[Strategic analysis and the drug industry]. / Analyse stratégique et industrie du médicament.

During the postwar decades, the quasi-spontaneous growth permitted less rigorous management than that of today in terms of the development of enterprises. The choice was made in a more or less well-considered way and often by 'feeling'. The economic upheaval that followed the oil crises, the acceleration of technological discoveries and their practical applications and the speeding up of the dissemination of information have imposed a new way of strategic decision making on society. This type of approach, used largely in the industrial world, ought to be better understood by doctors so that they may appreciate the changes and also so that they can eventually use these methodologies in their field of activity.

[The rational basis for the short-, medium-, and long-term evolution of the pharmaceutical industry]. / Les bases rationnelles de l'évolution de l'industrie pharmaceutique à court, moyen et long terme.

In the last few years, a worldwide reorganization affecting the entire pharmaceutical industry has begun and is now accelerating. This intense trend of mergers, acquisitions, market entires++ and exits, reorientation and diversification reflects a new environment. This article sets out to explain the reasons behind this inescapable and rapid evolution.

Antioxidant micronutrients and childhood malignancy during oncological treatment.

Serum antioxidant vitamins A (retinol) and E (alpha-tocopherol), beta-carotene, zinc, and selenium, and cholesterol and related proteins for 170 children with newly diagnosed malignancy were measured at diagnosis and 6 months after initiation of treatment, and compared with those of 632 cancer-free controls. Incident cancer cases and controls were 1-16 years old and recruited between 1986 and 1989. At diagnosis, age- and sex-adjusted serum concentrations of retinol, beta-carotene, zinc, and alpha-tocopherol were significantly inversely associated with cancer. No significant decreases in mean values were observed at 6 month, except for the alpha-tocopherol-to-cholesterol ratio in patients with bone tumors and serum zinc in bone tumors and central nervous system malignancies. An increase during the period of treatment was found for retinol and selenium in leukemia patients. beta-carotene was maintained at the initial concentrations determined prior to therapy. These findings provide further information about micronutrient requirements in children with cancer.

Assessment of serum antioxidant micronutrients and biochemical indicators of nutritional status in children with cancer in search of prognostic factors.

Serum vitamins A (retinol) and E (alpha-tocopherol), beta-carotene, zinc and selenium, and related proteins for 157 children with newly diagnosed and histologically proven malignancy were compared with those of 632 cancer-free controls. Incident cancer cases and controls were 1-16 years of age and recruited in 1986-1989. Age and sex-adjusted serum concentrations of beta-carotene and alpha-tocopherol were significantly inversely associated with cancer. No significant association with cancer was observed for serum values of selenium. Although low levels of antioxidants might in part be involved through a causality link, the reported decreased peripheral nutrient levels are considered rather as an impairment of the body's defence system, occurring during the cancer-related metabolic and nutritional disturbances and inflammation processes. The cancer cases group was followed-up and examined 6 months after diagnosis. Among the 157 subjects, 24 had died and 133 were reported to be alive. No substantial difference for any antioxidant or chemistry variable at onset was observed as a function of clinical outcome and health status.

[Opposable medical references in pediatrics]. / Les références médicales opposable en pédiatrie.

Recommended guidelines for medical practice are instituted in France as a contribution to a reduction of health care expenses. The methodology, applications, and implications in pediatrics, are presented.

[Efficacy of oral administration of a micellaar solution of vitamin K during the neonatal period]. / Efficacité de l'administration orale d'une solution micellaire de vitamine K en période néonatale.

BACKGROUND: Oral administration of vitamin K to neonates is quite satisfactory for preventing hemorrhagic disease of the newborn. The aim of this study is to test efficacy of a micellar solution of vitamin K at birth. POPULATION AND METHODS: Thirty full term infants, exclusively breast-fed during the first month of life, were included in this study. Seven of them (control group Cos) were given oral supplementation with 5 mg vitamin K1, cremophor; 15 other infants were given oral supplementation with 3 mg micellar solution of vitamin K1 (group MMos) and 7 were given an intramuscular injection of 1.5 mg micellar solution of vitamin K1 (group MMim). Prothrombin time activity and plasma vitamin K concentration were measured in the cord blood, 24 +/- 12 hours and 1 month after supplementation. RESULTS: No hemorrhage was seen and tolerance to vitamin K was good in the 3 groups. Mean prothrombin time activity was 54% in the cord blood, around 55% and 75%, 24 hrs and 1 month after supplementation, respectively; only one infant had low value (41%) by 1 month despite normal plasma vitamin K concentration. Two infants had low plasma vitamin K1 concentration by the second control despite normal prothrombin time activity; one belonged to the MMos group and the other to the Cos group. Mean values of plasma vitamin K1 concentration were higher by 1 month in the MMos group. CONCLUSION: A unique dose of micellar solution of vitamin K given orally at birth seems effective to prevent hemorrhagic disease.

Serum beta-carotene and antioxidant micronutrients in children with cancer. The 'Cancer in Children and Antioxidant Micronutrients' French Study Group.

Serum antioxidant vitamins A (retinol) and E (alpha-tocopherol), beta-carotene, zinc and selenium for 418 children with newly diagnosed malignancy were compared with those of 632 cancer-free controls. Incident cancer cases and controls were 1-16 years old and recruited in 1986-1989. Age- and sex-adjusted serum concentrations of retinol, beta-carotene and alpha-tocopherol were significantly inversely associated with cancer. In similar models, the odds ratio (OR) comparing the highest with the lowest quintile was 2.06 (95% confidence interval [CI] 1.40-3.02) for retinol, 3.87 (95% CI: 2.54-5.90) for beta-carotene, 2.15 (95% CI: 1.48-3.10) for alpha-tocopherol, 1.29 (95% CI: 0.75-2.23) for selenium, and 1.94 (95% CI: 1.17-2.23) for zinc. The cancer sites that were associated with serum beta-carotene were, in general, leukaemia, lymphoma, central nervous system, bone and renal tumours. Moreover, leukaemia was associated with low mean serum levels of retinol, selenium and zinc. Subjects with lymphoma, bone and renal tumours also had lower mean retinol and alpha-tocopherol levels than controls. Brain tumour patients had low vitamin E levels. Low serum values of antioxidant vitamins were associated with childhood neoplasm occurrence. Some site-specific effect was reported. Low peripheral nutrient levels are not considered as cancer promoters but rather as an impairment of the body's defence mechanism occurring during the cancer-related metabolic and nutritional disturbances and inflammation processes.

A randomised controlled trial to test equivalence between retinyl palmitate and beta carotene for vitamin A deficiency.

OBJECTIVES: To determine whether beta carotene is therapeutically equivalent to retinyl palmitate in the formulation currently recommended by the World Health Organisation. DESIGN: Randomised blind equivalence trial. SETTING: Rural area in Senegal. SUBJECTS: Children aged 2-15 years suffering from vitamin A deficiency as defined by abnormal results on eye cytology were randomly allocated treatment with retinyl palmitate (n = 256) and beta carotene (n = 254). MAIN OUTCOME MEASURE: Reversion to normal results on eye cytology as defined by the reappearance of goblet cells and normalisation of the epithelial cells. RESULTS: Seven weeks after the supplement was given the percentages were 51.2% (124/242) children taking retinyl palmitate and 50.0% (123/246) of those taking beta carotene, who had reverted to normal eye cytology, a difference of 1.2% (95% confidence interval 6.2% to 8.6%) [corrected]. According to an equivalence testing procedure, the two treatments were statistically equivalent; the null hypothesis of non-equivalence was rejected (one tailed p value = 0.03). CONCLUSIONS: beta Carotene supplementation seems to be a promising candidate for the alleviation of vitamin A deficiency. It could be given either as high dose capsule or through increased dietary intake. The challenge now is to improve dietary intake of vitamin A in programmes that are effective and sustainable at the community level.

Serum retinol, beta-carotene, alpha-tocopherol and cholesterol in healthy French children.

Age- and sex-specific reference intervals of data derived from a healthy paediatric population are presented for retinol, beta-carotene, alpha-tocopherol, cholesterol and related proteins in serum. Age was an important covariate for the micronutrient concentration values. Retinol was highly correlated with alpha-tocopherol and cholesterol. Strong correlation was found with both beta-carotene and cholesterol. Serum levels were considered for their appropriateness as indicators of micronutrient status.

Reference values for serum zinc and selenium of French healthy children.

Age - and sex-specific reference intervals derived from a healthy pediatric population are presented for zinc, selenium and related analytes in serum. No strong correlations were found between age, sex and trace elements in serum. Serum variables were discussed to assess their ability as biochemical indicators of micronutrient status in the field of biological epidemiology.

Immunonephelometry and radial immunodiffusion compared for measuring serum retinol-binding protein.

We compared a nephelometric method and a radial immunodiffusion (RID) assay for the measurement of retinol-binding protein in samples of serum from children with malignancies. The mean (+/- standard deviation) retinol-binding protein concentration as measured by the Behring Nephelometer was 31.0 +/- 15.6 mg/l; the mean by RID was 31.2 +/- 15.7 mg/l. This difference was not statistically significant by Student's t test (P = 0.6), and the correlation coefficient (r) was 0.87. Thus, the Behring Nephelometer method measures retinol-binding protein rapidly and as accurately as radial immunodiffusion.

Impression Cytology with Transfer in xerophthalmia and conjunctival diseases.

During a countrywide survey, we assessed the prevalence of clinical signs of xerophthalmia and of major conjunctival diseases in a randomized sample of 2,445 subjects representative of the population of the Republic of Djibouti. On a part of this sample, conjunctival Impression Cytology with Transfer (ICT) test and a plasma retinol determination were performed. Xerophthalmia as a public health problem was displayed by clinical signs (Bitot's spots, corneal scars among preschool children), low plasma retinol levels and ICT test results: 9.3% with deficient cytology in the rural area and 12.3% in the urban one (age-standardized rates). Results of ICT were related to age (p < 0.00001). Vitamin A deficiency was prevalent not only in preschool children but also up to 15 years. Moreover, ICT results are influenced by conjunctival diseases: compared to age-matched controls, there were more abnormal cytologies among patients with trachomatous inflammation (p = 0.025), conjunctivitis (p = 0.024) or Limbal Vernal Keratoconjunctivitis (p = 0.015). Thus ICT shouldn't be performed among children with conjunctival diseases. In the region under study conjunctival diseases had high rates of prevalence: 16.4% of trachomatous scarrings in the urban area (standardized rate), 8% of conjunctivitis among rural preschool children, and 5% of Limbal Vernal Keratoconjunctivitis among children between 5 and 14 years in both areas.

Efficacy of massive oral doses of retinyl palmitate and mango (Mangifera indica L.) consumption to correct an existing vitamin A deficiency in Senegalese children.

Administration of large oral doses of retinyl palmitate has become the most widely practised vitamin A deficiency prevention strategy in developing countries. We conducted a follow-up study among 220 Senegalese children aged 2-7 years suffering from moderate undernutrition to determine the efficacy of vitamin A treatment on their vitamin A status assessed by biochemical and cytological (impression cytology with transfer) methods. The first examination (T = 0 m[onth]) was carried out during April 1989, before the mango (Mangifera indica L,) harvest. The second examination (T = 2 m) was carried out 2 months after vitamin A treatment during June 1989 when ripe mangoes become widely available. Conjunctival cells of the eyes of the children with or without ocular inflammation were responsive to vitamin A administration (P < 0.01). There was a significant increase (P < 0.001) in mean serum retinol and beta-carotene levels between T = 0 m and T = 2 m. Mean serum retinol-binding protein (RBP) and transthyretin (TTR) levels did not differ significantly (P > 0.05) at T = 0 m and T = 2 m. Despite the intake of vitamin A, 54% of the children who had abnormal cytology at T = 0 m remained abnormal at T = 2 m. This was due to inadequate levels of TTR and RBP, presumably due to the cereal diet eaten by the Senegalese population. children with abnormal eye cytology had lower serum retinol levels than those with normal eyes at T = 0 m, and beta-carotene values did not correlate with eye cytological abnormalities at T = 0 m. Children with normal cytology had higher serum retinol and also beta-carotene levels than those with abnormal cytology after massive oral doses of vitamin A and consumption of mangoes at T = 2 m. Retinyl palmitate may, therefore, only lead to partial cytological improvement due to a lack of retinol-carrier proteins but dietary beta-carotene may also be involved.

Conjunctival impression cytology with transfer as a field-applicable indicator of vitamin A status for mass screening.

The increasing importance of vitamin A deficiency in even its mild subclinical form underlines the need for a mass screening test. Clinical, biochemical and cytological methods of assessing vitamin A deficiency in a public health setting have been described and widely used. The cytological method shows promise because it enables early detection of vitamin A deficiency. However interpretation is problematic since histopathological changes are gradual with the progressive disappearance of goblet cells and appearance of enlarged epithelial cells. The reliability and validity of the impression cytology with transfer (ICT) test were assessed in order to produce a meaningful standard for this cytological method. The ICT test was performed in Senegal on 1451 children, in the course of two surveys conducted in 1989 and 1990 in rural areas. Reliability, estimated by Cohen's kappa test for evaluating intra-reader variability, and sensitivity were highest for the abnormal-normal classification (kappa = 0.91; 95% confidence interval (CI): 0.89-0.93; and sensitivity = 74%; 95% CI 66-82%). The ICT method is a cheap, noninvasive and easy test to perform in the field. This method is also reproducible and fairly sensitive according to the abnormal-normal classification. As illustrated by our proposed 50% cutoff of abnormal cytology calculated in relation to 5% of serum retinol values below 0.35 mumol/L criterion, ICT only requires a small sample for the assessment of the overall health of a community in contrast to xerophthalmia and blood vitamin A deficiency tests.

PIP: In Senegal an ophthalmologist conducted eye examinations on 192 preschool children from 2 rural villages in Niakhar district in the Diourbel region in April 1989 and on 1259 preschool and school age children from 30 rural villages from Malicounda community in the Thies coastal region in February-March 1990 to assess the reliability and validity of the impression cytology with transfer (ICT) test as a field indicator of vitamin A status. Researchers also intended to standardize the cytological results. Cohen's kappa test revealed almost perfect agreement between the observed and expected interpretations of the conjuctival imprints for the classification abnormal-normal (kappa=0.91; 95% confidence interval [CI] for ICT=0.89-0.93). Thus the ICT test was reliable. Serum retinal concentrations indicated that the ICT test was specific for the deficient-nondeficient classification (serum retinal concentrations [SRC]=96%; 95% CI 93-97%) and fairly sensitive for the abnormal-normal classification (SRC=74%; 95% CI=66-82%). These serum retinal concentration results indicated that the ICT test was valid. The researchers proposed 2 classifications--normal and abnormal--to increase reproducibility of the ICT test. Since the ICT test can detect insufficient peripheral supply of vitamin A to the eye at an early stage and has only a 50% cut off, the ICT test can determine the public health of a community with only a small sample. Further the ICT test is a reproducible diagnostic test that is inexpensive, noninvasive, and easy to perform in the field.

Laser immunonephelometry reference intervals for eight serum proteins in healthy children.

Eight serum proteins were analyzed with the Behring nephelometer in samples from 479 healthy French children, ages three to 16 years. Girls had higher concentrations of IgM and albumin than boys had. Age appeared to be a main factor of variation for the proteins tested. Reference intervals are presented for IgG, IgA, IgM, albumin, transthyretin (prealbumin), retinol-binding protein, alpha 1-acid glycoprotein, and C-reactive protein. The significance of increased concentrations of C-reactive protein within a community is discussed.

The role of interleukin-6 in vitamin A deficiency during Plasmodium falciparum malaria and possible consequences for vitamin A supplementation.

Kinetics of serum levels of interleukin-6 (IL-6) were studied in patients with acute Plasmodium falciparum malaria in relation to vitamin A and its binding proteins, retinol binding protein (RBP) and pre-albumin. It was found that IL-6 levels followed the rise and decrease of parasitaemia by 12 hr and correlated inversely with levels of vitamin A and its binding proteins. These data suggest that vitamin A supplementation alone might still be insufficient to restore a malaria-induced vitamin A deficiency.