Ensuring the safety of aseptic mixtures of injection drugs is one of the most important tasks of hospital pharmacists.At Asahikawa Medical College Hospital,we have established an“Aseptic Injection Mixture Center”,where we aseptically mix injection preparations containing parenteral nutrition agents and anti-cancer drugs for in- and out-patients,in collaboration with nursing staff.To solve the problem of the small amount of available data on the stability of anti-cancer drugs when mixed with injection solutions,we calculated pseudo-first-order rate constants for the disappearance of anti-cancer drugs in distilled water for injection,saline and 5% glucose solution using stability data in the literature,and also obtained Arrhenius parameters.Using them,we determined expiration dates,the times at which 95% of active elements remained in the injection mixture,and based on this assigned 43 anti-cancer drugs to 4 categories:“mix on use”, “use within 24 hr”,“use within 2 days”and“use within 3 days”.Drugs categorized as“use within 3 days”accounted for around 50% of anti-cancer drugs used in our hospital.
The data we obtained has been extremely useful in the provision of aseptic mixtures by our hospital pharmacists and the method of predicting the stability of anti-cancer drugs in injection solutions could be applied to other injection drugs as well.

View full abstract

The purpose of this study was to identify drugs with a risk of causing Stevens-Johnson syndrome (SJS),toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS) and the risk factors involved.From the CARPIS (Case Reports of Adverse Drug Reactions and Poisoning Information System) database,which contains 40,000 case reports of adverse drug reactions,we determined 258 cases (case group) matching the criteria for SJS/TEN/DIHS stated by the Japanese Ministry of Health,Labour and Welfare.We also selected 774 control cases (control group) which were sex- and age- matched (±1)with the case group.
Next,various data were compared between the case group and the control group and the results analyzed statistically.In this regard,logistic regression analysis identified 2 drugs - carbamazepine (odds ratio : OR=5.21,95% confidence interval : 95% CI=2.68-10.06)and acetaminophen (OR=3.41,95% CI=1.12-10.51)that were associated with a significant elevation of the risk of SJS and TEN.Further,mexiletine hydrochloride (OR=205.48,95% CI=28.04-2330.89)and diaminodiphenylsulfone (OR=981.56,95% CI=94.84-25212.82),were found to be associated with a significant elevation of the risk of DIHS.By identifying certain risk factors for SJS,TEN and DIHS,the results of the present study would be useful in preventing severe drug reactions.

View full abstract

The drug interactions between tandospirone citrate,a non-benzodiazepine antianxiety drug,and oxazolam,a minor benzodiazepine tranquilizer and antianxiety agent,and valpronic acid (VPA),an anti-convulsant,were studied in rats.When tandospirone citrate or citric acid was administered orally immediately following oral administration (p.o.) of sodium valproate (VPA-Na),the plasma VPA levels were significantly lower than those in the control.In addition,pharmacokinetic parameters such as plasma VPA concentration and area under the plasma concentration-time curve up to 3 hr (AUC) were significantly decreased.However,when tandospirone citrate was administered intraperitonally,or both it and oxazolam were administered orally with VPA-Na,the VPA pharmacokinetic parameters were unchanged.These results suggest that decreases in plasma VPA concentrations (including those for AUC) may be due to a reduction in VPA-Na adsorption from the intestinal tract due to tandospirone citrate.

View full abstract

Utilizing the standard generalized markup language (SGML) of drug package inserts,extensible markup language (XML) documents were prepared through detailed markup based on the definitions of pharmaceutical markup language (PML).The prepared PML documents were stored in an XML-native database,enabling content searches of indexes based on the detailed markup of phrases and sentences describing signs and symptoms.This made it possible to search not only for whole sentences indicating signs and symptoms but also various expressions describing changes in blood pressure and pulse that do not necessarily match as regards spelling.
In the present study,we investigated detailed markup methods for PML using existing SGML documents,and converted package inserts for 196 products into PML documents.With special emphasis on adverse reactions,we examined the usefulness of the PML documents by retrieving content from the database using XPath.

View full abstract

For particulates forming as a result of precipitation in intravenous injections and those arising from injection devices,we examined their distribution in tissue distribution following intravenous administration.
Barium sulfate was used as the particulate and 100% (w/v) suspensions of varying particle size (1.5,5.0,10.0μm) were prepared.Each test suspension was injected into the caudal vein of ICR mice in a single dose of 0.1 mL/10 g and wholebody radiography was performed.Each suspension was also injected into the internal jugular vein of Hartley guinea pigs in a single dose of 5 mL/kg and major organs were collected for radiographic examination.The experiments were model-like and barium sulfate was injected in large quantities.
The whole-body radiography of the mice revealed the presence of barium sulfate in the lungs,heart,kidneys,liver and external carotid arteries and the radiography of the guinea pig organs showed that barium sulfate was present in the lungs,heart,coronary artery,kidneys and liver.There were no obvious differences in tissue distribution for the three different particle sizes.
Our findings indicate that particulates of less than 10.0μm could possibly be distributed throughout the body by passing through the lungs after intravenous dosing.The Japanese Pharmacopoeia places no restriction on particle fineness of 10μm or less to prevent pulmonary embolism and the results of the present study indicate that it is essential to eliminate particles of such size through the incorporation of a final filter (0.22μm).

View full abstract

We developed a chitosan (CHI) gel containing alcohols and l-menthol (MEN) as skin permeation enhancers,and succinic acid (SUC) as a cross-linking agent and examined the permeation of morphine hydrochloride (MPH) from the CHI gel into human skin.The solubility of CHI and MEN was measured beforehand in order to create a system saturated with these 2 substances.Solubility varied with the content of ethanol and 1,3-butylene glycol.The saturated CHI gel displayed sufficient elasticity to be applied to a fixed area of skin.The permeation of MPH into the skin from the CHI gel was compared with its permeation into the skin for a polyvinyl alcohol (PVA) gel having a similar composition.Permeation was greater for the CHI gel in the later stages of the experiment.Our CHI gel should thus be useful for the transdermal delivery of MPH.

View full abstract

The FOLFOX 4 regimen,a combination of oxaliplatin (L-OHP) plus fluorouracil (5-FU)/levofolinate calcium (l-LV) which is administered bimonthly,has become standard therapy for advanced and recurrent colorectal cancer.We evaluated the safety of this regimen in 22 patients with advanced and recurrent colorectal cancer.
The average relative dose intensities of bolus 5-FU (400 mg/m²),infusional 5-FU (600 mg/m²),and L-OHP (85 mg/m²)were 91.5,90.0 and 90.0%,respectively.The most frequent adverse events were hematologic toxicity,gastrointestinal tract toxicity,and peripheral neuropathy.Neutropenia occurred in 17 patients (77.3%),in whom the incidence of grade 3/4 was 36.4% and thrombocytopenia of grade 1/2 occurred in 8 patients.Peripheral neuropathy occurred in 16 patients (72.7%) including one case of grade 3.Other non-hematologic adverse events included nausea (68.2%),vomiting (27.3%),fatigue (45.5%),stomatitis (22.7%),anorexia (54.5%),vision dysfunction (27.3%),dysgeusia (9.1%),alopecia (18.2%),phlebitis (27.3%),diarrhea (18.2%).Allergic reactions were observed in 3 patients and one of them experienced anaphylactic shock of grade 4 during the 7 th course.
Our results suggest that adverse effects are relatively frequent events during systemic chemotherapy with the FOLFOX 4 regimen.Patients should therefore be carefully monitored for adverse events and rapid intervention with supportive care is important in ensuring that chemotherapy with this regimen is conducted safely.

View full abstract

Oseltamivir (Tamiflu^®),an oral neuraminidase inhibitor,has recently become the most common treatment for influenza in Japan.In the present study,we conducted a questionnaire survey to evaluate efficacy,adverse events and compliance in outpatients prescribed oseltamivir at the University of Fukui hospital during the period January to April 2006.The questionnaire was given to 221 patients,of whom 96 (43.4%) provided responses.
The results obtained showed that 78 patients (81.3%) had influenza A and none had influenza B.Of the total 96 patients,29 (30.2%) were less than 10 years old and 29 (30.2%) were teenagers.Oseltamivir alleviated the fever of 79 of the patients (82.3%) within two days.Though almost all prescriptions for oseltamivir in our hospital were for five days,only 45.8 % of the patients replied that they took the drug for the full five days.Adverse events were reported by 24 patients (25.0 %).The most common were digestive system-related.Five patients (5.2%) reported neuropsychiatric symptoms which included hallucination and abnormal behavior.
The results of our study showed that oseltamivir was effective in the treatment of influenza A,and suggested that some patients discontinue the regimen before completion.As it was a small scale study,further investigation will be needed in order to provide patients with adequate information on the proper use of oseltamivir.

View full abstract

The coadministration of fluoroquinolones with metallic cation-containing compounds such as aojiru (green juice) products inhibits the gastrointestinal absorption of fluoroquinolones and decreases their antimicrobial activity.Classified as health foods,aojiru products are easy to obtain and used widely.While the reaction between the vitamin K in aojiru products and warfarin is well-documented,no studies had been done on the interaction between metallic cations in aojiru products and various drugs.
In the present study,we investigated the current use of health foods by 124 patients visiting three pharmacies in Fukuoka city by having them complete a questionnaire.Two-thirds of the patients regularly took various health foods (46 items) and 14 of them contained metallic cations.Seven patients were taking aojiru products.
We then examined the interaction between the aojiru products and several fluoroquinolones (norfloxacin,ciprofloxacin and ofloxacin) by measuring absorbance in their maximum absorption spectra.The results suggested that chelation occurred when some aojiru products were combined with fluoroquinolones.Since the use of health foods as self-medication is on the increase,it is essential to be aware of the potential interactions between drugs and health foods.

View full abstract

We investigated the effectiveness of pharmacist interventions in determining formulas of injectable medicines by examining 887 inquiries concerning such medicines made between April 2002 and March 2005.The number of inquiries increased after the seasonal rotation of physicians and residents,this showing the importance of providing information and guidance to physicians and residents concerning injectable medicines.
Inquiries concerning dose and interactions among drugs accounted for two-thirds of total number of inquiries,suggesting that it is important for pharmacists to intervene in determining formulas when necessary.The inquiries avoided about 3,240,000 yen of unnecessary hospital expenditure,and their number decreased annually.These results were achieved through the provision of information to doctors by pharmacists.
Thus pharmacist inquiries concerning formulas of injectable medicines were seen to be effective in increasing patient safety and raising efficiency in hospital management.

View full abstract

Using Microsoft Excel^®,we explained in simple terms how the times of taking drugs are determined to patients at a pharmacy counter,in the case of medicines for children.We highlighted the change in drug concentrations with time using pharmacokinetics parameters,such as time of peak concentration,half-life,and area under the blood concentration-time curve,whose values were indicated in the interview-form.
Prediction of the blood drug concentration curve was based on the one-compartment absorption model.We found that various drugs,such as aciclovir (Astric^® dry syrup),oseltamivir phosphate (Tamiflu^® dry syrup),clarithromycin (Clarith^® dry syrup),cefditoren pivoxil (Meiact MS^® fine granules),oxatomide (Celtect^® dry syrup) and procaterol hydrochloride (Meptin^® dry syrup),had characteristic concentration patterns that could be understood visually.We also noted that the indices provided by our simple evaluation using Microsoft Excel^® enabled drug concentrations in blood-time profiles to be compared visually in the case of patients complying with medication schedules and those not complying e.g.in the case that schedules are modified,the patient misses taking medicine or takes more than 1 dose at once.It was also possible to examine the relationship between the predicted blood concentration patterns of drugs and their efficacy or safety for each medicine.This technique would be useful means of helping pharmacists to fully realize their role in the community pharmacy.

View full abstract

As cefotiam hydrochloride dissolves,carbon dioxide is generated due to the buffer agent used to reconstitute the powder form of the medication.The carbon dioxide causes a depression in the level of the injection liquid,which may facilitate the entry of air into the blood stream.
As the safety of cefotiam hydrochloride with a decreased liquid level has not been evaluated,we compared 2 branded (A and B) and 2 generic forms (C and D) of cefotiam hydrochloride for capacity to generate carbon dioxide and lower the liquid level in the drip cylinder.In the case of Product A,we knew that a substance reducing carbon dioxide production had been added to the buffer agent but had no information in this regard for the other products tested.During the evaluation,there were no problems related to drip speed,or medication density and none arose due to differences in infusion sets.The decrease in the liquid level was greater for products B,C,and D than product A.
In the case of dissolution in Pigybotol,it would be easy to eliminate the carbon dioxide but care would be needed in the case of TN,2 port,and bag kit products,since little air has been removed.

View full abstract