Development and validation of a stability-indicating high performance liquid chromatographic assay for determination of cariprazine in bulk form and in drug product.

The aim of the present study is to develop a stability indicating high performance liquid chromatographic method for the determination of cariprazine in bulk substance and in drug product. The chromatographic separation was carried out using a Phenomenex Kinetex® C18 column (5µm, 250×4.6mm) and a mobile phase consisting of acetonitrile-potassium dihydrogen orthophosphate buffer (pH 4; 50mM) (30:70, v/v), at a flow rate of 1mlmin -1 and UV detection at 248nm. The column was maintained at 25°C and an injection volume of 20µL was used. Stress testing of cariprazine bulk substance and drug product was performed according to the International Conference on Harmonization (ICH) Q1A (R2) guideline. Various stress conditions were tested including acidic, alkaline and neutral hydrolysis, humidity, oxidation, dry heat and photolysis. A total of three degradation products (DPs) were formed. Among them two DPs were successfully characterized with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis.

[Characteristics of cardiac involvement in eosinophilic granulomatosis with polyangiitis]. / Caractéristiques de l'atteinte cardiaque au cours de la granulomatose éosinophilique avec polyangéite.

AIM OF THE STUDY: Our study aimed to identify the characteristics of cardiac involvement in eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: We conducted a retrospective analytic study including EGPA cases diagnosed between 2000 and 2019 in an internal medicine department. Diagnosis was made according to the 1990 American College of Rheumatology criteria and the 2012 Chapel Hill Concensus. RESULTS: Eleven EGPA cases were included, 64% of patients were female. Median age at diagnosis was 52 years [42-58]. Heart damage revealed EGPA in 55% of cases with a significant predominance of women (p=0.015). The main cardiac manifestations were myocarditis, ischemic cardiomyopathy due to small vessel vasculitis, cardiac tamponade and intracardiac thrombus. Cardiac magnetic resonance imaging (MRI) mainly showed subendocardial hyposignal in early infusion and late enhancement in the same areas, nodular by locations, associated with impaired left ventricle function and micro-infarctions by distal vasculitis. Cardiac damage was associated to ANCA negativity in 83.3% of cases. The median Birmingham Vasculitis Activity Score version3 (BVAS v3) was 16 [10-17]. Under conventional treatment, no relapses had occurred. The median vasculitis damage index (VDI) was 2 [1-2.3] and the mortality rate was zero after a mean follow-up of 43 months. CONCLUSION: Cardiomyopathy is a frequent revealing mode of EGPA. A late onset asthma and hypereosinophilia should guide the diagnosis. As ANCA research often turns out to be negative, histological evidence is recommended in this context. The contribution of cardiac MRI in the diagnosis of EGPA remains to be defined.

[A rare cause of pulmonary arterial hypertension: Thoracic amyloidosis]. / Une cause rare d'hypertension artérielle pulmonaire : l'amylose thoracique.

Isolated thoracic involvement in amyloidosis is a rare and serious condition. Its association with pulmonary arterial hypertension (PAH) usually weakens the prognosis. We report the case of a 40-year-old man with a smoking history, hospitalized for chest pain, abdominal pain and acute respiratory distress. The cardiac ultrasound revealed a circumferential pericardial effusion as well as a pulmonary artery systolic pressure (PAPS) at 80mmHg. Chest imaging (computed tomography scan and magnetic resonance imaging) showed a tissue process developed in the pericardial sheath (60×45mm) sheathing the ascending aorta and infiltrating the trunk of the pulmonary artery and its right branch. Anatomopathological and immunohistochemical study of the process revealed AL amyloidosis. Note that the patient had no signs of extrathoracic amyloidosis. Blood and urine electrophoresis and immunoelectrophoresis as well as bone marrow mylogram and biopsy were normal. The patient was put on oral anticoagulant as he presented with PAH. A therapeutic protocol with thalidomide and dexamethasone has been initiated. The course of the disease was marked by total regression of the clinical signs, a marked decrease in the amyloid process on imaging and a normalization of the PAPS; our follow-up being three years.

[Nutritional status and dietary intake in patients with chonic obstructive pulmonary disease]. / Apports nutritionnels et état nutritionnel au cours de la broncho-pneumopathie chronique obstructive.

INTRODUCTION: Undernutrition is a predictor of mortality in chronic obstructive pulmonary disease (COPD). The objectives of our study were to assess nutritional intake in COPD and to study its relationship with disease severity. METHODS: A cross-sectional study that included 66 patients followed for COPD. Patients included had a body composition study and a respiratory and nutritional assessment. RESULTS: The mean age of the population was 66±9 years. The lean body mass index (LMI) was reduced in 26.1% of patients. It was significantly associated with the GOLD group (P=0.04) and significantly correlated with the forced expiratory volume in the first second (FEV1) (P=0.02) and the distance covered during the six-minute walk test (TM6) (P=0.01). A significant difference was found between the caloric intakes and the different GOLD groups (P=0.04). Mean intakes of calories (P=0.002; r=0.07), protein (P=0.01; r=0.16), carbohydrates (P=0.02; r=0.2) and iron (P=0.01; r=0.13) were significantly correlated with the TM6 results. Caloric intake was significantly correlated with LMI (P=0.01; r=0.16), body mass index (P=0.04; r=0.12), FEV1 (P=0.04; r=-0.12) and GOLD stage (0.002). Similarly, protein intake was significantly correlated with LMI (P=0.001; r=0.11), body mass index (P=0.02; r=0.16), FEV1(%) (P=0.001; r=-0.16) and GOLD stage (P=0.002). CONCLUSION: Undernutrition in COPD is caused by decreased food intake and increased resting energy expenditure. Adequate intakes of glucose, protein, fibers, vitamins and zinc are associated with improved ventilatory function.

Pheochromocytoma presenting as an authentic small vessel vasculitis and complicated with pulmonary embolism: An original presentation.

Diagnosis of pheochromocytoma can be simple when classic manifestations are present. It can also be challenging and complicated in some cases because of its wide array of faces and presentations. We present a case of a 30-year-old female patient who came with acute respiratory distress, chest pain, hemoptysis, asthenia, anorexia, weight loss of 20kg, and paresthesia in her lower limbs. Clinical examination found high blood pressure, accelerated heart and respiratory rates, signs of acute right heart failure with jugular venous distention and ankle edema, reticularis livedo in the four limbs, ulcers in both knees and in the 3rd metacarpo-phalangeal articulations and necrotic lesions in both calcaneal tendons and in the right toes. Further investigations concluded on myocarditis associated with alveolar hemorrhage, pericardic and pleuritic effusions and a segmental pulmonary embolism of the right inferior lobe. Neuro-muscular biopsy was suggestive of myositis. Cutaneous biopsy found nonspecific chronic dermatitis. ANCA antibodies were tested twice and were negative. Cryoglobulinemia was also negative. Thoraco-abdomino-pelvic scan was performed showing a large right adrenal mass suggestive of pheochromocytoma. Diagnosis of right adrenal pheochromocytoma was confirmed by MIBG-I123 hyperfixation findings and urinary normetanephrin levels. The patient was treated surgically. Postoperative outcomes were remarkably favorable with a complete regression of the cutaneous lesions and normalization of the blood pressure. Paresthesia significantly decreased. Control echocardiography at 3 months showed an improved heart function with a persistent apical and septal akinesis.

[Assessment of body composition during pulmonary tuberculosis]. / Évaluation de la composition corporelle au cours de la tuberculose pulmonaire.

BACKGROUND: Although the body mass index (BMI) is the most commonly used tool to assess the nutritional status of patients with active tuberculosis (TB), it does not assess changes in body composition. This study aims to assess the contribution of bioelectrical impedancemetry (BIA) for the assessment of body composition during the course of TB compared to BMI and to examine the associated factors. METHODS: Cross-sectional study carried out in patients with active TB at the pulmonology department of CHU la Rabta in Tunis, Tunisia. The nutritional assessment was based on the measurement of BMI and the analysis of body composition by BIA. Malnutrition was accepted when the lean mass index (LMI) was ≤16kg/m2 in men and 15kg/m2 in women. RESULTS: Ninety-five patients were included. According to their LMI, 38 patients were undernourished. The decline in LMI was associated with the severity of TB. Although BMI and LMI were correlated, the use of BMI alone failed to recognize lean mass loss in one in ten patients. CONCLUSION: Undernutrition is frequent in patients with active TB. It is correlated with the severity of the disease. In addition to anti-tuberculosis drugs, nutritional management of these patients is essential.

[Testosterone and chronic obstructive pulmonary disease]. / Testostéronémie et bronchopneumopathie chronique obstructive.

INTRODUCTION: Testosterone level has been shown to be associated with respiratory function and loss of lean body mass in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the relationship between testosterone level and functional respiratory parameters during COPD. METHODS: We conducted a cross-sectional study that included 95 male patients with stable COPD. Functional tests (body plethysmography, six-minute walk test (6MWT), arterial blood gas) were performed in all patients and serum levels of testosterone, prolactin, FSH, LH and C-reactive protein were determined. Lean body mass was measured using bioelectric impedance. RESULTS: The average age was 63.78±8.90years. COPD was classified as stage 3 in 38% of cases and stage 4 in 11% of cases, group C in 10% of cases and group D in 18% of cases. The average testosterone was 20.87±8.60nmol/L. A significant positive correlation was found between FEV1 (P=0.005), FVC (P=0.005), FEV1/FVC ratio (P=0.001), lean mass index (P=0.021), and testosterone. However, testosterone was not correlated with 6MWT or blood gas parameters. Similarly, it was not correlated with FSH, LH, prolactin and C-reactive protein. CONCLUSION: This study found that serum testosterone level was associated with lung function and lean mass during COPD. Further investigations are required to better evaluate the relationship between COPD and serum testosterone levels and the effect of androgen substitution in lung function.

[Assessment of insomnia among Tunisian patients with lung cancer]. / Évaluation de l'insomnie chez les patients tunisiens atteints de cancers bronchopulmonaires primitifs.

INTRODUCTION: Sleep disorders are relatively common in oncology. However, they have not been well studied and are often treated insufficiently. AIM: To assess the prevalence and severity of insomnia in lung cancer patients and evaluate the relationship between insomnia and certain clinical parameters. METHODS: A cross-sectional study was undertaken of patients in Tunis with primary lung cancer. Socio-demographic and clinical data were obtained from the medical records Patients were then asked to answer questionnaires related to insomnia (ISI), depression-anxiety (HAD) and quality of life (QLQ-C30). RESULTS: Fifty patients with lung cancer were included (46 men, 4 women). The average age was 59±9 years. Insomnia was found in 24 patients (48%) and 60% of patients had depression. HAD was significantly higher in the insomniac patients (21.54±8.96 vs. 9.81±5.28, P<0.0001). Similarly, the QLQ-C30 was significantly lower in these patients (41.24±12.55 vs. 56±16.88, P<0.01). ISI was significantly correlated with HAD and QLQ-C30. CONCLUSION: Insomnia is common in patients with lung cancer. It is responsible for impaired quality of life and psychological distress. Diagnosis and management of insomnia in patients with lung cancer is therefore mandatory.

[Tuberculous pseudotumour, a challenging diagnosis]. / La tuberculose pseudotumorale, un diagnostic difficile.

INTRODUCTION: The pseudotumorous form of tuberculosis is a rare entity. Whatever its location, it can simulate neoplasia by its radiological and/or endoscopic appearances. We highlight the diagnostic difficulties associated with this type of presentation. METHODS: We performed a retrospective study of inpatient records from 2003 to 2016 in the pneumology department of La Rabta Hospital to identify cases of thoracic tuberculous pseudo-tumor. RESULTS: Seventeen patients were identified. The median age was 41 years and their symptomatology was dominated by cough and general debility. All had abnormal radiology with 10 cases of suspect lesions. Fibre-optic bronchoscopy revealed endobronchial abnormalities in 11 cases. The median overall diagnostic delay was 97 days. The diagnosis was confirmed bacteriologically in five cases, histologically in 14 cases and based on clinical presumption in one case. The progression was favourable: 13 patients have been declared cured and four patients are still undergoing treatment. CONCLUSION: Making a positive diagnosis of thoracic tuberculous pseudotumour can be difficult, as bacteriological samples are often negative. This can lead to a significant delay in diagnosis and treatment.

[Home non-invasive ventilation for chronic obstructive pulmonary disease]. / Ventilation non invasive à domicile au cours de la broncho-pneumopathie chronique obstructive.

INTRODUCTION: The benefits of long-term non-invasive ventilation (NIV) in the management of chronic obstructive pulmonary disease (COPD) patients remain controversial. AIM: To analyze the characteristics of COPD patients under home NIV and to evaluate its impact among this population. METHODS: We carried out a retrospective study between January 2002 and April 2016 of COPD patients under long-term NIV at "la Rabta" and the Military Hospital. RESULTS: There were 27 patients with an average age of 64 and a sex ratio (M/F) of 0.92. Active smoking was reported in 96.3%. A persistent hypercapnia following an acute exacerbation of COPD with failure to wean the NIV was the main indication of long-term NIV. We noted a reduction in hospital admissions in the first year of 60% and in intensive care of 83.3% (P<10-3). There was no non-significant decrease of PaCO2 (4.5mmHg). There was no modification in FEV 1 and in FVC (P>0.05). The survival rate was 96.3% at 1 year, 83.3% at 2 years and a median survival of 24 months. CONCLUSIONS: Our study suggests that home NIV contributes to the stabilization of some COPD patients by reducing the hospitalizations rates for exacerbation. More prospective studies are needed to better assess the impact of NIV on survival and quality of life and to better define the COPD patients who require NIV.

[Clinical and microbiological profile of patients experiencing relapses of tuberculosis in Tunisia]. / Profil clinique et microbiologique des patients en situation de rechute tuberculeuse en Tunisie.

INTRODUCTION: Relapse of tuberculosis (TB) is known to be as one of the major risk factors for resistant TB. The aim of this study is to focus on clinical, radiological and bacteriological features of patients with pulmonary TB relapse. METHODS: We performed a retrospective survey in the respiratory department of the teaching hospital La Rabta in Tunis between January 2000 and December 2014. Data of patients with a pulmonary TB relapse were analyzed. RESULTS: During the study period, among 1250 patients hospitalized for pulmonary TB, 44 had a TB relapse. The TB relapse rate was estimated to be at 3.5%. The average age was 43.95±16.7 years. Sex ratio was 5,2. Eighty one percent of patients were current smokers. Alcoholism was found in 40.9% of cases. The mean time to relapse was 6.37±3.7 years. The radiological lesions were moderately extended at least in 54.6% of cases. A resistant TB was found in 33% of cases (mono-resistance: 33.3%, multi-drug resistance (TB-MR): 11,1%, poly-resistance: 55.5%). The most incriminated drugs were isoniazid, rifampicin and pyrazinamide. One patient received TB-MR treatment regimen for 18 months. In the other cases, the duration of treatment was prolonged. Recovery was obtained in 72.7% of cases, two patients died and 22.7% of patients were lost to follow up. CONCLUSION: In Tunisia, TB relapse usually affects young male patients who are often alcoholic and smokers. Resistant TB is frequent among these patients. These findings lead us to emphasize the need of rapid diagnosis tools and adapted treatment regimen in these patients.

[Occupational asthma: Clinical and professional profile of the Tunisian asthmatic worker]. / Asthme professionnel : profil clinique et professionnel du travailleur asthmatique tunisien.

INTRODUCTION: Asthma takes up a great importance in occupational diseases but remains underestimated as it is insufficiently diagnosed. OBJECTIVE: We aimed to access the clinical and professional profile of the Tunisian asthmatic worker. MATERIALS AND METHODS: It was a retrospective descriptive study in a professional pathology unit in a university hospital. All patients referred by their doctor for symptoms suggestive of occupational asthma, during a period from 2000 to 2008, were included. RESULTS: Forty-eight patients were selected from 172. The mean age was 40 years, with a male predominance (56 %). In 2/3 of the cases, it was the textile workers, food and chemical industry. The etiological agents incriminated were textile dust in 18.8 % of cases followed by isocyanates and flour. Typical episodes of wheezing dyspnea were present in 52 % and atopy in 54.2 % of workers. In 2 % of cases, symptoms disappeared and worsened in 18.8 %. CONCLUSIONS: The prognosis of OA depends on early end accurate diagnosis. The physician's role is to initiate the appropriate diagnostic approach, which must comply with the Tunisian conditions.

[Night-to-night variability of the obstructive sleep apnoea-hypopnoea syndrome]. / Variabilité inter-nuits du syndrome d'apnée-hypopnée obstructive du sommeil.

The apnoea-hypopnoea index (AHI) is the primary measurement used to characterize the obstructive sleep apnoea-hypopnoea syndrome (OSAHS). Despite its popularity, there are limiting factors to its application such as night-to-night variability. AIM: To evaluate the variability of AHI in the OSAHS. PATIENTS AND METHODS: A prospective study was designed in our university hospital's sleep unit. Adults with clinical suspicion of OSAHS underwent 2 consecutive nights of polysomnographic recording. The population was divided in two groups according to an AHI>or<10. Patients with psychiatric disorders or professions that might result in sleep deprivation or an altered sleep/wake cycle were excluded. RESULTS: Twenty patients were enrolled. The mean age was 50.6±9.3 years. OSAHS was mild in 4 cases, moderate in 6 cases and severe in 8 cases. AHI was less than 5 in two cases. AHI values were not significantly altered throughout both recording nights (33.2 vs. 31.8 events/h). A significant positive correlation was found between AHI measured on the first and the second night. However, a significant individual variability was noted. Comparison between both patient's groups showed a correlation between AHI and the body mass index. CONCLUSION: This study demonstrates that the AHI in OSAHS patients is well correlated between two consecutive nights. However, a significant individual variability should be taken into consideration, especially when AHI is used in the classification of OSAHS or as a criterion of therapeutic success.

[Primary infection and pulmonary tuberculosis]. / La primo-infection et la tuberculose pulmonaire.

Tuberculosis is a major public health problem worldwide. Indeed, a third of the world population is infected with Mycobacterium tuberculosis and more than 8 million new cases of tuberculosis each year. Pulmonary tuberculosis is the most common location. Its diagnosis is difficult and often established with a delay causing a spread of infection. The diagnosis of tuberculosis infection is mainly based on immunological tests represented by the tuberculin skin test and detection of gamma interferon, while the diagnosis of pulmonary tuberculosis is suspected on epidemiological context, lasting general and respiratory symptoms, contrasting usually with normal lung examination, and a chest radiography showing suggestive lesions. The radioclinical feature may be atypical in patients with extreme ages and in case of immunodeficiency. Confirmation of tuberculosis is bacteriological. Conventional bacteriological methods remain the reference. Innovative tests using the technique of molecular biology have improved the diagnosis of tuberculosis in terms of sensitivity and especially speed. However, those techniques are of limited use.

[Epidemiology of tuberculosis]. / Épidémiologie de la tuberculose.

Tuberculosis is a contagious disease caused by Mycobacterium tuberculosis. It represents, according to World Health Organization (WHO), one of the most leading causes of death worldwide. With nearly 8 million new cases each year and more than 1 million deaths per year, tuberculosis is still a public health problem. Despite of the decrease in incidence, morbidity and mortality remain important partially due to co-infection with human immunodeficiency virus and emergence of resistant bacilli. All WHO regions are not uniformly affected by TB. Africa's region has the highest rates of morbidity and mortality. The epidemiological situation is also worrying in Eastern European countries where the proportion of drug-resistant tuberculosis is increasing. These regional disparities emphasize to develop screening, diagnosis and monitoring to the most vulnerable populations. In this context, the Stop TB program, developed by the WHO and its partner's, aims to reduce the burden of disease in accordance with the global targets set for 2015.

[Diagnosis delay of pleural and pulmonary tuberculosis]. / Délai diagnostique de la tuberculose pulmonaire et pleurale.

Tuberculosis (TB) is still being endemic in our country. Time until management determines both evolution and prognosis of this condition. The aim of this work is to evaluate the delay in diagnosis of TB in a respiratory unit from a university hospital series. The authors conducted a cross-sectional study including patients with pulmonary TBC and/or pleural. An evaluation of time management was conducted from the beginning of symptoms and various consultations with reference to the date of hospitalization and treatment set up. One hundred patients were included (pulmonary TB: 68 cases, pleural TB 23 cases, miliary pulmonary TB: 4 cases, pulmonary TB associated with other extrathoracic locations: 5 cases). The mean time of patient delay and total delay institution were respectively 43.6, 25.7 and 69.3 days. Variables responsible for long delays were: number of consultations more than 3 before hospitalization, empirical antibiotic therapy, of a regional hospital first consultation and the presence of extra-respiratory impairment. The patient delay was considered long. A reorganization of the TB control program, in particular by partial decentralization of care and health education is imperative in order to improve the quality of tuberculosis management in our country.