Pediatric pheochromocytoma in association with Von Hippel-Lindau disease: Focus on screening strategies.

INTRODUCTION: Von Hippel-Lindau disease (VHL) is a syndrome of familial predisposition to the development of malignant and benign tumours, due to mutations in the VHL tumour suppressor gene. Pheochromocytoma is a tumour that develops in the adrenal gland, rare in pediatric age, and may be associated with genetic abnormalities including mutations in the VHL gene. Systematic screening of pheochromocytoma in children carrying a VHL mutation has been proposed. However, some VHL patients who have been screened may develop symptoms associated with pheochromocytoma despite screening. Here, we report on such a case. CLINICAL CASE: A 13-year-old boy, known to be a carrier of a mutation of the VHL gene, undergoing annual screening, was admitted to our hospital for clinical symptoms related to a right adrenal pheochromocytoma discovered on abdominal imaging. After hemodynamic stabilisation, the pheochromocytoma was surgically resected. Histology confirmed the diagnosis of pheochromocytoma. The postoperative care was simple. The event-free period is currently 2 years. DISCUSSION: The present case has led us to reflect on the French and international screening strategies for pheochromocytoma in children carrying a mutation of the VHL gene. Between 2013 and 2018, six different recommendations were proposed for pheochromocytoma screening in secondary prevention for children with a VHL mutation, with variability regarding the age of onset and complementary examinations to be carried out. Despite the existence of these recommendations, our case demonstrates that a pheochromocytoma can develop by escaping well-performed screening. The role of early abdominal imaging should be redefined to improve the efficiency of screening. CONCLUSION: The discovery of a pheochromocytoma in a child must be systematically investigated for an underlying genetic cause. In the particular case of children carrying a mutation of the VHL gene, annual abdominal imaging should be included in the pheochromocytoma screening protocol from the age of 5 years.

[Acute epiglottitis due to Haemophilus influenzae b: A severe consequence of increased skepticism about vaccination]. / Épiglottite aiguë à Haemophilus influenzae b : conséquence grave du scepticisme vaccinal.

Acute epiglottis is a life-threatening disease in relation with the occurrence of an acute upper airway obstruction. Its incidence has fallen dramatically since the widespread introduction of Haemophilus influenzae type b (Hib) conjugate vaccine. We report the case of a 26-month-old child who was not fully immunized and presented acute upper airway respiratory distress with fever. The symptoms quickly evolved to a respiratory arrest condition with bradycardia, revealing epiglottitis due to Hib. Despite high immunization coverage with great efficacy and occurrence of herd immunity, this entity still exists because of the French population's skepticism of the routine vaccination schedule.

[Unusual presentation of a severe Mycoplasma pneumoniae infection: report of 2 cases]. / Présentation inhabituelle d'une infection grave à Mycoplasma pneumoniae, à propos de 2 observations.

Mycoplasma pneumonia is responsible for multisystemic infection. Pulmonary symptoms are most common in children. We describe herein two unusual severe forms of M. pneumoniae infection without initial pulmonary symptoms. The first case is an 8-month-old boy who was hospitalized in the pediatric intensive care unit with severe sepsis. There were no initial pulmonary symptoms, nor obvious clinical infection. Initial blood tests and x-ray did not aid the diagnosis. The blood tests came back positive for M. pneumonia. Pulmonary symptoms eventually appeared 24h later, and there was a pneumonia outbreak on the chest radiograph. The boy was given josamycin and improved quickly. The second case concerns an 8-year-old child who was hospitalized in the pediatric intensive care unit with toxic shock. No clinical infectious origin was found. A broad-spectrum antibiotic therapy was started with ceftriaxone and josamycin. The M. pneumoniae blood test came back positive, which confirmed the diagnosis of septic shock in M. pneumoniae, requiring adjustment of the antibiotic therapy. Current guidelines for the choice of probabilistic antibiotic therapy in case of severe sepsis do not include the case of M. pneumoniae. The early initiation of antibiotic therapy plays a major role in the prognosis of these patients. It seems useful to search for M. pneumoniae in cases of severe atypical infections, particularly in the absence of pulmonary symptoms.

[One magnet is better than two]. / Un aimant vaut mieux que deux.

Accidental foreign body ingestion by children is not exceptional and occurs in most cases in children less than 5 years old. The impact is not well known. We present the case of a 31-month-old boy affected by peritonitis caused by several bowel perforations after swallowing three magnets at different times. A single foreign body magnetic ingestion does not often cause trouble, but if the ingestions are spaced out, then consequential complications can occur. This is why, in case of stomachaches in a child less than 3 years or a child with behavior problems, it is important to perform standard abdominal X-ray examination.

[Community-acquired Staphylococcus aureus necrotizing pneumonia secreting Panton-Valentine leukocidin in an infant]. / Un cas de pneumopathie nécrosante à Staphylococcus aureus sécréteur de toxine leucocidine de Panton Valentine chez un nourrisson.

Staphylococcus aureus (SA) necrotizing pneumonia secreting Panton-Valentine leukocidin (PVL) has a high mortality rate, approximately 50% according to recent data, mainly in children and young adults. Recently, 2 cases of the disease have been reported in newborn twins with a good outcome. We report a third case of community-acquired necrotizing pneumonia due to SA sensitive to methicillin (SASM) secreting Panton-Valentine leukocidin (PVL) in an infant, initially paucisymptomatic, in the context of familial furunculosis, with a fatal outcome. Cases of necrotizing pneumonia in this age group are emerging, and extensive information for clinicians is needed due to the high mortality rate of the disease.

Update on counterfeit antibiotics worldwide; public health risks.

Antibiotics are the most counterfeited medicines and account for 28% of global counterfeit medicines. Counterfeit antibiotics are estimated at 5% of the global antibiotic market. No area in the world seems to be spared from counterfeiting of antibiotics. However, these are rare in developed countries, whereas the strong demand for antibiotics in emerging countries creates a highly attractive market for counterfeiters. Thus, 78% of counterfeit antibiotics come from South-East Asia and their destination is mainly emerging countries (South-East Asia: 44%; sub-Saharan Africa: 30%; Europe, North America: 9%; others: 16%). Counterfeit antibiotics are antibiotics that have been commonly used for years (beta-lactams: 50%; quinolones: 12%; macrolides, lincosamides, and synergistins: 1%; cyclins: 7%; others: 20%). The main counterfeit formulations (77%) concern oral administration (tablets, syrup, capsules) whereas injected drugs account for only 17% of counterfeit formulations, and eye drops and ointments 6%. The kind of counterfeiting for antibiotics is similar to that of other drugs (no active ingredients: 43%; bad quality: 24%; insufficient quantity of active ingredients: 21%; wrong active ingredients: 7%; counterfeit packaging: 5%). Beyond the harmful effects for patients, counterfeit medicines favor the emergence of bacterial resistance with a worldwide impact. Great efforts have been made to fight global counterfeiting of medicines since 1985.

Influence of carrier on the performance of dry powder inhalers.

The aim of this work is to study carriers which can become alternatives to monohydrate lactose in dry powder inhalers and to consider particle parameters that influence adhesion between drug and carrier in dry powder inhalers. Different forms of mannitol, lactose and maltitol were mixed with either terbutaline sulphate or formoterol fumarate. The blends were submitted to different adhesion tests where drug detachment from the carrier was obtained either through mechanical vibration or by aspiration. Parameters like particle shape, roughness, amorphous content and cristalline form may affect interactions between drug and carrier. In our case, crystallized forms of the carrier offered lower adhesion but better release of the active ingredient than spray-dried forms. The crystallized mannitol produced maximal fine particle dose. The blends of the mannitols and the two active ingredients gave different results. The two techniques used to assess the adhesion of drugs to carrier particles provide complementary information about drug/carrier interactions and detachment. The mechanical sieving allows to assess blend stability and the air-jet sieving makes it possible to determine how easily the drug separates from carrier. For the drugs tested, the results of fine particle doses are in agreement with the Alpine air-jet sieve results. The tests used are helpful for the choice of a new carrier in the field of the development of new carriers for dry powder inhalers.

Aerosolization potential of cyclodextrins--influence of the operating conditions.

The aim of this work is to characterize the aerosols obtained by jet nebulization with cyclodextrin solutions and to study the influence of operating conditions on nebulization efficiency. Two cyclodextrins, an hydroxypropyl cyclodextrin (Kleptose HP) and a polydisperse methyl beta cyclodextrin (Crysmeb), were tested with 14 nebulizers that differ geometrically. We first determined the physicochemical properties of density, viscosity, and surface tension for the cyclodextrin solutions. Nebulization efficiency was evaluated by measuring droplet size, nebulization rate, quantity of solution nebulized, and nebulization time. We studied the influence of the technological parameters of pressure and nebulizer type and the influence of the formulation on performance efficiency. The use of different nebulizers and different pressure conditions results in variable efficiency. Regardless of the type of nebulizer, an increase in pressure decreases droplet size and increases nebulization rate. The influence of the nebulizer design is considerable. The aqueous cyclodextrin solutions studied can generate aerosols in particle size ranges suitable for pulmonary deposition. Large quantities of aerosol can be nebulized in acceptable nebulization times. The cyclodextrin concentration does not modify nebulization efficiency in the range tested.

Influence of granulation and compaction on the particle size of ibuprofen--development of a size analysis method.

The aim of this work was to study the impact of the process on drug particle size. We chose ibuprofen, practically insoluble in water, as granulometry greatly influences its dissolution rate. We developed an original method using a laser granulometer to assess the size of ibuprofen within a blend before and after granulation and then compression. Wet granulation was performed with a Lodige and a Diosna granulator. The granules were then compressed. The evolution of ibuprofen particle size after these operations was checked. Two grades of ibuprofen differing in size were studied: ibuprofen 25 and ibuprofen 50. After the wet granulation of ibuprofen 50 with a Lodige or a Diosna granulator, a decrease in size was observed. This could be caused by shocks occurring in the granulator. On the other hand, after compression of the granules, ibuprofen particle size increased and was greater than that measured before granulation. Compression could induce some fragmentation of ibuprofen associated with the plastic deformation and then, under pressure, a closeness of the fragments or deformed particles which could bind or associate with one another because the melting point of ibuprofen is not very high. In the case of ibuprofen 25, the same phenomena were observed after compression. But, after granulation, particle size was not modified. There was little breaking of ibuprofen particles in the granulator because they are much smaller than those of ibuprofen 50. This work shows the impact of the process on drug particle size when producing tablets. The method developed made it possible to differentiate and measure the size of ibuprofen particles in a blend.

Controlled drug release from Gelucire-based matrix pellets: experiment and theory.

The aim of this work was to elucidate the underlying drug release mechanisms from lipidic matrix pellets, using theophylline and Gelucire 50/02 as model drug and carrier material, respectively. Pellets were prepared by two different techniques: melt-solidification and extrusion-spheronization. The effects of different formulations and processing parameters on the resulting drug release kinetics in 0.1N HCl and phosphate buffer pH 7.4 were studied and the obtained results analyzed using adequate mathematical models in order to get further insight into the underlying mass transport mechanisms. The type of preparation technique was found to strongly affect the underlying drug release mechanisms. Drug release from pellets prepared by the melt-solidification method was primarily controlled by pure diffusion, whereas drug release from pellets prepared by the extrusion-spheronization method was purely diffusion-controlled only at early time points. After approximately 2h, the pellets started to disintegrate, resulting in decreased diffusion pathway lengths and, thus, increased drug release rates. Furthermore, the curing conditions significantly affected the theophylline release kinetics, whereas varying the initial drug loading from 20 to 50% (w/w) resulted only in a slight increase in the relative drug release rate. Interestingly, the effects of the size of pellets prepared by the melt-solidification method on the resulting drug release kinetics could be quantitatively predicted using an analytical solution of Fick's second law of diffusion. These predictions could be verified by independent experiments.

Influence of the morphogranulometry and hydrophobicity of talc on its antisticking power in the production of tablets.

Antisticking power varies according to the talc considered. It is difficult to define the physical properties of talc implicated in its antisticking power. In this work, different talcs were characterized and an evaluation made of their performance in reducing sticking in tablet manufacturing. Determination of the specific surface area was made by permeametry, morphogranulometric analysis by laser diffractometry using a method, which made it possible to assess the mean thickness of talc particles, and measurement of water absorption kinetics was taken to assess hydrophobicity. The relationship between the characteristics of talcs and their antisticking power was then considered. There is a correlation between the particle size of talc and surface hydrophobicity. The detaching force of tablets appears to be dependent on the basal dimension of talc.

Cyclodextrins as a potential carrier in drug nebulization.

The inhalation route is widely studied for many drug applications focusing on either local or systemic distributions. One matter of concern is the solubilization of hydrophobic drugs. We have studied the feasibility of using different cyclodextrins (CDs) to elaborate pharmaceutical formulations for the inhalation route and tested the short-term toxicity of such formulations administered by inhalation to C57BL/6 mice. We have shown that HP-beta-CD, gamma-CD, as well as RAMEB aqueous solutions can undergo aerosolization and that the resulting droplet-size ranges are compatible with pulmonary deposition. In vivo, we have demonstrated that short-term exposure to inhaled HP-beta-CD, gamma-CD and RAMEB solutions are non-toxic after assessing bronchoalveolar lavage (BAL), lung and kidney histology, bronchial responsiveness to methacholine and blood urea. The only change noted is a slight increase in lymphocyte count in the BAL after HP-beta-CD and gamma-CD inhalation. We conclude that CDs are useful in significantly enhancing the solubility of apolar drugs with a view to inhalation therapy although an increase in lymphocyte counts in the BAL after CDs inhalations needs further investigations.

Development of 400 microm pellets by extrusion-spheronization: application with Gelucire 50/02 to produce a "sprinkle" form.

The aim of this study was to develop monodimensional, spherical particles of 400 microm by extrusion-spheronization. An Alexanderwerk GA65 cylinder extruder with two counter-rotating rollers associated with a Caleva model 15 spheronizer were used. The study was made with an auxiliary substance of fatty consistency and with amphiphilic properties: Gelucire 50/02. The plasticity of the mass can be deduced using a piston extruder. Pellet quality can be determined by particle-size analysis and shape estimation by microscopy. Modifications to the cylinders and the extruder itself are required for feasibility studies of extruded materials of 400 microm. The horizontal plate of the spheronizer had to be adapted to take into account the small size of the extruded materials. For the chosen auxiliary substance, Gelucire 50/02, the formulation of the wet mass to be extruded and the conditions required to obtain this mass were defined. The results show the feasibility of 400 microm pellets with Gelucire 50/02. At least 90% of the pellets have a particle size of between 250 microm and 500 microm and particle shape is acceptable. In this form the dose can be adapted to individual patients. After proving the feasibility of 400 microm spheroids of Gelucire 50/02, the association of a drug with it was considered.

Relation between structural characteristics of talc and its properties as an antisticking agent in the production of tablets.

Antisticking power varies according to the talc considered. Besides its chemical properties, it is necessary to assess its physical properties related to functionality. It is difficult to define the physical properties of talc implicated in its antisticking power. In this work, different talcs were characterised and their performance in reducing sticking in tablet manufacturing was evaluated. The following parameters were studied: apparent density, morphogranulometry, roughness, and the specific surface through the adsorption-desorption of argon. Next, the relationship between the characteristics of talcs and their antisticking power was considered. Talc before and after delamination-which is a way to obtain talcs with different physical characteristics-was compared. Antisticking power appeared to be dependent on the basal dimensions of talc, and on the ratio value of the external specific surface measured by diffractometry to the total specific surface by the BET method. Models to express the effect of textural factors of talc particles on antisticking power were defined.

Developing a study method for producing 400 microm spheroids.

The aim of this work was to obtain 400 microm spheroids that can be sprinkled on food to improve patient compliance particularly in the case of children and old people. A methodology to select wet masses for extrusion-spheronization through a 400 microm orifice was developed. The first step was to define the parameters that make it possible to assess the qualities required by the wet mass and the extrudates and evaluation norms: plasticity, cohesiveness, brittleness of the mass and the extrudates, and appearance of extrudates. A feasibility assay was then performed on the cylinder extruder, showing that extrusion of the lactose/Avicel PH 101/water (50/50/60) mass is not feasible through the 400 microm orifice. Precirol ato 5 and Gelucire 50/02 wetted with a sodium lauryl sulfate solution at 0.5% show plastic flow through the 400 microm diameter orifice. The presence of Avicel PH 101 does not improve plasticity for this orifice. Micropellets of 400 microm have been proved feasible as long as excipients with suitable pharmaceutical technological properties are used. After proving the feasibility of 400 microm spheroids of Gelucire 50/02, we considered the association of a drug with it.

Study of the technological parameters of ultrasonic nebulization.

The principle of an ultrasonic nebulizer is based on the vibrations of a piezoelectric crystal driven by an alternating electrical field. These periodic vibrations are characterized by their frequency, their amplitude, and their intensity, which corresponds to the energy transmitted per surface unit. When the vibration in tensity is sufficient, cavitation occurs, and droplets are generated. Ventilation enables airflow to cross the nebulizer and to expel the aerosol droplets. For a given nebulizer, the vibration frequency of the piezoelectric crystal is fixed, often in the range 1-2.5MHz. In most cases, an adjustment in vibration intensity is possible by modifying vibration amplitude. The ventilation level is adjustable. The vibrations may be transmitted through a coupling liquid--commonly water--to a nebulizer cup containing the solution to be aerosolized. In this work, we studied the influence of the technological parameters of ultrasonic nebulization on nebulization quality. Our study was carried out with a 9% sodium chloride solution and a 2% protein solution (alpha1 protease inhibitor). Three different ultrasonic nebulizers were used. An increase in vibration frequency decreased the size of droplets emitted. The coupling liquid absorbed the energy produced by the ultrasonic vibrations and canceled out any heating of the solution, which is particularly interesting for thermosensitive drugs. An increase in vibration intensity did not modify the size of droplets emitted, but decreased nebulization time and raised the quantity of protein nebulized, thus improving performance. On the other hand, an increase in ventilation increased the size of emitted droplets and decreased nebulization time and the quantity of protein nebulized because more drug was lost on the walls of the nebulizer. High intensity associated with low ventilation favors drug delivery deep into the lungs.

[Feasibility of 400 microm spheroids by extrusion-spheronization]. / Faisabilité de microgranules de 400 micromètres par extrusion-sphéronisation.

Extrusion-spheronisation technology is an agglomeration process that makes it possible to obtain spheroids. The aim of this work was to obtain 400microm spheroids that could be sprinkled on food to improve patient observance in particular with children and old people. A methodology to select wet masses for extrusion-spheronisation through a 400microm orifice was developed. First, it was nesessary to define the parameters that make it possible to appreciate the qualities that the wet mass and the extrudates have to possess and their method of evaluation: plasticity, cohesiveness, brittleness of the mass and the extrudates, appearance of extrudates. A feasibility assay made on the drum extruder was then performed. After proving the feasibility of 400microm spheroids of Gelucire 50/02 we considered the association of a drug with it.

Formulation of activated charcoal for per os administration to addicted subjects.

The objective of this work was to develop a galenic form of activated charcoal appropriate for the needs of clinical toxicology. To preserve the adsorption capacity of charcoal, we developed an extemporaneous preparation of activated charcoal intended for clinical toxicology. To improve the wettability of activated charcoal, we used densification by wet granulation. The presence of a viscosity agent is necessary to ensure the homogeneity of the suspension and its adhesiveness on gastric mucous membrane. Five formulations with different viscosity agents were prepared, and their adsorption capacity, wettability, viscosity, and adhesiveness were studied.

Influence of the technological parameters of ultrasonic nebulisation on the nebulisation quality of alpha1 protease inhibitor (alpha1PI).

The principle of an ultrasonic nebuliser is based on the vibrations of a piezo-electric crystal driven by an alternating electrical field. These periodical vibrations are characterised by their frequency, their amplitude and their intensity which corresponds to the energy transmitted per surface unit. When the vibration intensity is sufficient, cavitation appears and generates droplets. Ventilation enables an airflow to cross the nebuliser and to expulse the aerosol droplets. For a given nebuliser, the vibration frequency of the piezo-electric crystal is fixed and is often in the range of 1-2.5 MHz. In most cases, an adjustment in vibration intensity is possible by modifying vibration amplitude. The ventilation level is adjustable. The influence of these two parameters on the efficiency of ultrasonic nebulisation is studied. The study was carried out with a protein solution that had to be administered into the lungs. The solution used presented a viscosity of 1.25 mPa and a surface tension of 53 mN/m. The integrity of the protein was checked which was submitted to different vibration conditions. Nebulisation efficiency was evaluated by determining droplet size, the percentage of drug nebulised and nebulisation time. An increase in vibration intensity does not modify the size of droplets emitted, but decreases nebulisation time and raises the quantity of protein nebulised, thus improving performance. On the other hand, an increase in ventilation increases the size of droplets emitted, decreases nebulisation time and the quantity of protein nebulised because more drug is lost on the walls of the nebuliser. High intensity associated with low ventilation favours drug delivery deep into the lungs.

Influence of formulation on jet nebulisation quality of alpha 1 protease inhibitor.

As foam appears during solution constitution and nebulisation of alpha 1 protease inhibitor (alpha 1 PI), we selected in a previous work, antifoams likely to be associated with an alpha 1 PI solution to be nebulised: span 65 at a 0.025% concentration and cetyl alcohol at a 0.05% concentration associated with tyloxapol at 0.025% concentration. The purpose of this study was, on the one hand to study the influence of the formulation on nebulisation quality by relating physicochemical properties and nebulisation capacity, and on the other hand, to define the alpha 1 PI that will be retained for a clinical study. The properties of the different alpha 1 PI formulations are compared: surface tension, viscosity, time required to constitute the protein solution and pH. Nebulisation quality is evaluated under different operating conditions by measuring the droplet size, the quantity of alpha 1 PI nebulised, nebulisation time and the quantity of alpha 1 PI likely to reach the lungs which was subjected to statistical analysis. The statistical analysis of results indicates that the addition of the cetyl alcohol/tyloxapol mixture improves nebulisation effectiveness by significantly increasing the quantity of drug nebulised and therefore the quantity of alpha PI likely to reach the lungs. It is this formulation that will be retained for clinical trials. We check that the nebuliser and operating conditions influence all the parameters, that is to say the respirable fraction, the quantity nebulised and the nebulisation time. Although there is no interaction between the nebuliser and the formulation, nebulisation quality is the combined result of the formulation, the nebuliser and the operating conditions.