A feasible HPTLC method for concurrent quantitation of allopurinol-montelukast co-therapy in plasma and evaluation of their hepatic and renal effects in rats: Analytical, biochemical, and histopathological study.

Recent studies presented the crucial role of montelukast (MON, a leukotriene receptor antagonist) against gouty arthritis and its protective effect on drug-induced liver and kidney injury. Allopurinol (ALO, a selective xanthine oxidase inhibitor) is also used for treatment of hyperuricemia, however, it induces hepatotoxicity and acute kidney injury. Therefore, this study introduces the first analytical/biochemical/histopathological assay for MON-ALO co-therapy and aims to: inspect the hepatic and renal impacts of ALO, MON and their combination in rats via biochemical and histopathological examinations, propose and validate a facile HPTLC method for concurrent estimation of ALO-MON binary mixture in human plasma, and employ this method to attain the targeted drugs in real rat plasma. First, the cited drugs in human plasma were simultaneously separated utilizing silica gel G 60 F254-TLC plates. The separated bands were scanned at 268 nm demonstrating appropriate linearities (50.0-2000.0 ng band-1 for each drug) and correlations (0.9986 and 0.9992 for ALO and MON, correspondingly). The calculated detection and quantitation limits, as well as recoveries confirmed the method's reliability. This procedure was validated, and the stability studies were achieved according to Bioanalytical Method Validation Guideline. This work was extended to investigate the possible hepatic and renal effects of ALO, MON and their co-therapy in rats. Using rat's gastric tube, the following was administered to four groups of male Wistar rats: Group Ia and Ib as control (received either saline or DMSO), Groups II, III, and IV were given MON, ALO, and MON+ALO, respectively. Good correlation between the measured biochemical parameters and the observed histopathological changes was encountered. Considerable drop in aspartate transaminase and alanine transaminase levels, in addition to lower liver damage changes were observed in the combination group compared to MON or ALO-treated groups. Regarding renal changes, ALO-MON co-therapy caused elevation in the serum creatinine and blood urea nitrogen levels when compared to controls and MON- or ALO-treated groups. Severe proteinaceous casts accumulation in kidney tubular lumen, severe congestion, and severe tubular necrosis were also noticed in the combination group. Lastly, this study suggests ALO-MON co-treatment not only as a preventive therapy against gouty arthritis but also as a new line to minimize ALO-induced hepatic injury. However, co-administration of ALO and MON should be further studied to assess the benefits and risks in various tissues, adjust the MON dosing, and monitor its nephrotoxic effect.

Value of therapeutic drug monitoring of endoxifen in Egyptian premenopausal patients with breast cancer given tamoxifen adjuvant therapy: A pilot study.

BACKGROUND: The complex metabolic profile of tamoxifen anticancer drug and polymorphism in its metabolizing enzymes particularly CYP2D6 contribute to the high-observed inter-individual variability in its main active metabolite endoxifen. Therapeutic drug monitoring of endoxifen may play a key role in optimizing tamoxifen therapy, and control of both adverse effects and cancer recurrence. This pilot study aims to assess the clinical benefits of applying endoxifen measurement during tamoxifen therapy in patients with breast cancer. METHODS: Adult premenopausal breast cancer patients ≥ 18 years who received tamoxifen at a fixed dose of 20 mg daily were included. The primary endpoint was to identify the inter-subject variability in serum concentration of the drug and its metabolites especially endoxifen, through fixation of the tamoxifen dose. The secondary endpoint was to check the correlation between endoxifen metabolite concentration and the development of tamoxifen's adverse effects and cancer recurrence. RESULTS: Sixty patients were included in the study with a mean age of 38.4 ± 0.6 years (range: 26-50). The mean concentration of tamoxifen and endoxifen was 181 ± 9.6 ng/mL and 31.49 ng/mL, respectively. The inter-individual variability in concentrations for the drug and its active metabolite as estimated by the coefficient of variation percentage was in 41% and 31%, respectively. Cancer recurrence was observed in a group of patients (n = 16) with an average endoxifen level of 24.48 ng/mL. Another group of patients (n = 25) developed different tamoxifen adverse effects including hot flashes, vaginal bleeding, endometrial thickness, and ovarian cysts with the average endoxifen level of 38.61 ng/mL. The rest of the patients (n = 19) who responded smoothly to the drug with no complications had an average endoxifen level of 31.37 ng/mL. Analysis of variance test showed a significant difference in endoxifen levels between the three groups (p = 0.002). CONCLUSION: The measurement of the endoxifen active metabolite of tamoxifen in breast cancer patients can help dose optimization in light of the observed wide inter-individual variability in drug fixed-dose related concentration of the metabolite. Monitoring of serum concentration of endoxifen can help to reveal, reduce and control tamoxifen's adverse effects and cancer recurrence.

Systemic isotretinoin has an impact on hemoglobin, ferritin, urea, ceruloplasmin, albumin, uric acid levels, and neutrophil to lymphocyte ratio in acne patients.

BACKGROUND: Patients suffering from moderate-to-severe acne are commonly treated with systemin isotretinoin; however, a great controverse about its safety had been raised. The aim of the present study is to evaluate the effects of isotretinoin on hepatic, renal, and hematologic functions and to evaluate the potential oxidative stress in relation to isotretinoin therapy. METHODS: Fifty-three female patients, treated from moderate-severe acne with isotretinoin (0.5 mg/kg/day), were included. Blood samples were taken for measuring low density lipoprotein (LDL), triglycerides, hemoglobin, erythrocyte sedimentation rate (ESR), bilirubin, total protein, albumin, globulin, blood urea nitrogen, ferritin, uric acid, creatinine, C-reactive protein (CRP), ceruloplasmin, alanine transaminase (ALT), aspartate transaminase (AST) levels, and red blood cells (RBC), white blood cells (WBCs), and platelet counts before starting isotretinoin treatment and 6 months later. RESULTS: Isotretinoin was associated with increased levels of triglycerides, LDL, ESR, CRP, uric acid, and ferritin after 6 months of therapy (p < 0.0001), blood urea levels were significantly elevated from 3.681 ± 0.91 to 3.838 ± 0.877 (p = 0.014), ALT, AST, hemoglobin, globulin, and total proteins were significantly elevated after 6 months. Platelets, WBCs, albumin, albumin/globulin ratio, copper, ceruloplasmin, and neutrophil/lymphocyte ratio were significantly decreased after 6 months. CONCLUSION: Isotretinoin therapy could be associated with oxidative stress and hepatic, lipid, and blood abnormalities in patients with acne. Serum ferritin was elevated while serum ceruloplasmin was decreased. Isotretinoin could also affect immune regulation (decreasing neutrophil to lymphocyte ratio), isotretinoin was associated with a possible positive nitrogen balance (increasing proteins) and with elevations of blood urea nitrogen and uric acid levels.

Celecoxib has Preventive and Therapeutic Benefits against Nephrotoxicity Caused by Gentamicin in Mice.

It's crucial to comprehend the impact of oxidative stress and pro-inflammatory cytokines in the gentamicin-induced kidney injury mechanism. Celecoxib was administered orally either before or after intraperitoneal therapy with gentamicin in mice. The serum levels of creatinine (SCr), blood urea nitrogen (BUN), IL-6, and TNF-α were measured by ELISA test, as well as the levels of the kidney tissue malondialdehyde (MDA), and glutathione (GSH) were also estimated spectrophotometrically. The renal expression of nuclear factor-κB (NF-κB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and cyclooxygenase 2 (COX-2) mRNAs were evaluated by qPCR. Histopathological evaluation and Immunohistochemical examination of kidney NF-κB, IL-6, and COX-2 were also, performed. Celecoxib successfully prevented gentamicin-induced kidney damage as indicated by reducing blood BUN, SCr, and tissue MDA levels and increasing renal tissue GSH levels as well as lowering the blood IL-6 and TNF-α in comparison to mice received gentamicin. Furthermore, celecoxib has inhibited COX-2, NF-κB, IL-6, and TNF-α expression in the renal tissue. It is noteworthy that celecoxib therapy after gentamicin administration brought about substantially the same results as celecoxib treatment before gentamicin injection in mice. Our results showed the role of celecoxib as a therapeutic tool for gentamicin-induced nephrotoxicity as well as raised its beneficial prophylactic role in this medical challenge by attenuating oxidative stress and inflammation.

Frequency and impact of DHODH, ABCG2 and CYP2C19 SNPs on the therapeutic efficacy, tolerability and toxicity of leflunomide.

Introduction: Leflunomide is one of the commonly used drugs in treatment of rheumatoid arthritis (RA), which on administration is converted into its active metabolite teriflunomide. Aim: Our aim is to evaluate the frequencies of dihydrooroate dehydrogenase (DHODH) (rs3213422), ABCG2 (rs2231142) and CYP2C19 (rs4244285) allele distribution among patients receiving leflunomide for RA and their possible impact on leflunomide performance in disease control. Patients & methods: Patients (>18 years) who fulfilled the 2010 ACR classification criteria for RA receiving leflunomide (20 mg/day) were included in the study. Disease activity score 28 was used to assess patients disease activity. Blood samples were collected for full blood count and blood chemistry. Genomic DNA was extracted from peripheral blood. The selection of SNPs was based on the criteria of minor allele frequency among Caucasians. Results: A significant association between the therapeutic outcome of leflunomide and DHODH genotyping was observed but not with CYP2C19 and ABCG2. Importantly, there is a significant association between DHODH (rs3213422) CC genotype and the number of patients with controlled disease. Conclusion: We strongly suggest that polymorphisms in the DHODH are the major factor affecting leflunomide pharmacogenetics and therapeutic efficacy.

Valproate attenuates hypertonic glycerol-induced rhabdomyolysis and acute kidney injury.

BACKGROUND AND AIM: The current study investigated the effects of treatment with 300 mg/kg valproic acid on rhabdomyolysis and acute kidney injury induced by intramuscular injection of hypertonic glycerol in rats. METHODS: Four groups of male wistar rats: control and hypertonic glycerol, valproic acid and valproic acid + hypertonic glycerol treated groups were used. Blood urea nitrogen, serum creatinine, creatinine kinase (CK) and CK MB, myoglobin and renal reduced glutathione (GSH) levels were measured. Histopathological examination of the kidneys was carried out to evaluate the degree of renal injury in each group. The expression of interleukin-1 beta "IL-1ß" in renal tissue was detected using immunohistochemistry. RESULTS: Hypertonic glycerol administration led to severe renal tubular damage with a significant elevation of blood urea nitrogen, serum creatinine, creatinine kinase, CK MB and myoglobin levels and overexpression of IL-1ß compared to control group. Valproic acid administration attenuated both the muscle injury and the acute kidney injury induced by hypertonic glycerol, estimated through a significant reduction of creatinine kinase, myoglobin, and serum creatinine. Valproic acid administration caused a significant increase in GSH in the hypertonic glycerol + valproic acid group compared to the hypertonic glycerol group. A significant decrease in tubular necrosis grade, and expression of IL-1ß in hypertonic glycerol + valproic acid group compared to the hypertonic glycerol group was observed. CONCLUSION: This study demonstrates, for the first time to the best of our knowledge, that valproic acid could ameliorate the rhabdomyolysis and the related acute kidney injury in rats.

High doses of digoxin increase the myocardial nuclear factor-kB and CaV1.2 channels in healthy mice. A possible mechanism of digitalis toxicity.

BACKGROUND: Toxic effects of digoxin may occur with normal therapeutic serum level. However, the underlying mechanisms are not fully understood. Nuclear factor kappa-B (NF-kB) is an important transcription factor in most organ systems and is often implicated in the harmful effects of cardiac injury. NF-kB promotes inflammatory responses, mediates adverse cardiac remodeling and has a function correlation with calcium. The voltage-gated L-type calcium channel CaV1.2 mediates the influx of Ca+2 into the cell in response to membrane depolarization. Our aim was to characterize the role of NF-kB during digoxin toxicity and to assess its correlation with Cav 1.2 in healthy mice in vivo. METHODS: To address these questions, digoxin was administered in doses of 0.1, 1 or 5 mg/kg orally daily for seven days to the animals. Serum digoxin, serum calcium, atrial and ventricular calcium levels were measured. We, also, looked for NF-kB and CaV1.2 channel expression in cardiac muscle of mice. RESULTS: Digoxin at a dose of 0.1 mg/kg did not enhance serum, atrial, and ventricular Ca+2 levels, but were increased when digoxin dose of 1 and 5 mg/kg were administered. Histologically, myocardial necrosis and cellular infiltration on day 7 were significantly more severe in the 5 mg/kg/day digoxin group. Immunohistochemical studies showed more expression of both NF-kB and CaV1.2 in 1 and 5 mg/kg/day digoxin groups. CONCLUSIONS: These data suggest that NF-kB may be responsible for digoxin toxicity, at least partially via modulation of CaV1.2 and intracellular calcium homeostasis in the myocardium.

Genetic variants in 6-mercaptopurine pathway as potential factors of hematological toxicity in acute lymphoblastic leukemia patients.

AIM: We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia. MATERIALS & METHODS: Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity and relapse were investigated using a Cox proportional hazard model in 70 acute lymphoblastic leukemia patients from upper Egypt. RESULTS: We found significant associations between ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3 and ABCC4 SNPs and one or more of the hematological toxicity manifestations (neutropenia, agranulocytosis and leukopenia); age was significantly related to relapse. CONCLUSION: Genetic polymorphisms in enzymes and transporters involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.