The discovery of a potent Nav1.3 inhibitor with good oral pharmacokinetics.

In this article, we describe the discovery of an aryl ether series of potent and selective Nav1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Nav channels, we propose this series binds in the same location. We describe the development of this series from a published starting point, highlighting key selectivity and potency data, and several studies designed to validate Nav1.3 as a target for pain.

Integration of titrimetric measurement, off-gas analysis and NOx- biosensors to investigate the complexity of denitrification processes.

The denitrification process, namely the reduction of nitrate (NO3-) to nitrogen gas (N2), often cannot be simply modelled as a single step process. For a more complete and comprehensive model the intermediates, particularly nitrite (NO2-) and nitrous oxide (N2O), need to be investigated. This paper demonstrates the integration of titrimetric measurements and off-gas analysis with on-line nitrite plus nitrate (NOx-) biosensors, highlighting the necessity of measuring process intermediates with high time-scale resolution to study and understand the kinetics of denitrification. Investigation of activated sludge from a full-scale treatment plant showed a significant accumulation of NO2-, which appeared to impact on the overall denitrification rate measured as NOx- reduction or N2 production. A different sludge obtained from a lab-scale bioreactor produced N2O instead of N2 as the end product of denitrification. The two examples both illustrate the complexity of denitrification and stress the need for the more versatile and detailed measurement procedures, as presented in this paper.

Managing peritoneal dialysis prescriptions.

Current literature (Blake et al., 1996) suggests prescribing peritoneal dialysis based on individual characteristics and a sound knowledge of factors known to improve clearances. According to the CANUSA study (1996), better clearances are associated with a decreased relative risk of death, a decreased relative risk of technique failure and decreased hospitalization. This article will discuss factors which will improve clinical practice by prescribing peritoneal dialysis on an individualized basis leading to optimal patient outcome.

What is the optimal frequency of cycling in automated peritoneal dialysis?

OBJECTIVE: The recent increase in the use of automated peritoneal dialysis (APD) has led to concerns about the adequacy of clearances delivered by this modality. Few clinical studies looking at the effects of varying the individual components of the APD prescription on delivered clearance have been done, and most published data are derived from computer modeling. Most controversial is the optimal frequency of exchanges per APD session. Many centers prescribe 4 to 6 cycles per night but it is unclear if this is optimal. The purpose of this study was to address at what point the beneficial effect of more frequent cycles is outweighed by the concomitant increase in the proportion of the total cycling time spent draining and filling. METHODS: A comparison was made between the urea and creatinine clearances (CCrs) achieved by 4 different APD prescriptions, used for 7 days each, in 18 patients. The prescriptions were for 9 hours each and were all based on 2-L dwell volumes, but differed in the frequency of exchanges. They were 5 x 2 L, 7 x 2 L, and 9 x 2 L, as well as a 50% tidal peritoneal dialysis (TPD) prescription using 14 L. Ultrafiltration, dwell time, glucose absorption, sodium and potassium removal, protein excretion, and relative cost were also compared. Clearances due to day dwells and residual renal function were not included in the calculation. RESULTS: Mean urea clearances were 7.5, 8.6, 9.1, and 8.3 L/night for the four prescriptions respectively. Urea clearance with 9 x 2 L was significantly greater than with the other three prescriptions (p < 0 0.05). Urea clearance with 7 x 2 L and TPD were superior to 5 x 2 L (p < 0.05). Mean CCr was 5.1, 6.1, 6.4, and 5.6 L/night, respectively. Compared to 5 x 2-L, the 7 x 2-L, 9 x 2-L, and TPD prescriptions achieved greater CCr (p < 0.05). Taking both urea and CCr into account, 9 x 2 L was the optimal prescription in 12 of the 18 patients. Ultrafiltration and sodium and potassium removals were all significantly greater with the higher frequency prescriptions. CONCLUSION: The 5 x 2-L prescription significantly underutilizes the potential of APD to deliver high clearances, and 7 x 2 L is a consistently superior prescription if 2-L dwells are being used. Although more costly, 9 x 2 L should be considered if higher clearances are required.

High creatinine excretion ratio predicts a good outcome in peritoneal dialysis patients.

The creatinine excretion (CrEx) ratio was first described as a method for detecting noncompliance in peritoneal dialysis (PD) patients. However, a high CrEx ratio is not specific for noncompliance and may also be found in compliant patients with a relatively greater lean body mass (LBM). A cohort of 44 PD patients was followed up for a mean of 13 +/- 8 months after measurement of baseline CrEx ratio to investigate whether greater values were predictive of good or poor clinical outcomes. During this follow-up, 11 patients died, 12 patients transferred to hemodialysis, 4 patients underwent transplantation, 1 patient recovered renal function, and 16 patients continued on PD. The mean CrEx ratio in all patients was 1.14 +/- 0.32. It did not differ between men and women (1.15 versus 1.13, respectively; P = 0.76) but showed a trend toward being less in patients with diabetes (1.03 versus 1.19; P = 0. 19). The mean weekly Kt/V, weekly creatinine clearance, normalized protein equivalent of nitrogen appearance, and serum albumin values were 2.18 +/- 0.57, 73.57 +/- 33.75 L/1.73 m(2), 0.80 +/- 0.22 g/kg/d, and 3.22 +/- 0.59 g/dL, respectively. Technique failure (P < 0.001) and death (P < 0.05) were significantly more common in patients with a CrEx ratio less than 1 compared with those with a CrEx ratio greater than 1. On Cox regression analysis, the CrEx ratio was the only significant predictor of technique failure and was also an independent predictor of death. High CrEx ratio is a predictor of good, rather than poor, outcome in PD patients, perhaps because it is primarily an index of nutrition. This further weakens the argument that it is a reliable or useful marker of noncompliance.

Overexpression of p53 in squamous cell carcinoma of the tongue in young patients with no known risk factors is not associated with mutations in exons 5-9.

BACKGROUND: This study investigated the status of the p53 tumor suppressor gene in patients less than 40 years of age who had squamous cell carcinoma of the tongue develop with no known risk factors. METHODS: Histologic sections from 21 patients were prepared from formalin-fixed, paraffin-embedded tissue and were processed for standard immunohistochemistry for detection of the p53 protein. In addition, tumors were evaluated by single-strand conformation polymorphism and by DNA sequencing to identify potential mutations in the conserved exons (5-9) of the p53 gene. RESULTS: Eighty-one percent (17 of 21) of the patients overexpressed p53 by immunohistochemical analysis. However, none of these patients demonstrated mutations in exons 5-9 of the gene. CONCLUSIONS: These data suggest that the molecular mechanisms by which the young individuals with no risk factors had altered p53 function in oral squamous cell carcinoma may differ from those of the more typical population of individuals who have this malignancy develop.

A multicenter study of noncompliance with continuous ambulatory peritoneal dialysis exchanges in US and Canadian patients.

Recent evidence suggested that noncompliance (NC) with continuous ambulatory peritoneal dialysis (CAPD) exchanges may be more common in US than in Canadian dialysis centers. This issue was investigated using a questionnaire-based method in 656 CAPD patients at 14 centers in the United States and Canada. NC was defined as missing more than one exchange per week or more than two exchanges per month. Patients were ensured of the confidentiality of their individual results. Mean patient age was 56 +/- 16 years, 52% were women, and 39% had diabetes. The overall admitted rate of NC was 13%, with a rate of 18% in the United States and 7% in Canada (P < 0.001). NC was more common in younger patients (P < 0.0001), those without diabetes (P < 0.001), and employed patients (P < 0.05). It was also more common in black and Hispanic than in Asian and white patients (P < 0.001). NC was more common in patients prescribed more than four exchanges daily (P < 0.0001) but was not affected by dwell volume. On multiple regression analysis, the independent predictors of NC, in order of importance, were being prescribed more than four exchanges per day, black race, being employed, younger age, and not having diabetes. Being treated in a US unit did not quite achieve significance as a multivariate independent predictor. These findings suggest that NC is not uncommon in CAPD patients and is more frequent in US than in Canadian patients. However, country of residence is less powerful as a predictor of NC than a variety of other demographic and prescription factors.

Impact of capitation on free-standing dialysis facilities: can you survive?

Proposed changes in the Medicare reimbursement method for end-stage renal disease (ESRD) patients prompted us to study the total cost of caring for the ESRD patients in northeast Indiana over a 1-year period. We hoped to ascertain the actual cost of caring for patients treated with different modalities, determine if we could compete in a capitated environment, and identify areas in which we might reduce these expenses. Six patients new to dialysis and 29 patients already receiving treatment underwent follow-up evaluation for 1 year. We tracked their cost of care for 1 year in the outpatient setting as well as in the hospital. We found the cost of caring for all patients was $43,044 per year. Patients new to dialysis cost $3,164 more to care for than patients already receiving dialysis treatment. Hospitalization expense was the primary component of that difference. Continuous ambulatory peritoneal dialysis (CAPD) patients were $14,570 less costly per year to care for than hemodialysis patients. This differential primarily related to decreased hospitalization. Vascular access expenses were a major component of both the outpatient and inpatient cost for hemodialysis patients. Our yearly expenditures for all patients compared with suggested capitated Medicare reimbursement rates suggested that our program could be successful in a new reimbursement model. Several areas of possible cost reduction were identified.

Peritoneal dialysis kinetic modeling: validation in a multicenter clinical study.

OBJECTIVE: To clinically validate the use of a computer-based kinetic model for peritoneal dialysis (PD) by assessing the level of agreement between measured and modeled values of urea and creatinine clearances and ultrafiltration (UF). DESIGN: An open multicenter observational study. PATIENTS: There were 111 adult continuous ambulatory peritoneal dialysis (CAPD) patients (47 female, 64 male) in four centers. All patients underwent a four-hour peritoneal equilibration test (PET) using 2.5% dextrose but with variable fill volumes (range: 1-3 L). Patients with a residual renal function greater than 10 mL/min were excluded. MAIN OUTCOME MEASURES: Correlations and limits of agreement between measured and modeled values of total weekly urea KT/V, total weekly normalized creatinine clearance (L/week/1.73 m2), daily drain volume (L), net ultrafiltration (L), daily peritoneal urea clearance (L/day), and daily peritoneal creatinine clearance (L/day). Measured values were obtained from 24-hour urine and dialysate collections while modeled values were based on results from the PET in combination with the PD ADEQUEST kinetic program. RESULTS: The results show there is excellent agreement between measured and modeled urea KT/V and creatinine clearances, with concordance correlations of 0.94 and 0.92, respectively. Given the excessive variation and limited range in ultrafiltration values, the concordance correlation between measured and modeled UF was only 0.50. In terms of daily peritoneal clearances and ultrafiltration, the level of precision (i.e., standard deviation) in the differences between modeled and measured values is +/- 1.05 L/day for urea clearance +/- 1.03 L/day for creatinine clearance, and +/- 0.919 L/day for ultrafiltration. By contrast, the level of precision (i.e., standard deviation) in the differences between two measured values is estimated to be +/- 0.979 L/day for urea clearance, +/- 0.802 L/day for creatinine clearance, and +/- 0.707 L/day for ultrafiltration. Defining the limits of clinical agreement to be +/- 2 standard deviations of the differences between two clinically measured 24-hour clearances (or ultrafiltration), we find that 94% of the modeled urea clearances, 87% of the modeled creatinine clearances, and 86% of the modeled ultrafiltration values fall within the limits of clinical agreement. CONCLUSION: Data for a carefully performed PET and overnight exchange can, in combination with a scientifically validated kinetic model, provide clinicians with a powerful mathematical tool for use in CAPD dialysis prescription management. Although not intended to replace actual measurements, kinetic modeling can prove useful as a means for predicting clearances for various alternative prescriptions and perhaps also as a means for checking certain types of noncompliance.

Comparison of measured and predicted creatinine excretion is an unreliable index of compliance in PD patients.

OBJECTIVE: To evaluate the use of the ratio of measured to predicted creatinine excretion as an index of compliance in peritoneal dialysis (PD) patients. DESIGN: A prospective analysis. SETTING: Academic teaching hospital dialysis unit. PATIENTS: Forty-three patients on PD. MEASUREMENTS: Creatinine excretion in daily dialysate and urine collections was measured on one occasion in 10 patients and on two occasions in 33 patients, and, after adding an estimate for extrarenal creatinine degradation, was divided by predicted creatinine excretion to give a creatinine excretion ratio, which has been proposed as an index of compliance with exchanges in PD patients. Values above 1.24 have been suggested to indicate noncompliance. Lean body mass was also estimated from creatinine excretion. RESULTS: The mean creatinine excretion ratio was 1.12, and 30% of patients had a value above 1.3. Only one patient admitted noncompliance. Studies on four consecutive days of guaranteed compliance in 7 patients with high ratios showed that creatinine excretion remained constant, suggesting that the patients were high creatinine producers rather than noncompliant. Creatinine excretion was stable when measured at intervals of days, but over months it tended to change markedly in many patients. Lean body mass estimations using creatinine excretion were low in most patients. CONCLUSION: Comparison of measured and predicted creatinine excretion is not a reliable indicator of noncompliance because many compliant patients consistently excrete more creatinine than predicted. The standard formulas were not validated in dialysis patients and underestimate creatinine excretion significantly in many PD patients. Existing estimates in the literature of noncompliance, using this methodology, may not be accurate. Better methods of detecting this problem are required.

High altitude medicine for family physicians.

High altitude medicine deals with a continuum of diseases ranging from a mild discomfort to serious ailments affecting all organ systems, including the lungs, brain, and eyes. Decreased oxygen tension is the primary cause. The main principles of prevention are staging and graded ascent to allow acclimatization. Adventure travel to high altitude destinations is becoming increasingly popular; family physicians should be informed of the medical problems associated with such travel.

Reliability of distal sensory latency measures of the median nerve using an electroneurometer.

Measurements of distal sensory latency are often used to support the clinical diagnosis of carpal tunnel syndrome (CTS). Currently, there is little research that documents the reliability of measuring distal sensory latency in adult populations. The purpose of this study was to determine intraexaminer and interexaminer reliability of antidromic distal sensory latency of the median nerve in normal subjects (n=37). Using a two factor design, three examiners obtained a total of six distal sensory latency measures using a supramaximal stimulus from each subject. Analysis consisted of intraclass correlation coefficients (ICC) for intraexaminer and interexaminer reliability, which were 0.89 and 0.83, respectively. The results indicate that this method of measuring median nerve sensory latency has a high degree of reliability and agreement within and between examiners.

Clinical experience with erythropoietin in continuous ambulatory peritoneal dialysis.

The purpose of this project was to determine a safe and effective Epogen (EPO) subcutaneous administration schedule for patients who were on continuous ambulatory peritoneal dialysis. To comply with the manufacturer's recommendation to enter a vial only once, a dosing regimen had to be established that used a standard dose of 2,000 or 4,000 units. The goal was to determine the frequency of administration that would achieve and maintain the target hematocrit. Twenty-six patients participated. The starting dose of 4,000 units was administered either two or three times per week. An average 8.3% point increase in hematocrit was seen in 8 weeks. When the target hematocrit of 33% to 35% was reached, the dose and or frequency of administration was decreased. Maintenance doses were established at 2,000 or 4,000 units weekly or biweekly. We were able to meet and maintain the target hematocrit by using 2,000 or 4,000 units per dose and adjusting the frequency.

Stickler syndrome.

Stickler syndrome is an autosomal-dominant disorder of connective tissue characterized by skeletal, orofacial, and ocular abnormalities. The most common specific roentgenographic findings include coxa valga and widening of the femoral neck. Acetabular protrusio, chondrolysis, avascular necrosis, and vertebral changes have also been described. Premature arthritic changes are to be expected. Congenital myopia and micrognathia are the most common nonskeletal findings. This syndrome should be considered when patients have unexplained coxa valga, especially with concomitant acetabular protrusio.