Asebotoxin III (ATX-III), a diterpenoid isolated from the leaves of Asebi, Pieris japonica, was found to produce hemorrhage into the lungs when the toxin in a dose of 2-8 micrograms was injected into the lateral ventricle of guinea pigs under urethane anesthesia (0.8 g/kg, i.p.). The occurrence of the lung hemorrhage was associated with a hypertensive response which was two times higher than the control level. The hemorrhage first occurred at a time when systemic blood pressure reached its highest level. This was verified by X-ray examination on the chest of the guinea pig. In contrast to the hemorrhage into the lungs, the other organs in the abdominal cavity were found to be rather ischemic in the autopsy cases. Death due to hemorrhage into the lungs was effectively prevented by pretreating the guinea pigs with phentolamine mesylate (1 mg/kg, i.v.) and 6-hydroxydopamine hydrobromide (40 mg/kg, i.p.). Time before death was significantly prolonged by treating the animals with reserpine (5 mg/kg, i.m.), chlorpromazine hydrochloride (10 mg/kg, i.v.), guanethidine sulfate (20 mg/kg, i.v.), and hexamethonium bromide (5 mg/kg, i.v.), though death from the lung hemorrhage was not completely blocked. The hemorrhage was aggravated by pretreatment with atropine sulfate (5 mg/kg, i.v.). EEG recordings from the hypothalamus of guinea pigs with ATX-III injection showed an exciting pattern of waves of high frequency and spike discharge. On the mechanisms for the lung hemorrhage induced by ATX-III, we concluded that the toxin produced depolarization of some neurones in the hypothalamus, thereby provoking massive sympathetic discharge for producing severe pulmonary hypertension and hemorrhage.
Three autopsy cases of acute Klebsiella pneumonia were reported. Two of them were male leprosy patients in Komyoen Leprosarium and the other a female patient of a general hospital. All of them were over 50 years old. The onset of each case was sudden and they died within one week. However, physical examination of the lungs revealed mild deterioration in all cases. Their symptoms were not limited to the respiratory system.Autopsy findings revealed typical lobar pneumonia due to Klebsiella pneumoniae. Infection of this gram negative bacilli did not relate to leprosy; it is the same as other bacterial pneumonia which occurrs equally between leprous and non-leprous patients. The histopathological findings of the lung showed remarkable lymphocytic infiltration rather than polymorphonuclear leukocytic one; it was different from the description of textbooks. Infiltrating cells of pulmonary lesion were slightly different among the three cases. Old lepromata with a mild lymphocytic infiltration was seen in the liver, spleen or adrenal of leprosy cases. Acid-fast bacilli were not found in these lesions.Klebsiella pneumoniae is thought to exist in normal flora of the human pharynx. In our cases, leukopenia was not the cause of this infection. One leprosy patient was a heavy drinker. Alcoholism seemed to relate to etiology of the pneumonia; there had been little reference in previously reported cases in Japan. Sulfon therapy of long duration for leprosy may effect the human flora, but it was not clear in our cases. For treatment and improvement of prognosis, it is necessary to identify the bacilli and choose sensible antibiotics.
1) This paper summarizes the history of D. D. S. antileprotic treatmentt and introduces a part of studies on D. D. S, reported by the workers in many countries.2) 38 leprous patients containing 22 lepromatous, 6 tuberculoid and 1 neural were administered with D. D. S. over the period from 1 month to 18 months.3) The per os administration of D. D. S. began with 15mg per day and increased to 30mg, 50mg and 100mg at the interval of 2 months, and 100mg was continued. 2 cc of D. D. S. saline emulsion was applied to intramuscular injection.4) In the 22 lepromatous treated per os with D. D. S., 4 improved strikingly, 8 improved, 7 a little improved, 3 unchanged and non aggravated.5) The treatment result of D. D. S, injection will be reported later.6) Toxic manifestations were observed such as slight anemia in 3, neuralgia in 2 and palsy of sural nerve in 1 patients. Erythema nodosum leprosum appeared in 4 cases.7) D. D. S, has an excellent therapeutic effect upon leprosy and can be administered without any fear.
The degradation of [5S-[5alpha,6beta,7alpha(R*)]]-2-butyl-5-(1,3-benzodioxol-5-yl)-7-[(2-carboxypropyl)-4-methoxyphenyl]-6-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid (J-104,132) was studied in aqueous solution as a function of temperature and pH. The degradation reaction does not proceed to completion; rather, a stable equilibrium is attained in which approximately 2% of the degradate is produced. Kinetic data for the formation of the degradate are analyzed using an integrated form of the rate law for a reversible first-order reaction, and the forward and reverse rate constants and overall equilibrium constants are presented. Isolation and spectroscopic structural determination indicate that the degradate is the C7 beta-epimer of the drug. A mechanism for the epimerization reaction involving a novel enamine-like intermediate is proposed and shown to be consistent with the kinetic data. The rate and equilibrium constants are used to predict the room temperature stability of an injectable formulation of J-104,132, and these predictions are compared to actual data from long-term stability studies. It is concluded that the preformulation kinetic studies provide essential data needed for optimum drug product development.
Abstract IL-5 is a T cell-derived lymphokine that induces B cell growth and differentiation in murine systems. In this study, we examined the role of carbohydrate moiety of IL-5 in the expression of biological function. IL-5 polypeptides translated in Xenopus oocytes were heterogeneous in terms of isoelectric point (pI 4.7 to 8.0) and m.w. (45,000 to 60,000 under nonreducing conditions) and yielded m.w. of 25,000 to 30,000 under reducing conditions. Treatment of rIL-5 with N-glycanase under reducing conditions yielded an IL-5 monomer of m.w. 12,000 to 14,000. Furthermore, deglycosylated rIL-5 that had been translated in the presence of tunicamycin showed very limited heterogeneity by two-dimensional gel electrophoresis (first dimension, nonequilibrium pH gradient electrophoresis; second dimension, SDS-PAGE). The m.w. was 27,000 to 28,000 under non-reducing conditions and migrated to m.w. 13,000 to 14,000 under reducing conditions. These results indicate that IL-5 is a glycoprotein carrying the N-glycosidically-linked carbohydrates. Treatment of IL-5 with sialidase caused the decrease in the heterogeneity in isoelectric point of IL-5. Deglycosylated rIL-5 that had been obtained from tunicamycin-treated oocytes could bind to IL-5-responding cells (T88-M), which express both high- and low-affinity IL-5 receptors, as efficient as intact rIL-5 under high-affinity conditions. Scatchard plot analysis of equilibrium binding of 35S-labeled rIL-5 to T88-M cells revealed that the dissociation constants (Kd) of glycosylated rIL-5 and deglycosylated rIL-5 were 127 pM and 110 pM, respectively. IL-5 activities determined by both B cell growth and differentiation assays were not affected by deglycosylation. These results indicate that N-linked glycoside moiety of IL-5 molecules may not play an essential role in the expression of its activity.
This trial has been carried out by thirteen National Leprosaria and the National Institute for Leprosy Research since October, 1971. Observation has been made clini cally, bacteriologically, histopathologically and serologically at regular intervals through the trial.Pure lepromatous cases were selected and divided into following five groups, i.e., Group A, B, C (C-1, C-2) and D. Group A consisted of untreated new cases, and Group B relapsed cases. Group C consisted of so-called resistant cases ; and divided into C-1 and C-2 according to the duration of the past treatment. Group C-1 were cases showing poor recovery in B.I. though treated regularly more than five years. Group C-2 were clinically aggravated cases by regular treatment more than one year. Group D were cases which confronted with blindness.The numbers of cases in this trial were 76 in total. Numbers of cases in each group were as follows ; Group A 4, Group B 9, Group C-1 55, Group C-2 5 and Group D 3.We administered RFP 450 mg orally before breakfast at a time. Two different methods of administration were compared ; twice a week and six times a week methods. We made a rule to use DDS together with RFP except for the Group D. The dose of DDS was gradually increased and reached the maximum dose, 75 or 100mg daily at the nineth week.Among 76 cases, 40 cases finished the scheduled administration of RFP for twelve months. 17 cases dropped from the trial by some reasons (Table 14). In the remaining 19 cases the treatment did not reach to twelve months yet. Clinical results of these 40 cases were shown in Table 6-7. As shown in these tables, all of these 40 cases which were administered RFP for twelve months showed effective results. In Group C-1 with poor response for sulfon treatment in the past, RFP was very effective. As for Group 8 9 A, B, C-2 and D, even though their numbers were too small to get a clear conclusion, favourable results were also obtained. We could not find statistically significant differences between two days method and six days method on clinical effect, fall of B. I. and MI., and frequency of ENL.The reasons of interruption of RFP administration in 17 cases were as follows, ENL or eye complications in 8 cases, borderline reaction in 2 cases, gastric disturbances in 2 cases, extra-medical reason in one case and high fever shortly after the intake of RFP in 4 cases. This symptom of high fever shortly after the intake of RFP was observed mainly in the fifth and sixth month since the start of administration. It is noticeable that these cases were found only in the two days method group. The symptom was suspected of allergic nature to RFP, but in some cases it was difficult to distinguish clini- cally the allergic response from ENL.Gastric disturbances were the most frequent side effects during the treatment, but they were not so severe. Three cases complained of itching or paresthesia after intake of RFP. Transient increase of S-GOT and GPT values was observed in 2 cases. One case showed thrombocytopenia, which recovered after stop of RFP administr-ation.The fall of M.I. during the treatment was satisfactory in almost all cases. Decrease of B.I. in twelve months was slight but statistically significant in C-1 Group.
