Safety and Efficacy of Sodium and Potassium Arachidonic Acid Salts in the Young Pig.

Arachidonic acid (ARA; 20:4n6) and docosahexaenoic acid (DHA; 22:6n3) are polyunsaturated fatty acids (FA) naturally present in breast milk and added to most North American infant formulas (IF). We investigated the safety and efficacy of novel sodium and potassium salts of arachidonic acid as bioequivalent to support tissue levels of ARA comparable to the parent oil; M. alpina oil (Na-ARA and K-ARA) and including a Na-DHA group. Pigs of both sexes were randomized to one of five dietary treatments (n = 16 per treatment; 8 male and 8 female) from postnatal day 2 to 23. ARA and DHA were included as either triglyceride (TG) or salt. Target dietary ARA/DHA concentrations as percent of total FA by weight were as follows: TT (0.47 TG/0.32 TG), NaT (0.47 Na-salt/0.32 TG), KT (0.47 K-salt/0.32 TG), and Na0 (0.47 Na-salt/0.00), NaNa (0.47 Na-salt/0.32 Na-salt). The primary outcome in this study was bioequivalence of ARA brain accretion. Growth performance; blood and tissue fatty acid levels; liver histology; complete blood cell counts; and serum chemistries were all evaluated. Overall, diets containing test sources of ARA and DHA did not affect growth performance; liver histology; or substantially influence hematological outcomes as compared with TT. The results confirm that the use of Na and K salt forms of ARA yield bioequivalent ARA accretion in the cerebral cortex and retinal tissue compared to TG-ARA. These findings confirm that use of Na-ARA and K-ARA salts in the young pig was safe and nutritionally bioequivalent to TG-ARA for critical neural tissues.

Complexions therapy and severe intoxication by Thallium salts.

The aim of this paper is to study the clinical features of severe intoxications with thallium salts and developing effective care schemes for the application of potassium hexacyanoferrate (II) and deferasirox for correction of detected disorders. A total of 39 patients diagnosed with severe thallium salt poisoning were examined in two groups. Group I comprised 20 patients with severe thallium salt poisoning, who were prescribed with potassium-iron hexacyanoferrate in a dose of 250 mg/kg/day per os, intravenous potassium infusions, furosemide intravenously in amount of 40 mg three times per, and hemodialysis until the thallium level in the blood dropped below 10 mg/L, lactulose 30 mL two times per day per os. Group II consisted of 19 people with severe thallium salt poisoning, which in addition to the above treatment, received Deferasirox in a dosage of 500 mg two times per day per os. The clinical picture of severe poisoning with thallium salts is characterized by lesions of the gastrointestinal tract, nervous system (central and peripheral), alopecia, heart rhythm disorders, and myocardial ischemia zones. Extension of standard therapy with potassium-iron by adding hexacyanoferrate deferasirox showed better effect on thallium elimination rate and improved functional state of liver and kidneys in patients with severe thallium salt poisoning.

Is cerebral salt wasting related to sympathetic dysregulation in tuberculous meningitis?

BACKGROUND: Cerebral Salt wasting (CSW) is common in Tuberculous Meningitis (TBM) and is suggested to be due to sympathetic dysregulation of renal blood supply but has not been proven. OBJECTIVE: To evaluate plasma Catecholamines in TBM patients with CSW and correlate with the markers of stress. MATERIALS AND METHODS: The diagnosis of TBM was based on clinical, CSF and MRI criteria. Catecholamines level was measured by LC-MS on admission, at the time of hyponatremia and on correction of hyponatremia. Catecholamine levels were correlated with clinical and laboratory markers of stress, hyponatremia and severity of CSW using pre-defined criteria. RESULTS: There were 24 patients with TBM (12 with CSW) and 12 controls. The median age of patients was 31 (18-75) years and 12 (50 %) were females. TBM patients with CSW had significantly higher levels of catecholamines compared to controls (p < 0.001). TBM patients with CSW had higher levels of norepinephrine than those without CSW (p = 0.034). Sequential studies revealed that dopamine and epinephrine increased at the time of hyponatremia and declined on its correction. Severity of TBM was related to dopamine (p = 0.04) and severity of CSW was related to epinephrine (p = 0.016). CONCLUSION: CSW in TBM seems to be related to catecholamine dysregulation.

Pharmacokinetic and metabolomic analyses of Mangiferin calcium salt in rat models of type 2 diabetes and non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver is one of the most common comorbidities of diabetes. It can cause disturbance of glucose and lipid metabolism in the body, gradually develop into liver fibrosis, and even cause liver cirrhosis. Mangiferin has a variety of pharmacological activities, especially for the improvement of glycolipid metabolism and liver injury. However, its poor oral absorption and low bioavailability limit its further clinical development and application. The modification of mangiferin derivatives is the current research hotspot to solve this problem. METHODS: The plasma pharmacokinetic of mangiferin calcium salt (MCS) and mangiferin were monitored by HPLC. The urine metabolomics of MCS were conducted by UPLC-Q-TOF-MS. RESULTS: The pharmacokinetic parameters of MCS have been varied, and the oral absorption effect of MCS was better than mangiferin. Also MCS had a good therapeutic effect on type 2 diabetes and NAFLD rats by regulating glucose and lipid metabolism. Sixteen potential biomarkers had been identified based on metabolomics which were related to the corresponding pathways including Pantothenate and CoA biosynthesis, fatty acid biosynthesis, citric acid cycle, arginine biosynthesis, tryptophan metabolism, etc. CONCLUSIONS: The present study validated the favorable pharmacokinetic profiles of MCS and the biochemical mechanisms of MCS in treating type 2 diabetes and NAFLD.

Comparative study of the bioavailability of magnesium salts.

Background High values of endogenous levels of magnesium (Mg) in the body and mechanisms of homeostasis regulation make it difficult to assess the bioavailability of these drugs. The aim of this study was to assess the Mg concentration in blood in volunteers and in erythrocytes in patients with hypomagnesemia. Methods The study included 20 healthy volunteers and 62 patients with chronic heart failure (CHF) I-III functional class (FC) NYHA classification. We studied the composition of Mgorotate and Mgorotate plus potassium (К)orotate. Blood sampling was carried out at 8 a.m. and within 10 h after administering the drugs. Measurement of Mg pharmacokinetic parameters: AUC (concentration of the active substance-time), and Cmax (maximum concentration) in volunteers and measurement of the concentration of Mg in erythrocytes of patients. Results The results indicated that both the AUC in volunteers and concentration of Mg in erythrocytes of patients are comparable, and the differences are not statistically significant. Conclusions The study showed that the standard method of calculating the AUC (total serum Mg) is insufficient for comparative evaluation of Mg absorption due to the high levels of its endogenous content and a small increase in concentration after taking the drugs. It is advisable to assess the concentration of Mg in the red blood cells of patients.

Clarithromycin laurate salt: physicochemical properties and pharmacokinetics after oral administration in humans.

OBJECTIVE: To prepare and characterize the physicochemical and pharmacokinetic properties of clarithromycin laurate (CLM-L), a fatty acid salt of clarithromycin (CLM). METHODS: CLM-L was prepared by a simple co-melting process. The formation of CLM-L was confirmed using FTIR, 1H NMR, and 13C NMR. Solubility, intrinsic dissolution rate (IDR), and partitioning properties of CLM-L were determined and compared to those of CLM. Bioavailability of CLM from CLM-L tablets was evaluated in healthy volunteers and compared to immediate release CLM tablets. RESULTS: CLM-L showed lower aqueous solubility, higher partitioning coefficient, and slower dissolution rate. Tablets of CLM-L also showed a significantly slower in vitro release in comparison to CLM tablets. Cmax, Tmax and AUC0→∞ of CLM-L tablets and immediate release CLM tablets did not show a significant difference. However, the AUC0→∞ for the CLM-L tablets tended to be higher than that of CLM tablets at all-time points. CONCLUSION: CLM-L was successfully prepared and its formation was confirmed. CLM-L was more hydrophobic than CLM. It exhibited a slight in vivo absorption enhancement in comparison to CLM. However, its pharmacokinetic behavior was comparable to that of CLM.

A comparative pharmacokinetic and tolerability analysis of the novel orotic acid salt form of tenofovir disoproxil and the fumaric acid salt form in healthy subjects.

A novel orotic acid salt form of tenofovir disoproxil (DA-2802) was developed and is expected to replace the fumaric acid salt form. The pharmacokinetic (PK) characteristics and tolerability profiles of DA-2802 were compared to those of tenofovir disoproxil fumarate (TDF, Viread®) in healthy subjects. A randomized, open-label, single-dose study was conducted in 36 healthy subjects using a two-treatment, two-period, and two-sequence crossover design. Subjects received a single oral dose of 319 mg DA-2802 or 300 mg TDF, during each period, with a 7-day washout. Serial blood samples were collected pre-dosing and up to 72 hours post-dosing in each period, for determination of serum tenofovir concentration, which was measured by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental method was used to obtain PK parameters of tenofovir. For comparison between the two tenofovir disoproxil salts, the 90% confidence intervals (90% CIs) of geometric mean ratios of DA-2802 to TDF for the maximum concentration (Cmax) and the area under the concentration-time curve to the last quantifiable concentration (AUC0-t) were determined. The tolerability profiles of tenofovir were assessed by evaluation of adverse events and vital signs, physical examination, ECG, and clinical laboratory tests. The serum tenofovir concentration-time profiles of DA-2802 or TDF were comparable in 32 subjects who completed the study. In both profiles, a two-compartmental elimination with first-order elimination kinetics in the terminal phase was reported in a few subjects, showing a secondary peak in the initial phase of elimination. The geometric mean ratio (90% CI) of DA-2802 to TDF was 0.898 (0.815-0.990) for Cmax and 0.904 (0.836-0.978) for AUC0-t. There were no clinically significant findings in the tolerability assessments. DA-2802 showed comparable PK characteristics and tolerability profiles to TDF.

Salt-water imbalance and fluid overload in hemodialysis patients: a pivotal role of corin.

Natriuretic peptides (NP) play a key role in regulation of salt and water balance. Corin, a serine protease which activates NP, plays a key role in regulation of blood pressure and cardiac function. The aim of the study was to evaluate the involvement of corin in renal physiopathology, analyze its levels in dialyzed patients and evaluate its relation with fluid overload and comorbidities such as heart failure and blood hypertension. We studied serum corin in uremic patients (n = 20) undergoing hemodialysis therapy (HD) and in healthy subjects (HS). Corin levels in uremic patients were higher than in HS (p < 0.0001). Moreover, its concentration did not change after a single HD session. Hypertensive patients and subject suffering from heart failure were characterized by high values of corin. After multivariate analysis, direct correlations were maintained between corin and dialysis vintage (ß = 0.83; p = 0.0002), heart failure (ß = 0.42; p < 0.0001), systolic blood pressure (ß = -0.70; p = 0.0002) and body weight (ß = -0.39; p < 0.0001). Corin might be implicated in the regulation of salt and water balance and the disturbances of volume homeostasis of HD patients. However, further studies are warranted to understand the role of corin in kidney diseases and to define its diagnostic and prognostic role.

From a binary salt to salt co-crystals of antibacterial agent lomefloxacin with improved solubility and bioavailability.

The cocrystallization of lomefloxacin (Lf) with barbituric acid (HBA) and/or isophthalic acid (H2ip) leads to novel binary and ternary salts via hydrogen-bonding recognition. X-ray single-crystal diffraction analyses show that zwitterionic lomefloxacin can adjust itself to fulfill a different supramolecular array in either binary salts or ternary salt co-crystals, formulated as [HLf]·[Hip]·H2O (1), [HLf]·[BA]·[HBA]·H2O (2) and [HLf]·[BA]·[H2ip]·CH3OH·H2O (3). These pharmaceutical agents present uniform charge-assisted hydrogen-bonding networks between HLf cations and acidic coformers with the lattice capturing water molecules. Structural comparison of (2) and (3) indicated that a delicate balance of geometries and hydrogen-bonding partners is required for stacking to favor the formation of ternary salt co-crystals. Cocrystallization was able to overcome the water insolubility of lomefloxacin. Both the salt co-crystals display enhanced solubility and better pharmaceutical applicability.

Interactions between maternal subtotal nephrectomy and salt: effects on renal function and the composition of plasma in the late gestation sheep fetus.

Effects of altered maternal salt intake between 122 and 127 days gestation (term is 150 days) were studied in eight fetuses carried by ewes which had renal insufficiency caused by subtotal nephrectomy (STNxF) and seven fetuses carried by intact ewes (IntF). Plasma sodium and osmolality were increased in ewes with subtotal nephrectomy on a high-salt intake (0.17 m NaCl in place of drinking water for 5 days; P < 0.05). The STNxF had normal body weights. A high maternal salt intake did not affect fetal blood pressure or heart rate. Plasma osmolality was higher in STNxF (P < 0.001), and plasma sodium and osmolality were increased by high salt (P < 0.001 and P < 0.04, respectively). The STNxF had higher urinary osmolalities (P = 0.002), which were also increased by a high maternal salt intake (P = 0.03). Renal blood flow fell in STNxF in response to a high maternal salt intake, but increased in IntF (P = 0.003). In STNxF but not IntF, glomerular filtration rate and urinary protein excretion were positively related to fetal plasma renin levels (P < or = 0.01). It is concluded that the salt intake of pregnant ewes with renal insufficiency affects maternal and fetal osmolar balance, fetal plasma sodium and fetal renal function. Since STNxF also had altered renal haemodynamic responses to high maternal salt and evidence of renin-dependent glomerular filtration and protein excretion, we suggest that interactions between dietary salt and pre-existing maternal renal disease impair glomerular integrity and function in the fetus.