Analysis of SIDS-related civil and criminal court cases in Japan.

Thirty-three sudden infant death syndrome (SIDS)-related civil and criminal lawsuits in Japan were retrieved from judicial precedent databases "Hanrei Masutar (Judicial Decisions Master)" and "Hanrei Taikei (Judicial Decisions System) using "SIDS" as a keyword. Sleeping posture and developmental stage of occurrence were studied in each of the cases retrieved, whether or not a legal autopsy had been performed. The influence exerted on court decisions by Japanese definitions of SIDS as well as the relationship between causes of death and court decisions were studied. Of 33, two were criminal cases (business/professional negligence on the part of the defendants, leading to death), and the rest were civil cases (claims for damages). Because the decision handed down in both criminal cases was "cause of death unknown", these defendants were found innocent. One of these cases was argued in both the court of appeals and the superior court: these courts found SIDS to be the cause of death and consequently the claim for damages was rejected. Both criminal and civil courts dealt with another case: the former found the cause of death to be "unknown" and the defendant innocent, while the latter, finding SIDS the cause of death, declined to review. In cases where the sleeping posture was prone, courts tended to decide the cause of death to be suffocation, especially with neonates. Because diagnosis by exclusion is required in cases of a legal autopsy for SIDS, the diagnosis is difficult without an autopsy. Disagreements between the results of legal autopsy and court decisions occurred in eight cases. With such a discrepancy, a detailed case examination is necessary. In 1983, SIDS was defined in Japan in two different ways; one in a more strict sense and the other being more inclusive. The wider and narrower definitions were unified in 1995 by requiring a survey of the circumstances of death in addition to the narrower definition. Because of this situation, the two cases in the 1980s when legal autopsy was not enforced fell into the category of "SIDS in a wider sense." In no case was a defendant found guilty when the cause of death was judged to be either SIDS/ALTE or unknown. Four cases were rejected when the cause of death was judged to be neither due to suffocation nor SIDS, while seven were accepted either as cases of "joint faults that canceled each other," or as "partial acceptance." In Japan, official views concerning a SIDS diagnosis differ among pediatricians, legal scholars of forensic medicine and pathologists. These differences appeared to influence the legal decisions. Several conferences should be convened as soon as possible to provide an opportunity to resolve the main points of difference between these three professional groups and, thus, attain a unified view.

Arthrotomographic sign of a 'double line' as an indicator of disc folding and sideways disc displacement in the temporomandibular joint.

Dual-space, single-contrast arthrotomolgraphy of the TMJ was performed on a 19-year-old woman with a history of pain and clicking. Simultaneous multi-layer arthrotomography with computed radiography was used for the present examination. Anterior disc displacement with reduction was observed in the sagittal plane, together with a double line in the lower joint space. The double line was interpreted as disc folding and sideways disc displacement and was confirmed in the coronal plane.

Synthesis of acylguanidine analogues: inhibitors of ADP-induced platelet aggregation.

Routine screening of compounds for inhibition of ADP-induced platelet aggregation in vitro revealed that 1,1'-hexamethylenebis[3-cyclohexyl-3-[(cyclohexylimino) (4-morpholinyl) methyl]urea] (1) was active and represented the first example of a bis(acylguanidine) with possible antithrombotic activity. In order to develop a structure-activity relationship for this class of compounds, we synthesized a number of new bis(acylguanidines). These were tested in vitro, and several analogues were also active. Ex vivo testing revealed that compounds 22, 41, 58, and 70-73 were orally active in rats or guinea pigs.

[Clinical study of primary pontine hemorrhage].

Forty-three cases of primary pontine hemorrhage were seen in our hospital from 1979 to 1986. We studied the correlations between clinical signs, CT, ABR findings and their outcomes, and then reported surgical results. The case consisted of 30 males and 13 females between 32 to 73 years with an average age of 54.5. Thirty cases were confirmed to have had hypertension prior to the hemorrhage. In ten other cases hypertension was suspected, although their past histories were not obtained. In the remaining three cases, no hypertension was detected. On admission, comatose state, ocular fixation, absence of light reaction, tetraplegia, decerebrate posture, respiratory disturbance, tachycardia and hyperthermia were the signs of unlikely recovery. On the CT, the hematomas of the group of likely recovery patients were less than 25% of the cross section of the pons and lower midbrain in vertical. Greater size of hematomas were seen exclusively among the groups of death and severe disability cases. Acute stage ABR and CT findings showed discrepancy. We suggest, if ABR, CT findings and clinical symptoms were studied more in depth, it is possible to determine a patient's prognosis more precisely. Three cases were treated by Stereotactic Aspiration, three cases by ventricular drainage and the remaining thirty-seven cases conservatively. There was, however, no significant difference in recovery between surgically treated cases and conservatively treated one. We think that surgical indication is doubtful except for limited cases.

Tolerance and pharmacology of ciprostene, a stable epoprostenol (prostacyclin) analogue in humans.

Safety, tolerance, and pharmacology of 9-beta-methylcarbacyclin calcium (ciprostene calcium) was investigated in healthy male volunteers. This stable prostacyclin analogue was infused intravenously into groups of 12, 11, and three volunteers for three, six, and eight hours, respectively, in doses up to 480 ng/kg/min. Based on the tolerance data obtained, a single-blind, placebo-controlled study was conducted. Seven subjects were infused for 8 hr/d for three days with ciprostene at a maximum dose of 160 ng/kg/min and seven subjects received placebo. One subject from each group did not complete the infusion schedule, and they were not included in the final analysis. During infusion of ciprostene, consistent changes in blood pressure and heart rate did not occur. Most frequent adverse drug reactions consisted of headache, restlessness, nausea, perspiration, flushing, and jaw pain. As compared with placebo, ADP-induced platelet aggregation was inhibited during the infusion period (P = .048). Significant (P = .04) elevations of platelet cyclic AMP were observed in subjects during infusion of ciprostene. Pre- versus postinfusion routine laboratory evaluations, fibrinogen concentration, antiplasmin activity, and plasminogen and template bleeding times remained unchanged. Placebo- and drug-treated subjects had a daily postinfusion shortening of euglobulin clot lysis time (ECLT). The preinfusion minus postinfusion ECLT for ciprostene subjects on days 2 and 3 (133 and 118 min, respectively) compared with placebo (239 and 217 min) suggest a trend to increased fibrinolytic activity. Based on the outcome of this trial, it is estimated that ciprostene is about 15 times less potent than prostacyclin.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and platelet aggregation inhibitory activity of 4,5-bis(substituted)-1,2,3-thiadiazoles.

Routine screening of compounds for inhibition of collagen-induced platelet aggregation in vitro revealed 4,5-bis-(4-methoxyphenyl)-1,2,3-thiadiazole (2) was active and it represents the first example of a 1,2,3-thiadiazole with possible antithrombotic activity. In order to develop a structure-activity relationship for this heterocycle, a number of new 4(5)-mono- and -disubstituted 1,2,3-thiadiazoles were synthesized. These were tested in our screen and a number of additional active compounds were found. The most active compounds (2, 5a, 5b, and 6c) were those in which the heterocycle was substituted with benzene rings possessing para electron-donating groups.

The formation of a thrombin-like material (TLM) following stimulation of leukocytes.

When thrombin, tissue thromboplastin or Russell's viper venom was added to a suspension of either lymphocytes or neutrophils containing normal plasma, aggregation of these cells ensued. The aggregate formed one gelatinous mass which was readily separable from the cell free supernatant, an aliquot of which caused platelet aggregation. This leukocyte derived platelet aggregatory substance had characteristics similar to thrombin but not AGEPC. When plasma deficient in Factor V was substituted for normal plasma, the platelet stimulatory substance was not produced. Substitution with plasma deficient in Factor VII, VIII, IX, X or XI was without effect. Thrombin clotting time measurements indicated a generation of activity, relative to thrombin, of about 3.0 U/5 X 10(6) cells.

Synthesis and platelet aggregation inhibiting activity of prostaglandin D analogues.

Several prostaglandin D (PGD) analogues have been synthesized, incorporating the following variations: (a) varying degrees of side-chain unsaturation, (b) C-9 hydroxy removed or in the unnatural 9 beta configuration, (c) metabolically stabilized analogues (e.g., 15-methyl, 16,16-dimethyl, 17-phenyl, etc.), and (d) delta 12 isomers resulting from decomposition of PGD2. With regard to their ability to inhibit adenosine diphosphate (ADP) induced human platelet aggregation: (a) PGD3 greater than or equal to PGD2 greater than PGD1 greater than 13,14-dihydro-PGD1, (b) the 9 beta- and 9-deoxy-PGD2 analogues are more potent than PGD2, (c) metabolically stabilized analogues with bulky substituents at or near C-15 have substantially reduced antiaggregatory activity relative to PGD2 and (d) the delta 12 isomers of PGD2 are much less active than PGD2.

Arachidonate induced aggregation of rat platelets may not require prostaglandin endoperoxides or thromboxane A2.

Platelet aggregation was measured in rat and human platelet-rich plasma (PRP) after the addition of various amounts of arachidonic acid (AA), prostaglandin H2 (PGH2), adenosine diphosphate (ADP), or collagen. AA but not PGH2 caused rat platelets to aggregate in citrated or heparinized PRP. Both AA and PGH2 produced significant amounts of thromboxane A2 (TxA2) measured as thromboxane B2 (TxB2). The lack of aggregation of rat platelets with PGH2 was not due to the formation of an inhibitor of aggregation such as a prostaglandin. Thus, the formation of TxA2 may not be necessary for aggregation of rat platelets. Human platelets were aggregated by PGH2 with the concomitant formation of TxB2.

A thiazole compound with potential antithrombotic activity.

A thiazole derivative, 4,5-bis(p-methoxyphenyl)-2-(trifluoromethyl)-thiazole was found to be a potent inhibitor of collagen-induced platelet aggregation, in vitro, using platelets from at at least six species, including man. It was active in human platelet-rich plasma at a concentration of 1 ng/ml. While its antiplatelet activity was greater than that of flurbiprofen, its cyclooxygenase activity was equivalent to that of flurbiprofen. Also, compared to flurbiprofen, the thiazole had less anti-inflammatory activity in the hind-paw edema test. The thiazole derivative inhibited platelet aggregation following oral administrative inhibited platelet aggregation following oral administration in five laboratory species. In the guinea pig it was active at 0.5 mg/kg. The LD50 in mice was greater than 1000 mg/kg (i.p.). This compound, which was designed through a systematic drug development program, may have high potential as an antithrombotic agent.

Synthesis and platelet aggregation inhibitory activity of 4,5-bis(aryl)-2-substituted-thiazoles.

In our continuing effort to discover compound which inhibit collagen-induced platelet aggregation, we have screened compounds in a mouse pulmonary thromboembolism screen. Methyl 4,5-bis(4-methoxyphenyl)-2-thiazoleacetate (3) was very active in the above screen. However, 3 was active for less than 5 min when given orally to guinea pigs. As a result, our synthetic goal was to prepare 2-substituted thiazoles with a much longer duration of activity. This paper describes the preparation of a number 4,5-bis(aryl)-2-substituted-thiazoles and their in vitro and ex vivo activity against collagen-induced platelet aggregation. It was determined that 4,5-bis(4-methoxyphenyl)-2-(trifluoromethyl)thiazole (16) is the most promising compound.

Hydrolysis of an orally active platelet inhibitory prostanoid amide in the plasma of several species.

The prostanoid 3-oxa-4,5,6-trinor-3,7-inter-m-phenylene-PGE1-amide (OI-PGE1-amide) has a prolonged duration of oral platelet aggregation inhibitory activity when compared to the parent free acid (OI-PGE1) in the rat. When incubated in rat plasma at 1 microgram/ml for 30 seconds prior to addition of ADP, OI-PGE1-amide inhibits in vitro rat platelet aggregation approximately 50%. OI-PGE1 inhibits at 1 ng/ml. Inhibition of platelet aggregation by plasma incubated with OI-PGE1-amide (1 microgram/ml) increases with time and the rate of this increase differs with species. Incubation of OI-PGE1 in plasma does not result in an increase of platelet inhibitory activity with time. The increase of platelet inhibitory activity was assumed to indicate hydrolysis of OI-PGE1-amide to the more active OI-PGE1. A compound, different from OI-PGE1-amide, was isolated by an ion exchange/silica gel separation sequence from an incubation of OI-PGE1-amide in rat plasma. It had potent platelet aggregation inhibitory activity. This material was shown to be OI-PGE1 by thin-layer chromatography, gas chromatography and mass spectral analysis. Studies with [3H]-OI-PGE1-amide confirmed the formation of OI-PGE1 in plasma incubations. Amide hydrolytic activity was significantly different between species, the rank order being: rat greater than guine pig greater than monkey = human greater than dog. This relationship corresponded with that determined by measuring the increase in platelet inhibitory activity with time in plasma incubations of OI-PGE1-amide reported above. Present data indicate that (a) OI-PGE1-amide is hydrolyzed to the parent acid by plasma enzymes of several species and (b) hydrolytic activity of plasma varies widely between species.

Duration of activity of the acid, methyl ester and amide of an orally active platelet aggregation inhibitory prostanoid in the rat.

The prostanoid 3-oxa-4,5,6-trinor-3,7-inter-m-phenylene PGE1 (OI-PGE1) has been shown to be a more potent inhibitor of ADP-induced human platelet aggregation than PGE1. OI-PGE1 inhibits ex vivo ADP-induced platelet aggregation for 60 minutes after an oral dose of 20 mg/kg to rats. Present studies compare duration of ex vivo inhibition of ADP-induced platelet aggregation in the rat by OI-PGE1, its methyl ester and amide after administration by various routes. All oral (p.o.) and intraduodenal (i.d.) doses were 20 mg/kg and all intravenous (i.v.) doses were 1 mg/kg. OI-PGE1 and its methyl ester had the same duration of activity after i.v. (60 min.) and p.o. (60 min.) administration, however, the methyl ester, when administered i.d., had a longer duration of activity than the free acid i.d. (greater than 90 min. vs. 60 min.). OI-PGE1-amide had significantly longer duration than the acid or methyl ester after i.v. (greater than 120 min.), p.o. (greater than 240 min.) or i.d. (greater than 240 min.) administration. Present data suggest that in the rat (1) intestinal absorption of OI-PGE1-methyl ester is more efficient than it is for the free acid and (2) due to metabolic and/or distributional differences between OI-PGE1 and its amide, the amide has a much greater duration of activity.

Synthesis and platelet aggregation inhibitory activity of 6-isobutyl-alpha-methyl-3-pyridineacetic acid.

2-(4'-Isobutylphenyl)propionic acid, ibuprofen, is an antiinflammatory agent which possesses moderate platelet aggregation inhibitory activity. It was therefore of interest to determine what effect the replacement of the phenyl group of ibuprofen by a 3-pyridyl ring would have on platelet aggregation inhibitory activity. As a result, 6-isobutyl-alpha-methyl-o-pyridineacetic acid (7) and its 2-chloro analogue 13 were synthesized. The key step in the synthesis of 7 and 13 involved the oxidative rearrangement of enol ether 11 to the carboxylic ester 12 with thallium trinitrate. The entire sequences of reactions for the synthesis of compounds 7 and 13 are described in detail. Platelet aggregation inhibitory evaluation of 7 and 13 showed 7 to possess activity equivalent to ibuprofen; however, 13 was devoid of platelet aggregation inhibitory activity at an equivalent dose.

Inhibition and potentiation of platelet function by lysolecithin.

The effects of lysolecithin (LPC) on aggregation, serotonin release, shape, and lysis of rabbit, pig, or human platelets in platelet-rich plasma (PRP) or Tyrode albumin solution were examined during prolonged incubation. LPC added to citrated or heparinized PRP from humans or rabbits at a final concentration above 100 muM caused instantaneous inhibition of platelet aggregation induced by adenosine diphosphate (ADP), epinephrine (human PRP only), collagen, or thrombin. The inhibitory effect of LPC was found to be partially reversible over a period of 60-90 min. LPC at final concentrations above 30 muM also caused inhibition of ADP-, collagen-, and thrombin-induced aggregation and collagen- and thrombin-induced release of serotonin in suspensions of rabbit, pig, or human platelets. With washed platelets, the inhibitory effect not only rapidly disappeared but was followed by transient potentiation of aggregation and serotonin release. This potentiating effect of LPC was most pronounced when thrombin was used as stimulus. Both inhibition and potentiation were observed at concentrations of LPC that did not cause a significant change in platelet shape or loss from platelets of lactic dehydrogenase. Inhibition and potentiation were also observed when platelets were added to suspending medium containing LPC, although considerably higher concentrations of LPC were required under these conditions. Potentiation was not observed when LPC was added to citrated or heparinized rabbit or human PRP or to washed rabbit platelets suspended in a medium containing 4% bovine serum albumin. It seemed likely that some or all of the observed effects of LPC on platelet function were due to structural modification of the platelet membrane insufficient to result in gross membrane damage or platelet lysis. In addition, the results of experiments using 14C-LPC seemed to indicate that the observed potentiating effect of LPC on platelet function may be related to its rapid uptake and metabolism by the platelets.

Synthesis of dl-4,5,6-trinor-3,7-inter-m-phenylene-3oxaprostaglandins including one which inhibits platelet aggregation.

The synthesis of dl-4,5,6-trinor-3,7-inter-m-phenylene-3-oxaprostaglandins of the E1 and F1alpha series from 6-endo-(1-heptenyl)-bicyclo[3:1:0]hexan-3-one (III), is described. Preliminary biological screening data for gerbil colon smooth muscle stimulation, rat blood pressure and substrate specificity toward 15-hydroxyprostaglandin dehydrogenase is presented. Platelet function studies, both in vitro and in vivo of dl-4,5,6-trinor-3,7-inter-m-phenylene-3-oxa-PGE1, methyl ester (VIII) are presented.

Preparation and anticoagulant activity of trimethylsilyl heparin in Carbowax.

Trimethylsilyl heparin, when administered intraduodenally or intragastrically to rats, did not increase intestinal absorption and, consequently, the clotting times were not influenced. However, suspension of sodium heparin in Carbowax 200 prolonged the whole blood clotting time at a dose of 50 mg/kg when given intraduodenally or intragastrically to rats.