F. Gilbert McMahon

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.

Evaluation of Intramuscular Levonantradol and Placebo in Acute Postoperative Pain

Abstract: Double‐blind administration of a single intramuscular dose of 1.5, 2.0, 2.5, or 3.0 mg levonantradol or placebo to 56 patients with moderate to severe postoperative or trauma pain showed significant analgesic effects of each dose of levonantradol as compared to placebo (P < 0.05). However, no significant dose response was observed. Compared to 2/16 patients on placebo, 23/40 patients (57 per cent) on levonantradol reported one or more side effect. Drowsiness was most frequent. Dry mouth, dizziness, “weird dreams,” mild hallucinations, nervousness, apprehension and confusion occurred less frequently. Changes in resting heart rate and blood pressure were minor and general acceptability was good.

Comparison of Amlodipine and Benazepril Monotherapy to Amlodipine Plus Benazepril In Patients with Systemic Hypertension: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study

A single‐blind, run‐in, randomized, double‐blind, parallel‐group, placebo‐controlled comparison trial was conducted to assess the safety and efficacy of low‐dose amlodipine 2.5 mg daily, low‐dose benazepril 10 mg daily, and the combination of the two drugs at the same doses used once daily in patients (n = 401) with mild to moderate (stages I and II) systemic hypertension. Both monotherapy regimens were shown to significantly reduce both systolic and diastolic blood pressure compared with baseline placebo values, and the combination regimen was shown to be superior in lowering systolic and diastolic blood pressure when compared with either of the monotherapy regimens. The combination therapy also resulted in a greater percentage of patients having successful clinical response in mean sitting diastolic blood pressure. The amlodipine and benazepril regimen was also shown to be associated with a similar incidence of adverse experiences as the active monotherapy or placebo regimens, although the group given combination therapy appeared to have a lower incidence of edema than the group given amlodipine alone. Low‐dose amlodipine (2.5 mg) plus benazepril (10 mg) provides greater blood‐pressure‐lowering efficacy than either monotherapy, and has an excellent safety profile.

UPPER GASTROINTESTINAL LESIONS AFTER POTASSIUM CHLORIDE SUPPLEMENTS: A CONTROLLED CLINICAL TRIAL

The effects of a new microencapsulated potassium chloride formulation on upper gastrointestinal tract mucosa was compared with that of a popular wax-matrix formulation in 48 healthy volunteers. After a week of KCl, subjects were gastroscoped, the endoscopist being blind to the type of preparation taken. Wax-matrix formulations were associated with a higher incidence of upper gastrointestinal lesions. The lesions were not accompanied by epigastric symptoms. Glycopyrrolate, given to some volunteers to decrease gastric emptying, aggravated the effects of potassium chloride.

ANALGESIC EFFICACY OF LOW-DOSE IBUPROFEN IN DENTAL EXTRACTION PAIN

A single‐dose, double‐blind, randomized, parallel trial was conducted to compare the analgesic efficacy of oral ibuprofen (I) 100, 200, or 400 mg, aspirin (ASA) 650 mg, and placebo in moderate to severe pain after extraction of impacted teeth. Subjective, self‐evaluated pain intensity and pain relief reports, hourly for 6 hours, were used as indexes of analgesic response. Data on 227 evaluable patients showed significant differences among the 4 active treatments and placebo (p < 0.001) by most measurements of analgesia. Although no consistent, significant differences were observed among the active drugs, I 400 mg performed the best, followed by I 200 mg, ASA 650 mg, and I 100 mg. Remedication was required by 59% patients receiving I 400 mg, 67% taking I 200 mg, 73% taking ASA 650 mg, 74% taking I 100 mg, and 96% receiving placebo. Differences between I 400 mg and I 100 mg were significant for remedication data (p < 0.05). Side effects were minor, infrequent, and not dose related. In this study, I 100 mg was distinctly superior to placebo and probably as effective as ASA 650 mg in relieving pain. Only a shallow dose response of ibuprofen was observed.

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.

Potentiation of Hypoglycemic Effect of Sulfonylureas by Halofenate

We investigated the possibility of a drug interaction between the antilipemic agent halofenate and sulfonylureas. Twelve young, healthy men were given 1 g of tolbutamide by mouth before and after 12 days of double-blind treatment with 1 g per day of halofenate, or placebo. There was a significant increase in serum tolbutamide at eight, 10 and 12 hours (P less than 0.01) and a significant (P less than 0.01) decrease in serum glucose at one, four and six hours after halofenate treatment, but not after placebo. In a long-term, double-blind study of halofenate or clofibrate treatment of patients with Type IV hyperlipoproteinemia, diabetic patients receiving a sulfonylurea and halofenate either required a reduction in the dose of the sulfonylurea or demonstrated significantly improved control of hyperglycemia (P less than 0.05) or both. No appreciable decrease in serum glucose levels was noted in diabetic patients receiving sulfonylurea and clofibrate. This interaction between halofenate and sulfonylureas is clinically important, especially in view of the association of hyperlipemia and diabetes.

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.

Effect of potassium chloride supplements on upper gastrointestinal mucosa

Eight controlled 1‐ or 2‐wk experiments involving 225 healthy male subjects and one study of 18 patients with hypertension, nine of whom were long‐term users of a wax‐matrix potassium chloride preparation, were conducted to evaluate the upper gastrointestinal safety of oral KCl supplements. All subjects in the short‐term studies had normal upper gastrointestinal tracts. Subjects were examined again after at least 7 days of treatment with one of three commonly prescribed wax‐matrix KCl tablets, KCl liquid, microencapsulated KCl, a potassium‐sparer, or placebo. Some received an anticholinergic drug with treatment to induce delayed gastric motility. Diet and compliance to treatment regimens were controlled. Results indicate that upper mucosal injury, particularly erosions (43%) and ulcerations (11%), were more frequent after wax‐matrix tablets. These changes occurred much less frequently after liquid KCl (0%), microencapsulated KCl (10.5% erosions, 1.2% ulcers), and the potassium‐sparing drug (0%). More serious and more frequent lesions were associated with slowed motility. No occult bleeding was noted. Symptomatic complaints did not correlate with endoscopic findings. In the long‐term study, patients with hypertension were examined endoscopically after 19 to 23 mo on KCl and again after 1 wk. Six of nine of the patients with hypertension treated for nearly 2 yr with a wax‐matrix KCl supplement had significant lesions. One had developed ulceration after 7 days. The incidence of lesions was lower in a carefully matched group of controls who received only placebo (erosions in three of nine; none had or developed ulcers). Incidence of upper mucosal injury with wax‐matrix tablets is higher than with other liquid or microencapsulated forms of KCl or with a potassium‐sparing drug.