Dual-directional regulation of drug permeating amount by combining the technique of ion-pair complexation with chemical enhancers for the synchronous permeation of indapamide and bisoprolol in their compound patch through rabbit skin.

To achieve the synchronous skin permeation of indapamide (IND) and bisoprolol (BSP) in their compound patch, the techniques of ion-pair complexation and chemical enhancers were combined to dual-directionally regulate drug permeating amounts. Ion-pair complexes of BSP and various organic acids were formed by the technique of ion-pair complexation. Among the complexes formed, bisoprolol tartrate (BSP.T) down-regulated the permeating amount of BSP to the same extent as that of IND. Then, to simultaneously up-regulate the amounts of the two drugs, an enhancer combination of 15.8% Span80 (SP), 6.0% Azone (AZ) and 2.2% N-methyl pyrrolidone (NMP) was obtained by central composite design and exhibited an outstanding and simultaneous enhancement on IND and BSP with enhancing ratio (ER) of 4.52 and 3.49, respectively. The effect of the dual-directional regulation was evaluated by in vitro permeation experiments and in vivo pharmacokinetic studies. For IND and BSP, their observed permeation profiles were comparable and their MAT (mean absorption time) showed no significant difference, which both demonstrated these two drugs achieved the synchronous skin permeation in their compound patch by the dual-directional regulation strategy of combining the technique of ion-pair complexation with chemical enhancers.

Electromembrane Extraction of Organic Acid Compounds in Biological Samples Followed by High-Performance Liquid Chromatography.

Electromembrane extraction (EME) coupled with high-performance liquid chromatography was developed for determination of organic compounds including citric, tartaric and oxalic acid in biological samples. Organic compounds moved from aqueous samples, through a thin layer of 1-octanol immobilized in the pores of a porous hand-made polypropylene tube, and into a basic aqueous acceptor solution present inside the lumen of the tube. This new set-up for EME has a future potential such as simple, cheap and fast sample preparation technique for extraction of organic compounds in various complicated matrices. The pH of acceptor phase, extraction time, voltage, ionic strength, temperature and stirring speed were studied and optimized. Optimum conditions were: the pH of acceptor phase, 7; extraction time, 30 min; voltage, 30 V and stirring speed, 500 rpm. At the optimum conditions, the preconcentration factors of 175-200, the limits of detection of 1.9-3.1 µg L(-1) were obtained for the analytes. The developed procedure was then applied to the extraction and determination of organic acid compounds from biological samples.

Calcium homeostasis and bone metabolic responses to high-protein diets during energy deficit in healthy young adults: a randomized controlled trial.

BACKGROUND: Although consuming dietary protein above current recommendations during energy deficit (ED) preserves lean body mass, concerns have been raised regarding the effects of high-protein diets on bone health. OBJECTIVE: The objective was to determine whether calcium homeostasis and bone turnover are affected by high-protein diets during weight maintenance (WM) and ED. DESIGN: In a randomized, parallel-design, controlled trial of 32 men and 7 women, volunteers were assigned diets providing protein at 0.8 [Recommended Dietary Allowance (RDA)], 1.6 (2 × RDA), or 2.4 (3 × RDA) g · kg(-1) · d(-1) for 31 d. Ten days of WM preceded 21 d of ED, during which total daily ED was 40%, achieved by reduced dietary energy intake (∼30%) and increased physical activity (∼10%). The macronutrient composition (protein g · kg(-1) · d(-1) and % fat) was held constant from WM to ED. Calcium absorption (ratio of (44)Ca to (42)Ca) and circulating indexes of bone turnover were determined at day 8 (WM) and day 29 (ED). RESULTS: Regardless of energy state, mean (±SEM) urinary pH was lower (P < 0.05) at 2 × RDA (6.28 ± 0.05) and 3 × RDA (6.23 ± 0.06) than at the RDA (6.54 ± 0.06). However, protein had no effect on either urinary calcium excretion (P > 0.05) or the amount of calcium retained (P > 0.05). ED decreased serum insulin-like growth factor I concentrations and increased serum tartrate-resistant acid phosphatase and 25-hydroxyvitamin D concentrations (P < 0.01). Remaining markers of bone turnover and whole-body bone mineral density and content were not affected by either the protein level or ED (P > 0.05). CONCLUSION: These data demonstrate that short-term consumption of high-protein diets does not disrupt calcium homeostasis and is not detrimental to skeletal integrity. This trial was registered at www.clinicaltrials.gov as NCT01292395.

Life-threatening hyperkalemia from cream of tartar ingestion.

INTRODUCTION: Cream of tartar (potassium bitartrate) has a long history as a cooking aid and medicinal purgative. Despite containing large amounts of potassium, there are no well-documented cases of it causing toxicity. We report two cases in which intentional ingestions of cream of tartar resulted in life-threatening hyperkalemia. In addition, we briefly review the use of cream of tartar as a historical purgative. CASE REPORTS: In both cases, individuals ingested a large quantity of cream of tartar in an effort to "clean themselves out". They manifested similar initial symptoms (vomiting), abnormal serum potassium (>8.0 mmol/L), and EKG's with peaked T waves. Both patients were treated for hyperkalemia and recovered without complication. A search for articles on an academic internet database failed to identify any cases specifically dealing with ill effects of potassium bitartrate and numerous websites continue to purport its beneficial health effects. CONCLUSION: Ingestion of cream of tartar can potentially result in life-threatening hyperkalemia.

Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling.

The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1(neo/neo) and K14cre:SmoM2(YFP)). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.

Responses of criterion variables to different supplemental doses of L-carnitine L-tartrate.

L-carnitine L-tartrate (LCLT) supplementation beneficially affects markers of postexercise metabolic stress and muscle damage. However, to date, no study has determined the dose response of LCLT to elicit such responses. Therefore, the purpose of this study was to determine the effects of different doses of LCLT on criterion variables previously shown to be responsive to LCLT supplementation. Eight healthy men (22 +/- 3 y, 174 +/- 5 cm, 83.0 +/- 15.3 kg) were supplemented with 0 g, 1 g, and 2 g of LCLT for 3 weeks and then performed a bout of resistance exercise (5 sets of 15-20 repetition maximum with a 2-min rest between sets) with associated blood draws. This procedure was performed in a balanced, randomized, repeated measures design. Serum carnitine concentrations increased (p < or = 0.05) following the 1 g and 2 g doses, with the 2-g dose providing the highest carnitine concentrations. The 1- and 2-g doses reduced postexercise serum hypoxanthine, serum xanthine oxidase, serum myoglobin, and perceived muscle soreness. In conclusion, both the 1- and 2-g doses were effective in mediating various markers of metabolic stress and of muscle soreness. Use of LCLT appears to attenuate metabolic stress and the hypoxic chain of events leading to muscle damage after exercise.

Effects of meluadrine tartrate and ritodrine hydrochloride on oxytocin-induced uterine contraction, uterine arterial blood flow and maternal cardiovascular function in pregnant goats.

This study was designed to elucidate the effects of meluadrine tartrate on oxytocin-induced uterine contraction and maternal hemodynamics in unanesthetized, chronically instrumented pregnant goats. After the administration of meluadrine tartrate or ritodrine hydrochloride to pregnant goats, changes in heart rate (HR), arterial blood pressure (AOP), and arterial blood pH and gasses (P(O2) and P(CO2)) in the mother, as well as changes in intrauterine pressure (IUP) and uterine arterial blood flow (UBF), were measured. The escalating administration of meluadrine tartrate (0.03, 0.1, 0.3 and 1 micro g. kg(-)(1). min(-)(1)) or ritodrine hydrochloride (1, 3, 10 and 30 microg. kg(-)(1). min(-)(1)) to the maternal femoral vein caused a marked and similar inhibition in oxytocin-induced uterine contraction (a rise in IUP). By these escalating dosings, maternal HR was increased dose-dependently in both treatment groups; however, the degree of the HR increase in the meluadrine tartrate-treatment group was significantly less than that in the ritodrine hydrochloride-treatment group. Furthermore, the degree of the UBF decrease in the meluadrine tartrate-treatment group was significantly less than that in the ritodrine hydrochloride-treatment group. The present study suggests that meluadrine tartrate has a mild influence on the maternal cardiovascular function relative to the effects of ritodrine taking the potent efficacy on oxytocin-induced uterine contraction into account.

Effects of meluadrine tartrate on maternal metabolic responses and fetal hemodynamics in pregnant goats.

This study was designed to elucidate the effects of meluadrine tartrate on maternal metabolic responses and fetal hemodynamics in unanesthetized, chronically instrumented pregnant goats. After the administration of meluadrine tartrate to pregnant goats or directly to fetuses, changes in heart rate (HR), arterial blood pressure and arterial blood pH, gasses, electrolytes and metabolic responses were measured. The constant administration of meluadrine tartrate (0.1 microg. kg(-)(1). min(-)(1)) to pregnant goats resulted in the increases of maternal HR, glucose and free fatty acid and the decrease of maternal blood K(+) concentration. The direct escalating administration of meluadrine tartrate (0.01, 0.03 and 0.1 microg. kg(-)(1). min(-)(1)) did not increase the fetal HR, while ritodrine hydrochloride (0.3, 1 and 3 microg. kg(-)(1). min(-)(1)) to fetuses increased the fetal HR dose-dependently. The present study suggests that meluadrine tartrate has a mild influence relative to the effects of ritodrine to the maternal metabolic responses and fetal cardiovascular function.

Different pharmacokinetics of nicotine following intravenous administration of nicotine base and nicotine hydrogen tartarate in rats.

Pharmacokinetics of nicotine was studied in rats following intravenous (i.v.) administration of nicotine base (NB) and nicotine hydrogen tartarate salt (NS) at a nicotine dose of 1 mg/kg. The area under the plasma concentration-time curve (AUC), mean residence time (MRT), systemic clearance (CL), distribution volume at steady state (V(ss)) and terminal plasma half-life (T(1/2,beta)) of nicotine were compared between NB and NS. Compared to NS, NB exhibited higher and sustained plasma nicotine levels, thereby yielding significantly (P<0.05) larger AUC (66.3 vs. 27.7 microg ml/min), MRT (165.7 vs. 58.3 min), T(1/2,beta) (144.2 vs. 51.4 min) and a lower CL (18.3 vs. 46.3 ml/min per kg). The V(ss) was comparable between the two compounds. The metabolic conversion to cotinine from NS was threefold larger than that from NB. The plasma protein binding and distribution to blood cells were comparable between the compounds. The apparent partition coefficient (APC) of NS decreased as a function of its concentration, while that of NB remained nearly constant. Particles of different mean sizes were observed for the 1% (w/v) aqueous solutions of NS (388.6 nm) and NB (123.8 nm). Different metabolism and/or elimination between NB and NS appear to be mainly responsible for their different pharmacokinetics.

[Biological profile and value of determination of tartrate-resistant acid phosphatase in children]. / Perfil biológico y valor de la determinación de la fosfatasa ácida tartrato resistente en niños.

The serum level of tartrate-resistant acid phosphatase (TRAP) was measured in 130 children (61 M: 69 F). TRAP was found to be significantly higher in children under 5 years (n = 20) than in those aged between 5 and 9 years (n = 47) (8.3 + 2.4 vs 6.3 + 1.3 U/L, p less than 0.05). This last group had significantly lower TRAP levels than the one composed by children between 10 to 14 years (n = 60) (6.3 + 1.3 vs 7.5 + 1.2 U/L, p less than 0.02). We observed that a significant correlation existed between TRAP and alkiline phosphatase (r = 0.672, p less than 0.001). There was no correlation between TRAP and age and no difference between sexes. These results suggest that TRAP is useful as a marker of bone remolding in children.

Clinical differential diagnosis of hairy-cell leukaemia.

The data on hairy-cell leukaemia (HCL) and resembling disorders in the literature and in our patients were analyzed to determine which clinical features and laboratory data are important for the recognition of HCL in an early stage. In pancytopenic patients the typical pattern of bone marrow involvement in HCL and the low number of monocytes in the peripheral blood appear to be essential for the differential diagnosis. In patients with many neoplastic cells in the peripheral blood, the presence of neutropenia and monocytopenia as well as tartrate-resistant acid phosphatase activity in the neoplastic cells, appears to be crucial for early diagnosis. Thus, the clinical features and routine laboratory data alone are sufficient in the majority of cases to suggest the diagnosis HCL. The monocytopenia proved to be most helpful in this respect. Nevertheless, in all patients, and certainly in patients presenting with atypical features, a bone marrow biopsy is indispensable for the correct diagnosis.

Renal and bone uptake of tartaric acid in rats: comparison of L(+) and DL-Forms.

Plasma concentrations of radioactivity declined biphasically with half-lives of about 15 and 58 h respectively in rats dosed with monosodium DL-[14C]tartrate for 7 days at a dose level of 2.73 g/kg/day. Uptake and retention of radioactivity occurred in blood cells, kidneys and bones where it was detected for at least 12 days after dosing. Renal retention (11202 +/- 4469 ppm at 6 h, n = 7) was probably due to precipitation of the poorly soluble calcium DL-tartrate in the tubules leading to increased kidney weight, nephrotoxicity and even death. The more soluble, naturally-occurring L(+)-[14C] tartrate was not retained in the kidneys (1287 +/- 118 ppm at 6 h, n = 8) when administered to rats under the same conditions, and the initial decline of plasma concentrations of radioactivity was more rapid (t 0.5 approx. 3 h). For this reason, monosodium L(+)-tartrate was non-toxic at 2.73 g/kg/day whereas monosodium DL-tartrate was toxic at this dosage.