Akira Yamaji

Pharmacokinetic and Pharmacodynamic Interactions between Furosemide and Hydrochlorothiazide in Nephrotic Patients

We examined the response of 8 patients with nephrotic syndrome (creatinine clearance 70.4 +/- 16.0 ml/min) to oral furosemide (F; 40 mg) in the absence (control) and in the presence of oral hydrochlorothiazide (HCT; 100 mg). In the 24-hour period after oral F, HCT was shown to increase urine volume and urinary sodium and chloride excretion. Increment was most significant during the 12- to 24-hour period. Enhancement of the diuresis with HCT was associated neither with a significant increase in the area under the curve of plasma F concentration nor an increase in urinary F excretion. Urinary excretion of glucuronidated F, one of the main metabolites of F, however, was decreased with HCT. In summary, HCT significantly enhanced the response to F in nephrotic patients.

Vitamin A and E Requirements During Total Parenteral Nutrition

Studies were undertaken to determine rational dosages of vitamin A and E during long-term total parenteral nutrition (TPN). Four kinds of vitamin prescriptions containing different amounts of vitamin A and E were prepared from commercially available products and/or hospital pharmacy products. Patients were divided into four groups according to the vitamin prescription used. Plasma vitamin levels of different patient groups were determined by a modified fluorimetric method and were compared with those of a normal subject group. The stability of vitamin A and E in TPN solution after admixing was determining by measuring the remaining vitamin contents by high pressure liquid chromatography. From the results, it was concluded that 1) about 50% of vitamin A was decomposed by sunlight (about 2000 lux) 3 hr after admixing and an orange-colored vinyl cover could protect its photodecomposition; 2) vitamin E was stable at any condition tested; 3) 2500 IU of vitamin A and 15 IU of vitamin E could meet the daily requirements; 4) the plasma levels of vitamin A and E were correlative (p less than 0.01); and 5) concomitant administration of vitamin E was essential to keep the poorer level of vitamin A in plasma.

EFFECT OF MORPHINE ON SECRETION OF AMYLASE FROM ISOLATED PAROTID ACINI

The effect of morphine on amylase secretion was studied in isolated rat parotid acinar cells. It was found that aluminum fluoride (AlCl3/NaF) and dibutyryl-cyclic AMP but not by cyclic AMP, enhanced amylase secretion. Cyclic AMP was effective in enhancing secretion following permeabilization of cells with alpha-toxin. Following treatment of cells with alpha-toxin, both GTP and GTP-gamma-S also enhanced secretion. Morphine reduced AlCl3/NaF- or GTP-induced secretion of amylase, but was without effect on GTP-gamma-S-induced secretion. Photoaffinity labeling by the use of [32P] 4-azidoanilido GTP revealed its incorporation into 43 kDa and 31 kDa proteins. Incorporation was further enhanced with AlCl3/NaF. Morphine reduced labeling of the 43 kDa protein. Immunoblot analysis identified the 43 kDa GTP binding protein as Gs. When [gamma 32P] GTP was preloaded into permeabilized acinar cells and its hydrolysis measured, morphine stimulated and AlCl3/NaF inhibited GTPase activity. These results suggested the involvement of Gs in secretion of amylase. Furthermore, morphine reduced secretion of amylase by stimulating GTPase activity and by reducing the incorporation of GTP into Gs.

The urinary excretion of frusemide and its metabolites by kidney transplant patients

SummaryUrine from 5 renal transplant recipients treated with frusemide was analyzed for unchanged frusemide (F), glucuronidated frusemide (G) and 4-chloro-5-sulfamoylanthranilic acid (CSA) by HPLC.In 3 recipients, whose renal function recovered steadily and whose hepatic function was normal throughout, the ratio of frusemide to its metabolites, F/(F+G+CSA), increased steadily in conjunction with the recovery of renal function. In one patient, who received frusemide 200–400 mg/day i.v., the urinary CSA concentration was 64–102 µg·ml−1. In 2 patients who experienced shock and/or hepatic dysfunction after transplantation, the F/(F+G+CSA) ratio fluctuated.

Analysis of 7-methylguanine in deoxyribonucleic acids by high-performance liquid chromatography.

Abstract Conditions for the analysis of 7-methylguanine (7-MG) in the presence of major nucleic acid bases and other minor bases by means of high-performance liquid chromatography (hplc) were established. Purine bases were obtained by Chargaffs method to yield apurinic acid and were analyzed by hplc with strong cation-exchange resin, Zipax SCX. The method was applied to the determination of 7-MG in the liver DNA from rats treated with DMN and it was revealed that the results were comparable to those obtained by radioisotope method in terms of sensitivity and reproducibility. The lower limits of quantitation and detection of 7-MG were determined to be 10 and 4 ng, respectively.

Interference by danazol with the Porter-Silber method for determination of urinary 17-hydroxycorticosteroids

Cortisol undergoes comprehensive metabolic conversions to tetrahydrocortisol (THF), tetrahydrocortisone (THE) and allo-tetrahydrocortisol (allo-THF), which are excreted into urine mostly in conjugated forms, together with a trace amount of unchanged cortisol. As these compounds are the major constituents of 17-hydroxycorticosteroids (17-OHCS), the measurement of urinary 17-OHCS provides a good assessment of adrenocortical and pituitary function. In clinical laboratories, colorimetric methods based on the Porter±Silber (PS) reaction are widely used for inclusively determining urinary 17-OHCS, but it is known that this reaction system is susceptible to interference by drugs, endogenous steroids and other excretory substances. In this paper we examine whether danazol (17a-pregna-2,4-dien-20-yno[2,3-D] isoxazol17b-ol), a synthetic androgen, interferes with the measurement of urinary 17-OHCS by the PS method.

Pharmaceutical Examination on Alterations in the Absorbability and Ingestible dose of Phenytoin Due to a Formulation Change of a Phenytoin Powder Preparation

In our hospital, the dosage form of phenytoin (DPH) was switched from hospital pharmacy-made 50% fine granules to commercial 10% powder. We surveyed the change in the serum DPH concentration in epileptic patients administered both DPH formulations, and examined the pharmaceutical differences associated with the disposition of DPH. About a 25% elevation in the steady-state serum DPH concentration was found after changing from 50% fine gfanules to 10% powder, thus indicating the increase in the amount of DPH absorbed from the gastrointestinal tract. In a dissolution test, the rate of DPH release of 10% powder was similar to that of 50% fine granules irrespective of the medium conditions. These results were strongly suggestive of a bioequivalence between 50% fine granule and 10% powder in clinical practice. In dispensing 50% fine granules, there was not only a significant weight reduction at the dividing and packing steps but also considerable adsorption by the package, although this phenomenon tended to be attenuated by mixing the drug with lactose as vehicle. On the other hand, the 10% powder was highly recovered probably owing to the enhanced fluidity. There was no change in the DPH content per weight before and after dispensing process in each formulation, thus showing that the degree of weight reduction was consistent with that of the DPH loss. Based on the relative weight recovery of the preparations during the dispensing process, it is presumed that the ingestible dose of DPH was increased by about 6% due to the formulation change. The significant increase in serum DPH concentration after formulation change is likely to be attributed to an improvement in the dispensation loss prior to administration, because DPH shows non-linear pharmacokinetics within the therapeutic range. We consider that monitoring the serum DPH concentration is required especially when the other dosage forms are prescribed.

Urinary excretion of frusemide and its metabolites in a diabetic nephropathy patient

For many years the metabolism of frusemide was a highly controversial subject [1, 2]. We reported that in kidney transplantation patients to whom large doses of frusemide was given, a considerable amount of the metabolites of frusemide proposed, i.e. glucuronidated frusemide (G) and 4-chloro-5sulfamoylanthranilic acid (CSA), was excreted in their urine [3]. The importance of the dosage history on the appearance of CSA in the urine was emphasized. We have received some inquiries as to whether the above findings were specific only to kidney transplantation patients or not. In order to clarify this point, we present here a case who suffered from chronic renal failure due to diabetic nephropathy and was administered large dose of frusemide. Unchanged frusemide, G and CSA were determined by the HPLC methods as previously reported [3]. The case was a 69 year-old male. He had been suffering from diabetes mellitus since 1970 and from liver cirrhosis since 1984. He had been under insulin therapy since 1983 after sulfonylurea therapy for 3 years. The patient was admitted to Osaka University Hospital in March 1986 because of oliguria and dyspnea. On admission, marked ascites was noted. Laboratory data revealed azotemia (blood urea nitrogen 123 mg/dl, creatinine 4.2 mg/dl) and liver dysfunction (GOT53U/1, y-GTP171U/1, ALP 510 U/l, total bilirubin 2.1 mg/dl). Large doses of frusemide (100-500mg i.v. daily) were administered to the patient for more than three weeks. A summary of the data for five consecutive days is shown in Table 1. A considerable amount of CSA (2.78-26.55 mg/day) was excreted in the urine. A positive correlation (r=0.955, P<0.02) was found between the 24 h excretion of unchanged frusemide and sodium excretion. Although the number of the Table 1. Summary of patient data for 5 consecutive days

Studies on dissolution behaviors of extended-release articles.

The dissolution behavior of fifteen commercial extended-release articles was examined by the dissolution test in order to characterize their behavior in vitro. The articles were classified into six groups according to the formation types. The paddle method for six hours was used for tests, and the media were the first solution (pH 1.2) and the second solution (pH 6.8) in JP XI.Five articles showed different patterns in the above two media, so that their dissolution seemed to depend on pH. A few articles were also effected by pH on the dissolution although they showed time-dependent behavior. The others showed pH-independent (time-dependent) dissolution. The dissolution curves of time-dependent articles approximated to zero-order or firstorder kinetic model. There was, however, no significant relation between the formation type of articles and their dissolution behavior.In addition, for time-dependent articles, simulation curves of dissolution were calculated by using “Weibull function” with the data obtained from the dissolution test up to six hours. Since most of all curves conformed to the observed curves, the parameters of the simulation curves were re-calculated only with the data up to three hours to obtain the prediction curves. The predicted rate fitted well to the observed rate after six hours in many articles. Therefore the prediction curves could be applicable to shorten time for the dissolution test.

Pharmaceutical evaluation of change of phenytoin dosage form from powder to fine granule.

Phenytoin (PHT) fine granule, which has the same bioavailability as the tablet, has recently been marketed. We projected a change of PHT dosage form from usual powder to fine granule. In view of the fact that 97% of PHT products prescribed and marketed are available in fine granules, 50% PHT preparations were produced in hospital pharmacy. 5 kinds of preparations using various lactoses as diluents were prepared and tested for their quality. Among them, the preparation from Aleviatin fine granule passing through a 42-mesh sieve and EFC lactose showed the best results in the mixing property and various sense tests. The change to this dosage form and its bioavailability tests were carried out by a cooperation of doctors and pharmacists. Serum PHT levels of all patients, assayed by EMIT method, showed a 20% to 30% increase after the administration of the new preparation (50% PHT fine granule with EFC lactose).