Effect of the H2-antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H1-antagonists hydroxyzine and cetirizine in patients with chronic urticaria

BACKGROUND: Concomitant administration of an H1-receptor antagonist with an H2-receptor antagonist may enhance the wheal and flare suppression produced by the H1-antagonist. This synergism may be due, at least in part, to a pharmacokinetic effect. METHODS: In a randomized, double-blind, parallel-group study in 16 patients with chronic urticaria, we investigated the pharmacokinetics and suppressive effect on the histamine-induced wheal and flare of a single dose of hydroxyzine 25 mg or cetirizine 10 mg, given before and after treatment with cimetidine 600 mg every 12 hours for 10 days. RESULTS: When hydroxyzine was administered with cimetidine, the partial hydroxyzine area under the curve increased significantly (p < 0.05) to 303 +/- 92 ng/ml/hr from 227 +/- 77 ng/ml/hr after administration of hydroxyzine alone, and the concentration of cetirizine arising from hydroxyzine was lower. When hydroxyzine was given with cimetidine, wheal and flare suppression increased compared with when hydrozyzine was given alone, but the differences were not statistically significant (p > 0.05). When cetirizine was administered with cimetidine, the pharmacokinetics of cetirizine did not change significantly, and no enhancement of wheal and flare suppression was observed. CONCLUSIONS: In this study co-administration of hydroxyzine with cimetidine resulted in significantly increased serum hydroxyzine concentrations and increased wheal and flare suppression, thus confirming the rationale for a trial of concomitant administration of these medications in some patients with chronic urticaria unresponsive to treatment with an H1-antagonist alone. We found no therapeutic rationale for co-administration of cetirizine with cimetidine in urticaria treatment. These medications may be co-administered safely without fear of medication interaction.     

Large colon resection

Early motor manifestations are the main components of focal seizures involving the frontal lobe. We examined the relationship between the initial ictal motor manifestations and interictal abnormalities of cerebral glucose consumption (rCMRGlc) as assessed by PET in 48 consecutive patients with focal seizures of neocortical origin. Group data analysis revealed that patients with predominantly unilateral clonic seizures had a significant contralateral perirolandic hypometabolism and to a lesser degree a contralateral frontomesial hypometabolism. Patients with predominantly focal tonic manifestations showed a hypometabolism within the frontomesial and perirolandic regions that was unilateral in all patients with lateralized tonic seizures. Patients with versive seizures had mainly contralateral metabolic depressions without a consistent regional pattern. Patients with hypermotor seizures had metabolic depressions involving frontomesial, anterior cingulate, perirolandic, and anterior insular/frontal operculum areas. In all patient groups, bilateral and symmetric hypometabolism of the thalamus and cerebellum was observed. We propose that this pattern of distinctly abnormal metabolic brain regions demonstrates not only possible epileptogenic zones but also symptomatogenic brain regions as shown by the associations between clinical manifestations and sets of abnormal brain regions, particularly if epileptogenic zones are in a clinically silent neocortical brain region. The detection and possible differentiation of symptomatogenic and epileptogenic zones might improve the effectiveness of presurgical noninvasive studies.     

Naloxone in the parturient and her infant

Eighteen women in labor received analgesia with moderately large total doses of meperidien. Various doses of naloxone (8, 12, 18, 27, 40, or 60mug/kg of body weight) were given intravenously to the mothers before delivery in an attempt to find the dose that would prevent neonatal narcotic depression. Maternal and neonatal blood gas values, Apgar scores, and postnatal neurobehavioral examinations were used to assess the effects. Infants born of mothers who had received neither meperidine, promethazine, nor naloxone served as controls. After the naloxone injection, the mothers showed an improvement in consciousness and blood gas values. When the study infants, as a group, were compared with control infants, there was very little difference in blood gas values or neurobehavioral examination. Infants in the groups receiving naloxone in doses of 18, 27, and 40mug/kg compared most favorably with the control infants, indicating that naloxone may be effective in preventing neonatal narcotic depression.     

Complete primary structure of the major component myoglobin of California gray whale (Eschrichtius gibbosus)

The complete primary structure of the major component myoglobin from the California gray whale, Eschrichtius gibbosus, was determined by specific cleavage of the protein to obtain large peptides for degradation by the automatic sequenator. Cleavage at the two methionine residues of the apomyoglobin with cyanogen bromide and at the three arginine residues of the methyl acetimidated protein with trypsin resulted in three and four easily separable peptides, respectively, which when sequenced accounted for 85% of the primary structure. The remainder of the covalent structure was obtained by further digestion of the central cyanogen bromide peptide with trypsin and S. aureus strain V8 protease. This protein differs from that of the sperm whale, Physeter catodon, at 12 positions, from that of the common porpoise, Phocoena phocoena, and the Black Sea dolphin, Delphinus delphis, at 14 positions, and from that of the Amazon River dolphin, Inia geoffrensis, at 7 positions. All substitutions observed in this sequence fit easily into the tertiary structure of sperm whale myoglobin.     

The fall in household size and the rise of the primary individual in the United States

The long-term fall in household size in the United States is discussed within the framework of the aging of the population, continuing as the effects of fertility and mortality decline accumulate. Using distributions of households by size from U.S. census data 1790-1970 and a components of change analysis on primary individuals for 1950-1974, household changes are related to demographic change for the periods 1790-1900, 1900-1950, and 1950-1974. Fertility and mortality declines have unambiguous impact on household size until the increases in primary individuals begin. But these, too, have a theoretically interesting, if indirect relationship to population structure.     

Androgen receptor dependent and independent activities of testosterone on hepatic microsomal drug metabolism

Administration of testosterone for 6 days to intact female and castrate male BALB/cJ mice stimulated hepatic microsomal ethylmorphine N-demethylase activity and cytochrome P-450 content by 50-75%. Testosterone also stimulated hepatic microsomal NADPH-oxidase activity, but to a lesser degree. To probe the mechanism of this effect of androgens, two antiandrogens (cyproterone acetate and flutamide) were employed. Since cyproterone acetate was a potent stimulator of hepatic microsomal ethylmorphine N-demethylase activity and cytochrome P-450 content, no antiandrogenic activity of this steroid could be detected. By contrast, flutamide alone had little effect on either ethylmorphine N-demethylase activity or cytochrome P-450 content. However, this drug effectively blocked the stimulatory effects of testosterone on ethylmorphine N-demethylase activity and cytochrome P-450 content but not on NADPH-oxidase activity. This effect was not species specific, since flutamide also prevented androgen stimulation of ethylmorphine metabolism in adult castrate and prepubertal male Fisher rats. The testosterone-induced increase of hepatic weight and microsomal protein content was not affected by the administration of flutamide. The observations are consistent with the hypothesis that androgens have two distinct effects on the liver. First, testosterone may act as a general, nonspecific stimulant of liver weight and microsomal protein content which is independent of the androgen receptor. Secondly, testosterone action in the liver may be expressed via an androgen-specific or androgen receptor-dependent mechanism which controls, in part, the cytochrome P-450-dependent demethylase system.     

Midtrimester amniocentesis and culture of aminiotic fluid cells

On the basis of the large, well-controlled, prospective study from the NICHD, it can be stated that midtrimester ammniocentesis is safe if properly performed. The details of performance, with emphasis on possible pitfalls, are presented in an effort to encourage more practicing obstetricians to begin performing the procedure in cooperation with their area genetics laboratories (11). Emphasis is also placed on performing this procedure in a manner most likely to produce success. This success is measured not only in obtaining the fluid, but more importantly in gaining useful information from the analysis of the fluid. Although the aspects of diagnosing and preventing genetic disease have been emphasized, perhaps the greatest value of midtrimester amniocentesis is the reassurance afforded the more than 95% of couples when the fluid analysis is normal (19). The consumer demand for amniocentesis is rapidly increasing. Although the medicolegal implications of the techniques are not fully understood at present, it is clear that failure on the part of a clinician to offer indicated diagnostic amniocentesis may make the clinician vulnerable to litigation if the pregnancy outcome is abnormal. The demand for amniocentesis and laboratory analysis of the fluid will soon overtax existing facilities. Until such time as new and expanded facilities are available, discretion must be used in offering the procedures. Governmental action may soon be forthcoming to provide facilities designed to make midtrimester diagnostic amniocentesis available to all for whom it is indicated.