Effects of the antihistaminergic drugs diphenhydramine and zolantidine on vestibular-induced hypothalamic neuronal activity in the guinea pig.

The mode of action of diphenhydramine in treating motion sickness is unknown. Using an electrophysiologic technique, we investigated the effects of intravenous diphenhydramine and zolantidine on the changes in neuronal activity produced by caloric stimulation in the hypothalamic paraventricular nucleus (PVN) in the guinea pig. Changes in neuronal activity were modulated by the administration of diphenhydramine in a high percentage of the neurons tested (71%), while zolantidine affected only a small number (29%). This finding reinforces the involvement of a histaminergic system in vestibular autonomic responses. The modulatory effect of diphenhydramine on PVN neuron activity may explain in part this drug's efficacy in treating motion sickness.

Comparison of survival rates of patients with nasopharyngeal carcinoma treated with radiotherapy, 5-fluorouracil and vitamin A ("FAR" therapy) vs FAR therapy plus adjunctive cisplatin and peplomycin chemotherapy.

The overall survival rate (OSR) of 36 patients with nasopharyngeal carcinomas (NPC) treated at Kyushu University hospital between 1983 to 1992 was analyzed. As primary treatment, 16 patients received a combination therapy of 5-fluorouracil, vitamin A, and radiation (FAR therapy); two patients received radiotherapy only; 18 patients received FAR therapy plus adjunctive systemic chemotherapy consisting of cisplatin and peplomycin. The radiation dose to the nasopharynx was 6000 to 7050 cGy while that to the neck was 4000-6000 cGy. The 5-year OSR of all the patients was 49%. Histological type (moderately differentiated squamous cell carcinoma) and patient age (> or = 55) were found to be significant prognostic factors for a worse OSR. Although survival decreased with increasing T stage, no significant difference was observed. The 5-year OSR of the patients treated with FAR therapy was 53% and was 51% with FAR therapy plus chemotherapy. Compared to FAR therapy alone, adjunctive chemotherapy did not increase OSR of the patients with NPC.

Japanese cedar pollinosis and HLA-DP5.

Japanese cedar pollinosis is a type I allergic disease caused by Japanese cedar (Cryptomeria japonica) pollen. We investigated the association between the disease and HLA class II alleles by HLA-DNA typing using a PCR-SSOP method and found that the frequency of HLA-DP5 (DPA1*02022 and DPB1*0501) was significantly increased in the patients. To investigate whether the HLA-DP5 molecule is directly involved in the pathogenesis of the disease, Japanese cedar pollen antigen (CPAg)-specific T cell lines were established from 3 patients who possessed HLA-DP5 (DPA1*02022/ DPB1*0501). By using these CPAg-specific T cell lines and HLA class II-expressing L-cell transfectants, we found that disease-associated HLA-DP5 restricted T cells specific for CPAg existed in the patients. Furthermore, among 38 synthesized overlapping peptides spanning the entire length of one of the major Japanese cedar pollen allergens, Cry j 1, an immunodominant peptide which induced HLA-DP5 restricted Th2 was identified. These observations suggest that the HLA-DP5 may be involved, at least in part, in the pathogenesis, by helping the IgE antibody production against CPAg.

Bio-feedback and the yawning breath pattern in voice therapy: a clinical trial.

A breathing technique, or effective breath method is important for both singers and speakers for effective vocalization, and also useful for helping people with a voice problem. Here a diaphragm support breath pattern was used in voice therapy for patients with vocal nodules, recurrent laryngeal nerve paralysis, and incomplete glottal closure. Singing teachers use a technique, called the diaphragm breath support. This is called the yawning breath pattern (YBP) in our voice clinic and is used in teaching the patients with some kinds of voice disorder. In order to correct patients' breath pattern, an equipment system was designed to check their breath patterns conveniently in voice therapy practice. A respiratory kinematic sensor which connected to a TV monitor was attached to the patients' rib cage near the diaphragm, and by bio-feedback, patients could observe and adjust their breath pattern to the desired pattern during vocalization. In each of the 10 outpatient sessions, the patients performed for 20 to 30 min, and were instructed to practice at home for 3 or more times daily. The YBP method was applied to 91 patients, 17 males and 74 females, with ages ranging from 17 to 79 years. Of the 91 patients 41 had vocal nodules, 20 had recurrent laryngeal nerve paralysis and 30 had incomplete glottal closure associated with chronic laryngitis and sulcus vocalis. Most of the patients could master the YBP technique successfully. The higher the patients' ability to master the YBP was the better the results of both voice tests and subjective evaluation. The scientific background of the YBP method and its clinical effects in voice therapy was reviewed.

Potentiation by vitamin A of the action of anticancer agents against murine tumors.

Combinations of retinol palmitate (RP) and six different anticancer agents were examined to determine their effects on the life-span of mice bearing ascites sarcoma 180 or P388 leukemia. With ascites sarcoma 180, administration of a fixed dose of RP (3.3 mg/kg) considerably enhanced the antitumor effects of 5-fluorouracil (5-FU) (5 mg/kg, or 20 mg/kg), methotrexate (MTX) (0.5 mg/kg, or 1 mg/kg) and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) (12.5 mg/kg), when given by intraperitoneal injection. However RP failed to potentiate the antitumor effects of adriamycin (ADM) and 6-mercaptopurine (6-MP) against sarcoma 180. With P388 leukemia, RP (167 mg/kg, or 333 mg/kg) enhanced the antitumor effects of 6-MP (25 mg/kg, or 50 mg/kg), MTX (1 mg/kg, or 2 mg/kg), ADM (0.2 mg/kg), ACNU (5 mg/kg) and cis-dichlorodiammine-platinum (CDDP) (1 mg/kg) to a considerable extent, but it did not potentiate the antitumor effect of 5-FU. The combination of RP with ACNU or CDDP was particularly effective against P388 leukemia.

Potentiation of anticancer agents by new synthetic isoprenoids. II. Inhibition of the growth of transplantable murine tumors.

The antitumor effects of combinations of synthetic isoprenoids-decaprenylamine.HCl, N-(p-methylbenzyl)decaprenylamine.HCl [N-(PMB)-decaprenylamine.HCl], and decaprenoic acid-with anticancer agents were studied in male ICR mice with ascites sarcoma 180 (S180) and in male BALB/c mice with fibrosarcoma Meth A. Decaprenylamine.HCl, N-(PMB)-decaprenylamine.HCl, and decaprenoic acid were tested in combination with bleomycin A2 (BLM) on S180. Decaprenoic acid was also examined in combination with BLM or 5-fluorouracil (FUra) for effects on fibrosarcoma Meth A. The dosages of synthetic isoprenoids used in the combination therapy were much below the median lethal dose. In the low-dosage schedule, decaprenylamine.HCl, N-(PMB)-decaprenylamine.HCl or decaprenoic acid considerably enhanced the antitumor effect of BLM on S180; e.g., the T/C value (mean survival time of treated mice/mean survival time of controls) for decaprenylamineHCl plus BLM, N-(PMB)-decaprenylamine.HCl plus BLM, or decaprenoic acid plus BLM was 294, 357, and 279% respectively, and the combinations increased life-span 2.4-fold, 2.3-fold, or 1.8-fold, respectively, as compared to the effects of BLM alone. The combination of BLM or FUra with decaprenoic acid, when administered by iv injection to mice with fibrosarcoma Meth A (solid tumor system), did not produce synergism. However, a preventive effect of decaprenoic acid monotherapy was observed: Decaprenoic acid at 3 mg/kg resulted in 38.9% suppression of tumor growth 21 days after inoculation.

Pimaricin potentiation of bleomycin activity against murine tumors.

Antitumor activity of bleomycin against Ehrlich ascites carcinoma in mice was examined in the presence and absence of a polyene antibiotic, pimaricin. A single intraperitoneal (ip) injection of bleomycin and pimaricin in combination into tumor-bearing mice on day 1 produced a synergistic life-prolongation effect as compared with that of each agent alone. Accumulation of abdominal ascites was almost completely blocked by bleomycin in combination with the tetraene antibiotic. Frequent ip injection of small doses of bleomycin and pimaricin on day 1 produced a much greater increase in life span than the single ip injection. To obtain effective synergism under these treatment schedules, it appeared that the dose of bleomycin should be reciprocally proportional to the dose of pimaricin.

[Experimental and clinical studies on application of vitamin A to cancer treatment].

Retinol-type vitamin A enhances cytocidal effect of several anticancer agents or radiation in in vitro as well as in vivo. We describe therapeutic effect fo a combination therapy of vitamin A and other agents which has been applied to cancer patients since 1972. We also discuss a possible role of vitamin A in the efficient synergistic effect.

[Moderate dose methotrexate with citrovorum factor rescue therapy in the treatment of head and neck cancer].

A clinical trial of moderate dose methotrexate (MTX)-CF rescue was conducted in 12 institutions. Thirty-seven patients with head and neck carcinoma entered this trial, of which 32 were evaluable. MTX was administered 350 mg/m2 (500 mg/body) by i.v. drip over 6 hours. Three hours after completion of MTX infusion, CF rescue was started. There was no complete response in 32 patients. Nine patients showed partial response with the response rate of 28%. The response rates were 21% for the group of patients treated previously, and 75% for the group untreated previously. MTX concentration in plasma was determined at 6, 24, 48 and 72 hours after the initiation of MTX infusion, and the assay results revealed a safe range. GI disturbances were seen at the rates of 11 to 38%. Bone marrow suppression was mild and no renal toxicity was observed. We concluded that the moderate dose MTX-CF rescue therapy was useful for head and neck carcinoma. As a next step, we are planning to conduct a clinical trial of high-dose MTX.

Biofeedback therapy for spastic dysphonia.

Spastic dysphonia is a disorder of phonation which is characterized by a strained, creaking, and choked vocal attack, a tense and squeezed voice sound. Spastic dysphonia in a functional voice disorder can be classified into two types from the viewpoint of activities of the extrinsic and intrinsic laryngeal muscle groups. A functional voice disorder pertaining to abnormal activities of the intrinsic and extrinsic laryngeal muscles results in spastic dysphonia. The adductor spastic dysphonia may be due to abnormal actions of the intrinsic laryngeal muscles as such is relieved by sectioning of the recurrent nerve, while spastic dysphonia mainly dealing with the extrinsic laryngeal muscles is relieved by relaxation on monitoring an electromyographic feedback system. Within 3 months we encountered two patients whose extrinsic laryngeal muscles were hyperactive on phonation. A trial on injection of lidocaine into extrinsic laryngeal muscles made their muscles relax. So, biofeedback therapy of relaxation was began using a monitoring system of EMG burst regarding to hypertonicity of the extrinsic laryngeal muscles. Normal vocal abilities were recovered using a biotrainer as a monitoring device of electromyographic feedback.