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.

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.

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.

Endoscopic management of pancreaticopleural fistulas: a report of three patients.

Pancreaticopleural fistulas are a rare complication of acute or chronic pancreatitis, and are usually treated by surgery. We report three patients whose pancreaticopleural fistulas were successfully treated by endoscopic retrograde cholangiopancreatography and drainage (stenting, nasopancreatic drainage). In one patient a pancreatic pseudocyst persisted despite successful initial closure of the leak using this method and, as it was also suspected to be infected, additional drainage of the pseudocyst was required. Endotherapy of pancreaticopleural fistulas could obviate the need for surgery when conventional medical treatment has failed in this condition.

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.

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.

Nicorandil versus isosorbide dinitrate as adjunctive treatment to direct balloon angioplasty in acute myocardial infarction.

OBJECTIVE: To compare the effects of nicorandil (a hybrid ATP sensitive potassium channel (K+(ATP) channel) opener/nitric oxide donor) with those of isosorbide dinitrate (ISDN) on myocardial microcirculation and cardiac function in patients with acute myocardial infarction (AMI) who had undergone reperfusion treatment by direct balloon angioplasty. DESIGN: Double blind randomised study. PATIENTS: 60 patients with AMI in Killip class I. INTERVENTIONS: Patients were assigned into two treatment groups: a nicorandil group (n = 30) and an ISDN group (n = 30). Each drug was infused intravenously at 6 mg/h for 72 hours starting at admission and was administered directly to the treated coronary artery immediately after angioplasty. RESULTS: Compared with ISDN, nicorandil more frequently caused recovery of ST segment elevation just after reperfusion (15 of 27 (55.5%) in the nicorandil group v 5 of 26 (19.2%) in the ISDN group, p = 0.006). The nicorandil group had higher values of averaged peak velocity 40 minutes after reperfusion (mean (SD) 24.8 (13.3) cm/s v 16.0 (11.1) cm/s, p = 0.045) and higher values of regional wall motion of the infarcted area three weeks after onset of AMI (-1.78 (1.11) v -2.50 (1.04) SD/chord, p = 0.046). CONCLUSIONS: A combination of nicorandil drip infusion starting before reperfusion and intracoronary injection immediately after reperfusion is more effective than a similarly performed infusion of ISDN in preserving myocardial microcirculation in the reperfused AMI area. The nicorandil regimen resulted in better left ventricular regional wall motion.

Effective and selective prevention of retinal leukostasis in streptozotocin-induced diabetic rats using gliclazide.

AIMS/HYPOTHESIS: Early stage leukocyte entrapment in the retinal microcirculation (retinal leukostasis) is considered to be one of the important pathogenetic events in diabetic retinopathy. Gliclazide, a sulphonylurea, was reported to reduce leukocyte adhesion to endothelial cells in hyperglycaemia in vitro, thus suggesting possible selective efficacy of this sulphonylurea in preventing leukostasis in diabetic patients. This study evaluated the effectiveness and selectivity of gliclazide treatment on retinal leukostasis of diabetic rats in vivo. METHODS: Streptozotocin (STZ) (65 mg/kg)-induced diabetic rats were divided into three groups (n = 8 each): an untreated diabetic group, a gliclazide-treated diabetic group, and a glibenclamide-treated diabetic group. Gliclazide or glibenclamide was administered orally during a 3-week period. Non-diabetic rats were used as a control (n = 8). Retinal leukostasis was quantitatively evaluated in vivo by acridine orange leukocyte fluorography using a scanning laser ophthalmoscope. RESULTS: The number of leukocytes trapped in the area around the optic disc in the untreated diabetic group (36.9 +/- 5.1 cells) increased significantly compared with the non-diabetic control group (21.9 +/- 2.9 cells; p = 0.0007). The number of leukocytes trapped in the gliclazide-treated diabetic group (23.5 +/- 4.0 cells) decreased significantly compared with untreated diabetic group ( p = 0.0008). In contrast, no reduction of retinal leukostasis was found in the glibenclamide-treated diabetic group (37.8 +/- 5.8 cells; p = 0.7923). CONCLUSION/INTERPRETATION: This suggests that gliclazide could directly improve abnormalities in the retinal microcirculation independent of blood glucose control and possibly have selective therapeutic benefits in preventing early, critical events in diabetic retinopathy compared with other sulphonylurea drugs.

[Apical ballooning by transient left ventricular dysfunction (so-called "ampulla" cardiomyopathy) associated with therapy for acute pulmonary thromboembolism: a case report].

An 86-year-old-woman presented with apical ballooning left ventricular dysfunction associated with therapy for acute pulmonary thromboembolism. She was referred to our hospital for advanced treatment for her shock state due to acute pulmonary embolism with normal left ventricular(LV) function. Her condition was stabilized using a percutaneous cardiopulmonary support system. Suction embolectomy was successfully carried out after pulmonary arteriography. After the therapy, echocardiography revealed apical ballooning and hyperkinesis of the base(LV ejection fraction = 28%), although coronary arteriography showed no fixed stenosis. LV wall motion significantly improved on day 3(LV ejection fraction = 45%). Pulmonary embolism relapsed on day 5 in spite of anticoagulation treatment. She died of multiple organ failure on day 9. Autopsy findings indicated no sign of myocardial infarction or myocarditis, patchy appearance of myocardial contraction band necrosis and few migrated lymphocytes. The mechanism for the flow mis-matched LV dysfunction remains unknown. The probable explanations include non-ischemic stress such as catecholamine or neurogenic stress, and possibly ischemic stress or ischemia/reperfusion injury.

Echocardiographical demonstration of a progressively expanding left ventricular aneurysm preceded by endomyocardial tearing.

A 70-year-old woman with acute myocardial infarction (AMI) had a narrow necked left ventricular (LV) aneurysm and pericardial effusion. Although there had been no obvious sign of pseudoaneurysm at the first operation on the 13th day after onset, LV volume increased so dramatically that dyspnea on mild exertion was induced only 2 months after the onset of AMI. She underwent Dor's operation for the expanded LV aneurysm. The histological findings of the resected tissue, which were fibrotic epicardial lesion with small myocyte islands, indicated a true aneurysm. The ultrasound manifestation of a narrow necked aneurysm with abrupt thinning of the myocardium at the hinge point may be a valuable predictor of free wall rupture in the early phase and severely progressive LV remodeling in the late phase. Such aneurysms need to be considered as high risk.

Vasospastic total occlusion at the left main tract in a single coronary artery.

A 64-year-old man was admitted to hospital under the suspicion of unstable angina pectoris. Coronary angiography showed that he has a single coronary artery originating from the right coronary artery (RCA) without significant fixed stenosis. Acetylcholine was superselectively infused into the left main coronary artery (LMCA), and confirmed the coronary vasospastic occlusion associated with chest pain and elevation of the ST-segment in the precordial leads. This is the first report of the induction of a totally occlusive spasm of the LMCA of a patient with a RCA type single coronary artery, and this case suggests that spasm of the aberrant coronary artery is a potential mechanism for sudden death in patients with a single coronary artery.

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.

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.

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.

Ultrasound contrast agents for echocardiography.

There is a need to monitor perfusion of the microcirculation in patients with minimal invasive approaches. The recent development of ultrasound contrast agents may open such an opportunity and permit to visualize online perfusion of cardiac muscle and other organs. An effective approach to achieve this objective is with gas filled microbubbles that provide strong ultrasound wave reflection and scatter. To interpret the ultrasound scattering profiles, it is necessary to understand the transport of microbubbles in the microcirculation, specifically their transport in blood stream, the attachment to blood cells and endothelium, as well as possible leakage across the microvascular wall. Each of these events provides an opportunity to monitor with ultrasound not only microvascular blood flow but also detect inflammatory sites in the circulation.

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.

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.

Acutely severe myocarditis successfully treated by percutaneous cardiopulmonary support applied by a newly developed heparin-binding oxygenator and circuits.

The feasibility of using the heparin-bound percutaneous cardiopulmonary support system (PCPS) for prolonged extracorporeal circulation in patients with acute severe myocarditis is demonstrated. The case histories of 2 patients with cardiogenic shock caused by acute myocarditis are presented; both were successfully treated with long-term PCPS using a newly developed heparin-binding oxygenator and circuits without changing the oxygenator. The courses of both patients remain uneventful more than 12 months after discharge. We also discuss the clinical aspects of using heparin-bound PCPS in patients with acute severe myocarditis.

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.