Lanthanum carbonate treatment, for up to 6 years, is not associated with adverse effects on the liver in patients with chronic kidney disease Stage 5 receiving hemodialysis.

AIMS: The efficacy and tolerability of the phosphate binder, lanthanum carbonate, have been evaluated in long-term comparative studies and subsequent open-label extensions. Animal studies show that lanthanum has a very low bioavailability and absorbed lanthanum is primarily excreted in bile. A specified subset of data from four Phase III clinical trials and subsequent extension studies is presented, in order to assess the effects of lanthanum carbonate on the liver. METHODS AND MATERIALS: Hepatic biochemical tests for alanine transaminase, aspartate aminotransferase, alkaline phosphatase and bilirubin were performed. Adverse events classified as "liver and biliary system events" were recorded. RESULTS: In the four initial clinical trials, lanthanum carbonate was not associated with any adverse changes in transaminases or bilirubin. The incidence and nature of adverse events associated with the liver during lanthanum carbonate treatment was similar to that in the comparator groups. For patients who enrolled into the subsequent long-term follow-up study (up to 6 years of treatment), changes in transaminases were not clinically relevant and mean values were similar to those observed in the earlier trials. Overall, there was no increase in the incidence of adverse events associated with the liver reported after up to 6 years of treatment when compared with the results of the initial studies. CONCLUSIONS: There was no evidence of adverse effects of lanthanum carbonate on the liver in patients who received treatment for up to 6 years.

Cognitive function in Stage 5 chronic kidney disease patients on hemodialysis: no adverse effects of lanthanum carbonate compared with standard phosphate-binder therapy.

Patients with Stage 5 chronic kidney disease who have hyperphosphatemia require treatment with phosphate binders to lower serum phosphorus levels. Existing binders are effective but may be associated with important safety disadvantages. Lanthanum carbonate is a phosphate binder with demonstrated efficacy, safety, and tolerability in clinical trials. Changes in cognitive function were evaluated over time using the Cognitive Drug Research computerized cognitive assessment system (Simple Reaction Time, Digit Vigilance Task, Choice Reaction Time, Numeric Working Memory, and Delayed Picture Recognition) in 360 hemodialysis patients who were enrolled in a 2-year, multicenter, comparative study of lanthanum carbonate versus standard therapy. A decline in cognitive function from baseline was observed in both groups. The deterioration in cognitive function was similar in both the lanthanum carbonate and standard therapy groups. One parameter - Numeric Working Memory - showed a statistically significant between-group difference in favor of lanthanum carbonate (P=0.02). Given the magnitude of the changes, however, and the differences that were observed at baseline between treatment groups, the clinical significance of this difference is doubtful. This study demonstrates that cognitive function deteriorates in hemodialysis patients over a 2-year time period. Use of lanthanum carbonate as a phosphate binder does not adversely affect cognitive function compared with standard therapy.

Detection of low levels of the amorphous phase in crystalline pharmaceutical materials by thermally stimulated current spectrometry.

PURPOSE: To demonstrate the applicability of thermally stimulated current (TSC) spectrometry for the detection of low levels of the amorphous phase in crystalline pharmaceutical materials. METHODS: A crystalline drug substance was melt quenched to produce an amorphous material. Blends of the crystalline and amorphous phases in different ratios (from 75:25 to 99:01) were prepared by serial dilution. TSC studies were performed by applying an electric field at a temperature above the glass transition temperature (Tg) to orient the dipoles, rapidly cooling to 0 degrees C, short circuiting for 1 min, and scanning at 7 degrees C/min to measure the depolarization current. The temperature of the peak in the spectrum corresponds to the Tg of the amorphous phase. Modulated differential scanning calorimtery (DSC) studies were performed using three different test protocols (varying linear heating rate, modulation amplitude, and time period). Powder X-ray diffraction (XRD) studies were performed using a Siemens D500 diffractometer. RESULTS: The ability to detect the amorphous phase by powder XRD is beset with problems due to indirect inference, orientation effects, and instrument-related intensity variations. Even using a consistent sampling procedure and an internal standard, the XRD could quantify the amorphous phase at a level of 5%. In the conventional or modulated DSC, the amorphous phase manifests itself as a shift in the baseline. Using modulated DSC it was possible to detect the amorphous phase at a level of 5% when tested at a heating rate of 2 degrees C/min and an amplitude of +/-1.0 degrees C with a period of 30 s. The moisture sorption method appears to have a similar detection capability. In TSC scans, the glass transition event due to molecular/segmental mobility in the amorphous phase was manifested as a peak/shoulder on the low-temperature side of the depolarization peak of the crystalline phase. The amorphous phase was unambiguously detected at 2% with a lower detection limit of approximately 1%. CONCLUSIONS: On the basis of the results of this preliminary investigation, TSC appears to be capable of detecting the amorphous phase at as low as approximately 1% in crystalline pharmaceuticals, thus offering a much needed capability in discerning factors.

Structure and activity of ClpB from Escherichia coli. Role of the amino-and -carboxyl-terminal domains.

ClpB is a member of a protein-disaggregating multi-chaperone system in Escherichia coli. The mechanism of protein-folding reactions mediated by ClpB is currently unknown, and the functional role of different sequence regions in ClpB is under discussion. We have expressed and purified the full-length ClpB and three truncated variants with the N-terminal, C-terminal, and a double N- and C-terminal deletion. We studied the protein concentration-dependent and ATP-induced oligomerization of ClpB, casein-induced activation of ClpB ATPase, and ClpB-assisted reactivation of denatured firefly luciferase. We found that both the N- and C-terminal truncation of ClpB strongly inhibited its chaperone activity. The reasons for such inhibition were different, however, for the N- and C-terminal truncation. Deletion of the C-terminal domain inhibited the self-association of ClpB, which led to decreased affinity for ATP and to decreased ATPase and chaperone activity of the C-terminally truncated variants. In contrast, deletion of the N-terminal domain did not inhibit the self-association of ClpB and its basal ATPase activity but decreased the ability of casein to activate ClpB ATPase. These results indicate that the N-terminal region of ClpB may contain a functionally significant protein-binding site, whereas the main role of the C-terminal region is to support oligomerization of ClpB.

Evolution of the medical record format during two years' use of an open-format microcomputer charting system.

In 1988, the authors implemented a microcomputer charting system (SmartChart) within a busy dialysis unit and an outpatient dialysis practice, to be used as the primary recording instrument for physicians and nurses. The program defined the organization of the medical record as three types of titles: problems, therapies, and numerics. Each title had a variety of associated data, such as comments, dosages, values and normals. Predefined care plans were created, and keyboard entry was in a completely open format. Over the next two years, the overall format of this medical record proved to be highly effective, and strict problem orientation allowed both nurses and physicians to use the same problem list. A more specific organization of the title lists in the medical record was needed, however. Separate symbols were placed in front of: problem titles related to prior therapies; problems recorded during current therapies; History and Physical (H&P) data; Plans/Orders; and inactive problems. PRN therapies, those therapies related to patient treatments, vital signs, and numeric data recorded during treatments were identified. The basic format of the medical record that evolved has proven suitable for outpatient, inpatient, and specialized treatment centers.

A sugar and electrolyte drinking solution for long-term maintenance of adrenalectomized rats.

Adrenalectomized rats maintained on a diet containing the normal concentration of electrolytes and given physiological saline to drink had low growth rates and abnormal serum electrolytes. The presence of 29 mM (10 g/liter) sucrose in the drinking solution stimulated the animals to drink. The enhanced drinking resulted in an increase in the growth rate and improved the animals electrolyte status. This treatment was used to maintain adrenalectomized rats for more than 16 weeks and adrenalectomized-diabetic rats for 8 weeks.