Saeko Anjo

A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin

AbstractA hypercholesterolemic patient medicated with cerivastatin for 22 days resulted in acute rhabdomyolysis. CYP2C8 and CYP3A4 are the major enzymes responsible for the metabolism of cerivastatin, and a transporter, OATP2, contributes to uptake of cerivastatin to the liver. In this study, the patients DNA was sequenced in order to identify a variant that would lead to the adverse effect of cerivastatin. Three nucleotide variants, 475delA, G874C, and T1551C, were found in the exons of CYP2C8. The patient was homozygous for 475delA variant that leads to frameshift and premature termination. Accordingly, the patient is most likely lacking the enzyme activity. The patients children were both heterozygous for the mutation. The patient had three nucleotide variants in exon 4 (A388G) and exon 5 (C571T and C597T) of OATP2 that were all heterozygous. No nucleotide variation in the exons of CYP3A4 was identified. To our knowledge, this is the first report showing that the adverse effect of cerivastatin might be caused by the genetic variant of CYP2C8.

Comparison of the complexation of fluoroquinolone antimicrobials with metal ions by nuclear magnetic resonance spectroscopy

The complexation of fluoroquinolone antimicrobials with various metal ions have been studied in aqueous solution (pD 2.5, 37 degrees C) by 1H and 13C-NMR spectroscopy. The compounds examined are levofloxacin, ciprofloxacin and lomefloxacin. In each drug, new signals have appeared by the addition of Al3+, suggesting that the complexes are formed between the drug and Al3+ and that the ligand exchange is slow on the NMR time scale. Solution structure of the major species in the presence of 2.0 mol equiv of Al3+ has been proposed based on the large downfield shifts of some specific protons. Signals of both the coordinated and free drugs have shown slight broadening at 90 degrees C due to the enhanced rate in ligand dissociation process, though the coalescence phenomena are not observed even at this temperature. Thus, the complexes are supposed to be stable at the physiological condition. Titration experiments have revealed that the binding ability of levofloxacin toward Al3+ is much stronger than that of ciprofloxacin and lomefloxacin at pD 2.5. In contrast to the complexation with Al3+, the binding of these drugs with other metal ions such as Ca2+ and Mg2+ is much weaker; NMR signals have shown no appreciable downfield shift by the addition of Ca2+ and Mg2+. Based on these results, it is concluded that the fluoroquinolone antimicrobials examined in the present study at pD 2.5 exist as stable complexes in the presence of Al3+ and the absorptivity of the drugs on oral administration could be affected by Al3+.

Clinical Usefulness of Losartan, an Angiotensin II Receptor Antagonist with a Uricosuric Effect, and the Influence of Aspirin on the Effect in Hypertensive Patients with Hyperuricemia

Losartan, an angiotensin II receptor antagonist, has been reported to decrease the serum uric acid (SUA) level and increase the urinary excretion of uric acid. This action might be beneficial in hypertensive patients, who frequently suffer from hyperuricemia and sometimes gout. The aims of this study were to evaluate the uricosuric effect of losartan on hypertensive patients with hyperuricemia (SUA>7mg/dL), identify factors that influence the uricosuric effect of losartan, and determine whether or not medication of hyperuricemia with other drugs is necessary.A total of 28 hypertensive patients with hyperuricemia were studied retrospectively (no medication for hyperuricemia). Aspirin was found to be a factor that influences the uricosuric effect of losartan (p= 0.088). In hypertensive patients with hyperuricemia treated with aspirin medication (N = 7), losartan did not significantly decrease the SUA levels from 8.56 ± 0.66 to 8. 29 ± 0. 40mg/dL. Moreover, none of the patients had their SUA controlled of a normal level by losartan. In hypertensive patients with mild hyperuricemia (7.0≤SUA<8.0, without aspirin medication, N=12), losartan decreased the SUA level significantly from 7.35±0.08 to 6.85±0.32mg/dL. In five of the 12 patients, losartan controlled SUA at a normal level. Therefore, when losartan is prescribed to these patients, the treatment of mild hyperuricemia may not require the use of other drugs. In hypertensive patients with severe hyperuricemia (8.0≤SUA, without aspirin medication, N=9), losartan decreased the SUA level significantly from 9.55±0.57 to 8.21±0.35mg/dL. However, none of the patients had their SUA controlled at a normal level by losartan. Although the decrease of SUA level by losartan can be expected in these patients, the control of SUA at a normal level could not be expected. Therefore, the treatment of hyperuricemia with other drugs is considered to be required for these patients. Losartan may be a useful therapeutic drug to control the blood pressure and SUA levels in hypertensive patients with mild hyperuricemia

Quality and clinical effects of ipecac syrup.

In our hospital we prepared ipecac syrup from various lots of powdered ipecac available on the market, and we made an alkaloid assay of ipecac using HPLC method.Total ether-soluble alkaloids of the lots of powdered ipecac were in conformity with the regulation by JP XI. However, the ratio of emetine to cephaeline, which affects the vomiting action, was found to be different for each lot of powdered ipecac.Ipecac alkaloid assay using HPLC was simple to perform, in comparison with the USP method: the HPLC method requires no extraction.At our hospital, 90% of 71 pediatric patients who had mistakenly ingested a dangerous substance, were clinically treated with ipecac syrup.Incidence of accidental ingestion of substances among young children is so high that the regulation of the content of emetine and cephaeline in powdered ipecac seems to be required.

The release of rifampicin from rifampicin gel containing polymer.

Rifampicin (RFP) gels were prepared by using polymer, surfactant and water, and their pharmaceutical characteristics were evaluated. Sodium polyacrylate (PAA-Na) and sodium carboxymethyl cellulose (CMC-Na) were used as polymers, and polysorbate 80 (Tween 80) and hydrogenated castor oil-polyoxyethylene castor oil (HCO-60) were used as surfactants. The release of RFP from the gel was measured through a cellulose membrane (Millipore Co.) using a dissolution test instrument (Toyama Sangyo Co.). Furthermore, the gels characteristics in viscosity were evaluated with a viscometer.The following results were obtained:1. As the viscosity of the gel base is increased, the release of RFP from the gel base decreases. 2. The RFP release rate from gel base containing PAA-Na was higher than that containing CMC-Na. 3. No significant effect of surfactant concentration on the release of RFP from the gel base was found. 4. The pharmaceutical design of RFP gel including a polymer may be possible by further studies of stability, rheology and bioavailability.