1. The aims of the study were to assess the pharmacokinetic parameters and the hormonal effects of the slow-release formulation of the somatostatin analogue (SR-L) in normal male volunteers. 2. Eight healthy males were studied. For the determination of basal values blood was sampled before the injection of vehicle and then every other hour for 8 h in order to measure plasma GH, prolactin (PRL), TSH, free thyroxin (fT4), insulin and glucagon levels. Plasma insulin-like growth factor 1 (IGF-1) levels were measured on a single sample. On day 1 of the study, 30 mg SR-L was administered intramuscularly. Blood was drawn just before injection and then every other hour for a period of 8 h. Thereafter, blood was sampled three times a week for 3 weeks in order to measure lanreotide, IGF-1, TSH, fT4 and PRL concentrations. Plasma GH was determined on days 6 and 11 of the study. 3. Plasma lanreotide concentrations rose to 38.3 +/- 4.1 ng ml-1 2 h following injection. The levels then progressively decreased, remaining above 1.5 ng ml-1 until day 11 and reaching 0.92 +/- 0.28 ng ml-1 2 weeks after injection. The apparent plasma half-life and mean residence time were 4.52 +/- 0.50 and 5.48 +/- 0.51 days respectively. 4. By comparison with the control day, plasma insulin concentrations only decreased 2 h following injection, whereas plasma glucagon did not change at any time. 5. Plasma TSH concentrations were significantly (P < 0.01) reduced from 2 h to day 4 following SR-L injection.2+ '

Abdominal Pain↗

PubMed1994

Effects of a slow-release formulation of the new somatostatin analogue lanreotide in TSH-secreting pituitary adenomas.

OBJECTIVE: Somatostatin analogues have been proposed for the treatment of thyrotrophinomas. However, this treatment requires several s.c. injections a day to be effective. The present study had the following aims: (i) appraisal of the efficacy of a single dose of two somatostatin analogues (lanreotide and octreotide) to acutely inhibit TSH secretion of TSH-secreting pituitary adenomas; (ii) assessment of the efficacy of a single injection of a slow release formulation of lanreotide (SR-L) in reducing TSH and thyroid hormone secretions in the same cases; and (iii) evaluation of the effects of SR-L used for 3-6 months on hormone secretion and tumour size. PATIENTS: Four patients with hyperthyroidism linked to a TSH-secreting pituitary adenoma found on pituitary magnetic resonance imaging (MRI) and subsequently proved by immunohistochemistry were studied. METHODS: In the first step of the study the patients received in a random order, vehicle, 150 micrograms octreotide and 500 micrograms lanreotide as a single s.c. injection. Measurements of plasma TSH, free T4 (fT4), free T3 (fT3) and free alpha subunit (fAS) levels were carried out before injection and then every other hour for 8 hours. In the second part of the study, after a basal blood sample (0800 h), each patient received 30 mg lanreotide as an i.m. injection of SR-L. Blood was sampled 2 hours later and then three times a week for 3 weeks in order to measure plasma TSH, fT4, fT3 and lanreotide levels using radioimmunoassays. The patients then received one SR-L injection twice or in one case three times a month for 3-6 months. Plasma TSH, fT4 and fT3 levels were measured monthly and a pituitary MRI was performed at the end of the treatment with SR-L. RESULTS: 500 micrograms lanreotide acutely reduced plasma TSH and fAS levels to the same extent as 150 micrograms octreotide. Two hours after a single i.m. injection of SR-L plasma lanreotide levels reached 7.8 +/- 0.6 micrograms/l and then progressively decreased, being 1.8 +/- 0.2 microgram/l on day 2 and 1.1 +/- 0.3 microgram/l on day 14 after the injection. Plasma TSH level decreased from basal value (mean +/- SEM 4.4 +/- 1.2 mlU/l) within 2 hours (2.5 +/- 0.8 mlU/l) and further declined to 0.8 +/- 0.2 ml/Ul on day 2 following the injection. Depending on the patient, plasma TSH levels were reduced for a period of 6-15 days. Plasma fT4, fT3 levels were normalized on day 2 and remained in the normal range for a period of time of 9-20 days. During long-term treatment, abdominal cramps and diarrhoea appeared, leading to interruption of the treatment in one patient. The treatment was well tolerated in the other three patients. Plasma TSH and thyroid hormone levels progressively decreased during the treatment. No change in adenoma volume was observed after 3-6 months of therapy. CONCLUSIONS: This study shows that (i) lanreotide is able to inhibit acutely TSH secretion in thyrotrophinomas and that a single s.c. injection of 500 micrograms lanreotide is as effective as 150 micrograms octreotide; (ii) SR-L appears to be able to reduce plasma TSH and to normalize fT4 and fT3 levels for 9-20 days in patients with thyrotrophinomas; (iii) this effect is maintained throughout the treatment using two or three SR-L injections monthly for months. These results suggest that SR-L could be used as a treatment of thyrotrophinomas and avoids the drawbacks of the modes of administration of other somatostatin analogues used in such cases.

Adenoma↗

PubMed1994

Transition from normal to premutated alleles in fragile X syndrome results from a multistep process.

In fragile X syndrome, the most common cause of inherited mental retardation, phenotypic expression has been linked to a region containing a repetitive sequence, (CGG)n, that appears to lengthen dramatically in fragile X patients and to show length variation in normal individuals. In order to investigate possible mechanisms responsible for further expansion of CGG in the normal population, we selected 31 normal unrelated X chromosomes carrying either the high-risk DX204-AC155 or DX196-AC151 haplotypes, as defined by the flanking microsatellites, DXS548 and FRAXAC2. Nearly 100% of CGGs with more than 35 repeats were found on DX204-AC155 haplotypes, with a mean length significantly higher and much more variable than in normal individuals carrying other haplotypes including the high-risk haplotype DX196-AC151. These findings suggest that the transition from the normal to the abnormal range occurs by a multistep process, a primary event, such as unequal crossing-over, leading to increased size and moderate instability of the repeat, and from which DNA polymerase slippage could lead to recurrent premutations. Our results also suggest that the upper limit of the normal range is roughly 35 repeats in the fragile X gene. The 36-54 repeats range would define an intermediate allele only observed, up to now, in DX204-AC155 fragile X chromosomes.

Analysis of Variance↗

PubMed1994

Angiopeptin inhibits oncogene induction in rabbit aorta after balloon denudation.

BACKGROUND: Angiopeptin, a synthetic cyclic octapeptide analogue of somatostatin, reduces neointimal hyperplasia after balloon denudation of rabbit aorta if administered before injury. The aim of this study was to analyze the effect of angiopeptin pretreatment on the level of expression of the c-fos and c-jun protooncogenes, early markers of smooth muscle cell proliferation, after balloon denudation of rabbit aorta. METHODS AND RESULTS: For histological analysis of the effect of angiopeptin on neointimal thickening after aortic balloon denudation, rabbits were randomized into three groups: group 1 (controls), twice-daily injections of saline begun 24 hours before balloon denudation (n = 9); group 2, twice-daily injections of angiopeptin 10 micrograms/kg begun 24 hours before balloon denudation (n = 9); and group 3, twice-daily injections of angiopeptin 10 micrograms/kg begun 1 hour after balloon denudation (n = 7). The degree of neointimal thickening 28 days after balloon denudation was significantly less in group 2 than in group 1 (neointimal area: group 1, 0.59 +/- 0.11 mm2; group 2, 0.22 +/- 0.05 mm2; P < .05. Neointima/media: group 1, 0.85 +/- 0.17; group 2, 0.23 +/- 0.05; P < .05). When angiopeptin was started 1 hour after denudation (group 3), however, the neointimal area (0.52 +/- 0.09 mm2) and the neointima/media ratio (0.76 +/- 0.10) were not statistically different from the control group. For analysis of protooncogene induction, rabbits received twice-daily subcutaneous injections of saline (n = 7), angiopeptin 10 micrograms/kg (n = 8), or angiopeptin 100 micrograms/kg (n = 4) begun 24 hours before balloon denudation. The animals were killed 30 minutes after balloon denudation, and total aortic RNA was hybridized with fos and jun probes. Expression of c-fos and c-jun was detected 30 minutes after injury; angiopeptin pretreatment at 20 micrograms.kg-1.d-1 induced a 41% reduction in c-fos expression and a 42% reduction in c-jun expression compared with control animals. The inhibitory effect at the higher dose of angiopeptin was similar. CONCLUSIONS: Our results show that the inhibitory effect of angiopeptin on neointimal thickening is related to events that occur very early after injury and suggest that the inhibition of smooth muscle cell activation may be responsible, at least in part, for this effect.

Animals↗

PubMed1994

Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome.

The impact of a new therapy that includes pressure-controlled inverse ratio ventilation followed by extracorporeal CO2 removal on the survival of patients with severe ARDS was evaluated in a randomized controlled clinical trial. Computerized protocols generated around-the-clock instructions for management of arterial oxygenation to assure equivalent intensity of care for patients randomized to the new therapy limb and those randomized to the control, mechanical ventilation limb. We randomized 40 patients with severe ARDS who met the ECMO entry criteria. The main outcome measure was survival at 30 days after randomization. Survival was not significantly different in the 19 mechanical ventilation (42%) and 21 new therapy (extracorporeal) (33%) patients (p = 0.8). All deaths occurred within 30 days of randomization. Overall patient survival was 38% (15 of 40) and was about four times that expected from historical data (p = 0.0002). Extracorporeal treatment group survival was not significantly different from other published survival rates after extracorporeal CO2 removal. Mechanical ventilation patient group survival was significantly higher than the 12% derived from published data (p = 0.0001). Protocols controlled care 86% of the time. Average PaO2 was 59 mm Hg in both treatment groups. Intensity of care required to maintain arterial oxygenation was similar in both groups (2.6 and 2.6 PEEP changes/day; 4.3 and 5.0 FIO2 changes/day). We conclude that there was no significant difference in survival between the mechanical ventilation and the extracorporeal CO2 removal groups. We do not recommend extracorporeal support as a therapy for ARDS. Extracorporeal support for ARDS should be restricted to controlled clinical trials.

Adult↗

PubMed1994

Slow release lanreotide treatment in acromegalic patients previously normalized by octreotide.

Several clinical studies reported the efficacy of the long-acting SRIH analog, octreotide (Octreotide, Sandoz) in the treatment of acromegaly. Recently, another SRIH analog (BIM 23014, Ipsen Biotech) was shown to decrease plasma GH levels in acromegalic patients. The recent availability of a long-acting formulation of BIM 23014 [slow release (SR) lanreotide] could avoid the inconveniences associated with either repeated sc injections or continuous sc infusions. In this study, we compared the clinical and biochemical efficacies of both drugs in a cohort of 19 acromegalic patients, considered initially as responsive to octreotide and sequentially treated with octreotide (3 sc injections of 100-200 micrograms/day) for 12 months and with SR lanreotide (30 mg, im, every 10 or 14 days) for 6 months. Before octreotide treatment, baseline plasma GH (mean +/- SE of 8 hourly samplings) was 29.0 +/- 10.0 micrograms/L and was lowered to 3.2 +/- .2 micrograms/L during the first 7 h after the first 100-micrograms sc octreotide administration. After 12 months of treatment with octreotide, 14 of 19 patients (74%) were considered normalized, as their mean individual GH profiles and insulin-like growth factor-I (IGF-I) values were within the normal range. After octreotide withdrawal for 1 week, plasma GH and IGF-I levels rose to 18.3 +/- 4.8 and 4.1 +/- 0.4 U/mL, respectively. The first 30-mg SR lanreotide im injection produced an acute suppression of plasma GH levels (mean GH value during the 7 h after the injection, 3.0 +/- 0.4 micrograms/L), not different from results previously observed after the first octreotide injection. After 3 months of treatment with 30 mg SR lanreotide every 14 days, normalization of baseline GH and IGF1 levels was achieved in 6 of 19 patients. Ten patients, who did not achieve normal GH levels, subsequently received a 30-mg SR lanreotide injection every 10 days. Among them, normalization of GH and IGF-I levels occurred in 7 of 10 patients after 3 months of such a regimen. After 6 months of SR lanreotide treatment, 13 of 19 patients (68%) were considered normalized, with mean GH and IGF-I values, respectively, of 3.1 +/- 0.4 micrograms/L and 1.5 +/- 0.1 U/mL. The overall tolerance of both drugs (glucose homeostasis and gallstone formation) was similar.(ABSTRACT TRUNCATED AT 400 WORDS)

Acromegaly↗

PubMed1994

PHYSICAL PROPERTIES OF GAMETES IN THREE SEA URCHIN SPECIES

Physical properties (density in kg m-3, viscosity, sinking rates and dispersion rate) of the gametes and associated spawned materials were measured for three species of sea urchin, Tripneustes gratilla, Echinometra mathaei and Colobocentrotus atratus, from habitats that differ in wave exposure. The gametes of all three species are negatively buoyant, highly viscous and exhibit shear-thinning (a decrease in viscosity with increasing shear rate). Female gametes are more viscous than male gametes, and the viscosity of female gametes differs among the three species. The viscosity of female gametes is highest for C. atratus, the species from habitats most exposed to wave action. Within the species T. gratilla, viscosity of female gametes is higher in habitats exposed to wave action than in more protected habitats. Evidence reported in this paper suggests that the shear-thinning of gametes may provide a performance advantage for these sea urchins. High viscosity of gametes at low shear rates may decrease gamete dispersal upon release and, under certain flow conditions, allow gametes to form strings and clumps on the surface of the urchin. Depending upon the morphology of the surface, these clumps or strings may be retained and fertilization may occur within these clumps or strings. Conversely, low viscosity of gametes at high shear rates decreases the power required to extrude gametes through the gonoduct during spawning.

Journal Article↗

PubMed1994

Pharmacokinetics and efficacy of the long-acting somatostatin analogue somatuline in acromegaly.

The aim of this work was to assess the use of a sustained-release formulation of somatuline, a long-acting analogue of somatostatin, in the treatment of acromegaly. Fifteen patients with active acromegaly, as defined by random growth hormone (GH) levels greater than 10 mU/l, which fail to be suppressed to less than 5 mU/l following an oral glucose load, were studied. Somatuline was administered as an intramuscular injection in two regimens: eight patients were given a single injection of the sustained-release formulation and blood samples taken over the next month for the measurement of both basal levels of GH and the GH response to thyrotrophin-releasing hormone; and eight patients were given injections of the sustained-release formulation at 2-week intervals over a 6-month period and basal plasma GH levels and the GH response to both an oral glucose load and to thyrotrophin-releasing hormone was assessed. Following a single intramuscular dose of the sustained-release preparation, random GH levels were reduced to below 10 mU/l in five patients and by greater than 50% of basal levels in the remainder. The insulin-like growth factor I (IGF-I) levels fell to within the normal range in three patients. In the long-term efficacy study. GH levels were reduced to < 10 mU/l in 7/8 patients. The IGF-I levels were normalized in four patients. Five of the eight patients experienced diarrhoea, two of mild and three of moderate severity; none of the patients withdrew from the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗

PubMed1994

Long-term treatment of acromegaly with the slow-release somatostatin analogue lanreotide.

Thirteen patients with active acromegaly despite previous surgery were treated with 30 mg lanreotide im twice a month for 9 months. In 10 subjects the treatment continued to 19 months. GH serum levels of all patients decreased significantly from an initial value of 32.0 (29.4) micrograms/l [median (standard error of median)] to 10.0 (3.6) and 19.1 (5.7) after 3 and 9 months of treatment, respectively. In the 10 patients with the treatment longer than one year the decrease in GH was from 46.8 (29.4) micrograms/l to 12.5 (5.0) and 16.1 (5.3) after 13 and 19 months, respectively. IGF-I serum levels decreased significantly from 1193 (73) micrograms/l to 782 (99) and 621 (103) after 3 and 9 months, respectively, and were normalized in 3 patients. In the 10 patients treated for longer than one year, levels decreased significantly from 1318 (74) micrograms/l to 653 (170) and 742 (180) after 13 and 19 months, respectively. IGF BP-3 levels were reduced to the normal range in 6 patients and decreased from 8.7 (1.5) mg/l to 6.4 (0.8) and to 5.4 (1.0) after 3 and 9 months, respectively. In the patients with the 19 months treatment the decrease was from 9.3 (1.6 mg/l to 3.9 (0.9) and 4.8 (0.9) after 13 and 19 months, respectively. The IGF BP-3 to IFG I ratio increased in 7 patients. This elevation significantly correlated with the decrease in bioassayable somatomedin. Prolactin serum levels fell in all patients with increased prolactin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗

PubMed1994

Maternal effect and familial aggregation in NIDDM. The CODIAB Study. CODIAB-INSERM-ZENECA Study Group.

Non-insulin-dependent diabetes mellitus (NIDDM) is known to have a strong genetic basis, but the mode of inheritance is still unknown. Recent studies have suggested that maternal inheritance is important; this complicates the transmission pattern of NIDDM. In our study, the familial aggregation of diabetes and the maternal effect were investigated through three generations. The CODIAB Study recruited 536 NIDDM patients between 35 and 74 years of age from 10 diabetes centers in France. Familial aggregation was confirmed: among 218 NIDDM patients, 66% had at least one diabetic relative. Mothers were implicated 2 times more frequently than fathers (P < 0.001). This maternal effect was confirmed because more diabetic cases were noted among maternal than paternal aunts and uncles (P < 0.02). When we considered the next generation, women had more diabetic offspring than men (P < 0.01). Other factors susceptible to modify the familial aggregation were considered. The maternal effect was not significantly related to the patients' ages (P > 0.2). The genetic component was more important when the diagnosis was made earlier, but the maternal effect was homogeneous (P > 0.3). In conclusion, we found a familial aggregation of diabetes that suggests a strong genetic component with a mode of inheritance that may be influenced by a maternal environment.

Adult↗

PubMed1994

Preparation and characterisation of poly(lactic acid) hemoglobin microspheres.

For many years, a lot of research effort has been carried out with a view to preparing blood substitutes. Our group has developed a process of encapsulation of hemoglobin in polylactid microspheres. An aqueous solution of hemoglobin was emulsified into a solution of polymer in methylene chloride to form a W/O emulsion. This primary emulsion was then added to a external aqueous phase under stirring until the evaporation of methylene chloride. The microspheres were separated by filtration and washed with distilled water. Microspheres were spherical and their sizes vary between 10 and 500 microns. More than 80% of the hemoglobin was encapsulated. From the absorption spectra of hemoglobin from microspheres, we did not notice any alteration of the oxygen carrier. The dissociation curve of the hemoglobin demonstrated the permeability of the polymeric wall of these microspheres to oxygen. This curve was relatively sigmoidal and presented a P50 similar to that of free hemoglobin in the same experimental conditions. A cellulose's acetate gel electrophoresis of hemoglobin extracted from the microspheres showed one band that correlates with intact hemoglobin. These results suggest that hemoglobin does not interact chemically with the polymer matrix and that the process of microencapsulation does not alter the hemoglobin molecule.

Blood Substitutes↗

PubMed1994

Flurbiprofen local action transcutaneous (LAT): clinical evaluation in the treatment of acute ankle sprains.

One hundred and thirty-one male and female outpatients, aged 18-70 yr, with acute pain in the ankle joint caused by a post-traumatic sprain, entered a multicentre, randomised, double-blind, parallel-group, study. The patients were assigned to a 40 mg flurbiprofen patch (n = 65) or a non-medicated (but otherwise identical) control (n = 66), 12-hourly over 7 days, and were assessed at entry and after 3 and 7 days treatment. On day 7, spontaneous pain (the prime efficacy parameter), as evaluated by the patient on a visual analogue scale in the physician's office, showed significant improvement in the 40 mg flurbiprofen patch group compared to control (change from baseline) (p = 0.039), a result corroborated by the evaluation of the periarticular oedema: a reduction of 77.4% was observed in the 40 mg flurbiprofen patch group, compared with 63.8% in the control group (p = 0.025). The other selected efficacy criteria showed changes with a trend in favour of the 40 mg flurbiprofen patch but without statistical significance. Two mild and local adverse events were reported by two flurbiprofen patch patients, but neither patients discontinued the treatment prematurely. Physicians and patients found the flurbiprofen patch to be efficacious and well tolerated. Compliance was excellent in both groups. The efficacy and tolerability of the 40 mg flurbiprofen patch are therefore confirmed in the treatment of acute ankle sprains.

Acute Disease↗

PubMed1994

[Treatment of central precocious puberty with sustained-release triptorelin].

Central precocious puberty is defined as the appearance of morphological and biological changes induced by the early maturation of the hypothalamic-pituitary-gonadal system before eight years of age in girls and ten years of age in boys. This early onset of the gonadotropin-releasing hormone pulse generator activation leads to secretion of gonadal steroids and therefore to the development of secondary sexual characteristics. The aim of medical treatment is to suppress the secretion of sex hormones. A dramatic improvement has been achieved with the development of gonadotropin releasing hormone agonists which induce a reversible suppression of gonadotropin secretion. Since 1986, triptorelin (Decapeptyl) (D-Trp6-LHRH) has been available for this indication as a sustained-release formulation allowing an intramuscular injection of 3.75 mg every 4 weeks. Results published up to now concern 352 children (325 girls and 27 boys). The pituitary-gonadal suppressive effect has been confirmed. The complete suppression of gonadal secretions induced a rapid regression of secondary sexual characteristics as early as the 3rd month of therapy, and decreased the growth rate acceleration which normalizes during the 3rd year of therapy. The progression of bone maturation clearly slowed down at the end of the first year of treatment so the final height prognosis significantly improved. Whatever length of the treatment period, the reversibility of the suppressive effect of triptorelin has been demonstrated. Puberty resumed 3 to 9 months after stopping the treatment. Tolerance of the medication was excellent. The rare side effects were minor and never led to treatment discontinuation: headaches (8% of the cases), hot flushes (12% of the cases). The percentage of drop out was very low.

Delayed-Action Preparations↗

PubMed1994

Ethical implications of standardization of ICU care with computerized protocols.

Ethical issues related to the use of computerized protocols to control mechanical ventilation of patients with Acute Respiratory Distress Syndrome (ARDS) are identical to the ethical issues surrounding the use of any therapy or intervention. Four ethical principles must be considered: nonmaleficence, beneficence, autonomy, and distributed justice. The major ethical challenges to computerized protocol use as a specific application of clinical decision support tools are found within the principles of nonmaleficence and of beneficence. The absence of credible outcome data on which ARDS patient survival probabilities with different therapeutic options could be based is a constraint common to most ICU clinical decision making. Clinicians are thus deprived of the knowledge necessary to define benefit and are limited to beneficent intention in clinical decisions. Computerized protocol controlled decision making for the clinical management of mechanical ventilation for ARDS patients is ethically defensible. It is as well supported as most ICU therapy options.

Clinical Protocols↗