Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial.

BACKGROUND: Periodontitis is an inflammatory condition of tooth-supporting tissues that is usually treated by mechanical removal of plaque and microorganisms that adhere to teeth. This treatment, known as scaling and root planing, is not optimally effective. Adjunctive therapy with locally delivered antimicrobials has resulted in improved clinical outcomes such as probing depth reduction. This article reports on the efficacy and safety of locally administered microencapsulated minocycline. METHODS: Seven hundred forty-eight (748) patients with moderate to advanced periodontitis were enrolled in a multi-center trial and randomized to 1 of 3 treatment arms: 1) scaling and root planing (SRP) alone; 2) SRP plus vehicle; or 3) SRP plus minocycline microspheres. The primary outcome measure was probing depth reduction at 9 months. Clinical assessments were performed at baseline and 1, 3, 6, and 9 months. RESULTS: Minocycline microspheres plus scaling and root planing provided substantially more probing depth reduction than either SRP alone or SRP plus vehicle. The difference reached statistical significance after the first month and was maintained throughout the trial. The improved outcome was observed to be independent of patients' smoking status, age, gender, or baseline disease level. There was no difference in the incidence of adverse effects among treatment groups. CONCLUSIONS: Scaling and root planing plus minocycline microspheres is more effective than scaling and root planing alone in reducing probing depths in periodontitis patients.

Survival with oral d-sotalol in patients with left ventricular dysfunction after myocardial infarction: rationale, design, and methods (the SWORD trial).

Impaired left ventricular function after acute myocardial infarction (AMI) is associated with an increased risk of death. Despite recent advances in the management of these patients, sudden death accounts for up to 50% of this mortality, and effective treatment strategies have yet to be identified. Preliminary trials with amiodarone have offered promise that drugs that prolong action potential duration by blocking the potassium channel may be useful in reducing this mortality. The Survival With Oral d-Sotalol (SWORD) trial is a multicenter, multinational study which tests the hypothesis that the class III agent d-sotalol will reduce all-cause mortality in high-risk survivors of AMI. The trial will enroll 6,400 patients with left ventricular dysfunction (ejection fraction < or = 40%) and a recent (6 to 42 days) or a remote (> 42 days) AMI with overt heart failure (New York Heart Association class II or III). In approximately 500 centers throughout the world, men and women aged > or = 18 years will be enrolled and randomized to placebo or d-sotalol (200 mg/day). The minimal follow-up will be 18 months. The trial has a 90% power to detect a 20% reduction in all-cause mortality. The rationale, design, and trial methods are described.

The Timolol Myocardial Infarction Study: an evaluation of selected variables.

The Timolol Myocardial Infarction Study was a completely randomized program of 1884 survivors of myocardial infarction comparing timolol maleate, 10 mg twice daily, with placebo for the secondary prevention of sudden death and reinfarction. In that study, timolol maleate reduced total mortality (152 placebo vs 98 timolol) and the incidence of first nonfatal reinfarctions (131 placebo vs 90 timolol). This report evaluates the effect of timolol in selected categories--age, sex, infarction site, heart size, transmural infarction, diabetes, smoking, multiple reinfarctions and pulse. These data document two important facts. First, the effects of timolol in the total sample were also seen in different subpopulations, and there were no major subgroups for which this positive effect would not be expected. Second, the consistency of the effects observed with respect to pulse, transmural infarction, age and infarct site are in contrast to some previous studies with practolol, propranolol, and alprenolol. Thus, beta blockers may not be identical with respect to reducing the mortality and morbidity associated with acute myocardial infarction.

Determining the probability of an important difference in bioavailability.

Bioavailability studies usually compare formulations of a drug under the premise of equal bioavailabilities. Analyses of such studies may be questioned when large differences exist, but are not statistically significant, or when small differences are found which do reach statistical significance. In either case, the question of clinical significance is not addressed and remains problematic regardless of the outcome. The important question is, "Given the results of the study, what is the probability that a clinically important difference exists?" To obviate dependence on statistical significance, we propose a methodology which permits computation of the probability that a clinically important difference in bioavailability exists between two products, regardless of the results of conventional tests of hypothesis. The methodology permits a strong statement which defines the likelihood of a meaningful difference, rather than the "nonstatement" of current approaches. The approach is illustrated by a study in which a 2% (nonsignificant) difference in bioavailability was observed. Using the proposed methodology the analysis concluded that the odds are about 5 to 1 against there being a 20% difference in bioavailability between the formulations.

GLC determination of acetohexamide and hydroxyhexamide in biological fluids.

A sensitive and specific GLC assay was developed for acetohexamide and hydroxyhexamide, its major metabolite, in plasma and urine. The assay uses tolbutamide as a mass internal standard. Compounds are extracted from acidified plasma or urine with toluene, converted to methylated derivatives with dimethyl sulfate, and measured by GLC using a flame-ionization detector. With GLC-mass spectrometry, the compounds measured are the N-methylsulfonamides resulting from GLC pyrolysis. Plasma and urine data are presented from a bioavailability study to demonstrate the utility of this method.

Subjective responses and excretion patterns of dextroamphetamine after the administration of therapeutic doses.

Twelve male medical and graduate students received dextroamphetamine sulfate in doses of 0, 5, 10, and 15 mg/70 kg body weight. The study was conducted in a double-blind manner, and treatments were assigned according to randomized, complete block design. The drug was given orally and subjects were instructed not to eat 3 1/2 h prior to administration. After administration, total urine output was collected for 12 h; no attempt was made to control urinary pH to more realistically approach the general clinical usage of amphetamines. The urine was pooled into two 6-h segments and analyzed for amphetamine concentration. Subjective impressions of the treatments were also evaluated by means of the Cornell Medical Index Questionnaire. Results showed that approximately 30% of the total dose was excreted unchanged within 12 h after administration. The amount excreted agreed very closely with the doses given and paralleled the scores for subjective impressions by the subjects. None of the subjects felt that their driving would be impaired for any of the doses administered. This study indicates that under ordinary conditions (in which pH is not artificially controlled), therapeutic doses of dextroamphetamine can be detected in urine for up to 12 h after oral administration.

Influence of cannabidiol on secobarbital effects and plasma kinetics.

To investigate the possible metabolic interaction between cannabidiol (CBD) and secobarbital, 6 male volunteers received 150 mg/70 kg sodium secobarbital orally immediately after smoking a marihuana cigarette prepared to deliver 0, 150, or 500 mug/kg CBD. The study was performed in a double-blind manner with each of the three treatments being assigned to every subject. Clinical effects and plasma secobarbital concentrations were recorded at periodic intervals. CBD did not alter the summary parameters which describe the secobarbital plasma concentration time curve. Secobarbital half-life, peak concentration, time of peak concentration, and area under the curve were unchanged by the coadministration of CBD. Clinical effects of secobarbital were also unaltered by CBD pretreatment. Thus at the doses administered, CBD does not appear to inhibit secobarbital metabolism in man.

Effects of marihuana-dextroamphetamine combination.

Under a double blind, randomized, complete block design, subjects were given either placebo and 10 mg/70 kg dextroamphetamine sulfate (A) orally followed 1 1/2 hr later by a marihuana cigarette (M) prepared to deliver 50 mug/kg delta-9-tetrahydrocannabinol (THC). Statistical analyses suggested that heart rate and blood pressure increased in an additive manner when both drugs were given. Electrocardiogram changes, when present, were nonspecific in character and appeared to be associated with marihuana. In a second study, psychomotor performance was evaluated by a similar design using doses of 10 mg/70 kg of A and M prepared to deliver 25 mug/kg THC. Impairment was related to smoking of M, and no difference could be distinguished between M alone and M-A combination. Subjective evaluation, as measured by the modified Cornell Medical Index (CMI) demonstrated only additive effects for the combination.

Effects of dextroamphetamine on psychomotor skills.

Twelve healthy male volunteers were given 0, 5, 10, 15 mg/70 kg dextroamphetamine orally in a randomized double-blind fashion. Blood pressure increased linearly with dose while heart rate was unchanged. Although selected individual tests of stance stability and motor function improved in a dose-related fashion, a generalized improvement in performance was not found. Delayed Auditory Feedback (DAF) failed to show improvement in mental performance after dextroamphetamine.

Analgesia, plasma levels, and dosage of propoxyphene.

It can be shown that both the mean plasma levels observed and the mean analgesic scores (effectiveness) are related to the dose of an orally effective analgesic agent, although wide individual variations exist. Based on the pharmacokinetic characteristics of propoxyphene, it can be predicted and confirmed that equilibrium (or steady state) plasma levels will be achieved after about six doses when administered on a q. 6h. schedule. Similar predictions indicate that an initial loading dose of 2 to 2 1/2 times the maintenance dose will produce more promptly plasma levels within or close to the equilibrium levels.

Influence of cannabidiol on delta-9-tetrahydrocannabinol effects.

Experiments investigating the possible interaction of tetrahydrocannabinol (THC) and cannabidiol (CBD), two major components of marihuana, were conducted under controlled laboratory conditions in a double-blind manner. In one study, 15 male volunteers were given placebo or 25 mug/kg of THC together with either placebo or 150 mug/kg of CBD by inhalation of the smoke of a single cigarette. All four treatments were assigned to each subject according to a series of Latin-square designs. CBD significantly attenuated the subjective euphoria of THC. Psychomotor impairment due to THC was not significantly altered by the simultaneous administration of CBD, but a trend indicating a decrease in THC-like effects was observed after the combination. When administered alone CBD was inactive for all the parameters measured. In a second study, 8 male subjects were given CBD (0 or 150 mug/kg) by smoke inhalation 30 min before THC (0 or 25 mug/kg) in a second cigarette. In contrast to the simultaneous administration of both drugs, CBD pretreatment did not alter the effects of THC on the parameters observed.

Optimal visualization of esophageal varices.

Twelve patients with known esophageal varices and willingness to cooperate were included in the study. Medications administered were placebo, 2 mg of glucagon, and 30 mg of propantheline bromide. All medications were given double-blind and crossover. On the basis of this study the authors believe that for optimal visualization of esophageal varices the following is the procedure of choice: (1) the patient should remain horizontal (this is best done in the left lateral position for comfort and ease of expectoration) for ten minutes after swallowing high density barium; (2) the patient should "clear his throat" frequently and expectorate all saliva (barium sticks to the pharynx and makes the patient want to swallow and "clearing his throat" by forced expiration helps the patient to expectorate this coating and prevents swallowing); (3) filming should be done in expiration in the supine (left posterior oblique to table top) position; and (4) in equivocal cases the examination can be repeated with an anticholinergic drug if the patient has no contraindications to its use. The patient should empty his bladder just before administration of the drug. The intelligent use of these factors should result in a saving of both fluoroscopic time and film, and give the radiologist a safe optimal diagnostic yield.

Effects of marihuana combined with secobarbital.

Twelve male volunteers smoked a marihuana cigarette prepared to deliver 0 or 25 mug/kg tetrahydrocannabinol (THC) 50 min after ingesting a capsule containing either placebo or 150 mg/70 kg sodium secobarbital. Drugs were administered in a double-blind manner, and all treatments were assigned to each subject in a randomized complete block design. Objective and subjective tests designed to measure mental and motor performance indicated that marihuana impaired stability, hand-eye coordination, and mental performance. Secobarbital affected motor performance, manual coordination, and mental performance. In combination, marihuana and secobarbital had an additive effect on subjective responses and impairment in certain psychomotor performance tests.

Problems and solutions to single-dose testing of analgesics: comparison of propoxyphene, codeine, and fenoprofen.

Discrepancies exist between reports arising from single-dose and multiple-dose studies intended to compare the efficacy of oral analgesics. D Differences in the pharmacokinetic characteristics of these drugs account for much of the discord. Codeine and fenoprofen rapidly achieve their ultimate plasma equilibrium levels (on a q. 6h. schedule), whereas, propoxyphene requires a longer period, doubtless due to its longer half-life and proportionately smaller maintenance dose. If the drugs are not to be compared during the steady state, then administration of appropriate loading doses permits satisfactory single dose comparisons at steady-state concentrations.