Iranian Journal of Basic Medical Sciences
Volume:14 Issue: 6, Nov-Dec 2011

Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal-insufficiency, inflammation and infection, gender, age, polymorphism and liver mass. Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus and mycophenolic acid.CyclosporineTherapeutic monitoring of immunosuppressive therapy with cyclosporine is a critical requirement because of intra- and inter-patient variability of drug absorption, narrow therapeutic window and drug induced nephrotoxicity.Mycophenolic acid (MPA)Some reasons for therapeutic drug monitoring of MPA during post-transplant period include: relationship between MPA pharmacokinetic parameters and clinical outcomes, Inter-patient pharmacokinetic variability for MPA despite fixed MMF doses, alternations of MPA pharmacokinetics during the first months after transplantation, drug- drug interaction and influence of kidney function on MPA pharmacokinetic. SirolimusA recent review of the pharmacokinetics of sirolimus suggested a therapeutic range of 5 to 10 μg l−1 in whole blood. However, the only consensus guidelines published on the therapeutic monitoring of sirolimus concluded that there was not enough information available about the clinical use of the drug to make recommendations.TacrolimusSudies have shown, in kidney and liver transplant patients, significant associations of low tacrolimus concentrations with rejection and of high concentrations with nephrotoxicity. Although the feasibility of a limited sampling scheme to predict AUC has been demonstrated, as yet, trough, or pre-dose, whole blood concentration monitoring is still the method of choice.

Objective(s)Wound healing represents a dynamic physiological process influenced by many factors. The aim of the present study was to evaluate the effects of Teucrium polium honey on the wound healing and tensile strength in rat.Materials and MethodsThirty-six Sprague-Dawley rats were randomly divided into four equal (n= 9) treatment and control groups. Two full-thickness wounds were made over the dorsal thoracic region according to the incision and excision models. Animals were treated with topical Teucrium polium honey twice a day post surgery until complete healing was achieved. Histopathology and tensiometry were then studied.ResultsThe wound healing process occurred faster in the incision model than excision ones (P< 0.05). Teucrium polium honey promoted wound contraction, closure time and tensile strength (P< 0.05). Histopathological study also showed relative epithelial proliferation, improved angiogenesis granulation, and fibrous connective tissue in Teucrium polium honey treated animals.ConclusionThe present study demonstrates that Teucrium polium honey can accelerate wound healing as well as tensile strength in rat skin wounds.

Objective(s)The Sst-I polymorphic site on the 3' untranslated region of the apo CIII gene, has been previously reported to be associated with hypertriglyceridemia. The aim of the present study was to explore the association between Sst-I polymorphism with plasma lipid and lipoprotein levels in hyperlipidemic (HLP) patients from Semnan province, Iran.Materials and MethodsGenomic DNA was prepared from 76 patients with HLP and 75 matched healthy subjects. DNA samples were amplified by polymerase chain reaction. The samples were analyzed by restriction fragment length polymorphism (RFLP) method using SstI enzyme. ResultsThe genotype and allelic frequencies for this polymorphism were significantly different between HLP and normolipidemic groups (P< 0.002). Plasma triglyceride (TG) level was higher in both groups, in S2S2 genotype was more than in the S1S1and S1S2 genotypes, however, there was no significant difference in comparison with the control group. Subjects with S1S2 + S2S2 genotypes in compare to S1S1 genotype had odd ratio of 2.8 (95% CI: 1.41-5.56, P< 0.003) for developing hypertriglyceridemia. ConclusionThe results showed that the presence of rare S2 allele was associated with change in TG level in the selected population.

Objective(s)Studies have shown that morphine, in addition to its analgesic properties, has several effects on cell proliferation and apoptosis. There is also evidence that opioid receptors are present on chondrocytes. Our main objective in the present study was to investigate the effects of morphine on rat femur growth cartilage.Materials and MethodsThis research was carried out on 18 4-week-old male rats. Animals were divided into four groups: groups 1 (n= 3) and 2 (n= 4) were non morphine-dependent and groups 3 (n= 6) and 4 (n= 5) were morphine-dependent. Groups 1 and 3 were followed up for 4 weeks and the others for 7 weeks. We prepared femur bone biopsies, fixed the samples in 10% formalin and 10% nitric acid and stained the samples with haematoxylin and eosin. The thickness of the growth cartilage and its proliferative zone (PZ) cell number were studied. In addition, the existence of necrosis, inflammation, fibrosis, and hyalinisation were evaluated.ResultsThere were no signs of inflammation, fibrosis, necrosis or hyalinisation in the growth cartilages of all rats. The morphine-dependent groups had a statistically significant difference (P< 0.001) in the number of cells in the proliferative zone and thickness of the growth cartilage compared to other groups using ANOVA analysis.ConclusionIt seems that morphine reduces the number of cell in the proliferative zone and decreases the thickness of the growth cartilage which may alter longitudinal growth of long bones.

Objective(s)The objective of this study was to prepare, characterize and evaluate the nanoliposomes containing safranal as a natural sunscreen and moisturizer factor. Materials and MethodsThe experimental formulations included homosalate reference, nanoliposomes containing 0.25, 0.5, 1, 2, 4 and 8% safranal and empty liposomes. The liposomes were prepared using fusion method and homogenization. Homosalate reference was prepared according to FDA standard. Sun protection factors (SPF) of the formulations were determined by two in vitro methods; diluted solution transmittance method and transpore tape method. Studies of in vitro penetration of the formulations across mouse skin were carried out with diffusion cells. The percentage of safranal penetrated and retained in the skin was determined for the formulations up to 24 hr. The amount of the moisture contents of the skin before application and after 30-minute, 1, 3 and 5 hr post-application of the formulations were measured in human volunteers using Corneometer.ResultsThe results indicated that, the SPF of liposomes containing 8% safranal (Lip-Safranal 8%) was significantly higher than 8% homosalate reference. The proportion of Lip-Safranal 1% that penetrated the skin was low. There was no significant difference between the skin moisture contents after application of Lip-Safranal 1 and 4% and empty liposomes during the 7 hr post-application period. ConclusionThese results showed that in equal concentrations, Lip-Safranal could act as a better antisolar agent compared to homosalate and have no moisturizing effect in 1 and 4% concentrations.

Objective(s)There are some reports in recent years indicating that renal ischemia – reperfusion (IR) induces deleterious changes in remote organs such as liver. The aim of this study was to investigate whether leukocytes have a role on the induction of oxidative stress in liver after renal IR.Materials and MethodsInbred mice in IR donor group were subjected to renal IR injury. In sham donor group the procedure was almost the same except that ischemia was not induced. Then, mice were anesthetized and blood was collected. Leukocytes were isolated from donor groups and were then transferred to intact recipient mice (from IR donor mice to IR recipient mice and from sham donor mice to sham recipient mice). ResultsAfter 24 hr, hepatic superoxide dismutase (SOD) and catalase (CAT) activities decreased significantly in recipient mice that received leukocytes from IR donor mice in comparison to recipient mice received leukocytes from sham donor mice. ConclusionThese findings indicate that leukocytes are one of the mediators that induce hepatic oxidative stress after renal IR.

Objective(s)Isoniazid (INH) is one of the main first line drugs used in treatment of tuberculosisand development of resistance against this compound can result in serious problems in treatment procedures. Resistance to INH is mediated mainly by mutation in KatG gene that is coded for the catalase enzyme. The proportional method for detection of INH-resistance is time consuming due to the slow growth rate of Mycobacterium tuberculosis. In this study, we used PCR-RFLP approach for screening of common mutations in KatG gene for detection of INH resistance, and compared the results to minimal inhibitory concentration (MIC) in M. tuberculosis isolates. Materials and MethodsFifty M. tuberculosis isolates were subjected to study of which, 25 strains were INH-resistant and 25 strains were INH-sensitive. ResultsOf 25 INH-resistant strains, the mutation was identified in 56% and 20% in the KatG315 and KatG463 loci, respectively. In 24% of INH-resistant strains, no mutation was observed in the studied loci. INH MIC was <0.2 μg/ml in all sensitive strains whereas among 25 INH -resistant isolates, INH MIC was higer than 0.2 μg/ml ranged from 0.2 to 3.2 μg/ml.ConclusionOur findings revealed that PCR-RFLP is capable to identify INH-resistance in more than 76% of INH- resistantM. tuberculosis strains, and could be used for rapid identification of INH resistance. High levels of INH MIC were observed in the strains which had mutation in the KatG gene in position 315.

Objective(s)The purpose of this study was assessment of the influence of acute manic phase on the steady state pharmacokinetics of valproic acid (VPA) in bipolar patients in comparison with those of epileptic patients. Materials and MethodsNinteen acutely manic and 25 epileptic patients who fulfilled inclusion and exclusion criteria were entered in this prospective study. Blood samples were collected at trough time in steady state and plasma concentrations were determined by fluorescence polarization immunoassay (FPIA). VPA apparent oral clearance (CL/F) values were calculated in each patient and were compared between groups. As VPA clearance is affected by different factors such as age, total body weight, VPA dosage and the use of concurrent medications, all of these confounding factors were made similar in both groups.ResultsComparison between two groups showed that CL/F values in acutely manic patients were significantly higher than epileptic patients (10.35±5.77 vs. 7.70±2.63 ml/kg/h, P= 0.047).ConclusionAcutely manic patients require more VPA dosage to achieve serum concentrations in comparison with those found in epileptic patients. It may be suggested that this increased VPA clearance in acute manic phase may be related to abnormalities in membrane transport systems that may affect on cellular uptake of the drug and its volume of distribution. Since our study is a preliminary investigation in this field, further detailed pharmacokinetic study in acute manic patients are warranted to confirm results of this study.

Objective(s)Recombinant adenoviruses are currently used for a variety of purposes, including in vitro gene transfer, in vivo vaccination, and gene therapy. Ability to infect many cell types, high efficiency in gene transfer, entering both dividing and non dividing cells, and growing to high titers make this virus a good choice for using in various experiments. In the present experiment, a recombinant adenovirus containing human IL-4 coding sequence was made. IL-4 has several characteristics that made it a good choice for using in cancer gene therapy, controlling inflammatory diseases, and studies on autoimmune diseases. Materials and MethodsIn brief, IL-4 coding sequence was amplified by PCR and cloned in pAd-Track-CMV. Then, by means of homologous recombination between recombinant pAd-Track-CMV and Adeasy-1 plasmid in bacteria, recombinant adenovirus complete genome was made and IL-4 containing shuttle vector was incorporated into the viral backbone. After linearization, for virus packaging, viral genome was transfected into HEK-293 cell line. Viral production was conveniently followed with the aid of green fluorescent protein. ResultsRecombinant adenovirus produced here, was capable to infecting cell lines and express interlukin-4 in cell. ConclusionThis system can be used as a powerful, easy, and cost benefit tool in various studies on cancer gene therapy and also studies on immunogenetics.

Objective(s)We investigated the effects of low-dose morphine on nitric oxide (NO) and angiogenesis in two-kidney one clip hypertensive (2K1C) rats.Materials and MethodsMale rats were divided into two groups: sham-clip operated and 2K1C. Each group subdivided into saline and morphine (3 mg/kg i.p. 8 weeks) groups. Blood pressure, heart rate, plasma renin activity (PRA), NO concentration and murine matrigel angiogenesis were evaluated.ResultsMorphine had no effects on blood pressures and HR in sham normotensive rats but attenuated diastolic blood pressure (DBP) (P< 0.01) and mean arterial pressure (MAP) (P< 0.01) in 2K1C compared with saline. PRA level was significantly higher in 2K1C compared with sham groups (P< 0.01) but morphine decreased it in 2K1C compared with saline (P< 0.01). After clipping, NO in 2K1C hypertensive rats was decreased (P< 0.01) and morphine increased it compared with saline (P< 0.01). Morphine promoted angiogenesis in both sham (P< 0.01) and 2K1C (P< 0.0001) groups.ConclusionLow-dose morphine stimulated angiogenesis in two-kidney one clip hypertensive rats probably via NO pathways.

Objective(s)Homocysteine, hs-CRP and fibrinogen are three novel cardiovascular risk factors. The aim of this study was to examine the effect of a single bout of circuit resistance exercise on homocysteine, hs-CRP and fibrinogen levels in healthy and inactive men. Materials and MethodsThesubjects were randomly divided into the experimental group (n= 14) and the control group (n= 9). Circuit training comprised ten exercises with 35% of one repetition maximum intensity. Blood samples were collected thirty minutes before and immediately after training. The data were analyzed using Kolmogorov Smirnov and independent samples T test in SPSS15.0 Software (P< 0.05 was regarded significant).ResultsAnalysis of data showed the significant elevation of serum homocysteine and hs-CRP levels after training in the experimental group but not in the control group. No significant changes of fibrinogen levels were observed in both groups. ConclusionsDuring the exercise, the elevation of creatine synthesis for ATP production increases homocysteine levels. Moreover, muscle-derived interleukin-6 (a stimulator of glycogenolysis in the liver) induces hepatic production of CRP. Pathological or beneficial consequences of these changes are not clearly specified. Furthermore, more research is needed to show the acute and chronic effects of physical activity on novel cardiovascular risk factors.

Objective(s)Malva sylvestris L. (Malvaceae), an annual plant, has been already commonly used as a medicinal plant in Iran. In the present work, we evaluate some bioactivities of the plant extracts.Materials and Methods The aired-dried plant flowers and leaves were extracted by soxhlet apparatus with n-hexane, dichloromethane and methanol. The antimicrobial, cytotoxic, and phytotoxic of the plant extracts were evaluated using disk diffusion method, MTT, and Lettuce assays, respectively.ResultsBoth flowers and leaves of M. sylvestris methanol extracts exhibited strong antibacterial effects against Erwinia carotovora, a plant pathogen, with MIC value of 128 and 256 µg/ml, respectively. The flowers extract also showed high antibacterial effects against some human pathogen bacteria strains such as Staphylococcus aureus, Streptococcus agalactiae, Entrococcus faecalis, with MIC value of 192, 200 and 256 µg/ml, respectively. The plant methanol extracts had relatively high cytotoxic activity against MacCoy cell line. ConclusionWe concluded that Malva sylvestris can be candidated as an antiseptic, achemopreventive or a chemotherapeutic agent.