Melanocins A, B and C, new melanin synthesis inhibitors produced by Eupenicillium shearii. II. Physico-chemical properties and structure elucidation

New melanin synthesis inhibitors, melanocins A, B and C, were isolated from the fermentation broth and extract of mycelium of Eupenicillium shearii F80695. The structures of melanocins were established by spectroscopic methods. They are formamide compounds. In particular, melanocin A has an isocyanide group.     

Neuroprotectins A and B, bicyclohexapeptides protecting chick telencephalic neuronal cells from excitotoxicity. I. Fermentation, isolation, physico-chemical properties and biological activity

Glutamate, an excitatory amino acid, is known to induce neurotoxicity in central nervous system under abnormal conditions such as ischemia, hypoglycemia, epilepsy, Huntington's chorea, Parkinson's disease and Alzheimer's disease. In our search for neuroprotective agents of microbial origin against excitatory neurotoxins, we have isolated two new bicyclohexapeptides, neuroprotectins A and B, together with a known compound complestatin, from the fermentation broth of Streptomyces sp. Q27107. Neuroprotectins protected primary cultured chick telencephalic neurons from glutamate- and kainate-induced excitotoxicities in a dose-dependant fashion.     

Ventral striatal D(3) receptors and Parkinson's Disease

Antiparkinsonian drugs are thought to act largely through the D2 receptor family that includes the D(2) and D(3) receptors. D(2) and D(3) receptors exhibit both complementary and overlapping expression at the macro and cellular level. The D(3) receptor appears to be a primary target of the mesolimbic dopamine system, is highly enriched in expression within the "limbic" striato-pallidal-thalamic loop, and is recognized as being regulated by dopaminergic activity in distinctly different ways from the D(2) receptor. In Parkinson's Disease it has been determined that loss of dopaminergic innervation results in elevation of the D(2) receptor but reduced levels of the D(3) receptor. In many late-stage Parkinson's Disease patients there is a loss of antiparkinsonian response to L-dopa and other antiparkinsonian drugs that is often correlated with clinical signs for dementia. We have determined that the reduction of D(3) receptor, and not that of the D(2) receptor, is associated with the loss of response to L-dopa and other antiparkinsonian drugs. The reduction of D(3) receptor is also related to the presence of dementia. An elevation of D(3) receptors was evident in those Parkinson's Disease cases with continued good response to L-dopa. Thus, we believe that reduced D(3) receptor number is correlated with certain subgroups of Parkinson's Disease and may also be related to a further diminishment in the mesolimbic DA system.     

Investigation of juxtasellar and cerebellopontine angle meningiomas and neurogenic tumours: two-phase helical CT

We performed two-phase helical CT in 31 patients with juxtasellar region and cerebellopontine angle tumours to evaluate its usefulness in differentiating meningiomas from neurogenic tumours. After the intravenous injection of 90 ml contrast medium at 3 ml/s, axial helical images were obtained with delays of 30 and 120 s. After the delayed axial images, we acquired coronal images. Changes in attenuation were assessed visually and quantitatively (by comparing the attenuation in Hounsfield units). There were 17 meningiomas and 14 neurogenic tumours, all pathologically proven. Two-phase helical CT showed a decrease in attenuation in 15 (88 %) meningiomas and an increase in 14 (100 %) neurogenic tumours from early to delayed axial images. Coronal images showed a decrease in attenuation in all 17 meningiomas and an increase in 13 (93 %) of the neurogenic tumours. The mean HU and their ratios were significantly different between meningiomas and neurogenic tumours. Received: 22 August 2000 Accepted: 13 October 2000     

Influence of menopause on high density lipoprotein-cholesterol and lipids

It has been generally accepted that high density lipoprotein cholesterol (HDL-C) level decreases with menopause in women. However, recent reports show different results. There is very little data concerning perimenopausal women. To verify these findings, lipids and lipoprotein(a) [Lp(a)] levels were compared among pre-, peri- and postmenopausal women of similar mean ages. Postmenopausal women had higher HDL-C levels than premenopausal women (p<0.001) and there was no difference between peri- and postmenopausal women. LDL-C level in perimenopausal women was lower than in postmenopausal women (p<0.001) and higher than in premenopausal women with borderline significance (p=.051). Total cholesterol levels showed stepwise elevation from premenopause to postmenopause. Perimenopausal women had lower Lp(a) levels than postmenopausal women (p<0.0005) and similar levels to premenopausal women. Lp(a) levels between 0.1 to 10.0 mg/dL were the most prevalent in pre- and perimenopausal women, and those between 10.1 to 20.0 mg/dL in postmenopausal women. In conclusion, menopause itself is associated with the elevation of HDL-C level, and the postmenopausal increase of coronary artery disease is not related to postmenopausal change of HDL-C level. Perimenopausal status, although transient, may favor Lp(a) and lipid profiles for delaying atherosclerosis.     

Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors: correlation between changes in covariates and imatinib exposure

A pharmacokinetic study in patients with gastrointestinal stromal tumors (GIST) suggested that imatinib plasma concentration may decrease following long-term exposure. We assessed changes in imatinib plasma trough levels (C(min)) during long-term treatment. Follow-up (FU) imatinib C(min) was measured in 65 patients who received the same dose of imatinib for at least 9 months after previous (initial) tests. After exclusion of 7 patients who had been treated with imatinib for over 2 years at the time of initial testing, 58 patients were included in this analysis. The median intervals from initiation of imatinib to initial testing and from initial to FU testing were 5.5 months (range, 0.5-24.0 months) and 13.0 months (range, 9.6-17.9 months), respectively. Mean inter- and intra-subject variability values were 47.7% and 20.9%, respectively, at initial measurements, and 45.2% and 19.4%, respectively, at FU. Mean FU imatinib C(min) (1,370 ± 661 ng/mL) was significantly higher than mean initial C(min) (1,171 ± 573 ng/mL; p = 0.003). Compared with initial C(min), FU C(min) was decreased in 22 patients and increased in 36, with median changes of 13% and 32%, respectively. Multivariate analysis showed a significant correlation between the ratio of FU to initial imatinib C(min) and that of albumin (r = -0.39, p = 0.003). During long-term treatment, imatinib C(min) did not decrease significantly but remained stable or increased in most patients. Changes in imatinib C(min) were associated with changes in albumin concentration. Monitoring of imatinib C(min) only for concerns about time-dependent increases in imatinib clearance is not necessary.     

Comparison of intralobar non-parenchyma, subcapsular non-parenchyma, and liver capsule thickness.

The intralobar and subcapsular areas of human liver were compared in terms of morphometry and morphology, and a correlation was made between the thickness of liver capsules and the amount of intralobar non-parenchyma in normal and diseased livers. Tissue was systematically sampled from 16 normal and 26 fibrotic livers taken at necropsy. The volume fraction of subcapsular and intralobar non-parenchyma and the capsule thickness were determined by morphometry on histological sections. The volume fraction of intralobar non-parenchyma not only correlated well (tau = 0.7, p less than 0.001) with but was also equivalent in each case to the actual volume fraction of subcapsular non-parenchyma. Morphologically, the intralobar and subcapsular areas were remarkably similar. The volume fraction of intralobar non-parenchyma also correlated well (tau = 0.5, p less than 0.001) with capsule thickness. These results show that pathological changes in liver architecture were essentially similar in the intralobar and subcapsular areas and that capsule thickness reflected intralobar non-parenchymal changes.     

Nicardipine versus nitroprusside infusion as antihypertensive therapy in hypertensive emergencies

This prospective study compared the efficacy of nicardipine and nitroprusside for treating hypertensive emergencies by measuring haemodynamic indices and serum catecholamine levels. Patients admitted to the emergency department with a hypertensive crisis and acute pulmonary oedema received intravenous infusions of nitroprusside (starting dose 1 microgram/kg per min, n = 20) or nicardipine (starting dose 3 micrograms/kg per min, n = 20). Both groups experienced significant declines in systolic and diastolic blood pressure after treatment, but there were no significant time-dependent differences between the groups. Heart rate decreased in the nicardipine group and increased in the nitroprusside group, but neither change was significant. Respiration rate decreased and capillary oxygen saturation rate increased after treatment in both groups. Adrenaline and noradrenaline levels decreased significantly after treatment in both groups; noradrenaline levels were significantly decreased in the nicardipine-treated group compared with the nitroprusside-treated group. Injectable nicardipine is easy to use and as effective as nitroprusside for treating hypertensive crisis with acute pulmonary oedema.     

Clinical evaluation of incadronate in korean patients with malignancy-associated hypercalcemia: An open-label, multicenter study

Abstract

Background:

Incadronate has been found to lessen the increase in corrected serum calcium levels in malignancy-associated hypercalcemia (MAH) in a Phase III study in Japan. The drug is currently used to treat MAH in Japan.

Objective:

The purpose of this study was to assess the clinical usefulness of incadronate in patients with MAH.

Methods:

This open-label study was conducted at 3 medical institutions in Korea. Korean patients with MAH (corrected serum calcium levels ≥11.0 mg/dL) were given a single 10-mg IV infusion of incadronate over 2 to 4 hours in 500 to 1000 mL of normal saline. Corrected calcium levels were determined and subjective symptoms and objective findings (ie, bone pain, spontaneous pain, pain from contusion, tenderness, other pain, loss of appetite, nausea and/or vomiting, thirst, constipation, fatigue, and disturbance of consciousness) were used to monitor the effectiveness of the drug for 6 days after the infusion. Symptoms were evaluated using a 4-point scale (0 = none to 3 = severe). Adverse events (AEs) were identified by patients'' reports, and adverse drug events (ADEs) were assessed by the investigators throughout the study.

Results:

Twenty-four Korean patients (18 [75%]male, 6 [25%]female; mean age, 56.5 years) were included in the study; data from 22 and 24 patients were used to assess effectiveness and tolerability, respectively. Corrected serum calcium level was significantly decreased on day 6 after treatment compared with pretreatment on day 0 (baseline) (9.51 [0.89] mg/dL vs 11.83 [0.89] mg/dL; P < 0.001). The antihypercalcemic effect of incadronate became apparent as an inhibition of bone absorption a few days after infusion. Corrected serum calcium level was significantly decreased on days 2 to 6 (P < 0.001) after treatment compared with pretreatment at baseline. Evaluation of symptoms showed significant improvement in the incadronate-treated group (mean total score [range] at baseline, 8 [1–23] and day 6, 5.5 [1–17]; P = 0.001). Eight (33.3%) of the patients were found to have ADEs. Some of the 8 patients experienced >1 ADE (mild and transient fever [13 events], chills [3], headache [1], and myalgia [1]). AEs were observed in 19 (79.2%) of 24 patients. The most frequently reported AE was fever (14 events).

Conclusion:

In this small, open-label study, Korean subjects with MAH treated with incadronate experienced significant improvement in symptoms and calcium levels from baseline.Key Words: incadronate, bisphosphonate, malignancy-associated hypercalcemia, Korea