[A Case of Total Hip Arthroplasty with Massive Bleeding due to Metastatic Tumor].

A male patient in his eighties was admitted to our hospital complaining of right coxalgia. Total hip arthro- plasty was performed under general anesthesia com- bined with epidural anesthesia. During the operation, massive bleeding occurred accidentally due to meta- static bone tumor. Intraoperative autologous blood transfusion was useful for maintenance of hemody- namics of the patient Intraoperative autologous blood transfusion may be effective in an oncologic operation with massive bleeding.

Synthesis and structure-activity relationships of novel benzofuran farnesyltransferase inhibitors.

A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC(50)=1.1nM) and antitumor activity in human cancer xenografts in mice.

Differential effects of isoflurane on A-type and delayed rectifier K channels in rat substantia nigra.

The authors previously demonstrated that isoflurane, a widely used volatile anesthetic, induced depolarization and increased the frequency of spontaneous action potentials in principal dopamine neurons in rat substantia nigra pars compacta. We studied the effects of isoflurane on voltage-dependent K channels to clarify the mechanisms of the increase in excitability in these neurons. Voltage-clamp whole-cell recordings were made in rat midbrain slices. We recorded the outward membrane currents in response to depolarizing voltage steps from -120 mV and -25 mV and isolated the transient outward current mediated through A-type K channels by subtraction. Isoflurane at clinically relevant concentrations accelerated the decay of the A-type K current and delayed the recovery from inactivation without changing the steady-state inactivation curves. Isoflurane did not affect the non-inactivating outward current. Addition of 4-aminopyridine partially occluded the excitatory effects of isoflurane in current-clamp recordings. These results demonstrate that isoflurane accelerated the inactivation and delayed the recovery from inactivation of A-type K channels in principal neurons in rat substantia nigra pars compacta without affecting delayed rectifier K channels. These effects may contribute in part to excitation of these neurons and the isoflurane-induced increases in dopamine release reported in vitro and in vivo.

Synthesis and biological activities of benzofuran antifungal agents targeting fungal N-myristoyltransferase.

The C-4 side chain modification of lead compound 1 has resulted in the identification of a potent and selective Candida albicans N-myristoyltransferase (CaNmt) inhibitor RO-09-4609, which exhibits antifungal activity against C. albicans in vitro. Further modification of its C-2 substituent has led to the discovery of RO-09-4879, which exhibits antifungal activity in vivo. The drug design is based on X-ray crystal analysis of a CaNmt complex with benzofuran derivative 4a. The optimization incorporates various biological investigations including a quasi in vivo assay and pharmacokinetic study. The computer aided drug design, synthesis, structure-activity relationships, and biological properties of RO-09-4879 are described in detail.

[Anesthetic management of a patient with tetra-amelia].

A 52-year-old man with Burger disease was admitted for hemorrhoidectomy. He lost upper and lower limbs 19 years earlier. We could not monitor his blood pressure with noninvasive technique. Bilateral superficial temporal arteries were not palpable. In the operating room, the external jugular vein was cannulated and an electrocardilgram and oxygen saturation was monitored. Anesthesia was induced with spinal anesthesia of 0.5% hyperbaric bupivacaine. His carotid artery was palpable and heart rate, oxygen saturation and his consciousness were stable during operation. He had an uneventful intra- and post-operative course. Preoperative evaluation of surgery and monitoring may be needed in patients with tetra-amelia.

[Sudden onset of EDTA-dependent pseudothrombocytopenia in a patient scheduled for open heart surgery].

A 60-year-old woman scheduled for mitral and aortic valve replacement had sudden onset of thrombocytopenia without clinical symptoms. The platelet count was found to decrease after the sampling. Microscopic examinations confirmed platelet aggregations. Changing anticoagulant added to blood samples from EDTA to heparin resolved such platelet aggregations. This phenomenon was diagnosed as demonstrating EDTA-dependent pseudothrombocytopenia and the operation was performed as scheduled without platelet transfusion. Postoperative course was almost uneventful and the patient was discharged on 26th day after surgery. EDTA-dependent pseudothrombocytopenia must be ruled out when patients have thrombocytopenia without certain causes such as infections, drugs, or autoimmune diseases.

[Severe hypotension and atrio-ventricular block in a patient of left lung cancer associated with myocardial bridging].

A 74-year-old man with myocardial bridging was referred to our hospital for operation of the left lung cancer. He underwent upper lobectomy of the lung under general anesthesia. After lobectomy and bilateral lymph node resection, severe hypotension occurred without ECG change. The blood pressure was restored by cardiac massage and the administration of fluids and vasoactive agents. After the closure of the sternum, hypotension occurred again and complete A-V block appeared. After resuscitation, A-V block disappeared. He was extubated the day after surgery without any neurogical deficit. We consider that hypovolemia and myocardial bridging induced hypotension and complete A-V block.

Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 3.

A new series of acid-stable antifungal agents having strong inhibitory activity against Candida albicans N-myristoyltransferase (CaNmt) has been developed starting from acid-unstable benzofuranylmethyl aryl ether 2. The inhibitor design is based on X-ray crystallographic analysis of a CaNmt complex with aryl ether 3. Among the new inhibitors, pyridine derivative 8b and benzimidazole derivative 8k showed clear antifungal activity in a murine systemic candidiasis model.

Crystal structures of Candida albicans N-myristoyltransferase with two distinct inhibitors.

Myristoyl-CoA:protein N-myristoyltransferase (Nmt) is a monomeric enzyme that catalyzes the transfer of the fatty acid myristate from myristoyl-CoA to the N-terminal glycine residue of a variety of eukaryotic and viral proteins. Genetic and biochemical studies have established that Nmt is an attractive target for antifungal drugs. We present here crystal structures of C. albicans Nmt complexed with two classes of inhibitor competitive for peptide substrates. One is a peptidic inhibitor designed from the peptide substrate; the other is a nonpeptidic inhibitor having a benzofuran core. Both inhibitors are bound into the same binding groove, generated by some structural rearrangements of the enzyme, with the peptidic inhibitor showing a substrate-like binding mode and the nonpeptidic inhibitor binding differently. Further, site-directed mutagenesis for C. albicans Nmt has been utilized in order to define explicitly which amino acids are critical for inhibitor binding. The results suggest that the enzyme has some degree of flexibility for substrate binding and provide valuable information for inhibitor design.

Cassette dosing approach and quantitative structure-pharmacokinetic relationship study of antifungal N-myristoyltransferase inhibitors.

Pharmacokinetic (PK) parameters of N-myristoyltransferase (Nmt) inhibitors were measured, and a multivariate quantitative structure-pharmacokinetic relationship (QSPKR) model for predicting rat elimination half-life (t(1/2)) values was constructed. One hundred seven benzofuran derivatives have been selected as the data set for QSPKR analysis. The correlation between the t(1/2) values and 30 physicochemical descriptors was examined by a stepwise multiple linear regression method. The statistical analysis gives a significant QSPKR model (r = 0.843) with the following three variables: partial negative surface area (PNSA), atomic-based octanol/water partition coefficient (AlogP), and the number of rotational bonds (Rotlbonds). The QSPKR model obtained is predictive and simple, and would give a direction for designing new Nmt inhibitors having good PK profiles.

[Clinical use of the VIA Blood Gas Monitor System].

VIA Blood Gas Monitor System (Baxter) withdrawals and reinforces blood automatically and measures pH, PaCO2, PaO2, sodium, potassium, and hematocrit. We evaluated VIA for use during cardiopulmonary bypass in 8 patients and during differential lung ventilation in 6 patients. The bias and precision were calculated on all the measured parameters. A total of 127 blood samples were obtained for comparison. Blood gas data measured by VIA were clinically acceptable except sodium. These findings suggest that VIA is useful for the management of patients in whom frequent arterial gas measurements are necessary.

Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 2.

Modification of the C-2 position of a benzofuran derivative 6 (RO-09-4609), an N-myristoyltransferase (Nmt) inhibitor, has led us to discover antifungal agents that are active in a murine systemic candidiasis model. The drug design is based on the analysis of a crystal structure of a Candida Nmt complex with 2. The optimization has been guided by various biological evaluations including a quasi in vivo assay and pharmacokinetic analysis.