Pharmacokinetics, pharmacodynamics, and safety of a platelet GPIIb/IIIa antagonist, RGD891, following intravenous administration in healthy male volunteers.

The pharmacokinetics (PK), pharmacodynamics (PD), and safety of a platelet GPIIb/IIIa receptor antagonist, RGD891, and its active metabolite, RGD039, were evaluated after administration of various intravenous regimens of RGD891 to healthy male volunteers in two Phase I studies. Plasma and urine concentrations of RGD891 and RGD039 were measured by validated LC/MS/MS methods with minimum quantifiable limit (MQL) of 1 ng/mL and 10 ng/mL, respectively. PD activity was assessed by percent inhibition of ADP (20 microM)-induced platelet aggregation. Following intravenous dosing, the RGD891 was the predominant compound in plasma. The PK of RGD891 was dose independent associated with modest between-subject variability. RGD891 was rapidly cleared (Cl, 11.2-15.5 L/h), exhibited a restricted distribution (Vss, 23.0-25.9 L) and a short terminal t1/2 lambda z (1.2-2.1 h). Plasma concentrations of the metabolite (RGD039) increased with dose but were variable. RGD039 had longer t1/2 lambda z of 4.5 to 6.6 hours. Renal excretion of unchanged drug played an important role in the elimination of the parent compound. Both RGD891 and RGD039 exhibited renal clearance values that were comparable to the glomerular filtration rate. Intravenous administration of RGD891 effectively inhibited platelet aggregation in a dose-dependent and reversible manner. At the highest dose (60 micrograms/kg bolus dose + 336 micrograms/kg 8-h infusion) > 90% inhibition of platelet aggregation was achieved. PD activity was primarily attributed to the parent compound. Inhibition of platelet aggregation was dependent on the anticoagulant present, with samples containing PPACK showing 20% to 30% lower activity as compared to citrate. RGD891 was safe and well tolerated across the various regimens studies.

Selection of healthy volunteers for phase I studies.

Healthy volunteers selection is one of the foundations for phase I results. Safety for volunteers, quality of data and reliability for study results depend on healthy volunteers selection. The selection aim is not to choose normal subjects but to exclude every people with diseases or risk factors which could result in increased danger for themselves or confuse the interpretation of study results. The selection procedure needs to define a list of relevant disease to be excluded depending on phase I objectives (tolerability, pharmacokinetic, pharmacodynamic). The choice of diseases is based on frequency, potential risk for the subjects or for the study. The selection is mainly a clinical process but because of asymptomatic diseases a laboratory screening is necessary and useful. This laboratory screening requires that a basic common list of relevant tests be determined and an appropriate method of cut-off point determination based on an evaluation of the risk of disease. According to the drug or the objective of the study adaptation of the procedure must be carried out. The percentage of erroneous inclusion of subjects is the best validation criterion for selection. The use of such a selection methodology by the author's group in Lyon results in a 50% exclusion for 494 first seen subjects with only 1% erroneous inclusion and 6% exclusion for laboratory test anomalies.

Bioavailability Study of Menorest®, a New Estrogen Transdermal Delivery System, Compared with a Transdermal Reservoir System.

The aim of this study was to compare the bioavailability and plasma profiles of estradiol and estrone after repeated applications of 2 types of estradiol transdermal systems: a new adhesive matrix system (Menorest®) compared with a reference membrane/reservoir system (Estraderm®) and to evaluate their short term safety. This was an open, randomised, crossover study, with 2 treatment periods of 10.5 days separated by a 10-day washout period and with a 1-week follow-up. Participants were studied at Institut Aster, Paris, and Association de Recherche Thérapeutique (ART), Lyon, France, and included 31 healthy postmenopausal women, all volunteers aged between 49 and 67 years (mean 58 years). Each transdermal system was applied for three successive 3.5 day-wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, before and after the third application of each transdermal system at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. Although the extent of availability [area under the plasma concentration-time curve (AUC) and average plasma concentration (Cav)] was similar with both transdermal systems, their pharmacokinetic profiles were different, with Menorest® producing less fluctuating and more sustained plasma estradiol levels than the reference system. The mean estradiol to estrone Cav ratio was similar with the 2 transdermal systems and in the physiological range of premenopausal status. The incidence of adverse events was similar for both treatments, but a lower incidence of local erythema was observed with Menorest® (8.9%) than with the reference system (18.3%). In conclusion, during the entire wear period, Menorest® produced more sustained plasma estradiol levels with less fluctuations (40 to 72 ng/L) than the reservoir/ membrane system (18 to 102 ng/L). Menorest® gave estradiol plasma levels approximating the concentrations observed during the early to mid-follicular premenopausal stage, with a 2-fold lower incidence of erythema than with the reservoir/membrane system.

[Critical value of bilirubin in the selection of healthy volunteers in for phase I]. / Valeur seuil de la bilirubine pour la sélection des voloñtaires sains en phase I.

10% of young male healthy volunteers have a total bilirubin value over 20 mumol/l; thus such a value appears not relevant as screening cut off point in clinical pharmacology. This study was intended to confirm if a 27 mumol/l cut off point previously defined by the authors does not support a risk. This study dealt with 487 subjects who had together measurements of total bilirubin value and lab. tests of liver cytolysis, cholestasis or hemolysis during the selection process. 48 subjects (9.8%) had a total bilirubin value over 20 mumol/l. Correlation tests do not provide arguments of cytolysis, cholestasis or hemolysis and there was no argument in favor of Gilbert's syndrome. Out of 48 hyperbilirubinemic subjects only 22 were included in clinical pharmacology studies. In more than 60%, the total bilirubin value returned to normal spontaneously and in no case appeared a significant clinical, biological, pharmacokinetic or dynamic abnormality. Except a possible increase of slow acetylor frequency, the medical literature analysis does not show any relevant modification in metabolism, pharmacokinetics or pharmacodynamics until a 40 mumol/l value of total bilirubin. Thus, the 27 mumol/l value of total bilirubin previously proposed is confirmed as a useful limit that does not lead to an additional risk.

[Primary biliary cirrhosis and idiopathic thrombopenic purpura. A new association]. / Cirrhose biliaire primitive et purpura thrombopénique idiopathique. Une association inédite.

A case of primary biliary cirrhosis with stage III histological changes associated with an asymptomatic thrombocytopenic purpura with raised antiplatelet antibody levels is described. This new association of two conditions in which an autoimmune participation is generally accepted suggests a predisposition to this form of disease and/or the intervention of common trigger factors; however, an analysis of known etiological mechanisms does not exclude the possibility of a fortuitous association.

[Myelopathy revealing lupus. Two cases and review of the literature]. / Myélopathie révélatrice d'un lupus. Deux observations et revue de la littérature.

INTRODUCTION: Myelopathy is a rare manifestation of systemic lupus erythematosus, occurring most often during the course of the disease. EXEGESIS: We report two cases of women with myelopathy as the first manifestation of systemic lupus erythematosus; both had an unusual course. We review the literature for previously reported cases. CONCLUSION: The clinical presentation of myelitis is heterogeneous. Usually, neurologic deficits evolve within a few hours (typically acute transverse myelitis) and outcome is usually poor. However, chronic or recurrent transverse myelitis has also been reported, including relapsing myelitis that resolved spontaneously. Myelopathy can be the first manifestation of the disease and this might be more common than initially thought. Magnetic resonance imaging (MRI) findings depend on the timing of the examination and the stage of the disease; the MRI may therefore be normal. An association with optic neuritis is frequently reported in the literature and differential diagnosis with multiple sclerosis may be difficult. Overlapping features between both diseases have been termed "lupoid sclerosis" and are actually classified as demyelinating syndromes associated with lupus. Myelopathy does not appear to be consistently associated with antiphospholipid antibodies, as has been previously suggested. The best treatment protocol has not been determined; however, in recent years, pulses of methylprednisolone and cyclophosphamide have gained acceptance by most authors.

[Diagnostic significance of low thyrotropin in internal medicine]. / Signification diagnostique d'une hormone thyréotrope abaissée en médecine interne.

In an attempt to determine the significance of low plasma thyrotropin (TSH) concentrations in internal medicine and the usefulness of systematic TSH assays in hospitals, 732 consecutive TSH measurements were performed in first-admission patients. TSH concentrations below 0.15 mU/l were found in 33 patients (4.5%) divided into 4 groups: a) in 5 patients a second assay made within 10 days of the first one showed no fall in TSH levels; b) 5 patients had known endocrine disease; c) in 8 patients hyperthyroidism could be asserted; the diagnosis had not been suspected in 3 elderly women and 1 pregnant women; d) 15 patients remained with low TSH concentrations but had normal free T3 and free T4 levels; in this group a goitre was detected in 7 patients and 8 had a severe chronic disease. These results showed that a TSH concentration below 0.15 mU/l corresponded to hyperthyroidism in less than one out of three patients in this population and that the 0.07 to 0.15 mU/l range is particularly misleading. A second TSH assay, free T3 and free T4 measurements ant thorough investigations in search of a goitre must be made. Severe organic diseases and several drugs may induce a fall in TSH. All considered, the 1% prevalence of hyperthyroidism in this population does not justify systematic TSH assays, but in subjects over 60 years of age, the clinical manifestations of hyperthyroidism may be misleading or unrecognized, and TSH assays should be widely performed.

A juvenile case of cerebellar arteriovenous malformation with gradual onset of dysphoria and headache.

A 25-year-old woman was admitted because of frequent vomiting and headache which had lasted over one week. She had initially clear consciousness but slowly progressive mild headache and dysphoria. Emergency cranial CT revealed a 4 cm haematoma in the left cerebellar hemisphere. CT angiography showed a 2×2 cm nidus of an arteriovenous malformation (AVM) in the left hemisphere fed from the left posterior inferior cerebellar artery and draining into the inferior hemispheric vein. We performed a surgical resection of the AVM after decompression therapy to counteract the brain oedema. She recovered completely without any neurological deficits. This case recalls the importance of cooperation between diagnostic neuroradiology and neurosurgery in emergency, considering AVM, even if infrequent, among possible diseases.

[Hypophosphatemia. A review (author's transl)]. / Les hypophosphorémies.

Hypophosphatemia with or without phosphorus depletion can be observed in various diseases--particularly diabetic ketoacidosis, respiratory alkalosis, alcoholism, parenteral nutrition and hyperalimentation--and may cause serious neurologic, muscular, and hematologic disorders. This review summarizes the knowledges about hypophosphatemia--etiological mechanisms, pathophysiology and therapeutic modalities--and suggests that some place be reserved for serum phosphate in systematic and emergency panels of blood tests.

Laboratory screening method for selection of healthy volunteers.

The aim of laboratory screening in Phase I is to exclude subjects with subclinical illness, who might be at increased risk in the study, and who might also adversely influence interpretation of the results. A new method for laboratory screening, based on Bayesian probability theory, is proposed, which consists of: 1. Drawing up a list of diseases to be excluded. 2. Defining for each disease, the maximum acceptable risk that an included subject could be affected by it. 3. Identifying one test for each disease. 4. Using a contingency table to calculate the specificity of the test and integrating the estimated prevalence of the disease from epidemiological data. 5. Applying the percentage obtained by the calculation of specificity to the previously determined distribution of values in the volunteer population to identify the threshold value for inclusion. Use of this deductive method in screening volunteers for Phase I trials affords increased security of selection, while reducing the number of non-pertinent exclusions because of laboratory findings.

[Complication caused by abuse of alkalies in the treatment of ulcers]. / Accident lié à l'abus des alcalins dans le traitement des ulcères.

The authors report the case of a 57 year old man who had taken for several years large quantities of alkaline drugs to relieve pain due to a gastric ulcer. This man presented acute digestive symptoms, and a confusional syndrome explained by various metabolic disturbance and especially hypercalcemia at 145 mg. Stopping the alkalis permitted within a few days the disappearance of the clinical symptoms and the correction of the laboratory disturbances. In the light of this case, the authors study the main clinical cases which have been described either in their acute form or in their chronic form (Burnett's syndrome). They discuss above all the physiopathology of these manifestations and it seems to them that the hypercalcemia is more important than the alkalosis. It remains to be explained why only a small number of subjects are exposed to these metabolic complications. There seems to be an individual hypersensitivity for under normal conditions, excess calcium is not sufficient to induce hypercalcemia.