Rikkunshito simultaneously improves dyspepsia correlated with anxiety in patients with functional dyspepsia: A randomized clinical trial (the DREAM study).

BACKGROUND: Functional dyspepsia (FD), a heterogeneous disorder, involves multiple pathogenetic mechanisms. Developing treatments for FD has been challenging. We performed a randomized, placebo-controlled, double-blind clinical trial to determine the efficacy of rikkunshito, a Japanese herbal medicine, in FD patients. METHODS: FD patients (n = 192) who met the Rome III criteria without Helicobacter pylori infection, predominant heartburn, and depression were enrolled at 56 hospitals in Japan. After 2 weeks of single-blind placebo treatment, 128 patients with continuous symptoms were randomly assigned to 8 weeks of rikkunshito (n = 64) or placebo (n = 61). The primary efficacy endpoint was global assessment of overall treatment efficacy (OTE). The secondary efficacy endpoints were improvements in upper gastrointestinal symptoms evaluated by the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), the Global Overall Symptom scale (GOS), and the modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (m-FSSG), and psychological symptoms evaluated by the Hospital Anxiety and Depression Scale (HADS). KEY RESULTS: Rikkunshito increased OTE compared to placebo at 8 weeks (P = .019). Rikkunshito improved upper gastrointestinal symptoms (PAGI-SYM, GOS, and m-FSSG) at 8 weeks, especially postprandial fullness/early satiety (P = .015 and P = .001) and bloating (P = .007 and P = .002) of the PAGI-SYM subscales at 4 weeks and 8 weeks. Improvement of HADS at 8 weeks (P = .027) correlated with those of PAGI-SYM (r = .302, P = .001), GOS (r = .186, P = .044), and m-FSSG (r = .462, P < .001), postprandial fullness/early satiety (r = .226, P = .014), dyspepsia (r = .215, P = .019), and PDS (r = .221, P = .016). CONCLUSION & INFERENCES: Rikkunshito may be beneficial for FD patients to simultaneously treat gastrointestinal and psychological symptoms.

High Helicobacter pylori cure rate with sitafloxacin-based triple therapy.

BACKGROUND: Bacterial resistance of Helicobacter pylori to antibiotics is increasing and it often leads to failure of antibiotic treatment. A new sitafloxacin-based triple therapy was developed to counter this situation; the fluoroquinolone sitafloxacin has a low minimum inhibitory concentration for H. pylori. AIM: To investigate the efficacy in Japanese patients of sitafloxacin-based triple therapy and document its efficacy in relation to anti-microbial susceptibility. METHODS: We investigated the efficacy of a 1-week sitafloxicin-based regimen of rabeprazole 10 mg four times daily (q.d.s.), metronidazole 250 mg twice daily (b.d.) and sitafloxacin 100 mg b.d. in 180 H. pylori-positive Japanese patients (first-line treatment: n = 45, second-line; n = 41, third-line: n = 94). At 8 weeks, patients were given the (13) C-urea breath test to assess eradication status. RESULTS: Eradication rate was 92.2% [95% confidence interval (CI): 87.3-95.7%, 166/180] in intention-to-treat analysis. Although the eradication rate was higher in patients treated with first-line therapy [45/45 (100%, 95% CI: 83.4-100%)] than in those with second- [38/41 (92.7%, 80.1-98.5%)] or third-line therapy [83/94 (88.3%, 80.0-94.0%)], no significant differences were noted with respect to the number of previous therapy attempts (P = 0.054). Eradication rates in patients infected with sensitive- and resistant strains to metronidazole were 96.6% (28/29) and 96.3% (77/80) (P = 0.941), respectively, while rates were 98.4% (60/61) in sitafloxacin-sensitive and 50.0% (1/2) in sitafloxacin resistant strains (P < 0.001). CONCLUSION: Sitofloxacin-based triple therapy with metronidazole b.d. and rabeprazole q.d.s. achieved an eradication rate exceeding 88%, irrespective of eradication history, CYP2C19 genotype, or metronidazole resistance status.

Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19.

BACKGROUNDS AND AIM: Lansoprazole is mainly metabolized by cytochrome P4502C19 (CYP2C19) in the liver. The effect of lansoprazole is assumed to be insufficient in subjects who are homozygous extensive metabolizers of CYP2C19. This study aimed to examine whether the CYP2C19 genotype status affected the acid-inhibitory effects of lansoprazole and to develop a strategy to overcome this pharmacogenetic problem. METHODS: Eighteen Helicobacter pylori-negative healthy volunteers, whose CYP2C19 genotypic status had been assessed, participated in the study. They consisted of 7 subjects who were homozygous extensive metabolizers, 7 subjects who were heterozygous extensive metabolizers, and 4 subjects who were poor metabolizers of CYP2C19, who took a placebo or lansoprazole 30 mg once daily in the morning for 8 days. On day 8 of dosing, 24-hour intragastric pH values were recorded. Five of the homozygous extensive metabolizer subjects underwent the 24-hour intragastric pH monitoring on day 8 of dosing of lansoprazole 30 mg 4 times daily. RESULTS: When lansoprazole 30 mg was given once daily, the mean 24-hour intragastric pH values in the subjects who were homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 4.5, 4.9, and 5.5, respectively (P <.005). On day 8 of dosing of lansoprazole 30 mg 4 times daily in subjects who were homozygous extensive metabolizers, the mean 24-hour intragastric pH value was 7.4. CONCLUSION: The effect of lansoprazole on intragastric pH depended significantly on CYP2C19 genotype status. Complete acid inhibition could be achieved by the frequent administration of lansoprazole (eg, 30 mg 4 times daily) in subjects who were homozygous extensive metabolizers. A genotyping test of CYP2C19 status appears useful for prescribing an optimal dosing scheme of lansoprazole.

Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin.

Rabeprazole is a potent proton pump inhibitor and is mainly reduced to thioether rabeprazole by a non-enzymatic pathway and partially metabolized to demethylated rabeprazole by CYP2C19 in the liver. We intended to determine a cure rate for Helicobacter pylori infection by dual rabeprazole/amoxicillin therapy in relation to CYP2C19 genotype status prospectively. Ninety-seven patients with gastritis and H. pylori infection completed the dual therapy with 10 mg of rabeprazole bid and 500 mg of amoxicillin tid for 2 weeks. At 1 month after treatment, cure of H. pylori infection was assessed on the basis of histology, a rapid urease test, culture, polymerase chain reaction (PCR), and 13C-urea breath test. CYP2C19 genotype status was determined by a PCR-restriction fragment length polymorphism method. Of the 97 patients, 33 were homozygous extensive metabolizers (homEM), 48 were heterozygous extensive metabolizers (hetEM), and 16 were poor metabolizers (PM). Cure of H. pylori infection was achieved in 79 of the 97 patients (81.4%, 95%CI = 71.9-88.7). Significant differences in cure rates among the homEM, hetEM, and PM groups were observed; 60.6% (95%CI = 42.1-77.3), 91.7% (95%CI = 80.0-97.7), and 93.8% (95%CI = 69.8-99.8), respectively (P = 0.0007). Twelve patients without cure after initial treatment (10 homEMs and 2 hetEMs) were successfully retreated with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. for 2 weeks. The cure rates for H. pylori infection by dual rabeprazole/amoxicillin therapy depended on the CYP2C19 genotype status. This dual therapy appears to be effective for hetEM and PM patients. However, high dose dual rabeprazole/amoxicillin therapy was effective even for homEM patients. Therefore, the genotyping test of CYP2C19 appears to be a clinically useful tool for the optimal dual treatment with rabeprazole plus amoxicillin.

Immunocytochemical localization of candidates for vesicular glutamate transporters in the rat cerebral cortex.

Brain-specific Na(+)-dependent inorganic phosphate cotransporter (BNPI) was recently reported to serve as a vesicular glutamate transporter (VGluT), and was renamed VGluT1 (Bellocchio et al. [ 2000] Science 289:957-960; Takamori et al. [2000] Nature 407:189-194). Ahead of these reports, cDNA encoding another brain-specific inorganic phosphate transporter, which showed 82% amino acid identity to VGluT1, was cloned and designated differentiation-associated Na(+)-dependent inorganic phosphate cotransporter (DNPI; Aihara et al. [2000] J Neurochem 74:2622-2625). In the present study, we produced a specific antibody against a C-terminal portion of DNPI, and studied the immunohistochemical localization of DNPI in the rat cerebral cortex in comparison with that of VGluT1. DNPI immunoreactivity was enriched in neuropil of layers I and IV and to a lesser extent in the upper portion of layer VI of the cerebral neocortex, whereas VGluT1 immunoreactivity was distributed more evenly in neuropil of the neocortex. Electron microscopic observation revealed that both DNPI and VGluT1 immunoreactivities were mainly located on synaptic vesicles in nerve terminals which made asymmetrical contacts in the neocortex. Furthermore, neither DNPI nor VGluT1 immunoreactivity in the neocortex was colocalized with gamma aminobutyric acid (GABA)ergic axon terminal markers, immunoreactivity for glutamic acid decarboxylase or vesicular GABA transporter. Neuronal depletion in the ventrobasal thalamic nuclei produced by the kainic acid injection resulted in a clear reduction of DNPI immunoreactivity in layers I, IV, and VI of the somatosensory cortex. These results indicate that DNPI is located on the membrane of synaptic vesicles in thalamocortical axon terminals, and that it may be a candidate for VGluT of thalamocortical glutamatergic neurons.

Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin.

BACKGROUND: Proton pump inhibitors such as omeprazole and lansoprazole are mainly metabolized by CYP2C19 in the liver. The therapeutic effects of proton pump inhibitors are assumed to depend on CYP2C19 genotype status. OBJECTIVE: We investigated whether CYP2C19 genotype status was related to eradication rates of H pylori by triple proton pump inhibitor-clarithromycin-amoxicillin (INN, amoxicilline) therapy and attempted to establish a strategy for treatment after failure to eradicate H pylori. METHODS: A total of 261 patients infected with H pylori completed initial treatment with 20 mg of omeprazole or 30 mg of lansoprazole twice a day, 200 mg of clarithromycin three times a day, and 500 mg of amoxicillin three times a day for 1 week. CYP2C19 genotypes of patients were determined with polymerase chain reaction-restriction fragment length polymorphism analysis. Patients without eradication after initial treatment were retreated with 30 mg of lansoprazole four times daily and 500 mg of amoxicillin four times daily for 2 weeks. RESULTS: Eradication rates for H pylori were 72.7% (95% confidence interval, 64.4%-81.8%), 92.1% (confidence interval, 86.4%-97.3%), and 97.8% (confidence interval, 88.5%-99.9%) in the homozygous extensive, heterozygous extensive, and poor metabolizer groups, respectively. Thirty-four of 35 patients without eradication had an extensive metabolizer genotype of CYP2C19. Nineteen of those patients were infected with clarithromycin-resistant strains of H pylori. However, there were no amoxicillin-resistant strains of H pylori. Re-treatment of H pylori infection with dual high-dose lansoprazole-amoxicillin therapy succeeded in 30 of 31 patients with extensive metabolizer genotype of CYP2C19. CONCLUSION: The majority of patients without initial eradication of H pylori had an extensive metabolizer CYP2C19 genotype but were successfully re-treated with high doses of lansoprazole and an antibiotic to which H pylori was sensitive, such as amoxicillin, even when the patients were infected with clarithromycin-resistant strains of H pylori.

FR901469, a novel antifungal antibiotic from an unidentified fungus No.11243. II. In vitro and in vivo activities.

FR901469 is a water-soluble macrocyclic lipopeptidolactone (C71H116N14O23) that has inhibitory activity against 1,3-beta-glucan synthase and exhibits in vitro and in vivo antifungal activity against both Candida albicans and Aspergillus fumigatus. The MICs of FR901469 against Candida albicans FP633 and Aspergillus fumigatus FP1305 in a micro-broth dilution test were 0.63 and 0.16 microg/ml, respectively. FR901469 showed excellent efficacy by subcutaneous injection against both Candida albicans and Aspergillus fumigatus in a murine systemic infection mode, with ED50s of 0.32 and 0.2 mg/kg, respectively. This compound also showed potent anti-Pneumocystis activity in the nude mice model with experimental Pneumocystis pneumonia. The hemolytic activity of FR901469 towards mouse red blood cells, is about 30-fold weaker than that of amphotericin B.

Cure of refractory duodenal ulcer and infection caused by Helicobacter pylori by high doses of omeprazole and amoxicillin in a homozygous CYP2C19 extensive metabolizer patient.

A 53-year old female patient with duodenal ulcer and Helicobacter pylori infection was treated three times with a proton pump inhibitor-based triple therapy, such as lansoprazole-clarithromycin-amoxicillin (INN, amoxicilline) and lansoprazole-minocycline-cefaclor. However, the H pylori infection was not cured. A culture test revealed that her infection was a clarithromycin-resistant but amoxicillin-sensitive strain of H pylori. Moreover, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis revealed that she was a homozygous extensive metabolizer of cytochrome P450 (CYP) 2C19 (wt/wt). The usual dose of the proton pump inhibitor was therefore assumed to be insufficient for her and then she was treated with a high dose of omeprazole (120 mg/day) and amoxicillin (2,250 mg/day) for 2 weeks. The H pylori infection and the ulcer lesion were then cured. One of the factors associated with success or failure of cure of H pylori infection by the proton pump inhibitor-based triple therapy appeared to be CYP2C19 genotype status. Dual treatment with a sufficient dose of a proton pump inhibitor plus amoxicillin could cure H pylori infection even after the failure to cure H pylori infection by a usual proton pump inhibitor-based triple therapy in patients with the wt/wt homozygous extensive metabolizer genotype of CYP2C19.

[Combination effect of hyperthermia and MX2 on cultured glioma cell lines].

MX2, a new lipophilic morpholino anthracycline, has been reported to have chemotherapeutic effects superior to those of adriamycin against murine and human glioma cells in vitro and in vivo. To assess the combination effect of MX2 and hyperthermia in vitro, the thermo-chemosensitivities of cultured human (U251MG and KC) and rat (C6 and 9L) glioma cell lines were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The number of viable cells in each cell line was markedly and dose-dependently decreased by MX2 treatment, but the sensitivity of U251MG to MX2 was less than that of the other cell lines. The survival of each cell line was decreased with the hyperthermic treatment at 43 degrees C for 60 minutes. Combined treatment with MX2 and hyperthermia had an additive effect on cultured glioma cells when MX2 was added to the medium at a dose below 50 ng/ml. However, combined treatment indicated neither an additive nor a synergistic effect when the dose of MX2 was above 50 ng/ml. We conclude that MX2 may be clinically useful against malignant gliomas when administered alone or in combination with hyperthermia.

Antimalarial activity of extracts of Malaysian medicinal plants.

In vitro and in vivo studies revealed that Malaysian medicinal plants, Piper sarmentosum, Andrographis paniculata and Tinospora crispa produced considerable antimalarial effects. Chloroform extract in vitro did show better effect than the methanol extract. The chloroform extract showed complete parasite growth inhibition as low as 0.05 mg/ml drug dose within 24 h incubation period (Andrographis paniculata) as compared to methanol extract of drug dose of 2.5 mg/ml but under incubation time of 48 h of the same plant spesies. In vivo activity of Andrographis paniculata also demonstrated higher antimalarial effect than other two plant species.

[Primary malignant lymphoma in the central nervous system treated with high dose methotrexate (MTX)-CHOP (M-CHOP)].

From December 1995 to July 1997, six patients with primary malignant lymphoma in the central nervous system were treated with 2 to 5 cycles of the M-CHOP regimen (methotrexate 3 g/m2 on day 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 40 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, and predonisolone 60 mg on day 1 to 14: folic acid was given 3 hours after methotrexate at 10 mg/m2 every 3 hours for 9 doses intravenously). Five patients achieved complete remission (CR) and one experienced partial remission (PR). Posttherapeutic studies were performed in all patients with an average follow-up period of 20.1 months (range 8.1-26.8 months) after confirming the diagnosis. There was no evidence of recurrence of the tumors or growth of residual tumors in any of the patients in this period. The major toxic effect was myelosupression with leukopenia. Alopecia was observed in all patients. No treatment-related deaths were observed. The M-CHOP regimen seems to be a promising treatment for primary malignant lymphoma in the central nervous system.

Proliferative potential and apoptosis in rat glioma cell lines after hyperthermia.

The proliferative potential of cultured rat glioma cells (C6 and 9L) was evaluated after hyperthermia using immunohistochemical staining with bromodeoxyuridine (BrdU) and Ki-67 monoclonal antibodies. Apoptosis was assessed by in situ end-labeling of deoxyribonucleic acid breaks. Both BrdU and Ki-67 labeling indexes decreased with increasing hyperthermia time. The decrease of the Ki-67 labeling index was not as great as that of the BrdU labeling index. The number of apoptotic cells increased with time after hyperthermia. These results indicate that the antitumor effect of hyperthermia may reflect the induction of apoptosis in the cells within the cell cycle, and the resultant reduction of the proliferative potential of surviving cells, especially in the S phase.

Therapeutic effects of water-soluble echinocandin compounds on Pneumocystis pneumonia in mice.

The therapeutic effectiveness of water-soluble echinocandin compounds obtained from Coleophoma empetri F-11899, which has a strong inhibitory effect on the growth of fungi, was examined in nude mice with experimental Pneumocystis pneumonia. The studies demonstrated the potential usefulness of the compounds.

The protective effect of dexamethasone against radiation damage induced by interstitial irradiation in normal monkey brain.

OBJECTIVE: The protective effect of dexamethasone against radiation damage is unclear. We examined the effect of early treatment of high-dose dexamethasone on iridium-192-induced damage to normal brain tissue. METHODS: Brain damage induced by interstitial irradiation with iridium-192 was evaluated with sequential magnetic resonance imaging and proton magnetic resonance spectroscopy in 11 adult monkeys, with or without short-term high-dose dexamethasone treatment. Dexamethasone (1 mg/kg of body weight/d) was administered intramuscularly to five irradiated animals every 24 hours, beginning 2 days before and ending 7 days after irradiation. Magnetic resonance imaging and proton magnetic resonance spectroscopy were performed 1 week, 1 month, and 3 months after irradiation. RESULTS: Magnetic resonance imaging performed 1 week after irradiation revealed marked edema in five nontreated animals. In dexamethasone-treated animals, the volume of edema was reduced significantly, compared to that of nontreated animals, 1 week and 1 month after irradiation. The volume of ring enhancement in dexamethasone-treated animals was also reduced significantly, compared to that of nontreated animals, 3 months after the irradiation. Proton magnetic resonance spectroscopy spectra revealed that N-acetylaspartate and choline peaks were reduced 1 week after irradiation in both groups. However, there were no statistically significant differences between the two groups at any time points. CONCLUSION: These results suggest that dexamethasone treatment may have an antiedema effect at an early stage and may modify subsequent development of vascular and inflammatory changes but may have no effect of preventing radiation-induced necrosis and the reduction of N-acetylaspartate after brachytherapy.

New method for the evaluation of the response of cultured cell lines to continuous low-dose-rate irradiation from encapsulated iridium-192 seeds with hyperthermia.

A new method was designed to investigate and evaluate the biological effectiveness of hyperthermia combined with continuous low-dose-rate irradiation (CLDRI) from encapsulated iridium-192 seed sources on glioma cells in vitro using the MTT assay. The system consists of 10 iridium seeds contained in a catheter bent into a circle, which is placed on a culture plate containing the cells. The effects of CLDRI and CLDRI combined with hyperthermia on a cultured rat glioma cell line (C-6) were studied. The number of surviving cells decreased as the total radiation dose increased. There was no significant difference in survival rates at dose rates of 0.1 Gy/hr and of 0.2 Gy/hr (p = 0.2811). An additive effect was observed in the cells treated with hyperthermia at 41 degrees C and 42 degrees C, combined with CLDRI, and synergistic effect between the two treatment modalities was observed at 43 degrees C. This new device is less expensive, easily reproducible, and can also be performed easily enough to examine a large number of samples in a short time period for sensitivity testing.

Effects of lansoprazole with or without amoxicillin on ulcer healing: relation to eradication of Helicobacter pylori.

We studied the effects of lansoprazole with or without amoxicillin on the quality of ulcer healing in relation to eradication of Helicobacter pylori. Ulcer healing rates for lansoprazole 30 mg q.d. alone (group A) were 100% for duodenal ulcers (DU; n = 20) and 92% for gastric ulcers (GU; n = 15). The healing rates for lansoprazole 30 mg plus amoxicillin 1-2 g q.d. (group B) were 100% for both DU (n = 20) and GU (n = 12). Endoscopic findings after treatment showed that the red scar/white scar ratio in group A was 16/4 for DU and 12/1 for GU. The red scar/white scar ratio in group B was 4/16 for DU and 6/6 for GU. The numbers of H. pylori in gastric mucus did not change throughout the course of treatment in group A but decreased significantly, without H. pylori relapse, in group B. Changes in ammonia concentration in gastric juice, as well as serum gastrin and pepsinogen I and II levels, differed between group A and group B. Concomitant treatment with lansoprazole and high-dose amoxicillin eradicated H. pylori and modified gastric secretory function, resulting in high-quality ulcer healing.

Synthesis and antitumor activity of 20(S)-camptothecin derivatives. A-ring-substituted 7-ethylcamptothecins and their E-ring-modified water-soluble derivatives.

Twenty-six novel A-ring-modified 7-ethylcamptothecins (6) were synthesized by Friedländer's condensation of the chiral tricyclic ketone (5) with aminopropiophenones (4). The compounds substituted with fluorine at the 11 position showed strong cytotoxicity to KB and L1210 cells. The 11-fluoro derivatives also exhibited strong inhibitory activity on DNA topoisomerase I. Nine compounds 6 with four to ten times stronger cytotoxicity than that of camptothecin were selected and converted into water-soluble 17-O-acyl amide derivatives (8). Compounds 8e (10-Me, O-COCH2CH2SCH3) and 8f (11-F, O-COC2H5) showed activity towards Meth A in mice that was comparable to that of CPT-11, at lower doses than CPT-11.

[Synergistic effect of carboplatin and hyperthermia in rat and human glioma cell lines].

To assess the interaction of carboplatin and hyperthermia in vitro, the thermochemosensitivities of three glioma cell lines, C6 rat glioma cell line, human glioma cell lines T98G and KMG4, were examined by 3-(4,5-dimethylthiazol-2-yl) -2,5 diphenyltetrazolium bromide (MTT) assay. The cell survival of each cell line decreased according to increasing CBDCA concentration and temperature. With a certain CBDCA concentration, the cell survival at following temperature was significantly decreased from that at 37 degrees: 43 degrees C and 44 degrees C for C6 cells (2.5 micrograms/ml); 41 degrees C, 42 degrees C, 43 degrees C and 44 degrees C for C6 cells (128 micrograms/ml); 42 degrees C, 43 degrees C and 44 degrees C for KMG4 cells (8 micrograms/ml) (CBDCA concentration within parentheses). It is generally considered that the highest tolerable temperature of normal brain is 42 degrees C for 60 minutes, while under 43 degrees C, there is a possibility that a sufficient tumoricidal effect might not be obtained. This study revealed enhanced cytotoxicity of CBDCA with hyperthermia at the temperature lower than 42 degrees C and suggests the possibility to gain increased tumoricidal effect without injuring normal brain by hyperthermia at the normal-tissue-tolerant temperature with systemic administration of relatively lower dose of CBDCA.

Acute effects of interstitial hyperthermia on normal monkey brain--magnetic resonance imaging appearance and effects on blood-brain barrier.

The magnitude and time course of histological and neuroradiological changes due to interstitial hyperthermia in normal cerebral white matter were investigated in eight adult Japanese monkeys. A cooling system enveloping a 2450-MHz microwave antenna was inserted stereotactically into the brain under general anesthesia. A point located 5 mm away from the surface of the cooling system was used as the reference point (RP). Hyperthermia was given to maintain the RP at 43 degrees C for 60 minutes. Two animals were sacrificed under general anesthesia following the intravenous administration of Evans blue, immediately and 1, 3, and 7 days after treatment. After removing the brain, histological changes were investigated. Magnetic resonance (MR) imaging was performed at 1, 3, and 7 days after treatment. Evans blue extravasation was most prominent in the region heated to 43 degrees C or above immediately after treatment. MR imaging showed obvious enhancement in the region heated to 43 degrees C or above 1 day after treatment, related to the disruption of the blood-brain barrier (BBB) by hyperthermia. Three days after treatment, ring-like enhancement with a central low-intensity area was seen in the region heated to about 43 degrees C, caused by BBB disruption and slight neovascularization. One week after treatment, an enhanced ring was observed in the region heated to less then 43 degrees C which surrounded a low-intensity area. The enhancement seen 1 week after treatment was caused by prominent neovascularization. T2-weighted imaging showed a high-intensity area, caused by edema, most prominent 3 days after treatment. Thus chemotherapeutic agents should be given just before the end of hyperthermia.

Thermal damage threshold of brain tissue--histological study of heated normal monkey brains.

The thermal damage threshold of normal brain tissue was evaluated from immediate and delayed histological changes caused by hyperthermia treatment of normal monkey (Macaca fuscata) brains. A 2450 MHz microwave antenna and an antenna cooling system devised by our group were used for interstitial hyperthermia treatment. The antenna within the cooling system was inserted through a small craniectomy under general anesthesia. The temperature at a reference point, 4 mm radially away from the surface of the cooling system, was maintained at 42, 43, 44, 45, or 46 degrees C for 60 minutes. Eighteen animals were treated and sacrificed immediately after the treatment, while nine animals were treated and sacrificed 7 days after the treatment. The histological changes were studied microscopically on sections stained with HE or Kluver-Barrera's method. The non-survival experiment demonstrated that areas heated at 44 degrees C or below showed no obvious irreversible changes. The survival experiment showed areas heated at 44 degrees C or above developed coagulative necrosis. These histological findings indicate that thermal damage occurs in normal brain tissue after heating at 44 degrees C or above for 60 minutes, suggesting that the safety limit for brain hyperthermia is 43 degrees C for 60 minutes.