Aplastic anemia secondary to tyrosine kinase inhibitor therapy in a patient with chronic myeloid leukemia.

INTRODUCTION: Nilotinib, as the second generation of tyrosine kinase inhibitor, has significant efficacy in patients with chronic myeloid leukemia resistant or intolerant to Imatinib. Aplastic anemia induced by tyrosine kinase inhibitors is an uncommon complication. CASE REPORT: A 34-year-old female case with CML in the chronic phase was treated with Imatinib in first-line therapy. Nilotinib was switched because of failure to achieve complete cytogenetic response at 6 months following Imatinib. Three years with Nilotinib, the patient developed a persistent pancytopenia grade 4 while a major molecular response was achieved. MANAGEMENT & OUTCOME: Nilotinib was discontinued. However, the hematologic finding of the patient had not recovered after three months. A bone marrow biopsy showed marked hypocellularity and fatty tissue without evidence of myelofibrosis. Immunosuppressive therapy was started. Unfortunately, the patient died due to septic and hemorrhagic shock nine months after Nilotinib interruption. According to Naranjo's algorithm, the causality relationship with the drug is probable with a score of 5. DISCUSSION: Aplastic anemia is an uncommon adverse event of tyrosine kinase inhibitors but it can be a fatal complication. The early diagnosis of aplastic anemia related to Nilotinib therapy is needed to avoid further detrimental effects of the drug.

Hypersensitivity pneumonitis related to imatinib mesylate therapy in a patient with chronic myeloid leukemia.

INTRODUCTION: Pulmonary toxicity causally related to Imatinib (IM) therapy is uncommon in patients with chronic myeloid leukemia. CASE REPORT: A 61-year-old patient with chronic myeloid leukemia was treated with IM at 400 mg daily dose. One month within IM, he developed skin lesions and then acute dyspnea and non-productive cough. Chest radiograph and high-resolution lung computed tomography (CT) revealed bilateral reticulonodular infiltration in both lungs. According to Naranjo's algorithm, the causality relationship with the drug is probable with a score of 7. The pharmacovigilance investigation was carried out and implicated IMManagement & outcome: IM was discontinued and started steroid therapy (Prednisolone®) at 1 mg/kg daily. Two weeks after, the dyspnea, and abnormal X-ray and CT findings are improved. DISCUSSION: The early diagnosis of pulmonary toxicity related to IM therapy is needed to avoid further determinal effects of the drug.

Protective effects of Cynara scolymus leaves extract on metabolic disorders and oxidative stress in alloxan-diabetic rats.

BACKGROUND: Diabetes mellitus (DM) is associated with hyperglycemia, inflammatory disorders and abnormal lipid profiles, currently the extracts from leaves of cynara scolymus has been discovered to treat metabolic disorders and has been stated by multitudinous scientists according to a good source of polyphenols compounds. The present study aimed to evaluate the protective effect of the ethanol leaves extract of C. scolymus in alloxan induced stress oxidant, hepatic-kidney dysfunction and histological changes in liver, kidney and pancreas of different experimental groups of rats. METHODS: We determinate the antioxidant activity by ABTS .+ and antioxidant total capacity (TAC) of all extracts of C. scolymus leaves, the inhibition of α-amylase activity in vitro was also investigated. Forty male Wistar rats were induced to diabetes with a single dose intraperitoneal injection (i.p.) of alloxan (150 mg/kg body weight (b.w.)). Diabetic rats were orally and daily administrated of ethanol extract from C. scolymus at two doses (200-400 mg/kg, b.w) or (12 mg/kg, b.w) with anti-diabetic reference drug, Acarbose for one month. Ethanol extract of C. scolymus effect was confirmed by biochemical analysis, antioxidant activity and histological study. RESULTS: The results indicated that the ethanol extract from leaves of C. scolymus showed the highest antioxidant activity by ABTS .+ (499.43g± 39.72 Trolox/g dry extract) and (128.75 ± 8.45 mg VC /g dry extract) for TAC and endowed the powerful inhibition in vitro of α-amylase activity with IC50=72,22 ug/uL. In vivo, the results showed that ethanol extract from the leaves of C. scolymus (200-400 mg/kg) decreased significantly (p < 0.001) the α-amylase levels in serum of diabetic rats, respectively associated with significant reduction (p < 0.001) in blood glucose rate of 42,84% and 37,91% compared to diabetic groups after 28 days of treatment, a significant lowered of plasma total cholesterol (T-Ch) by 18,11% and triglyceride (TG) by 60,47%, significantly and low-density lipoproteins (LDL-C) by 37,77%, compared to diabetic rats, moreover, the administration of ethanol extract appears to exert anti-oxidative activity demonstrated by the increase of CAT, SOD and GSH activities in liver, kidney and pancreas of diabetic rats. This positive effect of the ethanol extract from C. scolymus was confirmed by histological study. CONCLUSION: These observed strongly suggest that ethanol extract from the leaves of C. scolymus has anti-hyperglycemic properties, at least partly mediated by antioxidant and hypolipidemic effects.

Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity.

AIMS: Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODS: Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTS: Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONS: Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.

[Statins Use in Elderly Patients]. / Place des statines chez le sujet âgé.

The risk of cardiovascular disease in elderly is significantly higher than in young subjects; paradoxically some treatments that have proven their efficacy in reducing cardiovascular risk are often under prescribed in this age group. The benefits of statins in secondary cardiovascular prevention are well established in patients <80 years. In primary prevention, these drugs reduce the risk of myocardial infarction and stroke, but their effects on cardiovascular mortality remain uncertain. In very elderly patients, there are no randomized trials relative to the impact of statins on morbi-mortality in primary prevention as well in secondary prevention. Adverse effects in the elderly seem to be statistically similar to those occurring in young people , but the prescription in very old people should be individualized, taking into account the life expectancy, the life quality, the comorbidities, and especially the risk of drug interactions.

Pharmacological Studies of Artichoke Leaf Extract and Their Health Benefits.

Artichoke (Cynara scolymus) leaf extract was one of the few herbal remedies which the clinical and experimental trials have complemented each other. Both experimental and clinical effects have been verified through extensive biomedical herbal remedy research. Specifically, antioxidant, choleretic, hepatoprotective, bile-enhancing and lipid-lowering effects have been demonstrated, which corresponded with its historical use. Ongoing research seems to indicate that artichoke indeed have medicinal qualities. Most significant appears to be its beneficial effect on the liver. In animal studies, liquid extracts of the roots and leaves of artichoke have demonstrated an ability to protect the liver, with possibly even to help liver cells regenerate. Although research is not yet conclusive, scientists were optimistic that its long-standing use in humans for digestive and bowel problems was indeed justified. It may also play a role in lowering cholesterol and thus help to prevent heart disease. Boiled wild artichoke reduced postprandial glycemic and insulinemic responses in normal subjects but has no effect on metabolic syndrome patients. This article intended to review the wide ranging pharmacological effects of artichoke leaf extract.

Bioequivalence evaluation of glibenclamide 5-mg tablets: diabenil® and daonil® (in 24 healthy volunteers).

BACKGROUND: Prescription of generic products is a way to reduce health expense. Bioequivalence is the most appropriate procedure to evaluate the quality and therapeutic efficacy of a generic product. Generic prescriptions are a strategic choice in Tunisia. OBJECTIVE: We expose in this work, a bioequivalence study witch compare a generic (test) product: DIABENIL* manufactured by a Tunisian pharmaceutical industry Dar Essaidaly to the innovative (reference) product: DAONIL* of Aventis pharma laboratories. METHODS: The bioequivalence of two glibenclamide 5-mg tablets was determined in healthy human, adult volunteers after a single dose in a randomized cross-over in double blind study. Test and reference were administered to twenty-four healthy volunteers of both sexes after overnight fasting. In total, 15 Blood samples were collected before and following the administration of the drug. Serum concentrations of glibenclamide were determined by validated HPLC method. The pharmacokinetic parameters AUC0t, AUC0 , Cmax and tmax were tested for bioequivalence. RESULTS: All parameters showed bioequivalence between both formulations as their confidence intervals were within the bioequivalence acceptable range of 0.80-1.25 limits. CONCLUSION: We conclude that the two formulations exhibited comparable pharmacokinetic profiles and that the two products can be considered interchangeable in medical practice.

[Study of cross reactivity between proton pump inhibitors]. / Étude de l'allergie croisée entre les différents inhibiteurs de la pompe à protons.

Although rare, anaphylactic reactions induced by PPIs have been reported. The presence of cross-reactivity between different members of the group is not clear. We analyzed all cases of allergic skin reactions to PPIs notified in regional pharmacovigilance center of Sfax during a 12 years period and assessed the possibility of cross-reactions between different molecules of this class. An enquiry of pharmacovigilance was conducted for each case according to the French imputation method. We called then, all patients who developed an allergic reaction to a PPI with a plausible or credible imputation. A patch test to all the molecules was carried out to study the possibility of cross-reactivity between PPIs. Thirty-seven patients have developed skin disease, with a total of 1 172 cutaneous adverse effects (3%) notified in our regional pharmacovigilance center. The skin disease most frequently observed was maculopapular rash (19 cases or 51%), followed by urticaria in 9 cases (24%). The omeprazole was the most implicated in the genesis of these adverse events (in 31 cases: 83.78%). Lansoprazole was administered to 5 patients having allergy to omeprazole with good tolerance. Patch tests were realized for6 patients having allergy to omeprazole. They were positive with omeprazole at 72 h in all cases and negative with lansoprazole in 5 cases. In one third of cases, lansoprazole was a good alternative at patients developing allergy to omeprazole, esomeprazole or pantoprazole. In one case we have contraindicated all PPIs. In the other cases we have preconized surveillance for the use of lansoprazole.

[Adverse effects of sulfasalazine: discussion of mechanism and role of sulfonamide structure]. / Effets indésirables de la sulfasalazine : discussion de leur mécanisme et du rôle de la composante sulfamidée.

Sulfasalazine is widely used in the treatment of chronic inflammatory bowel disease (IBD) and certain rheumatic diseases. However, its use is associated with a high rate of adverse effects (AEs) which can be cutaneous, hematological, renal, hepatic, gastrointestinal or neurological. The aim of our study was to collect all cases of AEs suspected to be associated with the use of sulfasalazine in patients hospitalized in the department of Gastroenterology from the Hospital Hedi Chaker of Sfax (Tunisia) for a period of 5 years and to search the incriminated fraction (sulfonamide or salicylate). Our study population included 69 patients who received sulfasalazine for the treatment of IBD. We collected, in 23 patients (33%), 25 AEs suspected to be related to sulfasalazine. Cutaneous and hematological reactions are the most common. The subsequent administration of mesalazine was performed in 15 patients. It was well tolerated in 14 patients. So we were suspecting probably the responsibility of sulfonamide fraction in these cases. The mechanism of sulfasalazine induced AEs may be toxic or immunoallergic with the possibility of a cross-reaction with the other antimicroacterial sulfonamides.

Effect of Artichoke (cynara scolymus) on cardiac markers, lipid profile and antioxidants levels in tissue of HFD-induced obesity.

Obesity plays a pivotal role in the insulin resistance disease, which is related to hypertension, hyperlipidemia, type 2 diabetes mellitus, and an increased risk of cardiovascular disease. The purpose of the present study was done to evaluate the effect of artichoke leaves extract (ALE) in the high-fat diet (HFD)-induced cellular obesity and cardiac damage in Wistar rats. Body and organ weights, serum lipid profile, cardiac markers, and antioxidants enzymes were measured. Oral administration of ALE at two doses 200 and 400 mg/kg for a period of 60 days showed a significant decrease in body and organ weights, serum total cholesterol, triglycerides, LDH, ALT accompanied by decreasing in oxidative stress biomarker (MDA, and AOPP) and increasing antioxidant enzymes (SOD, CAT, and GPx) levels as compared to HFD groups. The histological findings showed a cardioprotective effect of ALE. These findings suggest that ALE exert anti-oxidant cardiac effects in HFD- induced obese rats.

Preventive effect of Artichoke (Cynara scolymus L.) in kidney dysfunction against high fat-diet induced obesity in rats.

A high-fat diet (HFD) promotes oxidative stress, which contributes to the development of kidney dysfunction. We examined the protective effects of an ethanol extract of artichoke leaves (EEA) compared to Atorvastatin (ATOR) in the kidney of Wistar rats fed a high-fat diet. The experimental animals were divided into five groups: control (Cont), HFD, HFD treated with EEA (200 mg/kg), HFD treated with EEA (400 mg/kg), and HFD treated with ATOR. Organ weights, lipid profile, renal markers, and antioxidants enzymes were measured. Oral administration of EEA (200 and 400 mg/kg) for 60 days showed a significant decrease in organ weights and kidney markers levels accompanied by decreasing in oxidative stress biomarkers as compared to HFD groups. The histological findings showed a renoprotective effect of artichoke extract. These findings suggest that EEA exerts anti-oxidant kidney effects in HFD- induced obese rats.

Protective effect of Urtica dioica in induced neurobehavioral changes, nephrotoxicity and hepatotoxicity after chronic exposure to potassium bromate in rats.

BACKGROUND AND PURPOSE: Chronic exposure to potassium bromate (KBrO3), a toxic halogen in the environment, has become a global problem of public health. The current study aims to elucidate for the first time the effect of Urtica dioica (UD) on behavioural changes, oxidative stress, and histopathological changes induced by KBrO3 in the cerebellum, kidney, liver and other organs of adult rats. STUDY DESIGN AND METHODS: The rats were divided into four groups: group 1 served as a control received physiological serum, Group 2 received KBrO3 (2 g/L of drinking water), group 3 received KBrO3 and Urtica dioica (100 mg/kg), and group 4 received KBrO3 and Urtica dioica (400 mg/kg). We then measured behavioural changes, oxidative stress, and biochemical and histological changes in the cerebellum, liver, kidney and others organs in these rats. After 30 days of treatment, the animals were sacrificed. RESULTS: We observed significant behavioural changes in KBrO3-exposed rats. When investigating redox homeostasis in the cerebellum, we found that mice treated with KBrO3 had increased lipid peroxidation and protein oxidation in the cerebellum. In addition, it inhibits hepatic and lipid peroxidation (malondialdehyde), advanced oxidation protein product (AOPP), attenuates KBrO3-mediated enzyme depletion, catalase, superoxide dismutase, glutathione peroxidase enzymatic and antioxidant activities in the liver and kidney. Rats that were co-managed with Urtica dioica at the high portion of 400 mg/kg indicated a higher effect than that treated with the low dose of 100 mg/kg practically in all the tests carried out. CONCLUSION: Our results demonstrate that Urtica dioica is a potential therapeutic agent for oxidative stress associated with neurodegenerative diseases.

Creation of an adequate animal model of hyperuricemia (acute and chronic hyperuricemia); study of its reversibility and its maintenance.

AIM: Hyperuricemia is defined by the European Rheumatology Society as a uric acid level greater than 6 mg/dl (60 mg/l or 360 µmol/l). Our goal was to evaluate the hypouricemic effect of nettle. For this reason, we have first of all try to create an hyperuricemic animal model which is very suitable because at the level of literature there is not an exact model, there are many models and our objective is to set an adequate model. MATERIALS AND METHODS: An attempt has been made to test acute and chronic hyperuricemia by varying the duration and method of induction of potassium oxonate. Similarly, attempts have been made to induce chronic hyperuricemia through an animal and vegetable diet. The reversibility of hyperuricemia was tested with a maintenance protocol. KEY FINDINGS: For the creation of the hyperuricemia model, it has been shown that acute hyperuricemia cannot be induced by short administration of potassium oxonate and persistent chronic hyperuricemia can be induced only after daily administration of oxonate of potassium by intraperitoneal injection for 15 days. Indeed, hyperuricemia was reversible after stopping the administration of potassium oxonate. The high-purine diet is also capable of inducing chronic hyperuricemia but to a less extent. SIGNIFICANCE: After creating an adequate model of hyperuricemia while setting the dose of potassium oxonate, route of administration and duration. A maintenance protocol was followed which subsequently made it possible to deduce that the daily administration of potassium oxonate must be continued to maintain the hyperuricemia.

Screening of pharmacological uses of Urtica dioica and others benefits.

BACKGROUND: Natural products, whether pure compounds or standardized plant extracts, offer unlimited opportunities for other drug sources due to the unequaled availability of chemical diversity. Stinging Nettle (Urtica dioica) is a unique herbaceous perennial flowering plant with stinging hairs. The leaf extract of nettle was one of the herbal remedies which the experimental, clinical and trials have complemented each other. It is a very well-known plant with a wide historical background use of stems, leaves and roots. It has a long history of use as power sources such as soup or curry, and also used as fiber and a medicinal plant. Urtica dioica has traditionally been used in the control of cardiovascular disorders especially hypertension. The leaf extract of Urtica dioica has been reported to improve glucose homeostasis in vivo. Nettle root could prevent some of the effects of prostatic hyperplasia. Extracts of nettle leaf are used as anti-inflammatory remedies for rheumatoid arthritis. Urtica dioica extract significantly increased the sensitivity of breast cancer cells to paclitaxel. This article aims to review the very wide ranging of pharmacological effects of Urtica dioica extract. METHODS: Articles on PuBmed between 1980 and 2019. RESULTS: Description and critical review of the pharmacological effects of Urtica dioica and other uses. CONCLUSION: The nettle is actually a plant with many qualities and uses. The interest in it is deserved and it is given by other studies and investigations.

Chronic exposure to cocaine is associated with persistent behavioral disturbances. A cross-sectional dimensional study in outpatients with multiple substance use disorders.

RATIONALE: Behavioral disturbances (BD) are prevalent in patients with substance use disorders (SUD). OBJECTIVES: To test the hypothesis that chronic exposure to cocaine could favor the acquisition of BD that were not present in childhood. METHODS: We used child and adult ADHD self-report screening scales (WURS-25 and ASRS-6, respectively, with their usual threshold) as assessment tools for significant BD. In a cross-sectional assessment of 382 patients with multiple SUD, we investigated BD and then "de novo" BD (i.e., by restricting the sample to patients below the threshold for childhood BD) (N = 214). We also tested for a gradient effect between patients' lifetime DSM IV cocaine and opioid dependence status and the prevalence of BD. RESULTS: BD were found in 188/382 (42.9%) subjects and in 74/214 (34.6%) subjects. Three clinical factors were associated with BD in the whole sample: the number of cocaine dependence criteria (OR = 1.36 [1.14-1.64], p = 0.001), the number of opioid dependence criteria (OR = 0.69 [0.52-0.91], p = 0.010), and a personal history of using cocaine through rapid routes of administration (OR = 0.41 [0.19-0.88], p = 0.022). The same three factors were associated with "de novo" BD in the restricted sample: OR = 1.35 ([1.11-1.63], p = 0.002), OR = 0.83 ([0.70-0.99], p = 0.046), and OR 0.37 ([0.16-0.86], p = 0.022), respectively. There were significant gradients for BD according to the cocaine exposure categories in the whole (Mantel-Haenszel, p < 0.001) and in the restricted sample (Mantel-Haenszel, p = 0.002). CONCLUSIONS: Cocaine exposure was positively associated with behavioral disturbances in a dose-dependent manner in this clinical sample, whilst opioid exposure showed a negative association.

Safety assessment of cefuroxime on male reproductive system: Subacute toxicity and potential reversibility after a complete cycle of spermatogenesis and epididymal maturation in Wistar rats.

The effects of cefuroxime on reproductive system were investigated in male rats. Doses of 0, 30, 60 or 120 mg/kg of cefuroxime were intraperitoneally injected daily, for 7 days. Half of the rats were euthanized 24 h after the last dose and other half were induced to death 70 days after the last treatment. After 8 days of the experiment, results showed that cefuroxime induced a significant reduction in the weights of testes, epididymis and accessory sex organs. In addition, it decreased sperm quality, plasma testosterone level, and antioxidant enzyme activities while increasing the level of malondialdehyde. After a complete cycle of spermatogenesis and epididymal maturation, the results indicated complete reversibility of the adverse effects previously mentioned. In conclusion, cefuroxime induced reversible dose-dependent adverse effects on testicular and epididymal functions of rats.

LC-MS/MS Analysis and Hepatoprotective Activity of Artichoke (Cynara scolymus L.) Leaves Extract against High Fat Diet-Induced Obesity in Rats.

Cynara scolymus L. (Artichoke) has been used for the treatment of metabolic disorders. The purpose of the present study was to investigate the hepatoprotective effect of Cynara scolymus leaves extract against a high fat diet (HFD) induced rats. This study investigated the most abundant phenolic compounds rich Cynara scolymus leaves extract and it is antihypercholesterolemic and antioxidative effects in vivo. The hypercaloric high fat diet (HFD) was treated with 200 mg/kg and 400 mg/kg of ethanol extract (EEA) from leaves of Cynara and atorvastatin (ATOR) (10 mg/kg/day) during an 8-week period. Lipid profile was measured and oxidative stress systematic in hepatic tissue was determined. Our data revealed that HFD-induced hepatic dysfunction manifested by significant abnormal levels of AST, ALT, ALP, LDH, and OCT was accompanied by increasing levels of oxidative stress biomarker (ROS, MDA, and AOPP) while decreasing in antioxidant status. Coadministration of EEA significantly reduced serum lipid profile and hepatic disorders which was confirmed to be histological by reducing the fatty liver deposition in hepatic lobule. These findings suggest that Cynara leaves exert antiobesity and antioxidant liver effects in HFD-induced obese rats.