Antiasthmatic effect of YM976, a novel PDE4 inhibitor, in guinea pigs.

YM976 is a novel and specific phosphodiesterase 4 inhibitor. In our previous report, we indicated that YM976 has less emetogenicity, a major adverse effect of PDE4 inhibitors, than rolipram. In the present study, we examined the antiasthmatic effects of YM976 in guinea pigs. YM976 orally administered exhibited inhibition of antigen-induced bronchoconstriction, airway plasma leakage, airway eosinophil infiltration, and airway hyperreactivity (AHR), with ED(50) values of 7.3, 5.7, 1.0, and 0.52 mg/kg, respectively. Rolipram also dose dependently suppressed these responses. Prednisolone suppressed eosinophil infiltration and AHR, whereas it failed to inhibit bronchoconstriction and plasma leakage. Theophylline moderately suppressed bronchoconstriction and edema, but neither eosinophil infiltration nor AHR. YM976 suppressed the peroxidase activity in the bronchoalveolar lavage fluid, and elevated the intracellular peroxidase activity and cAMP contents of infiltrated cells, suggesting that YM976 inhibited not only the infiltration but also the activation of leukocytes. In vitro studies revealed that YM976 potently suppressed eosinophil activation (EC(30) = 83 nM), and exerted a little relaxation on LTD(4)-precontracted tracheal smooth muscle (EC(50) = 370 nM). Rolipram exhibited a potent tracheal relaxation activity (EC(50) = 50 nM). In vivo studies indicated that the inhibitory effect of YM976 on LTD(4)-induced bronchospasm was marginal even at 30 mg/kg p.o., although rolipram significantly inhibited the bronchospasm at the same dose. These results suggested that YM976, unlike rolipram, showed the inhibition of antigen-induced airway responses due to anti-inflammatory effects, but not to direct tracheal relaxation. In conclusion, YM976 may have potential therapeutic value in the treatment of asthma through its anti-inflammatory activities.

Adult aortic arch atresia.

Atresia in the aortic arch is a rare and severe congenital cardiovascular anomaly. Without surgical therapy, only a few patients can survive to adulthood. A 29-year-old woman with atresia of the aortic arch (Celoria-Patton Type A) without any intracardiac shunt underwent primary surgical correction involving reconstruction of the aortic arch with prosthetic interposition between the transverse aortic arch and the descending aorta and division of the persistent ductus arteriosus. Her postoperative course was uneventful, and she is now doing well at three years to date after surgical treatment.

Effect of combined leukotriene D(4) and thromboxane A(2) receptor antagonist on mediator-controlled resistance in guinea pigs.

The effects of YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl )propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene D(4) and thromboxane A(2) receptors, on antigen-induced increases in airway resistance were investigated in mediator-controlled novel asthmatic models using actively sensitized guinea pigs. While the predominant mediator was thromboxane A(2), complete inhibition of cyclooxygenase induced mediation by cysteinyl-leukotrienes. About 1-mg/kg indomethacin induced a state where both mediators participated equally. YM158 inhibited increases in resistance whether only one or both mediators were involved. When leukotriene D(4) and thromboxane A(2) equally participated, ED(50) values for 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4 H-1-benzo pyran hemihydrate (pranlukast; 3.9 mg/kg) and 7-(3,5,6-trimethyl-1, 4-benzoquinon-2-yl)-7-phenylheptanoic acid (seratrodast; 2.1 mg/kg) were similar to that for YM158 (8.3 mg/kg), although those effects on the corresponding mediator-induced reaction were 10 times stronger than those of YM158. Additionally, the maximum inhibition of YM158 was stronger than those of either single receptor antagonist. In conclusion, YM158 has a potentially greater efficacy in wider types of experimental asthmatic models than single receptor antagonists.

In vivo pharmacologic profile of YM158, a new dual antagonist for leukotriene D4 and thromboxane A2 receptors.

The antagonistic activity of oral YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl)propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene (LT) D4 and thromboxane (TX) A2 receptors, was investigated. Oral YM158 caused dose-dependent inhibition of LTD4-induced increases in plasma leakage and LTD4- or U46619-induced increases in airway resistance, with ED50 values of 6.6, 8.6 and 14 mg/kg, respectively. The dose-range of YM158's inhibitions was almost the same for both LTD4 and TXA2 receptors, and repeated oral doses did not affect its efficacy. Furthermore, oral YM158 inhibited antigen-induced bronchoconstriction. Although the potency of pranlukast for LTD4 receptor antagonism (ED50 = 0.34 mg/kg) is greater than that of YM158 (ED50 = 8.6 mg/kg), the doses of both pranlukast and YM158 for significant inhibition of the antigen-evoked airway response were the same, indicating that the TXA2 receptor antagonism of YM158 plays an important role in its anti-asthmatic effects. In conclusion, YM158 promises to be a novel agent for treating bronchial asthma.

Effect of YM158, a dual lipid mediator antagonist, on immediate and late asthmatic responses, and on airway hyper-responsiveness in guinea pigs.

The effects of lipid mediator antagonists: the LTD4-receptor antagonist pranlukast, the TXA2-receptor antagonist seratrodast, and the novel dual LTD4- and TXA2-receptor antagonist YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl) propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) were investigated in animals exhibiting immediate asthmatic response (IAR), late asthmatic response (LAR) and airway hyper-responsiveness (AHR). Antigen-induced LAR and AfR are inhibited by orally administered pranlukast (30, 100 mg/kg) and seratrodast (3, 10 mg/kg). YM158 (30 mg/kg), orally administered before or after IAR induction, also inhibited both LAR and AHR. However, while the inhibitory effects of pranlukast and seratrodast on IAR were marginal, the effects of YM158 (3, 10, 30 mg/kg) were dose-dependent, probably due to its multiple sites of action. Additionally, orally administered YM158 (30 mg/kg) inhibited ozone-induced AHR in guinea pigs. Thus, an antagonist that inhibits several lipid mediators might exhibit greater efficacy in treating asthmatic responses than antagonists with a single site of action. Therefore, YM158 shows great promise as a drug that will be able to treat bronchial asthma and related disorders more potently than currently used single-pathway inhibitors.

[A case report of surgical repair of ruptured aneurysm of sinus valsalva in aged (84 years old)].

An 84-year-old man with ruptured aneurysm of Valsalva sinus was operated. Diagnosis was made by two dimensional echocardiography, cardiac catheterization, and cardiac angiography. A aneurysm was found at the right-coronary sinus region, and ruptured into the right ventricle. The ruptured aneurysm of sinus Valsalva was repaired with direct closure and Woven patch from inside the right ventricle through the pulmonary valve. This case was defined as congenital because there was no sign of inflammatory or atherosclerotic changes in the aorta, aortic valve and aneurysm. The ruptured aneurysm of sinus Valsalva is very rare in aged patients. As far as we know, this patient is one of the oldest cases who underwent successful surgical repair in this country.

Effects of lipid mediator antagonists on predominant mediator-controlled asthmatic reactions in passively sensitized guinea pigs.

The role of cysteinyl leukotrienes (cys-LTs) and thromboxane A(2) (TXA(2)) in guinea pig models of aspects of bronchial asthma was investigated. In a novel antigen (BSA)-induced asthmatic model using passively sensitized guinea pigs, pretreatment with varying doses of indomethacin controlled the ratio of followed lipid mediators, LTC(4)/D(4)/E(4) and TXB(2), in lungs of challenged guinea pigs. The predominant mediator in indomethacin-untreated asthma was TXA(2), and complete inhibition of cyclooxygenase by i.v. injection of 5-mg/kg indomethacin-induced cys-LTs mainly mediated asthmatic response. Furthermore, a 1-mg/kg indomethacin dose induced an asthmatic state where both cys-LTs and TXA(2) equally participated. Either LTD(4) or TXA(2) receptor antagonists given alone inhibited the asthmatic response in conditions where the corresponding mediator plays a predominant role. The combination of LTD(4) and TXA(2) receptor antagonists exhibited significant effects irrespective of the condition used. Under conditions where both mediators equally participate, a combination of both receptor antagonists showed additive inhibition. YM158, a newly synthesized and orally active dual antagonist for LTD(4) and TXA(2) receptors, showed the same antiasthmatic effect as a combinated LTD(4) receptor antagonist and a TXA(2) receptor antagonist mixture. Therefore, broad-acting compounds such as YM158 are expected to have antiasthmatic efficacies in a broader class of asthmatic patients than single-acting drugs.

In vitro pharmacologic profile of YM158, a new dual antagonist for LTD4 and TXA2 receptors.

YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl ) propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) antagonizes leukotriene (LT) D4 and thromboxane (TX) A2 receptors. Functional assays in vitro showed that YM158 exhibits competitive dual antagonism of LTD4 and TXA2 receptor-mediated contraction of isolated guinea pig tracheae, with pA2 values of about 8.87 and 8.81, respectively. Its antagonistic activity for the LTD4 receptor was approximately 6.5 times less potent than that of montelukast, and that for the TXA2 receptor was 2.5 times more potent than that of seratrodast. YM158 also inhibited PGD2- and PGF2alpha-induced tracheal contractions. YM158 showed no antagonism against LTC4-, histamine- or carbachol-induced contractions of guinea pig tracheae. Furthermore, YM158 antagonized the stable TXA2 analog U46619-induced aggregation of both guinea pig and human platelets and inhibited the LTD4-induced contraction of guinea pig ileum. From these results, YM158 appears to be a novel, selective dual antagonist for both LTD4 and TXA2 receptors.

Binding of YM158, a new dual antagonist for leukotriene D4 and thromboxane A2 receptors, to guinea pig lung membranes.

Arachidonic acid metabolites mediate inflammatory responses at a cellular level. The affinity of the newly synthesized compound YM158, 3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesuf onyl)propyl-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate, for leukotriene D4 and thromboxane A2 receptors was examined in radioligand binding assays. YM158 inhibited [3H]leukotriene D4 and [3H]U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha) binding to guinea pig lung membrane preparations, with Ki values of 0.64+/-0.06 nM for leukotriene D4 and 5.0+/-0.88 nM for thromboxane A2 receptors. The Hill coefficients (nH) did not significantly differ from unity, indicating that this antagonism is competitive. In contrast, YM158 showed no affinity for several other receptors, including neurotransmitter-related (alpha1-, alpha2-, beta-adrenoceptors, histamine, 5-HT, muscarinic, sigma), C5a, opioid, Ca2+ channel, K+ channel, protein kinase C, bradykinin, endothelin, neurokinin and platelet activating factor receptors. These studies indicate that YM158 is a highly selective dual antagonist for leukotriene D4 and thromboxane A2 receptors, and this has potential clinical and research applications.

Persistent isolated proximal renal tubular acidosis--a systemic disease with a distinct clinical entity.

We describe a 16-year-old female with persistent isolated proximal renal tubular acidosis, cerebral calcification, mental retardation, band keratopathy, cataracts, glaucoma and short stature. Severe metabolic acidosis and hypokalaemia were linked to an abnormally low renal threshold for bicarbonate reabsorption (8 mmol/l). Maximal rates of urinary excretion of titratable acid and ammonium were normal; erythrocyte carbonic anhydrase II was normal. This rare case represents a systemic disease with a distinct clinical entity which may be transmitted by autosomal recessive inheritance.

[Metabolism of Ca2+ in myocytes and peroxidation products in ischemia-reperfusion injury under extracorporeal circulation].

The metabolism of calcium ion (Ca2+) in myocytes in ischemia-reperfusion injury under extracorporeal circulation (ECC) was studied by cytochemistry and electron microscopy. Ten mongrel dogs were under ECC with aortic cross-clamping for 120 minutes. A cold GIK crystalloid cardioplegic solution was infused via the aortic root intermittently during ischemia, and the myocardial temperature was maintained at 5-10 degrees C with ice slush. The morphological changes of Ca(2+)-ATPase activity in myocytes were estimated using the "lead citrate method". The activities of mitochondria, which had been temporarily decreased just before reperfusion, increased immediately after reperfusion and decreased again 60 minutes later. Electromicroscopy revealed swelling of mitochondria and laceration of myofibrils as well as intracellular edema 60 minutes after reperfusion. Immediately after reperfusion and 60 minutes later, creatine phosphokinase iso-enzyme (CK-MB) release in coronary sinus blood was significantly (p < 0.01) greater than that before the start of ECC. Anaerobic metabolism immediately after reperfusion was more active than that before aortic cross-clamping, as demonstrated by changes in excess lactate (delta XL) and redox potential (delta Eh) of lactate and pyruvate (delta XL, p < 0.05; delta Eh, p < 0.01). Thus, in ischemia-reperfusion injury, alterations of Ca(2+)-ATPase activity of mitochondria reflect the functional and morphological viability of the myocardium. Immediately and 60 minutes after reperfusion, the level of thiobarbituric acid was significantly (p < 0.01) higher and the level of alpha-tocopherol was significantly (p < 0.01) less than respective levels before the start of ECC.(ABSTRACT TRUNCATED AT 250 WORDS)

[A ruptured thoracic aortic aneurysm with 4 cm diameter].

The size of a thoracic aortic aneurysm (TAA) is an important factor of the operative indication. We experienced a ruptured TAA the diameter of which was only 4 cm. A 71 years old man was admitted due to the severe back pain under the shocked condition. We diagnosed him a ruptured TAA by CT scan. Because he had no progressive anemia and the hemodynamics was very stable, we followed him conservatively. Two months later, the operation was performed. We resected the aneurysm and inserted an aortic prosthetic graft. From the operative findings, the aneurysm was certified as a true aneurysm, and the maximal diameter was only 4 cm. First choice for the treatment of ruptured TAA is the emergent operation. But when the hemodynamics is extremely stable and the anemia does not progress at all, a conservative therapy can be selected. Even if the aneurysm is very small, the control of hypertension is quite important.

[Giant seroma following the Blalock-Taussig shunt using expanded polytetrafluoroethylene (EPTFE) graft: a case report].

A 15-month-old girl, who was diagnosed asplenia, underwent Blalock-Taussig shunt using EPTFE tubular graft. Postoperatively, discharge containing high concentrations of protein continued to drain from pleural drainage. On the 23rd postoperative day, extirpation of seroma (4 x 3 x 3 cm) and wrapping of the graft using processed porcine pericardium were performed. However, pleural discharge did not decrease and caused atelectasis. On the 38th postoperative day, extirpation of seroma (4.5 x 6 x 14 cm) and partial lobectomy were performed. Pleural effusion persisted with decreasing quantity until the graft was obstructed. Ultimately on the 79th postoperative day, central shunt using Golaski tubular graft was successfully replaced. Thus, the occurrence of seroma should be borne in mind when EPTFE graft is used for shunt operation.

[Usefulness of ulinastatin as a radical scavenger for protection of reperfusion injury after myocardial ischemia in open heart surgery].

The usefulness of ulinastatin for protection of reperfusion injury after myocardial ischemia was evaluated in 25 patients undergone open heart surgery (18 cases with coronary artery bypass grafting and 7 with valve replacements). Twenty five patients were divided into two groups; U (+)-group consisted of 12 patients with ulinastatin (10,000 IU/kg) injected via the aortic root just before aortic declamping, and U (-)-group of 13 patients without ulinastatin. There were no significant differences between the two groups in age, body weight, total cardiopulmonary bypass (CPB) time, and aortic cross clamp time. Blood samples were obtained from coronary sinus before the start of CPB, just before the aortic cross clamp and immediately after reperfusion, and 1 and 3 hours later. Levels of thiobarbituric acid (TBA), alpha-tocopherol (alpha TOC), polymorphonuclear elastase (PMNE), creatine phosphokinase (CK) and creatine phosphokinase isoenzyme (CK-WB) release were measured, and myocardial aerobic metabolism was also evaluated. At each time point after reperfusion, TBA levels in U (+)-group were significantly less (p less than 0.05), and alpha TOC levels were significantly higher (p less than 0.05) than those in U (-)-group. PMNE increased progressively during CPB and showed a peak at 3 hours after reperfusion. And both groups showed increased lactate production and anaerobic metabolism immediately after reperfusion and 1 hour later, as evidenced by changes in excess lactate and redox potential of lactate and pyruvate. There was, however, no significant difference between the two groups with CK-MB as well as CK release.(ABSTRACT TRUNCATED AT 250 WORDS)

[Digital subtraction angiography for congenital heart disease].

From January 1988 to May 1989, ten infant patients (15 times) with congenital heart disease were studied by digital subtraction angiography (DSA) pre and/or postoperatively. The diagnoses of the patients include total anomalous pulmonary venous return (TAPVR), transposition of great arteries, patent ductus arteriosus with pulmonary hypertension, giant hemangioma of the left leg, asplenia (two cases), tetralogy of Fallot (two), and tricuspid atresia (two). Two newborn patients (TAPVR, giant hemangioma) were in critical condition preoperatively, but were diagnosed precisely and nonivasively by DSA. Ten cases were studied for estimation of operative repair and consequently five of them were diagnosed to require reoperation. It is concluded that DSA is of use for diagnosis of congenital heart diseases and for postoperative evaluation of infant patients under critical condition.

[A case of tetralogy of Fallot with absent pulmonary valve].

A 3-month-boy weighing 1,968 gm with absent pulmonary valve associated with tetralogy of Fallot, who suffered from severe respiratory distress, underwent emergency operation. Preoperatively, the patient had atelectasis of left lung, since left main bronchus was compressed by aneurysmal dilatation of the main pulmonary artery. Aneurysmorraphy and suspension of the pulmonary artery with retrosternal fascia was performed successfully. This procedure is a simple and useful method of relief from airway obstruction at the first stage for such critically ill infants.

[A case report of successful treatment using ECMO in severe status asthmaticus during open heart surgery].

A 6-year-old boy who had a history of asthma attack since 3 years old, but whose symptom was well controlled with medication received a radical operation for ASD. During the operation, he suffered from severe asthma attack. In blood gas analysis, PCO2 was increased to 302 mmHg with a decrease of pH to 6.740. Every conventional treatment for asthma attack was not effective, and then extracorporeal membrane oxygenation (ECMO was performed within 2 hours after operation. Blood gas data normalized and his hemodynamic condition was well maintained by ECMO. After 4 hours 20 minutes, he was weaned off from ECMO. Post operative course was uneventful except for pneumothorax.

Ultrastructural studies of peripheral blood of neonates with Down's syndrome and transient abnormal myelopoiesis.

Ultrastructural studies were performed on blood samples from five neonates with Down's syndrome and transient abnormal myelopoiesis (TAM). Three methods of fixation were employed to detect diaminobenzidine (DAB) reactivity. The first method used glutaraldehyde solution, while the second and third methods used tannic acid-glutaraldehyde mixtures. Before fixation by the second method, specimens were washed in order to eliminate plasma, and before fixation by the third were diluted to lessen the effects of plasma protein. The latter two methods were more sensitive than the first for detection of DAB reactivity, while the third also resulted in better preservation of morphology than did the second. Even the first method was able to detect DAB reactivity in cells of megakaryocyte-platelet series in appropriate sections. Although the majority of blasts appeared with light microscopy to be undifferentiated, their ultrastructural morphology and ultrastructural cytochemistry were in fact found to be quite heterogeneous, consisting of cells of the megakaryocyte-platelet and granulocytic series, including basophils, and erythroid precursors. This finding supported the view that TAM was the result of unstable hematopoiesis rather than true leukemia.

Hyperunstable hemoglobin Koriyama anti-Hb Gun Hill insertion of five residues in the beta chain.

A new hyperunstable hemoglobin was found in a Japanese girl who had very severe, chronic hemolytic anemia. Her parents and siblings were hematologically normal. The abnormal hemoglobin comprised a very small proportion of the total hemoglobin, although it was produced almost at the same rate as normal hemoglobin. Sequencing of an abnormal peptide which was liberated from the beta chain by hydrolysis with a protease from Staphylococcus aureus V8 disclosed the tandem insertion of a five-residue segment which included the proximal histidine at beta 92(F8).