Anti-edematous effects of epinastine, cetirizine and its enantiomers in λ-carrageenan-induced edema in rat hind paw.

Urticaria is induced by the histamine released from mast cells which develops wheals (edema) as a visual feature. In clinical practice, second-generation histamine H1 -receptor blockers are routinely used as the first-line symptomatic treatment for urticaria. Nevertheless, not much research has directly examined the second-generation histamine H1-receptor blockers' ability to reduce edema. In this study, we directly evaluated the anti-edematous activities of three second-generation histamine H1-receptor blockers available in the market (epinastine hydrochloride, cetirizine hydrochloride, and levocetirizine hydrochloride) using a λ-carrageenan-induced footpad edema model. One hour before the induction of edema with 1% λ -carrageenan injection, all second-generation histamine H1 -receptor blockers (5, 10, 50 and 100 mg/kg) were subcutaneously administered to rats. At 0.5 and 3 hours after λ -carrageenan administration, the edema volume was evaluated using a Plethysmometer. Epinastine hydrochloride significantly suppressed the edema growth in a dose-dependent manner. Cetirizine hydrochloride showed a slight anti-edematous effect, while levocetirizine significantly inhibited the development of edema in a dose-dependent manner. On the other hand, dextrocetirizine did not prevent edema from growing. In summary, second-generation histamine H1 -receptor blockers, at least those examined in this study, may be able to reduce the clinical symptoms of urticaria associated with edema. Levocetirizine hydrochloride is also anticipated to have stronger anti-edematous effects than cetirizine hydrochloride because levocetirizine is responsible for cetirizine's anti-edematous activity.

Direct comparison of anti-inflammatory effects of 14-, 15-, and 16-membered macrolide antibiotics in experimental inflammation model induced by carrageenan in rats.

Some macrolide antibiotics, which share a basic lactone ring structure, also exhibit anti-inflammatory actions in addition to their antibacterial activities. However, no study has directly compared anti-inflammatory effects on acute inflammation among macrolide antibiotics with the distinct size of the lactone ring. In this study, we evaluated and compared the anti-inflammatory activities of four 14-membered macrolides (erythromycin, clarithromycin, roxithromycin, oleandomycin), one 15-membered macrolide (azithromycin), and three 16-membered macrolides (midecamycin, josamycin, leucomycin) using a rat carrageenan-induced footpad edema model. All macrolide antibiotics were intraperitoneally administered to rats one hour before the induction of inflammatory edema with 1% λ -carrageenan. The anti-inflammatory effects on acute inflammation were evaluated by changing the edema volume. All 14-membered and 15-membered macrolide antibiotics significantly suppressed the development of edema. Conversely, none of the 16-membered macrolide antibiotics inhibited the growth of edema. In conclusion, compared to 16-membered macrolide antibiotics, 14-membered and 15-membered macrolide antibiotics have stronger anti-inflammatory effects. Further research should be done to determine why different lactone ring sizes should have distinct anti-inflammatory effects.

Anti-Inflammatory Actions of Expectorants in a Rat Carrageenan-Induced Footpad Edema Model.

S-Carboxymethyl-L-cysteine (SCMS) exhibits sputum-regulating and anti-inflammatory actions. Previous studies reported the anti-inflammatory effects of SCMS on chronic inflammatory diseases, but no study has examined these effects on acute inflammatory diseases. In this study, we investigated the anti-inflammatory effects of SCMS in a rat carrageenan-induced footpad edema model, which is routinely used as an acute inflammation model. Expectorants were administered to rats with footpad edema induced by subcutaneously administering 1%λ-carrageenan to the footpad of the left posterior limb, and the dose dependency of the anti-inflammatory effects was evaluated. As a result, even when the dose of SCMS was increased to 400 mg/kg, there were no inhibitory effects on edema. Furthermore, we examined the inhibitory effects of other expectorants (ambroxol hydrochloride, N-acetyl-L-cysteine, L-cysteine ethylester hydrochloride, and L-cysteine methylester hydrochloride), which were reported to exhibit anti-inflammatory effects on chronic inflammation, on edema. However, none of these expectorants inhibited edema.

Application of the PKCYP-test to predict the amount of in vivo CYP2C11 using tolbutamide as a probe.

Previous reports have shown that the determination of drug metabolism capacity can be made by the pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test), in which an apparent liver-to-blood free concentration gradient in vivo (qg) is introduced, which is useful for evaluating fluctuations of CYPIA2 in rats. The aim of the present study was to examine the application of the PKCYP-test to evaluate the quantity of in vivo CYP2C11 by using tolbutamide as a probe, to confirm its validity using a physiologically-based pharmacokinetic rat model. Rats treated with carbon tetrachloride (CCl4-treated rats) were used as a model for low levels of CYP2C11 in the liver. In CCl4-treated rats, the total body clearance (CLtot) of tolbutamide and the amount of CYP2C11 fell to about a quarter and a third of that in control rats, respectively. The time-course of tolbutamide concentrations in serum in control rats could be simulated by a physiologically-based pharmacokinetic model. In CCl4-treated rats, take into consideration the qg value of control rats, the level of CYP2C11 was accurately predicted by the PKCYP-test, and the time-course of tolbutamide concentrations in serum could be predicted by the same physiologically-based pharmacokinetic model. In conclusion, we have shown that the PKCYP-test can be used to predict levels of CYP2C11. It was also demonstrated that the qg and amount of CYP are useful parameters in the PKCYP-test by constructing a physiologically-based pharmacokinetic model which was applied to the PKCYP-test.

Preparation and clinical application of 2% diflunisal oral ointment for painful lesions of the oral mucosa.

We previously reported the development and clinical efficacy of a 2% aspirin oral ointment and 2% ethenzamide oral ointment as hospital preparations for painful lesions of the oral mucosa. This study investigated methods of preparing a more stable oral ointment with a more effective analgesic action, using diflunisal, another salicylic acid derivative, with an analgesic effect stronger than that of aspirin. A two-percent diflunisal oral ointment was prepared similarly to the aspirin ointment using plastibase and CMC-Na as the ointment base. From the results of spreadability measurement, a CMC-Na content of 20% was considered appropriate. The stability of diflunisal in 2% diflunisal oral ointment stored at 5 degrees C, 20 degrees C and 30 degrees C, was determined using HPLC, and a high stability of diflunisal at room temperature for more than 100 days was confirmed. We also investigated its antinociceptive effect using the Randall-Selitto paw pressure test in rats, which showed that 2% diflunisal oral ointment was as effective as 2% aspirin oral ointment. On clinical application of 2% diflunisal oral ointment to 8 patients with painful oral mucous diseases, it was found to be significantly (p = 0.014) more effective than 2% aspirin oral ointment. The results of this study demonstrated that 2% diflunisal oral ointment is a clinically useful analgesic for painful oral lesions.

Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease.

Previously, we established a method to assess drug metabolism capacity based on a pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test) by introducing an apparent liver-to-blood free concentration gradient in vivo (qg). The qg values were determined as the ratio of in vivo-in vitro clearance. In this study, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rat models in which the levels of CYP enzymes were reduced. Rats fed a choline-deficient diet (CD-fed) and aged rats were used as models for a low level of CYP in the liver. In both rat models, the contribution (fCYP) of CYP1A2 to the in vivo intrinsic clearance values (CLint) of acetanilide and caffeine metabolism was less than unity, suggesting that other metabolic pathways are involved in the CLint. The in vivo clearance for CYP1A2 was estimated by multiplying fCYP by CLint, then the value of qg was determined as the ratio of in vivo-in vitro clearance. We predicted the level of CYP1A2 in CD-fed and aged rats, based on the clearance of acetanilide mediated by CYP1A2, using the qg value of control rats. The clearance of caffeine mediated by CYP1A2 in CD-fed and aged rats, as estimated from the predicted level of CYP1A2, correlated with the observed values. In conclusion, we have demonstrated that the PKCYP-test can be applied to CYP1A2 for drugs metabolized by multiple CYP isozymes, and/or to models involving reduced CYP.

[Establishment of an optimum bowel preparation method before gynecologic laparoscopic surgery].

OBJECTIVE: To establish a new method for preoperative bowel preparation that facilitates nursing care and minimizes the patient's discomfort during the clinical pathway of laparoscopic surgery. METHOD: A randomized controlled trial was conducted for the following two preparation methods. Twenty cases were assessed with Method 1 and 18 cases with Method 2. Method 1 (the conventional procedure): oral magnesium citrate is given in the afternoon of the day before surgery, followed by a glycerin enema in the night of the day before surgery and in the morning of the day of surgery. Method 2 (a new procedure): oral magnesium citrate is given in the afternoon of the day before surgery, followed by oral picosulfate in the night before the day of surgery and a bisacodyl suppository in the morning of the day of surgery. To evaluate the two methods we sent questionnaires to the surgeons (blinded to the method used), nurses, and patients. RESULTS: No statistical difference existed between the two methods in their effectiveness as a preoperative treatment. Facilitation of nursing care was significantly better in Method 2, and patients had considerably reduced discomfort with Method 2. DISCUSSION: Patients who received oral picosulfate and a bisacodyl suppository experienced much less discomfort and nursing care was easier when compared with the conventional method of administering a glycerin enema. Since an enema is disliked by young women and an effect comes out with discomfort very shortly after the administration, the degree of discomfort of patients would have become high. Picosulfate is an oral medicine and thereby the effect comes out mildly. That would be the reason why the degree of discomfort of patients was low. In the nursing care, an enema requires time for preparation and administration, while picosulfate is easy to administer, making the nursing care easier. Therefore, Method 2 was chosen as a preoperative bowel treatment for the clinical pathway. Thus, we could establish a new evidence-based method useful for the preoperative bowel preparation in the clinical pathway of laparoscopic surgery.

The participation of pharmacists in a team to introduce a clinical pathway to laparoscopic cystectomy in obstetrics and gynecology.

In the Department of Obstetrics and Gynecology at our hospital, a team of doctors, pharmacists, nurses, and other medical staff was established to prepare a clinical pathway for laparoscopic cystectomy. Various data on clinical charts including the use of drugs were collected from 57 patients by pharmacists and nurses. Based on the analysis of these data, hospitalization period, method of preoperative bowel preparation, time to initiation of food intake, duration of antibiotic administration, and time and content of pharmaceutical instructions to patients of dosage and administration were determined. Criteria for variances requiring the doctor's directions were determined for fever, wound pain, and vomiting. The clinical pathway established here allows of not only the efficient and uniform care of patients, but also the active exchange of opinions among members of the medical team. Moreover, most patients who replied to a questionnaire said that they were at ease during hospitalization because they had received detailed information about the clinical pathway including the use of drugs before surgery. Thus, the participation of pharmacists on a medical team that is introducing a clinical pathway is particularly important because the use of drugs and pharmaceutical care are an important part of good patient care.

[Simultaneous determination of theophylline and its metabolites by HPLC].

A high performance liquid chromatography (HPLC) method has been developed for the simultaneous determination of theophylline and its metabolites, with caffeine and its metabolites. The method is simple and applicable to planning the administration of theophylline. We used a column-switching system in combination with atmospheric pressure chemical ionization liquid chromatography-mass spectrometry (LC-APCI-MS) for the determination of theophylline and its metabolites in biological samples. In the mass spectrum, the molecular ions of these drugs and metabolites were clearly observed as base peaks. The method is sufficiently sensitive and accurate for the pharmacokinetic studies of these drugs.

Determination of theophylline and its metabolites in biological samples by liquid chromatography-mass spectrometry.

Liquid chromatography-mass spectrometry (LC-MS) is a powerful tool for analysis of drugs and their metabolites. We used a column-switching system in combination with atmospheric pressure chemical ionization LC-MS (LC-APCI-MS) for the determination of theophylline and its metabolites in biological samples. The separation was carried out on a reversed-phase column using methanol-20 mM ammonium acetate as a mobile phase at a flow-rate of 1 ml/min in 30 min. In the mass spectrum, the molecular ions of these drugs and metabolites were clearly observed as base peaks. This method is sufficiently sensitive and accurate for the pharmacokinetic studies of these drugs.

Enhanced theophylline metabolism in patients with bronchial asthma at age 4 and under.

The plasma levels of theophylline (TP) and its metabolites were measured in patients with bronchial asthma who were treated with a slow-release preparation of TP. The ratios of the plasma levels of these metabolites to TP levels in the group aged 1-4 years were larger than those in the group aged 5 years and older, suggesting enhanced activity of drug-metabolizing enzymes during infancy.

Development and clinical application of high performance liquid chromatography for the simultaneous determination of plasma levels of theophylline and its metabolites without interference from caffeine.

A high performance liquid chromatography (HPLC) method has been developed for the simultaneous determination of plasma levels of theophylline and its metabolites without interference from caffeine or caffeine metabolites. The method is simple and of practical use because it is applicable even to plasma samples from patients who take caffeine-containing beverages. The method was also reproducible with a coefficient of variation of less than 5% for each analyte. The levels of theophylline, determined by HPLC, were validated by their high correlation to the levels obtained by fluorescence polarization immunoassay. HPLC was used to determine theophylline levels in patients with bronchial asthma. The data revealed that the ratio of 1,3-dimethyluric acid, the major metabolite of theophylline, to theophylline concentration in the plasma was within a narrow range in most patients (0.055 +/- 0.01, n = 66), regardless of the method of theophylline administration or the time of blood sampling. Conversely, this ratio was as low as 0.027 +/- 0.005 in the patient with a long plasma half-life of theophylline. These results suggest that it may be possible to predict the plasma half-life of theophylline for each patient from a single blood sample. This may be useful when planning theophylline administration, especially in patients with abnormal theophylline metabolism.