Development of HPLC plasma assays for CAM 4515 and CAM 4750, two new nonpeptide tachykinin antagonists, and application to bioavailability studies

CAM 4515 and CAM 4750 are new nonpeptide tachykinin NK₁ receptor antagonists with different lipophilicities. Two separate, simple, and sensitive HPLC methods for the quantitation of these two compounds in plasma and the evaluation of their oral bioavailability in rats were developed and validated. Extraction of CAM 4515 from plasma involved protein precipitation with acetonitrile, while that for CAM 4750 involved a one-step liquid-liquid extraction with methylene chloride. The analytes in extracts were chromatographed on a C18 column using two different separation buffers, 47% 0.02 M sodium citrate (pH 3.5)-53% acetonitrile for CAM 4515 and 59% 0.02 M potassium phosphate dibasic (pH 7.0)-41% acetonitrile for CAM 4750, and both compounds were detected by fluorescence (excitation 278 nm; emission 342 nm). Stability profiles of both drugs at −20°C or room temperature in plasma and in reconstituted buffers were good. The limit of quantitation for both drugs was 5 ng ml⁻¹ with good linearity from 5 to 1000 ng ml⁻¹ using 100–200 μl of plasma. Excellent precision (relative standard deviation < 8.3%) and accuracy (relative error ± 9.2%) were observed for both CAM 4515 and CAM 4750. Oral bioavailability studies were conducted for each compound in rats receiving a p.o. dose of 20 mg kg⁻¹ and an i.v. dose of 5 mg kg⁻¹. The absolute oral bioavailability of CAM 4750 (80%) was estimated to be 40-fold greater than that of CAM 4515 (2%). The experimental results suggest that incorporation of a pyridine group into the structural backbone may greatly improve bioavailability.     

BIOCHEMICAL CORRECTION IN THE SYNDROME OF HYPERTENSION AND HYPERKALAEMIA BY SEVERE DIETARY SALT RESTRICTION SUGGESTS RENIN-ALDOSTERONE SUPPRESSION CRITICAL IN PATHOPHYSIOLOGY

1. Plasma potassium and chloride concentrations were raised and plasma renin activity, aldosterone, bicarbonate and arterial pH were reduced in two brothers with the syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate (Gordon's syndrome), on unrestricted or moderately restricted sodium diets. 2. These abnormalities were corrected in both patients within 10 days of severe sodium restriction. 3. Pressor sensitivity to cold and angiotensin II decreased on low sodium diet, associated with a fall in blood pressure. 4. Increasing distal tubular sodium delivery by infusion of normal saline increased fractional excretion of potassium when aldosterone had been stimulated by severely restricted sodium diet, but not when aldosterone levels were low on unrestricted sodium diet. 5. These findings are consistent with excessive sodium reabsorption as the primary renal lesion in Gordon's syndrome, leading to volume expansion and suppression of renin and aldosterone. Severe dietary sodium restriction leading to volume contraction, by stimulating renin and aldosterone and promoting kaliuresis, corrects the abnormalities.     

APPROACHES TO PROMOTING MORE WIDESPREAD PARTICIPATION IN PHYSICAL ACTIVITY

Exercise is associated with a reduced risk of coronary heart disease, has beneficial effects on cardiovascular risk factors, and has other health benefits. No more than 10 per cent to 20 per cent of adults in Australia and other developed countries participate in regular vigorous physical activity, while over 65 per cent of Australian adults are almost totally sedentary. Survey data from the U.S.A. suggest that levels of participation in jogging and walking have increased in the past 10 years but that the proportion of people who take no deliberate exercise has also increased. Large-scale community interventions to promote exercising have not been subject to rigorous evaluation and it is difficult to reach any firm conclusions about the effects of exercise promotion. However, it is possible to identify some of the factors which may influence exercise participation, and there is information from trials of large-scale, multifactorial interventions to reduce cardiovascular risk which provides some helpful guidelines about how it may be useful to proceed. Approaches to increasing levels of exercise participation should emphasise community-based efforts which provide appropriate settings and social support for exercising, making exercise a more appealing and accessible option for large numbers of people; the use of mass media for community education about exercising should be co-ordinated carefully with specific community activities. Personalized fitness instruction, groups and classes should place more emphasis on exercise as a pattern of behaviour to be integrated into a person's way of life and maintained over time; and there is the potential for more widespread and systematic use of self-instructional exercise materials to assist people who wish to exercise independently. Because there exist only limited local research findings and work in other countries does not yet provide conclusive information, research and development priorities for these areas are suggested.     

RENIN GENE POLYMORPHISM ASSOCIATED WITH ALDOSTERONE RESPONSIVENESS TO THE RENINANGIOTENSIN SYSTEM IN PATIENTS WITH ALDOSTERONE-PRODUCING ADENOMAS

1. Aldosterone levels in patients with unilateral aldosterone-producing adenomas may be responsive or unresponsive to the renin-angiotensin system, with the former often previously misdiagnosed as bilateral adrenal hyperplasia. 2. In tumours from patients in the responsive subgroup, renin mRNA is expressed in greater amounts than in tumours from patients in the unresponsive subgroup, or in normal adrenals. 3. We compared the frequency of four renin gene polymorphisms in peripheral blood DNA from the two subgroups and found significant associations between BglI, TaqI and HinfI restriction fragment length polymorphisms (RFLP) and aldosterone responsiveness. 4. Allelic variation in the constitutive renin gene was associated with a specific cause of hypertension.     

Oral and dental manifestations in diabetic and nondiabetic uremic patients receiving hemodialysis.

OBJECTIVE: The aim of this study was to examine the dental condition and oral manifestations in diabetic and nondiabetic uremic patients undergoing hemodialysis. STUDY DESIGN: A total of 128 patients undergoing hemodialysis therapy were classified into the diabetic and nondiabetic groups and examined for uremic oral manifestations, dental caries, and the periodontal status. All the patients received predialytic salivary pH examination. In the diabetic group, the correlation between oral findings and glycemic controlled levels, which was collected based on Hb A1C values, were further studied. RESULTS: The diabetic group exhibited significantly higher prevalence of caries and more severe dry mouth, taste change, and mucosa pain than the nondiabetic group. The diabetic group tended to have lower predialytic salivary pH, and patients with poor glycemic control (ie, Hb A1C > 9%) showed higher incidence of dry mouth, mucosal pain, and tongue coating. However, the DMFT and CPI index were not associated with glycemic control in the diabetic group. CONCLUSIONS: This study reveals that diabetic uremic patients undergoing maintained hemodialysis exhibited a potentially higher risk for dental decay and xerostomia. Lower salivary pH and poor glycemic control may affect oral manifestations. Further research is needed to clarify the combined influence of diabetic nephropathy on oral health.     

Demonstration of human papillomavirus types 6 and 11 in juvenile laryngeal papillomatosis by in-situ DNA hybridization

A study is reported in which an in situ hybridization technique for the demonstration of human papillomavirus (HPV) employing a biotin--streptavidin polyalkaline phosphatase complex has been successfully applied to formalin-fixed paraffin-processed tissue obtained from ten patients with juvenile laryngeal papillomatosis. In all cases, positive results were obtained for either HPV type 6 or 11. Normal vocal cord epithelium was negative.     

Pulmonary function following surgical repair of pectus excavatum: a meta-analysis.

The purpose of this study was to use a meta-analytical technique to examine the efficacy of surgical repair of pectus excavatum on pulmonary function. Studies were retrieved via computerized literature searches, cross-referencing from original and review articles. Inclusion criteria were as follows: (1) reporting quantitative measures of preoperative and postoperative pulmonary function; (2) published in the English language; (3) indexed between January 1960 and September 2005; (4) reporting the duration between which preoperative and postoperative assessments were conducted; and (5) describing the pulmonary assessment procedures. The titles and abstracts of potentially relevant articles were reviewed to determine whether they met the criteria for inclusion. Twelve studies representing 313 pectus excavatum patients met the inclusion criteria and were used for the meta-analysis. Random-effects modeling yielded a mean weighted effect size (ES) for pulmonary function which was statistically nonsignificant (ES=0.08, 95% CI=-0.20 to 0.35; P=0.58). The findings of the present study indicated that surgical repair of pectus excavatum does not significantly improve pulmonary function. These findings, however, may be a result of testing pulmonary function under conditions in which pectus excavatum does not manifest itself.