Synthesis of 1- and 2-substituted indazoles as anthelmintic agents.

Selective synthesis of 1- and 2-acyl-, alkoxycarbonyl-, and carbamoylindazoles are described. Spectroscopic data which were the basis for structural assignments are presented. These compounds, particularly methyl 2H-indazole-2-carboxylate and N-heptyl-N-methyl-2H-indazole-2-carboxamide, lack the spectrum of anthelmintic activity of the benzimidazole and benzotriazole anthelmintics to which they are structurally related.

Clinical pharmacokinetics of theophylline and levels of alpha 1-acid glycoprotein in smokeless tobacco users.

Elimination half-life and apparent volume of distribution of theophylline were determined in ten healthy volunteers who used smokeless tobacco (snuff or chewing tobacco) regularly but did not smoke cigarettes. Serum concentrations of the acute phase reactant alpha 1-acid glycoprotein (AAG) were also measured. The elimination half-life of theophylline was 9.32 +/- 3.40 hours (mean +/- standard deviation), the apparent volume of distribution was 0.45 +/- 0.03 L/kg, and AAG concentrations were 63.8 +/- 15.76 mg/dL. All these values are comparable to values reported for nonsmokers. These results suggest that nonsmoking users of ST should be considered to be tobacco nonusers for purposes of planning theophylline dosing and monitoring strategies.

Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update.

The angiotensin converting enzyme (ACE) inhibitors are a group of effective drugs with a unique mechanism of action. These drugs have proven to be useful for hypertension and congestive heart failure. Early clinical trials of captopril used doses that are now known to be inappropriately high, and dose-related adverse effects were observed frequently. The recognition that lower doses are effective has reduced the incidence of adverse reactions and resulted in improved patient tolerance. When patients are properly selected and correctable risk factors are removed, serious side effects are uncommon. Unfortunately, the early reputation of nephrotoxicity persists, as does the belief that significant blood dyscrasias, endocrine effects and rash are serious risks for the average patient. After wide use of captopril, enalapril and lisinopril, and investigational trials of nearly a dozen newer agents, a sufficiency of clinical observation, experimental evidence and accurate postmarketing recording of events is accumulating to allow insight into the major toxicities with regard to more intelligent patient selection, more rational dosing and proper identification of risk factors. The most common adverse reactions are cough and skin rash. It appears that the agents are generally not cross-reactive with regard to skin rash, although it is not clear whether this effect is drug-specific or class-specific with regard to cough. Statistically but not clinically significant lowering of haemoglobin and hematocrit is common; these effects are inconsequential in most patients. Neutropenia, once thought to be prevalent, now appears to be so only in patients with autoimmune or collagen-vascular disease; the majority of patients outside these groups are at low risk. Hyperkalaemia is a frequent occurrence. This should not be surprising in view of the effect of the ACE inhibitors on plasma aldosterone. When dietary potassium intake is regulated and sources of altered potassium excretion are identified, hyperkalaemia is seldom a serious problem. Identification of sodium and water deficits allows correction before the drugs are started, and the frequency of hypotension and hyperkalaemia caused by the drugs is quite low if these factors are properly managed. An unexpected finding emerging in recent years is the dry cough associated with ACE inhibitor therapy. Its mechanism is not definitely known. Nonsteroidal anti-inflammatory drugs may control this symptom in some patients. The frequent observation of proteinuria in patients taking ACE inhibitors has gained notice and sometimes caused undue alarm. It is difficult to separate disease effects in diabetes and hypertension from true drug effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Lack of effect of a high-fat meal on the volume of distribution of theophylline in humans.

The pharmacokinetics of intravenously administered theophylline were studied in five healthy nonsmokers. Each subject received 5 mg/kg of theophylline as aminophylline after an overnight fast and again after a standard high-fat meal. Although there was wide between-day variation in the elimination rate constant in three of the five subjects, no statistically significant differences were observed in area under the time-versus-concentration curve, maximum serum theophylline concentration, elimination rate constant, or apparent volume of distribution between the two treatments. A statistical power analysis indicated that if differences in volume of distribution and maximum serum theophylline concentration occur in the general population, the mean differences are less less than 15% and 20%, respectively. This suggests that alterations in intravascular drug distribution resulting from eating a high-fat meal do not contribute importantly to previously reported effects of food on serum theophylline concentrations after oral dosing.

Prokinetic effects of erythromycin after antimotion sickness drugs.

Motion sickness and the antimotion sickness drugs scopolamine (SCP) and promethazine (PMZ) inhibit gastric emptying (GE). This study was conducted to determine if erythromycin would exert its well-known prokinetic effects in normal and motion-sick subjects given antimotion sickness drugs. Fifteen fasted volunteers (11 males, 4 females) participated in the study. In control tests, 8 subjects were given intramuscular (i.m.) saline (SAL, 0.5 ml), SCP (0.1 mg), or PMZ (25 mg). GE of liquid (300 ml) containing 1 mCi of Tc 99m diethylenetriaminepentaacetic acid (DTPA) was measured by sequential gastric scintigraphy 30 minutes after i.m. treatments. In other tests, GE was measured in 8 subjects after each i.m. treatment, followed 10 minutes later by 200 mg of erythromycin ethylsuccinate (ESS) suspension given orally. In a third group of tests, 7 subjects received an i.m. treatment, oral EES 10 minutes later, and were then brought to an advanced level of motion sickness short of vomiting. To induce motion sickness, blindfolded subjects made timed head movements while seated in a rotating chair. GE was measured immediately after rotation. GE half-life, rate constant, area under the curve (AUC), and lag time were calculated using conventional mathematical methods for analyzing exponential rate processes. GE parameters calculated for normal and motion-sick subjects given antimotion sickness drugs and EES were compared with those from subjects given i.m. treatments (control) only. In normal subjects, EES significantly (p < 0.05) increased the GE rate constant for all i.m. treatments and reduced the AUC for SAL, SCP, and PMZ by 49% (p < 0.05), 44% (p < 0.05), and 69% (p < 0.01), respectively. In motion-sick subjects, lag time was significantly (p < 0.05) increased, and the rate constant and AUC values were unchanged from control for all i.m. treatments. The authors conclude that oral EES reverses the gastrostatic actions of the antimotion sickness drugs but does not affect the inhibition of gastric emptying associated with motion sickness. The results suggest that motion sickness and antimotion sickness drugs reduce GE through different mechanisms.

Single-dose pharmacokinetics of bupropion in adolescents: effects of smoking status and gender.

Sustained-release (SR) bupropion (Zyban) is approved as a smoking cessation aid for adults. Since smoking often begins in adolescence, we determined the single-dose pharmacokinetics of bupropion SR in 75 adolescent subjects ranging from 13 to 18 years old. Subjects self-reported their smoking status. Urinary cotinine concentration was used to verify smoking status. Thirty-seven subjects (18 males, 19 females) were classified as cigarette smokers and 38 were nonsmokers (19 males, 19 females). Fasted subjects received one tablet (150 mg) of bupropion SR, and plasma samples were collected before (0) and 1/2, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours after dosing. Plasma samples were analyzed for bupropion and its three major metabolites (hydroxybupropion and the aminoalcohol isomers, erythrohydrobupropion plus threohydrobupropion, expressed as a composite) by solid-phase extraction, followed by LC/MS/MS. Factorial analysis of variance (ANOVA) was used to evaluate the effects of smoking and gender on pharmacokinetic parameters. Smokers and nonsmokers differed significantly (p < 0.05) in age and urinary cotinine (p < 0.01) concentration but did not differ significantly in mean weight, height, body surface area, or body mass index. The pharmacokinetic (PK) parameters for bupropion and hydroxybupropion did not differ between smokers and nonsmokers, but differences were found between male and female subjects. Mean values for area under the plasma concentration versus time curve (AUC0-->infinity), volume of distribution (Vd beta) normalized to body weight, maximum plasma concentration (Cmax), and elimination half-life (t1/2 beta) for bupropion were significantly (p < 0.05) greater in females than males, while clearance of bupropion normalized to body weight (CL/f) did not differ between males and females. Females also exhibited significantly (p < 0.05) larger values for hydroxybupropion mean AUC0-->infinity and Cmax than males. The mean ratio of hydroxybupropion to bupropion AUC for adolescents was approximately 4 to 5, which is lower than that previously reported for adults. In conclusion, smoking status does not affect the single-dose pharmacokinetics of bupropion SR in adolescents. However, females differ from males in several potentially important PK parameters for bupropion and its major metabolite, hydroxybupropion.

Effects of diaryliodonium chemicals on rumen fermentation in vitro and in vivo.

In vitro fermentation studies demonstrated that diaryliodonium chemicals were inhibitors of amino acid utilization. Only small differences were found in comparative effectiveness of different analogs and salt forms of chemicals tested. Protection against degradation and(or) uptake was greatest for valine, methionine, isoleucine, leucine and phenylalanine. Although changes were not as large, animals fed 4,4'-dimethyldiphenyliodonium chloride for 112 d had higher ruminal concentrations of amino acids and lower concentrations of ammonia. Decreased production of acetate in conjunction with increased production of propionate and butyrate resulted in improved fermentation efficiencies. Fermentative shifts in vivo were not as large as those observed in vitro and additional investigations are needed to determine whether feeding diaryliodonium chemicals increases the transfer of energy in digested carbohydrates to volatile fatty acids.

Effects of diaryliodonium chemicals on nitrogen utilization in growing steers.

Diaryliodonium chemicals increased nitrogen (N) absorption, utilization of absorbed N and N retention in growing steers. Fifty parts per million of the chemicals (diphenyliodonium chloride, diphenyliodonium bromide, 4,4'-difluorodiphenyliodonium chloride or 4,4'-dimethyldiphenyliodonium chloride) in the diet appeared sufficient to promote significant (P less than .05 or .10) improvements in N utilization. Diet digestibility was either not affected or improved slightly. We suggest that diaryliodonium chemicals improve N utilization by adjusting the ruminal degradation of dietary protein to yield more amino-N and less ammonia-N.

Effects of 4,4'-dimethyldiphenyliodonium chloride on performance of growing cattle.

Two 112-d studies were conducted to evaluate effects of the deaminase inhibitor, 4,4'-dimethyldiphenyliodonium chloride, on performance of growing cattle. With diets containing low levels of crude protein (i.e., 11%), 25 ppm of chemical in the diet increased (P less than .05) gain and improved (P less than .05) feed efficiency. Feed intake was not affected. Higher levels of chemical (50 and 100 ppm) produced equivalent responses. With a higher level of dietary crude protein (i.e., 14%) gain and feed efficiency were not improved and some decreases in feed intake were observed. Performance responses resulting from adjustments in ruminal nitrogen transactions to provide more alpha-amino-N depend upon whether the animal needs additional amino acids for maintenance and production. Our data demonstrated that the supply of amino acids can be increased either by adjustment of ruminal nitrogen transactions with a chemical agent or by increasing concentration of dietary protein.

Effect of diet particle size and feeding of H2-receptor antagonists on gastric ulcers in swine.

Four experiments were conducted to evaluate the effect of diet and the administration of H2-antagonists in feed on gastric ulcer formation and performance of growing-finishing swine. Pigs receiving a finely ground diet (less than lmm) grew faster (.73 vs .68 kg/d, P less than .01) and had better feed utilization (3.47 vs 3.76, P less than .01) than pigs receiving a cracked corn-based diet. Incidence of ulcers in the esophageal region of the stomach of pigs fed the finely ground diet was greater (P less than .01) than in pigs fed cracked corn. The average daily gain of pigs receiving the finely ground diet was inversely related to ulcer incidence (r = .403, P less than .01, df = 59). The addition of 5, 10, 20 or 100 ppm of the H2-antagonist, metiamide, or 6, 18 or 54 ppm of SK&F 93479 to the finely ground diet did not improve pig performance or affect the incidence of gastric ulceration. The addition of 2, 6 and 18 ppm of SK&F 93479 to a corn-soy diet containing 4.5% alfalfa meal caused a reduction in gastric ulceration (P less than .05) and improved feed utilization by 3.2% (P less than .05). These data suggest that finely ground diets improve the performance of growing-finishing swine, but increase the incidence of ulcers in the esophageal region of the stomach. Severe gastric ulceration adversely affects swine performance. Feeding H2-antagonists does not reduce the ulcerogenic properties of finely ground diets, suggesting factors other than gastric acid secretion are involved in ulcerogenesis. The use of H2-antagonists in corn-soy diets improves feed utilization and reduces ulceration.

Comparison of linear regression methods when both variables contain error: relation to clinical studies.

Five common linear regression methods were evaluated for their ability to determine the correct values of slope and intercept of a known function after random errors were added to x and y. The error variances were controlled to simulate research problems commonly studied by linear regression. The total error of each method was assessed by the absolute value of the bias in the estimate of slope. Whenever differences among methods were observed, the mean of the slope determined by two reciprocal techniques performed as well as or better than orthogonal regression, regression of y upon x, or x upon y. All the methods studied appeared to perform equally well when x and y errors were heteroscedastic or when the data set was small (n = 7). Regression of y upon x was equal or superior to other methods when n = 7 or n = 20 and y and x errors were homoscedastic. When the data set was large (n = 50) and the error in x greater than that in y, the standard method (regression of y upon x) was inferior to all other methods. It is suggested that linear regression by the traditional method of y upon x (a method present in many hand-held calculators) is appropriate in the majority of clinical situations, but when n is large and errors in x are much larger than those in y, orthogonal regression or the averaging method may be preferable.

Stability of phenytoin in blood collected in vacuum blood collection tubes.

The stability of phenytoin in blood collected in plain and serum separator tubes (SSTs) was investigated under simulated storage and transport conditions. The drug was generally more stable in plain collection tubes than in SSTs. No degradation occurred in plain red-top tubes or in refrigerated SSTs, but clinically significant degradation was present in SSTs stored at room temperature (25 degrees C) and at elevated temperature (32 degrees C) 24 h after collection. The mean loss was 17.9% at 25 degrees C and 25.9% at 32 degrees C. It is recommended that if blood is to be transported or stored in SSTs, the samples be refrigerated unless assay can be performed within 8 h.

Treatment of Amanita mushroom poisoning: a review.

Poisoning with mushrooms of the genus Amanita, members of which occur frequently in both North America and Europe, accounts for a significant number of deaths annually. Liver damage is the main clinical feature and death rates are variously reported to be from 11.3% to 51.3% of patients. The amount of mushroom ingested appears to be the main prognostic indicator and a fatal outcome appears inevitable if a large amount is eaten. In sublethal exposures, supportive therapy seems effective; when definitive treatment is considered, hyperbaric oxygen, penicillin and silymarin are indicated in conjunction with careful management of blood glucose concentration. Charcoal hemoperfusion, forced diuresis, hyperbaric oxygen, and thioctic acid may also be considered, although these treatment modalities are not clearly associated with increased survival.

Influence of menstrual cycle phase on serum concentrations of alpha 1-acid glycoprotein.

Serum concentrations of alpha 1-acid glycoprotein (AAG) were studied in nine healthy women at four times in their menstrual cycles. AAG concentrations were significantly higher on day 4 than on days 12, 20, and 28 (with the first day of menstrual flow considered to be day 1). The mean AAG concentration (mg dl-1) on day 4 was 78.55 +/- 5.03 (mean +/- s.e. mean), 70.19 +/- 4.80 on day 12, 70.63 +/- 6.67 on day 20, and 70.40 +/- 5.97 on day 28. Although these results should be considered preliminary because of the small sample size, we conclude that physiologic changes over the course of the menstrual cycle may affect serum AAG concentrations. Since AAG is a major binding protein for several important drugs, the potential exists for altered drug binding and drug effects, and further study of individual drugs is justified.