Little is known about the innate defense mechanisms of the male reproductive tract. We cloned a 385-base pair complementary DNA and its genomic DNA named Bin1b that is exclusively expressed in the caput region of the rat epididymis and that is responsible for sperm maturation, storage, and protection. Bin1b exhibits structural characteristics and antimicrobial activity similar to that of cationic antimicrobial peptides, beta-defensins. Bin1b is maximally expressed when the rats are sexually mature and can be up-regulated by inflammation. Bin1b appears to be a natural epididymis-specific antimicrobial peptide that plays a role in reproductive tract host defense and male fertility.

Animals↗

PubMed2001

Pathomorphological and quantitative bacteriological findings in various forms of primary surgery on gunshot wounds of extremities.

It is well-known that 'wound excision' is essential in the primary treatment of wounds in war, particularly thorough debridement of the devitalized tissues around the path of a penetrating projectile. Nowadays, the gunshot wounds in peacetime have become prevalent. Instead of the traditional method of 'wound excision' (excision), we used the method of 'incision and drainage' (incision) in the primary surgery of these gunshot wounds of extremities. To determine the treatment effectiveness of these different surgical methods (incision and excision), two groups of dogs were shot in the proximal part of one hind leg with an American M-16 rifle. One group was treated by the method of 'excision'; in the other group 'incision' were performed. No difference in infection rate was noted between the two groups. Similarly, no difference in bacterial count was found between the two groups during the observation period. Also, there was no difference in healing time; the wounds in both groups had healed by 19.2-21.4 days. Microscopic examination revealed a little normal muscle tissue in the necrotic zone of the incision group which might augment the repair process. These results suggest that there are no differences in the effectiveness in preventing infection between the two methods. 'Incision' might be superior to 'excision' for the management of the gunshot wounds of extremities in peacetime, as it involves a simple operation and there are advantages for tissue healing.

Animals↗

PubMed2001

Terbinafine-associated inhibition of dextromethorphan metabolism in Chinese subjects.

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Adult↗

PubMed2001

Intestinal expressions of eNOSmRNA and iNOSmRNA in rats with acute liver failure.

AIM: To observe the gene expression change of eNOSmRNA and iNOSmRNA in the small and large intestines with acute liver failure (ALF), and to reveal the biological function of NO on the pathogenesis of ALF and multiple organs dysfunction at the molecular level. METHODS: Sixty male Wistar rats were selected, weighing from 250g to 350g, and divided into 5 groups randomly: SO, ALF (6h, 12h), L-Arg, L-NAME, L-Arg and L-NAME, each group with 10 rats. The dose of L-Arg was 300mg.kg(-1), and L-NAME was 30mg.kg(-1), the reagents diluted by normal saline were injected through tail vein 30 minutes pre and post operation. The rats in the ALF group were respectively sacrificed postoperatively at 6h, 12h, and the rats in the other groups were sacrificed postoperatively at 6h. The tissues of small and large intestines were harvested in 4% paraforaldehyde containing the reagent of DEPC and fixed at 6h, embedded in paraffin, and 4 microm section was cut. The expression of eNOSmRNA and iNOSmRNA in these tissues was determined with in situ hybridization, and analyzed with the imaging analysis system of CMM-3 and SPSS statistical software. RESULTS: The expression of eNOSmRNA in the large intestine and iNOSmRNA in the small and large intestines increased significantly at 6h after ALF, but the expression of iNOSmRNA in the small and large intestines reduced notably at 12h after ALF (P<0.05); the expression of eNOSmRNA in the large intestine and iNOSmRNA in the small and large intestines decreased significantly with the reagents of L-Arg at 6h ALF, but the expression of eNOSmRNA and iNOSmRNA in the small and large intestines decreased totally with the reagents of L-NAME or association with L-Arg 6h ALF. CONCLUSION: The expression of eNOSmRNA in the large intestine increased notably at the early stage of ALF, NO induced by the enzyme of eNOS from the transplantation of eNOSmRNA can protect the function of the large intestine, the high expression of iNOSmRNA is involved in the damaged function of the small and large intestines. NO precursor can reduce the expression of iNOSmRNA in the small and large intestines and the damage to intestines; NOS inhibitor or association with NO pre-cursor can totally lower the expression of eNOSmRNA and iNOSmRNA in the small and large intestines, it cannot notably influence the NOS inhibitor in the gene expression of eNOSmRNA and iNOSmRNA to supply the additional NO precursor.

Acute Disease↗

PubMed2001

Simultaneous modeling of pharmacokinetics and pharmacodynamics of propafenone in healthy subjects.

AIM: To study the simultaneous modeling of pharmacokinetics and pharmacodynamics (PK-PD) of propafenone (Pro) in healthy subjects. METHODS: Ten healthy Chinese volunteers, 5 extensive metabolizers (EM) and 5 intermediate metabolizers (IM) of CYP2D6, received a single dose (400 mg) of Pro hydrochloride. The blood samples and electrocardiogram (ECG) measurements were taken after administration over 15 h period. The concentrations of Pro in plasma were measured by a reverse-phase HPLC. PR interval was used as an average value of 10 PR interval measurements. RESULTS: There was a delay between Pro level and percentage of PR interval prolongation. After PK-PD simulating, the relationship between effect concentration (Ce) and the effect met the sigmoid E(max) model. CYP2D6 (EM & IM) played an important role in both pharmacokinetics and pharmacodynamics which produced by Pro. The AUC (microg . h . L-1) of IM group was significantly higher than that of EM group (5126 +/- 1030 vs 2948 +/- 1230, P < 0.05). Whereas Ce50 (microg/L) was also greater in IM group than in EM group (747 +/- 281 vs 359 +/- 123, P < 0.05). On the other hand, gamma of EM group was about one fold larger than that of IM group (P < 0.05). CONCLUSION: CYP2D6 phenotype of human may influence not only pharmacokinetic of Pro but also its pharmacological effects.

Adult↗

PubMed2001

Correlation between decrease of 11beta-hydroxysteroid dehydrogenase activity and hypokalemia induced by furosemide in rats.

AIM: To investigate the correlation between decrease of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity and hypokalemia induced by furosemide (Fur) in rats. METHODS: SD rats were given single dose or successive doses of Fur by gavage. The activity of 11beta-HSD was evaluated by measuring the ratio of 11-dehydrocorticosterone (A) and corticosterone (B) in urine and conversion rate of B to A in renal cortex microsome preparation was determined with HPLC. RESULTS: After giving single dose of Fur (40, 100, and 250 mg/kg) or multiple doses of Fur (10, 20, and 100 mg/kg, bid x 20 d), the ratio of A/B was reduced by 29.0 %, 58.6 %, and 60.9 % at 0 - 2 h; 14.4 %, 36.0 %, and 44.9 %, respectively; the conversion rate of B to A was decreased by 29 %, 33 %, and 37 %; 6 %, 17 %, and 23 %, respectively. The serum potassium was significantly reduced by multiple doses of Fur (20 and 100 mg/kg, bid x 20 d) (P < 0.01). The reduction in serum potassium was positively correlated with the lowering of A/B ratio and the conversion of B to A (P < 0.01). CONCLUSION: The inhibition of renal 11beta-HSD activity may be another new biochemical mechanism for hypokalemia induced by Fur.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed1999

Fluoxetine impairs the CYP2D6-mediated metabolism of propafenone enantiomers in healthy Chinese volunteers.

OBJECTIVE: To determine the effect of 20 mg/day fluoxetine on the pharmacokinetics of propafenone enantiomers and CYP2D6 activity by phenotyping with dextromethorphan. METHODS: Nine healthy Chinese volunteers (seven men and two women) were included in a two-phase study. Dextromethorphan (20 mg) was given before and after subjects took 20 mg/day fluoxetine for 10 days, and the dextromethorphan metabolic ratio was calculated to determine CYP2D6 phenotype. Pharmacokinetic studies of propafenone enantiomers after a single oral 400 mg dose before and after pretreatment with 20 mg/day fluoxetine for 10 days were also conducted in these subjects. Reversed-phase HPLC with precolumn derivatization was used to determine enantiomeric concentrations of propafenone in plasma. RESULTS: Mean CYP2D6 dextromethorphan metabolic ratios before and after fluoxetine therapy were 0.028 +/- 0.031 and 0.080 +/- 0.058, respectively (P = .001), indicating that a strong inhibition of CYP2D6 by fluoxetine activity was observed in Chinese subjects. Propafenone metabolism was also impaired significantly after fluoxetine treatment. The elimination half-life, peak concentration, and area under the curve from 0 hours to infinity of two enantiomers after fluoxetine therapy were significantly increased compared with those at baseline (P < .01), whereas oral clearance decreased from 75.01 +/- 17.69 L/h to 49.36 +/- 8.62 L/h for S-propafenone (P = .005) and from 107.62 +/- 33.82 L/h to 70.60 +/- 12.42 L/h for R-propafenone (P = .027). In addition, fluoxetine increased the peak concentration of S-propafenone by 39% and that of R-propafenone by 71% (P < .05). A significant increase of the time to reach peak concentration was observed only in the R-enantiomer and not in the S-enantiomer of propafenone after fluoxetine therapy. There were no differences in the percentage changes of PR and QRS intervals before or after fluoxetine pretreatment at the time observed (P > .05). CONCLUSION: We conclude that fluoxetine may cause significant inhibition of the CYP2D6 activity as determined by dextromethorphan phenotyping. This inhibition impairs the metabolism of propafenone enantiomers in Chinese subjects. Caution must be exercised when fluoxetine and propafenone are coadministered to avoid potential toxicity.

Administration, Oral↗

PubMed1999

The influence of CYP2D6 activity on the kinetics of propafenone enantiomers in Chinese subjects.

AIMS: To determine role of CYP2D6 activity in the pharmacokinetics of propafenone (PPF) enantiomers in native Chinese subjects. METHODS: Sixteen extensive metabolizers (EMs) and one poor metabolizer (PM), whose phenotype had been previously assessed with dextromethorphan metabolic phenotyping, were enrolled. Blood samples (0 approximately 15 h) were taken after oral administration of a single dose (400 mg) of racemic-propafenone hydrochloride. A reverse-phase h.p.l.c. method with pre-column derivatization was employed to quantitate enantiomeric concentrations of propafenone in plasma. RESULTS: For the EM subjects, S-PPF was less rapidly metabolized and had higher peak plasma concentrations than R-PPF (413+/-143 vs 291+/-109 ng ml-1, P<0.001). The AUC was markedly higher for S-PPF than for R-PPF (2214+/-776 vs 1639+/-630 microg h l-1, P<0.001), whereas the clearance of S-PPF was significantly lower than that of R-PPF (96.0+/-39.0 vs 138+/-78 l h-1, P<0.01). There were no differences in t1/2, and Cmax between the two isomers (P >0.05). In the one PM subject, not only did S-PPF appear to undergo less rapid metabolism than R-PPF, but the subject also showed 2 approximately 3 fold differences in Cmax, CL and AUC compared with EMs. The correlation coefficients (rs ) between dextromethorphan metabolic ratio (lg MR) and pharmacokinetic parameters (Cmax, CL and AUC) were 0.63, -0.87, 0.87 for S-PPF and 0. 57, -0.73, 0.86 for R-PPF, respectively. CONCLUSIONS: Our results suggest that CYP2D6 activity contributes to the pharmacokinetic variability of propafenone enantiomers in Chinese subjects.

Administration, Oral↗

PubMed1999

CYP2D6 phenotype determines pharmacokinetic variability of propafenone enantiomers in 16 HAN Chinese subjects.

AIM: To determine the role of the CYP2D6 phenotype in the metabolism of propafenone (Pro) enantiomers in 16 HAN Chinese subjects. METHODS: Seven very extensive metabolizers (VEM) and nine intermediate metabolizers (IM) were enrolled from a Chinese population whose phenotype had been previously assessed with a dextromethorphan metabolic phenotyping. The blood samples (0-15 h) were taken after oral administration of a single dose (400 mg) of rac-Pro hydrochloride. Enantiomeric concentrations of propafenone in plasma were measured by a reverse-phase HPLC with precolumn derivatization. RESULTS: S-Pro was less metabolized and had higher plasma concentrations than R-Pro in both CYP2D6 phenotypes. Besides, the T1/2 of R-Pro was longer than that of S-Pro in IM, but not in VEM. However, there were significant differences in the metabolism of Pro enantiomers between VEM and IM. The Cmax and AUC of both isomers in the IM group were higher than those in the VEM group (P < 0.01). The Cl of Pro enantiomers in IM group was only about half of that in VEM group [(67 +/- 17) vs (133 +/- 28) L.h-1 for S-Pro, (90 +/- 24) vs (200 +/- 87) L.h-1 for R-Pro, P < 0.01]. The S/R ratios of T1/2, Tmax, Cmax, Cl, and AUC were not significantly different (P > 0.05). CONCLUSION: CYP2D6 phenotype determines the pharmacokinetic variability of propafenone enantiomers and existence of IM may be relevant to diminished capacity of CYP2D6 enzyme in Chinese subjects.

Adult↗

PubMed1999

Pharmacokinetics of sustained-release capsule of 5-isosorbide mononitrate in 20 healthy Chinese young men.

AIM: To compare the pharmacokinetics of domestic and imported sustained-release capsule of 5-isosorbide mononitrate (5-IM). METHODS: A single and 5-d-repeated oral doses of 5-IM 50 mg were performed on 2 groups of 20 Chinese healthy subjects (10 subjects for each group) in a randomized crossover protocol. The 5-IM in plasma were measured by gas chromatography with electron-captured detector method. Data were analyzed automatically by using a CAPP program on a PC computer. RESULTS: Fitting the 5-IM concentration-time curves to one-compartment model or following trapezoidal rule, the parameters such as Tmax, Cmax, Ke, MRT, and AUC were calculated and there were no significant differences between the two kinds of capsule. The major pharmacokinetic parameters of domestic and imported 5-IM sustained-release capsule with a 5-d multiple dose were respectively: Cmax (677 +/- 103) and (702 +/- 76) micrograms.L-1; Tmax (5.1 +/- 2.0) and (5.6 +/- 1.3) h; MRT (11.5 +/- 0.5) and (11.4 +/- 0.7) h; AUC0-infinity (12,121 +/- 1346) and (12,352 +/- 988) micrograms.h.L-1. The fraction of drug absorbed in vivo was correlated well with the percentage amount of drug released in vitro at corresponding time (P < 0.05), and the fluctuation indices on d 5 in multiple dose study were not significantly different between the two formulations (P > 0.05). The relative bioavailability of the domestic capsule for single and multiple dose were 96% +/- 11% and 98% +/- 10%, respectively. CONCLUSION: Domestic 5-IM sustained-release capsule showed bioequivalence compared with the imported capsule and provided the same nitrate-low interval in the latter part of the 24-h dosing interval.

Adult↗

PubMed1998

Stereoselective metabolism of metoprolol in isolated rat liver.

AIM: To study the stereoselective pharmacokinetics of the enantiomers of metoprolol (Met). METHODS: The enantiomers of Met were metabolized in isolated rat liver with hemoglubin-free medium. The enantiomers of Met were analyzed with HPLC. RESULTS: The linear kinetics were found in 3 doses (0.16, 0.32, and 0.64 mg) of R-(+)- and S-(-)-Met. The time-concentration curve of Met was fitted in first order-kinetics compartment model. There were differences in the pharmacokinetic parameters (K, T1/2, and Cl) between the enantiomers at the same dose (P < 0.01). The ratio of liver clearence of S-(-)-Met/R-(+)-Met was 0.14-0.17. CONCLUSION: Pharmacokinetics of enantiomers of Met in the isolated rat liver were stereoselective, with a preferential clearance of R-(+)-Met, which elimination was not a saturable process.

Adrenergic beta-Antagonists↗

PubMed1997

Inhibition of 11 beta-hydroxysteroid dehydrogenase obtained from guinea pig kidney by some bioflavonoids and triterpenoids.

AIM: To study the inhibitory effect of some bioflavonoids and triterpenoids on 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) from guinea pig kidney. METHOD: The 11 beta-OHSD of kidney cortex microsomes in addition of cortisol was incubated in the presence of NADP, Triton DF-18, and the test compounds at 37 degrees C for 1 h. The enzyme activity was assayed by measuring the rate of conversion of cortisol to cortisone eluted with HPLC gradient analysis. RESULTS: The IC50 (95% confidence limits) values of glycyrrhizic acid, naringenin, fisetin, emodin were 254 (202-320), 336 (270-418), 470 (392-564), and 527 (425-653) mumol.L-1, respectively. The inhibitory effect of oleanolic acid was 2-fold stronger than that of astramembranin I. The mode of action of naringenin was competitive inhibition. CONCLUSION: The test compounds inhibited the 11 beta-OHSD in kidney cortex with different potencies as glycyrrhizic acid did.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1997

Pharmacokinetic-pharmacodynamic modeling of metoprolol stereoisomers in spontaneously hypertensive rat.

AIM: To study the combined pharmacokinetic-pharmacodynamic (PK-PD) model of metoprolol stereoisomers, and compare their inhibitory effects on cardiovascular system in the spontaneously hypertensive rats (SHR). METHODS: The drug concentration in plasma was measured by the reversed phase HPLC and the drug effects were recorded by polygraph. The pharmacokinetic parameters and the PK-PD model parameters were calculated. RESULTS: The plasma concentration-time profiles were adequately described by two-compartment model. Differences of Vd between (+)-Met and (-)-Met were found. The relationships between effects and concentration of effect compartment were represented by the sigmoid-Emax model. The Css50 of Vmax, dp/dtmax, and HR inhibitory effects of (+)-Met were larger than those of (-)-Met. CONCLUSION: Stereo-selective drug distribution and different potencies of the inhibitory effects of (+)-Met and (-)-Met existed in SHR.

Adrenergic beta-Antagonists↗