The prognosis of lipid reprogramming with the HMG-CoA reductase inhibitor, rosuvastatin, in castrated Egyptian prostate cancer patients: Randomized trial.

AIM: The role of surgical castration and rosuvastatin treatment on lipid profile and lipid metabolism related markers was evaluated for their prognostic significance in metastatic prostate cancer (mPC) patients. METHODS: A total of 84 newly diagnosed castrated mPC patients treated with castration were recruited and divided into two groups: Group I served as control (statin non-users) while group II treated with Rosuvastatin (20 mg/day) for 6 months and served as statin users. Prostate specific antigen (PSA), epidermal growth factor receptor (EGFR), Caveolin-1 (CAV1), lipid profile (LDL, HDL, triglycerides (TG) and total cholesterol (TC)) and lipid metabolism related markers (aldoketoreductase (AKR1C4), HMG-CoA reductase (HMGCR), ATP-binding cassette transporter A1 (ABCA1), and soluble low density lipoprotein receptor related protein 1 (SLDLRP1)) were measured at baseline, after 3 and 6 months. Overall survival (OS) was analyzed by Kaplan-Meier and COX regression for prognostic significance. RESULTS: Before castration, HMG-CoA reductase was elevated in patients <65 years (P = 0.009). Bone metastasis was associated with high PSA level (P = 0.013), but low HMGCR (P = 0.004). Patients with positive family history for prostate cancer showed high levels of EGFR, TG, TC, LDL, alkaline phosphatase (ALP), but low AKR1C4, SLDLRP1, CAV1 and ABCA-1 levels. Smokers had high CAV1 level (P = 0.017). After 6 months of castration and rosuvastatin administration, PSA, TG, LDL and TC were significantly reduced, while AKR1C4, HMGCR, SLDLRP1, CAV1 and ABCA-1 were significantly increased. Overall survival was reduced in patients with high baseline of SLDLRP1 (>3385 pg/ml, P = 0.001), PSA (>40 ng/ml, P = 0.003) and CAV1 (>4955 pg/ml, P = 0.021). CONCLUSION: Results of the current study suggest that the peripheral lipidogenic effects of rosuvastatin may have an impact on the treatment outcome and survival of castrated mPC patients. TRAIL REGISTRATION: This trial was registered at the Pan African Clinical Trial Registry with identification number PACTR202102664354163 and at ClinicalTrials.gov with identification number NCT04776889.

Health literacy among Saudi population: a cross-sectional study.

Health literacy is a major problem worldwide and adversely affects an individual's health. The aim of the present study was to assess health literacy level among Saudi population. A cross-sectional study was conducted among a randomly selected population (n = 500) in Saudi Arabia. The questionnaire comprised of questions pertaining to demographic characteristics, health literacy and health information. Health literacy was measured by REALM-R test. Internal reliability was determined using Cronbach's alpha coefficient. The majority of the respondents had intermediate (43.8%) and basic (34.4%) health literacy levels. A higher percentage among men had intermediate (59.8%) and basic (70.93%) health literacy levels compared with women. About 30% of respondents had difficulty in understanding health screening tests and disease treatment. More than half of participants (52.4%) had difficulty in finding health information. The REALM-R test revealed that about 42.6% of individuals with score of >6 had adequate health literacy compared with 57.4% with score of ≤6 had inadequate health literacy. The present study demonstrated that a majority of Saudi individuals had inadequate health literacy that associated with poor knowledge of health information. Our findings highlighted the importance of understanding the status of health literacy among Saudis and the need for educational programs to raise the health literacy awareness among Saudi population.

A qualitative study to explore the perception and behavior of patients towards diabetes management with physical disability.

BACKGROUND: This study aimed to determine self-monitoring practices, awareness to dietary modifications and barriers to medication adherence among physically disabled type 2 diabetes mellitus patients. METHODS: Interview sessions were conducted at diabetes clinic-Penang general hospital. The invited participants represented three major ethnic groups of Malaysia (Malay, Chinese and Indians). An open-ended approach was used to elicit answers from participants. Interview questions were related to participant's perception towards self-monitoring blood glucose practices, Awareness towards diet management, behaviour to diabetes medication and cues of action. RESULTS: A total of twenty-one diabetes patients between the ages 35-67 years with physical disability (P1-P21) were interviewed. The cohort of participants was dominated by males (n = 12) and also distribution pattern showed majority of participants were Malay (n = 10), followed by Chinese (n = 7) and rest Indians (n = 4). When the participants were asked in their opinion what was the preferred method of recording blood glucose tests, several participants from low socioeconomic status and either divorced or widowed denied to adapt telemonitoring instead preferred to record manually. There were mixed responses about the barriers to control diet/calories. Even patients with high economic status, middle age 35-50 and diabetes history of 5-10 years were influenced towards alternative treatments. CONCLUSIONS: Study concluded that patients with physical disability required extensive care and effective strategies to control glucose metabolism. PRACTICE IMPLICATION: This study explores the patients' perspectives regarding treatment management with physical disability.

Mechanism and implication of cephalosporin penetration into oropharyngeal mucosa.

The aim of this study was to explore the mechanism(s) by which oral cephalosporins penetrate into human oropharyngeal mucosa, and thus, the availability of sufficient concentrations at the site of infection. Two oral cephalosporin prototypes, cephalexin (first generation) and cefixime (third generation), were administered to five healthy subjects at two different visits with a 1-week washout period. Plasma and saliva samples were collected and drug concentrations were measured using an appropriate HPLC method. The maximum plasma concentrations (Cmax) of cefixime and cephalexin were 2.97+/-0.24 microg ml(-1) and 77.65+/-18.91 microg ml(-1), respectively. These concentrations were associated with a maximum salivary concentration (CSmax) of 0.56 microg ml(-1) for cefixime and 3.34 microg ml(-1) for cephalexin. Such levels exceed the reported minimal inhibitory concentration (MIC) for Streptococcus pyogenes and Streptococcus pneumoniae. The average concentration of cefixime in saliva corresponded to its plasma free fraction (saliva/plasma [S/P] ratio; 0.34). However, this observation was not true for cephalexin, for which antibiotic concentrations in the saliva did not appear to correspond to its plasma free fraction (0.8-0.85), with an S/P ratio of only 0.092. Our findings indicate that an active transport mechanism exists for cefixime excretion into human oropharyngeal mucosa, whereas cephalexin is passively diffused, although to a limited extent, as measured by its salivary concentrations.

Effects of mycophenolate mofetil on cisplatin-induced renal dysfunction in rats.

PURPOSE: Inflammation and oxidative stress are important events among the plethora of mechanisms involved in cisplatin (CDDP)-induced nephrotoxicity. The aim of this study was to evaluate the effect of mycophenolate mofetil (MMF), an immunosuppressive, in the protection against CDDP-induced renal dysfunction. METHODS: Rats were divided into four groups; untreated-control group, CDDP-treated group (7 mg/kg, single intraperitoneal dose), MMF-treated group (40 mg/kg/day orally for 5 successive days) and the fourth group was treated with both drugs and MMF treatment was started 1 day prior to CDDP administration. Nephrotoxicity was assessed 7 days after the CDDP treatment by measuring serum indices of nephrotoxicity, kidney weight as a percentage of total body weight, kidney's tissue peroxidative alterations and total nitrate/nitrite concentration (NOx) and the results were confirmed histopathologically. RESULTS: Rats treated with CDDP showed marked nephrotoxicity as evidenced from the significant increase in serum creatinine and urea levels and decrease in serum calcium and albumin levels. Kidneys of CDDP-treated rats showed significant increases in kidney weight and malondialdehyde (MDA) production level and decreases in total NOx concentration, glutathione peroxidase (GPx) activity and reduced glutathione (GSH) content levels. Histopathological assessment of kidneys of CDDP-treated rats revealed extensive tubular necrosis with "sloughing off" of the renal tubular lining cells, intratubular hyaline casts and mononuclear cell infiltration. Treatment with MMF significantly protected the rats against CDDP-induced nephrotoxicity. The rise in serum creatinine and urea levels, kidney weight and kidney tissue MDA production, depletion of "endogenous antioxidant reserve" including GPx activity and reduced GSH content levels and the deleterious histopathological changes induced by CDDP treatment were significantly mitigated by MMF treatment. CONCLUSIONS: MMF treatment dramatically ameliorates CDDP-induced renal dysfunction.

Cardioprotective effects of subcutaneous ebselen against daunorubicin-induced cardiomyopathy in rats.

Daunorubicin is an anthracycline antitumour agent that can cause severe cardiomyopathy leading to a frequently fatal congestive heart failure. Although the exact molecular mechanisms of cardiotoxicity are not well established, oxidative mechanisms involving daunorubicin-induced superoxide anion production have been proposed. In the present study, we showed that ebselen a seleno-organic compound exhibiting glutathione peroxidase-like and antioxidant activities, significantly ameliorated daunorubicin-induced cardiomyopathy. Subcutaneous administration of ebselen to daunorubicin-treated rats showed significant improvement in serum cardiac indices including creatine kinase isoenzyme and lactate dehydrogenase as well as serum glutathione (GSH) peroxidase. Moreover, myocardium of daunorubicin/ebselen-treated rats showed significant improvement in daunorubicin-induced depletion of GSH peroxidase activity and reduced glutathione content, in addition to attenuation of daunorubicin-induced increase in cardiac malondialdehyde production and total nitrate/nitrite concentration levels. These results were confirmed by histopathological examination of ventricles of daunorubicin/ebselen-treated rats that revealed significant improvement of the characteristic cardiomyopathic changes induced by daunorubicin treatment. Interestingly, control rats treated with ebselen showed significant elevation in serum lactate dehydrogenase activity, cardiac malondialdehyde production and total nitrate/nitrite concentration levels compared with the untreated control animals. In conclusion, ebselen treatment significantly alleviates daunorubicin-induced cardiomyopathy.

Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats.

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg(-1) intraperitoneally and 30 mg kg(-1) orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction.

Effects of STZ-induced diabetes and its treatment with vanadyl sulphate on cyclosporine A-induced nephrotoxicity in rats.

The aim of this study was to analyze the effect of streptozotocin (STZ)-induced diabetic state and the insulin-like acting, vanadyl sulphate (VS) on cyclosporine A (CyA) related nephrotoxicity in rats. Male Wistar rats were divided into six groups, of 12 animals each: The control, diabetic rats and diabetic rats whose drinking VS in the drinking water in a concentration of 1 mg/ml. Another three similarly treated groups were injected intra-peritoneally (ip) with CyA in a dose of 25 mg/kg/day for ten doses, 10 days after diabetic induction by using a single dose of STZ of 65 mg/kg. Rats were sacrificed 48 h after the last CyA dose and serum as well as kidneys were isolated and analyzed. Treatment with CyA to control normoglycemic rats resulted in significant increases in kidney weight, serum creatinine, urea nitrogen, cholesterol and triglycerides (TG) levels. Also, the kidney tissue of CyA-treated control animals showed significant increases in total nitrate/nitrite (NO(x)) concentration and malondialdehyde (MDA) production level as well as depletion of glutathione (GSH) content and glutathione peroxidase (GSH-P(x)) activity level. Histopathologic evaluation of CyA-treated control rats revealed tubular atrophy, hyaline casts and focal tubular necrosis. However, treatment of diabetic rats with CyA showed significant reduction in serum creatinine and elevation in TG level as well as reductions in the kidney NO(x) concentration and MDA production level and increase in GSH concentration compared to CyA-treated control rats. Moreover, histopathology of the kidney of CyA-treated diabetics showed typical changes of the diabetic controls revealing glomerular hypertrophy and tubular dilation. On the other hand, treatment with CyA to those diabetic animals administered VS in the drinking water resulted in exacerbation of renal dysfunction, manifested by significant increases in serum indices of nephrotoxicity, cholesterol, TG and bilirubin levels. Also, VS administration to CyA-treated diabetics showed significant increase in kidney NO(x) concentration compared to those CyA-treated diabetics drinking plain tap water, and to a level significantly lower than those CyA-treated controls. Histopathologically, kidney of CyA/VS-treated diabetic showed marked CyA related changes. In conclusion, STZ-induced diabetes might provide partial protection against CyA-induced renal dysfunction. Also, treatment of hyperglycemia with VS might exacerbate CyA related nephrotoxicity.

Cardiotoxicity of doxorubicin/paclitaxel combination in rats: effect of sequence and timing of administration.

The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administered intraperitoneally (i.p.) at a single dose of 5 mg x kg(-1) every other 2 days, 2 doses per week for a total cumulative dose of 20 mg x kg(-1). PTX was administered by an i.p. route at a dose of 20 mg x kg(-1) every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrate/nitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment.

Role of non-selective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin-induced nephrogonadal toxicity in rats.

1. It is well documented that cisplatin (CDDP) treatment increases the expression of adenosine A(1) receptors in both kidney and testes. However, the effect of adenosine at these receptors is controversial. Adenosine A(1) receptors have been documented to be involved in either cytoprotection or aggravation of nephrotoxicity. The aim of the present study was to examine the effect of the non-selective adenosine receptor inhibitor theophylline and the phosphodiesterase inhibitor pentoxifylline on CDDP-induced renal and testicular toxicity. 2. Male Wister rats were divided into six groups. Two control groups received plain drinking water and a third control group received theophylline 0.8 mg/mL in the drinking water for 2 weeks. One group of animals drinking plain water was injected intraperitoneally (i.p.) with pentoxifylline 50 mg/kg per day for 2 weeks. The remaining groups were treated in the same manner and received single dose of CDDP 7 mg/kg, i.p., 1 week after starting theophylline and pentoxifylline treatment and all animals were killed 1 week after CDDP treatment. 3. Rats treated with CDDP developed nephrotoxicity, as demonstrated by increased kidney and testes weight as a percentage of total bodyweight, blood urea nitrogen and serum creatinine levels and decreased serum calcium and albumin levels. In addition, CDDP treatment resulted in an increase in the production of malondialdehyde (MDA) and decreases in total nitrate/nitrite levels, as well as depletion of reduced glutathione (GSH) content and glutathione peroxidase (GPX) activity in both the kidney and testes. Administration of theophylline in the drinking water to CDDP-treated rats resulted in exacerbation of the indices of nephrotoxicity, depletion of GSH content and GPX activity levels, with increased MDA production and platinum accumulation in both the kidney and testes. However, pentoxifylline administration reduced CDDP-induced biochemical changes and reduced platinum accumulation in both organs. Histopathological examination of the kidney revealed that CDDP treatment produced multifocal tubular atrophy, atypical reparative changes of the tubular epithelium and marked tubular necrosis. Animals treated with the theophylline/CDDP combination showed extensive widespread damage with intratubular calcification. However, pentoxifylline treatment ameliorated the overt changes induced by CDDP treatment. 4. Theophylline exacerbates the deleterious effects of CDDP on rat kidney and testes. However, pentoxifylline alleviates CDDP-induced renal and testicular toxicity.

Protection effects of Taurine supplementation against cisplatin-induced nephrotoxicity in rats.

BACKGROUND: Taurine, which is the major intracellular free beta-amino acid, is known to be an antioxidant and a membrane-stabilizing agent. This study was designed to investigate the protective role of taurine supplementation against cisplatin-induced nephrotoxicity. METHODS: Male Wistar rats were divided into six groups and treated as follows: (1) saline-treated control drinking tap water, (2) saline-treated plus taurine-supplemented (1.5% taurine in the drinking water), (3) saline-treated plus taurine-depleted (3% beta-alanine in the drinking water), (4) cisplatin-treated, CDDP 6 mg/kg intraperitoneally, (5) taurine-supplemented plus CDDP-treated and (6) taurine-depleted plus CDDP-treated. Rats were sacrificed 7 days after CDDP treatment, and serum as well as kidneys were isolated and analyzed. RESULTS: CDDP-treated rats showed increased kidney weight as a percentage of total body weight, serum creatinine and BUN levels and decreased serum albumin and calcium levels. Also, CDDP treatment resulted in a depletion of kidney GSH content, a reduction in the kidney glutathione peroxidase (GSH-Px) activity and increased kidney MDA production level. Taurine supplementation attenuated CDDP-induced nephrotoxicity which was manifested by jeopardizing the elevation in serum creatinine and BUN levels and the reduction in serum albumin and calcium levels. Moreover, taurine supplementation restored kidney GSH content and GSH-Px activity and reduced platinum accumulation and MDA production levels in the kidney tissue following CDDP treatment. Histopathological examination of the kidney of CDDP-treated rats revealed tubular atrophy, tubular necrosis and desquamation of renal tubular cells. However, taurine supplementation protected against CDDP-induced histopathological changes. CONCLUSIONS: The data suggest that taurine supplementation effectively attenuates the accumulation of platinum within kidney tissue and counteracts the deleterious effect of CDDP on the renal tubular function.

Inhibition of nitric oxide synthase aggravates cisplatin-induced nephrotoxicity: effect of 2-amino-4-methylpyridine.

BACKGROUND: Nitric oxide (NO) has been shown to play a role in maintaining normal renal function. However, the role of NO in cisplatin (CDDP)-induced nephrotoxicity is still unclear. The aim of the present work was to examine the effect of the NO synthase (NOS) inhibitor, 2-amino-4-methylpyridine, on the severity of CDDP-induced nephrotoxicity. METHODS: Male Wistar rats were divided into six groups. Three control groups received plain drinking water or water containing 1.5% L-arginine. One of the two groups receiving plain water was treated with an intraperitoneal injection of 2-amino-4-methylpyridine (1 mg/kg in normal saline), and the other two control groups were injected intraperitoneally with normal saline. Another three groups were treated in the same manner and injected with CDDP (6 mg/kg, i.p.). CDDP was injected 1 h after 2-amino-4-methylpyridine treatment. Rats were sacrificed 7 days after CDDP treatment, and serum as well as kidneys were isolated and analysed. RESULTS: CDDP-treated rats showed increases in the kidney weight as a percentage of the total body weight and serum creatinine and urea levels and decreases in serum albumin and calcium levels. Also, CDDP treatment induced reductions in the kidney total nitrate/nitrite (NO(x)), reduced glutathione (GSH) and glutathione peroxidase activity (GSH-Px) levels and an increase in the kidney malondialdehyde (MDA) production level. In contrast, 2-amino-4-methylpyridine treatment 1 h prior to CDDP injection induced marked exacerbation of CDDP-induced nephrotoxicity, as manifested by severe aggravation of the indices of nephrotoxicity. Also, 2-amino-4-methylpyridine plus CDDP-treated rats showed exaggeration of the reduction in the kidney total NO(x) content and GSH-Px activity and elevation of the kidney platinum accumulation level with normalization of the kidney MDA production level and rebound in the kidney GSH content. Histopathologically, CDDP-treated rats showed marked interstitial nephritis, tubular atrophy and tubular necrosis. However, treatment with 2-amino-4-methylpyridine 1 h prior to CDDP injection revealed marked exacerbation of CDDP-induced histopathological changes. CONCLUSIONS: The present findings suggest that NO plays a role in CDDP-induced nephrotoxicity. Administration of 2-amino-4-methylpyridine, an NOS inhibitor, exacerbates CDDP-induced nephrotoxicity.