Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration.

The pharmacokinetics and tissue penetration, as judged by skin blister fluid, of cefprozil and cefaclor were examined in 12 healthy male volunteers. Doses of 250 and 500 mg of each drug were given to fasting subjects in a crossover fashion. Serially obtained plasma, skin blister fluid, and urine samples were analyzed for cefprozil or cefaclor by validated high-pressure liquid chromatographic methods. After oral administration of 250 and 500 mg of cefprozil, mean concentrations in plasma rose to peak levels (Cmax) of 6.1 and 11.2 micrograms/ml, respectively, and those of cefaclor were 10.6 and 17.3 micrograms/ml, respectively. The elimination half-life of cefprozil (1.3 h) was significantly longer than that of cefaclor (0.6 h), and as a result, the area under the curve for cefprozil was about two times greater than that for cefaclor. Both cephalosporins were primarily excreted unchanged in urine. The mean skin blister Cmax values were 3.0 and 5.8 micrograms/ml for cefprozil and 3.6 and 6.5 micrograms/ml for cefaclor after the 250- and 500-mg oral doses, respectively. The mean Cmax values in skin blister fluid for both cephalosporins were comparable and were significantly lower than the corresponding Cmax values in plasma. However, the levels of cefprozil and cefaclor in skin blister fluid declined more slowly than they did in plasma. The skin blister fluid half-life estimates for cefprozil were significantly longer than they were for cefaclor. Parallel to the observation in plasma, the mean skin blister fluid areas under the curve for cefprozil were significantly higher than they were for cefaclor. The plasma and skin blister fluid pharmacokinetic analyses suggest that the exposure of humans to cefprozil is significantly greater than that to cefaclor at the same dose.     

Lack of pharmacokinetic interaction between cefepime and amikacin in humans.

The interaction potential between cefepime and amikacin was investigated in a steady-state pharmacokinetic study in 16 healthy male subjects. Eight subjects (group A) received a first course of 2,000 mg of cefepime; this was followed by a second course of 2,000 mg of cefepime with 300 mg of amikacin and a third course of 2,000 mg of cefepime. Eight other subjects (group B) received a first course of 300 mg of amikacin, a second course of 300 mg of amikacin with 2,000 mg of cefepime, and a third course of 300 mg of amikacin. Each course consisted of four consecutive doses administered every 8 h as 30-min intravenous infusions. Serial plasma and urine samples, which were collected after administration of the fourth dose of each course, were assayed for cefepime and/or amikacin by validated high-performance liquid chromatographic assays. Trough levels of cefepime and amikacin indicated that these antibiotics attained a steady state prior to administration of the fourth dose of each course. Key pharmacokinetic parameters for each antibiotic were determined by noncompartmental methods. The peak concentrations of cefepime and amikacin in plasma when the drugs were given alone were about 160 and 27 micrograms/ml, respectively. Levels of each antibiotic in plasma declined, with an apparent half-life of approximately 2.2 h. Urinary recovery of cefepime and amikacin accounted for more than 85% of the administered dose of each antibiotic. Mean renal clearances for cefepime and amikacin ranged from 79 to 95 ml/min and suggested that glomerular filtration is the primary excretion mechanism. The results of the statistical analyses indicated that the pharmacokinetic parameters of cefepime following the concurrent administration of amikacin and following the discontinuation of the amikacin following the concurrent administration of cefepime and following the discontinuation of the cefepime therapy were not significantly altered. Cefepime and amikacin can be coadministered to patients with normal renal function by using the standard recommended dosing regimens.     

Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses.

In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min intravenous infusion) received each antibiotic, according to a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 ml/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime.     

Pharmacokinetics of the novel cephalosporin cefepime (BMY-28142) in rats and monkeys.

The disposition of the novel cephalosporin cefepime (BMY-28142) was characterized for intravenous administration of single doses to rats and cynomolgus monkeys, the species used most extensively for safety evaluation of the compound. Serial blood samples were collected from individual animals, and plasma was analyzed for intact cefepime by a high-pressure liquid chromatography-UV method. Assay results were evaluated by compartmental and noncompartmental methods to characterize pharmacokinetics for each species and dosage regimen. For intravenous (i.v.) bolus administration of 28 to 386 mg/kg (body weight) to rats, total body clearance (CL; 11.0 ml/min per kg) was essentially invariant with the dose; however, the terminal half-life (t1/2) and the steady-state distribution volume (Vss) increased with increasing dose level. After administration of 87 to 1,502 mg/kg by i.v. infusion, CL (12.5 ml/min per kg) was again similar for all dose groups. Mean t1/2 values (1.3 to 4.6 h) appeared unusually long for a cephalosporin in rats, and inordinately variable. No consistent differences among dose group mean Vss values were found. The maximal concentration of drug in plasma at the end of infusion was not a linear function of dose. For the cynomolgus monkey, kinetic parameters for 5-min i.v. infusions were linearly related to dose over the range of 10 to 600 mg/kg. Mean parameter values were t1/2 = 1.7 h, CL = 1.6 ml/min per kg, and Vss = 0.21 liters/kg. The pharmacokinetic results indicate substantive differences between the two species with respect to their response to toxicologic doses of cefepime.     

生殖腺及生殖腺外畸胎瘤的超声诊断

目的；探讨超声对各部位畸胎瘤的诊断价值。方法：对42例经手术及病理证实的畸胎瘤与超声检查结果对照，并回顾分析其声像特征。结果：畸胎瘤具有一些特征性声像图表现，其肿块检出率100％，诊断符合率89．8％，其中生殖腺畸瘤诊断符合率96．8％，生殖腺外畸胎瘤诊断符合率82．0％。结论：畸胎瘤的超声诊断符合率较高，应为目前首选检查方法。少见部位畸胎瘤因认识不足易造成误诊，良恶性的鉴别亦存在误差。     

Preclinical training in bronchoscopic diagnosis of cancer

This study evaluated educational effectiveness of preclinical training of residents in diagnostic bronchoscopic techniques which used videotaped programs. Sixty-five residents in eleven medical centers were randomized. Experimental subjects viewed five videotaped programs dealing with bronchoscopic anatomy and pathology. Following their tenth clinical experience in bronchoscopic diagnosis, performance of both experimental and control subjects was objectively evaluated using a Visual Discrimination Test (VDT) that contained six videotaped sequences in suspected cancer patients. Clinical performance was subjectively evaluated by teachers who used a list of Minimum Competency Requirements (MCRs). Experimental subjects provided a significantly greater number of correct answers in the VDT and achieved higher scores for the MCRs that were specifically related to recognition of bronchoscopic anatomy and pathology. This study demonstrated that preclinical training using videotaped programs could improve visual perception and discrimination skills of residents in their bronchoscopic examination of patients with suspected cases of cancer.     

Impaired 3,5,3'-triiodothyronine (T3) production in diabetic patients.

Serum concentrations of thyroxine (T₄), 3,5,3′-triiodothyronine (T₃), and 3,3′,5′-triiodothyronine (RT₃) were measured in 50 patients with diabetes mellitus. The mean concentrations of serum T₄, T₃, and RT₃ were 8.5 ± 3.7 (SD) μg/dl, 134 ± 41 ng/dl, and 30 ± 13 ng/dl, respectively, which were not significantly different from values of 33 normal control subjects. The serum $\text{T}{}_3\text{T}{}_4$ ratio showed a significant inverse correlation with the level of fasting blood sugar (FBS) (p < 0.01). Turnover studies were carried out in seven normal control subjects and in 5 insulin-independent diabetic patients on T₄ replacement. T₄ turnover was similar in both groups. The T₃ metabolic clearance rate of the diabetic patients was also normal (20.7 ± 4.0 liter/day/70 kg), but the T₃ disposal rate was reduced when compared to that of normal control subjects (17.0 ± 5.6 vs. 40.6 ± 4.8 μg/day). The RT₃ metabolic clearance rate (80.6 ± 20.2 vs. 105.0 ± 14.0 liter/day/70 kg) and the RT₃ disposal rate (29.4 ± 10.8 vs. 49.4 ± 11.6 μg/day) were both reduced in the diabetic patients. In five other diabetic patients on 3 wk of oral T₄ replacement, the serum $\text{T}{}_3\text{T}{}_4$ ratio was below the normal range (0.0059 ± 0.0041 vs. 0.0152 ± 0.0011) and remained unchanged during insulin infusion during 10 hr. The $\text{T}{}_3\text{T}{}_4$ ratio increased but remained below the normal range after 10 days of dietary and insulin treatment (0.0083 ± 0.0032; p < 0.05). Our results suggest that T₃ production from peripheral T₄ monodeiodination is impaired in uncontrolled diabetic patients. This impairment in T₃ production is correlated with the impairment of glucose utilization.     

Mitral and aortic valve orifice area in normal subjects and in patients with congestive cardiomyopathy: Determination by two dimensional echocardiography

Previous determinations of normal valve orifice areas have been mainly from postmortem studies. In this study mitral and aortic valve orifice area were determined from two dimensional echocardiograms in 20 normal subjects and 20 patients with congestive cardiomyopathy. Mitral valve orifice area was larger than quoted in standard textbooks. Both mitral and aortic valve orifice area were reduced in patients with cardiomyopathy. Valve opening was assessed relative to left ventricular and aortic root size. The ratio of mitral valve orifice area to left ventricular cross-sectional area was markedly reduced in patients with cardiomyopathy compared with normal subjects. The ratio of aortic valve orifice area to aortic root size also was reduced in patients with cardiomyopathy.Anterior mitral leaflet E point-septal separation was similar to that in previous reports contrasting normal subjects with patients with myopathy. Among patients with cardiomyopathy, mitral E point-septal separation was primarily a function of left ventricular size and was not significantly correlated with fractional shortening or ejection fraction within this group having uniformly poor systolic function.     

Neonatal Programming by Neuroimmune Challenge: Effects on Responses and Tolerance to Septic Doses of Lipopolysaccharide in Adult Male and Female Rats

A mild immune challenge experienced during the neonatal period leads to attenuated febrile responses to a similar challenge experienced later in life. However, the immune response to an endotoxin differs depending upon the severity of the challenge and it is not clear whether a neonatal immune challenge will also affect responses to a severe, potentially life‐threatening stimulus, such as sepsis. In the present study, we examined the effects of a neonatal immune challenge with lipopolysaccharide (LPS) on adult sickness responses, as well as the development of endotoxin tolerance, to a septic dose (1 or 3 mg/kg) of the same LPS in male and female rats. We demonstrate significant differences, particularly in males, in the fever profiles of neonatally LPS‐treated rats compared to neonatally saline‐treated controls. Specifically, male rats treated neonatally with LPS have reduced hypothermic and enhanced hyperthermic responses to both septic doses of LPS in adulthood. A somewhat different profile is seen in females, with neonatally LPS‐treated females having reduced hypothermia and enhanced hyperthermia compared to controls with 1 mg/kg but no differences with 3 mg/kg LPS. The results obtained demonstrate that alterations in innate immune responses previously reported for low doses of LPS can, for the most part, also be observed after severe immune challenge in later life.