Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy

Background: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Methods: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. Results: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44–0.79]; P <0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33–0.99]; P =0.05) and wild-type transthyretin amyloidosis (0.61 [0.43–0.87]; P =0.006); and baseline New York Heart Association class I and II (0.56 [0.38–0.82]; P =0.003) and class III (0.65 [0.41–1.01]; P =0.06). Conclusions: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01994889 and NCT02791230.

Synthesis of Organic-Inorganic Hybrid Material with a Synergistic Interface as a Release Agent for Free Acid β-Hydroxy-β-Methyl Butyrate

We report the preparation and characterization of a new organic-inorganic hybrid system composed of type-I collagen and ZnAl layered double hydroxide (LDH) particles loaded with β-hydroxy-β-methyl butyrate (HMB) by coprecipitation reaction. X-ray diffraction (peaks well agree with those reported in the literature), infrared spectroscopy (stretching bonds for both organic-inorganic compounds), and X-ray photoelectron spectroscopy confirmed the hybrid system retained HMB in the carboxylate form, and a small fraction turned to the acid form. In both cases, the HMB molecules are assembled to the LDH surface. The hybrid compound results in improved thermal stability for HMB and collagen, as shown by thermal analysis. Scanning electron microscopy data reflects different arrangements from LDH sheets with interesting physicochemical properties since LDH and collagen protect free HMB and make it more bioavailable and functional. In vitro studies as part of high-throughput screening strategies indicated that LDH hybrids reduced cell viability around 75-90%, which is an acceptable viability value because of the L6 cell line susceptibility. However, all new nanomaterials must be carefully analyzed by different toxicity tests because a single test does not evaluate complete physiological compartments.

Permeability of Ibuprofen in the Form of Free Acid and Salts of L-Valine Alkyl Esters from a Hydrogel Formulation through Strat-M™ Membrane and Human Skin

This paper aimed to evaluate the effect of vehicle and chemical modifications of the structure of active compounds on the skin permeation and accumulation of ibuprofen [IBU]. In vitro permeation experiments were performed using human abdominal skin and Strat-M™ membrane. The HPLC method was used for quantitative determinations. The formulations tested were hydrogels containing IBU and its derivatives and commercial gel with ibuprofen. The results obtained indicate that Celugel® had an enhancing effect on the skin penetration of IBU. The average cumulative mass of [IBU] after 24 h permeation test from Celugel® formulation through human skin was over 3 times higher than for the commercial product. Three ibuprofen derivatives containing [ValOiPr][IBU], [ValOPr][IBU], and [ValOBu][IBU] cation were evaluated as chemical penetration enhancers. The cumulative mass after 24 h of penetration was 790.526 ± 41.426, 682.201 ± 29.910, and 684.538 ± 5.599 μg IBU cm−2, respectively, compared to the formulation containing unmodified IBU-429.672 ± 60.151 μg IBU cm−2. This study demonstrates the perspective of the transdermal hydrogel vehicle in conjunction with the modification of the drug as a potential faster drug delivery system.

Recovery of Spent Sulphuric Acid by Diffusion Dialysis Using a Spiral Wound Module

In this study, we assess the effects of volumetric flow and feed temperature on the performance of a spiral-wound module for the recovery of free acid using diffusion dialysis. Performance was evaluated using a set of equations based on mass balance under steady-state conditions that describe the free acid yield, rejection factors of metal ions and stream purity, along with chemical analysis of the outlet streams. The results indicated that an increase in the volumetric flow rate of water increased free acid yield from 88% to 93%, but decreased Cu2+ and Fe2+ ion rejection from 95% to 90% and 91% to 86%, respectively. Increasing feed temperature up to 40 °C resulted in an increase in acid flux of 9%, and a reduction in Cu2+ and Fe2+ ion rejection by 2–3%. Following diffusion dialysis, the only evidence of membrane degradation was a slight drop in permselectivity and an increase in diffusion acid and salt permeability. Results obtained from the laboratory tests used in a basic economic study showed that the payback time of the membrane-based regeneration unit is approximately one year.

PHARMACOKINETICS OF THE LONG-ACTING CEFTIOFUR CRYSTALLINE-FREE ACID IN ARABIAN SHE-CAMELS (Camelus dromedarius)

Ceftiofur is an important broad-spectrum 3rd generation cephalosporin antibiotic. Owing to its time-dependent antimicrobial actions, the length of time of being above bacterial MIC is the critical point in using ceftiofur for chemotherapy rather than its peak of concentration. Consequently, this experiment was carried out to evaluate, for the first time, the pharmacokinetics of the long-acting ceftiofur crystalline acid-free form (ceftiofur-CAF) in camels. Ceftiofur-CAF 200 mg/ml suspension sterile solution was injected i/m at a dose 6.6 mg/kg. Blood samples were collected from the jugular vein in vacutainer tubes at 0, 0.13, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, and 144 hours after administration of the drug. Ultrahigh Performance Liquid Chromatography-Mass Spectrometry (UPLC MS/MS) was used to measure serum concentration. Pharmacokinetic modeling was by a two-compartment model. Pharmacokinetics of ceftiofur-CAF after single i/m injection in she-camels was best modeled in the two-compartment model, where the drug slowly distributed to a second compartment with poor tissue penetration and high preference to the central compartment. In this study, the maximum plasma concentration (Cmax) was 9.29±0.42 μg/ml at Tmax equals 9.41±1.35 h. The area under the curve (AUC0-∞) was 354.1±57.22 μg/ml*h. The distribution and elimination half-lives were 7.42 and 46.13 h, respectively. The mean residence time (MRT) was 42.01 h. Compared with the rapidly absorbed form of ceftiofur (ceftufor-RAF) in camels, there was almost similar maximal serum concentration but with delayed time to maximal concentration (Tmax), longer means residence time (MRT) and higher distribution and elimination half-lives. In terms of antibacterial efficacy, ceftiofur-CAF stayed above a previously recommended level of 0.2 μg/ml for 7 days, which can be achieved after a single i/m injection of 6.6 mg/kg. The obtained pharmacokinetics data in camels recommends repeated administration of 2 days apart for bacteria requiring MIC levels above 2 μg/ml.Key words: Ceftiofur; pharmacokinetics; camel; cephalosporinsFARMAKOKINETIKA DOLGODELUJOČE CEFTIOFURNE KRISTALINIČNE PROSTE KISLINE PRI SAMICAH ARABSKIH KAMEL (Camelus dromedarius) Izvleček: Ceftiofur je pomemben širokospektralni antibiotik 3. generacije cefalosporinov. Zaradi njegovih časovno odvisnih protimikrobnih učinkov je čas, ko je raven ceftiofura nad bakterijskim MIC in ne pri njegovem vrhu koncentracije kritična točka pri uporabi tega antibiotika. Poskus je bil izveden z namenom ovrednotenja farmakokinetike dolgo delujoče ceftiofurjeve kristalinične brezkislinske oblike (ceftiofur-CAF) pri kamelah. Ceftiofur-CAF v koncentraciji 200 mg/ml suspenzije sterilne raztopine smo injicirali i/m v odmerku 6,6 mg/kg. Vzorci krvi so bili zbrani iz vratne vene v vakuumskih epruvetah ob injiciranju antibiotika in nato 8, 15 in 30 minut po injiciranju ter 1, 2, 4, 8, 12, 24, 48, 72, 96, 120 in 144 ur po injiciranju antibiotika. Za merjenje serumske koncentracije je bila uporabljena tekočinska kromatografija ultra visoke ločljivosti (UPLC MS/MS). Farmakokinetično modeliranje je bilo izvedeno z dvokomponentnim modelom. Farmakokinetiko ceftiofur-CAF-a po enkratnem i/m injiciranju v kamele je bilo najbolje modelirati v modelu z dvema predelkoma, kjer se je zdravilo počasi razdeljevalo v drugi predelek s slabo penetracijo v tkiva in veliko prednostjo do osrednjega predelka. Najvišja koncentracija antibiotika v plazmi (Cmax) je bila 9,29 ± 0,42 μg/ml pri Tmax 9,41 ± 1,35 ure. Površina pod krivuljo (AUC0-∞) je bila 354,1 ± 57,22 μg/ml*h. Razpolovni čas razporeditve in izločanja je bil 7,42 oziroma 46,13 ure. Povprečni čas prisotnosti antibiotika (MRT) je bil 42,01 h. V primerjavi s hitro absorbirano obliko ceftiofurja (ceftufor-RAF) pri kamelah je bila skoraj podobna največja koncentracija v serumu, vendar z zakasnjenim časom do največje koncentracije (Tmax), daljšim časom zadrževanja (MRT) in večjim razpolovnim časom porazdelitve in izločanja. Ceftiofur-CAF ostal dni nad predhodno priporočeno ravnijo učinkovitosti 0,2 μg/ml kar 7 dni, kar je bilo mogoče doseči po enkratni i/m injekciji 6,6 mg/kg. Pridobljeni podatki o farmakokinetiki v kamelah priporočajo večkratno dajanje v razmaku 2 dni za bakterije, ki potrebujejo ravni MIC nad 2 μg/ml.Ključne besede: Ceftiofur; farmakokinetika; kamela; cefalosporini

TEMPO/TCC as a Chemo Selective Alternative for the Oxidation of Hyaluronic Acid

Hyaluronic acid (HA)-based hydrogels are very commonly applied as cell carriers for different approaches in regenerative medicine. HA itself is a well-studied biomolecule that originates from the physiological extracellular matrix (ECM) of mammalians and, due to its acidic polysaccharide structure, offers many different possibilities for suitable chemical modifications which are necessary to control, for example, network formation. Most of these chemical modifications are performed using the free acid function of the polymer and, additionally, lead to an undesirable breakdown of the biopolymer’s backbone. An alternative modification of the vicinal diol of the glucuronic acid is oxidation with sodium periodate to generate dialdehydes via a ring opening mechanism that can subsequently be further modified or crosslinked via Schiff base chemistry. Since this oxidation causes a structural destruction of the polysaccharide backbone, it was our intention to study a novel synthesis protocol frequently applied to selectively oxidize the C6 hydroxyl group of saccharides. On the basis of this TEMPO/TCC oxidation, we studied an alternative hydrogel platform based on oxidized HA crosslinked using adipic acid dihydrazide as the crosslinker.

Sorbates and benzoates in meat and meat products: Importance, application and determination

Recent views on the use of preservatives sorbic and benzoic acids and their salts in meat products are presented from the point of accordance with current legislation in the Republic of Serbia and the EU, food safety and public health risks, and mainstreams in the methodology for their determination. These preservatives are permitted to be added individually or in combination, the maximum level is applicable to the sum and the levels are expressed as the free acid. Currently set values of the recommended daily intake of sorbate and benzoate are 25 mg/kg and 5 mg/kg, respectively. These values vary and depend on regulations in different countries. Considering control of the use of these additives, the most common methods for their determination are chromatographic methods based on high performance, or high pressure, liquid chromatography with diode array detectors.