The cascading origin of the 2018 Kilauea eruption and implications for future forecasting.

The 2018 summit and flank eruption of Kilauea Volcano was one of the largest volcanic events in Hawai'i in 200 years. Data suggest that a backup in the magma plumbing system at the long-lived Pu'u 'O'o eruption site caused widespread pressurization in the volcano, driving magma into the lower flank. The eruption evolved, and its impact expanded, as a sequence of cascading events, allowing relatively minor changes at Pu'u 'O'o to cause major destruction and historic changes across the volcano. Eruption forecasting is inherently challenging in cascading scenarios where magmatic systems may prime gradually and trigger on small events.

Identification of a novel, putative Rho-specific GDP/GTP exchange factor and a RhoA-binding protein: control of neuronal morphology.

The small GTP-binding protein Rho has been implicated in the control of neuronal morphology. In N1E-115 neuronal cells, the Rho-inactivating C3 toxin stimulates neurite outgrowth and prevents actomyosin-based neurite retraction and cell rounding induced by lysophosphatidic acid (LPA), sphingosine-1-phosphate, or thrombin acting on their cognate G protein-coupled receptors. We have identified a novel putative GDP/GTP exchange factor, RhoGEF (190 kD), that interacts with both wild-type and activated RhoA, but not with Rac or Cdc42. RhoGEF, like activated RhoA, mimics receptor stimulation in inducing cell rounding and in preventing neurite outgrowth. Furthermore, we have identified a 116-kD protein, p116(Rip), that interacts with both the GDP- and GTP-bound forms of RhoA in N1E-115 cells. Overexpression of p116(Rip) stimulates cell flattening and neurite outgrowth in a similar way to dominant-negative RhoA and C3 toxin. Cells overexpressing p116(Rip) fail to change their shape in response to LPA, as is observed after Rho inactivation. Our results indicate that (a) RhoGEF may link G protein-coupled receptors to RhoA activation and ensuing neurite retraction and cell rounding; and (b) p116(Rip) inhibits RhoA-stimulated contractility and promotes neurite outgrowth.

The 2017-19 activity at Mount Agung in Bali (Indonesia): Intense unrest, monitoring, crisis response, evacuation, and eruption.

After 53 years of quiescence, Mount Agung awoke in August 2017, with intense seismicity, measurable ground deformation, and thermal anomalies in the summit crater. Although the seismic unrest peaked in late September and early October, the volcano did not start erupting until 21 November. The most intense explosive eruptions with accompanying rapid lava effusion occurred between 25 and 29 November. Smaller infrequent explosions and extrusions continue through the present (June 2019). The delay between intense unrest and eruption caused considerable challenges to emergency responders, local and national governmental agencies, and the population of Bali near the volcano, including over 140,000 evacuees. This paper provides an overview of the volcanic activity at Mount Agung from the viewpoint of the volcano observatory and other scientists responding to the volcanic crisis. We discuss the volcanic activity as well as key data streams used to track it. We provide evidence that magma intruded into the mid-crust in early 2017, and again in August of that year, prior to intrusion of an inferred dike between Mount Agung and Batur Caldera that initiated an earthquake swarm in late September. We summarize efforts to forecast the behavior of the volcano, to quantify exclusion zones for evacuations, and to work with emergency responders and other government agencies to make decisions during a complex and tense volcanic crisis.

The 2018 rift eruption and summit collapse of Kilauea Volcano.

In 2018, Kilauea Volcano experienced its largest lower East Rift Zone (LERZ) eruption and caldera collapse in at least 200 years. After collapse of the Pu'u 'O'o vent on 30 April, magma propagated downrift. Eruptive fissures opened in the LERZ on 3 May, eventually extending ~6.8 kilometers. A 4 May earthquake [moment magnitude (M w) 6.9] produced ~5 meters of fault slip. Lava erupted at rates exceeding 100 cubic meters per second, eventually covering 35.5 square kilometers. The summit magma system partially drained, producing minor explosions and near-daily collapses releasing energy equivalent to M w 4.7 to 5.4 earthquakes. Activity declined rapidly on 4 August. Summit collapse and lava flow volume estimates are roughly equivalent-about 0.8 cubic kilometers. Careful historical observation and monitoring of Kilauea enabled successful forecasting of hazardous events.

Activation of RhoA by lysophosphatidic acid and Galpha12/13 subunits in neuronal cells: induction of neurite retraction.

Neuronal cells undergo rapid growth cone collapse, neurite retraction, and cell rounding in response to certain G protein-coupled receptor agonists such as lysophosphatidic acid (LPA). These shape changes are driven by Rho-mediated contraction of the actomyosin-based cytoskeleton. To date, however, detection of Rho activation has been hampered by the lack of a suitable assay. Furthermore, the nature of the G protein(s) mediating LPA-induced neurite retraction remains unknown. We have developed a Rho activation assay that is based on the specific binding of active RhoA to its downstream effector Rho-kinase (ROK). A fusion protein of GST and the Rho-binding domain of ROK pulls down activated but not inactive RhoA from cell lysates. Using GST-ROK, we show that in N1E-115 neuronal cells LPA activates endogenous RhoA within 30 s, concomitant with growth cone collapse. Maximal activation occurs after 3 min when neurite retraction is complete and the actin cytoskeleton is fully contracted. LPA-induced RhoA activation is completely inhibited by tyrosine kinase inhibitors (tyrphostin 47 and genistein). Activated Galpha12 and Galpha13 subunits mimic LPA both in activating RhoA and in inducing RhoA-mediated cytoskeletal contraction, thereby preventing neurite outgrowth. We conclude that in neuronal cells, LPA activates RhoA to induce growth cone collapse and neurite retraction through a G12/13-initiated pathway that involves protein-tyrosine kinase activity.

Adalimumab for refractory pulmonary sarcoidosis.

BACKGROUND: Ireland has one of the highest prevalence of sarcoidosis globally. Currently anti-TNF treatment in sarcoidosis is considered on a case-by-case basis particularly in patients who have a sub-optimal response to corticosteroid therapy. AIMS: We report our experience of Adalimumab in a series of refractory pulmonary sarcoidosis and discuss implications for treatment. CONCLUSION: Symptomatic improvement was found in all patients as well as stabilisation or improvement in DLCO sb. Improvements in pulmonary function tests correlated well to radiological stage and length of disease.

Intravenous dilevalol. Effects of the R-R optical isomer of labetalol in patients with severe hypertension.

Dilevalol hydrochloride, the R-R optical isomer of labetalol hydrochloride, was administered intravenously to subjects with severe hypertension. Twelve subjects with supine diastolic blood pressure of more than 115 mm Hg (mean, 124 +/- 2 mm Hg) were studied. Initial doses of 25 mg of dilevalol administered as a slowly given bolus reduced blood pressure by 14/16 mm Hg. With subsequent additional boluses to a total dose of up to 600 mg, supine diastolic blood pressure was reduced to less than 95 mm Hg in ten of 12 subjects studied (mean reduction, 28 mm Hg). Side effects were minimal and upright blood pressure at the time of reduction of blood pressure to goal was not significantly different from supine blood pressure. Plasma renin activity decreased in 11 of 11 subjects studied. Plasma epinephrine concentrations did not change significantly, whereas plasma norepinephrine concentrations increased 2 1/2-fold, probably reflecting the effect of beta 2-agonism on norepinephrine release. Dilevalol appears to be a safe and effective way of lowering blood pressure short term when intravenous antihypertensive therapy is indicated.

Renal function effects of dilevalol, a nonselective beta-adrenergic blocking drug with beta-2 agonist activity.

The effects of dilevalol, a new beta-adrenergic blocking agent with beta-agonism, on renal function were determined in two groups of patients. Patients in group 1, all with normal renal function, received either dilevalol or atenolol. Patients in group II, all with impaired renal function, received either dilevalol or metoprolol. Parameters of renal function determined before and after chronic oral treatment included glomerular filtration rate (GFR), effective renal plasma flow, filtration fraction, mean arterial pressure (MAP), renal blood flow, and renal vascular resistance. Dilevalol lowered MAP by 14 mm Hg (P less than 0.005) in group I and 25 mm Hg (P less than 0.01) in group II but had no effect on other parameters of renal function, at either peak or trough drug levels. Atenolol and metoprolol also lowered MAP by 11 mm Hg (P less than 0.01) and 15 mm Hg (P less than 0.05), respectively. Atenolol reduced GFR by 23% at peak drug level, an effect that was partially ameliorated at trough drug level. The effect of atenolol on GFR appeared to vary as a function of baseline renal function in that greater reductions were seen in groups of patients with increasing baseline GFR. Metoprolol significantly decreased renal vascular resistance by 17% (P less than 0.05). These data suggest that dilevalol effectively lowers blood pressure in hypertensive patients with normal or compromised renal function with no negative impact on parameters of renal function.

Efficacy and safety of nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in the elderly.

In a randomized, open-label, controlled, multicenter, 12-week study, the efficacy and safety of nabumetone (1,000-2,000 mg/day) versus diclofenac (100-200 mg/day), naproxen (500-1,500 mg/day), ibuprofen (1,200-3,200 mg/day), or piroxicam (10-20 mg/day) were evaluated in patients with osteoarthritis (OA) or rheumatoid arthritis (RA). The results in elderly patients (> or = 65 years of age) are presented. Nabumetone was as effective as the comparator nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of elderly OA and RA patients. Ibuprofen and diclofenac caused significantly (p < 0.05) more abdominal pain than nabumetone (8.5%, 13.1%, and 4.1%, respectively). The frequency of abdominal pain was dose related for all NSAIDs except nabumetone. Diarrhea was reported by significantly (p < 0.02) more nabumetone-treated (6.6%) than ibuprofen-treated (0.9%) elderly patients, but the incidence of diarrhea was not dose related. There were no clinically significant changes in renal function with nabumetone or the comparator NSAIDs. A significant change in hepatic enzymes occurred in elderly patients treated with diclofenac (3.3%), which was different than for patients treated with nabumetone (p < 0.04), naproxen (p < 0.06), or ibuprofen (p < 0.06). With regard to withdrawals for adverse events, more (p < 0.04) piroxicam-treated patients (4.9%) withdrew than nabumetone-treated patients (1%). In addition, doubling the dose of nabumetone from 1,000 mg/day to 2,000 mg/day did not result in a proportional increase in adverse events. However, with the comparator NSAIDs, proportional increases in adverse events occurred with increased dose. Finally, the efficacy and safety of nabumetone in elderly patients were similar to the efficacy and safety observed in nonelderly patients.

Efficacy of nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis.

The efficacy of nabumetone was compared with that of diclofenac, naproxen, ibuprofen, and piroxicam in patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a randomized, controlled, open-label, multicenter trial. Patients > or = 18 years with clinical and radiographic evidence of OA or RA (functional class I, II, or III), who provided written informed consent, were eligible. To mimic real-life therapy, no washout phase preceded randomization. Eligible patients were assigned in a 3:1 ratio to receive nabumetone or a comparator NSAID for 12 weeks. Thus a total of 4,411 eligible patients were randomized to receive nabumetone (N = 3,315) or one of the comparator NSAIDs (N = 1,096). Initial daily doses were: nabumetone, 1,000 mg; diclofenac, 100 mg; naproxen, 500 mg; ibuprofen, 1,200 mg; piroxicam, 10 mg. Dosage increases were permitted after a 2-week trial period. All patients were evaluated at baseline, and at 4 and 12 weeks. Of all patients randomized, approximately 46% had RA and approximately 54% had OA. Demographic characteristics were similar for the nabumetone and comparator NSAID treatment groups. In OA, nabumetone was as effective as the comparator NSAIDs in the physician and patient global assessments of disease activity, in improving the Activities and Lifestyle Index, and in decreasing the degree of pain. There was no significant difference in the percentage of patients withdrawn for lack of efficacy when treated with nabumetone or one of the comparator NSAIDs. In contrast, nabumetone was significantly (p < or = 0.02) more effective than the comparator NSAIDs in RA patients for the global assessments of disease activity, pain relief, and improving the Activities and Lifestyle Index, primarily due to the poor response in the ibuprofen and piroxicam treatment groups. Furthermore, fewer nabumetone-treated RA patients (8.8%) withdrew for lack of efficacy than those treated with diclofenac (10.3%), naproxen (11%), piroxicam (13.5%), or ibuprofen (13.2%). In conclusion, in a large, randomized, open-label trial that mimicked real-life therapy, nabumetone was as effective as diclofenac, naproxen, piroxicam, and ibuprofen for the treatment of patients with OA. However, in RA, nabumetone was significantly more effective than the comparator NSAIDs, and fewer patients were withdrawn because of lack of efficacy.

Safety experience with nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis.

The comparative safety of nabumetone (1,000-2,000 mg/day) versus diclofenac (100-200 mg/day), naproxen (500-1,500 mg/day), piroxicam (10-20 mg/day), and ibuprofen (1,200-3,200 mg/day) was evaluated in a 12-week, randomized, open-label, multicenter study. Patients with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in a 3:1 ratio (nabumetone:one of the four comparator NSAIDs). The incidence of > or = 1 adverse event considered by the investigator to be related or probably related to therapy was similar in all groups. However, significantly (p < 0.02) more diclofenac-treated patients experienced abdominal pain and/or gastritis than nabumetone-treated patients. Naproxen-treated patients experienced significantly (p < 0.002) more dyspepsia as compared with patients treated with nabumetone or ibuprofen and significantly (p < or = 0.001) more nabumetone-treated patients experienced diarrhea than patients treated with naproxen, ibuprofen, or piroxicam. Ulcers occurred in one (0.03%) nabumetone-treated patient versus six (0.5%) patients treated with one of the comparator NSAIDs (p = 0.001). A decrease in hemoglobin > or = 1.5 g/dL occurred in fewer nabumetone-treated patients than in patients treated with diclofenac (p < 0.04), ibuprofen (p < or = 0.04), or piroxicam (p = 0.055). Finally, a similar percentage of patients in all treatment groups withdrew from the study because of adverse events related or probably related to treatment. More (p < 0.001) diclofenac-treated patients withdrew because of elevated hepatic transaminases than patients treated with the other agents. Withdrawal because of gastritis was also noted for more diclofenac-treated patients than nabumetone-treated patients (p < 0.04). In conclusion, nabumetone was demonstrated to be at least as safe as diclofenac, piroxicam, ibuprofen, and naproxen as related to subjective complaints, such as dyspepsia or gastritis. However, more serious events, such as ulcers or meaningful decreases in hemoglobin, seem to occur less often with nabumetone.

Monotherapy with labetalol in the treatment of mild hypertension: a double-blind study.

The antihypertensive effects of oral labetalol compared with placebo were evaluated in 74 mildly hypertensive patients (standing diastolic blood pressure 95 to 110 mm Hg) in a bicentric double-blind parallel group study. Following a four-week placebo phase, 36 patients were randomly assigned to receive labetalol and 38 to receive placebo. A five-week titration phase followed during which the dose of labetalol was increased weekly from 100 mg twice a day to 600 mg twice a day to achieve a standing diastolic blood pressure of less than 90 mm Hg and decreased 10 mm Hg or more from baseline. A matching number of placebo capsules for each dose of labetalol was dispensed for blinding purposes. Patients then entered a two-month maintenance phase. A thiazide diuretic could be added when the standing diastolic blood pressure was 100 mm Hg or greater at the highest dose of the study drug. At the end of this phase, the administration of labetalol (or placebo) was abruptly discontinued and patients were given the same number of placebo capsules twice a day taken during maintenance. Blood pressure and heart rate in the supine and standing position were measured eight to 10 hours after a dose at each visit. This study demonstrated that labetalol (median daily doses of 600 mg) was significantly more effective than placebo (p less than 0.05) in lowering the supine and standing blood pressures. Significantly more (p less than 0.001) placebo-treated patients than labetalol-treated patients (six versus 20) required the addition of a thiazide diuretic. Control of hypertension (that is, standing diastolic blood pressure less than 90 mm Hg) was achieved in significantly (p less than 0.001) more labetalol-treated patients than placebo-treated patients at the monotherapy endpoint (26 of 36; 72 percent versus six of 38; 16 percent). Blood pressure overshoot did not occur when labetalol was abruptly discontinued. Not one labetalol-treated patient discontinued the study because of adverse experiences. Labetalol is a safe and effective treatment for patients with mild hypertension.

Multiclinic comparison of labetalol to metoprolol in treatment of mild to moderate systemic hypertension.

The antihypertensive effects of oral labetalol, a new alpha- and beta-adrenergic blocking agent, and metoprolol, a relatively beta1 selective adrenergic blocker, were evaluated in 91 patients with mild to moderate hypertension (standing diastolic blood pressure of 90 to 115 mm Hg) in a double-blind parallel group multicenter clinical trial. The effects of the two drugs on plasma lipids and lipoprotein fractions were also assessed. Following a four-week placebo phase, 44 patients were randomized to receive labetalol and 47 metoprolol. During a four-week titration phase, the labetalol dose was increased from 100 mg twice daily to a maximum of 600 mg twice daily to achieve a standing diastolic blood pressure of 90 mm Hg that was decreased by 10 mm Hg or more. Metoprolol was titrated from 50 mg to 200 mg twice daily. An eight-week maintenance period followed during which hydrochlorothiazide could be added. At the end of the maintenance phase, the doses of labetalol and metoprolol were tapered over a two to four day period after which patients received a placebo for one week. Blood pressure in the supine and standing position was measured at each visit. Labetalol and metoprolol both significantly (p less than 0.01) lowered the supine and standing blood pressure from baseline with no significant difference found between the two treatment groups. Both drugs lowered the heart rate; however, the rate-lowering effect was significantly greater with metoprolol (p less than 0.01). There were no significant effects of either drug on plasma lipids or lipoprotein fractions. Fatigue was the most frequently reported complaint with both drugs. Dizziness, dyspepsia, and nausea were more common with labetalol; bradycardia was more common with metoprolol. There was no blood pressure "overshoot" after withdrawing drug treatment; however, a heart rate "overshoot" was seen after metoprolol was tapered off and stopped. Labetalol is as safe and effective as metoprolol in the treatment of patients with mild to moderate hypertension.

Step II treatment with labetalol for essential hypertension.

Labetalol, a new alpha- and beta-adrenergic blocking agent, was administered to 57 patients with essential hypertension whose standing diastolic blood pressure was 105 to 120 mm Hg after three and four weeks of placebo therapy and greater than 90 mm Hg after three to four weeks of therapy with hydrochlorothiazide, 25 mg twice a day. Patients were then randomly assigned on a double-blind basis to receive either labetalol, 100 mg twice a day, or placebo combined with hydrochlorothiazide. Thereafter, the dose of labetalol was titrated weekly in both groups to a maximum of 400 mg twice a day to achieve a standing diastolic blood pressure of less than 90 mm Hg that was also decreased from the hydrochlorothiazide baseline by 10 mm Hg or more (therapeutic goal). Labetalol was abruptly discontinued after four weeks of treatment and patients were given hydrochlorothiazide alone for two additional weeks. After one week of labetalol therapy, 100 mg twice a day (added to hydrochlorothiazide), there was a significantly greater reduction in supine systolic/diastolic blood pressure (6/5 mm Hg, p less than 0.04/less than 0.03) and standing blood pressure (9/7 mm Hg, p less than 0.01/less than 0.01) than with placebo therapy (3/0.5 and 3/1 mm Hg, respectively). The blood pressure reduction in the labetalol-treated group was associated with a 4 and 5 beats per minute reduction in the supine and standing heart rates, respectively. The median labetalol dose required to achieve the standing diastolic blood pressure goal was 400 mg twice a day. After four weeks of labetalol treatment, the mean reduction in blood pressure from the hydrochlorothiazide baseline was 12/13 mm Hg (p less than 0.01/0.01) in the standing position and 8/8 mm Hg (p less than 0.01/0.01) in the supine position. These blood pressure reductions were accompanied by a mean reduction in heart rate of 7 beats per minute. The most frequently reported complaints other than thiazide-induced nocturia included dizziness, fatigue, nausea, rash, and/or pruritus. Most of these complaints were reported at a similar incidence while patients were receiving placebo or hydrochlorothiazide alone as when receiving labetalol with hydrochlorothiazide. After abrupt withdrawal of labetalol, no evidence of rebound hypertension was observed. Labetalol is a safe and effective step II drug when added to hydrochlorothiazide for the treatment of patients with moderate to moderately severe hypertension.

Treatment of severe hypertension with labetalol compared with methyldopa and furosemide. Results of a long-term, double-blind, multicenter trial.

Eighty-one severely hypertensive patients were enrolled in a multicenter, double-blind, parallel group study evaluating the efficacy and safety of labetalol alone or in combination with furosemide versus methyldopa in combination with furosemide. A one day to four week placebo lead-in phase was followed by a one- to six-week titration period and a one-year maintenance period. Treatment with labetalol alone or in combination with furosemide, as well as methyldopa plus furosemide, was associated with significant reductions in supine and standing blood pressure levels. Moreover, after six months and one year of treatment, respectively, labetalol caused a significantly (p less than 0.05) greater reduction in the systolic blood pressure than the methyldopa regimen. The antihypertensive effect of labetalol was associated with small, yet significant reductions in heart rate; in contrast, resting tachycardia was observed in methyldopa-treated patients. Side effect profiles of the two treatments were different, with nausea being the most commonly reported side effect during labetalol therapy, and asthenia, somnolence, and dry mouth during methyldopa therapy. Overall, 33 of 65 (53 percent) labetalol-treated and 28 of 60 (47 percent) methyldopa-treated patients had at least a good response (that is, standing diastolic blood pressure 90 to 94 mm Hg) to therapy, including 26 (40 percent) and 22 (37 percent) patients, respectively, who had standing diastolic blood pressure levels of less than 90 mm Hg. Thus, labetalol is a potentially safe and effective agent in the long-term management of the patient with severe hypertension.

Intravenous labetalol in the treatment of severe hypertension and hypertensive emergencies.

The antihypertensive effects of intravenous labetalol were evaluated in 59 patients with hypertensive crises or severe hypertension in need of rapid lowering of blood pressure in a multicenter study. Patients appearing with a supine diastolic blood pressure 125 mm Hg or greater, or a supine systolic blood pressure of more than 200 mm Hg received an initial mini-bolus injection (20 mg) of labetalol. This was followed by repeated incremental doses of 20 to 80 mg given at 10 minute intervals to achieve a supine diastolic blood pressure of less than 95 mm Hg or decrease 30 mm Hg or greater, or a satisfactory decrease in systolic blood pressure. Patients were stratified into those who had taken antihypertensive medication within 24 hours and those who had not. The initial mini-bolus injection caused rapid but not abrupt reduction in blood pressure; the baseline mean blood pressure decreased 23/14 mm Hg. Further injections were needed in the majority of patients (mean: 197 mg). The blood pressure reduction after the last dose of labetalol was 55/33 mm Hg. In pretreated patients and in those who had no medication for 24 hours prior to the intravenous labetalol, the response was similar. Heart rate decreased 10 beats per minute in the total population. In patients pretreated with beta-adrenergic blockers, blood pressure response was similar to that in the total group (59/35 versus 55/33 mm Hg), but heart rate remained essentially unchanged. The dose required to achieve the therapeutic effect was less in pretreated patients than in untreated patients, but the duration of action was shorter. No serious adverse effects were encountered even in patients with concomitant diagnoses of acute left ventricular failure, myocardial infarction, stable congestive heart failure, atrial fibrillation, angina pectoris, acute stroke, transient ischemic attack or encephalopathy. Labetalol is a safe and effective treatment for a rapid blood pressure reduction in hypertensive emergencies.

Effects of dilevalol, metoprolol and atenolol on left ventricular mass and function in nonelderly and elderly hypertensive patients.

Using serial M-mode echocardiographic determinations of left ventricular (LV) mass and function, the effects of dilevalol, a selective beta 2 agonist with nonselective beta-antagonist properties, were compared with those of metoprolol in 2 centers in double-blind, randomized clinical trials using similar protocols in nonelderly hypertensive patients (aged less than 65 years) (study 1). In a separate bicenter study with a similar design, dilevalol was compared with atenolol in elderly hypertensive patients (aged greater than or equal to 65 years) (study 2). Patients in both studies received placebo for 2 to 4 weeks, and were then randomized to receive increasing doses of dilevalol (200, 400, 800, 1,600 mg) or metoprolol (100, 200, 300, 400 mg) in study 1, and dilevalol (100, 200, 400, 800 mg) or atenolol (50, 100 mg) in study 2, to achieve a supine diastolic blood pressure (BP) of less than 90 mm Hg. In both studies, LV function and mass (Penn convention) were determined by echocardiographic examinations performed before randomization and at the end of the active treatment phase. Dilevalol, metoprolol and atenolol significantly reduced BP compared with placebo. In the nonelderly patients, a modest reduction in LV mass was observed with dilevalol (p less than 0.03) but not with metoprolol. Indexes of LV function--as assessed by end-diastolic and end-systolic dimensions, LV ejection time and ejection fraction--were better preserved by dilevalol than by metoprolol. In the elderly, neither dilevalol nor atenolol affected LV mass; however, indexes of LV function were better preserved with dilevalol than with atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Dilevalol compared with propranolol and placebo for systemic hypertension.

Dilevalol is a new antihypertensive agent that is both a vasodilator, through its beta 2-agonist action, and a nonselective beta antagonist. Two multicenter, double-blind studies were performed: study 1 compared dilevalol administered once-daily with either dilevalol or propranolol every 12 hours; study 2 compared dilevalol administered once daily with placebo. Both studies had a placebo run-in period to establish that the baseline supine diastolic blood pressures were consistent in the mild to moderate severity range (95 to 115 mm Hg) at 2 consecutive visits for study 1 and in the mild severity range (95 to 105 mm Hg) in study 2. Patients then were randomized to the double-blind titration phase, during which doses were titrated over a 9-week period to achieve a supine diastolic blood pressure of less than 90 mm Hg and a decrease from baseline of greater than or equal to 10 mm Hg. Patients were then maintained on a fixed dose for 2 months (study 1) or for 1 month (study 2). Dilevalol given once daily was as effective in reducing supine diastolic blood pressure as dilevalol every 12 hours and propranolol every 12 hours (study 1) and was superior to placebo (p less than 0.001) (study 2). In both studies, dilevalol given once daily was effective and well tolerated. The side-effect profile of dilevalol was similar to that of placebo and different from that of propranolol. Treatment with dilevalol resulted in significantly less fatigue (p less than 0.05), bradycardia (less than 50 beats/minute) and mental depression than with propranolol, but significantly (p less than 0.05) more diarrhea/loose stools.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of antihypertensive action of dilevalol compared with that of "cardioselective" beta-blocking agents.

The hemodynamic effects of dilevalol, a nonselective beta-adrenergic blocking agent with vasodilating properties, were evaluated in 34 hypertensive patients and compared with those of the "cardioselective" beta blockers atenolol and metoprolol in 21 patients. Hemodynamic measurements were obtained at baseline, after acute treatment (first dose) with dilevalol (400 mg) and atenolol (50 mg) or metoprolol (100 mg), and again after subchronic treatment with these agents. After both acute and subchronic treatment (mean daily dose 1,042 mg), dilevalol significantly reduced mean arterial pressure (MAP, p less than 0.0001), by significantly reducing systemic vascular resistance index (SVRI, p less than 0.001), and by not significantly altering cardiac index (CI). In contrast, atenolol and metoprolol significantly reduced MAP (p less than 0.002) by significantly reducing CI (p less than 0.0001), with a concomitant increase in SVRI (p less than 0.007). Heart rate (HR) was reduced significantly less (p less than 0.006) with dilevalol than with the cardioselective agents. Correlation of the decrease in MAP with other hemodynamic parameters revealed that the effects on MAP of acute treatment with the cardioselective drugs are related to a decrease in HR (r = 0.63, p = 0.002), whereas those of subchronic treatment are correlated to a decrease in CI (r = 0.59, p = 0.01). The decrease in MAP after acute and subchronic dilevalol treatment is correlated primarily with SVRI (r = 0.46 to 0.49, p less than 0.01) and only secondarily with HR (r = 0.34, p less than 0.05). Therefore, the main mechanism of antihypertensive action for dilevalol is vasodilation, in contrast to the cardioselective agents, which is beta blockade.

Randomized comparison of the efficacy and safety of cerivastatin and pravastatin in 1,030 hypercholesterolemic patients. The Cerivastatin Study Group.

OBJECTIVE: To determine the relative efficacy and safety of cerivastatin and pravastatin in patients with type II hypercholesterolemia. PATIENTS AND METHODS: In this prospective, double-blind, parallel-group study, hypercholesterolemic patients were randomized to treatment with cerivastatin, 0.3 mg (n=250) or 0.4 mg (n=258), or pravastatin, 20 mg (n=266) or 40 mg (n=256), for 8 weeks. RESULTS: Cerivastatin, 0.3 mg, was significantly more effective than pravastatin, 20 mg, in reducing low-density lipoprotein (LDL) cholesterol from baseline (-29.6% vs -26.8%; P=.008). Cerivastatin, 0.4 mg, was significantly more effective than pravastatin, 40 mg, in reducing LDL cholesterol (-34.2% vs -30.3%; P<.001). A larger proportion of cerivastatin-treated patients had greater than 40% reductions in LDL cholesterol than those receiving pravastatin (11.1% vs 6.0%). The percentage of patients who achieved the National Cholesterol Education Program (NCEP) target was 71.3% with cerivastatin, 0.3 mg, compared with 67.5% with pravastatin, 20 mg, and 74.0% with cerivastatin, 0.4 mg, compared with 71.1% with pravastatin, 40 mg (no significant difference). Cerivastatin, 0.3 mg, reduced total cholesterol to a greater extent than did pravastatin, 20 mg (P<.03). Both agents reduced triglycerides and increased high-density lipoprotein cholesterol to a similar degree (no significant differences). Cerivastatin and pravastatin were well tolerated. CONCLUSIONS: Cerivastatin, 0.3 mg and 0.4 mg, showed greater efficacy than pravastatin, 20 mg and 40 mg, respectively, in lowering LDL cholesterol. Cerivastatin is safe and effective for patients with hypercholesterolemia who require aggressive LDL cholesterol lowering to achieve NCEP-recommended targets.