Microneurographically recorded Ia discharge from the tibial nerve mainly transmits the angular velocity of the ankle joint in humans

Investigations of the Ia afferent discharge in clarifying problems in disused and malused skeletal muscles have been carried out mainly in muscles of the upper extremities. However, such problems actually occur more frequently in the antigravity muscles of the lower extremities, such as the triceps surae muscle. An analysis of microneurographically recorded Ia discharges from the tibial nerve innervating the triceps surae muscle during dynamic movement of the ankle joint indicated that they mainly transmitted information on the angular velocity of the joint. However, the information on the position sense of the joint was not as well transmitted through Ia discharges. There was no correlation between the joint angle and the static response. However, the dynamic response of a Ia afferent was well correlated to the angular velocity. It is concluded that the human proprioception of the triceps surae muscle was not dependent on the position of the ankle joint, but largely on its movement by the stretching of the muscle.     

Interactions of crizotinib and gefitinib with organic anion-transporting polypeptides (OATP)1B1, OATP1B3 and OATP2B1: gefitinib shows contradictory interaction with OATP1B3

1.?The drug–drug interaction (DDI) mediated by organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and OATP2B1 has a major impact on the hepatic clearance of drugs. The effects of tyrosine kinase inhibitors (TKIs) on OATPs have not been well studied. In the present study, we evaluated the contribution of OATPs to the hepatic uptake of crizotinib and gefitinib and the interaction of those TKIs with OATPs to estimate DDIs.

2.?To clarify whether crizotinib and gefitinib were substrates for OATPs, we performed uptake studies. We examined the effects of the TKIs on uptake of typical substrates and fluvastatin via OATPs. IC₅₀ and EC₅₀ values of the TKIs were calculated.

3.?OATP1B3- and OATP2B1-mediated crizotinib uptake and OATP2B1-mediated gefitinib uptake were observed. Gefitinib accelerated OATP1B3-mediated [³H]TCA uptake and inhibited OATP2B1-mediated [³H]E₃S uptake. On the other hand, gefitinib inhibited OATP1B1- and OATP2B1-mediated fluvastatin uptake.

4.?We provided basic information to estimate the DDI on OATPs caused by TKIs. The DDI on OATPs caused by gefitinib could occur in a normal clinical situation. And the uptake of crizotinib into the intrahepatocellular environment via OATPs may induce DDI and liver damage. We therefore emphasize the necessity of careful use of TKIs.     

4-[5-Fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6- tetrahydro-2H-pyran-4-carboxamide, an orally active inhibitor of 5-lipoxygenase with improved pharmacokinetic and toxicology characteristics

Described herein are structure-activity relationships (SARs) of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1, CJ-12,918), an imidazole 5-lipoxygenase (5-LO) inhibitor. When 1 was tested in preclinical studies, cataract formation was observed in rats; however, this compound was metabolized extensively in vivo and showed low systemic exposure. To eliminate this side effect and enhance bioavailability, structural modification was focused on replacing the methoxy group of 1 by modulating lipophilicity (i.e., predicted log D at pH 7.4). The SARs led to the discovery of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (10, CJ-13,454), which was less lipophilic by 1.2 log D units and showed in vivo potency (ED(50) = 4-9 mg/kg) equipotent to 1. Enhanced metabolic stability resulted in fewer in vivo metabolites, as well as improved bioavailability and a better toxicological profile. Thus, 10 was found to be a more practical lead for an orally active 5-LO inhibitor.     

Central muscle relaxant activities of 2-methyl-3-aminopropiophenone derivatives

In this experiment, we synthetized new 2-methyl-3-aminopropiophenone (MP) derivatives, whose structure is known to have central muscle relaxant activities, and quinolizidine and indan . tetralin derivatives derived from MP by cyclization, and we investigated the central muscle relaxant activity. Among the quinolizidine derivatives, there was a very strong central depressant agent, trans (3H, 9aH)-3-(p-chloro) benzoyl-quinolizidine (HSR-740), and among the indan . tetralin derivatives, there was an excitant agents, trans (1H, 2H)-5-methoxy-3, 3-dimethyl-2-piperidinomethyl indan-1-ol (HSR-719). From the results, these derivatives were not considered to be adequate for central muscle relaxant. Among the MP derivatives, (4'-chloro-2'-methoxy-3-piperidino) propiophenone HCl (HSR-733) and (4'-ethyl-2-methyl-3-pyrrolidino) propiophenone HCl (HSR-770) strongly inhibited the cooperative movement in the rotating rod method using mice, and it exerted almost the same depressant activity on the cross extensor reflex using alpha-chloralose anesthetized rats. However, the inhibitory effects of HSR-733 on the anemic decerebrate rigidity and the rigidity induced by intracollicular decerebration in rats were weaker than those of HSR-770 and eperisone. In spinal cats, at a low dose (5 mg/kg, i.v.), HSR-733 depressed monosynaptic and dorsal root reflex potentials as compared with polysynaptic reflex potentials, and inhibitory effects of HSR-733 on these three reflex potentials were more potent than those of eperisone and HSR-770. Although HSR-770 acts on the spinal cord and supraspinal level on which eperisone has been reported to act, HSR-733 may mainly act on the spinal cord. These results indicate that the MP derivative with a 2-methyl group may be suitable as a central muscle relaxant. HSR-770, which has equipotent muscle relaxant activity to eperisone, exerted strong inhibitory effects on oxotremorine-induced tremor and weak inhibitory effects on spontaneous motor activity in the Animex method using mice, as compared with eperisone.     

Minimal impact of hepatic and renal impairment on plasma protein binding of lenvatinib,and identification of its major plasma binding protein

Plasma protein binding (PPB) can be different depending on the status of hepatic or renal functions. In this study, the PPB of lenvatinib was determined using equilibrium dialysis in plasma from healthy volunteers and from subjects with mild, moderate, or severe hepatic impairment or renal impairment. Plasma from these subjects, fortified with lenvatinib at four concentrations (20, 200, 500, or 1200 ng/ml), was dialysed against phosphate buffered saline (PBS), and then determinations of the total concentrations of lenvatinib in plasma and unbound concentrations in PBS were made. In addition, the binding of lenvatinib was determined in human serum albumin (HSA), α₁‐acid glycoprotein (AAG), and human γ‐globulin (HG) in order to identify major binding proteins in human plasma. The PPB of lenvatinib in subjects with HI or RI ranged from 97.5% to 98.2% in hepatic impairment and 98.0% to 98.4% in renal impairment, which was similar to that of healthy volunteers. The binding of lenvatinib to HSA, AAG, and HG was 96.6%–97.1%, 46.4%–69.9%, and 19.1%–23.9%, respectively. These findings suggest that lenvatinib mainly binds to HSA and neither renal nor hepatic impairment impacts the PPB of lenvatinib.     

Separation and determination of diastereomeric flurbiprofen acyl glucuronides in human urine by LC/ESI-MS with a simple column-switching technique

Endogenous and exogenous compounds having a carboxyl group, such as alpha-arylpropionic acid derivatives, undergo a phase II metabolic reaction to produce an amino acid conjugate through the acyl CoA thioester as well as the acyl glucuronide. It was previously shown that flurbiprofen, one of the nonsteroidal anti-inflammatory drugs, is not subjected to activation of the carboxyl group by the CoA thioester ligase, suggesting that acyl glucuronidation is the main phase II metabolic pathway. Recent observations, however, have demonstrated that the nonenzymatic formation of a covalently protein-bound drug, which is produced by the action of the acyl glucuronide, may cause hypersensitive reactions. Accordingly, a reliable method to measure diastereomeric flurbiprofen glucuronides in human biological fluids is required. In this study, we describe a liquid chromatographic/mass spectrometric method with a simple column switching technique to determine diastereomeric flurbiprofen acyl glucuronides in human urine specimens. The optimal conditions for the electrospray ionization were established based on the effects of orifice and ring lens voltages as well as mobile phase additives. The proposed method applied to urine specimens demonstrates high accuracy and reproducibility for the determination of flurbiprofen glucuronides in a quantitative range from 0.74 to 146.5 microg/mL, with a detection limit of 7.4 pg (17.6 fmol)/injection of S-flurbiprofen glucuronide, at a signal-to-noise ratio of 10 under the selected ion-monitoring mode. The urinary concentration of R-flurbiprofen glucuronides in healthy subjects determined by the proposed method were 6.8-29.4 microg/mL, and those values were slightly higher than that of S-flurbiprofen glucuronides (3.9-18.0 microg/mL).     

Acute decompression illness following hyperbaric exposure: clinical features of central nervous system involvement

Decompression illness (DCI) is a general term encompassing all pathological changes secondary to reduction of environmental pressure. This condition has two forms: decompression sickness (DCS) and arterial gas embolism (AGE) secondary to pulmonary barotrauma. Moreover, DCS is categorized as minor, such as limb and/or joint pains or skin rash (Type I), and serious, as in cardiopulmonary and/or central nervous system involvements (Type II). Cerebral and spinal injuries have been symptomatically classified into AGE and DCS. Brain scans of patients with AGE or DCS showed multiple cerebral infarctions in the terminal and/or border zones of the cerebral arteries. Brain involvements of patients in both AGE and DCS show no differences in neurological or neuro-radiological findings. From the neurological and radiological standpoint, it is therefore impossible to distinguish these two conditions. Despite established treatments for neurological DCI (both AGE and DCS), it is unclear whether US Navy treatment Table 6 is preferable to standard hyperbaric oxygen therapy such as 2.4 atmospheres pressure for 90 minutes. Japanese laws and regulations have peculiarities that permit air diving to 90 meters depth, but with explicit prohibition of the use of oxygen for decompression, albeit a limited use of mixed gas is permissible. Moreover, currently the health screening for hyperbaric workers does not include detailed examination of the cardiopulmonary or the central nervous system.     

Nanostructured and thermoresponsive recombinant biopolymer-based microcapsules for the delivery of active molecules

Multilayer capsules conceived at the nano- and microscales are receiving increasing interest due to their potential role as carriers of biomolecules for drug delivery and tissue engineering. Herein we report the construction of microcapsules by the sequential adsorption of chitosan and a biomimetic elastin-like recombinamer into nanostructured layers on inorganic microparticle templates. The release profile of bovine serum albumin, which was studied at 25 and 37 °C, shows higher retention and Fickian diffusion at physiological temperature. The self-assembled multilayers act as a barrier and allowed for sustained release over 14 days. The capsules studied are non-cytotoxic towards L929 cells, thereby suggesting multiple applications in the fields of biotechnology and bioengineering, where high control of the delivery of therapeutics and growth/differentiation factors is required.From the Clinical EditorIn this paper, the construction of microcapsules by sequential adsorption of chitosan and a biomimetic, elastin-like recombinamer into nanostructured layers on inorganic microparticle templates is reported. The layers demonstrated sustained drug release over 14 days. These microcapsules are non-cytotoxic toward L929 cells, suggesting multiple applications where high control of drug or growth factor delivery is required.