Quantitative determination of flufenamic acid and its major metabolites in plasma by high-performance liquid chromatography.
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Biomedical subjects
Publications and source records attributed to O Kubo.
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Absorption rates of monobasic beta-lactam antibiotics were measured as a function of lumen solution pH between 4 and 9 by utilizing the rat intestinal recirculating method in situ. Between pH 6.5 and 9, the absorption rate constants of ionized antibiotics were almost identical; but, at pH 4, the unionized species were highly absorbed, depending on their lipophilicity through the GI membrane lipoidal barrier. The structure-absorption rate relationship was established with the unstirred layer model.
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Newly defined lipophilic indexes, log k', of a series of penicillins and cephalosporins were rapidly and reliably determined by reversed-phase high-pressure liquid chromatography (HPLC) on bonded octadecylsilane supports. The log k' values obtained from their retention times exhibited a linear relationship with methanol concentration (v/v%) in the mobile phase. The extrapolated log k' values to zero and those at 30% correlated well with the partition coefficients, log P, in 1-octanol-water and with Rm values from TLC. This HPLC technique provided some new log P and Rm values for highly ionizable beta-lactam antibiotics. The HPLC method for the determination of partition coefficients of drugs has some advantages and is a useful alternative for the determination of log P and Rm.
Apparent partition coefficients Papp, of beta-lactam antibiotics were determined in octanol-water and 2-methylpropanol-water systems at various pH values. The pKa values also were determined by potentiometry under the conditions of partition experiments. The intrinsic partition coefficients for the unionized form, Pu, and the ionized form, Pi, of beta-lactam antibiotics were calculated from the equation Papp = Pu[aH+/(Ka + aH+)] + Pi[Ka/(Ka + aH+)]. The correlation between Pu and Pi values and lipophilic parameters of penicillins measured in other systems was examined.
A case of FSH and LH secreting pituitary adenoma which was not preceded by hypogonadism is reported. The patient, a 50-year-old man, was admitted to the hospital because of left temporal hemianopsia. No clinical evidence of hypogonadism was demonstrated. Endocrine studies of hypogonadism was demonstrated. Endocrine studies revealed markedly elevated plasma FSH of 295 mIU/ml and slightly elevated LH of 35 mIU/ml (2nd IRP-HMG). Plasma FSH and LH did not respond to the administration of LRF, conjugated equine estrogens and testosterone. Plasma testosterone was 691 ng/dl and rose nromally after pregnant mare's serum gonadotropin. Sperm count was 46 X 10(6)/ml. Transfrontal hypophysectomy was followed by a marked decrease of both FSH (to 19mIU/ml) and LH (to 22 mIU/ml). Histologic examination of the tumor revealed 90% chromophobe cells and 10% slightly eosinophilic cells. Two sizes of secretory granules were demonstrated. Tumor cells in tissue culture secreted both FSH and LH.
Pituitary adenomas obtained from 6 patients with acromegaly and 8 patients with chromophobe adenoma were subjected to the tissue culture to correlate in vitro secretion of growth hormone (GH) and prolactin (PRL) to preoperative in vivo endocrine studies and endocrinilogical manifestations. Tissue culture demonstrated that all of the acromegalic tumors secreted large amounts of GH for 2-4 weeks and some of the PRL-secreting chromophobe adenoma without any clinical and endocrinological evidences of GH secretion secreted considerable amounts of GH; however, no recognizable GH secretion was noted in the remaining chromophobe adenomas. PRL was secreted in vitro in large amounts by tumors obtained from patients with hyperprolactinemia with and without acromegaly. It is interesting to note that tumors obtained from 2 patients who showed very slight elevation of plasma PRL of less than 40 ng/ml secreted large amounts of PRL in vitro. This finding suggests that PRL-secreting adenoma could not be ruled out in patients with mild hyperprolactinemia. The duration of in vitro PRL release was longer than that of GH and its rate of decrease was slower than that of GH.
A case is reported in which a human chorionic gonadotropin (HCG-)-producing ectopic pinealoma was found in a 5-year-old girl with precocious puberty. Physical examination revealed abnormal breast enlargement. Endocrinological study disclosed a high plasma HCG concentration of 1192 ng/ml with a normal follicular stimulating hormone (FSH) level. The HCG content of the tumor was as high as 400 ng/mg of acetone dried tissue, but no FSH was detectable. This is the first reported case of precocious puberty associated with pineal tumor in a female.
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HCG-producing ectopic pinealoma of two cell pattern type was demonstrated in a 5-year old girl who presented precocious puberty and bilateral choked discs. The tumor was localized at the anterior third ventricle and suprasellar region. Endocrinological findings are as following: Plasma basal LH was markedly elevated to 306 mIU/ml and HCG was elevated to 1,192 ng/ml. Provocative test of hypophyseal function revealed low response. Plasma estrogen was not detectable. HCG content of resected tumor tissue was elevated to 400 ng/mg. FSH, however, was not detectable. Histological findings of this tumor showed atypical teratoma, so-called two cell pattern pinealoma. Electron microscopic findings revealed two types of cells, dark and clear cells. Many secreting granules were found in the dark cells. In this case, HCG in plasma, CSF and tumor tissue was remarkably elevated. In addition, plasma FSH was also elevated to 8.9 mIU/ml. Precocious puberty associated with tumor in the pineal-suprasellar region has been seen only in boys. There has been no case report of precocious puberty in girls. This case is the first female case is which HCG-producing ectopic penealoma is caused in precocious puberty.
We have performed tissue culture of pituitary adenomas (5 acromegalies, 7 non-acromegalies) and measured GH, PRL, LH and FSH in the media of tissue culture by radioimmunoassay (RIA) for 30-40 days. In addition, GH, PRL, LH and FSH were measured in the plasma and tumor tissue by RIA. GH concentration in the culture media was markedly high in all cases with acromegaly and high also in 2 out of 7 non-acromegaly cases (case 6 and 7). GH concentration in the media rapidly decreased almost as a straight line on a semilogarithmic scale until the 30-40 in day, when GH level became less than 10 ng/ml. PRL concentration in the culture media was high in 5 patients (3 acromegalies, 2 non-acromegalies). PRL concentration regressed more slowly than GH, but still remained higher than 10 ng/ml in all of the patients on the 25-40th day when the studies were discontinued. LH and FSH concentrations in the culture media was high in two patients. One patient was a pituitary adenoma secreting LH and FSH, and another case was a false high secreting one, possibly contaminated with gonadotropin in normal pituitary gland at surgical operation. LH and FSH concentrations rapidly decreased as that of GH. A rare case of primary LH and FSH secreting pituitary adenoma was demonstrated.
Hyperosmolar nonketotic coma is characterized by hyperglycemia, hyperosmolarity and dehydration in the absence of ketoacidosis. Two cases of hyperosmolar nonketotic coma, in which both the patients recovered, were presented. One of the cases was a 59-year-old female who had suffered from a metastatic brain tumor. After removal of the tumor, the patient's condition improved for a period. This was followed by a period of frequent vomiting, subsequently followed by coma. The laboratory data showed the absence of ketoacidosis in the blood sugar measured at 672 mg/dl and serum osmolarity at 343.1 mOsm./kg. The other case was a 74-year-old female who was admitted to the clinic because of cerebral thrombosis. Her caloric in-take was restricted and insulin was administered because of a mild diabetes mellitus which occured after admission. Then she entered a hyperosmolar non-ketotic coma. The laboratory data revealed blood sugar to be 1068 mg/dl and serum osmolarity to be 418 mOsm./kg. Immediately after large amounts of intravenous drip infusion and insulin were administerd, she recovered from the syndrome. The clinical observations and the pathogenesis of this syndrome were discussed.
A female case of precocious puberty associated with HCG-producing ectopic pinealoma was reported. The patient, a 5-year-old girl, was referred to the hospital because of headache and choked discs. Physical examination revealed normal physical growth with breast enlargement. Endocrinological study revealed a high plasma HCG concentration of 1192 ng/ml with a normal FSH level. None of HCG, LH and FSH did respond to the LH-RH test. A partial resection of the tumor and an external X-ray irradiation relieved the symptoms and breast enlargement subsided with a remarkable decrease in the plasma HCG level. Histological examination revealed two-cell-pattern pinealoma and electron microscopic findings showed abundant secretory granules in the dark cells. HCG content in the tumor was as high was 400 ng/mg of acetone dried tumor tissue, but no FSH was detectable. Hitherto, all of the reported cases of precocious puberty associated with pineal tumors have been exclusively boys. A normal level of plasma FSH concentration with a somewhat elevated prolactin level might be a contributory factor for the development of precocial sexual development in the present case.
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10 acoustic neurinomas, 2 spinal cord neurinomas and 3 neurofibromas of von Recklinghausen's disease were elaborately studied by monolayer tissue culture method and Gelfoam organ culture method. Four morphological types were found in the acoustic and spinal cord neurinoma. (1) multinucleated cells (type I), dividing into bipolar spindle-shaped cells. (2) bipolar spindle-shaped cells (type II), forming of palisade fashion in the monolayer tissue culture method. (3) fibroblastic cells (type III), tending to predominate in the long-term cultures. (4) round cells (type IV), gathering to the Gelfoam mesh in the organ culture method. Neurofibroma of von Recklinghausen's disease was divided into cells of two types in the tissue culture. (1) spindle-shaped cells, rarely observed, and have been thinking that the cells originated from schwann cells. (2) round cells, having the macrophagic character, are predominant in the long-term culture.
Immune deficiency of immunocompetent cells or of humoral factors are essential causes of tumor growth. The authors have investigated the transfer of immunocompetent cells - allogeneic bone marrow cell transfusion and white blood cell intracranial infusion - for the treatment of 11 malignant gliomas in infants and children as an adjuvant to surgery, radiation and/or chemotherapy. Ten cases, from 3 months to 11 years, received bone marrow cell transfusion. Two medulloblastomas and 3 pontine gliomas are dead. Five cases are alive and well 37-65 months following surgery. Among these two posterior fossa neoplasms, a medulloblastoma and a glioblastoma have survived 46 and 65 months, respectively. One cerebral glioblastoma received allogeneic white blood cells infused locally into the tumor bed: it recurred 1 year following surgery, chemotherapy, and immunotherapy. Cytolysis of the tumor cells by sensitized lymphoid cells were demonstrated in this case. The role of immunotherapy should be limited at the present time to adjuvant therapy until its effect on tumor growth is statistically confirmed. The results so far are promising, and improvement of the immunological approach in treating malignant brain tumors is under way.
Two cases of primary intracerebral malignant lymphoma were reported. Case 1 was a 42-year-old man who had been suffering from headache and mental disturbances for about 3 months prior to admission. These complaints progressed insidiously. He was admitted to our hospital on March 31, 1973. On neurological examinations he was in somnolence state and had neck rigidity, positive of Kernig's sign, disorientation and dyscalculia. Lumbar puncture gave a C.S.F. pressure of 240 mmH2O and the fluid contained 180 mg/dl of protein. A left vertebral angiogram via brachial artery demonstrated thalamic and cerebellar mass lesions. For the development of symptoms of increased intracranial pressure, a ventriculoperitoneal shunt operation was performed on April 7. A right carotid angiogram after ventriculoperitoneal shunt operation disclosed a frontal mass lesion. On May 2, a right frontal craniotomy was carried out and the frontal lobe was removed together with the tumors. After the operation his consciousness remained stupor. Thereafter consciousness and clinical pictures gradually worsened, and he died on May 30. Autopsy was performed, and gross examinations revealed tumors in the bilateral frontal and temporal lobes, right parietal lobe, and left cerebellar hemisphere. On coronal sections, there were neoplastic proliferation extending from the right thalamus to the putamen and a tumor in the right midbrain. No evidence of neoplastic proliferation was found outside the central nervous system. Microscopic examinations showed a diffuse proliferation of tumor cells with mitosis and polymorphism. The tumor was consisted of small lymphoid cells. Reticulin fibers were not found in the tumor with Watanabe's silver method. It was also unable to impregnate the tumor cells with silver carbonate. This case may be classified the primary interacerebral lymphosarcoma. Case 2 was a 48-year-old man, who was admitted to the hospital complaining of occipitalgia, speech disturbances and diffculty in walking. On neurological examinations, he had a right spastic hemiparesis and dyscalculia. A right carotid angiogram showed the frontal mass lesion. On April 18, a left frontal craniotomy was performed and frontal lobe was removed with the tumor. He made a good recovery from the operation and remained well for about 1 month. However, it culminated in a gradual diminution in the level of consciousness. Unfortunately, he died on June 20. No autopsy was performed. Histologically, the tumor cells had round or ovoid nuclei, mitosis and polymorphism. The perivascular arrangement of the tumor tissue showed tendency to confluence. There were reticulin fibers in the tumor tissue, particularly around the blood vessels. Microglial cells were not impregated with silver carbonate. It is supposed that this case belongs to the primary intracerebral "reticulum cells sarcoma-microglioma" described by Rubinstein or reticulum cell sarcoma. Both the case 1 and the case 2 should be filed to be malignant lymphoma in the wide category.
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