Changes in the Solid State of Nicergoline, a Poorly Soluble Drug, Under Different Grinding and Environmental Conditions: Effect on Polymorphism and Dissolution.

Nicergoline native crystals (Form I) were subjected to different grinding methods for 15, 30, 45, and 60 min: Method A, grinding at 20°C under air atmosphere; Method B, grinding in presence of liquid nitrogen under air atmosphere; Method C, grinding at 20°C under nitrogen atmosphere; and Method D, grinding in presence of liquid nitrogen under nitrogen atmosphere. Scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, thermogravimetry, and infrared spectroscopy were used to follow changes in the particle size and in crystalline structures. Batches from Methods A and C underwent partial amorphization immediately after grinding; Form II was obtained by heating these partially amorphous forms or after spontaneous crystallization after 1 and 5 months storage. Method B promoted the hydration of nicergoline to a monohydrate form. Batch D was stable under grinding and neither amorphization nor hydration were observed. The best intrinsic dissolution rate was that of metastable Form II, followed by Form I, while the worst was that of the Method B monohydrate form. The slowest particle dissolution was observed for hydrated particles, because of the lowest IDR, while the most rapid was exhibited by batch D, because of the very small particle size.

Fabrication of Naftopidil-Loaded Tablets Using a Semisolid Extrusion-Type 3D Printer and the Characteristics of the Printed Hydrogel and Resulting Tablets.

The production of three-dimensional (3D)-printed drugs holds promise for future personalized medicine. Here, we prepared tablets containing naftopidil as a model drug using a semisolid extrusion-type 3D bioprinter applicable for tissue engineering. A hydrogel is typically used as the printer ink for 3D bioprinters, and we incorporated various amounts of hydroxypropyl methylcellulose hydrogel (30%, 40%, and 50% gel) into the printer ink. The resulting 3D-printed gel product was dried to obtain tablets. The rheological properties of the printer ink changed as its composition was changed, and tablets were prepared successfully from several formulations. Increasing the amount of hydroxypropyl methylcellulose hydrogel in the printer ink led to delayed drug dissolution, decreased weight, and decreased hardness of the tablets. Delayed drug dissolution was also observed when the amount of disintegrating agent typically used in powder compression tablets was increased in the ink, and increasing the incorporated amount of the disintegrating agent crospovidone increased the hardness of the tablets. Our results will provide useful information for the preparation of tablets using semisolid extrusion-type 3D printers.

Mirtazapine.

Mirtazapine is one of antidepression which is used mainly in the treatment of depression, moreover, it is sometimes used in the treatment of anxiety disorders, insomnia, nausea, and vomiting, and to produce weight gain when desirable. The action of mirtazapine is an antagonist of certain adrenergic and serotonin receptors, and, furthermore, the drug is used strong as antihistamine, and it is occasionally defined as a noradrenergic and specific serotonergic antidepressant (NaSSA). The comprehensive profile of mirtazapine gives more detailed information about nomenclature, formulae, elemental analysis, and appearance. In addition, the numerous methods of drug synthesis are summarized. Also the profile covers the physicochemical properties as: the value of pKa, drug solubility, melting point, X-ray powder diffraction, and analysis methods for example: (compendial, electrochemical, spectroscopic, and method of chromatographic). Besides that, the profile covered pharmacological profile and clinical pharmacokinetics in subtitle's (absorption, distribution, metabolism, and elimination). About 100 references were given as a proof of the above-mentioned studies.

Efficacy of α-blocker in improving ureteral stent-related symptoms: a meta-analysis of both direct and indirect comparison.

OBJECTIVE: To critically evaluate the efficacy of an α-blocker in improving ureteral-stent-related symptoms and preliminarily investigate the difference between different types of α-blockers. METHODS: Relevant randomized controlled trials were identified through searching PubMed, the Cochrane Library, Embase, and other sources. After quality assessment and data abstraction, direct comparison based on the Ureteral Stent-related Symptom Questionnaire (USSQ) between α-blockers and control was performed by RevMan 5.3. Indirect comparison between different types of α-blockers was performed by ITC 1.0. Sensitive and subgroup analyses were used to handle important clinical factors. RESULTS: Sixteen randomized controlled trials containing 1,489 cases were included. Compared with control, α-blockers significantly reduced the overall urinary symptom, pain index, general health index, and scores related to sexual matters, while no significant difference was found in work performance and additional problem scores. Subgroup analysis showed that the duration of stent insertion, patient's age, stent size, and the type of α-blocker had the potential to influence the outcomes. Through indirect comparison, we found alfuzosin and terazosin to be better than tamsulosin in pain relief and general health improvement. CONCLUSION: α-Blocker was effective in treating ureteral stent-related symptoms, as it improved the major indexes of USSQ post-insertion or post-removal. Alfuzosin and terazosin seemed to be better than tamsulosin, which needs further verification because of the lack of direct comparison currently.

A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists.

N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that play key roles in brain physiology and pathology. Because numerous pathologic conditions involve NMDAR overactivation, subunit-selective antagonists hold strong therapeutic potential, although clinical successes remain limited. Among the most promising NMDAR-targeting drugs are allosteric inhibitors of GluN2B-containing receptors. Since the discovery of ifenprodil, a range of GluN2B-selective compounds with strikingly different structural motifs have been identified. This molecular diversity raises the possibility of distinct binding sites, although supporting data are lacking. Using X-ray crystallography, we show that EVT-101, a GluN2B antagonist structurally unrelated to the classic phenylethanolamine pharmacophore, binds at the same GluN1/GluN2B dimer interface as ifenprodil but adopts a remarkably different binding mode involving a distinct subcavity and receptor interactions. Mutagenesis experiments demonstrate that this novel binding site is physiologically relevant. Moreover, in silico docking unveils that GluN2B-selective antagonists broadly divide into two distinct classes according to binding pose. These data widen the allosteric and pharmacological landscape of NMDARs and offer a renewed structural framework for designing next-generation GluN2B antagonists with therapeutic value for brain disorders.

α2-adrenoceptor binding in Flinders-sensitive line compared with Flinders-resistant line and Sprague-Dawley rats.

OBJECTIVES: Disturbances in the noradrenergic system, including alterations in the densities of α2-adrenoceptors, are posited to be involved in the pathophysiology of depression. In this study, we investigate the binding of α2-adrenoceptors in regions relevant to depression in an animal model of depression. METHODS: Using in vitro autoradiography techniques and the selective α2-ligand, [3H]RX 821002, we investigated the density of α2-adrenoceptors in female Flinders-sensitive line (FSL) rats, a validated model of depression, and in two traditional control groups - female Flinders-resistant line (FRL) and Sprague-Dawley (SD) rats. RESULTS: The α2-adrenoceptor density was increased in most regions of the FSL rat brain when compared with SD rats (10% across regions). Moreover, the α2-adrenoceptor density was further increased in the FRL rats compared with both FSL (10% across regions) and SD rats (24% across regions). CONCLUSIONS: The increase in α2-adrenoceptor binding in cortical regions in the FSL strain compared with the SD control strain is in accord with α2-adrenoceptor post-mortem binding data in suicide victims with untreated major depression. However, the differences in binding observed in the two control groups were unexpected and suggest the need for further studies in a larger cohort of animals of both sexes.

Painful orgasm in an adolescent after seminal-sparing cystoprostatectomy: a puzzling symptom.

An 18-year-old boy, followed up after seminal-sparing cystectomy for bladder rhabdomyosarcoma, presented complaining of recurrent episodes of left scrotal/inguinal pain arising after orgasms. Full work-up ruled out disease recurrence, but showed enlarged seminal vesicles. Ligation of the vas deferens was unsuccessful. The patient was started on α-blockers to reduce vas contractions with improvement of symptoms. The possible pathophysiology and treatments of this symptom are discussed.

Nano-structured complexes of reserpine and quinidine drugs with chloranilic acid based on intermolecular H-bond: spectral and surface morphology studies.

The study of the drug-acceptor interaction may be useful in understanding the drug-receptor interactions and the mechanism of drug action. Here, complexes of reserpine (Res) and quinidine (Qui) drugs with chloranilic acid (CLA) have been synthesized. Then, these complexes were characterized chemically and structurally using CHN elemental analysis, infrared (IR) and electronic absorption spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM). The stoichiometry of the H-bonded complex was found to have a 1:1 ratio, so these complexes can be formulated as [(Drug)(CLA)]. IR measurements confirmed the presence of intermolecular H-bond. Application of Debye-Scherrer equation indicates that the formed complexes are in the range of nano-size. The Res complex exhibits a remarkable crystalline morphology. It was also found that the particle size of Res complex is 1.533 time higher than that of Qui complex. Interestingly, free Res molecular weight is higher than that of free Qui by the same ratio (precisely; 1.525).

6-methoxy-7-benzofuranoxy and 6-methoxy-7-indolyloxy analogues of 2-[2-(2,6-Dimethoxyphenoxy)ethyl]aminomethyl-1,4-benzodioxane (WB4101):1 discovery of a potent and selective α1D-adrenoceptor antagonist.

Previous results have shown that replacement of one of the two o-methoxy groups at the phenoxy residue of the potent, but not subtype-selective, α1-AR antagonist (S)-WB4101 [(S)-1] by phenyl, or by ortho,meta-fused cyclohexane, or especially by ortho,meta-fused benzene preferentially elicits α1D-AR antagonist affinity. Such observations inspired the design of four new analogues of 1 bearing, in lieu of the 2,6-dimethoxyphenoxy residue, a 6-methoxy-substituted 7-benzofuranoxy or 7-indolyloxy group or, alternatively, their corresponding 2,3-dihydro form. Of these new compounds, which maintain, rigidified, the characteristic ortho heterodisubstituted phenoxy substructure of 1, the S enantiomer of the dihydrobenzofuranoxy derivative exhibited the highest α1D-AR antagonist affinity (pA2 9.58) with significant α1D/α1A and α1D/α1B selectivity. In addition, compared both to α1D-AR antagonists structurally related to 1 and to the well-known α1D-AR antagonist BMY7378, this derivative had modest 5-HT1A affinity and neutral α1-AR antagonist behavior.

Novel 4-substituted-2(1H)-phthalazinone derivatives: synthesis, molecular modeling study and their effects on α-receptors.

Novel 4-(4-bromophenyl)phthalazine derivatives connected via an alkyl spacer to amine or N-substituted piperazine were designed and synthesized as promising α-adrenoceptor antagonists. The structures of the phthalazine derivatives were established using elemental and spectral analyses. Twelve of the tested compounds displayed significant α-blocking activity. Molecular modeling studies were performed to rationalize the biological results. Among the tested compounds, 7j displayed the best-fitting score and the highest in vitro activity.

Effect of counterions on physicochemical properties of prazosin salts.

This study evaluated the effect of counterions on the physicochemical properties of prazosin salts. Salt forms of prazosin, namely, mesylate, besylate, tosylate, camsylate, oxalate, and maleate, were prepared and compared with the marketed anhydrous and polyhydrate forms of prazosin hydrochloride. Physicochemical characterization was performed in the order of crystallinity, hygroscopicity, solubility, and stability to select the optimal salt(s). Permeability study in Caco-2 cell lines and in vivo bioavailability study in rat model were investigated to ascertain their biopharmaceutical advantage. All salt forms were crystalline, nonhygroscopic (except the anhydrous hydrochloride salt), and had solubility in the range of 0.2 to 1.6 mg/ml. All salts were physically and chemically stable at 40°C/75% relative humidity, but degraded in UV-visible light, except the anhydrous hydrochloride salt. Prazosin mesylate was selected as the optimal salt, as it possessed higher solubility, permeability, and bioavailability, compared to the commercial hydrochloride salts. Hydrochloride salt is reported to have poor bioavailability that is partially attributed to its low solubility and extensive common-ion effect in the gastric region. Factors like hydrophilicity of the counterion, hydration state of the salt, and melting point of the salt contribute to the physicochemical properties of the salts. This study has implications in the selection of an optimal salt form for prazosin, which is suitable for further development.

Matrix effects and recovery calculations in analyses of pharmaceuticals based on the determination of ß-blockers and ß-agonists in environmental samples.

In recent years substantial progress has been made in analytical methods for determining pharmaceutical residues in environmental samples. Although much work has attempted to establish the influence of sample matrix complexity on results through the determination of matrix effects (ME), extraction efficiency (EE) and absolute recovery of analytes (AR), comparison of these parameters is very complicated because different authors use different methods to obtain them. Moreover, there are few literature data describing the influence of aqueous matrices (tap water and waste water) on results obtained with GC-MS methods. For these reasons, the main aims of the present study were: (1) to critically review the determination of matrix effects and recovery parameters using the two most common techniques for analyzing drugs in environmental samples: gas and liquid chromatography coupled with mass spectrometry or tandem mass spectrometry (GC-MS, GC-MS/MS and LC-MS, LC-MS/MS); (2) to postulate a uniform method for determining ME, EE and AR using GC techniques; (3) to investigate the influence of different aqueous matrices on the solid-phase extraction, derivatization and final determination of drugs using GC. ß-Blockers and ß-agonists, drugs commonly found in the environment, were chosen as model compounds for this investigation. The values of ME, EE and AR obtained were compared with analogous (or similar) data obtained by other researchers using LC-MS measurements. All the results confirmed that GC-MS analyses are much less sensitive to the complexity of sample matrices than LC-MS, so GC-MS measurements appear to be a very good alternative to LC-MS methods of determining pharmaceutical residues in environmental samples.

Synthesis and biological activities of 2-[(heteroaryl)methyl]imidazolines.

A series of 2-[(heteroaryl)methyl]imidazolines was synthesized and tested for their activities at α(1)- and α(2)-adrenoceptors and imidazoline I(1) and I(2) receptors. The most active 2-[(indazol-1-yl)methyl]imidazolines showed high or moderate affinities for α(1)- and α(2)-adrenoceptors. However, their intrinsic activities at α(2A)-adrenoceptors proved to be negligible. A selected 7-chloro derivative behaved as a potent α(1)-adrenoceptor antagonist and exhibited peripherally mediated hypotensive effects in rats.

Stability and compatibility of doxofylline with phentolamine mesilate in 0.9% sodium chloride or 5% dextrose injection for intravenous infusion.

WHAT IS KNOWN AND OBJECTIVE: The use of extemporaneously prepared admixtures of drugs must be supported by documentation of their chemical stability. The objective was to assess the physical compatibility and the chemical stability of doxofylline with phentolamine mesilate in 0.9% sodium chloride or 5% dextrose injection for intravenous infusion. METHODS: Total volumes of 20 and 1 mL of doxofylline solution and phentolamine mesilate solution, respectively, were added to 250 mL polyolefin bags containing 5% dextrose injection or 0.9% sodium chloride injection. Bags were stored for 24 h at 20-25 °C. Chemical compatibility was measures with high-performance liquid chromatography, and physical compatibility was determined visually. RESULTS: The samples were clear and colourless when viewed in normal fluorescent room light. The pH value and particulate content of the admixtures exhibited little change. The retentions of the initial concentration of doxofylline and phentolamine mesilate in the admixtures were within 97-105%. Doxofylline and phentolamine mesilate were stable in 5% dextrose injection or in 0.9% sodium chloride for up to 24 h at 20-25 °C. WHAT IS NEW AND CONCLUSION: Doxofylline and phentolamine mesilate mixed in both 5% dextrose injection and 0.9% sodium chloride injection in 250 mL multilayer polyolefin bags at concentrations of 0.74 mg/mL and 36.9 µg/mL, respectively, were stable for up to 24 h at 20-25 °C.

Rigid analogues of the α2-adrenergic blocker atipamezole: small changes, big consequences.

We report the discovery of a new family of α(2) adrenergic receptor antagonists derived from atipamezole. Affinities of the compounds at human α(2) and α(1b) receptors as well as their functional activities at hα(2A) receptors were determined in competition binding and G-protein activation assays, respectively. Central α(2) antagonist activities were confirmed in mice after oral administration. Further studies on a selected example: (+)-4-(1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole, (+)-1 (F 14805), were undertaken to probe the potential of the series. On the one hand, (+)-1 increased the release of noradrenaline in mouse frontal cortex following acute systemic administration, the magnitude of this effect being much larger than that obtained with reference agents. On the other, (+)-1 produced minimal cardiovascular effects in intact, anesthetized rat, a surprising outcome that might be explained by its differential action at peripheral and central α(2) receptors. A strategy for improving the therapeutic window of α(2) antagonists is put forward.

Matrix tablets based on carrageenans with dual controlled release of doxazosin mesylate.

The use of polymeric polyelectrolytes as matrix-forming agents is far from optimally or fully understood. Polyelectrolyte carrageenan (CARR) matrices loaded with oppositely charged active substance doxazosin mesylate (DM) were investigated according to their water-uptake/erosion properties, in situ complexation ability of CARR with DM, and the possibility to achieve dual drug release control. Interactions between different CARR types (ι-, κ-, and λ-) and DM were confirmed by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and zeta potential measurements. Combination of water-uptake/erosion with in situ complexation prolonged DM release from CARR matrices for more than 24 h. The rate order of drug release was in accordance with the number of ester sulfate moieties per disaccharide unit of CARRs (κ (1)>ι (2)>λ (3)). The higher the charge on the CARR backbone, the higher the number of interactions with DM and the slower the drug release. Low pH, more vigorous hydrodynamics, and higher ionic strength resulted in faster drug release. Based on zeta potential measurements of DM and CARRs, proposed influence of counterion condensation and its effect on screening polyelectrolyte-drug interactions was confirmed to lower in situ DM-CARR complexation. Dual drug release control from polyelectrolyte matrices by water-uptake/erosion and in situ complexation offers many new approaches for designing controlled-release systems.

Interactions of biopolymers carrageenans with cationic drug doxazosin mesylate characterized by means of differential scanning calorimetry.

When ionic polymers (polyelectrolytes) are used as excipients in pharmaceutical formulations, the properties of oppositely charged drugs may be strongly affected by the charge-charge interactions or complex formation. Usually these effects are considered as a negative event resulting in a drug-excipient incompatibility. Sometimes ionic interactions are preferred to prolong drug release from dosage forms in a controllable manner. Ionic interactions of carrageenans with doxazosin mesylate were confirmed by differential scanning calorimetry (DSC). Evident peak shifts and shape changes of assumed desulfation peak of carrageenans in concordance with disappearance of melting peak of doxazosin mesylate (DM) in DSC curves were obtained. The range of thermal effects is depended on the ratio of doxazosin mesylate and carrageenans. The higher the ratio of DM compared to CARRs the more evident are the interactions.

Modeling the interactions between alpha(1)-adrenergic receptors and their antagonists.

As crucial members of the G-protein coupled receptor (GPCR) superfamily, alpha (1)-adrenergic receptors (alpha(1)-ARs) are recognized to intervene the actions of endogenous catecholamines such as norepinephrine and epinephrine. So far three distinct alpha(1)-AR subtypes, alpha(1A), alpha(1B) and alpha(1D), have been characterized by functional analysis, radio-ligand binding and molecular biology studies. The alpha(1)-ARs are of therapeutic interest because of their distinct and critical roles in many physiological processes, containing hypertension, benign prostatic hyperplasia, smooth muscle contraction, myocardial inotropy and chronotropy, and hepatic glucose metabolism. Accordingly, designing subtype-selective antagonists for each of the three alpha(1)-AR subtypes has been an enthusiastic region of medicinal research. Even though a large number of studies on GPCRs have been conducted, understanding of how known antagonists bind to alpha(1)-ARs still remains sketchy and has been a serious impediment to search for potent and subtype-selective alpha(1)-AR antagonists because of the lack of detailed experimental structural knowledge. This review deliberates the simulation of alpha(1)-ARs and their interactions with antagonists by using ligand-based (pharmacophore identification and QSAR modeling) and structure-based (comparative modeling and molecular docking) approaches. Combined with experimental data, these computational attempts could improve our understanding of the structural basis of antagonist binding and the molecular basis of receptor activation, thus offering a more reasonable approach in the design of drugs targeting alpha(1)-ARs.

Investigating contamination of phytotherapy products for benign prostatic hyperplasia with alpha-blockers and 5alpha-reductase inhibitors.

PURPOSE: Complementary and alternative medicine, including phytotherapeutic agents, or those derived from plant or herb extracts to treat symptoms, is widely accepted in the community. Men with bothersome lower urinary tract symptoms due to benign prostatic hyperplasia increasingly use such preparations. Phytotherapeutic agent quality is unregulated and in most instances the contents are unknown while erectile dysfunction and prostate cancer treatments have shown contamination with standard pharmaceuticals. Since trial results for benign prostatic hyperplasia phytotherapeutic agents are inconsistent, they may also be contaminated. Thus, we determined whether pharmacological doses of alpha-blockers and/or 5alpha-reductase inhibitors were present in a sample of phytotherapeutic agents for benign prostatic hyperplasia. MATERIALS AND METHODS: We analyzed 15 phytotherapeutic products marketed for benign prostatic hyperplasia. Only oral tablets or capsules were considered with teas, tonics and foods excluded from study. We made random purchases from shop front health stores and Internet retailers. All batches of commercial phytotherapy were analyzed by high performance liquid chromatography. Analysis was semiquantitative using extracts from alfuzosin, doxazosin, terazosin, tamsulosin, dutasteride and finasteride. RESULTS: In the 15 batches of different phytotherapeutic agents tested no interference secondary to contamination with alpha-blockers or 5alpha-reductase inhibitors was observed. CONCLUSIONS: All phytotherapeutic agents for benign prostatic hyperplasia in this study tested negative for alpha-blockers and 5alpha-reductase inhibitors. Inconsistent results in trials using phytotherapeutic agents are probably not explained by the presence of standard pharmaceuticals.

Dihydrobenzo[1,4]oxathiine: A multi-potent pharmacophoric heterocyclic nucleus.

2,3-dihydrobenzo[b][1,4]oxathiine represents a valuable pharmacophoric heterocyclic nucleus known since very long time. Initially, together with some patents reporting the use of these compounds as herbicides or lipogenesis inhibitors, several papers reported their ability as melatonin, histamine and serotonin receptor ligands, alpha-adrenoreceptor blockers as well as non-glycoside sweeteners. This wide range of biological activities has been recently further improved by studies stating their activity as antimycotics, multi-defense antioxidants and estrogen receptor ligands. The last insights regarding the preparation, the biological activity and the structure activity relationship (SAR) of derivatives containing the dihydrobenzoxathiine skeleton will be discussed in this review.