Ramon Vargas

Can garlic reduce levels of serum lipids? a controlled clinical study

PURPOSE To assess the effects of standardized garlic powder tablets on serum lipids and lipoproteins, glucose, and blood pressure. SUBJECTS AND METHODS Forty-two healthy adults (19 men, 23 women), mean age of 52 +/- 12 years, with a serum total cholesterol (TC) level of greater than or equal to 220 mg/dL received, in a randomized, double-blind fashion, either 300 mg three times a day of standardized garlic powder in tablet form or placebo. Diets and physical activity were unchanged. This study was conducted in an outpatient, clinical research unit. RESULTS The baseline serum TC level of 262 +/- 34 mg/dL was reduced to 247 +/- 40 mg/dL (p < 0.01) after 12 weeks of standard garlic treatment. Corresponding values for placebo were 276 +/- 34 mg/dL before and 274 +/- 29 mg/dL after placebo treatment. Low-density lipoprotein cholesterol (LDL-C) was reduced by 11% by garlic treatment and 3% by placebo (p < 0.05). There were no significant changes in high-density lipoprotein cholesterol, triglycerides, serum glucose, blood pressure, and other monitored parameters. CONCLUSIONS Treatment with standardized garlic 900 mg/d produced a significantly greater reduction in serum TC and LDL-C than placebo. The garlic formulation was well tolerated without any odor problems.

Blocking of Responses to Endotoxin by E5564 in Healthy Volunteers with Experimental Endotoxemia

E5564 is a second-generation synthetic analogue of the lipid A component of endotoxin (lipopolysaccharide [LPS]). The ability of E5564 to block the toxic activity of LPS was assessed in a double-blind, placebo-controlled study. A bolus infusion of endotoxin (4 ng/kg) was administered to healthy subjects to induce a mild transient syndrome similar to clinical sepsis. Single E5564 doses of 50-250 microg ameliorated or blocked all of the effects of LPS in a dose-dependent manner. All E5564 dose groups had statistically significant reductions in elevated temperature, heart rate, C-reactive protein levels, white blood cell count, and cytokine levels (tumor necrosis factor-alpha and interleukin-6), compared with placebo (P<.01). In doses of > or = 100 microg, E5564 acted as an LPS antagonist and completely eliminated these signs. E5564 also blocked or ameliorated LPS-induced fever, chills, headache, myalgia, and tachycardia (P<.01). These results demonstrate that E5564 blocks the effects of LPS in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.

Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers.

Celecoxib is a novel cyclooxygenase‐2‐specific inhibitor for the management of acute pain, primary dysmenorrhea, and the signs and symptoms of arthritis. This double‐blind, placebo‐controlled study in 16 healthy volunteers evaluated whether celecoxib alters the effect of concomitant aspirin on platelet function. Volunteers received celecoxib (400 mg/day) or placebo for 4 days. On day 5, they also received a single 325 mg dose of aspirin with either 200 mg celecoxib or placebo. Thromboxane and platelet aggregation response to adenosine 5′‐diphosphate (ADP), collagen, and arachidonic acid were measured before the first dose of celecoxib or placebo (baseline) and before dosing and 2 and 8 hours postdose on day 5. There was no significant difference in thromboxane inhibition between the two groups (percent inhibition: placebo 99.4%, celecoxib 99.0%; p = 0.555). There was also no significant difference in the effect of aspirin on platelet aggregation due to ADP, collagen, or arachidonic acid between the groups. Therefore, these data indicate that celecoxib does not alter the effects of aspirin on platelet function.

Pharmacokinetics and Safety of the Ketolide Telithromycin in Patients with Renal Impairment

The pharmacokinetics and safety of the ketolide telithromycin were evaluated in two separate studies after single and repeat oral dosing in patients with varying degrees of renal impairment and in subjects with normal renal function. The single‐dose study was an open‐label, nonrandomized, parallel‐group design in which all 40 patients received a single oral dose of telithromycin 800 mg. The repeat‐dose study was an open‐label study with a randomized, balanced, incomplete three‐block treatment crossover design. In this study, each of the 36 patients received two of three telithromycin regimens (400, 600, or 800 mg once daily for 5 days), with a washout period of ≥ 7 days between treatments. Telithromycin was well tolerated. Adverse events were generally mild in severity, and no serious drug‐related adverse events were reported. Plasma exposure to telithromycin (Cmax, AUC) showed a tendency to increase with increasing severity of renal impairment in both studies. In patients with severe renal impairment (CLCR < 30 mL/min) receiving telithromycin 800 mg in the repeat‐dose study, Cmax,ss and AUC(0–24 h)ss increased 1.5‐fold (p < 0.05) to 2.0‐fold (p = 0.0005), respectively, compared with healthy subjects. The percentage of dose excreted in urine and renal clearance (CLR) of telithromycin was found to decrease significantly with increasing severity of renal impairment in both studies, and CLR was found to be independent of telithromycin dose in the repeat‐dose study. In conclusion, telithromycin dosage adjustment is not necessary in patients with mild to moderate renal impairment (CLCR ≥ 30 mL/min). In patients with severe renal impairment (CLCR < 30 mL/min), dosage adjustment could be considered.

Cirrhosis Does Not Affect the Pharmacokinetics and Pharmacodynamics of Clopidogrel

Clopidogrel, a new platelet ADP receptor antagonist used for the prevention of vascular ischemic events, is converted to an active metabolite via the cytochrome P450 system. Patients with cirrhosis may not metabolize drugs normally and may, in addition, have a number of defects in the coagulationsystem. To assess the effect of cirrhosis on the pharmacokinetics and pharmacodynamics of clopidogrel, the authors performed an open‐label, parallel‐group study of 12 patients with Child‐Pugh Class A or B cirrhosis and 12 matched controls. All 24 subjects received clopidogrel 75 mg PO QD for 10 days. Pharmacokinetics of clopidogrel and the major metabolite SR 26334 were analyzed on Days 1 and 10; pharmacodynamics were assessed by the inhibition of ADP‐induced platelet aggregation and by bleeding time prolongation factor. Pharmacokinetic analysis of clopidogrel was limited due to low plasma concentrations arising from rapid hydrolysis to SR26334. The Cmax at SS for clopidogrel was higher in cirrhotics than in normals. However, exposures to the metabolite SR 26334, as measured by AUC(tau), were comparable. At Day 10, there was not a statistically significant difference in mean inhibition of platelet aggregation (49.2% ± 38.6% in cirrhotics vs. 66.7% ± 7.5% in normals) or in bleeding time prolongation factor (1.64 ± 0.49 in cirrhotics vs. 1.54 ± 0.87 in normals) between groups. No significant adverse events, including bleeding events, were reported. In conclusion, there were no significant differences in the pharmacokinetics and pharmacodynamics of clopidogrel in this group of subjects with cirrhosis and matched normals. Therefore, no dos age adjustment of clopidogrel is required in patients with Child‐Pugh Class A or B cirrhosis.

Evaluation of the Antipyretic Effect of Ketorolac, Acetaminophen, and Placebo in Endotoxin‐Induced Fever

The authors studied the antipyretic effect of three intramuscular doses of ketorolac (15, 30, and 60 mg), acetaminophen 650 mg PO, and placebo in healthy male volunteers using an endotoxin‐induced fever model. In this double‐blind, double‐dummy, parallel study, subjects were assigned randomly with equal probability to one of the above treatment groups. Thirty minutes after study medication administration, a 20 unit per kilogram dose of reference standard endotoxin (RSE) was administered intravenously, and temperature was determined every 15 minutes for an 8‐hour period. Compared with placebo, all active treatment groups demonstrated a statistically significant reduction in both adjusted area under the temperature‐by‐time curve (AAUC) and the maximum increase over baseline temperature (dTmax). Furthermore, the 30 mg intramuscular dose of ketorolac demonstrated approximately the same antipyretic activity as the 650 mg oral dose of acetaminophen, and there was a statistically significant dose response across the three ketorolac doses studied (P < .0001). The majority of side effects reported during this study were symptoms associated with fever, including chills, headache, myalgia, and dizziness, all of which are effects of RSE. The frequency of side effects tended to be less in the treatment groups with the greatest antipyretic activity.

Role of misoprostol in reducing aspirin-induced gastrointestinal blood loss in arthritic patients

Nonsteroidal anti-inflammatory drugs are used to control pain and inflammation in arthritic disorders. When used at recommended anti-inflammatory dose levels, however, they often produce injury to the gastric and duodenal mucosa and concomitant blood loss. A double-blind, parallel, placebo-controlled study was conducted to assess the effectiveness of misoprostol, a synthetic analogue of prostaglandin E1, in preventing gastrointestinal blood loss induced by acetylsalicylic acid in patients with degenerative joint disease. Forty-five arthritic patients (22 women and 23 men) were admitted to the study. All patients had received treatment with 3,900 mg of acetylsalicylic acid per day in four divided doses for at least two weeks and continued to receive that regimen for the duration of the study. Red blood cells were tagged with chromium-51, and fecal blood loss was determined from Days 4 to 7. Patients with a mean blood loss of at least 1.5 ml per day were randomly allocated to receive either placebo or 200 micrograms of misoprostol four times daily for seven days. Fecal blood loss was measured daily, and the results were compared with baseline determinations. Of 41 patients who completed the study, 19 were treated with misoprostol. Of these, 11 patients (57.9 percent) had at least a 50 percent reduction in blood loss. Of 22 patients receiving placebo, only one had a 50 percent reduction in blood loss (p = 0.003; Fishers exact test). Mean blood loss in patients using misoprostol was reduced from 3.65 +/- 2.51 to 1.57 +/- 0.86 ml per day, whereas among those taking placebo, mean blood loss did not significantly change (2.98 +/- 1.24 to 2.79 +/- 1.63 ml per day). The difference in blood loss between the misoprostol and placebo groups was significant (p = 0.0023; Wilcoxon test). In those patients who completed the study, no significant changes were detected on laboratory tests. In conclusion, misoprostol effectively reduced fecal blood loss in arthritic patients treated with acetylsalicylic acid.

Efficacy and acceptability of different dosage schedules of clonidine

In 12 hospitalized patients with hypertension, clonidine 3 times a day led to better control of blood pressure than did the same total dose administered once daily. Compared to the uniform control of blood pressure on divided dose regimen, the single daily 8 p.m. dose led to wider fluctuations and inadequate control 18 hr after dosing. However, 10 of the 12 patients preferred the single daily dose at 8:00 p.m. to the divided dose regimen because of no drowsiness during the day. In 2 patients administration of clonidine twice daily resulted in better control of blood pressure than that du ring the single or thrice‐daily dose regimens. Since there appeared to be a correlation between the dose and the duration of adequate blood pressure control, administration of clonidine twice a day with a larger dose at bedtime and a sm aller dose before noon could limit unwanted drowsiness and combine the convenience of less frequent dosing with superior blood pressure control.

Guanabenz in essential hypertension.

Fifty‐five patients with mild to moderately severe essential hypertension were treated with guanabenz (2,6‐dichlorobenzylidene aminoguanidine acetate) in doses from 4 to 16 mg twice daily in a randomized, placebo‐controlled study. The patients treated with placebo in the initial phase of the study were subsequently treated with guanabenz. The mean arterial pressure in the guanabenz group decreased from 130.6 to 107.6; that in the placebo group decreased from 129.6 to 126.6 standing and from 126.6 to 109.9 and 128.8 to 120.5, respectively, supine. The principle adverse effects included sedation, dry mouth, weakness, and tiredness. Of the guanabenz‐treated patients 84% had sustained decrease in supine diastolic blood pressure of 10 mm Hg or more, whereas in the placebo‐treated patients only 32% had such a response. There was no signijicant orthostatic hypotension. Guanabenz thus appears to be an effective antihypertensive drug in patients with mild to moderately severe hypertension.

Enteric coating of fenoprofen calcium reduces gastrointestinal microbleeding

The effects of plain and enteric‐coated fenoprofen calcium (Nalfon, Dista, Indianapolis, Ind.) on gastrointestinal microbleeding were studied in 32 normal male volunteers in a randomized, open‐label, parallel trial at two inpatient research facilities. A 1‐week placebo (baseline) period preceded 2 weeks of fenoprofen therapy (enteric coated or plain, 600 mg q.i.d.). Fecal blood loss was measured by 51Cr‐tagged erythrocyte assay and averaged over days 4 to 7 (baseline) and 11 to 14 and 18 to 21 (active therapy). At one center gastrointestinal irritation was evaluated endoscopically before and after active therapy. Endoscopy showed both formulations to cause mucosal damage not evident by subject‐reported symptoms. Four of the 16 subjects developed asymptomatic duodenal ulcers. Mean daily fecal blood loss was significantly lower (P = 0.03) with enteric‐coated (mean ± SD, 1.104 ± 0.961 ml/day) than with plain fenoprofen calcium (mean ± SD, 1.686 ± 0.858 ml/day), suggesting that tolerance of fenoprofen can be improved with administration in an enteric‐coated form.