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The prognosis of patients with early re-ruptured intracranial aneurysms is discouraging. We compared the data on patients suffering re-rupture before the onset of late vasospasm (Early-Re) with those suffering rebleeding thereafter (Late-Re). The operability in the Early-Re group was lower (p0.05) and the outcome less satisfactory than that of Late-Re group. Of the Early-Re patients, 83% had a re-rupture within 24 hours of the initial subarachnoid haemorrhage; moreover 46% of these experienced rebleeding within three hours of the initial bleeding. Cases in the Early-Re group tended to belong to Hunt-Hess grade III or IV on admission, of wide spread subarachnoid haemorrhage on CT and of "bump" type aneurysms on angiograms. Based on our experience we propose that early re-rupture may be attributable to the following factors: a gradual and progressive thinning of the wall of bump type aneurysms results in such a large laceration through the fundus of the aneurysm. Re-rupture may occur within a short period after the first rupture because the fibrin net covering the wide laceration cannot tolerate the slight increase in internal pressure within the aneurysmal dome. Therefore, in the patients of Hunt-Hess grade III or IV, conventional angiography, tight holding during CT examination and lumbar puncture, should be avoided during the first three hours after the first bleed. Although early direct operations on patients with high Hunt-Hess grades tend to produce an unsatisfactory outcome, we cannot help these patients with Early-Re without surgical treatment. Not only early direct operation but also first conservative treatment to control systolic blood pressure are very important in patients with Early-Re.

A clinically tonic seizure phase, immediately followed by psychomotor features (right hand dystonic posture, left hand and oral automatisms), was recorded by video and EEG, in a patient who had gliosis of the left temporal lobe and left hippocampal atrophy. Interictal epileptiform discharges were frequently seen in the left temporal area, and at the time of the tonic seizure phase, ictal spike discharges were continuously observed at the left posterior temporal area, which was recognized only by applying a high frequency filter (HFF) of 15 Hz to the digitally recorded EEG because EMG artifacts totally obscured the EEG with a HFF of 60 Hz. It is most likely that tonic seizure can occur in an adult patient with temporal lobe epilepsy, and it is speculated that an epileptogenic focus might activate a certain brain area which is regarded as a symptomatogenic zone for tonic seizures. If the tonic seizure phase is immediately followed by psychomotor features as seen in the present patient, the former could be due to focal epilepsy.

A boy with Down syndrome who developed myelodysplastic syndrome after regression of transient abnormal myelopoiesis (TAM) is described. His blast cells in TAM had other chromosome abnormalities in addition to trisomy 21;50,XY,+21c,+12,+14,+21. Serial chromosome analysis in follow-up showed abnormal clones involving monosomy 7. Myelodysplastic syndrome was diagnosed. Because two clones had different karyotypes, they might have derived from different clones.

This study examined the effects of mechanical destructive forces on drug release from controlled release (CR) multiple unit dosage forms in vitro and in vivo and their colonic release, using two CR granules of acetaminophen, AG and BG, which differed in hardness (AG was hard and BG was soft), but which did not depend on agitation speed or pH for their release.In vitro release rates were determined using several official methods and the rotating dialysis cell method. Granules were administered to healthy volunteers under fasting and fed conditions.Both granules showed similar release rates under mild destructive conditions in official dissolution tests, but BG showed a faster release rate in the rotating dialysis cell method. In the fasting state, the drug absorption-time profiles of AG and BG were almost equal. In the fed state, the drug release rate of BG increases whereas that of AG is almost equal to the fasted state. The food effect on BG could be caused by an increase in the mechanical stress of the GI tract due to food intake judging from the findings in vitro and in dogs. The colonic release from multiple unit CR products was larger than that from single unit ones.In vivo release of drug from a multiple unit CR product that is structurally weak is affected by mechanical stresses, which differ among human subjects but are increased by food ingestion. Colonic release from multiple unit CR products is larger than that from single unit products.

This study was undertaken to examine the effects of mechanical destructive forces on drug release from controlled release (CR) dosage forms in vitro and in vivo and their colonic release, using two CR tablets of acetaminophen A and B, showing slower and faster erosion rates, respectively.In vitro release rates were determined by several official methods. Tablets were administered to healthy volunteers under fasting and fed conditions.Both tablets showed similar release rates under mild destructive conditions (e.g., paddle method at 10 rpm) but CR-B showed faster release under highly destructive conditions (e.g., rotating basket method at 150 rpm), where the tablet was eroded. The in vivo release from CR-B was faster than from CR-A, possibly because of enhanced erosion. The variable in vivo release from CR-B indicated large inter-subject differences in destructive GI forces. The fastest in vivo release from CR-B among individuals was approximated by the in vitro dissolution determined by destructive methods such as the rotating basket at 150 rpm. The slowest in vivo release from tablets A and B was lower than the dissolution by the paddle method at 10 rpm. The release from both tablets was markedly reduced at 3-4 hrs after dosing irrespective of feeding conditions which can be attributed to release inhibition in the colon.Effects of GI destructive forces on the tablet erosion and the release inhibition in the colon must be considered in the development of CR dosage forms.

In this study, we assessed the hydrodynamic flow around a dosage form in the GI tract in humans by comparing the characteristics of in vitro and in vivo release of two different types of controlled release acetaminophen (paracetamol) tablets, A and B. The former tablet showed an agitation speed-dependent release at a high speed range (50-100 rpm), whereas the latter showed this characteristic at a low speed range (10-50 rpm). The mean release amount-time profiles of tablets A and B in humans showed biphasic characteristics, and the first phase of the absorption profiles of A and B was close to their in vitro profiles at a paddle speed of 10 rpm. The in vivo profiles were also superimposable on in vitro dissolution curves obtained by the flow-through cell method at a flow rate of 1 mL/min (velocity 0.89 cm/min) or less. These results indicate that the hydrodynamic flow around the dosage forms in the human GI tract could be extremely low. The in vivo release rate of these tablets in dogs was greater than in humans, and was estimated to be equivalent to the release rate determined by the paddle method at 100 rpm. This indicates that a higher agitation intensity in the GI tract in dogs than in humans may be one cause of the discrepancies between humans and dogs in drug absorption studies.

We analyzed 70 patients (64 from the literature and 6 of our own cases) who had suffered from rerupture of their aneurysms during angiography. When these cases are compared with those who had suffered rupture of their aneurysms only once and a rerupture, which did not coincide with angiography, they were clinically distinguished by a higher Hunt-Hess grade, a higher rate of IC aneurysms, less operability, far miserable outcome and concentration of aneurysmal rerupture within three hours after the initial subarachnoid haemorrhage. It is suggested waiting at least 3 hours after SAH before performing angiography and to use digital subtraction angiography in order to prevent aneurysmal rerupture during angiography.

Experience with Radio Isotope Myelography is reported here. 169Yb-DTPA as a tracer was intrathecally injected at lumbar region in twenty three patients with various spinal cord lesions. The first scanning is perfomed after comfirming by gamma-camera that the tracer reaches to the lesion, the second and the third scannings are done according to the ascending rate of the tracer. (I) Normal scintimyelogram (A) In normal case, the shape of the Radio Isotope Myelogram well corresponds the shape of anatomical subarachnoid space. (B) In normal adult cases, the tracer comes up to the cisterna magna in 20-25 minutes after the lumbar injection. Therefore, the scintimyelographic diagnosis should be made not only by the shape but also by the ascending rapidity of the tracer. (II) Abnormal scintimyelogram Abnormal scintimyelograms could be summarized as following three categories. (A) "Delay": It means delay of the ascending of the tracer. Besides, "Transient delay" found in a case of Arnord-Chiari's malformation was proposed. (B) "Partial block": It meas a defect at the level of the lesion. This "Partial block" were observed in cases of spinal cord angioma, cervical spondylosis and spinal cord tumor etc. (C) "Complete block": It means the stagnation of the tracer below the lesion. To sum up, Rario Isotope Myelography, especially in partial block, can more easily and more sensitively represent the maximum extent of the spinal cord lesion than other myelographic study or angiographic one. On the other hand, we can not qualitatively diagnose about the lesions by its indistinct border.

Spinal intradural arachnoid cysts (S-IAC) are rarely found and only 80 cases have been reported since 1915. We report two of them. A 68-year-old male had slowly progressive dull pain in both thighs for about 6 years prior to admission. Neurological examination and plain x-ray on admission showed no abnormality. Myodil myelography showed a S-IAC at T4 vertebral level. Surgical treatment of cyst wall excision resulted in success. The other case, a 39-year-old male suddenly noticed monoparesis and sensory disturbance of left leg in the morning. On admission were observed spastic monoparesis of the left leg, analgesia at right T2-3 cord segment and sensory disturbance (hypesthesia, dysesthesia, paresthesia) below T3-4 cord segment on the left side. Plain X-ray showed no abnormality. Myodil myelography revealed a S-IAC at T3-4 vertebral level. This patient was treated not surgically but conservatively because all neurological deficits but numbness in the left leg almost subsided after bed rest. The patient has experienced no neurological deterioration for five years since then. We also discuss the clinical feature, treatment and etiology of the S-IAC, by analyzing these 82 cases. There is a slight male preponderance. The age ranges between 3 and 66 years (mean 38 years). The duration from onset to admission is 2 days to 30 years. Sixty percent (48/80) of the cases were ill far longer than a year (mean 6.7 years). Of 82 cases, 83% suffered from motor disturbance, 70% had sensery disturbance, 62% local pain and 24% urinary with/without fecal disturbance.(ABSTRACT TRUNCATED AT 250 WORDS)

We reviewed 40 cases of intracranial ruptured aneurysm with intracerebral hematoma (An-ICH) and compared those with 177 cases of intracranial single ruptured aneurysm causing only subarachnoid hemorrhage (An-SAH). An-ICH accounted 11.6% of the intracranial aneurysm, ruptured at the mean age of 54 years, and occurred equally in both sexes. The localization of An-ICH was 50% in the middle cerebral artery (MC), 43% in the anterior cerebral artery (AC) and 8% in the internal carotid arterial region. Forty percent of An-ICH were treated conservatively and the outcome was very misery (no useful life and 94% was poor or dead). Sixty percent of An-ICH were treated surgically (neck-clipping and removal of the hematoma) and the outcome was poor (17% useful life and 46% poor and dead). Especially in MC aneurysm, operability was 85% and post-operative useful life was 12% and post-operative poor or dead was 53%. In AC aneurysm, operability was 35% and post-operative useful life was 33% and poor or dead was 33%. These miserable results raised a question of operative indication for An-ICH. The five clinical indices (decerebration, hypertension greater than or equal to 200 mmHg, Hunt-Hess grade V, anisocoria in AC, severe shift of midline structure on X-CT) were selected, because any patients who presented with even only one of them became fatal or vegetative state regardless of conservative or surgical treatment. Assuming them as the non-operative standards, operability decreased in 35% MC, 29% AC, useful life outcome came up to 20% MC, 40% AC, and misery outcome came down to 20% MC, 20% AC.(ABSTRACT TRUNCATED AT 250 WORDS)

The bioavailabilities of five indomethacin capsules were studied in ten beagle dogs and correlations with the in vivo results in humans and dissolution rates were investigated. The difference in bioavailability between two commercial products was smaller in dogs than in humans, which seemed to be due to strong disintegration forces in dogs. The difference in the dissolution rate among the products was reflected less in the Tmax in dogs than in humans, and the Tmax was shorter in dogs which seems to be due to faster gastric emptying and passage of the drug through the absorption site in dogs. Gastric acidity effects on the indomethacin availability found in humans were not observed in dogs. The Cmax and Tmax correlated well with the in vitro dissolution rates, but AUC24 did not. The Cmax and Tmax in dogs also correlated with the corresponding parameters in humans, especially those in high gastric acidity humans, but AUC24 did not.

Bioavailabilities of three commercially available tablets and two trial tablets of nalidixic acid were determined. The correlation between in vivo bioavailability parameters and in vitro dissolution rates derived by eight methods (oscillating basket I and II, beaker I, II, and III, rotating basket, paddle and rotating flask) is discussed. Nalidixic acid and its metabolite, 7-hydroxynalidixic acid, were determined in serum by HPLC with a strong anion-exchange resin column. All parameters for nalidixic acid bioavailability showed significant differences among the tablets tested. The relationship between Cmax and AUC was not linear but concave. However, Cmax decreased linearly in proportion to the delay of Tmax. The rank order of tablets according to bioavailabilities was just the same as the rank order obtained when comparing dissolution rates determined by any of the above methods, with the exception of one tablet which had a poor disintegrating ability. The parameters for the rate of bioavailability (Cmax and Tmax) showed good linearity with 1/T50 determined by all of the methods. However, AUC showed significant correlation with neither T50 nor 1/T50.

Reviewing 223 cases of intracranial ruptured aneurysms including 46 cases of re-ruptured aneurysms, the following results were obtained. 1) The outcome of the re-rupture aneurysms was more miserable than that of the first rupture. Even low grade cases (Hunt and Hess 0-II) of re-rupture showed no better outcome than high grade cases (Hunt and Hess IV) of first rupture. 2) Re-rupture most often occurred on the 12th (11.6 +/- 6.7) day after the first attack of the subarachnoid hemorrhage. Re-rupture more often occurred in the vertebrobasilar system. In the internal carotid artery and its branches, aneurysms with daughter or bleb tended to rupture again. Aneurysms with daughter, regardless of these location, showed greater incidence of re-rupture than those without daughter. Also rupture often occurred in the cases of lower grade with less vasospasm and with the acute hydrocephalus. 3) It was suggested that the sequential changes of some factors of both the coagulating system and fibrinolytic system might forecast the vasospasm, infarction, re-rupture and prognosis of the patient of intracranial ruptured aneurysms. And therefore, in the cases in which re-rupture is likely, operation should be performed as early as possible, except in those showing diffuse vasospasm or clinical down hill course or in grade V.

The bioavailabilities of five indomethacin capsules, two commercial and three experimental products, were studied in ten human subjects. The bioavailabilities of the products increased in proportion to their in vitro dissolution rates, although one of the commercial products provided a relatively lower bioavailability than was expected. Comparison of the bioavailabilities between high and low gastric acidity humans revealed that the serum levels of the drug during the absorption phase following oral administration of all the indomethacin products, except for one commercial product, were higher in the low acidity subjects than in the high acidity subjects. Also, the mean peak serum level of the most rapidly dissolving product was 1.6 times higher in the low acidity subjects than in the high acidity ones. These gastric acidity effects indicated enhanced dissolution of indomethacin from the capsules in the stomach of low acidity humans.

The effect of food on the bioavailability of metronidazole from three commercial sugar-coated tablets varying markedly in drug dissolution behavior relative to pH was determined after oral administration in healthy male subjects with low gastric acidity. Four subjects, whose gastric acidities were evaluated as low (hypo- or anacidity) by using a non-intubation method (Gastrotest tablets administration method), received, in a cross-over fashion, a single 250 mg dose in sugar-coated tablet during periods of fasting and non-fasting. The tablet having the fastest and most pH-independent dissolution rate gave significantly higher Cmax and AUC0-32 than the other tablets having extremely slow dissolution at pH 5 or 7.2, when the drug was administered in the fasting state. However, there were no statistically significant differences in the above parameters among the tablets tested when they were administered postprandially. The improvement of the bioavailability of the tablets exhibiting poorer dissolution in the pH range of 5 to 7.2 is ascribed to suggestible vigorous agitation in the digestive tract stimulated by food intake.