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.

Acute, recurrent fosfomycin-induced liver toxicity in an adult patient with cystic fibrosis.

We report a very unusual adverse effect--fosfomycin-induced repeat liver toxicity--in a female adult with cystic fibrosis (CF).

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.

[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.

Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials.

OBJECTIVE: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event limits for analysis during study implementation. SUBJECTS AND METHODS: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5-97.5% interval of distribution of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had been specified in previous articles. RESULTS: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal values and the 2.5-97.5% interval for each laboratory parameter. CONCLUSION: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies.

Adverse events in phase-I studies: a report in 1015 healthy volunteers.

OBJECTIVE: This report describes all clinical, laboratory and electrocardiographical adverse events detected in healthy volunteers in a phase-I centre over a 10-year period: 54 phase-I studies are involved, including 1015 healthy young volunteers (993 males) who received 1538 treatments (23 different active drugs or placebo) corresponding to 12143 days of follow-up. This updates a similar report published previously in the European Journal of Clinical Pharmacology. METHODS: Adverse events were defined as all events noted in case-report forms. Incidence of adverse events was defined as the ratio between the number of adverse events and the number of follow-up days. Severity was rated as death, life-threatening, severe or minor. Incidences or occurrence rates were compared using the Chi-squared test with Yates' correction. RESULTS: The overall incidence of adverse events was 12.8% with a significant difference between active-drug (13.7%) and placebo (7.9%) treatments. There were 1558 adverse events of 110 distinct kinds. Only for three (headache, diarrhoea and dyspepsia) was the incidence superior to 10 per thousand. Most of these adverse events were also observed with placebo. Ninety-seven percentage of adverse events were of minor intensity; forty three (3%) were rated as severe, including nine worrying cases - six malaises with loss of consciousness, one atrial fibrillation, one hyperthyroidism and one bicytopenia. Some of the adverse events were not related to the tested drugs, but to a vagal reaction or to study conditions. There was no death or life-threatening event. The global rate of occurrence was one adverse event per treatment, one and a half per subject and one out of eight follow-up days. No difference in the overall incidence with placebo was observed between the two successive 5-year periods. CONCLUSIONS: This report confirms that adverse events in phase I studies are very common, usually of minor intensity and rarely severe; even though exceptional, life-threatening adverse events are possible. Adverse events occurring in phase I are rarely published, leading to lack of information. Thus, authors invite clinical research organization (CROs) and phase-I centres to regularly publicise at least severe adverse events; they also suggest that the life-threatening adverse events reported to health authorities should be publicised, for example by the World Health Organization (WHO).

Critical limits to define a lab adverse event during phase I studies: a study in 1134 subjects.

OBJECTIVE: The first goal of phase I drug development is the determination of maximal tolerated dose, which must be established by case-by-case analysis, sometimes using a laboratory adverse event. Since no accurate rule defining lab adverse events, has been validated yet, we propose a new "combined method" based on combination of two thresholds: inclusion values and magnitude of variation. Using this combined method, the label "lab adverse event" is applied if any lab value exceeds the inclusion threshold and is associated with a variation from baseline exceeding the variation threshold defined from reference change limit. Thus, this study aimed to test this combined method on a large healthy volunteer population, studied in 19 phase I centres worldwide, and on five lab parameters: alanine amino transferase, aspartate amino transferase, alkaline phosphatases, creatinine and polymorphonuclear leukocytes. METHODS: The inclusion threshold from each center was used. Reference change limits were defined from volunteers previously included in comparable studies and were expressed as absolute values: increases of 10 IU.l-1 for alanine amino transferase or aspartate amino transferase, 15 IU.l-1 for alkaline phosphatases, 15 mumol.l-1 for creatinine and a 0.34 10(9).l-1 decrease for polymorphonuclear leukocytes. Comparison between the "combined method" and a normal range method was made using positive predictive value and a ratio between relevant and irrelevant results. This application was implemented in all young healthy volunteers (1134) included in 38 phase I studies sponsored by Rhone Poulenc Rorer from 1991 to 1993. RESULTS: Seventy seven subjects (6.7%) were indicated in final study reports as having a lab adverse event (reference group). Of 179 subjects with lab abnormalities defined by the normal range method, 77 belonged to the reference group, inducing a poor 0.43 positive predictive value. Of ninety subjects with lab adverse events defined by the "combined method", seventy-five belonged to the reference group, inducing a two-fold higher 0.83 positive predictive value. The combined method produced a high ratio of relevant/irrelevant results (5 = 75/15) compared with the low ratio (0.76 = 77/102) achieved using the normal range method. CONCLUSION: This new "combined method", leading to a better definition of lab adverse event, seems an accurate and useful tool for routine case-by-case analysis within phase I drug development studies.

Upper limit of plasma alanine amino transferase during phase I studies.

In Phase I clinical studies, the maximum tolerated dose has to be determined by a case by case analysis sometimes using a laboratory adverse effect, e.g. an increase in alanine amino transferase (ALT). For this reason a threshold to discriminate between significant or non significant adverse changes in ALT is required particularly in Phase I studies, in order to deal with the very common "close to the limit values". Previous methods (limit of normal range or normal range plus an arbitrary margin) do not solve this problem. The authors propose a new method taking into account the threshold used as inclusion criteria for ALT (R) and the range of spontaneous variations measured under identical Phase I study conditions (V). The (R) and (V) thresholds, respectively, are defined as 50 IU.l-1 and a 50% increase, from baseline. Thus an ALT value is recognized as a "significant adverse experience" if it exceeds 50 IU.l-1 above an increase from baseline exceeding 50% of the baseline value. To highlight the value of the method, it was implemented in a one year period including 8 studies and 134 subjects. The sensitivity, specificity and positive predictive value of various methods were compared. The results showed the following: Six out of 134 subjects had significant adverse changes in ALT (4%); and all these 6 subjects were detected by the proposed new method without error. Eight subjects including two false positives, were detected by an use of the normal range limit, and only 4 were detected using, the 10% margin.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Adverse events in phase one studies: a study in 430 healthy volunteers.

All the clinical, laboratory and electrocardiographic adverse events detected during 24 Phase I studies in the same unit over a 5 y period are reported here. 430 healthy male volunteers were involved, corresponding to 5488 days of follow-up. The overall incidence of adverse events was 13.5%, with a significant difference between active drug (15.3%) and placebo (7.4%) treatments. There were 69 distinct types of adverse events. Headache was the most frequent symptom (2%). There were severe adverse events in 20 cases (0.36%), with an incidence of 20/430 per subject (4.6%). There were no deaths or life-threatening events. Although the main objective of Phase I studies is to determine the maximum dose tolerated, cause-effect relationships with adverse events are hard to establish, because of the frequency of adverse events with placebo, and because of the limited number of subjects included such studies.

[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.

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.