Hydrochloride Research Articles

Multiorgan Crystal Deposition of an Amphoteric Drug in Rats Due to Lysosomal Accumulation and Conversion to a Poorly Soluble Hydrochloride Salt.

Poor solubility of drug candidates mainly affects bioavailability, but poor solubility of drugs and metabolites can also lead to precipitation within tissues, particularly when high doses are tested. RO0728617 is an amphoteric compound bearing basic and acidic moieties that has previously demonstrated good solubility at physiological pH but underwent widespread crystal deposition in multiple tissues in rat toxicity studies. The aim of our investigation was to better characterize these findings and their underlying mechanism(s), and to identify possible screening methods in the drug development process. Main microscopic features observed in rat RO0728617 toxicity studies were extensive infiltrates of crystal-containing macrophages in multiple organs. Matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry revealed that these crystals contained the orally administered parent compound, and locality was confirmed to be intracytoplasmic and partly intralysosomal by electron microscopic examination. Crystal formation was explained by lysosomal accumulation of the compound followed by precipitation of the hydrochloride salt under physiological conditions in the lysosomes, which have a lower pH and higher chloride concentration in comparison to the cytosol. This study demonstrates that risk of drug precipitation can be assessed by comparing the estimated lysosomal drug concentration at a given dose with the solubility of the compound at lysosomal conditions.

Synthesis and coordination of a neutral phosphaguanidine and comparison of its basicity with a guanidine

A phosphaguanidine [Me2NC(PPh2)=NiPr], the analogous guanidine [Me2NC(NPh2)=NiPr], and their hydrochloride (HCl) salts were prepared to study the influence of substituting a phosphorus atom for a nitrogen atom on the basicity of the two compounds and the bonding in their conjugate acids. The pKavalues of both HCl salts were measured in acetonitrile by NMR titration. Surprisingly, the substitution of P for N has essentially no effect on basicity even though the geometry at that atom is changed. The presence of phenyl substituents in the protonated guanidine reduces the resonance in the CN3core, whereas poor orbital overlap between P and C reduces the resonance in the N2CP core of the protonated phosphaguanidine. The neutral phosphaguanidine binds to a Cu(I) halide through both the Nimineand the P, which suggested that the basic N atom on the bound ligand may have little utility as a Brønsted base. Fortunately, however, a Cu(I) halide complex of the protonated phosphaguanidine is stable. Thus, the tendency of the basic N to bind to metals does not proscribe it serving as a metal-proximate Brønsted base.

Study on the Interaction Between Chlortetracycline Hydrochloride and Pepsin by Multispectral and Molecular Docking

Study on the Interaction Between Chlortetracycline Hydrochloride and Pepsin by Multispectral and Molecular Docking

Review Paper on Iontophoresis

The ongoing endorsement of lidocaine hydrochloride and epinephrine joined iontophoresis for confined agony treatment by FDA has empowered the picking up enthusiasm for iontophoresis tranquillize conveyance system for the transdermal conveyance of medications. This system of encouraged development of particles over a film affected by a remotely implied electric potential contrast remains one of utmost encouraging bodily skin infiltration improving strategy. The justification overdue utilizing this procedure remains the capacity of technique to build the foundational conveyance of great atomic weight mixes with precise information energy and least between topic changeability in any case accomplished just when parenteral course of organization is utilized. As of late, great saturation of bigger peptides alike insulin has had been accomplished by this method being mixed through concoction accompaniments. This audit quickly depicts the features that influence iontophoresis tranquillize conveyance and abridges the investigations directed as of late utilizing this procedure so as to accomplish higher foundational ingestion of the medications having low latent dispersion in any case. The impact of pervasion enhancers (synthetic enhancers) on iontophoresis motion of medications has likewise been depicted. Present survey additionally gives an understanding into invert iontophoresis. Different constraints that influence transdermal retention of medications by iontophoresis comparable medication fixation, extremity of medications, and pH of contributor arrangement, nearness of co-particles, ionic quality, and terminal extremity and so on have additionally been inspected in detail.

Asymmetric copper-catalyzed propargylic amination with amine hydrochloride salts.

The highly enantioselective copper-catalyzed propargylic amination of propargylic esters with amine hydrochloride salts has been realized for the first time using copper salts with chiral N,N,P-ligands. This method features a broad substrate scope and wide functional group tolerance, generating propargylic amines in good to excellent yields with high enantioselectivities (up to 99% ee). The utility of the approach was demonstrated by late-stage functionalization of marketed pharmaceuticals.

Amine hydrochloride salts as bifunctional reagents for the radical aminochlorination of maleimides

Amine hydrochloride salts have been typically used as amination reagents.

Condensation Methods for the Determination of Methoxamine Hydro Chloride in Pure and Pharmaceutical Formulations

Condensation Methods for the Determination of Methoxamine Hydro Chloride in Pure and Pharmaceutical Formulations

Synergistic activity of tetrasodium EDTA, ethanol and chlorhexidine hydrochloride against planktonic and biofilm cells of clinically relevant pathogens

ObjectivesBiofilms associated with implantable medical devices and wounds are clinically relevant, often requiring repeated use of antibiotics without success. A search for non-antibiotic antimicrobial and antibiofilm solutions is warranted, in line with antimicrobial stewardship. Our study aimed to evaluate the broad-spectrum antimicrobial efficacy of tetrasodium EDTA, ethanol and chlorhexidine hydrochloride (HCl) alone and in combination against clinically relevant planktonic and biofilm cells of bacterial and fungal pathogens. MethodsMICs and MBCs were determined for tetrasodium EDTA, ethanol and chlorhexidine HCl against planktonic cells of test pathogens. The MBEC Assay® biofilm inoculator device was used to evaluate the biofilm eradication ability of test antimicrobials alone and in combination against clinically relevant pathogens. The checkerboard microbroth dilution assay was performed to analyze the synergism between test antimicrobials. ResultsAgainst planktonic cells, the combination of tetrasodium EDTA with ethanol or chlorhexidine HCl resulted in synergistic to indifferent activity, with no antagonism observed. Against mature biofilms, all combinations were synergistic. The MBEC of each test antimicrobial was decreased from 4- to -64-fold when used in combination as compared to when agents were used alone. We optimised the concentration of antimicrobials to achieve rapid eradication of pre-formed biofilms. A triple combination of 3% tetrasodium EDTA, 20% ethanol and 2.5 μg/mL chlorhexidine HCl completely eradicated 48-h-old biofilms of all test strains within 2 h. ConclusionAll three antimicrobial agents can be used together for prevention and treatment of biofilms and biofilm-related infections. The observed in vitro efficacy should be tested further through in vivo and clinical studies.

Evaluation of pyrrolidine-based analog of jaspine B as potential SphK1 inhibitors against rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitise, and its pathogenesis is complicated. Sphingosine-1-phosphate (S1P) is a lipid produced by sphingosine kinase 1 and 2 (SphK1/2), which participate in some of most-spread skeletal diseases such as rheumatoid arthritis or osteoarthritis. To explore the anti-inflammatory activity of 2-epi-jaspine B analogs as SphKs inhibitors, we used LPS-induced rheumatoid arthritis fibroblast-like synovial cells (HFLS-RA) as the research object to evaluate the anti-inflammatory activity of 16 2-epi-jaspine B analogs and the newly synthesized salt CHJ01. We found that 2-epi-jaspine B analog CHJ01 in hydrochloride salt form has excellent SphK1 inhibitory effect and better anti-RA effect. CHJ01 showed an anti-inflammatory effect similar to that of MTX in vitro, its IC50 value is 8.64 μM. Moreover, the anti-RA effect of CHJ01 was also studied by using a Complete Freund’s Adjuvant (CFA)-induced arthritis (AIA) in a rat mode. Pharmacological experiments show that CHJ01 can help to significantly improve the symptoms of rheumatoid arthritis by reducing the swelling volume, arthritis score, spleen index and the level of IL-1β, TNF-α, IL-6 of AIA rats. Therefore, CHJ01 holds high potential for the treatment of RA.

An improved synthesis of 4-aminobutanenitrile from 4-azidobutanenitrile and comments on room temperature stability

4-Aminobutanenitrile (1) is an important synthetic intermediate for neurological disorder therapeutics including Parkinson’s and Alzheimer’s diseases, and is an industrial precursor to pyrroline and pyrrolidine. Synthesis of 1 by Co(II) catalyzed reduction of 4-azidobutanenitrile (2) with NaBH4, or by a one-pot Staudinger reduction of 2 in THF, was low yielding. 1H-NMR analysis of the Staudinger reduction revealed the formation of iminophosphorane intermediate (3) after 22 h at rt, and that increasing the reaction temperature from rt to 40 °C promoted hydrolysis of 3 to 1. A modified Staudinger reduction of 2 involving pyridine as solvent, addition of water 3 h after triphenylphosphine, and a temperature increase to 40 °C, gave rise to 1 in 69% yield. 1 is unstable at rt, thus the hydrochloride salt of 1 (1⋅HCl) was prepared by bubbling HCl(g) through a solution of 1 in chloroform. 1⋅HCl is stable at rt and is hence the preferred form for storage.

Efficient Synthesis of New Fluorinated β-Amino Acid Enantiomers through Lipase-Catalyzed Hydrolysis.

An efficient and novel enzymatic method has been developed for the synthesis of β-fluorophenyl-substituted β-amino acid enantiomers through lipase PSIM (Burkholderia cepasia) catalyzed hydrolysis of racemic β-amino carboxylic ester hydrochloride salts 3a–e in iPr2O at 45 °C in the presence of Et3N and H2O. Adequate analytical methods were developed for the enantio-separation of racemic β-amino carboxylic ester hydrochlorides 3a–e and β-amino acids 2a–e. Preparative-scale resolutions furnished unreacted amino esters (R)-4a–e and product amino acids (S)-5a–e with excellent ee values (≥99%) and good chemical yields (>48%).

Berberine Improves Meat Quality and Carcass Traits in Broilers Challenged with Mycotoxins

Background and Aim: Mycotoxin-contaminated feed causes significant concern in poultry production and public health because of serious economic losses and health problems caused by them. Berberine hydrochloride (Berberine), a natural plant alkaloid derived from Chinese medicine, is characterized by diverse pharmacological effects. This study is designed to evaluate the effects of different levels of Berberine (BBR) on carcass traits and meat quality of broilers fed diets contaminated with Aflatoxin B1 (AFB) and Ochratoxin A (OCT). Methods: A 42-day floor pen trial was performed with 288 Ross 308 broilers. A randomized design, with 4 replicates of 8 birds each, was conducted with the following 9 treatments: (1) negative control diet with no additives (NC); (2) NC + 2 ppm AFB (positive control AFB; PCAFB); (3) NC + 2 ppm OCT (positive control OCT; PCOCT); (4) PCAFB + 200 mg/kg BBR; (5) PCAFB + 400 mg/kg BBR; (6) PCAFB + 600 mg/kg BBR; (7) PCOCT + 200 mg/kg BBR; (8) PCOCT + 400 mg/kg BBR; and (9) PCOCT + 600 mg/kg BBR. At the end of the experiment, from every group, eight birds were selected, slaughtered, and subjected to analyses. The analyzed parameters carcass and cut yields and meat quality according to water-holding capacity (WHC) and breast level MDA. Results: Both PCAFB and PCOTA diets decreased carcass relative weight, breast level MDA, and WHC values compared with the NC diet (p 0.05). Carcass efficiency in PCAFB and PCOTA treatments was lower than in the NC treatment (p˂0.05), and supplementation with BBR at multiple levels partially or fully reversed these effects. The addition of 600 mg/kg BBR to PCAFB diet increased carcass relative weight compared to PCAFB alone (p>0.05). Conclusion: These data provided supplementation of BBR (600 mg/kg) improves meat quality in broiler fed diet contaminated with mycotoxins. *Corresponding Author: Nazar Afzali; Email: nafzali@birjand.ac.ir Please cite this article as: Malekinezhad P, Afzali N, Farhangfar SH, Omidi A, Mohammadi A. Berberine Improves Meat Quality and Carcass Traits in Broilers Challenged with Mycotoxins. Arch Med Lab Sci. 2020;6:1-9 (e23). https://doi.org/10.22037/amls.v6.33330

ALTERATIONS OF SERUM CALCIUM, PHOSPHORUS, MAGNESIUM, AND COPPER IN HYPERTHYROIDISM PATIENTS: A CASE–CONTROL STUDY

Objective: The objective of the study was to estimate the levels of serum calcium, phosphorus, magnesium, and copper in hyperthyroid cases and to correlate each of the parameter with serum T3, T4, TSH, FT3, and FT4, respectively.
 Methods: The study was conducted on 60 newly confirmed hyperthyroid cases based on the thyroid profile and 60 euthyroid cases were recruited as controls. Blood samples were collected from all these subjects and estimation of serum T3, T4, TSH, FT3, FT4, calcium, phosphorus, and magnesium was done by autoanalyzer method. Serum copper was measured by modified spectrophotometric micro-method using guanidine hydrochloride and bathocuproine disulfonate disodium salt. The statistical analysis was done by paired test and Pearson’s correlation.
 Results: Study results in hyperthyroid cases show mean serum calcium and copper levels were significantly (p<0.001) increased, serum phosphorus levels were significantly (p<0.001) decreased when compared to euthyroid. However, there was no significant change in magnesium when compared with euthyroid controls (p=0.556). We also found a significant positive correlation among serum Ca versus T3, T4, FT3, and FT4. A negative correlation with serum Ca versus TSH as observed. We also found significant positive correlation between serum phosphorus with TSH and significant negative correlation of phosphorus with T3, T4, FT3, and FT4. No suggestive significant correlation was found between serum Mg with T3, T4, TSH, FT3, and FT4 and serum copper with serum T3, T4, TSH, FT3, and FT4.
 Conclusion: The present study has shown that metabolism of minerals is altered in hyperthyroid cases. Impaired metabolism of calcium, phosphorus, magnesium, and copper can lead to various metabolic disorders. Estimation of serum calcium, phosphorus, magnesium, and copper may be helpful in better management to prevent further complication and can be used as diagnostic or prognostic aid in patients with hyperthyroidism along with other biochemical parameters.

Single-crystal X-ray structure determinations of vardenafil, vardenafil dihydrate, vardenafil monohydrochloride trihydrate and vardenafil dihydrochloride hexahydrate

Abstract The crystal and molecular structures of vardenafil (free, unprotonated base), vardenafil dihydrate and the hydrochloride salts, vardenafil monohydrochloride trihydrate and vardenafil dihydrochloride hexahydrate, were determined by single-crystal X-ray diffraction. The crystal structure of vardenafil monohydrochloride trihydrate is in good agreement with the published crystal structure obtained by powder diffraction using synchrotron radiation. This work shows that the crystal structure of anhydrous vardenafil free base is very similar to the crystal structure of sildenafil free base.

Discovery of Novel and Highly Potent Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment.

A series of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors based on the resorcinol diphenyl ether scaffold were discovered by incorporating hydrophilic moieties into the side chain and converting into the corresponding hydrochloride salt. Among these compounds, P18 showed the highest inhibitory activity against PD-1/PD-L1 with an IC50 value of 9.1 nM in a homogeneous time-resolved fluorescence binding assay. Besides, P18 promoted HepG2 cell death dose dependently in a HepG2/PD-L1 and Jurkat/PD-1 coculture cell model. Further, P18 demonstrated significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics (e.g., t1/2 of ∼20 h and oral bioavailability of 12%) than the previous analogues. Moreover, P18 was highly effective in suppressing tumor growth in an immune checkpoint humanized mouse model without apparent toxicity. Collectively, these results suggest that compound P18 represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.

Utilization of coffee pulp waste for rapid recovery of pectin and polyphenols for sustainable material recycle

Coffee pulp is one of the major underutilized byproduct of coffee processing in farm level. Disposal of this agro-industrial waste has become one of the most challenging tasks for coffee planters. However, most of the efforts are towards the management of coffee pulp as an effluent, and not-on re-use. The problem is compounded due to the large volumes produced in diluted forms, which makes it expensive to reuse. The preliminary proximate analysis of coffee pulp indicated it to be rich in pectin and polyphenols. The efficacy of various chemicals like ethanol, sulfuric acid, hydrochloric acid, nitric acid, ammonium oxalate and metal salts for effective precipitation of pectin from coffee pulp was evaluated. HPLC characterization of the extracted and concentrated polyphenols fractions was analyzed. The maximum extraction of pectin was achieved by using metal salts and ethanol with 6.0% and 6.7% on wet weight basis respectively. The equivalent weight of extracted pectin (1180.5 mg/g) was found to be higher than that of commercial pectin (724.8 mg/g). The methoxyl content of the commercial pectin and crude pectin were 9.3 and 5.6% respectively. Gallic, vanillin, catechin, ethyl catechol, coumaric, Caffeic, and ferulic acid were the major polyphenols as quantified by the HPLC. The polyphenol fraction showed a good antioxidant activity with phosphomolybdate, FRAP, DPPH, and ABTS radicals respectively. The sustainable utilization of coffee pulp as a source of pectin and polyphenols with good antioxidant activities could help to solve the problem of waste generated in coffee processing in farm level.

The hydro-chloride salt of 4-hy-droxy-N,N-di-n-propyl-tryptamine (4-HO-DPT).

The title compound, 4-hy-droxy-N,N-di-n-propyl-tryptammonium (4-HO-DPT) chloride {systematic name: N-[2-(4-hy-droxy-1H-indol-3-yl)eth-yl]-N-propyl-propan-1-aminium chloride}, C16H25N2O+·Cl-, has a singly protonated trypt-ammonium cation and one chloride anion in the asymmetric unit. A series of N-H⋯Cl and O-H⋯Cl hydrogen bonds connect the ions together in ladder chains along [010].

Regulating and regenerating the valuable metals from the cathode materials in lithium-ion batteries by nickel-cobalt-manganese co-extraction

Effective recycling of valuable metals from the spent lithium-ion batteries (LIBs) is conducive to the rational utilization of resources and environmental protection. To shorten the recovery process and directly obtain the high-pure regenerated products, solvent extraction (co-extraction) method was employed in this work. Here, 3 mol/L (M) hydrochloride (HCl) without reductant was used as leaching agent for the leaching of cathode material, resulting in the leaching efficiency of all metals exceeding 99%. Subsequently, di-(2-ethylhexyl) phosphinic acid (P227) was used to co-extract transition metals directly from the leachate and separate them from lithium (Li). The composition of nickel (Ni), cobalt (Co), and manganese (Mn) extracted into the organic phase can be controlled by changing the extraction conditions, and the type of the cathode material was also regulated simultaneously. Finally, the loaded organic phase with a Ni-Co-Mn ratio of 1:1:1 was completely stripping with 0.4 M HCl, and the LiNi1/3Co1/3Mn1/3O2 was regenerated by oxalic acid co-precipitation the stripping solution and high temperature calcination. The regenerated LiNi1/3Co1/3Mn1/3O2 exhibits excellent electrochemical performance with 150.0 mA h g−1 discharge capacity at 0.5 C. Therefore, the demonstrated separation and preparation integration process not only realizes the regeneration of the battery but also promotes the co-extraction technique to practical application.

SAR Investigation and Discovery of Water-Soluble 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazoles as Potent Tubulin Polymerization Inhibitors.

Taking the previously discovered 1-methyl-1,4-dihydroindeno[1,2c]pyrazol derivative LL01 as a lead, systematic structural modifications were made at the phenolic 6- and 7-positions and the aniline at the 3-position of the indenopyrazole core to investigate the SARs and to improve water solubility. Among the designed indenopyrazoles ID01-ID33, a series of potent MTAs were identified. As the hydrochloride salt(s), ID09 and ID33 showed excellent aqueous solubility and favorable Log P value and displayed noteworthily low nanomolar potency against a variety of tumor cells, including those taxol-resistant ones. They inhibited tubulin polymerization, disrupted cellular microtubule networks by targeting the colchicine site, and promoted HepG2 cell cycle arrest and cell apoptosis. In the HepG2 xenograft mouse model, ID09 and ID33 effectively inhibited tumor growth at an oral dose of 25 mg/kg. At an intravenous (iv) injection dose of 10 mg/kg every other day, ID09 suppressed tumor growth by 68% without obvious toxicity.

Short-term Efficacy and Predictive Index of Anlotinib Hydrochloride Capsule on Advanced Non-small Cell Lung Cancer

Short-term Efficacy and Predictive Index of Anlotinib Hydrochloride Capsule on Advanced Non-small Cell Lung Cancer