Glutamate Activates the Histaminergic Tuberomammillary Nucleus and Increases Wakefulness in Rats.

Glutamate is the major excitatory neurotransmitter in the brain and plays an essential role in regulating wakefulness. Histaminergic neurons, which are exclusively localized in the tuberomammillary nucleus (TMN) of the hypothalamus, have a pivotal role in the regulation of sleep-wake patterns by sending widespread projections into many brain areas implicated in sleep-wake control. The role of glutamate in histaminergic neurons within the TMN and the resulting sleep-wake profile remains unknown. We found that glutamate, NMDA, AMPA or dihydrokainate, a glutamate-uptake inhibitor, dose-dependently increased wakefulness when microinjected into the rat TMN. Glutamate, NMDA, and AMPA also increased the firing rate of action potentials in TMN histaminergic neurons. The arousal-promoting effect of glutamate was inhibited by NMDA and histamine H1 receptor antagonists. Furthermore, MK-801, an NMDA receptor antagonist, inhibited the firing rate of histaminergic neurons and increased non-rapid eye movement sleep after microinjection into rat TMN. Taken together, these findings demonstrated that glutamate activated histaminergic neurons in the TMN and increased wakefulness in rats, possibly via the action of NMDA and histamine H1 receptors.

Paeoniflorin exerts analgesic and hypnotic effects via adenosine A1 receptors in a mouse neuropathic pain model.

RATIONAL: Neuropathic pain is frequently comorbid with sleep disturbances. Paeoniflorin, a main active compound of total glucosides of paeony, has been well documented to exhibit neuroprotective bioactivity. OBJECTIVE: The present study evaluated effects of paeoniflorin on neuropathic pain and associated insomnia and the mechanisms involved. METHODS: The analgesic and hypnotic effects of paeoniflorin were measured by mechanical threshold and thermal latency, electroencephalogram (EEG) and electromyogram, and c-Fos expression in a neuropathic pain insomnia model. RESULTS: The data revealed that paeoniflorin (50 or 100 mg/kg, i.p.) significantly increased the mechanical threshold and prolonged the thermal latency in partial sciatic nerve ligation (PSNL) mice. Meanwhile, paeoniflorin increased non-rapid eye movement (NREM) sleep amount and concomitantly decreased wakefulness time. However, pretreatment with l,3-dimethy-8-cyclopenthylxanthine, an adenosine A1 receptor (R, A1R) antagonist, abolished the analgesic and hypnotic effects of paeoniflorin. Moreover, paeoniflorin at 100 mg/kg failed to change mechanical threshold and thermal latency and NREM sleep in A1R knockout PSNL mice. Immunohistochemical study showed that paeoniflorin inhibited c-Fos overexpression induced by PSNL in the anterior cingulate cortex and ventrolateral periaqueductal gray. CONCLUSIONS: The present findings indicated that paeoniflorin exerted analgesic and hypnotic effects via adenosine A1Rs and might be of potential use in the treatment of neuropathic pain and associated insomnia.

Combination of active components of Xiexin decoction ameliorates renal fibrosis through the inhibition of NF-κB and TGF-ß1/Smad pathways in db/db diabetic mice.

Xiexin decoction, a herbal therapeutic agent commonly used in traditional Chinese medicine, is recognized for its beneficial effects on diabetic nephropathy exerted through the combined action of multiple components, including Rhizoma Coptidis alkaloids (A), Radix et Rhizoma Rhei polysaccharides (P), and Radix Scutellaria flavones (F). Our previous studies have shown that a combination of A, P, and F (APF) exhibits renoprotective effects against diabetic nephropathy. This study was aimed at determining the effects of APF on renal fibrosis in diabetic nephropathy and elucidating the underlying molecular mechanisms. To evaluate the effects of APF, in vivo, db/db diabetic mice were orally administered a low or high dose of APF (300 or 600 mg/kg, respectively) once a day for 8 weeks. We evaluated the blood and urine indices of metabolic and renal function, renal tissue histopathology, renal inflammation, and fibrosis. APF treatment significantly ameliorated glucose and lipid metabolism dysfunction, decreased urinary albumin excretion, normalized creatinine clearance, and reduced the morphological changes in renal tissue. Additionally, APF administration in db/db diabetic mice reduced the elevated levels of renal inflammation mediators such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin-1ß, and active nuclear factor κB (NF-κB). APF treatment also reduced type I and IV collagen, transforming growth factor-ß1 (TGF-ß1), and TGF-ß1 type II receptor expression levels, and decreased the phosphorylation of Smad2/3 in the kidneys of db/db diabetic mice. These results suggest that APF reduces renal fibrosis in diabetic nephropathy through the NF-κB and TGF-ß1/Smad signaling pathways. In vitro, APF treatment reduced cell proliferation and protein expression of α-smooth muscle actin, collagen I, TGF-ß1 and NF-κB in mesangial cells cultured with high glucose concentrations. Our findings indicate that treatment with multi-component herbal therapeutic formulations may be a useful approach for the treatment of diabetic nephropathy.

[Proteomic study on effect of tangcao pill on microsome CYP450].

Tangcao pill is commonly applied in adjuvant and even alternative therapy for patients with AIDS. However, the herb contains complex ingredients, but with unknown effect against anti-HIV drug and unknown function. Because CYP450 emzyme is the main metabolic enzymes of the drug, it is of important significance to study the regulation of CYP450 enzymes before and after the combined administration of Tangcao pill and EFV. Proteomics, due to its high throughout and high sensitivity, has been widely applied in CYP450 enzyme study. In this paper, liver microsomes were separated through differential centrifugation. Their proteins were separated through SDS-PAGE. The three protein bands that CYP450 enzymes were located were cut and identified by liquid chromatography tandem mass spectrometry. Totally 16 CYP450 isoenzymes were identified. Furthermore, in order to make a quantitative analysis on the effect of tang herb on CYP450 emzyme, the multiple reaction monitoring (MRM) technology based on MS was adopted. The CYP2C11 was selected based on the results of the mass spectrum identification of proteins. The characteristic polypeptides were obtained through searching Expasy blast database. The m/z of the fragment ions was less than 800. In the paper, the m/z of ion pairs of CYP2C11 were 711.5/232.1, 711.5/319.2, 711.5/466.2 and 711.5/595.3, and the m/z of ESAT-6 (internal standard, IS) were 735.5/215.3, 735.5/389.3, 735.5/460.3 and 735.5/524.3. The relative peak (analyte/IS) area was adopted for the relative quantitative analysis. Compared with the EFV single administration group, the EFV and Tangcao pill combined administration group showed a 1.6-fold increase in CYP2C11. The results of the paper indicated that Tangcao pill may affect drug metabolism by regulating metabolic enzymes such as CYP2C11, but the specific mechanism still unknown.

Effects of combinations of Xiexin decoction constituents on diabetic nephropathy in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiexin decoction (XXD) has been used as a treatment for diabetes mellitus for more than 1300 years. XXD constituents with protective effects against diabetic nephropathy (DN) include Rhizoma Coptidis alkaloids (RA), Radix et Rhizoma Rhei polysaccharides (RP), and Radix Scutellaria flavones (RF). The aim of the study is to investigate the effects of combinations of RA, RP, and RF on DN and their mechanisms of action. MATERIALS AND METHODS: In vitro, high glucose-induced rat mesangial cells were treated with RA, RP, RF, and combinations thereof. Cell proliferation and levels of inflammatory factors were measured. In vivo, high-fat diet and streptozotocin-induced diabetic rats were treated with different combinations of RA, RP, and RF once per day for 12 weeks. Blood and urine biochemical parameters, renal tissue morphology, and inflammation were investigated. RESULTS: In vitro, the combination of the three groups of components inhibited mesangial cell proliferation and reduced the levels of monocyte chemotactic protein-1 (MCP-1) and collagen IV. The effects of the three constituent groups in combination were stronger than those of each group alone or combinations of two groups. In diabetic rats, combinations of the three groups of herb components ameliorated blood glucose, urinary albumin excretion and decreased renal mesangial matrix expansion and basement membrane thickening. In addition, the combinations reduced renal tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) protein levels, down-regulated the expression of nuclear factor κB (NF-κB) and transforming growth factor beta 1 (TGF-ß1), and up-regulated the expression of inhibitor of nuclear factor κB (IκB) protein. Among the three groups of herb components, RA produced the strongest effects, followed by RP, and then by RF. CONCLUSIONS: The combination of the three groups of herb components produced anti-DN effects through inhibition of inflammation mediated by NF-κB. Among the three groups of herb components, RA produced the strongest effect while RP and RF produced weaker effects.

Piromelatine exerts antinociceptive effect via melatonin, opioid, and 5HT1A receptors and hypnotic effect via melatonin receptors in a mouse model of neuropathic pain.

RATIONALE: An effective and safe treatment of insomnia in patients with neuropathic pain remains an unmet need. Melatonin and its analogs have been shown to have both analgesic and hypnotic effects; however, capacity of them on sleep disturbance with neuropathic pain as well as the precise mechanism is unclear. OBJECTIVE: The present study evaluated effects of piromelatine, a novel melatonin receptor agonist, on sleep disturbance in a neuropathic pain-like condition as well as the underlying mechanisms. METHODS: A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSL) was employed. The antinociceptive and hypnotic effects of piromelatine were evaluated by measurement of thermal hyperalgesia, mechanical allodynia, and electroencephalogram (EEG) recordings in PSL mice. Pharmacological approaches were used to clarify the mechanisms of action of piromelatine. RESULTS: PSL significantly lowered thermal and mechanical latencies and decreased non-rapid eye movement (NREM) sleep, and PSL mice exhibited sleep fragmentation. Treatment with 25, 50, or 100 mg/kg of piromelatine significantly prolonged thermal and mechanical latencies and increased NREM sleep. Moreover, the antinociceptive effect of piromelatine was prevented by melatonin antagonist luzindole, opioid receptor antagonist naloxone, or 5HT1A receptor antagonist WAY-100635. The hypnotic effect of piromelatine was blocked by luzindole but neither by naloxone nor WAY-100635. CONCLUSIONS: These data indicate that piromelatine is an effective treatment for both neuropathic pain and sleep disturbance in PSL mice. The antinociceptive effect of piromelatine is likely mediated by melatonin, opioid, and 5HT1A receptors; however, the hypnotic effect of piromelatine appears to be mediated by melatonin receptors.

Renal Protective Role of Xiexin Decoction with Multiple Active Ingredients Involves Inhibition of Inflammation through Downregulation of the Nuclear Factor-κB Pathway in Diabetic Rats.

In Chinese medicine, Xiexin decoction (XXD) has been used for the clinical treatment of diabetes for at least 1700 years. The present study was conducted to investigate the effective ingredients of XXD and their molecular mechanisms of antidiabetic nephropathy in rats. Rats with diabetes induced by high-fat diet and streptozotocin were treated with XXD extract for 12 weeks. XXD significantly improved the glucolipid metabolism disorder, attenuated albuminuria and renal pathological changes, reduced renal advanced glycation end-products, inhibited receptor for advanced glycation end-product and inflammation factors expression, suppressed renal nuclear factor- κ B pathway activity, and downregulated renal transforming growth factor- ß 1. The concentrations of multiple components in plasma from XXD were determined by liquid chromatography and tandem mass spectrometry. Pharmacokinetic/pharmacodynamic analysis using partial least square regression revealed that 8 ingredients of XXD were responsible for renal protective effects via actions on multiple molecular targets. Our study suggests that the renal protective role of XXD with multiple effective ingredients involves inhibition of inflammation through downregulation of the nuclear factor- κ B pathway, reducing renal advanced glycation end-products and receptor for advanced glycation end-product in diabetic rats.

[Dual effects of extract of Schisandra chinensis Baill on rat hepatic CYP3A].

This study is to investigate the effects of aqueous extract of Schisandra chinensis Baill (WWZ), kadsurin, schisandrin A, schisandrin B and schisandrol B on rat hepatic CYP3A. Rats received a daily gavage of aqueous extract of WWZ for different times. The livers were harvested after gavage and subjected to microsome preparation. Microsomal CYP3A activity was determined by measuring the amount of the metabolite of testosterone (6 beta-hydroxytestosterone) with HPLC. Aqueous extract of WWZ, kadsurin and schisandrin A were incubated with microsomes obtained from rat. Microsomal CYP3A activity was determined by HPLC. Primary hepatocytes were separated and extracted from rat, then were treated with aqueous extract of WWZ, schisandrin A, schisandrin B and schisandrol B. Then, the expression of CYP3A1 mRNA was analyzed by RT-PCR. As for the in vivo assay, aqueous extract of WWZ significantly inhibited the enzyme activity of CYP3A after 12 h gavage. The inhibitory effect was converted to inductive effect after 3-day gavage. Aqueous extract of WWZ could induce the enzyme activity of CYP3A after 6-day gavage. Aqueous extract of WWZ and kadsurin showed a dose-dependent inhibition of CYP3A (IC50 of 487.8 microg mL(-1) and 6.2 micromol L(-1), separately). In rat primary hepatocytes, aqueous extract of WWZ (2.5 mg mL(-1)), schisandrin A (0.1 micromol L(-1)), schisandrin B (0.1 micromol L(-1)) and schisandrol B (10 micromol L(-1)) increased significantly the expression of CYP3A1 mRNA by 23%, 55%, 42% and 27%, respectively. Aqueous extract of WWZ could show dual effect on the enzyme activity of CYP3A in rat in vivo. Meanwhile, kadsurin showed a dose-dependent inhibition of the enzyme activity of hepatic CYP3A in vitro. And schisandrin A, schisandrin B and schisandrol B showed significant inductive effect on the expression of rat CYP3A1 mRNA.

Study of the process of secondary failure of sulphonylurea by a Markov model.

PURPOSE: The study was to reflect and forecast the evolutive tendency and influence factors of secondary failure of sulphonylurea (SFS) changing with time by using a Markov (MKV) model in the elderly diabetic population in Shanghai. METHODS: A total of 549 patients with elderly diabetes mellitus (DM) were enrolled and grouped in the study. A door-to-door retrospective epidemiological survey was used to collect data. The MKV model was used to assess the process and influence factors of SFS and the MKV process decision support system was adopted to calculate state probability of the MKV process. RESULTS: The rate of SFS in the group of all cases, FPG < or = 10 mmol . L(-1) before treatment and FPG > 10 mmol . L(-1) before treatment, taking single type of sulphonylurea (SU) and taking two types of SU and over respectively was 9.11%, 3.55%, 11.03%, 8.54% and 11.21%. The years of changing into the state of secondary failure in half patients was 5 years, 11-12 years, 4 years, 5 years, 4 years, respectively in the following groups: all cases, FPG < or = 10 mmol . L(-1) before treatment and FPG > 10 mmol . L(-1) before treatment, taking single type of SU and taking two types of SU and over. CONCLUSIONS: A MKV model could predict the long-term evolutive process of SFS by a short-term observation; the speed of SFS was related to the degree of DM patients' condition, patients with higher glucose levels prior to treatment would develop SFS faster; but we cannot postpone the development of secondary failure by exchanging SU types.

Increased secretion and expression of amylin in spontaneously diabetic Goto-Kakizaki rats treated with rhGLP-1 (7-36).

AIM: To investigate the effect of recombined human glucagon-like peptide 1 (rhGLP-1 [7-36]) on the secretion and expression of amylin in Goto-Kakizaki (GK) rats. METHODS: The GK rats were treated with rhGLP-1 (7-36) 56 and 133 mug/kg subcutaneously for 12 weeks. The fasting and post-prandial blood glucose levels were measured. The plasma amylin concentration was measured by ELISA. The transcription levels of amylin and insulin mRNA were evaluated by fluorescent-quantitative- PCR. Immunohistochemistry was utilized to detect the amylin protein. Histological examination was assayed by light microscopy. RESULTS: Treatment with rhGLP-1 (7-36) caused a significant reduction of post-prandial blood glucose levels in the GK rats (P<0.05). The plasma amylin levels of the GK rats were lower than those of Wistar rats after the glucose administration (P<0.01). Treatment with rhGLP-1 (7-36) exhibited a marked elevation of the glucose-stimulated plasma amylin level (P<0.05) and slight histological amelioration. The amylin expression was augmented in the rhGLP-1 (7-36)-treated GK rat pancreas. Amylin and insulin mRNA were also highly expressed in the treated GK rats (P<0.05). However, the ratio of amylin to insulin mRNA was significantly decreased by treatment with rhGLP-1 (7-36). CONCLUSION: RhGLP-1 (7-36) stimulates the secretion and expression of amylin, and exerts a beneficial effect on the ratio of amylin to insulin mRNA. These findings suggest that GLP-1 and GLP-1 analogs are ideal candidates for the treatment of type 2 diabetes.

Effect of esomeprazole and rabeprazole on intragastric pH in healthy Chinese: an open, randomized crossover trial.

BACKGROUND AND AIM: Esomeprazole is the S-isomer of omeprazole, with a stronger acid suppressive effect than omeprazole. This open, randomized crossover study was designed to evaluate the effect of esomeprazole and another proton-pump inhibitor, rabeprazole, on intragastric pH in healthy Chinese. METHODS: Thirty-six healthy volunteers (26 men and 10 women, aged between 20 and 31 years) were enrolled. Subjects were given either esomeprazole 40 mg (n = 18) or rabeprazole 10 mg (n = 18) orally once daily for 5 days during the first dosing period, then the other medicine at the set dosage for the second dosing period. The two periods were separated by a 14-day washout phase. The doses were chosen according to the State Food and Drug Administration of China for the treatment of acid-related diseases. Intragastric pH was continuously monitored for 24 h on days 1 and 5 of each dosing period. CYP2C19 genotypes were analyzed to identify the extensive metabolizers (EM) and poor metabolizers (PM). RESULTS: The percentage of time with intragastric pH >4 was significantly higher (P < 0.001) in subjects receiving esomeprazole than in those receiving rabeprazole in the first 4 h after administration of the first dose (70.65% vs 44.87%), at 24 h on day 1 (73.7% vs 54.8%) and at 24 h on day 5 (84.2% vs 76.2%). The median intragastric pH was also higher in subjects receiving esomeprazole than in those receiving rabeprazole in the first 6 h, day 1 and day 5 (P 4 for at least 16 h on day 1 (63.9% vs 33.3%) and on day 5 (88.9% vs 61.1%) was higher after administration of esomeprazole than after rabeprazole (both P < 0.05). On genotype analysis, 28 of the subjects were EM and eight were PM. Those who were PM tended to have a higher, albeit not statistically significant, percentage of time with intragastric pH >4 and the median 24-h intragastric pH than those who were EM. Both drugs were well tolerated. CONCLUSIONS: Esomeprazole 40 mg orally once daily is more effective and faster in increasing intragastric pH than rabeprazole 10 mg orally once daily, and thus offers a potential for improved efficacy in acid-related diseases.

Changes in brain interleukin-1beta following the coadministration of norfloxacin with biphenylacetic acid in rats.

We sought to determine the changes in brain interleukin-1beta (IL-1beta) following the coadministration of norfloxacin (25 mg/kg, i.p.) with biphenylacetic acid (100 mg/kg, p.o.) in rats. Norfloxacin provoked clonic convulsions in rats treated concomitantly with biphenylacetic acid, a major metabolite of the nonsteroidal anti-inflammatory drug fenbufen. Seizure activity was analyzed by EEG monitoring. Behavioral changes were also monitored. IL-1beta expressions in the prefrontal cortex and hippocampus at different time intervals were studied by reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The epileptiform discharges appeared in all the rats, accompanied with limb twitching and clonic-tonic seizures after administration of norfloxacin coadministered with biphenylacetic acid. Norfloxacin plus biphenylacetic acid-induced convulsions rapidly and transiently enhanced IL-1beta mRNA in the prefrontal cortex and hippocampus. IL-1beta mRNA expression in the prefrontal cortex and hippocampus was detected as soon as 30 min after norfloxacin injection, and decayed to control levels by 6 h. ELISA analysis revealed significant increase of the IL-1beta protein in the prefrontal cortex and hippocampus at 2 h and 6 h. Administration of either norfloxacin or biphenylacetic acid alone did not elicit convulsions and increase in IL-1beta mRNA and protein expressions. The results suggest that the increased IL-1beta expressions in the prefrontal cortex and hippocampus induced by norfloxacin with biphenylacetic acid relate to seizure activities, and that these brain regions play pivotal roles in norfloxacin-induced convulsions.

Assessment of quality of life and relevant factors in elderly diabetic patients in the Shanghai community.

PURPOSE: The study was to assess the quality of life (QOL) of the elderly diabetes mellitus (DM) in Shanghai community and to screen the possible risk factors. METHODS: A total of 951 patients with elderly DM and 1007 elderly subjects with normal glucose tolerance from the same community as control group were enrolled in the study. A door-to-door retrospectively epidemiological survey was used to collect data of QOL, demographic, and diabetic information. The SF-36 instrument (Chinese edition) was used to assess QOL. Multiple stepwise linear regression analysis was also used to identify possible risk factors of QOL in elder DM. RESULTS: In subjects with elderly DM, the general assessment of perceived health was worse, compared with the normal elderly people; the mean score of multi-item dimensions assessment had been decreased, the lowest and highest scores of which on SF-36, respectively, were general health and body pain (ranged from 42.08 to 77.00). Based on the multiple stepwise regression analysis, 23 risk factors entered 9 multiple regressive models (9 dependent variables of which stand for the scores of 8 dimensions and the total score on SF-36) with different amount ultimately. Within the 13 risk factors that affect QOL of the elderly diabetic patients, the negative correlated factors were gender, age, payment ability of medical treatment, tumor, level of fasting plasma glucose (FPG), medicines purchasing channels, diabetic microvascular complications, diabetic macrovascular complications, acute complications, while the positive correlated factors were occupation, income, exercises, knowledge of DM. The multiple correlation coefficient square (R2) represented the above 13 risk factors had a totally 30.5% impact on the entire QOL. CONCLUSIONS: QOL of elderly DM population had significantly been decreased; QOL of the elderly patients in Shanghai community had many risk factors, which on one hand stated the complexity of elderly DM, and on the other hand gave us many useful and practical methods to improve QOL of elderly DM.

Effect of pirenzepine ophthalmic solution on form-deprivation myopia in the guinea pigs.

BACKGROUND: Nonselective muscarinic receptor antagonist, atropine, was believed to inhibit myopic progression. The purpose of this study was to determine the efficacy, through topical administration, of the M1-selective muscarinic antagonist pirenzepine in preventing experimentally induced form-deprivation myopia in guinea pigs. METHODS: Fifty-three guinea pigs, which underwent monocular deprivation with their eyelids sutured, were divided into 6 groups. Three groups were treated with 1%, 2% or 4% pirenzepine ophthalmic solutions; the fourth group with atropine; the fifth with saline and the last group left untreated. Ocular refraction, in vivo biometric measurements and wet eye weight were collected before and after the experiment. All the eyes were finally enucleated for histopathological examination to evaluate the possible toxic effects on ocular structures. RESULTS: Animals untreated or treated with saline produced (-2.31+/-1.47) D and (-2.25+/-0.88) D of axial myopia respectively. Those treated with 1% pirenzepine ophthalmic solution produced relative myopia of (-1.63+/-0.48) D, and those under the treatment of 2% and 4% pirenzepine ophthalmic solution only developed a relative myopia of (-0.89+/-0.42) D and (-0.70+/-0.41) D (F=9.56, P<0.05). The significant reduction in myopia in 2% and 4% pirenzepine treated animals was caused by significantly less vitreous chamber elongation and axial elongation of the deprived eyes [2% group: (0.009+/-0.052) mm, 4% group: (0.006+/-0.078) mm] when compared with untreated, saline treated or 1% pirenzepine treated guinea pigs (0.057+/-0.056) mm, (0.064+/-0.053) mm and (0.033+/-0.035) mm, respectively]. Histological examinations revealed no obviously toxic effects on the eyes treated with pirenzepine. CONCLUSION: Topical administration of the M1-selective muscarinic antagonist, pirenzepine, can prevent induced form-deprivation myopia in guinea pigs by inhibiting axial elongation without obvious damage to ocular tissues.

[High risk factors of upper gastrointestinal bleeding after neurosurgical procedures].

OBJECTIVE: To analyze high risk factors of postoperative upper gastrointestinal (GI) bleeding after neurosurgery so as to give guidance for prevention of GI bleeding. METHODS: A questionnaire was developed to investigate the medical records of 1500 patients who were hospitalized and underwent neurosurgical operations in 1997. Logistic regression analysis was made. RESULTS: 1430 valid questionnaires were obtained. Postoperative upper GI bleeding occurred in 75 patients (5.24%). The incidence of upper GI bleeding were 6.64% (54/813) in the male patients and 3.40% (21/617) in the female persons (P = 0.007); 9.88% (41/415) in those aged > 50 and 3.35% in those aged < or = 50 (P = 0.001). Glasgow Coma Score less than 10 pre- and post-operation, the incidence of upper GI bleeding was more than 17.5% (14/80, pre-operation GCS 7-10) and 20.9% (14/67, pre-operation GCS 3-6), and 20.25% (16/79, first day of post-operation GCS 7-10) and 23.75% (19/80, first day of post-operation GCS 3-6). The incidence of upper GI bleeding of the patients with intracerebral hematoma, intraventricular hemorrhage, subdural hematoma, and extradural hematoma were 15.7%, 10.0%, 6.00%, and 2.94% respectively (P = 0.02). The incidence of upper GI bleeding of the patients with tumors of fourth ventricle of cerebrum, brainstem, cerebral hemisphere, and sellar hypothalamus were 15.79% (3/19), 7.89%, 5.71%, and 3.74% respectively. In the emergent cases, the incidence of upper GI bleeding was higher in those with hypertension. The incidence of upper GI bleeding was 5.46% in the patients undergoing adrenocortical hormone treatment, significantly higher than that in those who did not receive such treatment (2.13%). CONCLUSION: Patients who are at high risk of developing postoperative upper GI bleeding including that: age greater than 50 years; male; Glasgow Coma Score less than 10 pre and post operation; The lesion was located in brain stem and forth ventricle; Hypertensive cerebral hemorrhage; Intracerebral and intraventricular hemorrhagic brain trauma; Postoperative pneumonia, brain edema, encephalic high pressure, pyogenic infection of the central nervous system and other postoperative complications. The mortality of patients with postoperative upper GI bleeding was evidently higher than that of the patients without postoperative upper GI bleeding.

In vivo and in vitro chondrotoxicity of ciprofloxacin in juvenile rats.

AIM: To study the relationship between chondrotoxicity and toxicokinetics of ciprofloxacin (CPFX). METHODS: Rats, 4-week old, were treated with CPFX 0, 400, 800, and 1200 mg/kg ig once daily on seven consecutive days. The knee joint cartilage was examined histopathologically. The concentration of CPFX in venous blood and knee joint cartilage samples were determined by a microbioassay using Escherichia coli 44102. The effects of CPFX on proliferation of chondrocytes and secretion of soluble proteoglycans were determined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 1,9-dimethylmethylene blue (DMB) assay, respectively. RESULTS: Cartilage was severely lesioned after treatment with CPFX 800 or 1200 mg/kg for 7 d, such as matrix swelling and loss of chondrocytes. The thickness of cartilage was significantly decreased compared with the control group. The maximum serum concentration (Cmax), the area under the plasma concentration-time curve (AUC(0-infinity)), and concentration in cartilage was 16.3 +/- 2.1 mg/L, 97.2 +/- 12.3 mg x h x L(-1), and 13.4 +/- 2.8 microg x g(-1) and 21.8 +/- 2.5 mg/L, 143.1 +/- 22.3 mg x h x L(-1), and 20.3 +/- 3.5 microg x g(-1) after oral administration of CPFX 800 or 1200 mg/kg on d 1, respectively. The data on d 6 were similar with that on d 1. CPFX inhibited proliferation of chondrocytes and the secretion of soluble proteoglycans. CONCLUSION: CPFX concentrations in serum and cartilage could provide a better basis for risk assessment.

Risk factors of adverse drug reaction from non-steroidal anti-inflammatory drugs in Shanghai patients with arthropathy.

AIM: The study was to screen the possible risk factors of adverse drug reaction (ADR) induced by non-steroidal anti-inflammatory drugs (NSAIDs) in Shanghai patients with arthropathy. METHODS: The subjects were randomly selected from a database of outpatients with arthropathy from 9 main hospitals in Shanghai. A door to door retrospective epidemiological survey was used to collect demographic information about the patients, both individual and familial. This included data on their medical histories, lifestyle and dietary habits, history of smoking and alcohol consumption, history of drug therapy, quality of life (QOL) prior to NSAIDs intake, history of NSAIDs therapy and its ADR events, etc. Descriptive statistical methods and univariate analysis were also used to identify possible risk factors for ADRs induced by NSAIDs. RESULTS: Of the 1002 patients surveyed, the average length of NSAIDs intake was 2 years. ADR incidence from different NSAIDs was high, in a range from 46.7 %-66.2 %. In general, the candidate risk factors for ADRs were different for each NSAID. Each of the candidate risk factors were defined and studied in order to evaluate its role in the determination of ADRs from NSAIDs. "Family history of ADRs caused by NSAIDs" was found to be a significant risk factor for the four commonly used NSAIDs: meloxicam, diclofenac, nimesulide, and nabumetone. CONCLUSION: A retrospective epidemiological survey was useful in detecting the risk factors for ADRs caused by NSAIDs. The study found that different NSAIDs might have different risk factors and that there is no single risk factor universally applicable to all NSAIDs.

[Meta-analysis on the effect and adverse reaction on patients with osteoarthritis and rheumatoid arthritis treated with non-steroidal anti-inflammatory drugs].

OBJECTIVE: To observe the rate of efficacy and adverse drug reaction of non-steroidal anti-inflammatory drugs (NSAIDs) in the population with osteoarthritis and rheumatoid arthritis, based on available clinical data. METHODS: Using Meta analysis to evaluate the data of effect and safety profile of NSAIDs from 19 articles on randomized clinical trials published from 1990 to 2001 in Chinese journals. The total number of patients enrolled for evaluation on rates of effectiveness and adverse drug reaction were 1 732 and 2 925, respectively. RESULTS: Data on the effect and safety were comparatively heterogeneous among different kinds of NSAIDs. The effective rates (95% CI) were as follows: nabunetone, 66.7% (61.9% - 71.4%); meloxicam, 68.4% (59.2% - 77.6%); naproxen, 64.5% (59.8% - 69.1%); nimesulide, 79.8% (75.7% - 84.0%); ibuprofen, 77.2% (70.7% - 83.8%); diclofenac, 77.1% (69.2% - 85.0%); oxaprozin, 65.8% (59.5% - 72.0%). Rates of adverse drug reaction (95% CI) were as follows: nabunetone, 16.3% (12.5% - 20.0%); meloxicam, 10.2% (4.2% - 16.2%); naproxen, 29.2% (24.8% - 33.6%); nimesulide, 20.2% (16.0% - 24.3%); ibuprofen, 16.7% (14.7% - 18.8%); diclofenac, 19.3% (11.9% - 26.7%); oxaprozin, 12.7% (8.9% - 16.7%) respectively. CONCLUSION: The rates of effect and adverse reaction on patients having osteoarthritis and rheumatoid arthritis with NSAIDs treatment would largely depend on the drugs being used. Within 2 - 8 weeks of treatment, the effective rate and rate of adverse drug reaction with commonly used NSAIDs as nabumeton, meloxicam, etc., were 59.2% - 85.0% and 4.2% - 33.6%, respectively.

Neurotoxicity and toxicokinetics of norfloxacin in conscious rats.

AIM: To study the neurotoxicity and toxicokinetics of norfloxacin (NFLX) in freely moving rats. METHODS: Rats were assigned randomly to four treatment groups that received a single iv dose of 50, 100, 200 mg/kg of NFLX and 0.9 % saline, respectively. Electroencephalogram (EEG) was continuously recorded with a computerized system in freely moving rats. Venous blood samples were collected for determination of the NFLX concentration by microbioassay method with Escherichia coli 441102 as the test strain. Toxicokinetic parameters were determined from serum concentration-time data with the 3p97 program. RESULTS: (1) The epileptiform discharges appeared in all NFLX groups with different latent periods, accompanied with limb twitching and clonic-tonic seizures. The relative total power of the EEG increased. (2) Drug serum concentration-time curves of different doses conformed to a two-compartmental model. The values of clearance, volume of distribution, and terminal half-life were dose-independent, while maximum serum concentrations (Cmax) and the areas under the concentration-time curve (AUC(0-infinity)) of NFLX increased with dosage. (3) The relative total powers of EEG were closely correlated with the administered dose, Cmax as well as AUC(0-infinity). CONCLUSION: The present study established a suitable approach to quantitatively determine central nervous system (CNS) stimulant effect of NFLX. There is a significant correlation between AUC(0-infinity) and the changes of relative total power, which may serve as the index for judgement and prediction of the CNS toxic effect induced by NFLX.

Inhibition by fluoroquinolones of K(+) currents in rat dissociated hippocampal neurons.

The effects of four fluoroquinolones (sparfloxacin, fleroxacin, ofloxacin and levofloxacin) on K(+) currents were investigated in pyramidal neurons acutely isolated from rat hippocampus, to evaluate their relative potencies for inhibiting these channels. Using patch-clamp electrophysiological techniques, we found that all four compounds inhibited the delayed rectifier K(+) current (I(K)), but with different potencies. Sparfloxacin was the most potent compound, displaying an IC(50) value of 6.44 x 10(-4) M, followed by fleroxacin, ofloxacin and levofloxacin, their IC(50) values being 7.09 x 10(-3), 8.42 x 10(-3) and 1.10 x 10(-2) M, respectively. In contrast, the fast transient K(+) current (I(A)) was blocked only by sparfloxacin (IC(50)=2.86 x 10(-3) M) and fleroxacin (IC(50)=4.38 x 10(-3) M), but not by ofloxacin and levofloxacin even at concentrations up to 1 mM. The K(+) current inhibition was reversible after washout of the compounds. Further study is needed to clarify the possible involvement of this novel action in the adverse effects of fluoroquinolones in the central nervous system (CNS).