فهرست مطالب
Advanced Pharmaceutical Bulletin
Volume:5 Issue: 2, Jun 2015
- تاریخ انتشار: 1394/03/25
- تعداد عناوین: 20
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Pages 141-149Although physiological and pathological role of hypoxia have been appreciated in mammalians for decades however the cellular biology of hypoxia more clarified in the past 20 years. Discovery of the transcription factor hypoxia-inducible factor (HIF)-1, in the 1990s opened a new window to investigate the mechanisms behind hypoxia. In different cellular contexts HIF-1 activation show variable results by impacting various aspects of cell biology such as cell cycle, apoptosis, differentiation and etc. Mesenchymal stem cells (MSC) are unique cells which take important role in tissue regeneration. They are characterized by self-renewal capacity, multilineage potential, and immunosuppressive property. Like so many kind of cells, hypoxia induces different responses in MSCs by HIF-1 activation. The activation of this molecule changes the growth, multiplication, differentiation and gene expression profile of MSCs in their niche by a complex of signals. This article briefly discusses the most important effects of hypoxia in growth kinetics, signalling pathways, cytokine secretion profile and expression of chemokine receptors in different conditions.Keywords: Hypoxia, Mesenchymal stem cells, Hypoxia, inducible factor, Niche
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Pages 151-159In recent years, nanomaterials have been widely applied as advanced drug and gene delivery nanosystems. Among them, solid lipid nanoparticles (SLNs) have attracted great attention as colloidal drug delivery systems for incorporating hydrophilic or lipophilic drugs and various macromolecules as well as proteins and nucleic acids. Therefore, SLNs offer great promise for controlled and site specific drug and gene delivery. This article includes general information about SLN structures and properties, production procedures, characterization. In addition, recent progress on development of drug and gene delivery systems using SLNs was reviewed.Keywords: Solid lipid nanoparticles, colloidal carrier, Drug delivery, Gene delivery
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Pages 161-168PurposeCell-penetrating peptides (CPPs) are used for delivering drugs and other macromolecular cargo into living cells. In this paper, we investigated the relationship between the structural/physicochemical properties of four new synthetic peptides containing arginine-tryptophan in terms of their cell membrane penetration efficiency.MethodsThe peptides were prepared using solid phase synthesis procedure using FMOC protected amino acids. Fluorescence-activated cell sorting and fluorescence imaging were used to evaluate uptake efficiency. Prediction of the peptide secondary structure and estimation of physicochemical properties was performed using the GOR V method and MPEx 3.2 software (Wimley-White scale, helical wheel projection and total hydrophobic moment).ResultsOur data showed that the uptake efficiency of peptides with two tryptophans at the C- and N-terminus were significantly higher (about 4-fold) than that of peptides containing three tryptophans at both ends. The distribution of arginine at both ends also increased the uptake efficiency 2.52- and 7.18-fold, compared with arginine distribution at the middle of peptides.ConclusionAccording to the obtained results the value of transfer free energies of peptides from the aqueous phase to membrane bilayer could be a good predictor for the cellular uptake efficiency of CPPs.Keywords: Cell_penetrating peptides (CPPs)_Wimley_White scale_GOR (Garnier_Osguthorpe_Robson) V method_Model amphipathic peptide (MAP)
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Pages 169-179PurposeCell-penetrating peptides (CPPs) are used for delivering drugs and other macromolecular cargo into living cells. In this paper, we investigated the relationship between the structural/physicochemical properties of four new synthetic peptides containing arginine-tryptophan in terms of their cell membrane penetration efficiency.MethodsThe peptides were prepared using solid phase synthesis procedure using FMOC protected amino acids. Fluorescence-activated cell sorting and fluorescence imaging were used to evaluate uptake efficiency. Prediction of the peptide secondary structure and estimation of physicochemical properties was performed using the GOR V method and MPEx 3.2 software (Wimley-White scale, helical wheel projection and total hydrophobic moment).ResultsOur data showed that the uptake efficiency of peptides with two tryptophans at the C- and N-terminus were significantly higher (about 4-fold) than that of peptides containing three tryptophans at both ends. The distribution of arginine at both ends also increased the uptake efficiency 2.52- and 7.18-fold, compared with arginine distribution at the middle of peptides.ConclusionAccording to the obtained results the value of transfer free energies of peptides from the aqueous phase to membrane bilayer could be a good predictor for the cellular uptake efficiency of CPPs.Keywords: Cell_penetrating peptides (CPPs)_Wimley_White scale_GOR (Garnier_Osguthorpe_Robson) V method_Model amphipathic peptide (MAP)
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Pages 181-188PurposeMicrobial assay is used to determine the potency of antibiotics and vitamins. In spite of its advantages like simplicity and easiness, and to reveal the slight changes in the molecules, the microbial assay suffers from significant limitations; these methods are of lower specificity, accuracy and sensitivity. The objective of the present study is to evaluate the efficacy of real time-PCR technique in comparison with turbidimetric method for microbial assay of amikacin.MethodsMicrobial determination of amikacin by turbidimetric method was performed according to USP. Also amikacin concentrations were determined by microbial assay using taq-man quantitative PCR method. Standard curves in different concentration for both methods were plotted and method validation parameters of linearity, precision and accuracy were calculated using statistical procedures.ResultsThe RT-PCR method was linear in the wider concentration range (5.12 – 38.08 for RT-PCR versus 8.00 – 30.47 for turbidimetric method) with a better correlation coefficient (0.976 for RT-PCR versus 0.958 for turbidimetric method). RT-PCR method with LOQ of 5.12 ng/ml was more sensitive than turbidimetric method with LOQ of 8.00 ng/ml and the former could detect and quantify low concentrations of amikacin. The results of accuracy and precision evaluation showed that the RT-PCR method was accurate and precise in all of the tested concentration.ConclusionThe RT-PCR method described here provided an accurate and precise technique for measurement of amikacin potency and it can be a candidate for microbial determination of the antibiotics with the same test organism.Keywords: Microbial assay, Real time, PCR, Turbidimetric method, Amikacin
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Pages 189-194PurposeComparison between the efficacy of ceftriaxone and monocytes on improvement of neuron protection and functional recovery after spinal cord injury (SCI) in rat.MethodsRats were randomly divided into three groups of ten. Spinal cord injury was performed on rats under general anesthesia using the weight dropping method. Ceftriaxone was injected intraperitoneally 200 mg/kg/day for seven days after SCI. Monocytes were injected 2 × 105 cells 4 days after SCI. Hind limb motor function was assessed using the Basso, Beattie and Bresnahan (BBB) scale. Corticospinal tract (CST) axons were traced by injection of biotin dextran amine (BDA) into the sensorimotor cortex.ResultsThere were statistically significant differences in BBB scores in ceftriaxone in comparison to both monocytes receiving and control groups. On the other hand there were statistically significant differences in axon counting in both ceftriaxone and monocytes receiving groups in comparison to control group.ConclusionOur findings suggest that ceftriaxone improves functional recovery more effective than monocytes in rats after SCI. These results are from an experimental model and validation is required for further investigation.Keywords: Spinal cord injury, Ceftriaxone, Monocytes, Rat model
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Pages 195-199PurposeProgrammed cell death or apoptosis, is a biochemical procedure that initiates due to some conditions, including hypoxia. Bax and Bcl-2 are among the agents that regulate apoptosis. The amplification of the first one triggers the initiation of apoptosis, and the second one prevents it. Ghrelin is an endogenous peptide that antiapoptosis is its new effect. The aim of this study is to examine the effect of ghrelin on the Bax/Bcl-2 ratio.MethodsTwenty four wistar rats were divided randomly in three groups; control, hypoxic + saline and hypoxic + ghrelin. Hypoxic animals lived in O2 11% for 2 weeks and received either saline or ghrelin subcutaneously daily. The bax and Bcl-2 gene expression were measured by Real-Time RT-PCR.ResultsChronic hypoxia increased the Bax gene expression significantly compared with normal animals (P = 0.008), but the Bcl-2 was not affected by hypoxia. The Bax/Bcl-2 ratio also amplified significantly (P=0.005). Ghrelin administration significantly increased the Bax/Bcl-2 ratio in the hypoxic animals compared to the hypoxic + saline and normal groups (p=0.042 and P= 0.001, respectively).ConclusionIn the present study, animals’ treatment with ghrelin leads to an increment of Bax/Bcl-2 ratio, which indicates a controversy related to cardioprotection of ghrelin.Keywords: Ghrelin, Bax, Bcl, 2, Heart, Chronic Hypoxia
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Pages 201-208PurposeRecent developments in the field of cell therapy have led to a renewed interest in treatment of acute kidney injury (AKI). However, the early death of transplanted mesenchymal stem cells (MSCs) in stressful microenvironment of a recipient tissue is a major problem with this kind of treatment. The objective of this study was to determine whether overexpression of a cytoprotective factor, nuclear factor erythroid-2 related factor 2 (Nrf2), in MSCs could protect rats against AKI.MethodsThe Nrf2 was overexpressed in MSCs by recombinant adenoviruses, and the MSCs were implanted to rats suffering from cisplatin-induced AKI.ResultsThe obtained results showed that transplantation with the engineered MSCs ameliorates cisplatin-induced AKI. Morphologic features of the investigated kidneys showed that transplantation with the MSCs in which Nrf2 had been overexpressed significantly improved the complications of AKI.ConclusionThese findings suggested that the engineered MSCs might be a good candidate to be further evaluated in clinical trials. However, detailed studies must be performed to investigate the possible carcinogenic effect of Nrf2 overexpression.Keywords: NF, E2, Related Factor 2(Nrf2), Mesenchymal Stromal Cells(MSCs), Acute Kidney Injury, Cisplatin
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Pages 209-216PurposeOral cancer is one of the most significant cancers in the world, and squamous cell carcinoma makes up about 94% of oral malignancies. The aim of the present study was to compare the efficacy of doxorubicin plus methotrexate - loaded nanoparticles on tongue squamous cell carcinoma induced by 4NQO and compare it with the commercial doxorubicin and methotrexate delivered orally on seventy SD male rats.Methods70 rats were divided into five groups. During the study, the animals were weighed by a digital scale once a week. Number of mortalities was recorded in the data collection forms. At the end of the treatment, biopsy samples were taken from rat tongues in order to evaluate the severity of dysplasia and the extent of cell proliferation. The results were analyzed using ANOVA, descriptive statistics and chi-square test.ResultsNo statistically significant difference was found in the mean weight of five groups (p>0.05). No significant relationship was found between groups and mortality rate (P = 0. 39). In addition, there was a significant relationship between groups and the degree of dysplasia (P <0.001). The statistical analysis showed a significant relationship between groups and the rate of cell proliferation (p <0.001).ConclusionThe results of the present study showed that the use of doxorubicin plus methotrexate - loaded nanoparticles orally had more therapeutic effects than commercial doxorubicin plus methotrexate.Keywords: Doxorubicin, Squamous cell carcinoma, Oral, 4, NQO, Rats, Nanoparticles
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Pages 217-222PurposeAs H1 and H3 receptors’ roles has been defined in peripheral pains in some papers and because histamine is known for its role in inflammatory responses; this study investigated the possible analgesic and anti-inflammatory effects of ketotifen and fexofenadine as relatively safe long acting anti histamines in both chronic chemical pain and acute inflammation in rats.MethodsIn this study, male Sprague-Dawley rats weighing 225-250 grams were used. In order to evaluate the chemical chronic pain, sub-plantar injection of formalin applied and the pain scores were recorded every 15 seconds during 60 minutes. Carrageenan injection to the right hind paw was used for induction of acute inflammation and the paw edema was measured every 60 minutes for 4 hours.ResultsBased on the results, both ketotifen and fexofenadine were able to significantly diminish chemical acute and chronic pain as well as inflammation in comparison with the control group and the effects were acceptable according to the standard treatment. Both effects for fexofenadine started later than those of ketotifen.ConclusionAccording to the outcomes of the study, ketotifen and fexofenadine demonstrated significant analgesic and anti-inflammatory characteristics in both models of chemical pain and acute inflammation in laboratory animals.Keywords: Ketotifen, Fexofenadine, Analgesic, Anti, inflammatory, Formalin test, Carrageenan test
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Pages 223-229PurposeThe aim of the study was the characterization of the electrophoretic behavior of cephalosporins from different generation having different structural characteristics in order to develop a rapid, simple and efficient capillary electrophoretic method for their identification and simultaneous separation from complex mixtures.MethodsTen cephalosporin derivatives (cefaclor, cefadroxil, cefalexin, cefazolin, cefoxitin, cefuroxime, cefoperazone, cefotaxime, ceftazidime, ceftriaxone) were analyzed by capillary zone electrophoresis using different background electrolyte solutions at different pH values. Electrophoretic mobilities of the analytes were calculated, the influence of the electrophoretic parameteres on the separation was established and the analytical conditions were optimized.ResultsTaking into consideration their structural and chemical properties cephalosporins can be detected over a pH range between 6 and 10. The best results were obtained using a buffer solution containing 25 mM disodium hydrogenophosphate - 25 mM sodium dihydrogenophosphate, at a pH – 7.00, + 25 kV voltage at a temperature of 25 °C, UV detection at 210 nm. Using the optimized analytical conditions we achieved the simultaneous baseline separation for seven cephalosporins in less then 10 minutes.ConclusionUsing the described optimized electrophoretic procedures, capillary electrophoresis can be used for the identification and determination of cephalosporins in formulated pharmaceutical products and for their separation from complex mixtures.Keywords: Cephalosporins, Electrophoretic mobility, Capillary zone electrophoresis, Method optimization
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Pages 231-236PurposeOxidative stress plays a key role in the onset and development of diabetes complications. In this study, we evaluated whether voluntary exercise could alleviate oxidative stress in the heart and blood of streptozotocin - induced diabetic rats.Methods28 male Wistar rats were randomly divided into four groups (n=7): control, exercise, diabetes and exercise + diabetes. Diabetes was induced by injection of streptozotocin in male rats. Rats in the trained groups were subjected to voluntary running wheel exercise for 6 weeks. At the end of six weeks blood and heart tissue samples were collected and used for determination of antioxidant enzymes (including SOD, GPX and CAT activities) and MDA level.ResultsExercise significantly reduced MDA levels both in the heart tissue (p<0.01) and blood samples (p<0.05). In addition, exercise significantly increased SOD (p<0.05), GPX (p<0.001) and CAT (p<0.05) in the heart tissue. Voluntary exercise also significantly increased SOD (p<0.01), GPX (p<0.05) and CAT (p<0.001) in the blood.ConclusionVoluntary exercise diminishes the MDA level in blood and heart tissue of diabetic rats. It also accentuates activities of SOD, GPX and CAT. Therefore, it may be considered a useful tool for the reduction of oxidative stress in diabetes.Keywords: Oxidative Stress, Diabetes, Voluntary running wheel, Heart
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Experimental Design to Predict Process Variables in the Microcrystals of Celecoxib for Dissolution Rate Enhancement Using Response Surface MethodologyPages 237-245PurposeThe purpose of the present investigation was to increase the solubility and dissolution rate of celecoxib (CLX) by preparing microcrystals of drug by solvent change precipitation.MethodsThis procedure was optimized in order to obtain stable and homogeneous particles with a small particle size, high yield and fast dissolution rate. CLX agglomerates were prepared with brij35 (stabilizer agent) using acetone as solvent, water as non-solvent, respectively. The agglomerates were characterized by DSC, XRD, FTIR studies. A full-factorial design was employed to study the effect of independent variables, the amounts of stirring rate (X1), volume of organic solvent (X2), volume of aqueous solvent (X3), time of stirring (X4), concentration of Brij (X5), concentration of Tween 80 (X6), concentration of HPMC (X7) on dependent variables, particle size (PS), drug content (DC), drug released after 15 min (Q15), crystal yield (CY), Gibbs free energy change (ΔG°tr), antalpy change (ΔH) and saturated solubility (Ss).ResultsThe DSC and FTIR results indicated the absence of any interactions between drug and stabilizers. These studies showed a decrease in crystalinity in agglomerates. The crystals exhibited significantly improved micromeritic properties compared to pure drug. The drug content and crystal yield were in the range of 32.84-48.22% and 64.55-83.33% with all formulations, respectively. The solubility and drug release rates increased with an increase in concentration of stabilizer.ConclusionThe results show that microcrystals of the drug in stabilizer considerably enhanced the dissolution rate.Keywords: Celecoxib, Brij 35, Microcrystal, Dissolution, Release
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Pages 247-253PurposePECAM-1 (CD31) is a glycoprotein expressed on endothelial and bone marrow precursor cells. It plays important roles in angiogenesis, maintenance and integration of the cytoskeleton and direction of leukocytes to the site of inflammation. We aimed to clone the cDNA coding for human CD31 from KG1a for further subcloning and expression in NIH-3T3 mouse cell line.MethodsCD31 cDNA was cloned from KG1a cell line after total RNA extraction and cDNA synthesis. Pfu DNA polymerase-amplified specific band was ligated to pGEMT-easy vector and sub-cloned in pCMV6-Neo expression vector. After transfection of NIH-3T3 cells using 3 μg of recombinant construct and 6 μl of JetPEI transfection reagent, stable expression was obtained by selection of cells by G418 antibiotic and confirmed by surface flow cytometry.Results2235 bp specific band was aligned completely to human CD31 reference sequence in NCBI database. Transient and stable expression of human CD31 on transfected NIH-3T3 mouse fibroblast cells was achieved (23% and 96%, respectively) as shown by flow cytometry.ConclusionDue to murine origin of NIH-3T3 cell line, CD31-expressing NIH-3T3 cells could be useful as immunogen in production of diagnostic monoclonal antibodies against human CD31, with no need for purification of recombinant proteins.Keywords: CD31, Cloning, NIH, 3T3, Angiogenesis, Antibody
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Pages 255-259PurposeOne of the advanced cancer therapy strategies is immune-stimulating compound based immunotherapy Staphylococcal enterotoxin B (SEB) is one of the potent superantigens, which can efficiently activate antitumor immune response to eradicate tumor growth and inhibit metastasis. Herein, we evaluated the effect of SEB on the expression of two master microRNAs, mir-335 and mir-10b, involved in metastasis.MethodsA metastatic breast cancer cell line MDA-MB231was treated with four differentconcentrations of SEB, including 10, 102, 103 and 104 ng/ml, for 24 and 48 hours. To identify the cytotoxic effect of SEB, treated cells were examined by MTT assay. The stem loop RT-PCR (TaqMan) was used to analyze the mir-335 and mir-10b expression.ResultsResults showed that SEB significantly increased the expression of mir-335 bothafter 24 and 48 hours (pv < 0.001 and pv < 0.05, respectively). No significant differences were found in the mir-10b expression.ConclusionMoreover, our findings demonstrated no cytotoxic effect of SEB on the treated cells. Our results suggest that SEB probably induces its anti-metastatic effect via the expression regulation of the main genes which contributes to metastasis.Keywords: Breast Cancer, Metastasis, Mir, 335, Mir, 10b, Staphylococcal Enterotoxin B
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Pages 261-267PurposeCurrently, cancer as a major problem around the world threatens human health and has a high incidence in developing countries. Many reports have indicated that patients suffering from cancer demonstrate decreased antitumor immune responses as well as a high prevalence of T regulatory population. It has been reported that Foxp3+Tregs exert suppression by cell contact-dependent mechanisms which are mediated by soluble factors such as immunosuppressive cytokines like IL-10, TGF-β and IL-35. Consequently there is a great need to identify prognostic and diagnostic biomarkers of regulatory T cells for vaccine and drug development.MethodsIn this study IL-10, TGF-β, IL-35 and Foxp3 mRNA gene expression has been measured in peripheral blood of 40 breast cancer patients and 40 normal age-matched women using quantitative real-time PCR (qRT-PCR) method with Master Mix reaction containing SYBER Green. GAPDH gene was used as housekeeping gene.ResultsOur data demonstrated a significant up-regulation of IL-10, TGF-β, P35, EBI3 and Foxp3 gene expression in patients’ peripheral blood compared to normal healthy controls (p<0.05).ConclusionThe data suggests that the immune system is suppressed in breast cancer patients, which may be due to elevated Treg cells population. These results may be useful for diagnostic or therapeutic purposes. However it may require more investigations.Keywords: Breast cancer, Foxp3, IL, 10, IL, 35, TGF, β
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Pages 269-275PurposeNanogel, a nanoparticle prepared from a cross-linked hydrophilic polymer network, has many biomedical applications. A radiation technique has recently been introduced as one of the appropriate methods for the preparation of polymeric nanogels due to its additive-free initiation and easy control procedure.MethodsWe have investigated the formation of nano-sized polymeric gels, based on the radiation-induced inter- and intra-molecular cross-linking of the inter-polymer complex (IPC) of polyacrylamide (PAAm) and polyacrylic acide (PAAc).ResultsThe results indicated that the prepared polymeric complex composed of PAAm and PAAc was converted into nanogel by irradiation under different doses (1, 3, 5 and 7 kGy). This was due to inter- and intra-molecular cross-linking at the range of 446-930 nm as characterized by the photon correlation spectroscopy method. Increasing the irradiation dose reduced the size of nanoparticles to 3 kGy; however, the higher doses increased the size and size distribution. Scanning electron microscopy images indicated the nanogel formation in the reported size by particle size and showed the microcapsule structure of the prepared nanogels. Biocompatibility of nanogels were assessed and proved by MTT assay.ConclusionIt was concluded that low dose irradiation can be successfully applied for nanometre-ranged hydrogel.Keywords: Nanogel, Cross, linked, Radiation, Inter, polymer complex
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Pages 277-282PurposeThe aim of this study was to prepare the optimized oral paste formulation of Triamcinolone acetonide intended to be used in aphtous stomatitis.MethodsPlastibases were prepared using mineral oil and polyethylene (95:5). Oral paste formulations were prepared with different mixtures of three hydrocolloids solids, including gelatin, pectin and sodium carboxymethylcellulose, with different ratios, as well as Plastibase. Long-term and short-term stability of prepared formulations were studied in the case of color and consistency of pastes. Franz diffusion cell and dialysis membrane were employed for release study. Release data were fitted in the kinetic models to find out the mechanism of drug release.ResultsFormulation containing 60% plastibase, 3.3% pectin, 6.6% gelatin and 30% carboxymethylcellulose showed desired durability of adhesion, spreadability and rheology property in healthy volunteers and was compared with reference formulation (Adcortyl®) in the case of release profile. Although, optimized formulation and Adcortyl followed the Higuchi and first order release kinetics respectively, optimized formulation showed similar release profile to reference formulation.ConclusionOptimized oral paste formulation of Triamcinolone Acetonide showed similar characteristics with reference formulation and could be used as an effective drug delivery system for the treatment of recurrent aphthous stomatitis.Keywords: Aphthous stomatitis, Triamcinolone acetonide, Plastibase, Oral paste
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Pages 283-288PurposeHypoxia is one of the important factors in formation of reactive oxygen species (ROS). Ghrelin is a peptide hormone that reduces oxidative stress. However, antioxidant effect of ghrelin on blood and brain in normobaric hypoxia condition has not yet been investigated.Methodsthirty-two animals were randomly divided into four (n=8) experimental groups: Control (C), ghrelin (Gh), hypoxia (H), hypoxic animals that received ghrelin (H+Gh). Normobaric systemic hypoxia (11% O2) was induced in rats for 48 hours. Effect of ghrelin (80 μg/kg, i.p) on serum TAC and MDA and brain SOD, CAT, GPx and MDA were assessed.ResultsHypoxia significantly (p<0.001) increased both blood and brain MDA Levels. Ghrelin treatment significantly (p<0.001) decreased blood MDA levels both in control and hypoxia, and brain MDA levels in hypoxia conditions. Brain SOD, CAT and GPx variations were not significant in two days of hypoxia. Ghrelin treatment also could not significantly increase activity of SOD, CAT and GPx in brain. Total antioxidant capacity of serum increased in ghrelin treatment both in control and hypoxic conditions, although it was only significant (p<0.01) in control conditions.ConclusionOur findings showed that administration of ghrelin may be useful in reducing blood and brain oxidative stress in normobaric hypoxia condition.Keywords: Normobaric Hypoxia, Ghrelin, Oxidative stress, Blood, Brain
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Pages 289-291PurposeThe present study is aimed to study the host-guest inclusion complexation of the naturally occurring cyclodextrins (CDs), namely; (a-CD,b-CD, and g-CD) with mitiglinide (MIT).MethodsHost-guest inclusion complexation was simulated using semi-empirical PM3 method.ResultsThe obtained results clearly indicate that the complexes formed are energetically favored in the presence of γ-CD (Ecomp = -17.884 kcal/mol) of the optimal configurations of (1:1) MIT/γ-CD inclusion complexes. Moreover, the results obtained reveal that the formation of more stable MIT/γ-CD complex compared to MIT/a-CD or MIT/b-CD complexes is primarily due to differences in intermolecular hydrogen bonding.ConclusionThe present theoretical results may be informative to scientists who are devoting themselves to developing effective methods for enhancing the drug solubility.Keywords: Host, guest inclusion, Mitiglinide, Cyclodextrins, PM3 method, Semi, empirical