Effect of Bakumondo-to on cytochrome P450 activities in rat liver microsomes

AbstractBakumondo-to is a traditional herbal medicine. It has been widely used for the treatment of chronic airway diseases. Recently, it was reported that several herbal medicines affected cytochrome P450 (CYP). However, there is little information about the effects of Bakumondo-to on CYP activities. In this study, we evaluated the effects of Bakumondo-to on CYP activities in rat liver microsomes. Rats were orally treated twice a day with Bakumondo-to at doses of 2.0g/kg body weight/day for 4days. CYP activities were determined in liver microsomes isolated from treated rats. CYP1A2, CYP2C, and CYP3A activities were measured using their specific substrates [7-methoxyresorufin, 7-methoxy-4-(trifluoromethyl)-coumarin, and 7-benzyloxyquinoline, respectively]. Bakumondo-to decreased CYP1A2 activity by 42.5±7.8%, increased CYP2C activity by 158.0±29.6%, and decreased CYP3A activity to 81.5±7.8% of the control level. Activities were expressed as percentages of the control.Bakumondo-to induced CYP2C activity and decreased CYP1A2 activity; it may cause drug-herbal interactions. It is suggested that combinations of Bakumondo-to and drugs that are metabolized by CYP1A2 and CYP2C should be carefully used in clinical settings

Injury due to extravasation of thiopental and propofol: Risks/effects of local cooling/warming in rats

AbstractInadvertent leakage of medications with vesicant properties can cause severe necrosis in tissue, which can have devastating long-term consequences. The aim of this study was to evaluate the extent of extravasation injury induced by thiopental and propofol, and the effects of cooling or warming of local tissue on extravasation injury at macroscopic and histopathologic levels. Rats were administered intradermally thiopental (2.5mg/100µL) or propofol (1.0mg/100µL). Rats were assigned randomly to three groups: control (no treatment), cooling and warming. Local cooling (18–20°C) or warming (40–42°C) was applied for 3h immediately after agent injection. Lesion sizes (erythema, induration, ulceration, necrosis) were monitored after agent injection. Histopathology was evaluated in skin biopsies taken 24h after agent injection. Thiopental injection induced severe skin injury with necrosis. Peak lesions developed within 24h and healed gradually 18–27 days after extravasation. Propofol induced inflammation but no ulceration, and lesions healed within 1–2 days. Local cooling reduced thiopental- and propofol-induced extravasation injuries but warming strongly exacerbated the skin lesions (e.g., degeneration, necrosis) induced by extravasation of thiopental and propofol. Thiopental can be classified as a “vesicant” that causes tissue necrosis and propofol can be classified as an “irritant”. Local cooling protects (at least in part) against skin disorders induced by thiopental and propofol, whereas warming is harmful

Pharmacokinetic Behavior of Cyclosporine A in Liver Dysfunction

The pharmacokinetic behavior of cyclosporine A (CyA), known as a potential immunosuppressive agent to prevent graft rejection in transplantation, was studied in patients with acute hepatitis and primary biliary cirrhosis (PBC). The ratios of blood concentration of total CyA (CyA and its metabolites), CyA, and CyA metabolites to dose/kg body weight, (t-CyA/dose, CyA/dose, and CyA-Met/dose, respectively) were significantly higher in patients with hepatitis than those in renal transplantation. In PBC patients these ratios showed a tendency to be smaller than those in renal transplantation, but were not significant. The ratio of CyA-Met/ CyA was higher in the patients with hepatitis and PBC than that in renal transplantation. It was highest in the patients with PBC. The ratio of CyA-Met/CyA was significantly increased with a decrease of liver functions evaluated by serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and total serum bilirubin (t-Bil). These results indicate that hepatic function affects the pharmacokinetic behavior of CyA and the increased ratio of CyA-Met/dose could be caused by a possible increased efflux of metabolites into the blood circulation due to impaired bile excretion. These results also indicate the importance of therapeutic drug monitoring (TDM) in the use of CyA with patients with hepatic dysfunction

Chronic inhibition of the norepinephrine transporter in the brain participates in the seizure sensitization to cocaine and local anesthetics

Involvement of chronic inhibition of monoamine transporters (MAT) in the brain concerning the sensitization of cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. Effects of 5 daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. The daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. The daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold with dose-dependent manner between 5 and 20 mg/kg. The daily treatments of citaloplam, a selective serotonin uptake inhibitor, 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and a norepinephrine transporter is an integral component of this sensitization

Inhibition of serotonin transporters by cocaine and meprylcaine

The present study examined whether the inhibition of serotonin transporters (SERT) contributes to cocaine- and other local anesthetics-induced convulsions, and which subtypes of 5-HT receptor are involved in the convulsions. For this purpose, cocaine, meprylcaine and lidocaine, all of which have different effects on SERT, were used as convulsants and the effects of serotonin reuptake inhibitors (SSRIs), specific agonists and antagonists for 5-HT receptor subtypes were evaluated in mice.Administration of SSRI, zimelidine, citalopram and fluoxetine, 5-HT2A,2C receptor agonist, R(-)-DOI and the 5-HT2C receptor agonists, mCPP and MK212 resulted in a marked increase in incidence of convulsions and a reduction in the threshold of lidocaine-induced convulsions, while the 5-HT2B receptor agonist, BW723C86, had little influence. On the other hand, SSRI did not affect the measured parameters in meprylcaine- and cocaine-induced convulsions. R(-)-DOI, mCPP and MK212 reduced the threshold of meprylcaine or cocaine with less extent than the reduction of lidocaine threshold. Incidence of cocaine- and meprylcaine-induced convulsions were significantly reduced by 5-HT2A,2B,2C antagonist, LY-53857 and 5-HT2C antagonist, RS 102221. The threshold of cocaine and meprylcaine was significantly increased by both antagonists. 5-HT2A antagonists MDL-11,939 and ketanserin, and 5-HT2B antagonist SB-204741 except at high doses had little effect on cocaine- and meprylcaine-induced convulsions. None of these antagonists altered the parameters of lidocaine-induced convulsions. Pretreatment with fluoxetine but not citalopram increased the plasma concentration of lidocaine. These results suggest that the increase of serotonergic neuronal activity through 5-HT2C receptor stimulation was responsible for increased activity of local anesthetics-induced convulsions and support the involvement of this mechanism in cocaine- and meprylcaine- but not in lidocaine- induced convulsions through their direct inhibitory action on central SERT

Timolol activates the enzyme activities of human carbonic anhydrase I and II.

Timolol, a beta-blocker, has been shown to be an effective ocular hypotensive agent when used alone or with carbonic anhydrase inhibitor on ocular hypertensive or open angle glaucoma patients. The effect of timolol hemihydrate on the CO(2) hydration activities of human carbonic anhydrase (HCA) I and II and their reaction mechanisms were investigated. Timolol activates the enzyme activities of HCA I and HCA II. In HCA I and II, the enzyme kinetic results clearly showed that timolol increases the value of V(max) but does not influence the value of K(m). The enzyme kinetic method showed that timolol noncompetitively activates HCA I and II activities through the formation of a ternary complex consisting of the enzyme, the substrate, and timolol. These results indicate that timolol binds apart from the narrow cavity of the active site. AutoDocking results showed that timolol binds at the entrance of the active site cavity in a region where the proton shuttle residue, His 64, of HCA I or II, is placed. The enzyme kinetic and AutoDocking results showed that timolol might weakly bind near the proton shuttle residue, His 64, to accelerate the proton transfer rate from His 64 to the buffer components. It is known that efficient activators of carbonic anhydrase possess a bulky aromatic/heterocyclic moiety and a primary/secondary amino group in their molecular structure. Timolol has a heterocyclic moiety and a secondary amino group, which are typical structures in efficient activators of carbonic anhydrase.Timolol, a beta-blocker, has been shown to be an effective ocular hypotensive agent when used alone or with carbonic anhydrase inhibitor on ocular hypertensive or open angle glaucoma patients. The effect of timolol hemihydrate on the CO(2) hydration activities of human carbonic anhydrase (HCA) I and II and their reaction mechanisms were investigated. Timolol activates the enzyme activities of HCA I and HCA II. In HCA I and II, the enzyme kinetic results clearly showed that timolol increases the value of V(max) but does not influence the value of K(m). The enzyme kinetic method showed that timolol noncompetitively activates HCA I and II activities through the formation of a ternary complex consisting of the enzyme, the substrate, and timolol. These results indicate that timolol binds apart from the narrow cavity of the active site. AutoDocking results showed that timolol binds at the entrance of the active site cavity in a region where the proton shuttle residue, His 64, of HCA I or II, is placed. The enzyme kinetic and AutoDocking results showed that timolol might weakly bind near the proton shuttle residue, His 64, to accelerate the proton transfer rate from His 64 to the buffer components. It is known that efficient activators of carbonic anhydrase possess a bulky aromatic/heterocyclic moiety and a primary/secondary amino group in their molecular structure. Timolol has a heterocyclic moiety and a secondary amino group, which are typical structures in efficient activators of carbonic anhydrase

Investigation of Patients' Satisfaction in Using Potent Topical Corticosteroid Preparations

The purpose of this study is to elucidate the physical properties of various commercially available topical corticosteroid preparations. We compared comfort after application and the physical properties affecting topical application among brands of commercially available topical corticosteroid ointments and creams to identify factors affecting quality of life after application. We investigated 12 commercially available brands of topical corticosteroid preparations (6 creams and 6 ointments), all classified as "potent" corticosteroid in Japan. Subjects were 122 healthy volunteers at 11 hospitals, all of whom had given their informed consent for this study. Physical properties were compared among test preparations as well as standard preparations. Ranked high in comfort, Nerisona(R) cream was easy to spread, odorless, and low in viscosity. Overall, it displayed better qualities than other creams tested. The spreadability of Rinderon(R)-DP ointment and Antebate(R) ointment ranked higher than other preparations, suggesting that these ointments may reduce mechanical irritation to lesions during topical application. The results of this study could be used by dermatologists and pharmacists to aid preparation choice and improve compliance with application recommendations

Development of a Surgical Site Infection (SSI) Surveillance System, Calculation of SSI Rates and Specification of Important Factors Affecting SSI in a Digestive Organ Surgical Department

We have developed an original system to conduct surgical site infection (SSI) surveillance. This system accumulates SSI surveillance information based on the National N osocomial Infections Surveillance (NNIS) System and the Japanese Nosocomial Infections Surveillance (JNIS) System. The features of this system are as follows: easy input of data, high generality, data accuracy, SSI rate by operative procedure and risk index category (RIC) can be promptly calculated and compared with the current NNIS SSI rate, and the SSI rates and accumulated data can be exported electronically. Using this system, we monitored 798 patients in 24 operative procedure categories in the Digestive Organs Surgery Department of Mazda Hospital, Mazda Motor Corporation, from January 2004 through December 2005. The total number and rate of SSI were 47 and 5.89%, respectively. The SSI rates of 777 patients were calculated based on 15 operative procedure categories and Risk Index Categories (RIC). The highest SSI rate was observed in the rectum surgery of RIC 1 (30%), followed by the colon surgery of RIC3 (28.57%). About 30% of the isolated infecting bacteria were Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. Using quantification theory type 2, the American Society of Anesthesiology score (4.531), volume of hemorrhage under operation (3.075), wound classification (1. 76), operation time (1.352), and history of diabetes (0.989) increased to higher ranks as factors for SSL Therefore, we evaluated this system as a useful tool in safety control for operative procedures