Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus.

AIM: As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin. METHODS: We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke. RESULTS: The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies. CONCLUSION: These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of aloglipin in patients with type 2 diabetes mellitus.

Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts.

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables. METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

The el nino cycle: a natural oscillator of the pacific ocean--atmosphere system.

Research conducted during the past decade has led to an understanding of many of the mechanisms responsible for the oceanic and atmospheric variability associated with the El Niño-Southern Oscillation (ENSO). However, the reason for one of the fundamental characteristics of this phenomena, its quasi-periodicity, has remained unclear. Recently available evidence from a number of sources now suggests that the ENSO "cycle" operates as a natural oscillator based on relatively simple couplings between the tropical atmospheric circulation, the dynamics of the warm upper layer of the tropical ocean, and sea surface temperatures in the eastern equatorial Pacific. This concept and recent field evidence supporting the natural coupled oscillator hypothesis are outlined.

Electron microprobe and optical absorption study of colored kyanites.

The characteristic blue color of the mineral kyanite is shown to be caused by traces of Ti(+++) in the range of a few parts per million. Evidence from the intensity and position of optical absorption bands indicates that the unusually intense color probably arises from electron delocalization into narrow d-bands.

Obsidian hydration profiles measured by sputter-induced optical emission.

The variation of concentrations of hydrogen, sodium, potassium, lithium, calcium, magnesium, silicon, and aluminum as a function of depth in the hydration layer of obsidian artifacts has been determined by sputter-induced optical emission. The surface hydration is accompanied by dealkalization, and there is a buildup of alkaline earths, calcium and magnesium in the outermost layers. These results have clarified the phenomena underlying the obsidian hydration dating technique.

Utility of semiautomatic clinic and 24-h ambulatory blood pressure measurements to evaluate combination therapy: the Ramipril-Hydrochlorothiazide Hypertension trial.

Angiotensin-converting enzyme inhibitors combined with higher doses of hydrochlorothiazide (HCT), that is, 25 mg daily, have been recognized as an effective form of antihypertensive therapy. To evaluate the coadministration of 20 mg ramipril with 25 mg HCT, we carried out a randomized, double-blind, controlled trial with two dose schedules of ramipril (20 mg q.d. and 10 mg b.i.d.) and HCT monotherapy arms as comparators in 354 patients with stage 2 hypertension. The clinic blood pressure (BP) was assessed using a semiautomatic digital device and 24-h BP was measured using ambulatory BP recordings at baseline and after 8 weeks of therapy. At baseline, the demographics and baseline BP values were similar in the four treatment groups (age: 51-53 years, 52-58% male, 64-68% non-black, clinic BP: 155-158/103-104 mm Hg). Ramipril-HCT induced significantly greater reductions in both the clinic and ambulatory BP than the HCT and ramipril monotherapy treatments (for example, additional reductions in ambulatory BP on ramipril-HCT ranged from -7.3/-5.2 to -10.3/-7.4 mm Hg compared to the monotherapies, all P<0.001). Reductions from baseline were still numerically greater for the clinic BPs derived from device measurements than those for the BP values derived from 24-h ambulatory BP measurements (changes in clinic diastolic BP ranged from -8.5 to -15.5 mm Hg across treatment groups, whereas changes in ambulatory diastolic BP were -4.7 to -12.0 mm Hg for the same groups). Thus, these data support the use of ambulatory BP monitoring even when automated BP devices are used for the assessment of clinical BP in trials that attempt to differentiate BP responses among active comparator groups. In conclusion, based on its efficacy and tolerability profile the combination of ramipril and HCT was shown to be effective therapy for the treatment of stage 2 hypertension.

Improved left ventricular filling accompanies reduced left ventricular mass during therapy of essential hypertension.

Abnormal left ventricular diastolic performance, an early manifestation of hypertension in the heart, may precede the development of left ventricular hypertrophy. To assess effects of antihypertensive therapy on the heart, left ventricular mass (determined by echocardiography) and rapid left ventricular filling rate (determined by radionuclide ventriculography) were compared before and after 6 months of treatment of 16 patients. Nitrendipine (a dihydropyridine calcium channel blocker) was given alone or in combination with either propranolol or hydrochlorothiazide, or both, and significantly reduced blood pressure (156/103 +/- 12/7 to 137/89 +/- 10/6 mm Hg). In 6 of the 16 patients, left ventricular mass decreased by more than 10% (270 +/- 95 to 193 +/- 47 g, p less than 0.01); in the same patients, left ventricular filling rate increased (2.03 +/- 0.35 to 2.30 +/- 0.45 end-diastolic counts/s [EDC/s], p less than 0.01). In the one patient whose left ventricular mass increased (137 to 195 g), left ventricular filling rate decreased from 2.01 to 1.78 EDC/s. In the remaining nine patients who had no change in left ventricular mass, there was no significant changes in left ventricular filling. The changes in ventricular mass and filling could not be related to the extent of change in blood pressure or heart rate. These data suggest that regression of left ventricular mass during antihypertensive therapy with nitrendipine is accompanied by improved diastolic function.

Rapid ventricular filling in left ventricular hypertrophy: II. Pathologic hypertrophy.

To define the extent of left ventricular ejection and filling abnormalities in patients with mild hypertension, a non-imaging nuclear probe was used to generate high resolution time-activity curves in 25 patients with an average systolic blood pressure of 154 +/- 20 mm Hg and diastolic pressure of 98 +/- 8 mm Hg. The hypertensive patients did not meet electrocardiographic criteria for left ventricular hypertrophy, and none had evidence of ischemic or other cardiac disease. Compared with 25 age-matched normal subjects who had average systolic and diastolic pressures of 123 +/- 10 and 79 +/- 8 mm Hg, respectively, the hypertensive patients had a significantly lower ejection rate (2.00 +/- 0.20 versus 2.34 +/- 0.36 end-diastolic counts/s for the control group, p less than 0.05) and ejection fraction (58 +/- 4.9 versus 62 +/- 4.4) (p less than 0.05). The hypertensive patients had a markedly lower average rapid left ventricular filling rate (1.87 +/- 0.32 versus 2.69 +/- 0.41 counts/s for the control group, p less than 0.001). Although there was a modest inverse relation between echocardiographic left ventricular mass index and filling rate in the hypertensive patients (r = -0.59, p less than 0.01), 4 of 12 hypertensive patients with normal left ventricular mass index had a depressed filling rate. All of the hypertensive patients with increased left ventricular mass index had an abnormal left ventricular filling rate (less than 1.89 end-diastolic counts/s).(ABSTRACT TRUNCATED AT 250 WORDS)

Selective dopamine-1 agonist therapy in severe hypertension: effects of intravenous fenoldopam.

To determine the effects of dopamine-1 agonist therapy in severe hypertension, blood pressure, heart rate, catecholamines and left ventricular function were studied in 18 patients (10 with renal disease) with diastolic blood pressure greater than 120 mm Hg (range 124 to 160) after intravenous fenoldopam therapy. Constant infusions of fenoldopam were titrated upward every 10 to 20 min from an initial dose of 0.1 microgram/kg per min to a maximal dose of 0.9 microgram/kg per min. The therapeutic goal of a supine diastolic blood pressure of less than 110 mm Hg was achieved in every patient within 1 h at an average dose of 0.34 +/- 0.22 microgram/kg per min. Blood pressure decreased from 214/134 +/- 33/10 mm Hg at baseline to 170/96 +/- 29/7 mm Hg (p less than 0.0001) at 3 h, whereas heart rate increased from 77 +/- 23 to 88 +/- 21 beats/min (p less than 0.01). Plasma norepinephrine increased during the fenoldopam infusion; epinephrine and dopamine levels did not change. Two indexes of left ventricular function (end-systolic dimension and isovolumic relaxation time) improved during the fenoldopam infusion, but mitral flow velocities during ventricular filling were unchanged. Side effects of intravenous fenoldopam were mild, transient and associated with the marked vasodilatory properties of the drug. Thus, fenoldopam is safe and effective as a parenteral monotherapy in patients with severe essential and renovascular hypertension. Preliminary data suggest that blood pressure reduction with selective dopamine-1 agonist therapy is accompanied by improved left ventricular function.

Hypotension with postural syncope secondary to the combination of chlorpromazine and captopril.

A 49-year-old man with severe hypertension and chronic schizophrenia developed marked hypotension with postural syncope following therapy with the combination of chlorpromazine and captopril. Previously, the patient's blood pressure (BP) had been poorly controlled on a regimen of chlorpromazine and hydrochlorothiazide, nadolol, and prazosin. The supine and standing BP and 24-hour ambulatory BP were subsequently studied while the patient was maintained on chlorpromazine and captopril, chlorpromazine alone, and on no therapy. Chlorpromazine alone caused a moderate reduction in supine and standing BP with a reversal of the circadian BP profile. The combination of chlorpromazine and small doses of captopril (12.5 mg/d) induced a reduction in supine BP of 84/32 mm Hg compared with chlorpromazine alone and exaggerated the postural hypotension. Hormonal investigation demonstrated low baseline renin activity that increased during therapy with captopril and a physiologic catecholamine response to change in posture. These data demonstrate that there is a synergism between captopril and chlorpromazine that may result in marked, symptomatic hypotension that is probably unrelated to the baseline level of plasma renin activity or catecholamines.

Assessment of patients with office hypertension by 24-hour noninvasive ambulatory blood pressure monitoring.

To assess the discrepancy between casual (office) and home blood pressure readings in patients performing home blood pressure monitoring, we analyzed office, home, and 24-hour ambulatory blood pressure and heart rates in 19 patients in a prospective four-week study. After the month of study, the average difference between mean office and manual home blood pressures in this office hypertensive group was 30 +/- 17/20 +/- 6 mm Hg. The blood pressures taken in the office were substantially greater than the 24-hour average blood pressures and ambulatory blood pressures during work or while at home (awake). An analysis of the automatic monitor readings while in the doctor's office and at 15-minute intervals after leaving the office showed a progressive reduction in blood pressure and heart rate during the first hour after leaving the office. A mean 24-hour blood pressure of less than 130/80 mm Hg was found in 13 (68%) patients. These data suggest that patients with office hypertension are usually normotensive but may have a persistent and recurrent pressor response in a medical care setting. Ambulatory blood pressure monitoring provides confirmation of not only the office-home disparity, but also suggests that stress other than office visits fails to elicit a hypertensive response.

Aggravated CNS depression with urinary retention secondary to baclofen administration.

A 74-year-old woman with a history of cerebrovascular disease developed profound central nervous system (CNS) and respiratory depression, generalized hypotonia, sinus bradycardia, and urinary retention following an increase in dose of baclofen, an antispasticity agent. Before receiving baclofen therapy the patient had had minor urinary dysfunction associated with a remote cerebrovascular accident but no urinary retention. Cessation of baclofen therapy and the relief of the urinary obstruction improved mental status and normalized motor function within 24 hours. A withdrawal syndrome of agitation, hallucinosis, and convulsive activity persisted for eight days following discontinuation of the baclofen. Our experience suggests that patients with various forms of CNS disease states may be at risk of serious CNS depression with even small therapeutic doses of baclofen.

Ambulatory blood pressure monitoring in patients with panic disorder.

To assess possible changes in blood pressure and heart rate associated with panic attacks, we performed automatic ambulatory blood pressure monitoring in 12 newly diagnosed, drug-free, and normotensive (casual blood pressure, less than 140/90 mm Hg) medical patients recently diagnosed with panic disorder. Detailed journals were designed for the study to assess the timing and symptoms of the panic attacks and the levels of activity. Systolic blood pressure increased by 27 +/- 9 mm Hg during the hour of the panic attack compared with the hour immediately prior to the episode of anxiety, while diastolic blood pressure increased by 5 +/- 2 mm Hg. The ambulatory heart rate increased by 14 +/- 6 beats per minute during the hour of panic attack vs the hour immediately prior to the attack. There was a strong relationship between the increase in heart rate and increase in systolic blood pressure. These data confirm that normotensive patients with panic disorder have episodically hypertensive blood pressure readings associated with an increase in heart rate; these hemodynamic alterations appear to be secondary to their panic attacks and not to increased physical activity. However, despite these episodic "hypertensive" periods, the mean ambulatory blood pressures remain within the normotensive range.

Episodic hypertension secondary to panic disorder.

Episodic elevation of blood pressure was evaluated in two middle-aged men by assessing home, clinic, and 24-hour ambulatory values following exclusion of secondary forms of hypertension. Both individuals had normotensive home and clinic readings. The 24-hour blood pressure was 125/85 +/- 12/9 mm Hg in patient 1 and 119/84 +/- 13/13 mm Hg in patient 2; however, both patients experienced large, sustained rises in blood pressure associated with panic attacks that were not abolished with prophylactic benzodiazepine therapy. Episodic blood pressure elevations were not associated with concomitant increases in heart rate. Patient 1 underwent extensive psychological investigation that diagnosed a panic disorder, and he underwent therapy that reduced the frequency and intensity of his panic-related hypertensive episodes. Because patient 2 demonstrated hypertensive readings at work, he was given a beta-blocking agent that ultimately controlled his blood pressure during episodes of anxiety and panic. These findings suggest that patients with panic attacks may present with episodic hypertension and that ambulatory blood pressure monitoring is useful in the diagnosis of this disorder and in assessment of treatment outcome.

Comparative renal effects of intravenous administration of fenoldopam mesylate and sodium nitroprusside in patients with severe hypertension.

We studied the renal effects of intravenous administration of fenoldopam mesylate, a dopamine-1 agonist, vs sodium nitroprusside following acute reduction of blood pressure (BP) in 11 patients with severe hypertension (supine BP, 168/124 to 252/135 mm Hg). Following randomization (open-label), timed urinary and plasma samples for clearance of urea and creatinine and excretion of sodium, potassium, and calcium were obtained as well as plasma renin activity for a two-hour collection prior to infusion, during a two-hour period of BP control (supine diastolic BP, 95 to 110 mm Hg), and following two hours off the drugs. Mean arterial pressure was lowered similarly with the two drugs (-22% on fenoldopam vs -20% on nitroprusside; P = NS), and neither plasma renin activity nor plasma aldosterone concentration were changed by either drug. However, patients receiving fenoldopam had significant increases in urinary flow and excretion of sodium, potassium, and calcium, whereas patients receiving nitroprusside had no changes in these parameters. Patients receiving fenoldopam had a net fluid balance of -334 mL from the end of baseline to the end of the treatment period, while the nitroprusside group had a positive balance of 382 mL. Thus, these findings show that acute BP reduction with fenoldopam is associated with both a diuresis and natriuresis in severely hypertensive patients while lowering BP with nitroprusside does not predictably alter renal function and causes a moderate expansion in volume.

Systemic herpes simplex virus type 2 infection. Proctitis, urinary retention, arthralgias, and meningitis in the absence of primary mucocutaneous lesions.

A 24-year-old heterosexual man had severe proctalgia associated with nonspecific proctitis. Within a few days, perineal and lower extremity paresthesias, intermittent urinary retention, inguinal lymphadenopathy, lower extremity arthralgias, and aseptic meningitis developed. Serologic studies demonstrated a fourfold rise in convalescent antibody titer to herpes simplex virus (HSV) consistent with an initial type 2 infection. Six months later, HSV type 2 was isolated from perianal vesicles, which we believe was the first cutaneous manifestation of a recurrence. This unusual syndrome, presumably the result of HSV ganglionitis, could be confused with other disorders that include multiple sclerosis, lumbar disk disease with radiculopathy, rheumatologic disease, and psychogenic illness. In the absence of typical herpetic mucocutaneous vesicles, serologic studies may be useful in the diagnosis of a systemic herpes simplex infection.

Pernicious anemia seen initially as orthostatic hypotension.

A 69-year-old man complaining of syncope was found to have pernicious anemia and orthostatic hypotension due to autonomic neuropathy. Following vitamin B12 replacement with cyanocobalamin, the blood pressure became normal. To our knowledge, this is the first reported case of neurogenic orthostatic hypotension as the initial feature of vitamin B12 deficiency.

Hydralazine hoarseness. A new appearance of drug-induced systemic lupus erythematosus.

Otolaryngologic involvement is rarely a manifestation of drug-induced systemic lupus erythematosus (SLE). Hoarseness developed in a 60-year-old man that was secondary to ulcerated lesions, which involved the epiglottis and aryteno-epiglottic folds, with serologic evidence of SLE after he had been treated with hydralazine for six months. Histopathologic study of an epiglottic "pseudotumor" disclosed necrotizing vasculitis. To our knowledge, this is the first reported case of laryngeal involvement as a complication of hydralazine-induced SLE.

Management of hypertension during lactation.

There has been a dramatic increase in the number of women breast-feeding during the last decade. Since little is known about the excretion of antihypertensive drugs into human breast milk, the management of hypertension during lactation can be problematical. To enable the clinician to better advise the hypertensive, lactating mother, the published literature on the excretion of antihypertensive agents into human milk has been reviewed and is presented in this report.

Circadian blood pressure variation in hypertensive patients with primary hyperaldosteronism.

A less-than-normal decline in nocturnal blood pressure (BP) has been associated with excessive hypertensive complications. This is concerning because secondary hypertension is often associated with this so-called nondipper BP profile. A nondipping pattern is more frequently found in the presence of pheochromocytoma, Cushing's syndrome, and sleep apnea syndrome, but the prevalence is unclear in patients with primary hyperaldosteronism. We therefore studied ambulatory BP profiles in 16 hypertensive patients with primary hyperaldosteronism and an equal number of essential hypertensive subjects. The awake-sleep BP difference of the hyperaldosteronism patients was similar to that of essential hypertensives (15/14 +/- 3/2 versus 14/9 +/- 3/2 mm Hg, P=NS). The prevalence of dippers and nondippers (according to two distinct criteria) in the two groups was similar. Repeat ambulatory BP monitoring in 12 subjects with primary hyperaldosteronism after specific intervention (3 after surgical removal of an adrenal adenoma and 9 after commencement and titration of spironolactone therapy) showed highly significant reductions in office BP (22/10 +/- 6/4 mm Hg, P<.05) and awake and sleep BP. However, the extent of nocturnal BP decline was unchanged between the two studies (17/16 +/- 3/3 versus 16/12 +/- 2/2 mm Hg, P=NS). There was no correlation between the awake-sleep difference and serum or urinary aldosterone levels or the aldosterone-to-renin ratio. In this study, we did not detect any differences in the awake-sleep differences between a group of hypertensives with primary hyperaldosteronism and a control group of essential hypertensives.