FR209602 and related compounds, novel antifungal lipopeptides from coleophoma crateriformis no. 738. II. In vitro and in vivo antifungal activity

The biological activities of the novel echinocandin-like lipopeptides, FR209602, FR209603 and FR209604, were evaluated. These compounds showed antifungal activity against Candida albicans and Aspergillus fumigatus attributed to inhibition of 1,3-beta-glucan synthesis. The minimum effective concentrations of these compounds against C. albicans and A1. fumigatus ranged from 0.02 to 0.04 microg/ml by microbroth dilution assay, and the IC50 values on C. albicans 1,3-beta-glucan synthase were 0.49, 0.64 and 0.72 microg/ml, respectively. FR209602 and FR209603 showed good efficacy by subcutaneous injection against C. albicans in a murine systemic infection model, with ED50 values of 2.0 and 1.9 mg/kg, respectively.     

Pharmacological profiles of the novel analgesic M58996 in rat models of persistent and neuropathic pain

We investigated the effects of 4-(N-{1-[2-(4-cyanophenyl)ethyl]-4-hydroxypiperidin-4-ylmethyl}-N-methylamino)benzoic acid monohydrochloride (M58996), a novel analgesic, on persistent and neuropathic pain in rats. In the formalin test, oral M58996 (0.3 - 10 mg/kg) reduced nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58996 (1 - 10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses of the uninjured paw. High doses (10 - 100 mg/kg) of oral M58996 did not influence normal motor function. Thus, M58996 had a wide dose range showing antinociceptive, antiallodynic, and antihyperalgesic effects without motor dysfunction. In addition, we studied the possible mechanisms involved in the M58996-induced antinociception. The antinociceptive effect of M58996 was reversed by intrathecal pertussis toxin, an inhibitor of the inhibitory- and other-GTP-binding protein (G(i/o) protein), but not by subcutaneous naloxone, an opioid-receptor antagonist. This effect was also reversed by intracerebroventricular or intrathecal tropisetron, a 5-hydroxytryptamine(3) (5-HT(3))-receptor antagonist, and intraperitoneal bicuculline, a gamma-aminobutyric acid(A) (GABA(A))-receptor antagonist. These results suggest that M58996 produces its antinociceptive effect by a pertussis toxin-sensitive G protein mechanism. In addition, the GABA released by the activation of supraspinal and/or spinal 5-HT(3) receptors is likely to contribute to the M58996-induced antinociception.     

Pyocephalus in a case of encephalocele and Arnold-Chiari anomaly: interactions between malformations and inflammation

This report deals with a 7-wk-old infant with an unusual tamponade empyema of the ventricular system associated with an occipital encephalocele and Arnold-Chiari anomaly. The infection extended from the ruptured encephalocele to the ventricular system. Arnold-Chiari malformation locked the infection within the ventricular system through herniation and occlusion of the ventricular foramina and prevented from spreading into subarachnoid space. The long survival of the infant allowed for the formation of pyocephalus. There was also an extensive coarctation of the ventricular walls and aqueductal occlusion which probably resulted from the infectious process in the early postnatal life.     

Studies on phage type, beta-lactamase activity and sensitivity of multiple drug-resistant Staphylococcus aureus isolated from clinical specimens to cefmetazole

The 868 strains of S. aureus were isolated at the Department of Pediatrics, Third Hospital and Aoto Hospital, The Jikei University, School of Medicine and the Kanagawa Prefectural Nursing and Hygienic School Hospital during 6 months from May to October in 1981. From them 66 strains not sensitive to CEZ were selected by a 3-concentration disk method. A total number of 54 strains except for 12 isolated from the same infant patient was examined for their MIC's for 6 drugs, CMZ, CEZ, CTM, CXM, MCIPC and GM. Moreover, phage typing and beta-lactamase activity determination were carried out in them. 1. Antibacterial activity Sixty-six (7.6) of 868 strains were not sensitive to CEZ. The MIC's of CMZ against these resistant strains were between 1.56 and 50 micrograms/ml with a peak between 3.13 and 6.25 micrograms/ml when the 10(5) cells/ml bacterial suspension were inoculated. CMZ was superior in antibacterial activity to CEZ and CXM by about 4 degrees and to CTM by about 3 degrees. MCIPC and GM has higher antibacterial activity against a few strains than CMZ. However, the number of strains with MIC higher than or equal to 50 micrograms/ml was 17 for MCIPC and 40 for GM, but only 2 for CMZ. Thus, the former 2 drugs were far inferior to the latter one. 2. Phage type (1) Nineteen strains (35.2%) had MIC's for CEZ greater than 50 micrograms/ml and CMZ less than 6.25 micrograms/ml. Seventeen of them belonged to the nontypable. (2) Fourteen (25.9%) had MIC's for CEZ greater than 100 micrograms/ml. Of them 9 were allocated to the group III, 3 to the mixed (I + II + III, I + III) group and 2 to the nontypable. (3) Of 20 strains (37.0%) which had MIC's for CEZ greater than 100 micrograms/ml and CMZ less than 6.25 micrograms/ml 5 belonged to the group I, 3 to the group III and 12 to the nontypable. (4) Five strains classified into the group I were all isolated at the Kanagawa Perfectural Nursing and Hygienic School Hospital. (5) Eleven of 15 strains belonging to the group III were isolated at the Third Hospital, The Jikei University, School of Medicine. (6) Seventeen of 21 strains isolated at the Aoto Hospital, The Jikei University, School of Medicine belonged to the nontypable. (7) Phage type was considered to be influenced by difference in areas, infection within hospitals, etc., 3. beta-Lactamase activity beta-Lactamase activity was demonstrated at levels between 0.07 and 3.26 mumol/min/mg in all 54 strains. There was no correlation between MIC for CEZ or CEZ and beta-lactamase activity. It was suggested that beta-lactamase might not contribute to mechanism of resistance of S. aureus to each drug examined.     

A case of thyroid carcinoma required the incision of the thyroid cartilage for inserting the silicone T tube after extensive tracheal resection and reconstruction

A 57-year-old female with thyroid carcinoma, who had developed tracheal stenosis, underwent extensive tracheal resection and reconstruction. After the tracheal sleeve resection 5.2 cm in length, primary tracheal reconstruction was performed. Although complication did not occur at the anastomotic site, the patient had dyspnea due to cord dysfunction by bilateral recurrent nerve paralysis. After 20 days transnasal intubation we reoperated to perform a tracheostomy under neck incision. But the reconstructed trachea was too short to pull out from the mediastinum. In order to insert the silicone T tube, the incision of thyroid cartilage must be done and vocal cords were injured. The patient inserting the T tube through the laryngeal stoma had no dyspnea and no aspiration about two years after the operation in spite of palliative operation. It seemed likely that the trouble that tracheostomy could not be done would occur in some patients who had undergone extensive tracheal resection and reconstruction. But the insertion of silicone T tube through the laryngeal stoma provided a satisfactory result for airway problem.     

New technique for measurement of microvascular pressure in normal and tumor vessels of rats

A new type of rat transparent chamber was developed to measure the microvascular pressure. One side of this chamber consists of an airtight space, covered with a thin plastic membrane, through which either normal or tumor microvascular pressure was measured. The microvascular pressure in tumor tissue was usually lower than that in normal subcutis. When the systemic blood pressure was elevated by continuous infusion of angiotensin II, the microvascular pressure in tumor increased markedly. The results are discussed in correlation with the mechanism of enhanced chemotherapeutic effect in cancer by angiotensin II.