A case of under-dosing after raltegravir formulation change in an elderly patient treated for HIV.

Our case was a 70-year-old male (height: 168 cm, weight: 74.3 kg) with polypharmacy (total 15 drugs including 10 tablets) who was treated for HIV infection. His dosing schedule of raltegravir was changed from BID (a 400 mg tablet, twice) to QD (2x600 mg tablet, once). After a month, we found that he miss-took raltegravir for 1x600 mg tablet at once. His HIV-1 RNA increased from undetectable levels to < 20 copies per mL. Pharmaceutical companies should therefore carefully consider swallowing difficulties in old patients, such as by reformulating medications so that only one dosing is required per day and decreasing the size of tablets to 7-8 mm in diameter or orally distinguish tablet.

Comparability and reproducibility of the carotid-femoral pulse wave velocity measurements using a multi-element carotid tonometry sensor.

To evaluate the comparability and reproducibility of the carotid-femoral pulse wave velocity (PWV) measured by the newly developed device compared to that measured by the standard device and the validity of brachial-ankle PWV as a substitute of carotid-femoral PWV. We measured aortic PWV twice in 21 normotensive males by using the standard devices and the newly developed device. We also measured brachial-ankle PWV in the same subjects. There was a strong, significant correlation between aortic (carotid-femoral) PWV measured by using two different devices (r = 0.741, P = 0.00012). Interquartile range of the differences of carotid-femoral PWV measured by Form (0.75 m/s (-0.36, 0.39)) was smaller than that by Complior (1.67 m/s (-1.03, 0.63)). There was no correlation between carotid-femoral PWV, measured by either device, and brachial ankle PWV. Our present results suggest that carotid-femoral PWV measured by using Form was comparable to, and may be more reproducible than, that measured by Complior that has been widely used as a predictable marker for cardiovascular events. Our results also suggest brachial-ankle PWV may not be a substitute for carotid-femoral PWV.

Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy.

AIM: This study evaluated the effects of a glucagon-like peptide-1 receptor agonist on gastrointestinal (GI) tract motility and residue rates by examining GI transit time and lumen using capsule endoscopy. MATERIAL AND METHODS: GI motility and lumen were assessed by capsule endoscopy before and after liraglutide administration in 14 patients with type 2 diabetes mellitus (T2DM). RESULTS: Gastric transit time in the group with diabetic neuropathy (DN) was 1:12:36±1:04:30h before liraglutide administration and 0:48:40±0:32:52h after administration (nonsignificant difference, P=0.19). Gastric transit time in the non-DN group was 1:01:30±0:52:59h before administration and 2:33:29±1:37:24h after administration (significant increase, P=0.03). Duodenal and small intestine transit time in the DN group was 4:10:34±0:25:54h before and 6:38:42±3:52:42h after administration (not significant, P=0.09) and, in the non-DN group, 3:51:03±0:53:47h before and 6:45:31±2:41:36h after administration (significant increase, P=0.03). The GI residue rate in the DN group was 32.1±24% before administration and 90.0±9.1% after administration (significant increase, P<0.001), and increased in all patients; in the non-DN group, it was 32.1±35.3% before and 78.3±23.9% after administration (significant increase, P<0.001), and also increased in all patients. CONCLUSION: Liraglutide causes delayed gastric emptying and inhibits duodenal and small intestine motility. However, these GI movement-inhibiting effects may be decreased or absent in patients with DN-associated dysautonomia.

Mechanisms for regulation of fluid shear stress response in circulating leukocytes.

We have shown that leukocytes retract their pseudopods and detach from substrates after exposure to physiological fluid shear stresses ( approximately 1.5 dyn/cm(2)). In inflammation, however, pseudopod projection during spreading and firm adhesion on endothelium is observed even in microvessels with normal blood flow and fluid shear stresses. Thus, we examined mechanisms that may serve to regulate the shear stress response of circulating leukocytes. In the presence of inflammatory mediators (platelet-activating factor [PAF] f-met-leu-phe), a subgroup of cells ceases to respond to shear stress. cGMP analogs and nitric oxide (NO) donors enhance the shear stress response and reverse the inhibitory effect of inflammatory mediators on the shear stress response, whereas depletion of cGMP leads to cessation of the shear stress response even in unstimulated leukocytes. The ability of cGMP to enhance the shear stress response is not associated with CD18 expression, because cGMP has no effect on CD18 expression in response to shear stress. The shear stress response of leukocytes in endothelial nitric oxide synthase (-/-) mice, in which NO level in blood is decreased, is attenuated compared with that in wild-type mice. In rat mesentery venules stimulated by PAF under normal blood flow, a cGMP analog diminishes pseudopod projection of leukocytes, whereas inhibition of NO leads to enhanced pseudopod projection and spreading. The evidence suggests that inflammatory mediators suppress the shear stress response of leukocytes leading to spreading even under normal physiological shear stress, whereas cGMP may serve to maintain shear stress response even in inflammation.

Detection of coronary blood flow associated with left main coronary artery stenosis by transesophageal Doppler color flow echocardiography.

Demonstration of disordered blood flow in a coronary artery may be helpful in anticipating the presence of stenosis. To examine the possibility of disordered coronary blood flow associated with left main coronary stenosis, left main coronary flow was visualized by transesophageal Doppler color flow echocardiography in 52 patients undergoing coronary angiography. Twenty patients had significant left main coronary stenosis (Group 1) and 32 patients did not (Group 2). Adequate two-dimensional echocardiographic images of the left main coronary artery were obtained in 17 patients in Group 1 and 30 patients in Group 2. Sixteen patients in Group 1, including five patients in whom the stenosis could not clearly be defined by two-dimensional echocardiography, exhibited the aliased reddish-yellowish elements producing the mosaic pattern at the stenotic or poststenotic segments, or both. In contrast, nonaliased bluish jets, suggesting laminar flow away from the transducer, were seen in echocardiograms from 27 patients in Group 2. This group included four patients with stenosis-like images on two-dimensional echocardiography. The aliased mosaic pattern was found in only three patients in Group 2 (p less than 0.01). Thus, sensitivity to detect the stenosis was improved when Doppler color flow imaging was applied. Flow velocity was significantly higher at the site of stenosis in patients in Group 1 (116 +/- 28 cm/s, n = 10, mean +/- SD) than in Group 2 (29 +/- 12 cm/s, n = 21, p less than 0.01), suggesting that the augmentation of flow velocity with or without turbulence due to the stenosis contributed to the appearance of the mosaic flow images.(ABSTRACT TRUNCATED AT 250 WORDS)

Flow dynamics of QW7437, a new dodecafluoropentane ultrasound contrast agent, in the microcirculation: microvascular mechanisms for persistent tissue echo enhancement.

OBJECTIVES: The purpose of this study was to test the hypothesis that a subgroup of QW7437 microbubbles, dodecafluoropentane-based ultrasound contrast microspheres, resides for prolonged periods in the microvasculature. BACKGROUND: QW7437 produces echo enhancement in myocardium which may persist relatively longer than opacification in the left ventricular cavity. The mechanism for this persistent enhancement remains unknown. METHODS: The transit of fluorescently labeled erythrocytes was examined by fluorescence intravital microscopy in the microvessels in five rat mesenteries. Ten rats were used to observe the behavior of fluorescently labeled QW7437 microbubbles in the mesenteric microcirculation. RESULTS: There was no significant change in erythrocyte velocity in the arterioles and venules after the administration of QW7437 microbubbles (0.05 ml/kg) preactivated by negative hydrodynamic pressure. Of 552 microbubbles observed in four arterioles and five capillaries, 549 (99.5%) passed without stoppage (> or = 0.1 s stoppage); only one stopped transiently in arteriole and two in capillaries, each for <0.5 s. Sixty-five of 478 microbubbles (13.6%) observed in six postcapillary venules 11 to 30 microm in diameter and 24 of 408 microbubbles (5.9%) in four venules 31 to 50 microm in diameter stopped transiently (0.1 to 180 s) with an attachment to venular endothelium; the remaining microbubbles passed through the venules without stoppage. CONCLUSIONS: Prolonged survival as microbubbles in the circulation and transient stoppage of a subgroup of microbubbles in the microvasculature, particularly in venules, are potential mechanisms for the persistent tissue echo enhancement by QW7437 microbubbles during contrast echocardiography.

Different patterns of renal prostaglandins I2 and E2 in patients with essential hypertension with low to normal or high renin activity.

OBJECTIVE: Differences in renal synthesis between prostaglandins I2 and E2, and the relationships of the amounts synthesized to renin release were investigated in patients with essential hypertension. METHODS: Of 12 inpatients, six had low to normal plasma renin activity and six had high renin activity. Before and 30 min after intravenous injection of aspirin D,L-lysine (18 mg/kg), abdominal aortic and renal venous plasma was sampled and assayed for renin activity, 6-ketoprostaglandin F1alpha (as an index of prostaglandin I2), and prostaglandin E2. RESULTS: In patients with low to normal renin activity, mean +/- SD plasma levels of 6-keto-prostaglandin F1alpha were lower in the right and left renal veins (3.6 +/- 1.4 and 4.1 +/- 1.5 pg/ml, respectively) than in the aorta (5.5 +/- 2.0 pg/ml), but in the other patients, the levels in these veins (7.0 +/- 2.4 and 6.5 +/- 1.5 pg/ml) were higher than in the aorta (5.4 +/- 0.9 pg/ml). Plasma prostaglandin E2 levels in both veins were higher than in the aorta in both groups and, at each site, the levels were similar in the two groups. Aspirin suppressed renin release in the patients with high renin activity. CONCLUSIONS: In patients with essential hypertension with low to normal renin activity, either less prostaglandin I2 than prostaglandin E2 is produced in the kidney or else more is metabolized there, and in such patients with high renin activity, the renal synthesis of prostaglandin I2, more than that of prostaglandin E2, seems to be related to the increased renin release.

Delayed improvement in skeletal muscle metabolism and exercise capacity in patients with mitral stenosis following immediate hemodynamic amelioration by percutaneous transvenous mitral commissurotomy.

The abrupt improvement in hemodynamics after successful percutaneous transvenous mitral commissurotomy (PTMC) does not immediately enhance exercise capacity. Improved exercise capacity several months after PTMC has been reported. We hypothesized that the delayed improvement in exercise capacity is due partly to the slow improvement in the metabolism of skeletal muscle. This study examined the short- and long-term effects of PTMC on exercise capacity and skeletal muscle metabolism in patients with mitral stenosis. Treadmill exercise testing with respiratory gas analysis was performed in 11 patients with symptomatic mitral stenosis before and 3, 30, and 90 days after successful PTMC. On the same schedule, forearm metabolism of high-energy phosphates was measured by magnetic resonance spectroscopy during and after handgrip exercise. Ten healthy volunteers were examined. PTMC resulted in an immediate symptomatic improvement. However, exercise capacity and skeletal muscle metabolism remained unchanged 3 days after PTMC. At 30 days after PTMC, there were significant improvements in peak oxygen consumption (p <0.05), intracellular pH at end-exercise (p <0.05), and time constant for phosphocreatine recovery (mean +/- SD 88.9 +/- 11.3 vs 106.3 +/- 11.7 seconds, p <0.01) compared with these baseline values. These improvements remained even at 90 days after PTMC. Exercise capacity improved with some time delay after immediate hemodynamic amelioration by PTMC. Long-term improvement in exercise capacity depends partly on the slowly progressing improvement in skeletal muscle metabolism after long-standing mitral stenosis.

Effects of aspirin DL-lysine on thrombin generation in unstable angina pectoris.

To evaluate the effects of aspirin on thrombin generation in patients with unstable angina, plasma levels of thrombin-antithrombin III complex (TAT) as a new marker of thrombin generation and of 11-dehydro-thromboxane B2 (11-dehydro-TXB2) as an indicator of platelet activation were measured in 18 patients with unstable angina, including 8 patients with prolonged rest angina (> 15 minutes). Aspirin DL-lysine (900 mg) was administered intravenously to 9 of the 18 patients (aspirin group); the other 9 were not given aspirin during the first 24 hours of hospitalization (non-aspirin group). Clinical characteristics, angiographic features and medications other than aspirin were similar between the 2 groups. Levels of plasma TAT and 11-dehydro-TXB2 were significantly higher (p < 0.05) in patients with prolonged rest angina than in those without the condition (n = 10). In 5 patients with prolonged rest angina who received aspirin, plasma TAT levels (ng/ml) were significantly decreased (4.52 +/- 1.18 at baseline, 2.50 +/- 0.65 at 1 hour and 2.16 +/- 0.42 at 24 hours after aspirin administration, p < 0.01) with a significant decrease in plasma 11-dehydro-TXB2 levels. However, the reduction in TAT after aspirin administration was slight in patients without prolonged rest angina (n = 4). In contrast, levels of plasma TAT and 11-dehydro-TXB2 in the non-aspirin group remained unchanged during the study period. These results suggest that aspirin rapidly reduces thrombin generation through inhibition of platelet activity in patients with unstable angina with prolonged rest angina.

Further ST elevation at reperfusion by direct percutaneous transluminal coronary angioplasty predicts poor recovery of left ventricular systolic function in anterior wall AMI.

Some patients with acute myocardial infarction (AMI) develop further ST elevation at reperfusion by percutaneous transluminal coronary angioplasty (PTCA). This study reports the ST deviation at reperfusion by direct PTCA in relation to the clinical factors and the recovery of left ventricular (LV) systolic function. Fifty-two patients with anterior wall AMI were treated with direct PTCA. They were classified into the following 3 groups according to the change in ST elevation at reperfusion: increase of > or = 20% (ST reelevation); reduction of > or = 20% (ST resolution); and the other (ST no change). Angina pectoris preceding AMI occurred less often in the ST reelevation group (ST reelevation group, 38%; ST no change group, 81%; ST resolution group, 70%; p < 0.05). Recovery of LV ejection fraction during the first month after direct PTCA was significantly poor in the ST reelevation group in contrast to the ST resolution group (ST reelevation group, -6.3 +/- 13%; ST no change group, 18 +/- 20%; ST resolution group, 45 +/- 29%; p < 0.0001). The change in ST elevation at reperfusion was an index predicting the recovery of LV systolic function in the reperfusion by direct PTCA.

Usefulness of extracorporeal membrane oxygenation for treatment of fulminant myocarditis and circulatory collapse.

Prognosis for fulminant myocarditis with cardiogenic shock refractory to conventional therapy is poor. This report describes mechanical circulatory support with extracorporeal membrane oxygenation as an effective alternative for treating fulminant myocarditis with circulatory collapse.

Nicorandil improves diabetes and rat islet beta-cell damage induced by streptozotocin in vivo and in vitro.

OBJECTIVE: N-(2-hydroxyethyl)-nicotinamide nitrate (nicorandil) is a unique anti-anginal agent, reported to act as both an ATP-sensitive K(+) channel opener (PCO) and a nitric oxide donor. It also has an anti-oxidant action. We examined the effects of nicorandil on streptozotocin (STZ)-induced islet beta-cell damage both in vivo and in vitro. DESIGN AND METHODS: STZ-induced diabetic Brown Norway rats (STZ-DM) were fed with nicorandil-containing chow from day 2 (STZ-DM-N48), 3 (STZ-DM-N72), and 4 (STZ-DM-N96) to day 30. Body weight, blood glucose, and plasma insulin were measured every week. For the in vitro assay, neonatal rat islet-rich cultures were performed and cells were treated with nicorandil from 1 h before to 2 h after exposure to STZ for 30 min. Insulin secretion from islet cells was assayed after an additional 24 h of culture. We also observed the effect of nicorandil on the generation of reactive oxygen species (ROS) from rat inslinoma cells (RINm5F). RESULTS: Body weight loss and blood glucose levels of STZ-DM-N48 rats were significantly lower than those of STZ-DM rats. Immunohistochemical staining of insulin showed preservation of insulin-secreting islet beta-cells in STZ-DM-N48 rats. Nicorandil also dose-dependently recovered the insulin release from neonatal rat islet cells treated with STZ in in vitro experiments. Nicorandil did not act as a PCO on neonatal rat islet beta-cells or RINm5F cells, and did not show an inhibitory effect on poly(ADP-ribose) polymerase-1. However, the drug inhibited the production of ROS stimulated by high glucose (22.0 mmol/l) in RINm5F cells. CONCLUSIONS: These results suggested that nicorandil improves diabetes and rat islet beta-cell damage induced by STZ in vivo and in vitro. It protects islet beta-cells, at least partly, via a radical scavenging effect.

Transient ST elevation and left ventricular asynergy associated with normal coronary artery in aneurysmal subarachnoid hemorrhage.

A 62-year-old woman presented with transient ST segment elevation and left ventricular asynergy in an acute phase of subarachnoid hemorrhage (SAH). A coronary arteriogram during ongoing ST elevation showed no fixed stenoses or spasm. These findings refute epicardial coronary vasospasm as a cause of transient ST elevation and left ventricular asynergy in patients with SAH.

Left main coronary flow velocity associated with stenosis. Evaluation by transesophageal color-guided pulsed Doppler technique.

To quantitatively estimate the extent of left main coronary artery (LMCA) stenosis, flow velocity of the LMCA in 33 patients was analyzed by a transesophageal color-guided pulsed Doppler technique. In 11 of 20 patients with LMCA stenosis, coronary flow velocity could be measured. The peak diastolic flow velocity at the stenotic segments was 90 +/- 32 (SD) cm/s which was significantly greater than that at the nonstenotic segments (n = 13; 34 +/- 8 cm/s; p < 0.01), and was correlated with the angiographically determined percentage of diameter stenosis of the vessel which ranged from 52 to 90 percent (r = 0.77; y = 6.34 square root of x + 10.4; p < 0.01). These results suggest that acceleration of flow velocity at the point of stenosis may be correlated with the severity of the stenosis. Measurement of flow at the point of stenosis by transesophageal color-guided pulsed Doppler technique may facilitate the quantitative assessment of LMCA stenosis, although its sensitivity requires improvement.

Effects of cicletanine on prostaglandin I2 and E2 levels in patients with essential hypertension.

Cicletanine is a new antihypertensive drug that seems to stimulate the synthesis of prostaglandin (PG) I2. However, there is little evidence that cicletanine increases the level of PGI2 in the systemic blood of human subjects long-term. To investigate the antihypertensive mechanism of cicletanine, we measured serially the systemic blood pressure and the levels of both 6-keto-PGF1alpha (a stable metabolite of PGI2) and PGE2 in plasma and urine after administration of cicletanine. Nine patients with essential hypertension on a diet with sodium intake of 120 mEq/day took 100 mg of the drug orally daily every day for 1 week. Systemic blood pressure was measured hourly for 24 h on day 7 of the control period and on days 1 and 7 of the cicletanine period. The two PGs of interest were extracted, purified by high pressure liquid chromatography, and measured by radioimmunoassay. Cicletanine decreased blood pressure without reflexial tachycardia. The plasma levels of 6-keto-PGF1alpha were slightly, but significantly, higher at 3 h after the administration of cicletanine on both days 1 and 7 of administration (on day 1, 3.88 +/- 1.44 pg/mL and on day 7, 4.07 +/- 0.76, means +/- SD, both P < .05 v before administration on day 1) than before administration on day 1 (3.21 +/- 1.25 pg/mL). Plasma PGE2 was higher before and at 3 h after administration on day 7 than at 12 noon on day 7 of the control period. Cicletanine increased the urinary excretion of the two PGs; the increased PG levels partly account for the increased natriuresis in the first 3 days. The antihypertensive effects of cicletanine taken for 1 week were based on natriuresis caused by increased systemic synthesis of the vasodilator PGI2 and partly by the increased renal synthesis of PGI2 and PGE2.

Short-term increase in prostaglandin I2 synthesis caused by cicletanine in patients with essential hypertension.

Cicletanine is a new antihypertensive drug that stimulates renal and vascular synthesis of prostaglandin (PG) I2 in experimental animals. However, there is little evidence that cicletanine increases the level of PGI2 in systemic blood of human subjects. To investigate the short-term antihypertensive mechanism of cicletanine, we measured serially the systemic blood pressure, the levels of 6-keto-PGF1 alpha (a stable metabolite of PGI2) and PGE2, and renin activity in plasma after administration of the drug. Nine patients with essential hypertension on a diet without severe sodium restriction took 100 mg of the drug by mouth. Systemic blood pressure was measured hourly for 24 h before and after cicletanine administration. The two PGs of interest were extracted, purified by high pressure liquid chromatography, and measured by radioimmunoassay. Cicletanine decreased blood pressure 3 and 6 h after administration and increased the plasma level of 6-keto-PGF1 alpha. The increase in 6-keto-PGF1 alpha was small but significant (mean +/- SD, from 3.21 +/- 1.26 to 3.88 +/- 1.44 and later 4.15 +/- 1.08 pg/mL by 3 and 6 h after administration; P < .05 and .01, respectively). The level of PGE2 had increased at 3 h after administration but returned to baseline by 6 h. Plasma renin activity was increased only at 24 h after administration. Cicletanine increased systemic PGI2 levels short-term, producing an antihypertensive effect in patients with essential hypertension.

Two molecular forms of plasma adrenomedullin during tilt test in healthy subjects.

There is accumulating evidence suggesting that adrenomedullin (AM) may participate in the regulation of circulatory homeostasis and pathophysiology of cardiovascular disease. A recent study revealed that two molecular forms of AM, an active form of mature AM (AM-m) and an intermediate inactive form of glycine-extended AM (AM-Gly), circulate in human plasma. The object of the present study was to evaluate the effect of orthostasis on a time course of two molecular forms of plasma AM and to compare them with the behavior of other vasoactive hormones. Twelve healthy male volunteers were studied. The experimental protocol consisted of 20 min of supine rest, tilting at 70 degrees for 20 min, and then 20 min of supine rest. Blood pressure and heart rate were measured every minute. Blood samples were obtained before, at 2 and 18 min during the tilt test, and 2 and 18 min after the test for the measurements of vasoacting hormones and hematocrit. Blood pressure and heart rate were slightly increased earlier during tilting and then remained elevated until the end of the test. The increase in heart rate and blood pressure returned to normal levels early after the tilt test. Plasma epinephrine and norepinephrine significantly increased during the tilt test. These hormones returned to normal levels 18 min after the test. The plasma renin activity, antidiuretic hormone and dopamine were also increased by the end of the tilt test, whereas plasma atrial natriuretic peptide was significantly decreased after the tilt test. Hematocrit increased slightly in the early phase of the tilt test and was further increased by the end of the test. In contrast, plasma AM-Gly or AM-m did not change during the tilt test or the recovery period. Nitric oxide metabolites did not change, either. There were no significant relationships between plasma catecholamines and AM. Plasma brain natriuretic peptide did not change during the tilt test or the recovery period, either. These results suggest that the two molecular forms of AM, AM-m and AM-Gly in plasma, did not respond to the short term tilting stress. These findings may support the hypothesis that plasma AM is secreted in a constitutive manner from the vascular wall.

A new form of retinopathy associated with myocardial infarction treated with percutaneous coronary intervention.

AIM: To report a new form of retinopathy that was observed in patients who had undergone percutaneous coronary intervention (PCI) following acute myocardial infarction (AMI). METHODS: Serial ophthalmological examinations were conducted in 40 patients who underwent PCI. Thirty patients were diagnosed with AMI, and another 10 had stable angina pectoris. RESULTS: Cotton wool spots developed in 17 (57%) patients from the group with AMI undergoing PCI (n = 30) within 2 months. Of these, 41% (seven patients) also developed superficial haemorrhages. Retinopathy was most prominent 1-2 months after AMI and then tended to become quiescent afterwards, without treatment. CONCLUSION: We have identified a new form of retinopathy in patients with AMI that spontaneously subsides without treatment.

[A case of unstable angina pectoris associated with an active phase of polymyositis].

We report a case of unstable angina in an active phase of polymyositis. A 51 year-old man was admitted with a diagnosis of polymyositis and unstable angina with ST elevation on prolonged rest chest pain. Rest anginal attack which had been refractory to conventional antianginal medications was controlled by high dose of glucocorticosteroid. Electrocardiography revealed multifocal premature ventricular contraction. Since silent ischemia on exercise persisted, percutaneous transluminal coronary angioplasty (PTCA) was performed on a stenotic lesion in the left anterior descending artery. Since there was recurrent anginal attack, re-PTCA was carried out at the same site. He was discharged in a good condition. This case is considered to be associated with cardiac involvement of polymyositis because of ventricular arrhythmia, persistent increased serum levels of CPK-MB, and the marked benefits of corticosteroid against unstable angina. In addition, clinical manifestations, coronary arteriographic findings, and increased plasma levels of thrombin-antithrombin III complex suggest that cardiac involvement in polymyositis accelerates intracoronary thrombus formation and/or coronary spasm.