Drug Delivery From Polymer-Based Nanopharmaceuticals-An Experimental Study Complemented by Simulations of Selected Diffusion Processes.

The success of medical therapy depends on the correct amount and the appropriate delivery of the required drugs for treatment. By using biodegradable polymers a drug delivery over a time span of weeks or even months is made possible. This opens up a variety of strategies for better medication. The drug is embedded in a biodegradable polymer (the "carrier") and injected in a particular position of the human body. As a consequence of the interplay between the diffusion process and the degrading polymer the drug is released in a controlled manner. In this work we study the controlled release of medication experimentally by measuring the delivered amount of drug within a cylindrical shell over a long time interval into the body fluid. Moreover, a simple continuum model of the Fickean type is initially proposed and solved in closed-form. It is used for simulating some of the observed release processes for this type of carrier and takes the geometry of the drug container explicitly into account. By comparing the measurement data and the model predictions diffusion coefficients are obtained. It turns out that within this simple model the coefficients change over time. This contradicts the idea that diffusion coefficients are constants independent of the considered geometry. The model is therefore extended by taking an additional absorption term into account leading to a concentration dependent diffusion coefficient. This could now be used for further predictions of drug release in carriers of different shape. For a better understanding of the complex diffusion and degradation phenomena the underlying physics is discussed in detail and even more sophisticated models involving different degradation and mass transport phenomena are proposed for future work and study.

Mutagenic, cytotoxic, and genotoxic properties of tobacco smoke produced by cigarillos available on the Canadian market.

Cigarillos (aka little cigars) have been increasing in popularity unlike cigarettes; but relatively little is known about the toxicology of the mainstream smoke (MSS) from such products. Therefore, the objective of this work was to compare the toxicological properties of the MSS (Health Canada Intensive smoking conditions) from a range of cigarillo products with the toxicological properties of MSS of cigarettes. Three in vitro assays were used to evaluate the toxicities of the MSS total particulate matter (TPM): (1) mutagenicity using Ames assay with Salmonella strains TA98 and TA100 with S9 metabolic activation (+S9); (2) cytotoxicity using the Neutral Red Uptake (NRU) assay with CHO (Chinese Hamster Ovary) cells; and (3) genotoxicity using the micronucleus assay with CHO cells and short-term exposures (3-h ± S9). The Ames assay (TA100+S9) and the NRU assay were also applied to the gas/vapour phase of the MSS that passed through the Cambridge pad. On a per-milligram-nicotine basis, the preferred way of comparing toxicities of different types of tobacco products, the MSS from cigarillos was not less toxic, and in some cases more toxic (TPM fraction TA98+S9, NRU), than the MSS from cigarettes. Thus, our findings support our prior work on smoke mutagenicity that showed MSS from cigarillos was not less toxic than MSS from cigarettes.

Free-base nicotine in tobacco products. Part II. Determination of free-base nicotine in the aqueous extracts of smokeless tobacco products and the relevance of these findings to product design parameters.

Reports in the peer-reviewed literature and popular press have alleged that smokeless tobacco product (STP) manufacturers increase the addictiveness of their products by adjusting formulae to increase the relative percentage of nicotine in STP that is not protonated. Such nicotine is more popularly, but incorrectly, known as free-base nicotine ("FBN") as it is a calculated amount as opposed to a real chemical species in the STP. Some regulators have mandated reporting of FBN as estimated by Henderson-Hasselbalch equation ("HHE") using the pH-value of an aqueous suspension (or extract) of STP. This is technically incorrect because the HHE is only valid in pure dilute aqueous solution of a single base and its conjugate acid. The aqueous suspensions (or extracts) of STP often contain high concentrations of salts and polymeric anions such as pectate and many other compounds, and there is a molar excess of ammonia over nicotine in some products. These are heretofore-unrecognized sources of error in use of the HHE to estimate relative amount of nicotine that is not protonated results in inaccurate FBN-values. Thus, it is not surprising that attempts to show the relevance of estimated value of FBN in STP to human physiology have failed.

Free-base nicotine in tobacco products. Part I. Determination of free-base nicotine in the particulate phase of mainstream cigarette smoke and the relevance of these findings to product design parameters.

The free-base nicotine (FBN) content of mainstream cigarette smoke (MSS) has been discussed in the peer-reviewed literature and popular press. It has been alleged that manufacturers adjust product design features to increase the percentage of total nicotine (TN) in the MSS gas-vapor phase that is unprotonated [P(g)(,nic)(%)] and/or the fraction of nicotine in the MSS total particulate matter (TPM) that is unprotonated (FBN/TN). Our research showed the Health Canada Intensive smoking conditions negated the effects of blend and cigarette design features reported to raise the pH of TPM collected under ISO or US FTC conditions. Our research also showed that when additive-free Canadian cigarettes were smoked under ISO conditions, the FBN/TN ratio increased as the tar/nicotine ratio decreased. Our findings are in line with other studies that have questioned allegations of a relationship between use of ammonia and its compounds as tobacco additives and amounts of unprotonated nicotine in MSS. In addition, the experimental work demonstrated how use of solid-phase microextraction to estimate FBN can yield erroneously high results due to improper conditioning and/or smoking of the cigarettes. Our research showed that there is no longer any scientific support for regulators to require smoke pH and FBN determinations on cigarette products.

Chemical and toxicological characterization of commercial smokeless tobacco products available on the Canadian market.

Some health experts are recommending that smokers who refuse to quit or refuse to use nicotine replacement therapy (NRT) such as nicotine-containing chewing gum switch to certain types of smokeless tobacco products (STP) such as Swedish snus. Other health experts disagree citing the uncertainty in the composition of commercially available STP, the lack of governmental regulations to ensure that STP advertised to meet certain standards (i.e., GothiaTek) do actually meet such standards, and the uncertainty that any STP can provide as safe as alternative to smoking as NRT. One reason for uncertainty is the dearth of detailed chemical and toxicological information on contemporary STP. Unlike the situation with cigarettes, there are few standardized methods for analytical and toxicological studies of STP. Consequently, the objective for this work was to characterize several types of STP available on the Canadian market using the modifications of the Official Health Canada chemical and toxicological methods developed for cigarettes. Moist snuff samples tested had TSNA and B[a]P levels somewhat above the GothiaTek standard while samples of Swedish snus, low-moisture snuff, and US-style chewing tobacco did not. Use of in vitro assays to assess STP toxicity was of limited utility in distinguishing product types.

Reductions in the tobacco specific nitrosamine (TSNA) content of tobaccos taken from commercial Canadian cigarettes and corresponding reductions in TSNA deliveries in mainstream smoke from such cigarettes.

Tobacco specific nitrosamines (TSNAs) are suspected to cause smoking-related neoplastic diseases. The change from direct-fired to indirect-fired barns (aka kilns) for curing bright (aka Virginia, flue-cured) tobaccos was made to reduce the TSNA concentrations. The effectiveness of such processes in reducing the deliveries of TSNAs to the users of the products should be monitored. However, it is difficult to assess the effects of this reduction on the TSNA levels in mainstream smoke when cigarette blends contain burley tobaccos and other blend components that can increase smoke TSNA concentrations. Canadian cigarettes made prior to and in the few years just after the conversion to indirect-fired curing should not be subject to such interferences. Thus, the TSNA content of tobaccos and mainstream smoke from six brands of Canadian cigarettes produced in 2003, 2004, and 2005 were determined. Reductions in NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone], the most important TSNA in flue-cured tobaccos, levels in the tobacco blends ranged from 60% to 85%. The corresponding reductions in mainstream smoke TSNA levels ranged from 59% to 72% (ISO smoking conditions) and 58-76% (Health Canada Intensive smoking conditions). These results show that other factors (microorganisms, nitrite levels) may be negating the TSNA reductions achieved by indirect-fired curing.

A comparative study of the mutagenicity of various types of tobacco products.

Toxicological data are an important aspect of tobacco product characterization. In this study, TPM (Total Particulate Matter) (three replicates) was collected from cigarettes [five brands, ISO conditions: puff volume, 35 mL; duration, 2s; interval, 60s (35/2/60)], cigars (two brands, 45/2/30), cigarillos (two brands, 35/2/60), bidis (two brands, 45/2/30), and pipe tobacco (two brands, 50/2/12). TPM was extracted from the Cambridge filter pad using dimethyl sulfoxide (DMSO). Smokeless tobacco (ST) (six brands) was extracted with DMSO using an ultrasonic homogenizer. Both types of extracts were filtered and stored at -80 degrees C. All extracts were analyzed for humectants, water and nicotine. Mutagenic activity was assessed per OECD guideline 471 using Salmonella typhimurium TA98+S9 and TA100+S9. TA98+S9 response (specific activity expressed as revertants/mg nicotine) was greatest for the cigarette fabricated with dark, air-cured tobaccos. Average product responses with TA98+S9 based on nicotine and relative to cigarettes (excluding dark tobacco) were cigars, 242%; cigarillos, 238%; bidis, 91%; and pipe tobacco, 44%. ST response was not significant for TA98+S9. Corresponding values for TA100+S9 were cigars, 189%; cigarillos, 155%; pipe tobacco, 130%; bidis, 114% and ST, 34%. ST TA100+S9 response ranged from a low of 501 to a high of 8547 revertants/mg nicotine, depending on ST composition.

Carcinogens in tobacco smoke: benzo[a]pyrene from Canadian cigarettes and cigarette tobacco.

We evaluated the benzo[a]pyrene (BaP) content in the smoke from 35 brands of Canadian cigarettes and 5 brands of Canadian tobaccos for roll-your-own cigarettes. For the cigarettes, mean values of BaP ranged from 3.36 ng to 28.39 ng per cigarette, roughly in proportion with declared tar values. The relationship between declared tar and yields of BaP, however, does not allow accurate prediction of one from the other. For the tobaccos, mean BaP values ranged from 22.92 ng to 26.27 ng (average, 24.7 ng) per cigarette. The implications of these findings are discussed with respect to overall exposure.

Handmade cigarettes: it's the tube that counts.

Thirty-one Canadian brands of fine-cut tobaccos for roll-your-own cigarettes (RYOs) were evaluated under standard conditions using mandated tube and filter combinations. Results indicate no evidence of a significant difference in the amounts of tar, nicotine, and carbon monoxide produced by the 31 brands. In addition, the data emphasize that it is primarily the tube and filter combination that determines delivery of toxic constituents.

Measuring the heaviness of smoking: using self-reported time to the first cigarette of the day and number of cigarettes smoked per day.

Two simple self-report measures have been used to assess the heaviness of smoking, 'number of cigarettes per day' (CPD) and 'time to the first cigarette of the day' (TTF). Little attention, however, has been given to the precise method of scoring this information. Using biochemical indicators of heaviness of smoking (alveolar carbon monoxide and cotinine), we explore the optimum data transformations for regression analysis and categorical analysis. We suggest a four category scoring scheme for both time to the first cigarette of the day (less than or equal to 5, 6-30, 31-60 and 61+ min) and average daily consumption of cigarettes (1-10, 11-20, 21-30, 31+ cigarettes) as the most powerful and practical categorical scoring of these variables. Due to possible ceiling effects on biochemical measures, we suggest using logarithmic transformations of CPD or TTF for regression or correlation analyses.

[Comparative description of the clientele of an educational psychotherapeutic home for children with behavior disorders]. / Vergleichende Klientelbeschreibung eines heilpädagogisch-psychotherapeutischen Heimes für verhaltensauffällige Kinder.

Two groups of children who were taken in care during two different periods (each of five years) by a psychotherapeutic institution are compared in respect to the multi-axial classification system and demographic variables. Each group consists of 80 children. Comparisons were made to check propagated preconceived ideas about aggravation of clientele. The number of social behavior disorders, of specific developmental retardation, social and familial adversities, age by residential placement, level of intelligence did not change. Significant decrease was found in the number of earlier non-familial placement, significant increase in the number of children with minimal brain dysfunction. The findings are discussed and the necessity of basic documentation accentuated.

Estimates of maximum or average cigarette tar, nicotine, and carbon monoxide yields can be obtained from yields under standard conditions.

Average yields of tar, nicotine, and carbon monoxide per liter of smoke and per cigarette were determined for 10 brands of cigarettes smoked under 27 different conditions (one standard and 26 nonstandard). Per cigarette yields were highly variable across smoking conditions due to differences in the total volume of smoke taken for analysis. The results of a simple linear regression analysis indicated that up to 95% of the variation in tar yield per cigarette could be explained by variations in the total volume of smoke produced per cigarette. Per liter yields for tar, nicotine, and carbon monoxide were almost constant over the conditions investigated. Since most smokers inhale less than this amount, yields per liter provide a rough estimate of the maximum amount to which a smoker might be exposed. Yields per liter, taken over all 26 conditions, are highly correlated with per cigarette yields under standard conditions. Consequently, values on one scale can be converted to the other, at least for the 10 brands investigated. The average conversion factor for tar, nicotine, and carbon monoxide is 2.5 when proceeding from milligrams per king-size cigarette under standard conditions to milligrams per liter. This relationship is true for both vented and nonvented cigarettes when ventilation holes are not blocked.

Characterization of tobacco products: a comparative study of the tar, nicotine, and carbon monoxide yields of cigars, manufactured cigarettes, and cigarettes made from fine-cut tobacco.

Yields of tar, nicotine, and carbon monoxide were compared in selected Canadian brands of manufactured and hand-rolled cigarettes, and small and large cigars. To control for varying volumes of smoke delivery per cigarette or cigar, standardized comparisons in milligrams of toxic substance per liter of smoke were made. The mean deliveries per liter of smoke and tar, nicotine, and carbon monoxide were highest for small cigars, followed by hand-rolled and manufactured cigarettes; large cigars had the lowest deliveries. Five out of six brands of cigarettes handmade from fine-cut tobacco delivered significantly more tar, nicotine, and carbon monoxide per cigarette or per liter than did the identically named manufactured brand.

Maintain levels of nicotine but reduce other smoke constituents: a formula for "less-hazardous" cigarettes?

Twenty-two volunteers who smoked more than 20 cigarettes with "high" nicotine yields (0.8 to 1.2 mg) per day participated in an 8-week study designed to test the hypothesis that smoking cigarettes with a constant level of nicotine but reduced deliveries of tar, carbon monoxide, and hydrogen cyanide leads to a decrease in smoke absorption. All subjects smoked their usual high-nicotine brand for the first 3 weeks (P1), and the absorption of smoke constituents was determined from levels of thiocyanate and cotinine in saliva and serum, levels of carbon monoxide in expired air, and levels of carboxyhemoglobin in the blood. During the final 5 weeks (P2), the treatment group (16 subjects) switched to the "light" version of their usual brands (similar yields of nicotine but with reduced yields of tar, carbon monoxide, and hydrogen cyanide); the control group (6 subjects) smoked their usual brands for the duration of the study. Average levels of cotinine for the subjects who switched during P2 were not significantly different from those of the control group as was expected. Slight reductions were noted in average expired-air carbon monoxide levels, blood carboxyhemoglobin, and saliva thiocyanate, but these reductions were smaller than anticipated based on brand characteristics. The results suggest that the ratio of smoke constituents is different when individuals, rather than machines, smoke cigarettes. Yields determined under subject-defined conditions are necessary in order to properly evaluate the role of nicotine in the design of "less-hazardous" cigarettes.

Yields of tar, nicotine, and carbon monoxide in the sidestream smoke from 15 brands of Canadian cigarettes.

Sidestream smoke yields for 15 brands of cigarettes were determined under conditions where mainstream yields were approximately equal to those used for determining the values which appear on packages of Canadian cigarettes. Sidestream yields of tar, nicotine, and carbon monoxide were much higher than mainstream yields for all brands tested. The average sidestream-to-mainstream ratios for the 15 brands were 3.5, 6.6, and 6.8 for tar, nicotine, and carbon monoxide, respectively. The highest yields of sidestream were obtained from the brands with the lowest mainstream yields.

A comparison of the yields of tar, nicotine, and carbon monoxide of 36 brands of Canadian cigarettes tested under three conditions.

A number of countries, including Canada, sponsor routine monitoring of cigarette tar, nicotine, and carbon monoxide yields which are evaluated by cigarette-smoking machines according to a standard protocol. These standardized yields continue to decline as tobacco companies modify their brands to meet consumers' demand for "light" products. This trend toward cigarettes with low average deliveries of toxic substances may reduce health risks for some people. However, switching to low-yield cigarettes may not result in reduced risks for smokers who smoke these cigarettes intensively. Thirty-six brands of Canadian cigarettes, including 28 with ventilated filters, were tested under standard conditions and 2 others in order to determine how yields of tar, nicotine, and carbon monoxide change when cigarettes are manipulated by smokers in order to increase their smoke intake. While the rank order yields of tar, nicotine, and carbon monoxide was preserved, the average yields of all three substances more than doubled when cigarettes were intensively smoked in comparison with standard smoking.