scholarly journals Development and Characterization of a Tacrolimus/Hydroxypropyl-β-Cyclodextrin Eye Drop

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 149
Author(s):  
Xurxo García-Otero ◽  
Victoria Díaz-Tomé ◽  
Rubén Varela-Fernández ◽  
Manuel Martín-Pastor ◽  
Miguel González-Barcia ◽  
...  
Keyword(s):  
Inclusion Complexes ◽  
Ex Vivo ◽  
New Drugs ◽  
Tacrolimus Concentration ◽  
Phase Solubility ◽  
Inflammatory Disorder ◽  
Eye Drops ◽  
Safe Alternative ◽  
Ophthalmic Administration

Uveitis is a vision inflammatory disorder with a high prevalence in developing countries. Currently, marketed treatments remain limited and reformulation is usually performed to obtain a tacrolimus eye drop as a therapeutic alternative in corticosteroid-refractory eye disease. The aim of this work was to develop a mucoadhesive, non-toxic and stable topical ophthalmic formulation that can be safely prepared in hospital pharmacy departments. Four different ophthalmic formulations were prepared based on the tacrolimus/hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes’ formation. Phase solubility diagrams, Nuclear Magnetic Resonance (NMR) and molecular modeling studies showed the formation of 1:1 and 1:2 tacrolimus/HPβCD inclusion complexes, being possible to obtain a 0.02% (w/v) tacrolimus concentration by using 40% (w/v) HPβCD aqueous solutions. Formulations also showed good ophthalmic properties in terms of pH, osmolality and safety. Stability studies proved these formulations to be stable for at least 3 months in refrigeration. Ex vivo bioadhesion and in vivo ocular permanence showed good mucoadhesive properties with higher ocular permanence compared to the reference pharmacy compounding used in clinical settings (t1/2 of 86.2 min for the eyedrop elaborated with 40% (w/v) HPβCD and Liquifilm® versus 46.3 min for the reference formulation). Thus, these novel eye drops present high potential as a safe alternative for uveitis treatment, as well as a versatile composition to include new drugs intended for topical ophthalmic administration.

Preclinical Assessment of Nanostructured Liquid Crystalline Particles for the Management of Bacterial Keratitis: in-vivo and Pharmacokinetics Study

2021 ◽  
Author(s):  
Shreya Kaul ◽  
Upendra Nagaich ◽  
Navneet Verma
Keyword(s):  
Residence Time ◽  
Liquid Crystalline ◽  
Ex Vivo ◽  
Research Work ◽  
Poloxamer 407 ◽  
Pharmacokinetic Studies ◽  
Eye Drops ◽  
Statistical Experimental Design ◽  
Bacterial Keratitis

Abstract The research work was driven to develop novel nanostructured liquid crystalline particles of vancomycin for its improved pre-ocular residence time, ocular bio-availability, enhanced targeting, increased permeability, reduced dosing frequency, controlled drug release and reduced systemic side-effects. Formulation was developed by fragmenting cubic crystalline phase of glycerol monooleate, water and poloxamer 407. A four-factor, three-level Taguchi statistical experimental design was constructed to optimize the formulation. Formulations exhibited internal-cubic structure of the vesicles with particle size in the range of 51.11 ± 0.96 nm to 158.73 ± 0.46 nm and negative zeta potential. Ex-vivo transcorneal permeation studies demonstrated that the optimized cubosomes had 2.4-fold increase in apparent permeability co-efficient as compared to vancomycin solution. Whereas, in-vivo studies in rabbits demonstrated that the severity of keratitis was considerably lowered in day 3 with optimized cubosomes. Ocular pharmacokinetic studies evaluated level of drug in aqueous humor and results revealed that the time to peak concentration (Tmax) of vancomycin loaded cubosomal formulation was about 1.9-fold higher and mean residence time was 2.2-fold greater than vancomycin solution. Furthermore, histological examination revealed that the corneal layers displayed well-maintained morphology without any stromal swelling, consequently indicating safety of formulation. In conclusion, results manifested that the developed vancomycin loaded cubosomes could be a promising novel ocular carrier and an ideal substitute for conventional eye-drops for the management of bacterial-keratitis.

scholarly journals Study on the Role of the Inclusion Complexes with 2-Hydroxypropyl-β-cyclodextrin for Oral Administration of Amiodarone

2019 ◽  
Vol 2019 ◽  
pp. 1-23 ◽  
Author(s):  
Andreea Creteanu ◽  
Daniela Pamfil ◽  
Cornelia Vasile ◽  
Gladiola Tantaru ◽  
Cristina Mihaela Ghiciuc ◽  
...  
Keyword(s):  
Inclusion Complexes ◽  
Matrix Tablets ◽  
Phase Solubility ◽  
Two Peaks ◽  
Amiodarone Hydrochloride ◽  
Zeta Potential Analysis ◽  
Powdered Form

The aim of this study was to improve the solubility of amiodarone hydrochloride (AMD) and the drug release using its inclusion complexes with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The inclusion complexes were prepared by coprecipitation and freeze-drying. The solubility enhancement of AMD/HP-β-CD inclusion complexes by 4–22 times was evaluated by the phase solubility method. The inclusion complexes were studied both in solution and in solid state by spectroscopic methods, dynamic light scattering (DLS) and zeta potential analysis, SEM, and DSC. The formulations of AMD/HP-β-CD inclusion complexes both as powdered form and as matrix tablets showed superior pharmacokinetic performance in improving loading and release properties in respect of those of the insoluble AMD drug. In vitro kinetic study reveals a complex mechanism of release occurring in three steps: the first one being attributed to a burst effect and the other two to different bonding existing in inclusion complexes. An in vivo test on matrix tablets containing Kollidon® and chitosan also reveals a multiple (at least two) peaks release diagram because of both structures of the inclusion complexes and also of different sites of absorption in biological media (digestive tract).

scholarly journals In vitro and in vivo activities of flavonoids – apigenin, baicalin, chrysin, scutellarin – in regulation of hypertension – a review for their possible effects in pregnancy-induced hypertension

2019 ◽  
Vol 65 (1) ◽  
pp. 55-70 ◽  
Author(s):  
Marcin Ożarowski ◽  
Radosław Kujawski ◽  
Przemysław Ł. Mikołajczak ◽  
Karolina Wielgus ◽  
Andrzej Klejewski ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Chemical Compounds ◽  
New Drugs ◽  
Future Application ◽  
Mediators Of Inflammation ◽  
And Function

Summary Flavonoids and their conjugates are the most important group of natural chemical compounds in drug discovery and development. The search for pharmacological activity and new mechanisms of activity of these chemical compounds, which may inhibit mediators of inflammation and influence the structure and function of endothelial cells, can be an interesting pharmacological strategy for the prevention and adjunctive treatments of hypertension, especially induced by pregnancy. Because cardiovascular diseases have multi-factorial pathogenesis these natural chemical compounds with wide spectrum of biological activities are the most interesting source of new drugs. Extracts from one of the most popular plant used in Traditional Chinese Medicine, Scutellaria baicalensis Georgi could be a very interesting source of flavonoids because of its exact content in quercetin, apigenin, chrysin and scutellarin as well as in baicalin. These flavonoids exert vasoprotective properties and many activities such as: anti-oxidative via several pathways, anti-in-flammatory, anti-ischaemic, cardioprotective and anti-hypertensive. However, there is lack of summaries of results of studies in context of potential and future application of flavonoids with determined composition and activity. Our review aims to provide a literature survey of in vitro, in vivo and ex vivo pharmacological studies of selected flavonoids (apigenin, chrysin and scutellarin, baicalin) in various models of hypertension carried out in 2008–2018.

scholarly journals Ex vivo and in vivo study of Kowa HA-2 applanation tonometer in the measurement of intraocular pressure in cats

2017 ◽  
Vol 38 (6) ◽  
pp. 3647
Author(s):  
Claudia Lizandra Ricci ◽  
Rogério Giuffrida ◽  
Glaucia Prada Kanashiro ◽  
Hilidia Stephania Rufino Belezzi ◽  
Carolina De Carvalho Bacarin ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Ex Vivo ◽  
Clinical Signs ◽  
In Vivo Study ◽  
Eye Drops ◽  
Significant Difference ◽  
Applanation Tonometer ◽  
Ex Vivo Study ◽  
Healthy Eyes

The objective of this study was to evaluate the use of the Kowa HA-2 applanation tonometer in measuring intraocular pressure (IOP) in cats. Ten healthy eyes were used in an ex vivo study in which the calibration curve for manometry vs. tonometry was determined by artificially raising the IOP in 5 mmHg increments up to 60 mmHg (10-60 mmHg). Both eyes of 10 anesthetized cats were studiedin vivo to compare manometry vs. tonometry. In the ambulatory study, 78 healthy eyes, 7 eyes with glaucoma and 20 eyes with uveitis were evaluated by tonometry, which was performed with topical anesthesia and 1% fluorescein eye drops for the formation of fluorescein semicircles. The correlation coefficient (r²) between the manometer and the Kowa HA-2 tonometer was 0.993 and the linear regression equation was y = 0.0915x + 0.0878 in the ex-vivo study. In the in vivo study, the IOP values (mean±SD, in mmHg) in manometry were 15.6 ± 1.1(14.0 – 17.5) and in tonometry were 15.5 ± 1.2(13.5 – 17.2), with no significant difference (P > 0.05) between manometry and tonometry. In ambulatory study, using the Kowa HA-2 tonometer, the IOP values (mean±SD, in mmHg) were 15.0 ± 1.5 (11.8 – 18.3) for the healthy eyes, 38.4 ± 8.1(29.6 – 53.7) for glaucomatous eyes and 10.4 ± 2.0(5.3 – 12.2) for eyes with uveitis. There was a strong correlation and accuracy between the IOP values with the manometry and the Kowa HA-2 tonometer. In the ambulatorystudy the IOP values obtained with the tonometer were compatible for animals with healthy eyes and with clinical signs of glaucoma and uveitis. We conclude that the Kowa HA-2 tonometer can be used in the measurement of IOP in cats, since it is a practical and accurate method in this species.

PHARMACOLOGICAL STUDIES OF PLATELET ANTIAGGREGANTS USING AN IN VITRO MODEL OF PRIMARY HEMOSTASIS.

1987 ◽  
Author(s):  
S Bellucci ◽  
E Cambau ◽  
B Candalot ◽  
J P Caen
Keyword(s):  
Ex Vivo ◽  
Repeated Measurements ◽  
New Drugs ◽  
Type Iii Collagen ◽  
Type I ◽  
Glass Capillary ◽  
New Device ◽  
Primary Hemostasis

We used a new device simulating in vitro primary haemostasis : more precisely the reactivity of blood to collagen and ADP. Thus an artificial vessel was created consisting of two main parts : a glass capillary (ID 140 um, length 16 mm, siliconized) simulating the haemodynamic resistance of an arteriole and an aperture (ID 150 um) reflecting the injured part of a cut arteriole. This aperture was performed in a cellulose acetate filter covered with collagen type I (3 mg/ml) to provide a defined surface for the adhesion of platelets and soaked with ADP in a concentration similar to that of injured endothelial cells (2 x 10-2 M). The mean - sd control values were 110 ± 24 s, 156 -± 40 ul (n = 25) and correlated well with in vivo bleeding time values (p< 0.01). We studied the effect on this test of classical antiaggregant drugs which act on primary hemostasis by different mechanisms of action. Acetylsalycilic acid (Egic laboratories) prolonged this test for concentrations above 10−5 M, ticlopidine (Millot-Solac laboratories) above 3 × 10−4 M, prostacyclin (Wellcome laboratories) above 5 Õ 10−9 M, the synthetic octapeptide LYS-PRO-GLY-GLU-PRO-GLY-PR0-LYS derived from type III collagen (gift from Y. Legrand) above 5 × 10−4 M. We evidenced a synergistic action between collagen octapeptide and ticlopidine. Thus this device permits the screening of new drugs for their effects on primary hemostasis and the study of ex vivo repeated measurements for the monitoring of antiaggregant therapy.

Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3781-3791 ◽  
Author(s):  
Enrique M. Ocio ◽  
Patricia Maiso ◽  
Xi Chen ◽  
Mercedes Garayoa ◽  
Stela Álvarez-Fernández ◽  
...  
Keyword(s):  
Cell Lines ◽  
Plasma Cells ◽  
Ex Vivo ◽  
High Sensitivity ◽  
Double Strand Breaks ◽  
New Drugs ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Histone H2ax

Abstract Multiple myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC50 values from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand breaks (DSBs), evidenced by an increase in phospho-histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53 wild-type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSBs and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumor plasma cells to DSBs and strongly supports the use of this compound in MM patients.

Guanylin peptide family: history, interactions with ANP, and new pharmacological perspectives

2011 ◽  
Vol 89 (8) ◽  
pp. 575-585 ◽  
Author(s):  
Manassés Claudino Fonteles ◽  
Nilberto Robson Falcão do Nascimento
Keyword(s):  
Guanylate Cyclase ◽  
Disulfide Bonds ◽  
Ex Vivo ◽  
New Drugs ◽  
Sodium Balance ◽  
Target Cells ◽  
Erectile Tissue ◽  
Surface Receptors ◽  
Redundant Mechanism

The guanylin family of peptides has 3 subclasses of peptides containing either 3 intramolecular disulfide bonds found in bacterial heat-stable enterotoxins (ST), or 2 disulfides observed in guanylin and uroguanylin, or a single disulfide exemplified by lymphoguanylin. These peptides bind to and activate cell-surface receptors that have intrinsic guanylate cyclase (GC) activity. These hormones are synthesized in the intestine and released both luminally and into the circulation, and are also produced within the kidney. Stimulation of renal target cells by guanylin peptides in vivo or ex vivo elicits a long-lived diuresis, natriuresis, and kaliuresis by both cGMP-dependent and independent mechanisms. Uroguanylin may act as a hormone in a novel endocrine axis linking the digestive system and kidney as well as a paracrine system intrarenally to increase sodium excretion in the postprandial period. This highly integrated and redundant mechanism allows the organism to maintain sodium balance by eliminating excess sodium in the urine. In addition, small concentrations of the atrial natriuretic peptide (ANP) can synergize with low concentrations of both guanylin or uroguanylin, which do not induce natriuresis per se, to promote significant natriuresis. Interestingly, the activation of the particulate guanylate cyclase receptors by natriuretic peptides can promote relaxation of animal and human penile erectile tissue and increase intracavernosal pressure to induce penile erection. These peptides can be prototypes for new drugs to treat erectile dysfunction, especially in patients with endothelial and nitrergic dysfunction, such as in diabetes.

scholarly journals Experimental design, formulation and in vivo evaluation of a novel topical in situ gel system to treat ocular infections

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248857 ◽  
Author(s):  
Anroop B. Nair ◽  
Jigar Shah ◽  
Shery Jacob ◽  
Bandar E. Al-Dhubiab ◽  
Nagaraja Sreeharsha ◽  
...  
Keyword(s):  
Drug Release ◽  
Ex Vivo ◽  
Adhesive Force ◽  
Gel Strength ◽  
Eye Drops ◽  
Lattice Design ◽  
Ocular Infections ◽  
Gel System

In situ gels have been extensively explored as ocular drug delivery system to enhance bioavailability and efficacy. The objective of present study was to design, formulate and evaluate ion-activated in situ gel to enhance the ocular penetration and therapeutic performance of moxifloxacin in ophthalmic delivery. A simplex lattice design was utilized to examine the effect of various factors on experimental outcomes of the in situ gel system. The influence of polymers (independent variables) such as gellan gum (X1), sodium alginate (X2), and HPMC (X3) on gel strength, adhesive force, viscosity and drug release after 10 h (Q10) were assessed. Selected formulation (MH7) was studied for ex vivo permeation, in vivo irritation and pharmacokinetics in rabbits. Data revealed that increase in concentration of polymers led to higher gel strength, adhesive force and viscosity, however, decreases the drug release. MH7 exhibited all physicochemical properties within acceptable limits and was stable for 6 months. Release profile of moxifloxacin from MH7 was comparable to the check point batches and followed Korsmeyer-Peppas matrix diffusion-controlled mechanism. Ocular irritation study signifies that selected formulation is safe and non-irritant for ophthalmic administration. In vivo pharmacokinetics data indicates significant improvement of moxifloxacin bioavailability (p < 0.0001) from MH7, as evidenced by higher Cmax (727 ± 56 ng/ml) and greater AUC (2881 ± 108 ng h/ml), when compared with commercial eye drops (Cmax; 503 ± 85 ng/ml and AUC; 978 ± 86 ng h/ml). In conclusion, developed in situ gel system (MH7) could offers a more effective and extended ophthalmic therapy of moxifloxacin in ocular infections when compared to conventional eye drops.

scholarly journals Phytochemicals Targeting JAK–STAT Pathways in Inflammatory Bowel Disease: Insights from Animal Models

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2824
Author(s):  
Sun Young Moon ◽  
Kwang Dong Kim ◽  
Jiyun Yoo ◽  
Jeong-Hyung Lee ◽  
Cheol Hwangbo
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Janus Kinase ◽  
New Drugs ◽  
Inflammatory Disorder ◽  
Chronic Inflammatory Disorder ◽  
Mediators Of Inflammation ◽  
Inflammatory Bowel ◽  
Stat Pathway

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that consists of Crohn’s disease (CD) and ulcerative colitis (UC). Cytokines are thought to be key mediators of inflammation-mediated pathological processes of IBD. These cytokines play a crucial role through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. Several small molecules inhibiting JAK have been used in clinical trials, and one of them has been approved for IBD treatment. Many anti-inflammatory phytochemicals have been shown to have potential as new drugs for IBD treatment. This review describes the significance of the JAK–STAT pathway as a current therapeutic target for IBD and discusses the recent findings that phytochemicals can ameliorate disease symptoms by affecting the JAK–STAT pathway in vivo in IBD disease models. Thus, we suggest that phytochemicals modulating JAK–STAT pathways are potential candidates for developing new therapeutic drugs, alternative medicines, and nutraceutical agents for the treatment of IBD.

P6342Subcutaneous delivery of NPA7, first-in-class novel bispecific designer peptide: enhances cardiorenal function and suppresses renin and aldosterone in vivo and in vitro

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Sugihara ◽  
T Ichiki ◽  
Y Chen ◽  
G J Harty ◽  
D M Heublen ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Ex Vivo ◽  
Plasma Renin ◽  
New Drugs ◽  
Preclinical Development ◽  
Effective Delivery ◽  
Canine Serum ◽  
Canine Plasma

Abstract Introduction The rapid increase of patients of heart failure (HF) is a major health burden worldwide. Most importantly is the need to develop innovative new drugs for treatment of HF, such as sacubitril/valsartan which in part functions by enhancing the natriuretic peptides (NPs). We engineered NPA7 as a novel 30 amino acid bispecific designer peptide which activates the particulate guanylyl cyclase A receptor (pGC-A)/cGMP and for which the NPs both ANP and BNP are ligands and the Mas-receptor (MasR)/cAMP pathways for Angiotensin 1–7 (Ang1–7) is the endogenous ligand. We previously reported that acute intravenous (IV) administration of NPA7 shows cardiorenal protective and renin-aldosterone suppressing actions that go beyond the native peptides, BNP or Ang 1–7, which may have therapeutic potential for HF. Purpose To support the clinical development of NPA7 as a potential therapy in HF which promotes NP and MasR pathways, we investigated the actions and stability of subcutaneous (SQ) administration of NPA7 in normal canines. We also defined NPA7's peptide stability and metabolites in canine plasma. Methods Plasma and urinary cGMP, cardiorenal and renin-aldosterone responses to SQ injection (10μg/kg) were determined over 4 hours in normal canines (n=5) in vivo. Ex vivo, we established stability of NPA7 and key metabolites in canine serum using liquid chromatography-mass spectrometry (LC-MS). Data are expressed as mean ± SEM. * P<0.05 vs. BL. Results In vivo, SQ NPA7 resulted in a sustained increase at 2 hours in plasma (BL: 10±3; 120 min: 30±6* pmol/ml) and urinary (BL: 1033±198; 120 min: 5792±857* pmol/min) cGMP, GFR (BL: 29±6; 120 min: 70±12* ml/min) and sodium excretion (BL: 18±10; 120 min: 144±33* ueq/min). We observed a gradual reduction in BP at 60 min (BL: 109±4; 60 min: 99±7* mmHg) with a sustained decrease in PCWP at 4 hours (BL: 5±0.9; 240 min: 3.1±0.6* mmHg). SQ NPA7 also suppressed plasma renin and aldosterone up to 3 hours after SQ injection. LC-MS revealed that NPA7 was highly stable with both the pGC-A and MasR activating moieties intact ex vivo in canine serum with a disappearance time of 2 hours. We also identified 2 major NPA7 metabolites NPA71–27 and NPA71–28. Conclusions SQ NPA7 possesses cGMP activating, cardiac unloading, diuretic, natriuretic, and renin-aldosterone suppressing actions in normal canines. NPA7 is also highly stable in serum. These studies support SQ administration as an effective delivery strategy for NPA7, a first-in-class innovative bispecific dual pGC-A/MasR activator now in preclinical development for HF.

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