Tacrolimus Pharmacotherapy: Infectious Complications and Toxicity in Organ Transplant Recipients; An Updated Review.

BACKGROUND: After allogeneic organ transplantation, in order to reduce the risk of rejection, tacrolimus is given. In fact, infection is reported as one of the most common side effects of tacrolimus that might be associated with graft failure. OBJECTIVE: This study aims to review the association between the occurrence of infections due to toxicity following the administration of tacrolimus in organ transplant recipients. METHODS: Scientific literature on the pharmacotherapy of tacrolimus after organ transplantation, infections, and neurotoxicity were searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/), Web of Science, and Scopus (n=108). All articles were screened, and the data associated with the topic of interest was extracted. The primary outcome was infection and neurotoxicity. RESULTS: Total area under the curve exposure, the ratio of parent drug/metabolites of tacrolimus was reported to be correlated with aggressive events such as infection episodes. A trough/dose ratio may demonstrate the net state of immunosuppression and drug-related events. The most frequent infectious complication of tacrolimus after organ transplantation was reported as urinary tract infections (UTIs). Virulent strains of recombinant Listeria monocytogenes, in addition to an increase in bacterial burden in the liver and spleen tissues, were reported in experimental animal studies. Patient survival was significantly lower in recipients with UTIs in the first post-transplant month. A higher degree of immunosuppression was associated with recurrent UTIs and drug-resistant organisms. By inhibiting the cerebral immune system, tacrolimus could cause neurodegeneration. CONCLUSION: Transplant type, gut dysmotility, acute or chronic condition before transplant surgery, use of azole, antifungal, hematocrit, tacrolimus methods of detection, the total area under the curve, and duration of hospital stay could define the risk of infection through the first month of transplant surgery. In addition, neurological and infectious complications could be associated with the higher amounts of tacrolimus trough levels (C0). Polypharmacy based on tacrolimus, antiviral, and antifungal drugs, in addition to neurotoxicity, could increase the risk of opportunistic infections such as cytomegalovirus within the first year of organ transplantation.

Tacrolimus and Cyclosporin Pharmacotherapy, Detection Methods, Cytochrome P450 Enzymes after Heart Transplantation.

BACKGROUND: Advances in organ transplantation were made after the discovery of the pure form of cyclosporine by Dr Jean Borel in the 1970s. In fact, in clinical practice achieving a delicate balance in circulating immunosuppressive necessitate focus on the difficult task of post-transplant therapeutic drug monitoring. OBJECTIVE: The purpose of this study was to determine the pharmacologic properties of cyclosporine-tacrolimus, detection methods, and the effects on the activity of cytochrome P450 enzymes when prescribing the most efficient treatments in forms of polypharmacy for the recipients of heart transplantation. METHODS: Scientific literature on the interactions of tacrolimus and cyclosporine with human cytochrome P450 enzymes was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/), Web of Science, and Scopus. RESULTS: Prescription immunosuppressive drugs based on polypharmacy accompanied by induction agents could result in hidden neurotoxicity and nephrotoxicity. A literature search shows that cyclosporine prescription with antihypertensives drugs needs close monitoring. Co-administration of tacrolimus and diltiazem or verapamil needs a decrease in the tacrolimus dose by 20-50%. Vigilant attention to the lowest possible statin dose is needed when coadministered with fluvastatin or pravastatin. Polypharmacy based on ticlopidine, clopidogrel, and cyclosporine or tacrolimus needs monitoring of immunosuppressive drug levels for several months. A prescription with clotrimazole or fluconazole needs close monitoring, and itraconazole or ketoconazole needs to reduce the initial dose by 50%. Combination with nefazodone needs to be avoided, and alternative drugs such as sertraline or citalopram could be prescribed in addition to further monitoring consideration. In prescription with phenytoin, the bound and free phenytoin levels need close monitoring. CONCLUSION: Polypharmacy based on tacrolimus or cyclosporine needs vigilant therapeutic drug monitoring due to the cytochrome P450 enzymes associated with biochemical variables in metabolic pathways. Further attention to polypharmacy should be given to circulate drugs that could hide pharmacokinetics interactions associated with infections, malignancies, chronic kidney disease, and rejection after organ transplantation.

Investigating the Outcome of Surgery in Patients with Penile Fracture.

PURPOSE: The aim of study was to investigate the outcome of surgery in patients with penile fracture in Al-Zahra hospital. MATERIALS AND METHODS: This cross sectional study was conducted on 187 patients with penile fracture underwent surgery in Al-Zahra hospital during 2016- 2020. Data such as penile fracture causes, erectile dysfunction, time of surgery after penile fracture, degree of penile curvature and etc were extracted from medical records. RESULTS: The most common reason of penile fracture in these patients was manipulation and trauma with frequency 70 (37.4%) and 69 patients (36.9%), respectively. Lower urinary tract symptom, urinary tract injury, penile curvature, penile nodule and erectile dysfunction were observed in 1 (0.54 %), 2(1.06 %), 76 (40.64%), 75 (40.1%), 43 (23%) patients, respectively. Mild and moderate erectile dysfunction was seen in 38 (88.3%) and 5 (11.62%) patients, respectively. There was a significant relationship between erectile dysfunction with the degree of penile curvature, surgical time and size of defect (P < .01). Furthermore, significant relation was observed between penile nodules and suture type (P = .000). CONCLUSION: According to findings, erectile dysfunction was observed in 23 % of patients; however most of these patients had mild erectile dysfunction. Moreover, erectile dysfunction was influenced by penile curvature, surgical time and size of defect. Therefore, early surgery and special attention to patients with severe penile curvature are proposed for prevention of erectile dysfunction in these patients.

Preliminary study of central nervous system tumors' prevalence and incidence in Isfahan Province Iran.

BACKGROUND: Metastatic or primary cancers of the central nervous system are a dissimilar cluster of neoplasms with different consequences and management plans. The aim of this study was to obtain prevalence and incidence of brain and other nervous system tumors. RESULTS: In all, 423 females and 620 males were identified. For the total population the period prevalence (PP) was calculated as 20.9 per 100,000 persons. This value corresponded to a PP of 24.5 for males and 17.2 for females. The mean (SD, range) age of the patients was 52.0 (20.7, 1-99) years. In the 7% of the population studied, age was under 20 years old of life, and in the 71%, it occurred around the age of 20 to 70 years old. In both genders, incidence rate (IR) increased from 4.2 to 5.7 per 100,000 persons. The changes of IR in males versus females were 8.2 versus 3.0 from 2011 to 6.4 versus 5.0 to 2015 per 100,000 persons. CONCLUSIONS: Among the total population studied, there were 586 reported deaths. The PP in the male population was 1.4-times higher than females. There was a 35.7% increase in the IR over the study period.

Bladder cancer: total antioxidant capacity and pharmacotherapy with vitamin-E.

PURPOSE: Free radicals play an important role in the different complex course of carcinogenesis. Higher concentrations of reactive oxygen species are highly associated with the presence of tumors. The urinary bladder organ is also a target for many carcinogens. The major objective of this investigation was to measure the role of redox state or total antioxidant capacity (T-AOC) and antioxidant functions of vitamin E in patients with low-grade papillary cancer of the bladder (BC). METHODS: The blood sample was used for measurement of the T-AOC by the Trolox-TAC assay kit. Thirty-five patients with BC and thirty-five healthy subjects that matched for age were entered in this study. The obtained data were analyzed using the Statistical Package (SPSS Inc, Chicago, IL, USA). The significance level was set at p ≤ 0.05. RESULTS: In healthy controls, the mean ± SD for T-AOC was 91.8 ± 16.6 (U/ml), that was significantly higher when compared to the mean value of 24.5 ± 28.9 (U/ml) in patients with BC (p = 0.00). The difference in concentration of T-AOC before and after prescription of vitamin E was encountered with a p value of 0.16. CONCLUSIONS: By reference to the significant difference between T-AOC in patients and healthy controls, our results strongly suggest a low level of T-AOC in patients with BC. The obtained changes in T-AOC before and after management with vitamin E recommended additional consideration associates with different stages and grade of tumor in patients with BC.

Preliminary study of prevalence for bladder cancer in Isfahan Province, Iran.

OBJECTIVES: To clarify period prevalence (PP), incidence rate (Ir), and reported mortality for patients with bladder cancer (BC) in Isfahan Province/Iran, as BC is the most common cancer of the urinary tract in Iran and other parts of the world. PATIENTS AND METHODS: Data from 21 March 2011 to 3 March 2015 was obtained from the Isfahan Cancer Registry. BC was distinguished by the related established topography code (C67). Ir and PP were calculated and expressed per 100 000 persons. RESULTS: In all, 279 females and 1376 males were identified. For the total population the PP was calculated as 33.2. This value corresponded to a PP of 54.4 for males and 11.4 for females (P < 0.001). Histologically, 63% of patients had invasive BC. Irs versus mortality rates were calculated for each year, i.e. 2011-2012, 2012-2013, 2013-2014, and 2014-2015, as 7.7 vs 0.56, 8.1 vs 0.74, 7.4 vs 0.98, and 9.9 vs 0.84, respectively. The mean (SD, range) age of the patients was 65.2 (13.9, 3-100) years. In relation to the age of the study population, BC occurred in 12% of patients aged <50 years and in 15% of those aged ≥80 years. CONCLUSION: The PP for BC in the male population was 4.8-times higher than females. There was a 28.6% increase in the Ir over the study period. Further study concerning environmental exposure, genetic factors, job-related exposure to various chemical carcinogens, and geographical distribution in Isfahan and its' rural provinces would seem to be valuable.

Prevalence of lung cancer in Isfahan Province, Iran.

OBJECTIVE: To describe for the first time period prevalence (PP) and incidence rate (Ir) for patients with lung cancer in Isfahan Province/Iran. DESIGN: Data associated to the Surveillance, Epidemiology, and End Results; (SEER) was collected from the Isfahan Cancer Registry from March 2011 to March 2015. Lung cancer was distinguished by the related established topography code. PP and Ir were calculated and expressed per 100,000 persons. RESULTS: In all, 548 females and 1399 males were identified. For the total population the PP was calculated as 39.1 (distinguished as: 30.7 for bronchus and lung, 7.9 for larynx and 0.5 for trachea). This value corresponded to a PP of 55.3 for males and 22.3 for females (p < 0.001). Irs versus mortality rates were calculated for each year, i.e. 2011-2012, 2012-2013, 2013-2014, and 2014-2015, as 9.3 vs 6.3, 10.1 vs 6.6, 9.9 vs 6.3, 9.6 vs 6.4, respectively. The mean (SD, range) age of the patients was 65.8 (14.7, 1-103) years. In relation to the age of study population, lung cancer occurred in 94% of patients aged between 40 and 90 years. CONCLUSION: The PP for lung cancer in male population was 2.5 times higher than females. There was a 3.2% increase in the Irs over the study period. To facilitate early diagnosis for better management associated to pharmacotherapy or surgical care, our findings emphasized the advantage of further research and greater effort toward environmental, job related exposure, genetic and geographical factors in Isfahan Province/Iran.

The investigation of correlation between Iminoral concentration and neurotoxic levels after kidney transplantation.

BACKGROUND: Neurotoxicity side effects related to cyclosporine kinetics could lead to dysfunction of kidney graft and patient outcome after transplantation. The aim of this study was evidence-based pharmacotherapy of kidney transplant recipients and to investigate neurotoxic levels of Iminoral. MATERIALS AND METHODS: The results of 2239 cyclosporine trough levels obtained from 743 patients were studied. Seventy-five adult kidney recipients who received Iminoral were studied for neurotoxicity symptoms. Demographic, clinical, hematology and biochemical data were recorded in d-base and analyzed using SPSS application for windows. RESULTS: The mean value related to cyclosporine C0 was 246.3 µg/l. In the 48% the signs of neurotoxicity such as tremor and headache were noted, but only in 9% the levels of cyclosporine C0 were >400 µg/l. Further studies on 75 patients showed that the incidence of neurotoxic side effects were as follows: Tremor in 35, headache in 24 and anxiety in 34 recipients of kidney. The prescribed drug regimens from the day of transplant in most patients were based on mycophenolic acid or cellcept, pulse therapy using methylprednisolone (daily from kidney transplant up to 3 days after transplant), cyclosporine or Iminoral plus other drugs related to each individual. Administrations of ganciclovir, thymoglobulin, clotrimazol and prednisolone were also distinguished with immunosuppressant-based therapy simultaneously. CONCLUSION: Evidence-based study related to pharmacotherapy of Iminoral showed that clinical presentation related to neurotoxic side effects such as tremor, headache and anxiety might be due to many factors such as polypharmacy. Planning immunosuppression to individual patients based on programmed therapeutic Iminoral monitoring, avoiding polypharmacy in terms of removal or drug minimization and focusing on first week after transplant seem to be a realistic option.

Antiepileptic drugs: a consideration of clinical and biochemical outcome in patients with epilepsy.

BACKGROUND: The challenge of antiepileptic drugs (AEDs) management is to attain the best compromise between the desire to maximize seizure control and the need to keep side-effects within tolerable limits for the individual patient. To reduce devastation in Iranian epileptic patients, the aim of this study was to explore the overall outcome following AEDs prescription. METHODS: A cross-sectional study of 36 patients located at the epilepsy ward, conducted to Isfahan Neurosciences Research Centre was carried out during the year 2011. Female (n = 17) and male subjects (n = 19) with a mean age of 27 years (range; 7-74 years) were studied. Variables including, sex, age, age of seizure onset, type, and number of AEDs, biochemical and hematological data were recorded in d-Base and statistical analyses were performed using SPSS (version 18) for windows. RESULTS: The main drug to control seizure attack was carbamazepine and valproic-acid. The following tests were the most frequently influenced; alkaline phosphatase (AP), lymphocyte (Lymph), white blood cell (WBC) counts and hemoglobin (Hgb). There was a significant increase in (AP) (mean; 534.6 u/l(↑); [P = 0.02] in three patients and (Lymph) (55%(↑); [43-84] %(↑); [P = 0.04] in seven patients. WBC was lower than 4400 mm(3↓) (P = 0.02) in six patients. Hgb was significantly lower in 70.6% of women (11.8(↓); [10-14.2] g/dl(↓); [P = 0.04] and 68.4% of men population (12.3(↓); [9.7-13.8] g/dl(↓); [P = 0.01]. Mean age of epilepsy onset was 15.6 years (range: Birth-74 years). Analysis of drug prescriptions showed that the incidence of monotherapy and polypharmacy (2 up to six AEDs simultaneously) was 19.4% plus 80.6% respectively. CONCLUSIONS: In Iranian epileptic population, effectiveness of treatment should be attributed by the close supervising of AEDs in relation to clinical circumstance, laboratory data, and therapeutic drug monitoring. Any significant change in patients' biochemical and hematological data may require close verifying for the rapid detection of severe anemia, leukopenia, lymphocytosis, osteomalacia, or liver failure.