp6,Des-Gly-NH2(10)]GnRH ethylamide, a potent GnRH agonist, was assessed in nine normal adult men over a period of 24 h after a rapid sc injection of 1 or 10 micrograms peptide/kg BW. The specific RIA of the GnRH agonist is characterized by a minimum detectable dose of 5.0 +/- 0.5 pg peptide, while the midrange effective dose is 73 +/- 8 pg. The within- and between-assay coefficients of variation range from 2-7% and from 10-15%, respectively. When the volume of the central compartment is set proportional to the logarithm of the plasma concentration of the GnRH agonist, the time courses of both doses are statistically well represented by a two-compartment model to which a source compartment is added to represent the sc route of administration. The sc diffusion to plasma is 5 times faster than any other fractional transport rate of the model (5%/min). Disposal occurs at a maximum rate of 0.55%/min from the central compartment, which includes plasma, and 0.25%/min from the peripheral compartment. As simulated with the model, 90% of the steady state is reached 13 h and 45 min after the onset of a sc continuous infusion. A molecule spends, on the average, from 6 h to 9 h and 45 min in the whole organism; 30-50% of this period is accounted for by residence in the central compartment. The volume of the central compartment reaches 208 mL/kg BW, and the MCR is estimated at 1.18 mL/min.kg BW for a steady state of 1 ng/mL plasma. The plasma dynamics of [D-Trp6,Des-Gly-NH2(10)]GnRH ethylamide in men are at least 10 times slower than those reported for the natural GnRH, thus indicating the relevance of its clinical use in suppressive therapy of LH secretion.
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This study examines the effect of treatment with controlled-release poly(DL-lactide-coglycolide) microsphere formulations of the LH-RH agonist [D-Trp6, des-Gly-NH10(2)]-LH-RH ethylamide (LH-RH-A) designed to release about 100 or 200 micrograms of the peptide per day for 3, 5 or 6 months in male dogs. Plasma levels of testosterone and LH-RH-A were measured at 2-day intervals. After the first injection of the 100-micrograms/day formulation, plasma testosterone increased from 1.6 +/- 0.2 to 3.5 +/- 0.6 ng/ml for 5-7 days before decreasing and remaining at 0.05 +/- 0.008 ng/ml for approximately 150 days (5 months). After two months of recovery, microspheres designed to release 100 micrograms for 6 months of LH-RH agonist per day were then injected. Plasma testosterone levels showed an elevation from 1.5 +/- 0.5 to 4.7 +/- 2.0 ng/ml during the first few days before gradually decreasing to castration levels for 200 days (6 months). One month later, plasma testosterone had returned to normal levels. When microspheres designed to deliver an average of 200 micrograms per day of the peptide for 3 months were injected in another series of animals, castration levels of plasma testosterone were maintained for 95 days with a progressive increase to normal values at later time intervals. The animals of the first series of experiments were then sacrificed after 4 months of recovery following maintenance of plasma testosterone at castration levels for a total period of 11 months. The testes, prostate and pituitary gland were kept for histological examination which was completely normal in all tissues. The efficacy and excellent tolerance of the controlled-release form of LH-RH-A as inhibitor of the pituitary-gonadal axis strongly support the use of such long-term controlled-release formulations of LH-RH agonists for the treatment of sex steroid sensitive diseases.
Adult male mongrel dogs were treated with the LHRH agonist [D-Trp6, des-Gly-NH10(2)]LHRH ethylamide, aminoglutethimide, ketoconazole or flutamide alone or in combination for 21 days before measurement of steroid levels in the testes, prostate, adrenals and serum. Ketoconazole alone caused a marked stimulation of the intra-testicular concentration of pregnenolone, 17OH-pregnenolone, progesterone and 17OH-progesterone with no or little change of androstenedione, testosterone and dihydrotestosterone. Aminoglutethimide caused a 30-95% inhibition in the concentration of all steroids in the tests while treatment with the LHRH agonist caused a near complete inhibition of all testicular steroids. When administered concomitantly with the LHRH agonist, ketoconazole partly prevented the inhibitory effect of the LHRH agonist on testicular steroid levels. Serum levels of dehydroepiandrosterone, androst-5-ene-3 beta,17 beta-diol, androstenedione and androstane-3 alpha, 17 beta-diol were 75 to 95% inhibited by the LHRH agonist while serum testosterone and dihydrotestosterone concentrations were reduced below detection limits by the same treatment. Moreover, treatment with the LHRH agonist caused a 70-95% reduction in the intraprostatic concentration of testosterone and dihydrotestosterone in all the groups although maximal effect was observed when the LHRH agonist was combined with any of the three other agents. The present data show that while treatment with ketoconazole, aminoglutethimide or Flutamide alone has only partial inhibitory effects on androgen levels, combination with an LHRH agonist provides maximal inhibition. In addition to its direct blockade of the androgen receptor, some of the effect of Flutamide could be related to its blockade of testicular 3 beta-hydroxy-steroid dehydrogenase activity.
Treatment of adult dogs for 15 days with the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (50 micrograms daily, s.c.) causes a 41.6% inhibition of prostatic weight while a 55% inhibition is achieved when the antiandrogen flutamide (250 mg, twice daily) is given in association with the LHRH agonist (p less than 0.01). At histology, the glandular acini in the prostate of animals treated with the combination therapy are more atrophied than with either treatment used alone. A 2-week treatment with the LHRH agonist is characterized by two distinct phases, namely a stimulation of testicular androgen secretion between days 0 and 8 followed by an inhibition between days 9 and 15. During the inhibitory phase, the concentration of all testicular steroids progressively decreased to castration levels, thus indicating that the differences observed at the prostatic level at 2 weeks are due to the inhibition of androgen action by the antiandrogen flutamide during the period which precedes complete chemical castration by the LHRH agonist. Flutamide administered alone had no effect on plasma or prostatic steroid levels measured after 2 weeks and it did not interfere with the potent and generalized inhibitory effect of the LHRH agonist on the serum and prostatic concentration of all steroids measured.(ABSTRACT TRUNCATED AT 250 WORDS)
This study is a multicentre, double-blind, double-dummy, two-way, parallel group comparison of the efficacy and safety of rioprostil and ranitidine in the treatment of active gastric ulcer. Ninety-one patients with gastric ulcer are randomly allocated to treatment with either rioprostil 300 micrograms b.d., or ranitidine, 150 mg b.d. The duration of treatment is 4 weeks, or 8 weeks for the patients who are improved but not healed at 4 weeks. Clinical, endoscopic and laboratory assessments are made before treatment, and after each treatment period. Therapeutic success is defined as complete endoscopic healing of the ulcer. At the end of the treatment period, either 4 or 8 weeks, healing rates are 69% in the rioprostil group, and 66% in the ranitidine group; this difference is not significant (p = 0.86). After the first 4 weeks of treatment the healing rates are 44% and 55% in the rioprostil and ranitidine groups, respectively. The incidence of adverse effects is 22% in the rioprostil group, and 7% in the ranitidine group (p = 0.036). Diarrhoea is the most common side effect (12%), but is usually intermittent and mild. We conclude that rioprostil, 300 micrograms b.d., for up to 8 weeks is as effective as ranitidine, 150 mg b.d., in the treatment of benign gastric ulcer.
The authors report the case of a 21-year old, non-immunocompromised girl who presented with severe acute heart failure associated with Toxoplasma infection. The outcome was favourable: cure without sequelae was obtained in a few months with a symptomatic and specific treatment consisting of spiramycin and methylprednisolone. This case is interesting for several reasons. The occurrence of such an acute heart disease is extremely rare in patients with toxoplasmic myocarditis, and so is the presence of a septal focus suspected on the basis of a predominantly septal hypokinesia at echocardiography and of enzymatic changes. The development of an acute heart failure should suggest a diagnosis of toxoplasmic myocarditis, which is rare but important since a specific treatment is available.
The authors report bilateral secondary tumors of the kidney in two patients: one previously treated for an epidermoid tumor, the other for an anaplastic bronchial tumor. In both patients, clinical and radiological features were those of a malignant process. Scan-guided percutaneous fine needle aspiration provided the material necessary to make a definitive cytological diagnosis; it was thus possible to assess the malignancy and recognize the histological type of lesions.
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Up to day 6 of treatment of adult dogs, daily subcutaneous administration of 50 micrograms of the LHRH agonist [D-Trp6, des-Gly-NH2-10]LHRH ethylamide causes up to a 3-fold increase in serum testosterone (T) concentration which is followed by a progressive decrease to castration levels (less than or equal to 0.2 ng/ml) at later time intervals (up to 21 days, the last time interval studied). Both aminoglutethimide and ketoconazole, two inhibitors of steroid biosynthesis, cause a 30-40% rise in serum T when administered alone. However, either drug administered in combination with the LHRH agonist completely blocks the transient rise in serum T observed when the LHRH agonist is administered alone. On the other hand, the LHRH agonist prevents the secondary rise in steroid secretion observed when either of the two inhibitors of steroid secretion is used alone. Administration of the pure antiandrogen Flutamide alone or in combination with LHRH-A and an inhibitor of steroid biosynthesis does not influence serum T levels. When the serum levels of pregnenolone, 17-OH-pregnenolone, progesterone, 17-OH-progesterone, dehydroepiandrosterone (DHEA), androstenedione (delta 4-dione), androst-5-ene-3 beta, 17 beta-diol (delta 5-diol), T, dihydrotestosterone (DHT), androstane-3 alpha, 17 beta-diol, androstane-3 beta. 17 beta-diol and 17 beta-estradiol (E2) are analyzed in detail, it can be seen that both aminoglutethimide and ketoconazole not only prevent the rise in serum steroids observed during the first 8 days of treatment with the LHRH agonist but that both compounds enhance the inhibitory effect of the LHRH agonist at later time intervals. A predominant inhibitory effect of ketoconazole is exerted on 17,20-desmolase activity. Aminoglutethimide has little influence on the loss of serum LH bioactivity induced by the LHRH agonist while ketoconazole stimulates the concentration of serum bioactive LH in the absence or presence of simultaneous treatment with the LHRH agonist. The present data clearly demonstrate that aminoglutethimide or ketoconazole can prevent the rise in serum androgens accompanying the first days of treatment with an LHRH agonist in the dog. Moreover, after 3 weeks of treatment, the inhibitory effect of the LHRH agonist on serum androgen levels is enhanced by addition of aminoglutethimide or ketoconazole. Moreover, Flutamide does not interfere with the inhibitory action of the LHRH agonist, aminoglutethimide or ketoconazole, thus suggesting that maximal inhibition of androgen action is likely to be achieved by a combination of these drugs.