Abdel-Moneim M. Osman

Progression of Cisplatin-Induced Nephrotoxicity in a Carnitine-Depleted Rat Model

Background: This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is an additional risk factor and/or a mechanism in cisplatin-induced nephrotoxicity and to gain insights into the possibility of a mechanism-based protection by L-carnitine against this toxicity. Methods: 60 male Sprague-Dawley rats were divided into six groups of 10 animals each and received one of the following treatments: The first three groups were injected intraperitoneally with normal saline, L-carnitine (500 mg/kg), and D-carnitine (750 mg/kg), respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, L-carnitine and D-carnitine, respectively, for 5 successive days before and after a single dose of cisplatin (7 mg/kg). Six days after cisplatin treatment, the animals were sacrificed, and serum as well as kidneys were isolated and analyzed. Results: A single dose of cisplatin resulted in a significant increase in blood urea nitrogen (BUN), serum creatinine, malondialdehyde (MDA) and nitric oxide (NO) and a significant decrease in total carnitine, reduced glutathione (GSH) and adenosine triphosphate (ATP) content in kidney tissues. Interestingly, L-carnitine supplementation attenuated cisplatin-induced nephrotoxicity manifested by normalizing the increase of serum creatinine, BUN, MDA and NO and the decrease in total carnitine, GSH and ATP content in kidney tissues. In the carnitine-depleted rat model, cisplatin induced a progressive increase in serum creatinine and BUN as well as a progressive reduction in total carnitine and ATP content in kidney tissue. Histopathological examination of kidney tissues confirmed the biochemical data, i.e. L-carnitine supplementation protected against cisplatin-induced kidney damage, whereas D-carnitine aggravated cisplatin-induced renal injury. Conclusion: Data from this study suggest that: (1) oxidative stress plays an important role in cisplatin-induced kidney damage; (2) carnitine deficiency should be viewed as an additional risk factor and/or a mechanism in cisplatin-induced renal dysfunction, and (3) L-carnitine supplementation attenuates cisplatin-induced renal dysfunction.

Effect of Desferrioxamine on Cisplatin-induced Nephrotoxicity in Normal Rats

Biochemical and histological evaluations of the effects of the iron chelator desferrioxamine on the nephrotoxicity induced by cisplatin in normal rats were carried out. A single dose of cisplatin (7.5 mg/kg, intravenously) caused nephrotoxicity that manifested biochemically as an elevation of blood urea nitrogen, serum creatinine and an increase in the kidney weight as a percent of body weight. Moreover, severe decreases in serum calcium and albumin were observed. Histopathological examination of kidney tissue revealed tubular necrosis with sloughing of tubular epithelium. Desferrioxamine treatment (250 mg/kg, intraperitoneally) 30 min before cisplatin administration does not protect the kidney from the damaging effects of cisplatin. A greater increase in blood urea nitrogen, serum creatinine and kidney weight was observed with significant tubular necrosis and a mild lymphocytic infiltrate. Desferrioxamine pretreatment decreased the lipid peroxidation induced by cisplatin but at the same time increased nonprotein sulfhydryl (-SH) concentrations in the kidney tissue. The findings of this study suggest that lipid peroxidation is not the main cause of cisplatin-induced nephrotoxicity and that desferrioxamine which was useful for prevention of cardiac and hematological damage induced by doxorubicin, aggrevated the cisplatin-induced nephrotoxicity. More investigations are needed to establish a definite assessment of its selectivity.

Enhancement of Doxorubicin-Induced Cytotoxicity by Hyperthermia in Ehrlich Ascites Cells

Hyperthermia (HPT) at 43 degrees C for 30 min increased the cytotoxic activity of doxorubicin against the growth of Ehrlich ascites carcinoma cells. There was more delay in tumor growth with 89% inhibition in the tumor volume and 90% increase in the survival of the tumor-bearing animals compared to control group. Combination of HPT with doxorubicin showed a more pronounced inhibitory effect on tumor content of DNA, RNA, protein, cholesterol, total lipid and acid phosphatase activity. HPT did not significantly affect the doxorubicin uptake into tumor cells, but it has some inhibitory effect on some vital components. Along with other results, our data suggest the benefit of using HPT to enhance the cytotoxic activity of doxorubicin with a consequent reduction of doxorubicin dose and hence a decrease of its serious side effects.

Dilemmas of the causality assessment tools in the diagnosis of adverse drug reactions

Importance: Basic essence of Pharmacovigilance is prevention of ADRs and its precise diagnosis is crucially a primary step, which still remains a challenge among clinicians. Objective: This study is undertaken with the objective to scrutinize and offer a notion of commonly used as well as recently developed methods of causality assessment tools for the diagnosis of adverse drug reactions and discuss their pros and cons. Evidence review: Overall 49 studies were recognized for all assessment methods with five major decisive factors of causality evaluation, all the information regarding reasons allocating causality, the advantages and limitations of the appraisal methods were extracted and scrutinized. Findings: From epidemiological information a past prospect is designed and subsequent possibility merged this background information with a clue in the individual case to crop up with an approximation of causation. Expert judgment is typically based on the decisive factor on which algorithms are based, nevertheless in imprecise manner. The probabilistic methods use the similar principle; however connect probabilities to each measure. Such approaches are quite skeptical and liable to generate cloudy causation results. Causation is quite intricate to ascertain than correlation in Pharmacovigilance due to numerous inherent shortcomings in causality assessment tools. Conclusions and relevance: We suggest that there is a need to develop a high quality assessment tool which can meticulously establish suitable diagnostic criteria for ADRs with universal acceptance to improvise the fundamental aspect of drug safety and evade the impending ADRs with the motive to convert Pharmacovigilance into a state of art.

Diltiazem Potentiation of Doxorubicin Cytotoxicity and Cellular Uptake in Ehrlich Ascites Carcinoma Cells

The calcium channel blocker diltiazem, which possesses coronary vasodilator activity, greatly enhanced the cytotoxicity of doxorubicin in Ehrlich ascites carcinoma cells. 20% of the doxorubicin-treated tumor-bearing animals (2 mg/kg, every other day, three doses) survived, with a mean survival time of 35 days. However, pretreatment with diltiazem increased survival to 70% with a mean survival time of 43 days. Diltiazem treatment increased the intracellular level of doxorubicin, and there was a good correlation between the high cellular level of doxorubicin and its cytotoxic activity. In tumor-bearing animals pretreated with diltiazem, doxorubicin showed a pronounced inhibitory effect on cellular DNA, RNA content and acid phosphatase activity of tumor cells. In addition, there was a marked increase in cellular cholesterol and lipid contents. This study may suggest the benefit of using diltiazem to potentiate the cytotoxic effect of doxorubicin, allowing its dose and consequently the serious side effects to be reduced.

Potentiation of Doxorubicin Cytotoxicity by the Calcium Channel Blocker Verapamil in Ehrlich Ascites Cells

The calcium channel blocker verapamil increased the intracellular level of doxorubicin in Ehrlich ascites cells. The high cellular drug level was directly related to the enhancement of the cytotoxicity of the antitumor agent. Tumor-bearing mice pretreated with verapamil showed a 2.3-fold increase in long-term survival effect of doxorubicin together with a pronounced inhibitory effect on tumor DNA, RNA and protein content. This study suggests the possible novel use of verapamil to enhance the antitumor activity of doxorubicin, allowing its dose, and consequently the serious side effects, to be reduced.

Perceptions and knowledge regarding antimicrobial stewardship among clinicians in Jeddah, Saudi Arabia

Objectives: To understand the perceptions, attitude, and prescribing practices of clinicians regarding antimicrobial resistance (AMR). Methods: A multidisciplinary cross-sectional study comprising 447 clinicians of university, public, and private hospitals of Jeddah, Saudi Arabia was carried out from August to October 2014 using a self-administered questionnaire. Results: Interestingly, 33% of the general physicians yielded to patient/parent’s demand for the choice of antimicrobials (AMs) as compared with only 13.2% of the residents, and 4.3% of the specialists. In addition, expensive AMs are more often prescribed by the general physician (70.4%) in comparison with 26.4% residents and 30.4% of the specialists. However, no significant differences were observed between the knowledge and perceptions regarding the current scope of AM agents, as well as their use and misuse. Furthermore, dependability of specialist and residents seems to be significantly higher than general physicians on pocketbooks and smartphone for AM education sources. Conclusion: This study revealed that despite a clear concept of AMR, general physicians lacks consistency in prescribing aptitude and use of effective educational resources, while all respondents lacks dedication to follow the guidelines of AM use. This highlights the requirement of AM stewardship with decisive objective of reduction in AMR.

Detection of adverse drug reactions by medication antidote signals and comparison of their sensitivity with common methods of ADR detection.

Objective To determine the PPVs of selected ten medication antidote signals in recognizing potential ADRs and comparison of their sensitivity with manual chart analysis, and voluntary reporting recognizing the same ADRs. Method The inpatient EMR database of internal medicine department was utilized for a period of one year, adult patients prescribed at least one of the ten signals, were included in the study, recipient patients of antidote signals were assessed for the occurrence of an ADR by Naranjo’s tool of ADR evaluation. PPVs of each antidote signal were verified. Result PPV of Methylprednisolone and Phytonadione was 0.28, Metoclopramide and Potassium Chloride – 0.29, Dextrose 50%, Promethazine, Sodium Polystyrene and Loperamide – 0.30, Protamine and Acetylcysteine – 0.33. In comparison of confirmed ADRs of antidote signals with other methods, Dextrose 50%, Metoclopramide, Sodium Polystyrene, Potassium Chloride, Methylprednisolone and Promethazine seem to be extremely significant (P value > 0.0001), while ADRs of Phytonadione, Protamine, Acetylcysteine and Loperamide were insignificant. Conclusion Antidote medication signals have definitive discerning evaluation value of ADRs over routine methods of ADR detection with a high detection rate with a minimum cost; Their integration with hospital EMR database and routine patient safety surveillance enhances transparency, time-saving and facilitates ADR detection.

Pharmacokinetic Profile of Methotrexate and 5-Fluorouracil in Normal and Bilharzial-infested Mice

The pharmacokinetics of two commonly used anticancer drugs, methotrexate (MTX) and 5-fluorouracil (5-FU), were investigated in normal and bilharzial-infested mice. Liver glucose-6-phosphatase activity and antipyrine clearance were used as parameters of liver function. Liver glucose-6-phosphatase activity was significantly reduced in bilharzial-infested mice compared with the normal controls. Bilharzial infestation caused a significant reduction in the elimination (beta) and clearance rate (Cl) of antipyrine, whereas its elimination half-life (t1/2 beta) was increased in comparison with the normal controls. A similar pattern was also obtained after MTX and 5-FU administration in bilharzial mice, compared to controls. These results indicate that hepatic bilharziasis causes a significant reduction in the hepatic clearance and elimination of MTX and 5-FU, whereas their areas under the concentration-time curve were significantly increased. These findings may have to be considered in the treatment of bilharzial cancer patients.