Fraction of free-base nicotine in fresh smoke particulate matter from the Eclipse "cigarette" by 1H NMR spectroscopy

Solution 1H NMR (proton-NMR) spectroscopy was used to measure the distribution of nicotine between its free-base and protonated forms at 20 degrees C in (a) water; (b) glycerin/water mixtures; and (c) puff-averaged "smoke" particulate matter (PM) produced by the Eclipse cigarette, a so-called "harm reduction" cigarette manufactured by R. J. Reynolds (RJR) Tobacco Co. Smoke PM from the Eclipse contains glycerin, water, nicotine, and numerous other components. Smoke PM from the Eclipse yielded a signal for the three N-methyl protons on nicotine at a chemical shift of delta (ppm) = 2.79 relative to a trimethylsilane standard. With alpha fb = fraction of the total liquid nicotine in free-base form, and alpha a = fraction in the acidic, monoprotonated NicH+ form, then alpha a + alpha fb approximately 1. (The diprotonated form of nicotine was assumed negligible.) When the three types of solutions were adjusted so that alpha a approximately 1, the N-methyl protons yielded delta a = 2.82 (Eclipse smoke PM); 2.79 (35% water/65% glycerin); and 2.74 (water). When the solutions were adjusted so that alpha fb approximately 1, the N-methyl protons yielded delta fb = 2.16 (Eclipse smoke PM); 2.13 (35% water/65% glycerin); and 2.10 (water). In all of the solutions, the rate of proton exchange between NicH+ and Nic was fast relative to the 1H-NMR chemical shift difference in hertz. Each solution containing both NicH+ and Nic thus yielded a single N-methyl peak at a delta given by delta = alpha a delta a + alpha fb delta fb so that delta varied linearly between delta a and delta fb. Since alpha fb = (delta a-delta)/(delta a-delta fb), then delta = 2.79 for the unadjusted Eclipse smoke PM indicates alpha fb approximately 0.04. The effective pH of the Eclipse smoke PM at 20 degrees C may then be calculated as pHeff = 8.06 + log[alpha fb/(1-alpha fb)] = 6.69, where 8.06 is the pKa of NicH+ in water at 20 degrees C. The measurements obtained for the puff-averaged Eclipse smoke PM pertain to the chemistry of the smoke PM as it might be initially inhaled at 20 degrees C. Upon inhalation, the volatilization of nicotine and other acid/base active compounds (as well as a warming toward a body temperature of 37 degrees C) will alter the pHeff value of the smoke PM during the time that it resides and ages in the respiratory tract.     

Differences between experienced and anticipatory distress

Differences between distress ratings of anticipated and experienced life events were examined (N = 168). Results showed significant differences between perceived and experienced aversion across events predicting symptoms of stress, depression, anxiety, and somatic discomfort in occupational, social, and familial situations. Gender differences were also found. Women reported significantly greater ratings of distress than men. Results reinforce the use of experienced events in overall distress assessment for individual clients, bring to question the existence of anticipated or perceived stress, and suggest that gender differences should be accounted for in the interpretation of distress measures.     

Microorganism track reconstruction: an image processing approach

This paper presents an automatic system for the analysis of microorganism behaviour. The movements of free swimming microorganisms are videotaped by means of a television camera mounted on a microscope. The analysis is performed off-line by digitizing the video signal through the use of an image processor unit. Microorganism tracks are reconstructed spatially and chronologically by means of image processing techniques. From these tracks cell movement parameters are obtained. The results of our experiment in testing photoinduced movements follow.     

A pharmacokinetic-based test to prevent severe 5-fluorouracil toxicity

BACKGROUND AND OBJECTIVES: Dihydropyrimidine dehydrogenase (DPD) plays a key role in the catabolism of 5-fluorouracil (5-FU) to 5-fluoro-5,6-dihydrouracil (5-FDHU), and as such, an impairment of DPD has been recognized as an important factor for altered 5-FU and 5-FDHU pharmacokinetics, predisposing patients to the development of severe 5-FU-associated toxicity. Our objectives were to avoid severe 5-FU toxicities in patients with greatly impaired 5-FU and 5-FDHU pharmacokinetics after the administration of a reduced test dose of 5-FU and to investigate possible 5-FU or 5-FDHU pharmacokinetic parameters of the test dose related to the most common drug toxicities that affect patients after the first cycle of 5-FU chemotherapy. METHODS: Pharmacokinetics of 5-FU/5-FDHU and DPD activity in peripheral blood mononuclear cells (PBMCs) were examined in 188 gastrointestinal cancer patients given a test dose of 5-FU, 250 mg/m2, 2 weeks before starting the planned 5-FU treatment of 370 mg/m2 plus l-folinic acid, 100 mg/m2, for 5 days every 4 weeks. Drug levels were examined by HPLC, and toxicities were graded according to World Health Organization criteria. RESULTS: The 5-FU test dose was well tolerated in all patients. Of 188 patients, 3 (1.6%) had marked alterations of 5-FU/5-FDHU pharmacokinetics (ie, 5-FU half-life [t(1/2 beta)] >5 hours, 5-FU total body clearance [CL(TB)] <1 L x h(-1) x m(-2), and 5-FDHU time to reach maximum plasma concentration [t max] > or = 45 minutes); they were excluded from 5-FU treatments and treated with irinotecan, which was well tolerated. The plasma disposition of 5-FU in the remaining 185 patients revealed an area under the curve (AUC) of 3.73 +/- 2.18 h x microg/mL (mean +/- SD), maximum plasma concentration (Cmax) of 16.78 +/- 8.61 microg/mL, and t(1/2 beta) of 0.16 +/- 0.15 hour, whereas the CL(TB) was 65.67 +/- 31.86 L x h(-1) x m(-2). The 5-FDHU plasma profile showed a Cmax value of 3.64 +/- 1.94 microg/mL, whereas the t max value was 26.63 +/- 10.06 minutes, with an AUC value of 3.71 +/- 1.90 h x microg/mL. The PBMC DPD activity was 202.15 +/- 141.14 pmol 5-FDHU x min(-1) x mg(-1) protein (95% confidence interval, 165-239.3 pmol 5-FDHU x min(-1) x mg(-1) protein). A significant correlation between 5-FU AUC and 5-FDHU AUC was found (r = 0.5492, P < .0001), whereas a weaker correlation between PBMC DPD activity and both 5-FDHU AUC (r = 0.328, P = .0121) and 5-FDHU Cmax (r = 0.369, P = .0044) was found. Interestingly, no relationships between PBMC DPD activity and common toxicities were found, whereas 5-FDHU t max values greater than 30 minutes were associated with the risk of moderate to severe neutropenia and diarrhea (P = .0323 and P = .0138, respectively; chi-square test). CONCLUSIONS: This study suggests a successful approach for preventing severe or life-threatening toxicities in gastrointestinal cancer patients who are candidates for standard 5-FU treatment by analyzing the 5-FU and 5-FDHU pharmacokinetic parameters after the administration of a reduced 5-FU test dose.     

Effects of intracellular pH and Ca2+ on the activity of stretch-sensitive cation channels in leech neurons

The effects of intracellular pH and calcium on the activity of the leech mechanosensitive cation channels have been studied. These channels exhibited two activity modes denoted as spike-like (SL) and multiconductance (MC). In the absence of mechanical stimulation, acidification of the intracellular side of membrane patches from 7.2 to 6.2 reversibly increased the mean channel open time as well as the opening frequency in the SL mode. Channels in MC mode were activated by a pH_i reduction from 7.2 to 6.2, but were inhibited at pH_i 5.5. Unlike MC mode, SL mode was strongly activated by intracellular Ca²⁺. Fura-2 imaging experiments showed that intracellular calcium was induced to increase by hypotonic cell swelling. The major component of this response did not require extracellular calcium. A component of the swelling-induced calcium response was sensitive to blockers of stretch-sensitive cation channels. The results indicate that the two activity modes of mechanosensitive channels of leech neurons respond differently to changes of intracellular pH and calcium. The sensitivity of the channel to micromolar concentrations of internal free calcium, along with its permeability to this ion, is consistent with a role in the amplification of mechanically induced Ca²⁺ signals in leech neurons.     

Structure-Based Drug Design of Novel,Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors

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Management of puberty in growth hormone deficient children

The pubertal growth spurt accounts for approximately one-eighth of adult height and is regulated by complex hormonal interactions involving the somatotropic and gonadal axes. The observation that children with growth hormone deficiency (GHD) may fail to achieve an appropriate pubertal growth spurt led to the development of strategies to optimize GH therapy during puberty. In one strategy the dosage of GH is increased during puberty to support pubertal growth and in keeping with the physiological increase in serum levels of the hormone seen at that age. A different approach is to combine a GnRH analog (GnRHa) to GH to stop pubertal development, delaying epiphyseal fusion and prolonging peripubertal growth. Both strategies require caution. As regards the first strategy, too high doses of GH may shorten the pubertal time for growth; we found a small, nonsignificant, improvement in final height by increasing the dose by less than half. Preliminary results on the second strategy are more encouraging. However, manipulation of puberty should be limited to selected patients who show a statural height SDS for bone age unfavorable in terms of height prognosis.     

Beneficial effects of dietary mineral restriction in dogs with marked reduction of functional renal mass.

Although studies in partially nephrectomized rats have identified a progressive nephropathy that is altered by dietary restriction of phosphorus intake, the response of dogs to similar perturbations has not been established. Functional renal mass was reduced by 15/16 in dogs to determine its long-term effects on renal function and to evaluate the effects of two levels of dietary mineral (calcium and phosphorus) intake (0.44% phosphorus/0.57% calcium versus 1.50% phosphorus/1.91% calcium). Following a 3-month stabilization period, dogs were fed either the lower mineral diet (group 1, N = 12) or the higher mineral diet (group 2, N = 12) for 24 months. Loss of renal function with the passage of time was observed in 10 of 12 dogs maintained on the higher mineral diet, with an average decrease in exogenous creatinine clearance of 11.1 +/- 6.3%/month, leading to a survival rate of 33% in this group. Restriction of dietary mineral intake slowed (P less than 0.05) the rate of decline of exogenous creatinine clearance in group 1 to 2.6 +/- 1.1%/month and improved 24-month survival to 75% (P less than 0.01). Deterioration of renal function was associated with renal calcium accumulation and histologic evidence of nephrocalcinosis, tubular atrophy and dilatation, and interstitial fibrosis. These events were more readily apparent in female than in male dogs. A role for glomerulosclerosis was not apparent, and neither glomerular pathology nor glomerular volume was related to the observed decrements in renal function.