[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. V. Drug-induced gastrointestinal system disorders].

OBJECTIVES: The purpose of this study was to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms (complaints) of patients. This time, we focused and studied on drug-induced gastrointestinal system disorders. METHODS: We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) since 1987. We studied 224 cases of drug-induced Gastrointestinal System Disorders (stomach or colon disorders: 148, esophagus disorders: 31, pancreas disorders: 45) cumulated in the CARPIS database. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. We estimated 224 cases using these evaluation scores. RESULTS: We could estimate 137 cases (92.6%) in 148 cases to be stomach or colon disorders by the use of these evaluation scores. The validity of this evaluation scores was estimated to be as follows: Sensitivity = 92.6%, Specificity = 95.0% and Predictive Value of Positive Test (PVP) = 96.5%. The positive likelihood ratio (LR) was 18.5 and negative likelihood ratio was 0.08. On the other hand, in the case of esophagus disorders, PVP was 84.8% and LR was 18.1. In the case of pancreas disorders, PVP was 90.7% and LR was 21.7. CONCLUSIONS: In this study, PVP and LR values were good. We thought that these evaluation scores could pick up the drug-induced gastrointestinal system disorders efficiently. We reported previously the evaluation scores about drug-induced liver disorders, extra-pyramidal symptoms, leukopenia and eruption before. In order to apply these evaluation scores onto the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions. As a result, the adverse reactions symptoms of each one defined more.

[Application study of drug information to proper use of drugs--estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients].

We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) since 1987, and the case reports of adverse drug reactions accumulated in the CARPIS database to be total about 20,000. The purpose of our study is to develop, implement, and assess an estimation procedure for preventing the adverse drug reactions by subjective symptoms (complaints) of patients using this CARPIS. The case reports of the adverse reactions are not a systematical study and are elapse reports by the case, which encountered on the way of the cure. Therefore, it might be possible to use as the data if not gaining enough evaluation. Especially, the abstracts in the annual meeting of the society are fragmentary and does not often have objective evidence. Therefore, we contrived an original evaluation method and carefully selected the case reports for our study. Also, the adverse reactions are very colorful and it is difficult to handle them at once. Therefore, we study every organ and want to aim to make a finally all-round format. We reported on the Liver disorders, the Extra-pyramidal symptoms, the Drug eruption, the Leukopenia and so on. We discovered that there was an adverse reaction which shows very peculiar subjective symptoms (ex. Extra-pyramidal symptoms) and unpeculiar subjective symptoms (ex. Leukopenia). We want to show our point of view and the future of our study below.

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. IV. Drug eruptions].

OBJECTIVES: The purpose of this study is to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms (complaints) of patients. This time, we focused and studied on drug eruptions. METHODS: We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) since 1987, and the case reports of adverse drug reactions accumulated in the CARPIS database to be total about 20,000. We studied 1473 cases of drug eruptions cumulated in CARPIS database. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. We estimated 1473 cases using this evaluation scores. RESULTS: We could estimate 1455 cases (98.8%) in 1473 cases to be drug eruptions using this evaluation scores. The validity of this evaluation scores were sensitivity = 98.8%, specificity = 91.0% and predictive value of positive test = 99.4%. The positive likelihood ratio was 11.0 and negative likelihood ratio was 0.01. CONCLUSIONS: This study confirmed the validity of our evaluation scores. We reported the evaluation scores about drug-induced liver diseases, drug-induced extra-pyramidal symptoms and drug-induced leukopenia before. In order to apply these evaluation scores to the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions.

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. III. Drug-induced leucopenia].

OBJECTIVES: The purpose of this study was to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms (complaints) of patients. This time, we carried out this study focusing on drug-induced leucopenia. METHODS: We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) since 1987, and the total number of case reports of adverse drug reaction accumulated in the CARPIS database amounts to about 16,000. Using the date obtained from 139 cases of drug-induced leucopenia accumulated in the CARPIS database, we investigated a relationship between leucopenia and patients. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. RESULTS: We could estimate 91 cases (65.5%) in 139 cases to be drug-induced leucopenia by the use of these evaluation scores. The validity of this evaluation scores was estimated to be as follows; sensitivity = 65.5%, specificity = 80.0% and predictive value of positive test (PVP) = 82.0%. The positive likelihood (LR) ratio was 3.3 and negative likelihood ratio 0.43. CONCLUSIONS: In this study, PVP and LR values were not good, because among the symptoms of leucopenia a very few specific symptoms could be detected. But we reported previous by the evaluation scores about drug-induced liver disorders. Therefore, in order to apply these evaluation scores to the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions. In the future, we plan to examine other adverse reactions which adds the data to this form.

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. II. Drug-induced extrapyramidal symptoms].

OBJECTIVES: The purpose of this study was to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms (complaints) of patients. This time, we focused and studied on drug-induced extrapyramidal symptoms. METHODS: We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information Systems) since 1987, and the case reports of adverse drug reaction accumulated in the CARPIS database to be total about 16,000. We studied for 180 cases of drug-induced extrapyramidal symptoms cumulated in CARPIS database. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. We estimated 180 cases using these evaluation scores. RESULTS: We could estimate 178 cases (98.9%) in 180 cases to be drug-induced extrapyramidal symptoms using these evaluation scores. The validity of these evaluation scores were sensitivity = 98.9%, specificity = 98.0% and predictive value of positive test = 98.9%. The positive likelihood ratio was 49.5 and the negative likelihood ratio was 0.01. CONCLUSIONS: This study confirmed the validity of our evaluation scores. We reported the evaluation scores about drug-induced liver diseases before. Therefore, to apply these evaluation scores onto the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions.

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. I. Drug-induced liver disorders].

The purpose of this study was to develop, implement, and assess an estimation procedure for preventing drug-induced liver disorders. We have built a database for CARPIS (case reports of adverse drug reaction and poisoning information services) since 1987, and the case reports of adverse drug reaction accumulated in the CARPIS database to be total about 11,000. We studied the estimation procedure by evaluating the subjective symptoms, backgrounds and laboratory data of patients in 199 cases cumulated in the CARPIS database. The evaluation scores were created on the basis of the subjective symptoms and backgrounds of the patients. Then, we re-estimated 199 cases with the evaluation scores, among which were 165 cases (82.9%) in 199 cases drug-induced liver disorders. For the rest of 34 cases (17.1%) drug-induced liver disorders could not be estimated from our evaluation scores. These 34 cases were either those which the subjective symptoms were not described in their reports, because the patients were hospitalized for other diseases and drug-induced liver disorders were discovered by a clinical examination, or cases of infants for whom it was difficult to confirm the subjective symptoms. The validity of this evaluation scores were sensitivity = 82.9%, specificity = 91.0% and predictive value of positive test = 94.8%. To apply this evaluation scores onto the clinical practice, we prepared an evaluation form for the subjective symptoms and backgrounds of the patients with drug suspecting-induced liver disorders.

Comparative study on the clinical efficacy of theophylline variable serum concentrations therapy and round-the-clock therapy.

Depending on the administration method, highly effective therapeutic variable serum concentrations (VSC) of theophylline can be attained only in the time range of frequent asthma attacks. We used an oral sustained-release theophylline preparation in seven patients with bronchial asthma (two males and five females; mean age: 38.7 years) who had required more than two admissions per year due to bronchial asthma attacks, despite being treated with round-the-clock (RTC) therapy of theophylline and inhalation of steroids. We examined the annual frequency of admissions and the peak expiratory flow rate (PEFR) in remission. Even though no difference was noted in the serum concentrations of theophylline in the morning (the time range of attack) between RTC therapy and VSC therapy, the mean number of admissions during VSC therapy was 1.14, compared with 3.86 recorded during RTC therapy (p < 0.001). PEFR in remission showed a significant improvement with VSC therapy, compared with PEFR recorded during RTC therapy (p < 0.05). VSC therapy proved to be useful for patients who failed to attain favorable control of asthma attacks by RTC therapy.

Significance of the therapeutic range of serum theophylline concentration in the treatment of an attack of bronchial asthma.

The purpose of this study was to evaluate the accuracy of the recommended theophylline therapeutic range in the treatment of acute airway obstruction. Twenty seven patients (20 to 64 years) with acute asthma attack were given aminophylline intravenously to obtain a theophylline concentration between 10 and 20 micrograms/ml. Peak expiratory flow rates (PEFR) and serum theophylline concentrations were measured before and after aminophylline injection. When a marked improvement was not seen after aminophylline injection, the treatment was followed by inhalation of a beta-agonist and intravenously administered hydrocortisone. In order to clarify the relationship between theophylline efficacy at a therapeutic level and PEFR, as measured before aminophylline administration, the patients were classified into four groups. Group A (n = 7): asthma attack persisted regardless of treatment with aminophylline, beta-agonist and hydrocortisone, group B (n = 7): asthma attack improved by aminophylline, beta-agonist and hydrocortisone, group C (n = 6): asthma attack improved by both aminophylline and beta-agonist, group D (n = 7): asthma attack improved by intravenous aminophylline alone. The means (+/- S.E.) PEFR before aminophylline administration were 94.3 +/- 11.31/min in group A, 114.3 +/- 10.01/min in group B, 196.7 +/- 22.21/min in group C, and 220.0 +/- 12.51/min in group D, respectively. There were significant differences in PEFR between the A and C, A and D, B and C, and B and D groups. These findings suggest that theophylline efficacy is not expected in patients with low PEFR (less than 2001/min) at the time of treatment of an attack, even if a therapeutic theophylline concentration was obtained.

[Radiation therapy for carcinoma of vagina].

Thirty-four patients with carcinoma of the vagina were treated by radiotherapy at the Hyogo Medical Center for Adults between April 1965 and May 1990. All patients were treated with a combination of external and intracavitary or intestinal irradiation. Twenty-three patients had squamous cell carcinoma, five had adenocarcinoma and two had malignant melanoma. The five-year survival of patients with squamous cell carcinoma was 70% in Stage I (10 patients), 40% in Stage II (seven patients), 50% in Stage III (three patients) and 0% in Stage IV (three patients). Local control was achieved in 72.7% of the patients with squamous cell carcinoma and 60% of those with adenocarcinoma. However, neither of the malignant melanomas was controlled. Five patients had severe complications that required surgical treatment: severe proctitis and small-bowel perforation, ileus, rectal stenosis, vesicovaginal fistula and small-bowel perforation. Local and pelvic failure was noted in three patients. Patients with previous hysterectomy were more likely to develop serious treatment-related complications.

[Assessment of urinary beta-core fragment of hCG as a tumor marker of cervical cancer].

Beta-core fragment (beta-CF), a fragment of the hCG beta-subunit missing its carboxyterminal peptide, can be detected in the urine of women throughout pregnancy or in trophoblastic disease. It is also found in the urine of patients with nontrophoblastic cancers. We examined the beta-CF level in urine samples from patients with cervical cancer and assessed its value as a tumor marker. beta-CF was measured by an enzyme immunoassay with hCG beta-core directed monoclonal antibody No. 229. Based on the cut-off value (0.2ng/ml) from control subjects, the overall positivity rate for urinary beta-CF in the cervical cancer group was 45% (57 of 128 patients), increasing from 32% (23 of 73) in stage I to 100% (2 of 2) in stage IV. These positivity rates exceeded or equaled those of the other markers, SCC, CEA, CA19-9 and CA125, simultaneously measured in the patients' serum. There was no significant difference between the positivity rates for the two histological types of cancer, squamous cell carcinoma and adenocarcinoma. Serial determination in 28 patients with increased urinary beta-CF prior to therapy showed that 24 patients had a decreased concentration after successful treatment, but 2 of 4 patients with still increased urinary beta-CF during or after treatment subsequently relapsed. The determination of urinary beta-CF may provide a useful tool in monitoring the response to treatment in patients with cervical cancer.

[The effect of mexiletine on theophylline pharmacokinetics in patients with bronchial asthma].

Reported side effects of mexiletine, a useful drug for managing premature ventricular contractions (PVC) and ventricular tachycardia (VT), are gastrointestinal symptoms including nausea and vomiting. Theophylline, a bronchodilator, also causes similar gastrointestinal symptoms with its frequency proportional to the increases in its serum concentration. The occurrence of gastrointestinal symptoms is known to increase in combination therapy of mexiletine and theophylline. However, the pharmacokinetic interaction between mexiletine and theophylline has not been clarified. We, therefore, investigated the effects of mexiletine on theophylline pharmacokinetics. Three patients with bronchial asthma complicating PVC and/or VT (one male and 2 females, aged 70.0 +/- 13.1 years) were studied. All patients were given prophylactic theophylline anticipatory for asthmatic attacks, which was followed by oral administration of mexiletine, 200-300 mg daily, for PVC and/or VT. The serum theophylline concentrations in 3 cases were increased from 13.8 to 25.3 micrograms/ml, from 14.6 to 27.8 micrograms/ml, and from 10.4 to 15.4 micrograms/ml, respectively, after the administration of mexiletine. However, significant decreases in theophylline clearance were observed after the administration of mexiletine by 46, 47 and 35%, respectively. (p < 0.05) With a decrease in theophylline dosage, the serum theophylline concentrations decreased, and gastrointestinal symptoms resolved. Theophylline is metabolized mainly in the liver through an oxidative reaction of p-450 enzyme, however, its metabolism is affected by many factors, such as medications and complications. The results of this study indicated that mexiletine decreases the theophylline clearance by inhibiting the p-450 oxidative reaction to theophylline.(ABSTRACT TRUNCATED AT 250 WORDS)

[Characterization of immunoreactive hCG beta-subunit in cultured fluids of the cell lines derived from gynecologic malignant tumors].

We characterize the hCG beta-like materials in cultured fluids from 12 different cell lines derived from gynecologic malignant tumors (SKG-1, -2, -3a and -3b cervical squamous carcinoma, SNG-M and -2 endometrial adenocarcinoma, SKN uterine sarcoma, RTSG ovarian undifferentiated adenocarcinoma, RMUG ovarian mucinous adenocarcinoma, RKN ovarian sarcoma, RMG ovarian clear cell carcinoma and NJG gestational choriocarcinoma) by three kinds of enzyme immunoassay (EIA) which were specific for whole hCG, free hCG beta and beta-core fragment, respectively. Of eleven nontrophoblastic cell lines, nine secreted hCG beta-like immunoreactive substance. The above-mentioned three EIAs for each fractionated specimens with gel chromatography on Sephadex G-100 revealed that the immunoreactivity in the SKG-2 and RTSG cultured fluids were totally attributable to free hCG beta but neither to whole hCG nor beta-core fragment. On the other hand, the NJG choriocarcinoma cell line secreted both whole hCG and free hCG beta, no beta-core fragment could be detected in the cultured fluid. The present results suggested that ectopically produced hCG beta-like material may represent the free hCG beta molecule, and that the beta-core fragment may not be a cellular secretory product.

[Electron microscopic and immunological studies concerning the effect on the antitumor activity of sizofiran (SPG) combined with radiotherapy for cervical cancer].

It has been well known that Sizofiran (SPG) cultured from the Schizophyllum commune Fries activates the macrophages and induces the cytotoxic lymphocytes in some cancers. In this study, we observed electronmicroscopically the macrophages around the cancer tissue from the patients with uterine cervical cancer after the treatment with SPG. At the same time, their immune responses were also examined by analyzing lymphocyte subsets, ADCC and NK activity in peripheral blood. A considerable number of erratic macrophage with well developed Golgi apparatus, endoplasmic reticulum and mitochondria were found in the uterine cervical cancer tissue from the patients treated with SPG under radiotherapy. Simultaneously, we identified the lysosome granules with a bright filament structure which appeared to be specific for SPG. In the immune responses evaluated by analyses of peripheral blood, the number of CD 16+ cells and NK activity significantly increased in the patients treated with SPG as compared with non-treated group. The present results indicate that SPG-immunotherapy combined with radiotherapy not only induces the cytotoxic activity of macrophage but also augments NK activity in the patients with uterine cervical cancer.

Evaluation of a new vasodilating beta-blocking agent, carvedilol, in exertional angina using holter monitoring.

Antianginal and antiischemic effects and clinical pharmacologic actions of carvedilol, a novel beta-blocking agent with a vasodilator action, were determined by Holter electrocardiographic monitoring in 13 patients with exertional angina. The patients were observed for 1 week prior to entry into the study, followed by 1 to 2 weeks of treatment with carvedilol. During the observation period the patients received one placebo tablet daily, and during the treatment period one 20 mg tablet of carvedilol daily. Before and after the treatment 24-hour Holter electrocardiographic tracings were obtained. The mean interval of Holter monitoring was 11.2 +/- 4.5 days for the observation and treatment periods, and the mean time of drug administration was 8:25 a.m. (+/- 30 min). The Holter electrocardiographic tracings which were obtained twice in 9 patients during the observation period showed a high degree of reproducibility with respect to the frequency, magnitude and duration of ST-segment depression. The total frequency of ST depression per patient was 4.5 +/- 3.4 events/day pre-drug and 2.1 +/- 2.1 events/day post-drug. There was a significant reduction in total frequency of ST depression post-drug (p less than 0.01). The frequency of asymptomatic ST depression was similarly decreased post-drug (p less than 0.01), and the total magnitude and duration of ST depression were significantly improved post-drug (p less than 0.01 and p less than 0.05, respectively). These effects of carvedilol lasted for 24 hours after administration. Considering that the heart rate was not excessively reduced during the night, and nocturnal myocardial ischemic episodes were not exacerbated, the mode of action of this drug seems to be based on not only a beta-blocking action but also on a vasodilator action. Carvedilol benefits exertional angina when used in a 20 mg s.i.d. regimen.

[Cytological and histological effects of regional hyperthermia and radiation in cancer of the uterine cervix].

Hyperthermia is known to produce tumor-specific effect. Its combination with radiotherapy has been found to enhance antitumor effect and hyperthermia is a new modality of cancer treatment. Here, we report a cytological and histopathological study of the effects of hyperthermia on uterine cervical cancer. Our subject cases were 63 patients with cervical cancer (squamous cell carcinoma). Thirteen cases were treated with hyperthermia. Of these, the clinical stage was I b in 2, stage II in 10, stage III in 1. Before radical operation, external irradiation was given at 40Gy. with Lineac. During this period, the lesion was treated with hyperthermia at 42-45 degrees C for 30-60 min. with a 13.56 MHz RF capacitive heating system "Endoradiotherm 100A" (Kureha Chemical Industry CO. Ltd.) and an intraluminal applicator designed for uterine cervix. The control cases received radiotherapy alone before radical operation. There were 15 cases in Stage I b, 19 in stage II, and 16 in stage III. After the completion of radiotherapy, radical hysterectomy was performed in all cases. The effects of irradiation on the lesion were compared cytologically and histologically for different doses. The evaluation of the irradiation damage in cancer cells in the cytological study was based on findings such as intracytoplasmic vacuolation, the formation of giant nuclei, intranuclear vacuolation and formation of polynuclei. The degree of irradiation damage was classified into 5 grades from Do (little irradiation effect) to Dx (no viable cancer cells remaining), and the irradiation effect in the histopathological study was classified in to 8 grades from Grade 0 to Grade IVC according the Oboshi and Shimosato's classification. Cytological changes at 10Gy. were rated as D3 (relatively extensive irradiation damage in cancer cells) in 38.5% of the hyperthermia group, as compared to about 20% in the control groups. The cases rated Grade II B histologically made up 38.5% of the hyperthermia group: this grade was about 10% in the control groups. This suggests that radiation was more effective in the hyperthermia group than in the control groups, as was also suggested by the cytological results. With irradiation at 30Gy., cytological changes were rated as Dx in 61.5% of the hyperthermia group, as compared to 25.0-26.7% of the control groups. Histological results were Grade III, with only cancer cells regarded as non-viable observed, in 38.5% of the hyperthermia group and Grade IV, with no cancer cells, in another 23.1%. In the control groups, there were no cases with Grade IV, and those with Grade III totalled 12.5-26.7%.(ABSTRACT TRUNCATED AT 400 WORDS)

[Cytologic studies of cervical adenocarcinoma].

Seventy three cases of cervical adenocarcinoma, classified histologically according to WHO classification, were cytodiagnostic examined for cellular arrangement, cellular shape, nuclear shape, chromatin pattern and appearance rate of nucleolus. In adenosquamous carcinoma, the observed cancer cells were classified further into five categories and the incidence of each type was clarified. The authors obtained the following conclusions. The cytological findings in cellular arrangement, cellular shape, chromatin pattern and nucleolus findings were closely related with the degree of differentiation of endocervical type adenocarcinoma. Since no substantial cytodiagnostic differences were seen between endometrioid adenocarcinoma and endocervical type adenocarcinoma, it appears to be difficult to differentiate between them. Clear cell adenocarcinoma is characterized by sheet-like cell arrangement, polycrystal cell shape, round nuclei, finely granular chromatin pattern and appearance of macronucleolus. Among them the occurrence of macronucleolus was clearly observed and appeared of high value in making a diagnosis. Adenosquamous carcinoma, showing no characteristic finding in cytology, is proved to have morphological diversity. Careful observation of the intermediate type cancer cells is necessary to presume the histology of adenosquamous carcinoma.

[Clinical studies on radical hysterectomy with preoperative external irradiation for stage III cancer of the cervix].

Full dose preoperative external irradiation was performed in cases of stage III cancer of the cervix (36 cases), and the effects were studied. The effects of preoperative irradiation on the operation, such as the time required for operation and the bleeding volume tended to be shorter and decreased, compared to stage III cases with postoperative irradiation (23 cases), and showed rather little difference when compared to cases of stage II with postoperative irradiation (85 cases). The postoperative effects, such as days required for the beginning of spontaneous urination, decrease in residual urine to less than 50 ml, and duration of fever (over 38 degrees C), did not differ from cases of stage III with postoperative irradiation, but there was a tendency to prolongation compared to cases of stage II. Histopathological examination of the specimen resected after the operation revealed that cancer parenchyma in the primary focus was influenced by irradiation in nearly 90% of cases, cancer cells showing degeneration and destruction with markedly decreased proliferative potentiality. Cases showing cancer infiltration into the vaginal stump and tip of the cardinal ligament were 8.3%, which was significantly lower than in stage III cases with postoperative irradiation. The frequency of metastasis to intrapelvic lymph node was 30.6%, significantly lower than 56.5% in stage III cases with postoperative irradiation, and lower than 36.5% in stage II cases. As to the postoperative complications raising clinical problems, disturbance of the urinary tract was noted in 52.8% and that of the rectum in 47.2%, but these complications became fatal in none.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-dependent pharmacokinetics of aprindine in healthy volunteers.

The disposition of aprindine following a single oral dose can best be described by a two-compartment open model. The mean plasma half-life (t 1/2 beta) increased from 8.0 +/- 2.1 h (SD) after a 25 mg dose of 9.4 +/- 2.9 h after 50 mg and to 15.8 +/- 2.6 h after 100 mg, with a decrease in total plasma clearance (Cl/F) and volume of distribution at steady state (V dss/F) and during beta-phase (V d beta/F). The area under plasma concentration-time curve (AUC), maximum plasma concentration (C max) and the amount of unchanged aprindine excreted in the urine increased in a non-linear fashion with the increase in dose. The t 1/2 beta after multiple oral doses showed a 3-fold increase over the single dose value. These results indicate that aprindine shows dose-dependent non-linear kinetics.