Combination chemotherapy with carboplatin and etoposide for elderly patients aged 76 years or older with small cell lung cancer

Eighteen elderly patients aged 76 years or older with small cell lung cancer were treated with carboplatin (AUC = 4 mg/ml.min, i.v. day 1) and etoposide (70 mg/m2 i.v. day 1-3) and 17 patients were evaluable. The median age of the study population was 77 years (range: 76-81). Eight patients had limited disease (LD) and nine did extensive disease (ED). The overall response rate was 88% for LD patients and 67% for ED patients. Median survival time was 219 days for LD patients and 158 days for ED patients. Grade 3 and 4 leukopenia, neutropenia, thrombocytopenia and anemia occurred in 41%, 76%, 24% and 6% of patients, respectively. There was one treatment-related death due to pneumonitis.     

Delta-opioid receptor antagonists as a new concept for central acting antitussive drugs

Our recent findings indicated that mu- and kappa-opioid receptors enhance each other's antitussive processes. However, delta-opioid receptors played an inhibitory role in antitussive processes mediated by the mu- and kappa-opioid receptors. We also concluded that delta(1)-opioid receptors may play an inhibitory role, whereas delta(2)-opioid receptors may play a synergistic role, in antitussive processes mediated by mu-opioid receptors. Furthermore, we clearly demonstrated that delta-opioid receptor antagonists, such as naltrindole and 7-benzylidenenaltrexone, produced potent antitussive effects. These delta-opioid receptor-mediated antitussive effects may be mediated by the antagonism of delta(1)-, but not delta(2)-opioid receptors. In this review, we study the possibility of the delta-opioid receptor antagonist as a new concept for central acting antitussive drugs.     

Effects of metabolic fragments of [Arg]-vasopressin on nerve growth in cultured hippocampal neurons

The effects of metabolic fragments of [Arg⁸]-vasopressin (AVP), [pGlu⁴, Cyt⁶]AVP (AVP_4–9), and desglycinamide-[pGlu⁴, Cyt⁶]AVP (AVP_4–8) on the growth of hippocampal neurons in culture were investigated in comparison with those of AVP. AVP_4–9 caused a significant increase in filopodial length following 96 h of exposure at concentrations higher than 300 nM. AVP_4–9 was more potent than AVP. AVP_4–8 also induced an increase in filopodial length, but this effect was less than that of AVP. The selective V₁ agonist [Phe², Ile³, Orn⁸]-vasopressin caused a significant increase in filopodial length, whereas the selective V₂ agonist [deamino-Cys¹, -Arg⁸]-vasopressin showed no such effect. OPC-21268, a vasopressin V₁ antagonist, blocked AVP and AVP fragment-induced increases in filopodial length. However, the V₂ antagonist OPC-31260 showed no such effect. A23187, a representative Ca ionophore, also increased filopodial length, and the A23187-induced increase in filopodial length was potentiated by AVP and AVP fragments. These results indicated that AVP_4–9 and AVP_4–8 increased filopodial length in cultured hippocampal neurons by activating V₁ receptors. Both phenomena induced by AVP_4–9 and AVP_4–8 were associated with intracellular calcium mobilization.     

Mechanism of the inhibitory effect of histamine on amygdaloid-kindled seizures in rats

PURPOSE: The mechanism of the inhibitory effect of histamine on amygdaloid-kindled seizures was investigated in rats. METHODS: Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus, and bipolar electrodes were implanted into the right amygdala. A guide cannula made of stainless steel tubing was implanted into the right lateral ventricle. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. EEG was recorded with an electroencephalograph; stimulation of the amygdala was applied bipolarly every day by a constant-current stimulator and continued until a generalized convulsion was obtained. RESULTS: Intracerebroventricular (i.c.v.) injection of histamine at doses of 2-10 microg resulted in a dose-related inhibition of amygdaloid-kindled seizures. I.c.v. injection of calcium chloride at doses of 10-50 microg and A23187 at doses of 2-10 microg also caused dose-dependent inhibition of amygdaloid-kindled seizures. Calcium chloride at a dose of 10 microg, which showed no significant effect on amygdaloid-kindled seizures when used alone, significantly potentiated the effect of histamine. Similar findings were observed with A23187 at a dose of 2 microg. In addition, EGTA and EGTA/AM antagonized the inhibition of kindled seizures induced by histamine. Moreover, the inhibition of kindled seizures induced by histamine was antagonized by KN62. However, calphostin C did not antagonize the inhibitory effect of histamine. CONCLUSIONS: These results indicated that histamine-induced inhibition of amygdaloid-kindled seizures may be closely associated with a calcium calmodulin-dependent protein kinase II activation pathway.     

The role of spinal cholecystokinin B receptors in thermal allodynia and hyperalgesia in diabetic mice

We examined the tail-flick response to various heat intensities in diabetic and non-diabetic mice. Heat intensities were set to one of six values by adjusting the source of voltage for a 50-W projection bulb to 20, 25, 35, 50, 65 and 80 V. Tail-flick latencies at source voltages of 35 and 50 V in diabetic mice were significantly shorter than those in non-diabetic mice. However, tail-flick latencies at 25, 65 and 80 V in diabetic mice were not significantly altered. Although tail-flick latencies in non-diabetic mice were not affected by i.t. pre-treatment with CI-988, a selective cholecystokinin B (CCK(B)) receptor antagonist, those at 35 and 50 V in diabetic mice were significantly increased. In non-diabetic mice, i.t. pre-treatment with cholecystokinin octapeptide (CCK-8), at a dose of 0.3 ng, decreased tail-flick latencies at 35 and 50 V. Furthermore, the attenuation of tail-flick latencies induced by i.t. pre-treatment with CCK-8 in non-diabetic mice was reversed by i.t. pre-treatment with CI-988. Protein kinase C (PKC) activator phorbol-12, 13-dibutyrate (PDBu)-induced reduction in the tail-flick latencies at heat intensities of 35 and 50 V in non-diabetic mice was dose-dependently and significantly reversed by i.t. pre-treatment with CI-988. On the other hand, the CCK-8-induced thermal hyperalgesia and allodynia at heat intensities of 35 and 50 V in non-diabetic mice were inhibited when PKC activity was inhibited by i.t. pre-treatment with calphostin C. These results indicate that the thermal allodynia and hyperalgesia in diabetic mice may be due, at least in part, to the activation of CCK(B) receptors followed by the activation of PKC in the spinal cord.     

The hypoglycemic effect of (7R*,9aS*)-7-phenyl-octahydroquinolizin-2-one in mice

(-)-Multiflorine (1), which was isolated from leguminous plants, produced a hypoglycemic effect when administered to mice with streptozotocin-induced diabetes. (-)-Multiflorine has an enaminone type conjugation on the A-ring, which is unusual in lupine alkaloids. Proceeding on the assumption that the A-B ring is responsible for the activity, several compounds bearing quinolizidin-2-one were synthesized and their hypoglycemic effects were examined. The hypoglycemic effect of (7R*,9aS*)-7-phenyl-octahydroquinolizin-2-one was approximately 4 times stronger than that of (-)-multiflorine measured by oral glucose tolerance test in normal mice. This result indicates that compounds possessing the quinolizidin-2-one ring system as the basic structure may be possible lead compounds for a new type of diabetes drug.     

Prediction of vertigo recurrences in Meniere's disease by the head-shaking test

Researchers have observed that when head-shaking nystagmus (HSN) is provoked in patients with peripheral vestibular disorders, usually (in more than 75% of cases) it beats toward the normal or unaffected ear. The reverse of this pattern occurs commonly in patients with Meniere's disease. This finding presumably reflects the changeable pathophysiological state of the labyrinth of Meniere's disease. We retrospectively analyzed clinical records of eight patients who had unilateral Meniere's disease and came to Gunma University Hospital for consultation in the period from 1984 through 1989. All patients satisfied the following condition: In the period prior to the attacks of vertigo, for which a 10-day period preceding the attack was arbitrarily considered (the forerunning period), HSN reversed its direction, appeared, or disappeared. When HSN showed a biphasic pattern, only the first phase was considered in this present analysis. In the period before the attack, HSN reversed its direction from the normal to the morbid ear five times in four patients, appeared toward the morbid ear in three patients, and disappeared from one beating toward the normal ear before the forerunning period of vertigo attacks in one patient. These findings suggest that the occurrence of HSN directed to the morbid ear in the recuperation period in Meniere's disease might indicate the impending recurrence of a vertigo attack in a few days. In the present group of patients, vertigo attacks occurred from 6 hours to 8 days (average, 3.2 days) after the observation of HSN beating toward the morbid ear. In three of these patients, the immediate administration of isosorbide (a hyperosmotic diuretic) in this stage successfully suppressed the recurrence of vertigo attacks.     

Ultrasonic level diagnosis of lumbar disc herniation

Although the use of diagnostic ultrasound to measure the spinal canal has been proposed, the value of ultrasound for lumbar disc herniation has not been yet fully assessed. The purpose of this investigation was to evaluate the effectiveness of ultrasound in the level diagnosis of herniated nucleus pulposus. Prospective ultrasound examinations were performed on 80 consecutive patients with clinically suspected lumbar disc herniation. In 41 discs of those 40 patients with surgically confirmed lumbar disc herniation, there were 32 discs (78%) with true-positive ultrasound diagnoses, 37 discs (90%) with true-positive myelographic diagnoses, and 20 patients (50%) with true-positive neurologic diagnoses. Conversely, ultrasound diagnoses showed positive echogram in 24 (60%) of 40 nonoperative patients. These results suggest that ultrasound is of value as an aid for diagnosing the level of lumbar disc herniation.     

A case of primary pulmonary sporotrichosis

We report the first case of primary pulmonary sporotrichosis in Japan. A 53-year-old man was admitted to our hospital for further examination of the abnormal shadows on chest X-ray film. Six months before admission, he was admitted to another hospital because of alcoholic liver disease and diabetes mellitus. Since the initial chest film showed cavities with infiltration in the left upper lung field, he was treated with antituberculous drugs despite negative sputum cultures for mycobacterium. In spite of the medication, his chest X-ray film revealed another cavitary lesion, so he was referred to our hospital. He had been asymptomatic during this period. Chest X-ray on admission disclosed multiple cavities in the left upper lobe and a cavity in the right lower lobe. Repeated sputum specimens, bronchial washings and brushings for cytology and cultures were all negative. In an attempt to clarify the pathogen, percutaneous lung aspiration (PLA) was performed. The PLA sample yielded a positive culture of Sporothrix shenckii. After the diagnosis, S. schenckii was also cultured from sputa. A sporothrix skin test and yeast agglutination test for S. schenckii were positive. In the absence of a history for skin lesion, the patient was diagnosed as a primary pulmonary sporotrichosis. As iodide therapy was ineffective, he was started on a regimen of intravenous amphotericin B. However his renal function progressively deteriorated, so amphotericin B was discontinued. Now he receives miconazole intravenously and is still under careful observation. As far as we know, this is the first report of primary pulmonary sporotrichosis in Japan. The possibility of sporotrichosis should be considered in any cases of undiagnosed cavitary lung diseases.