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The introduction of sildenafil (SDF) to treat erectile dysfunction has solved a widespread condition with negative on the quality of life. Recently, the co-administration of tramadol (TMD) with SDF to manage premature ejaculation has illegally increased and thus drug-drug interaction studies of these drugs became of great importance. Although certain biological functions have been altered upon co-administration of the two drugs, methods for their determination in vivo to understand their interactions have yet to be published. Herein, therefore, an HPLC method with photometric detection was developed for the determination of a binary mixture of TMD and SDF in rabbit plasma after oral administration. In this study, a reversed-phase chromatography was performed at room temperature on a C18 column with a mobile phase composed of 10 mM Na2HPO4 solution (pH 7.5): acetonitrile (45:55, v/v) at a flow rate of 0.8 mL min−1 using caffeine (CAF) as an internal standard. The detector was set at 220 nm. The total analysis time was 6 min. Calibration graphs were linear in the concentration ranges of 0.1–10 and 0.05–10 μg mL−1 with a detection limit of 0.05 and 0.02 μg mL−1 for TMD and SDF, respectively. The method was validated in terms of accuracy, precision, limit of detection and quantitation, recovery, and stability as per US FDA bioanalytical guidelines. In addition, the metabolites N-desmethylsildenafil (UK-103,320) and O-desmethyltramadol were quantified in rabbit plasma after 2 h of oral administration using LC–MS/MS. The simultaneous administration of TMD with SDF has affected peak plasma concentration (Cmax), Tmax, area under the concentration-time curve (AUC), and the elimination rate constant (Kel) of SDF. The present study is the first to give valuable insights into the drug-drug interaction and the pharmacokinetic implications associated with the co-administration of SDF and TMD.

Cancer is a multifactorial disease necessitating identification of novel targets for its treatment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is considered a promising strategy for cancer treatment. Within the current work, we aimed to design and synthesize a new series of benzimidazole- and indole-based derivatives as inhibitors of Bcl-2 protein. The market pan-Bcl-2 inhibitor, obatoclax, was the lead framework compound for adopted structural modifications. The obatoclax’s pyrrolylmethine linker was replaced with straight alkylamine or carboxyhydrazine methylene linkers providing the new compounds. This strategy permitted improved structural flexibility of synthesized compounds adopting favored maneuvers for better fitting at the Bcl-2 major hydrophobic pocket. Anti-cancer activity of the synthesized compounds was further investigated through MTT-cytotoxic assay, cell cycle analysis, RT-PCR, ELISA and DNA fragmentation. Cytotoxic results showed compounds 8a, 8b and 8c with promising cytotoxicity against MDA-MB-231/breast cancer cells (IC50 = 12.69 ± 0.84 to 12.83 ± 3.50 µM), while 8a and 8c depicted noticeable activities against A549/lung adenocarcinoma cells (IC50 = 23.05 ± 1.45 and 11.63 ± 2.57 µM, respectively). The signaling Bcl-2 inhibition pathway was confirmed by molecular docking where significant docking energies and interactions with key Bcl-2 pocket residues were depicted. Moreover, the top active compound, 8b, showed significant upregulated expression levels of pro-apoptotic/anti-apoptotic of genes, Bax, Bcl-2, caspase-3, -8, and -9 through RT-PCR assay. Improving the compound’s pharmaceutical profile was undertaken by introducing 8b within drug-solid/lipid nanoparticle formulation prepared by hot melting homogenization technique and evaluated for encapsulation efficiency, particle size, and zeta potential. Significant improvement was seen at the compound’s cytotoxic activity. In conclusion, 8b is introduced as a promising anti-cancer lead candidate that worth future fine-tuned lead optimization and development studies while exploring its potentiality through in-vivo preclinical investigation.

The membrane-bound human carbonic anhydrase (hCA) IX is widely recognized as a marker of tumor hypoxia and a prognostic factor within several human cancers. Being undetected in most normal tissues, hCA-IX implies the pharmacotherapeutic advent of reduced off-target adverse effects. We assessed the potential anticancer activity of bumetanide-based analogues to inhibit the hCA-IX enzymatic activity and cell proliferation of two solid cancer cell lines, namely kidney carcinoma (A-498) and bladder squamous cell carcinoma (SCaBER). Bumetanide analogues efficiently inhibit the target hCA-IX in low nanomolar activity (IC50 = 4.4&ndash, 23.7 nM) and have an excellent selectivity profile (SI = 14.5&ndash, 804) relative to the ubiquitous hCA-II isoform. Additionally, molecular docking studies provided insights into the compounds&rsquo, structure&ndash, activity relationship and preferential binding of small-sized as well as selective bulky ligands towards the hCA-IX pocket. In particular, 2,4-dihydro-1,2,4-triazole-3-thione derivative 9c displayed pronounced hCA-IX inhibitory activity and impressive antiproliferative activity on oncogenic A-498 kidney carcinoma cells and is being considered as a promising anticancer candidate. Future studies will aim to optimize this compound to fine-tune its anticancer activity as well as explore its potential through in-vivo preclinical studies.

Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing a global public health burden affecting more than 366 million people worldwide. We recently reported the discovery of three series of novel agents showing balanced activity on two metabolic receptors, peroxisome proliferator activated receptor-γ (PPAR-γ) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied on linking the thiazolidinedione head with known GPCR privilege structures. To further investigate this concept, two new scaffolds, the benzhydrol- and indole-based chemotypes, were introduced here in. Our optimization campaign resulted in three compounds; 15a, 15c, and 15d, with affinities in the low micromolar range on both targets. In vivo study of selected test compounds, revealed that 15c possesses a significant anti-hyperglycemic and anti-hyperlipidemic activities superior to rosiglitazone in fat-fed animal models. Molecular docking analysis was conducted to explain the binding modes of both series. These compounds could lead to the development of the unique antidiabetic agent acting as insulin sensitizer as well as insulin secretagogue.

Graphical abstract, The rise in multidrug resistant (MDR) cases of tuberculosis (TB) has led to the need for the development of TB drugs with different mechanisms of action. The genome sequence of Mycobacterium tuberculosis (Mtb) revealed twenty different genes coding for cytochrome P450s. CYP121A1 catalyzes a C—C crosslinking reaction of dicyclotyrosine (cYY) producing mycocyclosin and current research suggests that either mycocyclosin is essential or the overproduction of cYY is toxic to Mtb. A series of 1,4-dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives were designed and synthesised as cYY mimics. The derivatives substituted in the 4-position of the phenyl rings with halides or alkyl group showed promising antimycobacterial activity (MIC 6.25 μg/mL), with the more lipophilic branched alkyl derivatives displaying optimal binding affinity with CYP121A1 (iPr KD = 1.6 μM; tBu KD = 1.2 μM). Computational studies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding.

A high-performance liquid chromatographic method has been developed for the simultaneous analysis of benzonatate (BNZ), diphenhydramine hydrochloride (DPH), guaifenesin (GFN), and phenylephrine hydrochloride (PEP). The separation was achieved using a Thermo C18 reversed-phase column (250 mm × 4.6 mm ID, particle size 5 µ). Dual mode gradient elution was used for the separation and UV detection was carried out at 222 nm. The method was specific and stability indicating as chromatographic conditions provided adequate separation of degradation products. The method showed good linearity in the range of 5–400, 1–120, 3–300, and 2–100 µg/mL for BNZ, DPH, GFN, and PEP, respectively. All the square of the correlation coefficients are 0.999. The degradation products were isolated and identified by NMR, IR, and mass spectroscopy. The proposed method proved to be accurate, precise, selective, and robust. The applicability of the method was evaluated in commercial dosage form analysis as well as in stability studies.

A series of 3,4-bis-chalcone-N-arylpyrazoles 3a-k was prepared from diacetyl pyrazoles 2a-e. The reaction of 2d and 2e with hydrazine hydrate gave pyrazolo[3,4-d]pyridazine derivatives 4a-b. Furthermore, the reaction of 2a-e with thiosemicarbazide afforded pyrazolo[3,4-d]pyridazine thiocyanate salts 5a-e. The synthesized compounds were subjected to in vivo anti-inflammatory and ulcerogenic activity measurements, in addition to determination of their in vitro COX selectivity, to give a full profile about their anti-inflammatory activities. Compounds 3c, 3f, 3i, and 3e showed significant anti-inflammatory activity among the synthesized compounds. Moreover, docking studies were performed to give an explanation for their anti-inflammatory activity through COX selectivity.

Sustained release diclofenac sodium (Df-Na) solid lipid matrices with Compritol® 888 ATO were developed in this study. The drug/lipid powders were processed via cold and hot melt extrusion at various drug loadings. The influence of the processing temperatures, drug loading and the addition of excipients on the obtained dissolution rates was investigated. The physicochemical characterization of the extruded batches showed the existence of crystalline drug in the extrudates with a small amount being solubilized in the lipid matrix. The drug content and uniformity on the tablet surface were also investigated by using energy dispersive X-ray microanalysis. The dissolution rates were found to depend on the actual Df-Na loading and the nature of the added excipients, while the effect of the processing temperatures was negligible. The dissolution mechanism of all extruded formulations followed Peppas-Korsemeyer law, based on the estimated determination coefficients and the dissolution constant rates, indicating drug diffusion from the lipid matrices.

Sustained-release mini-tablets are a potentially suitable for paediatric drug delivery or as multi-particulate dosage forms.To evaluate the potential for developing lipophilic matrix mini-tablets and to assess the effects of Compritol® 888 ATO concentration on drug release from differently sized mini-tablets prepared by direct compression.A formulation comprising theophylline as a model soluble drug, 15% w/w Compritol® 888 ATO as the inert matrix-forming agent, with dibasic dicalcium phosphate anhydrous and lactose as diluents was evaluated by producing 12 mm tablets at a range of compression speeds and forces. The same formulation and further formulations with 25, 35 or 45% w/w Compritol® 888 ATO were evaluated by producing 2, 3 and 4 mm mini-tablets.Drug release from matrix tablets was sustained over a period of 12 hours and release rate varied according to the compression force and speed employed. The rate of drug release from matrix mini-tablets was more rapid and increasing Compritol® 888 ATO concentration resulted in slower release rates. The rate of drug release from matrix mini-tablets was inversely proportional to mini-tablet size (2 mm3 mm4 mm). Drug release from the matrix tablets and mini-tablets followed square-root of time kinetics.Tailored drug release from matrix mini-tablets may achieved by altering the size of mini-tablet or level of Compritol® 888 ATO in the formulation and this may have potential in the development of paediatric formulations or multi-particulate dosage forms.

A simple, sensitive and rapid chromatographic method was developed and validated for the simultaneous quantification of atenolol and chlorthalidone in human plasma using hydrochlorothiazide as internal standard (IS). The method utilized proteins precipitation with acetonitril as the only sample preparation involved prior to reverse phase-HPLC. The analytes were chromatographed on Shim-pack cyanopropyl column with isocratic elution with 10mM KH2PO4 (pH 6.0) – methanol (70:30, v/v) at ambient temperature with flow rate of 1mLmin−1 and UV detection at 225nm. The chromatographic run time was less than 10min for the mixture. The calibration curves were linear over the range of 0.1–10μgmL−1. The method was validated in terms of accuracy, precision, absolute recovery, freeze–thaw stability, bench-top stability and re-injection reproducibility. The within- and between-day accuracy and precision were found to be within acceptable limits

A spectrophotometric method was described for the determination of the antibacterial quinolone derivatives, ciprofloxacin , enrofloxacin and pefloxacin through charge transfer complex formation with three different acceptors. Chloranilic acid (CL) was utilized for their determination, forming charge transfer complex with λ max 520 nm. The proposed method was applied for determination of Ciprocin tablets , Enroxil oral solution , Peflacin ampoules and Peflacin tablets, with mean percentage accuracies, 99.58±1.25, 99.94±0.96, 100.91±1.59 and 99.86±1.003. Also, tetracyanoethylene (TCNE) was utilized in the determination of the concerned compounds forming charge transfer complexes with maximum absorbances at λ max 335 nm for ciprofloxacin and at λ max 290 nm for both enrofloxacin and pefloxacin . The procedure was applied for determination of Ciprocin tablets , Enroxil 10% oral solution, Peflacine tablets and Peflacine ampoules with mean percentage accuracies 99.40±1.27, 99.95±0.90, 98.98±1.565 and 99.88±0.998, respectively. Also, 2,3-dichloro-5,6-dicyano- p -benzoquinone (DDQ) was utilized for determination of pefloxacin forming charge transfer complex with maximum absorbance at λ max 460 nm. The procedure was applied for determination of peflacine tablets and peflacine ampoules with mean percentage accuracies 100.40±0.76 and 99.91±0.623, respectively. Statistical analysis of the obtained results showed no significant difference between the proposed method and other official and reported methods as evident from the t -test and variance ratio.

The preparation of lipophilic matrix tablets for the sustained release of water soluble drugs via direct compression is not always feasible due to poor flow and rapid drug release. The aim was to evaluate the potential for developing sustained-release diclofenac sodium tablets, using Compritol® 888 ATO as a lipid matrix, by a wet granulation technique. The effects of wet granulation method (planetary mixer and fluid-bed) and liquid binder type (HPMC Metolose® 603, 606 or 615) on weight uniformity, tensile strength and release rates were investigated. The influence of compression force and speed during tablet manufacture under simulated rotary press production conditions were also evaluated. Rapid release of diclofenac sodium from directly compressed matrices was observed. A wet granulation technique using different HPMC binders produced free-flowing granules and matrices which released diclofenac sodium in a sustained manner over several hours. When the formulation comprising the lowest viscosity grade HPMC (Metolose® 603) was further evaluated using a laboratory scale fluid-bed system, consistently sized granules with good flowability and matrices with good weight uniformity and tensile strengths were produced. Release rates were consistent over a range of compression speeds and forces indicating the suitability of the formulation for production on a rotary tablet press.

Two simple, quick and sensitive spectrophotometric methods are described for the determination of enrofloxacin and Pefloxacin. The methods are based on the reaction of these drugs with bromophenol blue (BPB) and methyl orange (MO) in buffered aqueous solution at pH 2.3-2.5 in case of bromophenol blue and at pH 3.6 with MO to give highly coloured complex species, extractable with chloroform. The coloured products are quantitated spectrophotometrically at 420 and 424 nm for BPB and MO, respectively. Optimisation of the different experimental conditions is described. Beer's law is obeyed in the concentration ranges 2-12 and 2-18 microg ml(-1) with BPB and in the ranges 1-12 and 4-40 microg ml(-1)with MO for enrofloxacin and pefloxacin, respectively. The proposed methods are applied for determination of Enroxil oral solution, Peflacine tablets and Peflacine ampoules with mean percentage accuracies 99.5+/-0.99, 99.39+/-1.05 and 100.02+/-0.895, respectively, with BPB and 100.30+/-0.89, 100.25+/-0.98 and 100.20+/-0.72, respectively, with MO.