Low concentrations of clarithromycin upregulate cellular antioxidant enzymes and phosphorylation of extracellular signal-regulated kinase in human small airway epithelial cells.

BACKGROUND: It is well known that low-dose, long-term macrolide therapy is effective against chronic inflammatory airway diseases. Oxidative stress is considered to be a key pathogenesis factor in those diseases. However, the mechanism of action of low-dose, long-term macrolide therapy remains unclear. We have reported that clarithromycin (CAM), which is a representative macrolide antibiotic, could inhibit hydrogen peroxide (H2O2)-induced reduction of the glutathione (GSH)/glutathione disulfide (GSSG) ratio in human small airway epithelial cells (SAECs), via the maintenance of GSH levels through an effect on γ-glutamylcysteine synthetase (γ-GCS) expression. In this study, we examined the influence of CAM against H2O2-induced activities of cellular antioxidant enzymes and phosphorylated extracellular signal regulatory kinase (p-ERK) using SAECs, the main cells involved in chronic airway inflammatory diseases. METHODS: SAECs were pretreated with CAM (1, 5, and 10 µM) for 72 h, and subsequently exposed to H2O2 (100 µM) for 0.5-2 h. Levels of GSH and GSSG, and activities of glutathione peroxidase (GPx)-1, glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), heme oxygenase (HO)-1 and p-ERK were assayed. mRNA expressions of GPx-1 and HO-1 were measured using the real-time reverse transcription polymerase chain reaction (RT-PCR). Tukey's multiple comparison test was used for analysis of statistical significance. RESULTS: Pretreatment with low-dose (1 and 5 µM) CAM for 72 h inhibited H2O2-induced reductions of GPx-1, GR, SOD, CAT and HO-1 activities, and mRNA expressions of GPx-1 and HO-1, and improved the GSH/GSSG ratio. However, these alterations were not observed after pretreatment with high-dose (10 µM) CAM, which suppressed phosphorylation of cell proliferation-associated ERK to cause a significant (p < 0.01) decrease in cell viability. CONCLUSIONS: CAM is efficacious against deterioration of cellular antioxidant enzyme activity caused by oxidative stress under low-dose, long-term treatment conditions. On the other hand, pretreatment with high-dose CAM suppressed phosphorylation of cell proliferation-associated ERK and decreased cell viability. The present study may provide additional evidence as to why low-dose, long-term administration of macrolides is effective for treating chronic inflammatory airway diseases.

Long-term treatment of clarithromycin at a low concentration improves hydrogen peroxide-induced oxidant/antioxidant imbalance in human small airway epithelial cells by increasing Nrf2 mRNA expression.

BACKGROUND: Clarithromycin (CAM), a representative macrolide antibiotic, has been used widely at low doses for long-term therapy of chronic inflammatory airway diseases. Anti-inflammatory effects of macrolide antibiotics were first discovered in clinical practice. Although oxidative stress is known as a key pathogenesis factor in chronic airway inflammatory diseases, the mechanism of action of low-dose, long-term CAM therapy remains unclear. We aimed to examine the cytoprotective action of CAM against hydrogen peroxide (H2O2)-induced cell dysfunction, focusing on CAM dose and treatment duration, and using human small airway epithelial cells (SAECs), the main cells involved in chronic airway inflammatory diseases. METHODS: SAECs were pretreated with CAM (1, 5 or 10 µM) for 24, 48 or 72 h, and were subsequently exposed to H2O2 for 0.5-4 h. Levels of interleukin (IL)-8, glutathione (GSH) and glutathione disulfide (GSSG), and the activities of nuclear factor (NF)-κB and γ-glutamylcysteine synthetase (γ-GCS) were assayed using specific methods. IL-8 mRNA and NF erythroid 2-related factor 2 (Nrf2) mRNA expression were measured using real-time reverse transcription polymerase chain reaction (RT-PCR). Tukey's multiple comparison test was used for analysis of statistical significance. RESULTS: Pretreatment with low-dose (1 or 5 µM), long-term (72 h) CAM inhibited H2O2-induced IL-8 levels, NF-κB activity, and IL-8 mRNA expression, and improved the GSH/GSSG ratio via the maintenance of γ-GCS expression levels. Similar to its enhancing effect on the GSH/GSSG ratio, pretreatment with low-dose CAM for 72 h significantly increased Nrf2 mRNA expression (p < 0.01 and p < 0.05). In contrast, these alterations were not observed after pretreatment with high-dose (10 µM) or short-term (24 and 48 h) CAM. CONCLUSIONS: CAM is efficacious against cell dysfunction caused by oxidative stress under low-dose, long-term treatment conditions. This effect depended on the suppression of NF-κB activation and improvement of the H2O2-induced oxidant/antioxidant imbalance that is achieved by increasing Nrf2 mRNA expression in SAECs. The present study may provide the first evidence of why low-dose, long-term administration of macrolides is effective for treating chronic inflammatory airway diseases.

[Dissolution behaviors of tablet and capsule covered with oblate or agar jelly for taking medicine easily].

Drugs are sometimes covered with oblate or agar jelly. It is said that the medicinal effect of drugs covered with oblate is slow, but no studies have reported results confirming this. Therefore, we examined the dissolution behavior when the drug was covered with oblate or agar jelly. Three types of commercially available formulations of benzodiazepine were used: medazepam sugarcoated tablets, prazepam uncoated tablets, and clorazepate dipotassium capsules. Dissolution tests were performed using solutions of pH 1.2 and 5.6 to simulate normal gastric juice and gastric anacidity, respectively. Drugs covered with oblate were tested by the paddle method, and those covered with agar jelly were tested using the rotating basket method. Dissolution of clorazepate capsules not covered with oblate increased by approximately 10% when the pH was adjusted from 1.2 to 5.6, while those of medazepam and prazepam tablets decreased by approximately 40-60%. In contrast, the dissolution decreased significantly at both pH values for each drug covered with oblate. Dissolution further decreased when the amount of oblate was doubled. No detectable dissolution of medazepam tablets or of clorazepate capsules occurred when the drug was covered with agar jelly. Dissolution of prazepam tablets covered with agar jelly was only about 10% at the end of the test. These results indicate that dissolution is slowed and prolonged when a drug is covered with oblate or agar jelly, permitting sustained release of the drug. But, it is necessary to improve a suitable method for the dissolution.

[Effect of the brand and generic medicine of pravastatin on dyslipidemia in rabbits fed a high cholesterol diet].

Mevalotin containing pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is the brand medicine and well known to be effective for patients with dyslipidemia. Now, more than 20 generic pravastatins are available for clinical therapy. We compared pharmaceutical property of Mevan,a generic pravastatin, with that of Mevalotin.According to the definition of the Japanese Pharmacopoeia, Mevalotin 10 mg tablets were uniform in pravastatin content, whereas 5 mg tablets were rather variable. Variation in pravastatin content of Mevan 5 mg tablets was the same as Mevalotin 5 mg, whereas that of 10 mg tablets was very variable. The plasma concentration of pravastatin in the normal rabbits continuously increased until 180 min after oral administration of 30 mg Mevan, whereas it increased in a biphasic pattern after 30 mg Mevalotin.All rabbits were fed 0.2% cholesterol diet throughout the experiment. After 8 weeks, oral administration of either Mevalotin or Mevan was started at the dose of 30 mg pravastatin/day for 16 weeks. After a transient increase for a few weeks, the plasma levels of total- and LDL-cholesterol gradually decreased in Mevalotingroup, whereas these levels did not significantly changed in Mevan group within 16 weeks. The level of HDL-cholesterol in Mevan group tended to increase but not in Mevalotin group. The triglyceride level in Mevan group changed as well as that in Mevalotin group until 10 weeks after administration, and then gradually increased. The present results suggest that pharmaceutical properties of Mevan are not always identical with those of Mevalotin.

Automation in drug inventory management saves personnel time and budget.

Automation in the drug distribution processes is helpful to pharmacists in creating new clinical services. We have ameliorated the drug inventory control system seamlessly connected with the physician order-entry system. This control system application, named Artima, allows inventory functions to be faster and more efficient in real time. The medicines used in our hospital are automatically fixed and arranged to sold-packages, and are ordered from each wholesaler by a fax-modem every day. Artima can search the lot number and expiration date of drug in the purchase and delivery records. These functions are powerful and useful in patient's safety and cost containment. We surveyed the inventory amount stored in the computer database, and evaluated time required for inventory management by tabulating working records of employees during past decades. Inventory decreased by 70% along with the continuous improvement of the system during the past decade. The workload in the inventory management in each section of the Pharmacy Department as well as in clinical units was dramatically reduced after the implementation of this system. The automation system in the drug inventory management allows creating new clinical positions for pharmacists. This system also could pay for itself in time.

A longitudinal analysis of antihypertensive drug interactions in a Medicaid population.

BACKGROUND: Drug interactions are a frequent cause of adverse drug events. We evaluated whether the frequency of previously reported antihypertensive drug-drug interactions could be reduced by pharmaceutical case management. METHODS: Patients >30 years of age with hypertension who were enrolled in the Iowa Pharmaceutical Case Management (PCM) program were evaluated. All prescription claims for patients were obtained on their date of eligibility and again 9 months later. A drug interaction database was developed to examine potential drug interactions in each patient's regimen. RESULTS: Antihypertensive drugs were taken by 1377 patients at baseline and at 9-month follow-up. Highly significant antihypertensive drug interactions were observed at baseline in 35% of patients (0.47 per patient), and interaction prevalence did not change over time. Decreases in the number of drug interactions tended to occur more commonly among patients of pharmacies that provided the highest intensity of service (11.5% in high-intensity pharmacies v 9% in low- or zero-intensity pharmacies, but this did not achieve statistical significance). Nearly 75% of patients had an interaction of any significance level, and the total number of interactions increased over time (P =.0067). CONCLUSIONS: This Medicaid population with hypertension had a very high prevalence of potential drug interactions. The prevalence of interactions did not change, but the mean number of all interactions actually increased over time. There was some suggestion that higher-intensity pharmacies might be more successful in minimizing the risk of clinically significant drug interactions when compared with lower-intensity pharmacies.

Protective effects of quinaprilat and trandolaprilat, active metabolites of quinapril and trandolapril, on hemolysis induced by lysophosphatidylcholine in human erythrocytes.

We examined the effects of the angiotensin converting enzyme (ACE) inhibitors captopril, enalaprilat, quinapril, and trandolapril, and their active metabolites quinaprilat and trandolaprilat, on hemolysis induced by lysophosphatidylcholine (LPC) in human erythrocytes. LPC induced hemolysis at the concentrations above the critical micelle concentration (4 microM). Propranolol, used as a reference drug, attenuated the 50% hemolysis induced by 6 microM LPC at concentrations ranging from 100 nM to 100 microM. Similarly, quinaprilat (10 microM) and trandolaprilat (10, 100 microM) significantly attenuated the LPC-induced hemolysis, but other ACE inhibitors did not. Since propranolol possesses a membrane stabilizing action correlated with high lipophilicity, it appears that the high lipophilicity of quinaprilat or trandolaprilat is responsible for the protection from the damage induced by LPC. However, quinapril and trandolapril were not effective, although both drugs have higher lipophilicity than quinaprilat and trandolaprilat. Hence, it is suggested that the high lipophilicity alone may not contribute to the protective effects of ACE inhibitors against LPC-induced hemolysis. None of ACE inhibitors attenuated the hypotonic hemolysis (60 mM NaCl), although propranolol did. Furthermore, neither propranolol (100 microM) nor quinaprilat (50 microM) and trandolaprilat (50 microM) affected LPC micelle formation, suggesting that these drugs do not directly bind to LPC. We therefore believe that the protective effects of quinaprilat and trandolaprilat on the LPC-induced hemolysis may be related physicochemically to their highly lipophilic and ACE inhibitory structures, which probably maintain erythrocyte membrane integrity by a mechanism other than ACE inhibition, prevention of LPC micelle formation or protection against osmotic imbalance.

Extent of services provided by pharmacists in the Iowa Medicaid Pharmaceutical Case Management program.

OBJECTIVE: To summarize the start-up experience with patients identified as eligible during the first four quarters of the Iowa Pharmaceutical Case Management (PCM) program and to characterize the extent of the services proved by pharmacists in the program. DESIGN: Prospective pharmaceutical care intervention project. SETTING: One hundred seventeen community pharmacies in Iowa. PATIENTS: Medicaid patients at high risk for drug-related problems based on using 4 or more nontopical medications and having 1 of 12 specific disease states. INTERVENTION: To become eligible to provide PCM services, licensed pharmacists had to undergo training and submit five care plans to the Iowa Department of Human Services. Community pharmacists were provided names of newly eligible patents each calendar quarter for 1 year. For each patient, pharmacists were asked to indicate by fax whether they had met with the patient, performed a written work-up of the patient, sent recommendations to the patient's physician, and whether the physician replied. When pharmacists were unable to provide the service, they were asked to state the reason. Both the pharmacist and the physician receive $75 for the initial assessment, with additional payments after each follow-up visit performed. MAIN OUTCOME MEASURES: An intensity score and the percentage of eligible patients for whom all steps were completed were calculated for each pharmacy. RESULTS: Fax survey results were retumed for 2,834 (96.7%) of the 2,931 patients eligible for PCM services. Pharmacists met with 943 (33.3%), worked up 763 (26.9%), sent recommendations to physicians for 500 (17.6%), and received replies from physicians for 327 (11.5%) patients. Pharmacists were unable to provide PCM services for 1,891 (66.7%) patients. The primary reasons given for this inability to provide services were patient access issues for 438 (23.2%) patients, pharmacy staffing or start-up issues for 419 (22.2%) patients, or no reason specified for 575 (30.4%) patients. A PCM intensity score was developed to represent the scope of services provided and the number of patients served. A higher intensity score indicated pharmacies that provided PCM to more patients and/or that offered higher levels of care (e.g., provided a written set of recommendations to the physician rather than simply assessing the patient without preparing or sending recommendations). Future evaluations will determine the validity of the score on the basis of patient outcomes. CONCLUSION: Some pharmacies implemented PCM services very effectively. However, 40% to 60% of the pharmacies provided little or no PCM services within 3 months of notification of patient eligibility. Future investigations will evaluate the quality of prescribing and quality of life for patients who received PCM services.

Extent of services provided by pharmacists in the iowa medicaid pharmaceutical case management program.

OBJECTIVE To summarize the start-up experience with patients identified as eligible during the first four quarters of the Iowa Pharmaceutical Case Management (PCM) program and to characterize the extent of the services proved by pharmacists in the program. DESIGN Prospective pharmaceutical care intervention project. SETTING One hundred seventeen community pharmacies in Iowa. PATIENTS Medicaid patients at high risk for drug-related problems based on using 4 or more nontopical medications and having 1 of 12 specific disease states. INTERVENTION To become eligible to provide PCM services, licensed pharmacists had to undergo training and submit five care plans to the Iowa Department of Human Services. Community pharmacists were provided names of newly eligible patients each calendar quarter for 1 year. For each patient, pharmacists were asked to indicate by fax whether they had met with the patient, performed a written work-up of the patient, sent recommendations to the patient's physician, and whether the physician replied. When pharmacists were unable to provide the service, they were asked to state the reason. Both the pharmacist and the physician receive $75 for the initial assessment, with additional payments after each follow-up visit performed. MAIN OUTCOME MEASURES An intensity score and the percentage of eligible patients for whom all steps were completed were calculated for each pharmacy. RESULTS Fax survey results were returned for 2,834 (96.7%) of the 2,931 patients eligible for PCM services. Pharmacists met with 943 (33.3%), worked up 763 (26.9%), sent recommendations to physicians for 500 (17.6%), and received replies from physicians for 327 (11.5%) patients. Pharmacists were unable to provide PCM services for 1,891 (66.7%) patients. The primary reasons given for this inability to provide services were patient access issues for 438(23.2%) patients, pharmacy staffing or start-up issues for 419(22.2%) patients, or no reason specified for 575(30.4%) patients. A PCM intensity score was developed to represent the scope of services provided and the number of patients served. A higher intensity score indicated pharmacies that provided PCM to more patients and/or that offered higher levels of care (e.g., provided a written set of recommendations to the physician rather than simply assessing the patient without preparing or sending recommendations). Future evaluations will determine the validity of the score on the basis of patient outcomes. CONCLUSION Some pharmacies implemented PCM services very effectively. However, 40% to 60% of the pharmacies provided little or no PCM services within 3 months of notification of patient eligibility. Future investigations will evaluate the quality of prescribing and quality of life for patients who received PCM services.

The extent of potential antihypertensive drug interactions in a Medicaid population.

BACKGROUND: Drug interactions are a frequent cause of adverse drug events and these might be avoided by computer alerts to physicians or pharmacists. We evaluated the frequency of potential drug-drug interactions in patients receiving medications commonly used for hypertension. METHODS: Patients more than 30 years of age with hypertension who were receiving Medicaid and who were enrolled in the Iowa Pharmaceutical Case Management (PCM) program were evaluated. All prescription claims for patients were obtained on their date of eligibility. A drug interaction database was developed to examine potential drug interactions in each patient's regimen. RESULTS: There were 1574 patients who received a drug typically used for hypertension. Depending on age and sex, 23% to 48% of patients had a potential interaction of high significance and 55% to 84% had at least one potential interaction. Both increasing age (P =.0007, odds ratio [OR] 1.012 [1.005,1.019]) and number of drugs (P <.0001, OR 1.120 [1.092,1.150]) were significantly associated with the potential for a highly significant drug interaction in the univariable models. Female sex was not significant (P =.56, OR 1.074 [0.845,1.364]). The multivariable model found that there was a significant interaction between age and the number of drugs in the regimen (P <.0001). CONCLUSIONS: This study found a very high frequency of potential drug interactions with agents typically used for hypertension. Because of the large volume of potential interactions, these data raise the concern that any attempt to provide physicians and pharmacists with computer alerts about these interactions will result in alerts for the vast majority of patients.