Evaluation of esophageal motility by endosonography using a miniature ultrasonographic probe in patients with reflux esophagitis.

BACKGROUND: Although there are several established methods used to evaluate esophageal motility, none allows for direct observation of esophageal wall motion. Esophageal dysmotility is thought to contribute to reflux esophagitis (RE). The aim of this study was to evaluate esophageal wall motility by endosonography using a miniature ultrasonographic probe (MUP) in patients with RE. METHODS: The subjects consisted of 10 healthy controls (10 men with a mean age of 31.5 years) and 9 patients with RE (4 men and 5 women with a mean age of 51.5 years). High-frequency endoluminal sonography was performed using a 20-MHz transducer through a 16F gastric tube to evaluate esophageal wall motion. Four sonographic phases of an esophageal peristaltic sequence were identified. In the resting phase, the esophageal wall was in direct contact with the transducer. In the passive distention phase, the esophageal lumen was stretched maximally; in the contraction phase, it contracted; and in the relaxation phase, it returned to baseline. The baseline thickness of the muscle layers of the esophageal wall was measured at rest. The width decreased during the passive distention phase, increased and reached a maximum during the contraction phase, and returned to baseline during the relaxation phase. RESULTS: The contractility index of the circular smooth muscle (CSM) in the distal esophagus and of the longitudinal smooth muscle (LSM) in the proximal esophagus were significantly lower in patients with RE. The duration of contraction in the distal esophagus was significantly longer in RE. CONCLUSIONS: We used a MUP to demonstrate abnormalities in esophageal wall motility in patients with RE. We conclude that the MUP is a potentially useful technique for evaluating esophageal dysmotility.

Influence of oral adsorbent AST-120 on anticonvulsive effect of zonisamide in rats.

The influence of oral adsorbent AST-120 (Kremezin) on the anticonvulsive effect and pharmacokinetics of zonisamide was investigated. Oral administration of zonisamide (50 mg/kg) blocked the appearance of the tonic extension induced by maximal electroshock seizure. This effect of zonisamide was inhibited by the oral coadministration of AST-120 (5 g/kg). In pharmacokinetics study, the serum zonisamide concentration after coadministration of zonisamide and AST-120 was significantly lower than that of single administration of zonisamide. However, the anticonvulsive effect of zonisamide was not affected by the administration of AST-120 1.5 h after zonisamide administration. In this condition, the serum zonisamide concentration was not changed. In the in vitro study, AST-120 completely adsorbed zonisamide. These findings suggest that when AST-120 is administered concurrently with zonisamide, a significant inhibition of the anticonvulsive effect of zonisamide occurs, and the decrease in serum zonisamide concentration by the adsorption effect of AST-120 is related to this phenomenon.

Extracorporeal ultrasound is an effective diagnostic alternative to endoscopic ultrasound for gastric submucosal tumours.

BACKGROUND: Although endoscopic ultrasonography (EUS) is the best modality in the diagnosis of gastric submucosal tumours (G-SMT), it is still invasive and expensive. We evaluated the usefulness of transabdominal ultrasonography (US) as an alternative to EUS in the assessment and clinical management of G-SMT. METHODS: This is a prospective study of 156 successive patients who had been diagnosed with G-SMT by direct endoscopic visualization. For each patient, US was performed prior to EUS by an examiner who had not been informed about the site or the size of the patient's G-SMT beforehand. US diagnoses were compared with those ascertained by EUS. Diagnostic grade by US was divided into three groups: diagnosed (G-SMT was clearly demonstrated including location, site and type), detected (G-SMT was demonstrable but the type was not clear) and undetected (G-SMT was not demonstrated by US). RESULTS: We found that US can be an alternative to EUS for: 1) diagnosis of extramural compression, 2) diagnosis of G-SMT with size >30 mm in diameter, 3) detection and measurement of the size of a G-SMT from 21 to 30 mm in diameter, and 4) detection and measurement of the size of a G-SMT at both the gastric angle and cardia, regardless of the size of the tumour. Overall sensitivity and specificity for the detection of G-SMT were 82.5% and 100%, respectively. The diagnostic rates of G-SMT in each group were 60.1% (86/143) for diagnosed, 22.4% (32/143) for detected and 17.5% (25/143) for undetected. Approximate 95% (21/22) of G-SMT over 20 mm in diameter were at least detected, and 97% (30/31) of G-SMT over 30 mm in diameter were diagnosed by US. CONCLUSION: US can be an alternative method in the assessment of G-SMT, especially in the follow-up of patients already diagnosed.

Dopaminergic neurotransmission triggers ischemia-induced hyperactivity in Mongolian gerbils.

It is recognized that sustained ischemia-induced hyperactivity is related to abnormalities in dopamine function. However, it is unclear that dopaminergic neurotransmission triggers such ischemia-induced hyperactivity. Therefore, the relationship between dopaminergic neurotransmission and ischemia-induced hyperactivity was investigated in an animal model using Mongolian gerbils. When haloperidol 2 mg/kg was administered i.p. 30 min after ischemia, the ischemia-induced hyperactivity at 24 h after ischemia was blocked. General behavior was similar to that of sham-operated animals. Haloperidol at doses of 0.1 and 0.2 mg/kg had no effect on locomotor activity in sham-operated animals and decreased ischemia-induced hyperactivity when the drug was administered 24 h after ischemia; these doses did not have any effect on ischemia-induced hyperactivity when the drug was administered 30 min after ischemia. On the other hand, when the animal was confined to a small, restrictive cage for the 24 h period immediately following ischemic injury, locomotor activity at 24 h after ischemia increased. Such behavior also increased in animals when they were returned to their original more permissive cages immediately after ischemia. It is conceivable that the decrease in the level of activity was not related to ischemia-induced hyperactivity. These data suggested that the inhibition of ischemia-induced hyperactivity can be induced by complete blockage of dopaminergic receptors immediately after ischemia.

Chronic methamphetamine administration inhibits cerebral ischemia-induced hyperactivity in Mongolian gerbils.

The effect of single and chronic methamphetamine (MAP) administration on ischemia-induced hyperactivity was investigated and the mechanism of ischemia-induced hyperactivity was discussed. Ischemia-induced hyperactivity was recognized 3 h after ischemia. However, ischemia-induced hyperactivity at 1 day after ischemia was inhibited when MAP, in a dose of 10 mg/kg, was administered for 7 days and withdrawn for 7 days. It was reported that MAP treatment caused an irreversible decrease in the number of dopamine (DA) uptake sites. In addition to this, monoamine oxidase and the uptake of DA into the nerve terminals are disturbed by cerebral ischemia. Therefore, a lot of DA release happened during and immediately after ischemia, and a marked down-regulation of DA receptor occurred 24 h after ischemia in MAP-injected group. It is conceivable that the DA receptor, especially the presynaptic DA uptake site, is related to the occurrence of ischemia-induced hyperactivity. Further studies appear to be necessary to clarify acceptor susceptibility when neurotransmitters are normalized after transient ischemia.

[The development of new drugs for osteoporosis in Japan].

In a rapidly aging society, the number of patients becoming bed-ridden due to osteoporosis-related fracture has become a socially important health issue that includes the problem of adequate nursing. Recently, the introduction of a rapidly acting bone absorption suppressant with a clear mechanism accelerated the development of osteoporosis treatment. A selective estrogen receptor modulator in a estrogen preparation is expected, because it has antagonism for the acceptor of the reproductive organ. It is noted that a new steroid with a weak androgen action and estrogen- and progestogen-like actions both prevents bone quantity decrease in women and increases bone quantity in osteoporotic patients after menopause. The second and third generation of bisphosphanate is more powerful than etidronate, the first generation of bisphosphanate, allows continual medication, and is now in clinical trial. The introduction of new drugs, which have clear efficacy and fewer side effects may be expected, along with the combined use of the drugs in which action mechanisms differ. The introduction of pharmaceutical new approaches is also expected as the expression mechanism of osteoporosis is further clarified by basic studies.

Severe fenitrothion poisoning complicated by rhabdomyolysis in psychiatric patient.

Non-traumatic rhabdomyolysis associated with organophosphate intoxication has not been generally reported. We report here in a severe case of fenitrothion poisoning complicated by rhabdomyolysis. A 43-year-old woman ingested approximately 100 ml of fenitrothion emulsion (50%) in an attempt to commit suicide. On day 3 after admission, her creatine phosphokinase (CPK) peaked at 47,762 IU/L. She received supportive treatment included sodium bicarbonate and fluid resuscitation. However, muscarinic symptoms including excessive miosis and salivation developed on day 5 when her CPK levels decreased. The delay in cholinergic symptoms might have been due to the trihexyphenidyl she took with the antipsychotic drugs. Fortunately, the present patient recovered from the acute cholinergic crisis, and acute renal failure was prevented by early diagnosis. This is a case of organophosphate poisoning complicated by rhabdomyolysis in a psychiatric patient. The masking of acute cholinergic symptoms should be taken into consideration in such patients.

Statistical analysis of functional regions in Ti and Ri sequenced plasmids in Agrobacterium.

The purpose of this paper is to examine functional regions of the completely sequenced DNA data of Ti and Ri plasmids, based on codon usage similarity. It is shown that a successful classification of functional regions is obtained by using statistical measures of codon usage dissimilarity and correspondence analysis.

Effects of long-term treatment with calcium antagonists on periarterial nerve function in the mesenteric artery of spontaneously hypertensive rats.

The effect of long-term treatment with dihydropyridine calcium antagonists (amlodipine, pranidipine, nicardipine) on the periarterial nerve function was investigated in the perfused mesenteric vascular bed isolated from spontaneously hypertensive rat (SHR). Male 8-week-old SHR received amlodipine (0.01% and 0.02%) and nicardipine (0.1%) in drinking water and pranidipine (0.0035% and 0.035%) in rat chow for 7 weeks. Mean blood pressure in SHR was significantly lowered by long-term treatment with each calcium antagonist. In mesenteric vascular preparations treated with each calcium antagonist, vasoconstriction induced by periarterial nerve stimulation (PNS; 4, 8 and 12 Hz) was significantly smaller than that in non-treated SHR. The PNS (8 Hz)-evoked norepinephrine (NE) overflow in the perfusate was significantly decreased by amlodipine and pranidipine treatment, whereas nicardipine-treatment significantly enhanced the overflow of NE. In preparations with active tone produced by methoxamine and guanethidine, the PNS-induced vasodilation mediated by calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves was not affected by these drugs. These results suggest that long-term treatment of SHR with long-acting drugs, amlodipine and pranidipine, reduces sympathetic adrenergic nerve function but calcium antagonists have no effect on CGRPergic nerve function.

Ultrasonography improves diagnostic accuracy of acute appendicitis and provides cost savings to hospitals in Japan.

A cost analysis based on changes in patient care was used to evaluate the utility of abdominal ultrasonography in both the clinical management of patients clinically suspected of having acute appendicitis and in reducing expenditure of hospital resources. Among the 200 patients suspected of having acute appendicitis, 57 actually had acute appendicitis. Interpretation of appendiceal ultrasonographic results was 98.5% accurate. The ultrasonographic result led to changes in the treatment of 103 patients. Moreover, ultrasonography led to the prevention of unnecessary appendectomy in 25 patients, providing a savings to the hospital of about Yen 8,013,450 ($65,150), and prevented unnecessary hospital admission for 78 patient-days, thus saving the hospital approximately Yen 1,199,250 ($9750). The cost of performing the 200 ultrasonographic examinations was about Yen 1,096,176 ($8912), and thus the overall savings to the hospital was approximately Yen 40,590 ($330) per patient. Ultrasonography performed in patients with suspected acute appendicitis improves patient diagnostic accuracy, thus leading to more appropriate selection of patient treatment and reduced hospital expenditure.

The effects of exposure to cigarette smoke on the pharmacokinetics and pharmacodynamics of zonisamide in rats.

The effects of exposure to cigarette smoke on the pharmacokinetics and pharmacodynamics of zonisamide, an antiepileptic drug, were investigated in rats. Absorption of oral zonisamide was significantly inhibited by exposure to cigarette smoke. The Cmax, T1/2 and the area under the plasma concentration-time curve 0-24 values in the cigarette smoke exposure group were significantly lower than those in the control group. Although tonic extension (TE) induced by maximal electroshock was completely blocked by the administration of zonisamide in the control group, 50% of rats showed TE in the cigarette smoke exposure group. Exposure to cigarette smoke influences both the pharmacokinetics and antiepileptic effects of zonisamide. The effects of smoking on epileptic patients using zonisamide warrants further attention.

Statistical analysis of DNA sequencing data (1): accuracy test of DNA data by partial re-sequencing.

To qualify DNA data, we have developed a statistical method of deciding whether the DNA data has an acceptable accuracy in sequencing process. The method is to test the probability of sequencing errors, based on partial re-sequencing. The method was successfully applied to a yeast mitochondrial DNA which is previously sequenced (1). The analysis indicates that the entire sequence is very accurate although we found one base change error on the ND1 gene sequence data by a partial re-sampling. This method is applicable to any DNA data.

Angiotensin inhibits neurotransmission of calcitonin gene-related peptide-containing vasodilator nerves in mesenteric artery of spontaneously hypertensive rats.

The role of angiotensin (Ang) in neurotransmission of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves in perfused mesenteric vascular beds isolated from spontaneously hypertensive rats (SHR) (8- and 15-week-old) and age-matched Wistar Kyoto rats (WKY) was investigated. In both SHR and WKY preparations precontracted by continuous perfusion of Krebs' solution containing 7 microM methoxamine plus 5 microM guanethidine, periarterial nerve stimulation (PNS; 1 and 2 Hz) produced a frequency-dependent vasodilation, which was abolished by 100 nM tetrodotoxin and 500 nM CGRP(8-37) (CGRP receptor antagonist). The PNS-induced vasodilation in the SHR decreased with age and was smaller than that in the WKY. The neurogenic vasodilation in the SHR but not WKY was significantly inhibited by N-acetyltetradecapeptide renin substrate (RS, 100 and 500 nM), AngI (50 and 100 nM) and AngII (50 and 100 nM). The inhibitory effects of RS, AngI and AngII were abolished by the AngII receptor antagonist, [Sar1,Ile8]AngII (500 nM). The effect of RS and AngI was inhibited by captopril (5 microM) and temocapril (500 nM). AngII (100 nM) had no effect on vasodilator response to exogenously infused CGRP (100 pmol). PNS (2 Hz) of perfused mesenteric vascular beds increased the release of CGRP-like immunoreactivities (CGRP-LI) in the perfusate, which was less in 15-week-old SHR than in age-matched WKY. AngII (100 nM) significantly inhibited the neurogenic release of CGRP-LI in the SHR but not in the WKY. These results suggest that exogenous and locally converted AngII, via AngII receptors, modulates the neurotransmission of CGRP-containing vasodilator nerves by inhibiting CGRP release from the nerve.

Age-related decrease in centrally-mediated pressor response to clonidine in conscious rats.

An age-related change in pressor response to intracerebroventricular (i.c.v.) injection of clonidine in conscious rats was investigated. In 15-week-old rats, clonidine (2 to 20 micrograms) caused a dose-dependent pressor response concomitant with decrease in heart rate. The depressor response to i.c.v. clonidine at lower doses (2 and 5 micrograms) but not higher doses (10 and 20 micrograms) was observed. The pressor response to clonidine in 20- and 30-week-old rats was markedly diminished, and the depressor response appeared at any of the doses injected. However, no age-related change in heart rate responses was observed. These results suggest that the centrally mediated pressor response to clonidine is age-related and masks the depressor response.

Micellar electrokinetic capillary chromatography for therapeutic drug monitoring of zonisamide.

The simultaneous determination of zonisamide, a new type of antiepileptic drug, and the typical antiepileptic drugs phenobarbital, phenytoin and carbamazepine in human serum was developed using micellar electrokinetic capillary chromatography (MECC) with a diode array detector. A high correlation was revealed between the zonisamide levels in human serum obtained by MECC and those obtained by high-performance liquid chromatography (r=0.981). The serum levels of phenobarbital, phenytoin and carbamazepine determined by MECC were almost equal to those obtained by fluorescence polarization immunoassay. The reproducibility of separation and quantification with MECC analysis was appropriate for the intra- and inter-day assay coefficients. Therefore, the MECC method established here could provide a simple and efficient therapeutic drug monitoring method for antiepileptic drugs in patients, especially those treated with a combination of zonisamide and other antiepileptic drugs.

Enhancement by morphine of radiographic contrast media-induced histamine release in rat peritoneal mast cells.

In intravascular application of radiographic contrast media causes hypersensitivity reactions, in which histamine release may play a major role. We examined the interaction between contrast medium and morphine. Among the four nonionic contrast media examined, iopamidol showed the most marked histamine release from rat peritoneal mast cells in vitro. Although iopamidol and morphine themselves did not induce histamine release at concentrations up to 65 mgI/ml and 3 mM, respectively, their combination resulted in a significant histamine release. These findings suggest that patients with exposure to medicines that induce histamine release may have a higher incidence and severity of hypersensitivity reactions to radiographic contrast media.

Application of high-performance thin-layer chromatography for the detection of organophosphorus insecticides in human serum after acute poisoning.

We developed a rapid and simple method for identifying 25 commonly used organophosphorus insecticides in human serum using high-performance thin-layer chromatography (HPTLC). These organophosphates were separated on plates with three different developing systems within 6-18 min and detected by means of ultraviolet radiation and coloring reactions with 4-(4-nitrobenzyl)pyridine-tetraethylenepentamine reagent (NT reagent) or palladium chloride reagent (PdCl2 reagent). Each organophosphate was accurately identified by means of the R(F) x 100 value and the spot color in three systems. The detection limits of dichlorvos, fenitrothion, malathion, methidathion, parathion and trichlorfon in serum by the liquid-liquid extraction method were 1.1, 0.12, 0.12, 0.05, 0.6 and 0.1 microg/ml, respectively. These sensitivities may be sufficient to detect those organophosphates in patient serum after acute poisoning.

Relapse and elevation of blood urea nitrogen in acute fenitrothion and malathion poisoning.

We observed 6 patients with severe fenitrothion and/or malathion poisoning necessitating artificial ventilation and intensive care monitoring. Three developed relapse following acute cholinergic crisis. In these patients the blood urea nitrogen (BUN) abnormally elevated before the development of relapse and the initial high concentration of plasma organophosphate (OP) decreased only gradually. However, the patients who did not develop relapse showed no elevation of BUN and a relatively low concentration of plasma OP. This observation was confirmed in a retrospective search of 14 patients. In addition, erythrocyte cholinesterase (EChE) activities were more helpful to diagnose the development of relapse than plasma cholinesterase activities. Therefore, careful monitoring of BUN in addition to plasma OP concentration may be useful to predict the development of relapse.

Rapid and sensitive detection of benzodiazepines and zopiclone in serum using high-performance thin-layer chromatography.

We developed a rapid and sensitive method of identifying benzodiazepines and zopiclone in human serum using high-performance thin-layer chromatography (HPTLC). These drugs were developed and separated on plates within 8-11 min and detected by means of UV radiation and colour. Each drug was accurately identified by means of the values of RF x 100 and the spot colour in three systems. The detection limit of the benzodiazepines in serum was 0.1-0.4 micrograms/ml, except for cloxazolam and haloxazolam. The sensitivity was increased about ten-fold over the conventional method. These results suggested that the HPTLC system is useful for the initial detection and identification of these drugs in emergencies.

Acute organophosphate poisoning after disulfoton ingestion.

A 75-year-old woman attempted suicide by ingesting a large quantity of granular Di-Syston which is an organophosphate insecticide containing 5% disulfoton (ethylthiometon). On admission, the total plasma phosphorodithioate sulfone concentration (disulfoton and its metabolites, phosphorodithioate sulfoxide and its sulfone) determined by gas chromatography was 1095 ng/mL. After gastric lavage, the concentration gradually decreased to 505 ng/mL. However, it began to increase again 20 h after admission and reached the peak concentration (1322 ng/mL) at 56 h. It was concluded that the secondary elevation of the plasma concentration was due to the prolonged absorption of the organophosphate from the residual granules in the stomach, despite the early gastric lavage. Pralidoxime iodide administration temporarily restored erythrocyte cholinesterase activity to almost normal and inhibited the excessive, delayed reduction of cholinesterase activity. It is recommended that poisoning with the granular form of disulfoton should be treated with repetitive or prolonged gastric and intestinal lavage, charcoal, and a continuous intravenous infusion of pralidoxime iodide in addition to atropine sulfate.