Pharmacokinetic and pharmacodynamic interactions among haloperidol, carteolol hydrochloride and biperiden hydrochloride.

A beta-adrenoceptor blocker and an anticholinergic agent are often prescribed concomitantly for the treatment of neuroleptic-induced akathisia. The aim of this study was to investigate possible pharmacokinetic interactions of neuroleptic haloperidol with the beta-blocker carteolol and the anticholinergic biperiden. In a 5-step, open-labeled, oral single-dose study, eight healthy male volunteers received 2 mg haloperidol, 10 mg carteolol hydrochloride, and 2 mg biperiden hydrochloride: first each drug alone, then a combination of haloperidol and carteolol, and then all three drugs concurrently. Serum concentrations of haloperidol, carteolol, and biperiden were determined up to 24 hr postdosing, and a safety evaluation was conducted throughout the study. Carteolol increased the area under the haloperidol serum concentration-time curve (AUC0-t) 1.4-fold (P = 0.0014) and decreased the serum clearance of haloperidol up to 67% (P = 0.0127). Biperiden reduced the serum haloperidol concentrations increased by the administration of carteolol. No significant changes of the serum pharmacokinetics of carteolol and biperiden were found as a result of any drug combinations. Adverse events of the central nervous system such as sleepiness and changes in pupil size were observed, but all were mild with clinical insignificance.

Squamous cell carcinoma of the prostate.

A primary squamous cell carcinoma occurring in the prostate is described. Local irradition, systemic anticancer chemotherapy using bleomycin and intraarterial administration of cis-platinum were done. Twenty-one months after the initial diagnosis there is no sign of tumor progression.

Whole bladder wall photodynamic therapy for refractory carcinoma in situ of the bladder.

Whole bladder wall photodynamic therapy (PDT) with haematoporphyrin derivative and an argon dye laser as a light source was performed on 34 patients with refractory carcinoma in situ (CIS) of the bladder. Twenty-five of the 34 patients (73.5%) had achieved a complete response (CR) at 3 months after the treatment. The median follow-up for these CR patients is 49.3 months. Although recurrence within 2 years of follow-up occurred in 14 (77.8%) of the 18 CR patients followed to that point, since most of the recurrent tumours were superficial and low-grade papillary tumours, transurethral resection of the bladder tumours appeared to be sufficient. Of the total of 34 patients, ten were alive with bladder intact with a mean follow-up period of 64.0 months. Skin photosensitivity and transient decrease in bladder capacity were noted as adverse reactions, caused by retention of haematoporphyrin derivative in the skin and normal portion of the bladder. These data suggest that PDT can be an effective form of therapy for CIS of the bladder.

[Blood pressure change and syncope during leg phlebography].

Although syncope attacks such as black-out, faint consciousness, and cold sweat are sometimes experienced during leg phlebography, no study of their incidence and mechanism has been reported. We measured blood pressure noninvasively by using a Finapress with ECG monitor during overall examinations (21 cases, 33 limbs; male 8, female 13) following anamnesis. Age, sex, and past history of drug, syncope, leg phlebography, and other diseases were determined. All examinations were done in the upright position. Three cases (14.3%) and four limbs (12.1%) showed syncope attacks during leg phlebography. Syncope occurred after steps taken for the evaluation of venous return in two limbs, during infusion of contrast medium in one, and after infusion in the other. In all cases, the systolic blood pressure measurement during syncope was below 80 mmHg, and the sudden decrease of both systolic blood pressure (-83.0 +/- 22.0 mmHg) and heart rate (-29.5 +/- 5.0/min) suggested vasovagal reaction as a mechanism of syncope. Other causes of syncope including anaphylaxy, hyperventilation syndrome, seizure, and arrhythmia (except for bradycardia) were not found. There were also significant changes in blood pressure and heart rate in the nonsyncope group during leg phlebography that seemed to trigger vasovagal excitation. Premedication, contrast media, and position might be important factors and should be discussed further.

Swallowing dysfunction and aspiration in neonates and infants.

In children, swallowing dysfunction and aspiration are common causes of recurrent pneumonia and can be fatal. The underlying mechanism is still unknown. In this study, we evaluated the swallowing function in 72 neonates and infants by fluoroscopy and followed the course of 39 patients for more than one year. The results of all the examinations were recorded on videotape or a digital imaging system. All 10 patients with neurologic disorder presented cricopharyngeal dysfunction. Of the 12 patients with near miss sudden infant death syndrome, 10 showed nasopharyngeal reflux, and 5 demonstrated cricopharyngeal dysfunction. In the 50 patients without neurologic disorder, 29 revealed cricopharyngeal dysfunction. Laryngeal elevation was not seen in 75%. Three of these 29 patients had no other abnormality. All patients without neurologic disorder recovered well. Seven patients demonstrated prolonged aspiration. Four of them had neurologic disorder, and the rest had near miss sudden infant death syndrome. Fluoroscopic examination showed two types of aspiration: one was caused not only by pharyngeal but also by lingual muscles. It was not associated with any neurologic disorders and the symptoms were transient. The other was caused by cricopharyngeal dysfunction and most of these patients had neurologic diseases and prolonged symptoms.

Effects of prophylactic use of alpha-interferon for patients with renal-cancer.

We conducted an investigation on the prevention of cancer recurrence in 68 renal cancer patients administered alpha-interferon as postoperative adjuvant therapy following curative resection of renal cancer. The incidence of recurrence and the survival rate of the patient group were compared with the value of a control group to investigate the prophylactic efficacy of alpha-interferon. The findings of this study revealed that alpha-interferon administration was effective in preventing postoperative recurrence in patients with Robson's stage I and II cancers.

Combined treatment of radiofrequency capacitive hyperthermia for urological malignancies.

During the period from April 1984 to July 1993, we investigated the clinical efficacy of local hyperthermia used to treat 110 patients with urological malignancies. We investigated the long-term outcome of 40 (36.4%) responders who exhibited an immediate, partial or better response to the therapy. The one-year survival rate was 75% for retroperitoneal tumor, 65% for bladder cancer, 33% for each of renal cell carcinoma and prostatic cancer and 29% for renal pelvic and ureteral cancer. The 5-year survival rate was 48% for bladder cancer, 29% for renal pelvic and ureteral cancer, 25% for retroperitoneal tumor, and 0% for renal cell carcinoma and prostatic cancer. Subsidence of intolerable pain caused by cancer invasion was achieved in 29 of 42 patients (69.0%), indicating an improvement in patient's quality of life through pain relief.

[Studies of combined treatment of radiofrequency hyperthermia with anticancer agents or irradiation for invasive bladder cancer].

Using an in vitro colony forming assay system, the cytotoxic effects of anticancer agents alone, adriamycin (ADM) and bleomycin (BLM), and the combined effects of hyperthermia and anticancer agents on cultivated KK-47 cells were investigated. When the hyperthermia was combined with various concentrations of ADM ranging from 0.005 to 0.1 microgram/ml and BLM from 0.01 to 1.0 microgram/ml, enhanced cell killing effects were obtained at the concentration of less than 0.02 microgram/ml of ADM and with an increase of BLM concentration. In DNA specimens obtained from the livers of chick embryos inoculated with human tumor cultivated cells, the polymerase chain reaction technique was used to amplify a DNA fragment specific to the beta-globin gene. By detecting these amplified DNA fragments, the feasibility of efficiently detecting metastatic cells present in chick embryo was demonstrated in vivo. Hyperthermic therapy showed inhibitory effects on the growth of metastasized cultivated cells in a thermal dose-dependent manner. Combination therapy of ADM, mitomycin and carboplatin and hyperthermia had an enhanced inhibitory activity on the growth of metastasized cultivated human tumor cells derived from bladder cancer. Hyperthermia using radiofrequency-capacitive heating in combination with irradiation or anticancer agents, was performed in a total of 56 patients with T2 to T4 invasive urinary bladder cancer. A tumor regression rate of 50 percent or more was obtained in 21 of these 56 patients. We have to follow up the patients for longer periods more precisely to evaluate the role of these treatments.

Photodynamic therapy for cancers: a clinical trial of porfimer sodium in Japan.

Photodynamic therapy utilizing Photofrin has proven to be an effective modality that can be used in the treatment of a wide variety of solid tumors and luminal cancers. An argon pumped dye laser or excimer dye laser was used to deliver 630 nm light via quartz fibers passed through the biopsy channel subsequent to i.v. injection of photosensitizer. In this study, 64 patients with superficial cancers were treated in this manner but only 58 patients, including 21 with roentgenographically occult lung cancer, 8 with stage I lung cancer, 5 with esophageal cancer, 12 with gastric cancer, 8 with cervical cancer and 4 with bladder cancer were evaluable. Complete remission was obtained in 48 out of 58 cases (82.8%). There was no serious complication except skin photosensitivity, which was seen in 13 patients. We conclude that photodynamic therapy is efficacious in the treatment of superficial cancers where complete remission may be achieved.

Hyperthermic intravesical peplomycin perfusion treatment for bladder cancer.

Thirty-three patients with malignant bladder tumours were treated by hyperthermic intravesical perfusion. The study group included 25 patients with superficial T1 bladder tumours, 4 with T2 tumours and 4 with T3 tumours. Physiological saline solution containing 40 micrograms/ml peplomycin with/without 2% ethanol was used as a perfusate. Perfusion was carried out for 2 h 3 times per week and this regimen was repeated every other week, totalling 6 sessions in 3 weeks. Three patients achieved a complete response (CR), 5 a partial response (PR) (more than 50% tumour reduction), 8 a minimal response (MR) (25-50% tumour reduction) and the remaining 17 patients showed no response (NC). Complete, partial and minimal responses were obtained only in patients with T1 tumours. The NC patients included 4 with T2 and 4 with T3 lesions. Profuse haematuria from invasive tumour was markedly reduced after treatment. A major side effect was irritation of the bladder and urethra. Our results indicate that hyperthermic perfusion with ethanol and peplomycin is clinically safe, is accompanied by very little pain and may be useful for the management of superficial bladder tumours in elderly patients.

[Blood flow measurement of renal artery branches, in special reference to interlobular artery by color Doppler].

Blood flow measurement was performed in 58 kidneys of healthy persons. Detection rate, maximum flow velocity (Vmax), pulsatility index (PI) and resistive index (RI) were measured at main renal artery, segmental artery, interlobar artery and interlobular artery with 2 D-Doppler ultrasound machines. Detection rate was highest at interlobar artery. Vmax and PI tended to fall down with arterial branching. Interlobular artery was usually not visualized by color flow mapping, but sometimes well visualized using Acuson machines. Additional measurement of interlobar and interlobular arteries were performed in such 15 cases, and the result was essentially equal to the above mentioned study.

[Local recurrence of non-functioning adrenocortical carcinoma 14 years following surgical treatment: a case report].

A 76-year-old woman with a complaint of left flank pain was referred to our department for extensive examination and treatment. In 1976, she had undergone transperitoneal left adrenalectomy and nephrectomy under a diagnosis of left adrenal tumor. The surgical specimen had histologically been diagnosed as adrenocortical carcinoma. There have been no physical or endocrinological abnormalities. Computed tomogram, magnetic resonance imaging and angiogram revealed a retroperitoneal multiple hypervascular tumor with a non-homogeneous inner density. On January 16, 1991, a transperitoneal resection of the tumor with splenectomy and partial pancreatectomy was performed under a diagnosis of local recurrence of non-functioning adrenocortical carcinoma. The specimen was histopathologically diagnosed as low grade adrenocortical carcinoma based on 3 mitoses/50 hpf. From the reference study, this was thought to be the second case of late recurrence adrenocortical carcinoma.

Comparative study of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and tritiated thymidine in a chemosensitivity test using collagen gel matrix.

An organ culture system using collagen gel matrix (CGM) was modified and established successfully as a rapid and convenient method for determination of anti-cancer drug sensitivities. The cell viability of a tumor fragment was measured by the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to a colored formazan product, which allowed for quantitative and simple analysis. The sensitivities of KK-47 bladder tumor from nude mice to various anti-cancer drugs tested corresponded closely to those determined in the original CGM assay system using tritiated thymidine, which has a high clinical correlation. Our modified method can be used as a practical and highly reproducible chemosensitivity test in vitro.

[Clinical studies of stage D2 prostatic cancer].

Between 1981 to 1991, 126 patients were diagnosed with prostatic cancer from histological reports. Stage D2 prostatic cancer was confirmed in 38 of these cases at the time of the initial diagnosis (group alpha). Of 38 patients in group alpha, 13 had recurrence of disease after a good response to the initial treatment, 19 had no recurrence after the treatment and the other 6 patients showed no response to the initial treatment for prostatic cancer. Seven patients showed progression of the disease to stage D2 during the observation period (group beta). These forty-five patients with stage D2 prostatic cancer were analyzed. Poorly differentiated adenocarcinoma was the most frequently observed histological grade, followed by moderately differentiated. The grade of the extent of the disease (EOD) on bone scan was classified as EOD I in 26, EOD II in 13 and EOD III in 4, with no significant differences in the survival rate found among these groups. The sensitivity rate of prostate specific antigen was higher than that of other serum tumor markers. Twenty-three patients died during the observation period. 18 of the 23 died of prostatic cancer.

Spontaneous passage of upper urinary tract calculi in relation to composition.

The composition of 2,755 calculi obtained from the upper urinary tract (1,409 by spontaneous passage and 1,346 by urological procedures) was analyzed using an infrared spectrophotometer, and the spontaneous passage rate was investigated in relation to the composition as well as other variables, such as stone size, and patient age and sex. Mixed stones of calcium oxalate and calcium phosphate were most frequently found, followed by those of calcium oxalate. The mean size (the maximum diameter) was largest in struvite stones and smallest in calcium oxalate ones. The sizes of stones from women were significantly larger than those from men (p < 0.01). As expected, the stone passage rates were inversely related to increasing stone size. The size of 55.6% of the stones passed was < or = 5 mm, and that of 96.6% of the stones < or = 10 mm.

Possible advantages of aluminum-chloro-tetrasulfonated phthalocyanine over hematoporphyrin derivative as a photosensitizer in photodynamic therapy.

The potency of aluminum-chloro-tetrasulfonated phthalocyanine (AlS4Pc) as a photosensitizer in photodynamic therapy was evaluated in in vitro and in vivo studies. Compared with hematoporphyrin derivative (HpD), the following advantages of AlS4Pc were revealed: (1) AlS4Pc was less toxic than HpD in vitro without light irradiation. (2) AlS4Pc showed more photodynamic-dependent cytotoxicity and anti-tumor effect in the red area of the spectrum (> 660 nm) at which tissue penetration is high. (3) AlS4Pc appeared to be removed more rapidly from normal tissues such as muscle and skin. (4) AlS4Pc showed less photodynamic-dependent cytotoxicity in vitro and milder cutaneous phototoxicity in vivo with UVA irradiation. On the basis of these observations, AlS4Pc shows considerable promise as a photosensitizer for PDT.

In vitro chemosensitivity test for human genitourinary tumors using collagen gel matrix.

An in vitro chemosensitivity test using collagen gel matrix assay with quantitative evaluation of cell viability using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide was applied to 40 human genitourinary tumor specimens. Chemosensitivity was determined in 34 (85%) of the 40 specimens. The anticancer drugs tested against 14 renal cell carcinomas showed lower activities than against 15 transitional cell carcinomas with different sensitivity patterns among the individual specimens demonstrated. Our assay system could be successfully applied to human genitourinary tumors and can be used as a practical and highly reproducible chemosensitivity test in vitro.

Percutaneous mitomycin C perfusion of bilateral ureteral carcinoma in situ.

We treated a 61-year-old patient with a diagnosis of bilateral ureteral carcinoma in situ with percutaneous perfusions of mitomycin C. After 16 sessions of mitomycin C therapy instilled through bilateral nephrostomy tubes, the urine cytology results became negative for malignancy. Bilateral ureteroscopy and cold-cup punch biopsies of the ureter revealed no evidence of disease. The patient did not experience side effects. He has remained free of disease during a 12-month follow-up period. Percutaneous perfusion of mitomycin C appears to be one of the effective and safe treatments for the carcinoma in situ of the upper urinary tract.

Immunopathology of alkaline phosphatase isozymes in seminoma.

An immunohistopathological study using monoclonal antibodies for alkaline phosphatases demonstrated placental alkaline phosphatase (PLAP)-like substance in the tumor cells of 11 pure seminomas, 1 seminoma with embryonal carcinoma and 1 seminoma metastasis. Liver alkaline phosphatase (LAP) could also be demonstrated in all seminomas but a third intestinal alkaline phosphatase (IAP) was not demonstrable in any tumor. The PLAP-like substance and LAP had considerable enzyme activities. This provides two tumor markers of seminomas detectable in histopathological specimens.

Magnetic resonance imaging of bladder hemangioma.

An 18-year-old woman with a bladder hemangioma is described. The tumor had a low signal intensity with multilocular pattern on T1-weighted magnetic resonance (MR) images and high signal intensity on T2-weighted MR images. MR images were useful in evaluating tumor character and its extent.