Hydrodynamic synchronization of light driven microrotors.

Hydrodynamic synchronization is a fundamental physical phenomenon by which self-sustained oscillators communicate through perturbations in the surrounding fluid and converge to a stable synchronized state. This is an important factor for the emergence of regular and coordinated patterns in the motions of cilia and flagella. When dealing with biological systems, however, it is always hard to disentangle internal signaling mechanisms from external purely physical couplings. We have used the combination of two-photon polymerization and holographic optical trapping to build a mesoscale model composed of chiral propellers rotated by radiation pressure. The two microrotors can be synchronized by hydrodynamic interactions alone although the relative torques have to be finely tuned. Dealing with a micron sized system we treat synchronization as a stochastic phenomenon and show that the phase lag between the two microrotors is distributed according to a stationary Fokker-Planck equation for an overdamped particle over a tilted periodic potential. Synchronized states correspond to minima in this potential whose locations are shown to depend critically on the detailed geometry of the propellers.

Pharmacokinetics, metabolism and bioavailability of the new anti-allergic drug BM 113. Part III: Pharmacokinetics, metabolism, dose dependency and gender effect after single or repeated administration to human healthy volunteers.

A new anti-allergic drug, BM 113 (1-(benzhydryloxyethyl)piperidino-4- ethylacetate, CAS 115313-90-1; BM 113 maleate: CAS 115313-91-2), with a piperidinic structure, showing anti-histaminic properties was studied after administration to healthy human volunteers. The focus was on the pharmacokinetics, the metabolism, the dose dependency and gender differences of the pharmacokinetic parameters of BM 113 and its main desacetylated metabolite, BM 212. Unchanged BM 113 was not recovered in plasma or in urine. The elimination of the radioactivity was essentially urinary with about 81% recovered within 24 h. The elimination was completed with 97% of the administered dose recovered after 120 h. HPLC dosage of BM 212, using a specific method, showed that BM 212 represented 62% of the urine radioactivity. The plasma profile of radioactivity was characterized by two decreasing phases with respective half-lives of 3.71 +/- 0.66 h and 24.67 +/- 25.01 h. A dose dependency study realised with 20, 40, 60 and 80 mg oral doses administered to 8 healthy volunteers has proven the linearity of the pharmacokinetics of BM 212 in the studied range. BM 212 disposition after single and repeated BM 113 oral doses in a 14-day study did not vary and permitted to conclude that no auto-induction or auto-inhibition phenomenon was involved. No significant difference between men and women was observed. The concentration profile was mono or biexponential, depending on the subject but whatever the gender. An inter-individual variability appeared for both sexes and caused some variations in the pharmacokinetic parameters.

Pharmacokinetics, metabolism and bioavailability of the new anti-allergic drug BM 113. Part II: Pharmacokinetics in primates after repeated oral or single intravenous administration.

The pharmacokinetics of BM 113 (1-(benzhydryloxyethyl)piperidino-4-ethylacetate, CAS 115313-90-1; BM 113 maleate: CAS 115313-91-2) was studied using 3H-BM 113 in the Cynomolgus primate. Oral repeated administration of 0.75 mg/kg was performed on 8 days. 40 days after the oral treatment, a single intravenous administration of 0.4 mg/kg was done. Whatever the administration route, the radioactivity excretion was essentially urinary (about 60%) and most of the radioactivity was excreted within the first 24 h. The faecal elimination was low, about 10% of the administered dose. 40 days after the treatment, some radioactivity was already present in the urine. For this reason, the excretion balance ranged from 70 to 83% of the dose. The elimination half-life of 3H-BM 113 was long, about 80 h.

Pharmacokinetics, metabolism and bioavailability of the new anti-allergic drug BM 113. Part I: Pharmacokinetics and tissular distribution in Sprague-Dawley rats.

A new anti-allergic drug, BM 113 (1-(benzhydryloxyethyl)piperidino-4-ethylacetate, CAS 115313-90-1; BM 113 maleate: CAS 115313-91-2) with a piperidinic structure, showing antihistaminic properties was studied in male and female Sprague-Dawley rats after i.v. or p.o. administrations of 0.750 mg/kg 3H-BM 113. This product presented a rapid faecal elimination after i.v. and oral administration. The total recovery of the dose was obtained after 144 h. Biliary elimination was very fast: 54% of the intravenous dose were biliarily eliminated within 2 h, essentially as a conjugated form. For both i.v. and p.o. routes, the blood kinetics were biexponential. Intravenous administration led to elimination half-lives of 1.36 h and 0.75 h for the first phase and 38.6 h and 56.5 h for the second one for males and females, respectively. After oral administration, rebounds corresponding to the presence of enterohepatic cycle or metabolites were observed. Thus, the determination of half-lives was not possible. Slight but significant differences of some pharmacokinetic parameters were observed between genders. The results obtained during the protein binding study corresponded to the BM 113 metabolite known as BM 212. The free fraction corresponded to 55.5%. Tissular concentrations showed a rapid distribution of 3H-BM 113 followed by a slow elimination. In most of the tissues, the decrease was biexponential. The organs containing most of the radioactivity were those of the intestinal tract and the liver. Other tissues presented concentrations close to those of plasma. Lipidic tissues, showing low BM 113 concentrations, presented a slower elimination, probably related to the high lipophilicity of molecule.

Synthesis and psychoanaleptic properties of new compounds structurally related to diphenhydramine.

A new series of benzhydryloxyalkylpiperazines carrying a trivalent function has been synthesized and studied for its effects on the central nervous system. Most of the compounds exhibit unexpected nonamphetaminic psychoanaleptic properties. The structure-activity studies revealed the importance of the nature and the position of the substituents on the phenyl rings. However, no significant correlation between atropinic or antihistaminic effects and psychoanaleptic properties was observed.