Prediction of steady state bioequivalence relationships using single dose data II-nonlinear kinetics

Two nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmax and area under the plasma-concentration time curve values from 0 to infinity (AUC 0-infinity) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing. The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC 0-infinity showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmax which showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmax and AUC 0-infinity from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmax confidence intervals following single and multiple dosing was at variance with the experimental data for formulations A and B.     

Statistical analysis of clinical, radiographic, and histologic features of temporomandibular arthropathy

For a variety of reasons, the past few years have brought about a tremendous emphasis on conditions affecting the temporomandibular joint and associated structures. Although important advances are being made relative to the diagnosis and treatment of these conditions, a myriad of problems remain for the practitioner who tries to sort through the literature or who attends courses in order to determine a means for properly diagnosing and treating these patients. This article attempts to develop correlations between certain clinical and radiographic findings documented by histologic evaluation as a beginning guide to more sound diagnosis.     

Phase I study of high-dose cytosine arabinoside and etoposide in patients with advanced malignancies

Summary Cytosine arabinsodie (ara-C) and etoposide (VP-16) display synergy in the laboratory. Twenty-six patients participated in a phase I study of high-dose ara-C in combination with VP-16. The dose of VP-16 was held constant at 50 mg/m² as an intermittent infusion over 33 h; escalating doses of ara-C were given as infusions during hours 9–12 and 21–24. Myelosuppression was the dose-limiting toxicity and occurred with doses considerably less than those expected from studies of the two drugs as single agents. The suggested initial doses for phase II trials with this schedule are 750 mg/m²×2 doses of ara-C and 50 mg/m² of VP-16. Nonhematologic toxicity was minimal; therefore, further dose escalation is feasible in patients in whom myelosuppression is acceptable.Supported in part by grants from the National Cancer Institute (CA-12197 and CA-09422) and the American Cancer Society CF-85-182     

Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man

1. The evidence is accumulating to suggest that glycine, the simplest amino acid, is conditionally essential in man. Benzoic acid, by conjugation with glycine to form hippuric acid, is known to deplete the free glycine pool of the body. Glycine is one substrate for the enzyme glutathione synthase (EC 6.3.2.3) and in the inborn error of metabolism in which glutathione synthase function is defective, increased quantities of 5-oxoproline are excreted in the urine. 2. An oral dose of 4-10 g sodium benzoate was given to six normal adults to deplete the metabolic pool of glycine, and the urinary excretion of 5-oxoproline was followed for 6 h. In five of the six, a significant increase in the urinary 5-oxoproline was seen within 3 h. 3. These findings show that 5-oxoprolinuria can result from limited glycine availability, and may provide a useful test for assessing glycine sufficiency in a range of physiological and pathological states.     

Cast-brace treatment of ankle sprains

Forty-two severely sprained ankles treated by a cast-brace have been reviewed. This method was devised to avoid the disadvantages of immobilization. Diagnosis was based on the history and clinical signs. Strain films were taken in 31 patients but it is submitted that this investigation may be misleading unless general anaesthesia is used. The results of the treatment by cast-brace compare favourably with those by other methods and it is considered that patients were able to return to sport in a shorter time.     

Prediction of steady-state bioequivalence relationships using single dose data I-linear kinetics

Simulated data using a linear one- and two-compartment body model with different absorption characteristics were used to evaluate the ability of single dose bioavailability data to predict the relationships that exist at steady state. This was done by comparing the confidence intervals obtained from single and multiple dose data sets for the parameters of Tmax, Cmax, and area under the curve from time zero to infinity (AUC0-infinity). As a consequence of Tmax and Cmax decreasing and increasing from single to multiple dosing regimens, the confidence intervals for these parameters reflected these changes. The 90 per cent confidence interval expressed as a percentage of the reference mean increased or decreased for Tmax dependent upon the ratio of Ka test/Ka reference, and decreased for Cmax while the interval for AUC0-infinity exhibited no predictable pattern and appeared to be influenced by the amount of error in the data set. Alteration of either the dosing interval or the fraction absorbed did not affect the pattern of change in the confidence intervals for Tmax and Cmax, but the latter did result in a decrease in the interval for AUC0-infinity. Analysis of the confidence intervals for Tmax, Cmax and AUC0-infinity in bioequivalency studies for quinidine gluconate and procainamide hydrochloride following administration of single and multiple doses to different subjects appeared to be consistent with the patterns observed for the simulated data sets.     

Hippocampal pathology in refractory temporal lobe epilepsy: T2-weighted signal change reflects dentate gliosis.

BACKGROUND: The MR and pathologic features of hippocampal sclerosis (HS) are well described and include volume decrease and T2-weighted signal increase for MRI, and neuron cell loss and gliosis for pathology. OBJECTIVE: To confirm the established correlation between hippocampal volumes and neuron cell counts, and to study the still controversial association between signal change and gliosis. METHODS: The authors studied 44 patients (22 men and 22 women; mean age at surgery, 37 years) with refractory temporal lobe epilepsy. Quantitative assessment of hippocampal volumes and T2 relaxometry, and neuron and glial cell count in the region CA1 and molecular layer of the dentate gyrus was performed. The proportion of glial fibrillary acidic protein (GFAP)-positive glial cells (reactive astrocytes) was indicated. RESULTS: In a stepwise regression, the ipsilateral hippocampal volume was predicted best by the neuron cell count in the dentate gyrus (p = 0.005, r = 0.4). Hippocampal T2 time, however, was predicted best by the glial cell count in the dentate gyrus (p = 0.01, r = 0.4). None of the other cell counts contributed to either model. In the dentate, 31% of the glial cells were reactive astrocytes, whereas in CA1, 5% were reactive. CONCLUSION: The results confirmed the correlation between hippocampal volumes and neuron cell counts. T2-weighted signal increase in the hippocampus was mainly influenced by gliosis in the dentate gyrus, where a high proportion of glial cells show abnormal activity. This activity may reflect changes important in the development of hippocampal epileptogenicity.     

The incidence of AIDS among blacks and Hispanics

Compared with whites, the acquired immune deficiency syndrome (AIDS) has affected blacks and Hispanics disproportionately. The cumulative incidence (CI) for black men was 2.6, and for Hispanic men 2.5, times the rate for white men. Intravenous (IV) needle use alone does not account for this difference. Not counting IV needle-using cases, the CIs for black and Hispanic men were 1.7 times the CI for white men. Although there were fewer cases in women than men, the white-to-minority disparity was greater for women. The CIs for black and Hispanic women were 12.2 and 8.5 times, respectively, the CI for white women. Prevention programs are urgently needed and should focus on risky behavior (IV needle sharing and receptive anal intercourse), not just risk groups.