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Background: Cigarette smoking increases the risk of chronic diseases; heating instead of burning tobacco can lower these risks, contributing to tobacco harm reduction. This study (with 984 adult American smokers) examined whether favorable changes occur in 8 co-primary endpoints (HDL-C, WBC, FEV1%pred, COHb, Total NNAL, sICAM-1, 11-DTX-B2, 8-epi-PGF2α) indicative of biological and functional effects when cigarette smokers switch to the heat-not-burn Tobacco Heating System 2.2 (THS). Additionally, these biomarkers of exposure (BoExp) were quantified: MHBMA, 3-HPMA, Total NNN, CEMA, 3-OH-B[a]P, HMPMA, Total 1-OHP, NEQ, and CO exhaled. Methods: Participants were randomized to continued smoking of their preferred cigarette brand (n = 496) or to using THS (IQOS brand; n = 488) for 6 months. THS has a maximum heating temperature of 350°C, delivering 1.21 mg nicotine/stick and 3.94 mg glycerin/stick under the Health Canada Intense smoking regimen. Results: The main outcome was a favorable change 6 months after baseline, with statistically significant improvements in 5 of 8 biomarkers of effect (HDL-C, WBC, FEV1%pred, COHb, Total NNAL) when smokers switched to THS compared with those who continued to smoke cigarettes. Likewise, BoExp were markedly reduced. Conclusions: All endpoints showed favorable changes in the same direction as with smoking cessation and improved biological effects were observed in smokers who predominantly used THS compared with continued cigarette smoking, with similar nicotine levels in both groups. Impact: Improvements in 5 of 8 biomarkers of effect are supportive of the research hypothesis, suggestive of disease risk reduction potential for smokers switching to THS instead of continuing to smoke cigarettes.

Introduction Tobacco Heating System (THS) 2.2, a candidate modified-risk tobacco product, aims at offering an alternative to cigarettes for smokers while substantially reducing the exposure to harmful and potentially harmful constituents found in cigarette smoke. Methods One hundred and sixty healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Subjects were randomized in a 2:1:1 ratio to menthol Tobacco Heating System 2.2 (mTHS), menthol cigarette, or smoking abstinence for 5 days in confinement and 86 subsequent ambulatory days. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents (reported in our co-publication, Part 1) and biomarkers of potential harm (BOPH). Results Compliance (protocol and allocated product exposure) was 51% and 18% in the mTHS and smoking abstinence arms, respectively, on day 90. Nonetheless, favorable changes in BOPHs of lipid metabolism (total cholesterol and high- and low-density cholesterol), endothelial dysfunction (soluble intercellular adhesion molecule-1), oxidative stress (8-epi-prostaglandin F2α), and cardiovascular risk factors (eg, high-sensitivity C-reactive protein) were observed in the mTHS group. Favorable effects in other BOPHs, including ones related to platelet activation (11-dehydrothromboxane B2) and metabolic syndrome (glucose), were more pronounced in normal weight subjects. Conclusions The results suggest that the reduced exposure demonstrated when switching to mTHS is associated with overall improvements in BOPHs, which are indicative of pathomechanistic pathways underlying the development of smoking-related diseases, with some stronger effects in normal weight subjects. Implications Switching to mTHS was associated with favorable changes for some BOPHs indicative of biological pathway alterations (eg, oxidative stress and endothelial dysfunction). The results suggest that switching to mTHS has the potential to reduce the adverse health effects of smoking and ultimately the risk of smoking-related diseases. Switching to mTHS for 90 days led to reductions in a number of biomarkers of exposure in smokers, relative to those who continued smoking cigarettes, which were close to those observed when stopping smoking (reported in our co-publication, Part 1). Initial findings suggest reduced levels of 8-epi-prostaglandin F2α and intercellular adhesion molecule 1, when switching to mTHS for 90 days. These changes are comparable to what is observed upon smoking cessation. In normal weight subjects, additional favorable changes were seen in 11-dehydrothromboxane B2, fibrinogen, homocysteine, hs-CRP, percentage of predicted forced expiratory volume in 1 second, systolic blood pressure, diastolic blood pressure, glucose, high-density lipoprotein, apolipoprotein A1, and triglycerides. Trial registration NCT01989156.

Introduction The Tobacco Heating System (THS) is a “heat-not-burn” tobacco product designed to generate significantly lower levels of harmful and potentially harmful constituents (HPHCs) and present lower risk of harm than cigarettes. This study assessed the exposure reduction to selected HPHCs in smokers switching to menthol Tobacco Heating System (mTHS) 2.2 compared with smokers continuing smoking menthol cigarettes (mCCs) and smoking abstinence (SA) for 5 days in a confined setting, followed by an 86-day ambulatory period. Methods A total of 160 healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Biomarkers of exposure to 16 HPHCs were measured in blood and 24-hour urine. Safety was monitored throughout the study. Information was also gathered on product evaluation, product use, subjective effects, and clinical risk markers (co-publication Part 2). Results Nicotine uptake was comparable in both exposure groups (mTHS:mCC ratio of 96% on day 90). On day 5, biomarker of exposure levels to other HPHCs were reduced by 51%–96% in the mTHS group compared with the mCC group, and these reductions were sustained for most biomarkers of exposure over ambulatory period. After 90 days of use, the level of satisfaction with mTHS and suppression of urge to smoke were comparable to mCC. Conclusion Switching from mCCs to mTHS significantly reduced the exposure to HPHCs to levels approaching those observed in subjects who abstained from smoking for the duration of the study. Implications This study compared the impact of switching to mTHS on biomarkers of exposure, relative to continued smoking or SA. Clinical Significance Trial Registration NCT01989156 (ClinicalTrials.gov).

Introduction Novel nicotine delivery systems represent an evolving part of the tobacco harm reduction strategy. The pharmacokinetic (PK) profile of nicotine delivered by P3L, a pulmonary nicotine delivery system, and its effects on smoking urges and craving relief in relation to Nicorette inhalator were evaluated. Methods This open-label, ascending nicotine levels study was conducted in 16 healthy smokers. Three different nicotine delivery levels, 50, 80, and 150 µg/puff, delivered by the P3L system were evaluated consecutively on different days after the use of the Nicorette inhalator. Venous nicotine PK, subjective effects, and tolerability were assessed. Results Geometric least-squares means for maximum plasma nicotine concentration (Cmax), generated by the mixed-effect model for exposure comparison, were 9.7, 11.2, and 9.8 ng/mL for the 50, 80, and 150 µg/puff P3L variants, respectively, compared to 6.1 ng/mL after Nicorette inhalator use. Median time from product use start to Cmax was 7.0 minutes for all P3L, compared to 30.0 minutes for the Nicorette inhalator. Craving reduction was slightly faster than with the Nicorette inhalator as assessed with the visual analog scale craving score. The mean Questionnaire of Smoking Urges -brief total scores did not differ for both products. P3L was well tolerated. Conclusions At all three nicotine levels tested, the inhalation of the nicotine lactate aerosol delivered with the P3L provided plasma nicotine concentrations higher and faster compared to the Nicorette inhalator. The plasma nicotine concentration–time profile supports a pulmonary route of absorption for P3L compared to the oromucosal absorption of the Nicorette inhalator. Implications The combination of nicotine and lactic acid with the P3L device shows potential over existing nicotine delivery systems by delivering nicotine with kinetics close to published data on conventional cigarettes and without exogenous carrier substances as used in current electronic nicotine delivery systems. Altogether, the PK profile, subjective effects, and safety profile obtained in this study suggest P3L is an innovative nicotine delivery product that will be acceptable to adult smokers as an alternative to cigarettes.

Introduction Modified-risk tobacco products are expected to reduce exposure to harmful and potentially harmful constituents of cigarette smoke, and ultimately reduce the health burden of smoking-related diseases. Clinically relevant risk markers of smoking-related diseases inform about the risk profile of new tobacco products in the absence of in-market epidemiological data. The menthol Tobacco Heating System 2.2 (mTHS) is a modified-risk tobacco product in development as an alternative to cigarettes (conventional cigarettes [CCs]). Methods In this parallel-group study, Japanese adult smokers (23–65 years; ≥10 mCCs/day) were randomized to mTHS, menthol CCs (mCC), or smoking abstinence (SA) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents and clinically relevant risk markers of smoking-related diseases. Results One-hundred and sixty participants were randomized to the mTHS (n = 78), mCC (n = 42), and SA (n = 40) groups. Switching to the mTHS was associated with reductions in biomarkers of exposure compared with continuing mCCs. Reductions in 8-epi-prostaglandin F2α (biomarker of oxidative stress), 11-dehydro-thromboxane B2 (biomarker of platelet activation), soluble intracellular adhesion molecule-1 (biomarker of endothelial function), and an increase in high-density lipoprotein cholesterol (biomarker of lipid metabolism) and forced expiratory volume in 1 second (biomarker of lung function) occurred in the mTHS group compared with the mCC group. The changes in the mTHS group approached those in the SA group. Conclusions Switching from mCCs to mTHS was associated with improvements in clinically relevant risk markers linked to mechanistic pathways involved in smoking-related diseases. Implications In this three-way randomized study, switching from menthol cigarettes to mTHS for 5 days in confinement and 85 days in ambulatory settings was associated with reductions in biomarkers of exposure to cigarette smoke, and changes were observed in clinically relevant biomarkers of oxidative stress (8-epi-prostaglandin F2α), platelet activity (11-dehydro-thromboxane B2), endothelial function (soluble intracellular adhesion molecule-1), lipid metabolism (high-density lipoprotein cholesterol) and lung function (forced expiratory volume in 1 second), similar to the SA group. The results suggest that switching to the mTHS has the potential to reduce the adverse health effects of conventional cigarettes.

Smoking conventional cigarettes (CCs) exposes smokers to harmful and potentially harmful constituents (HPHCs). The Tobacco Heating System 2.2 (THS 2.2), a candidate modified risk tobacco product, was developed to reduce or eliminate the formation of HPHCs, while preserving as much as possible the taste, sensory experience, nicotine delivery profile and ritual characteristics of CC. This randomized, controlled, open-label study in confinement for 5 day exposure aimed to demonstrate the reduction in exposure to selected HPHCs, to assess nicotine uptake and subjective effects, in participants switching to THS 2.2 (n = 80) compared to participants continuing smoking CCs (n = 40) and abstaining from smoking (n = 40). The subjects were randomized according to sex and daily CC consumption. The levels of biomarkers of exposure to HPHCs were significantly reduced in participants switching to THS 2.2, compared to CC use. More importantly, the magnitude of exposure reduction observed was close to that which was seen in participants who abstained from smoking for 5 days, while nicotine uptake was maintained. Reduction in urge-to-smoke was comparable between THS and CC groups, however THS 2.2 was slightly less satisfactory than CCs. The new, alternative tobacco product THS 2.2 was well tolerated.

The Tobacco Heating System (THS) 2.2, a candidate Modified Risk Tobacco Product (MRTP), is designed to heat tobacco without burning it. Tobacco is heated in order to reduce the formation of harmful and potentially harmful constituents (HPHC), and reduce the consequent exposure, compared with combustible cigarettes (CC). In this 5-day exposure, controlled, parallel-group, open-label clinical study, 160 smoking, healthy subjects were randomized to three groups and asked to: (1) switch from CCs to THS 2.2 (THS group; 80 participants); (2) continue to use their own non-menthol CC brand (CC group; 41 participants); or (3) to refrain from smoking (smoking abstinence (SA) group; 39 participants). Biomarkers of exposure, except those associated with nicotine exposure, were significantly reduced in the THS group compared with the CC group, and approached the levels observed in the SA group. Increased product consumption and total puff volume were reported in the THS group. However, exposure to nicotine was similar to CC at the end of the confinement period. Reduction in urge-to-smoke was comparable between the THS and CC groups and THS 2.2 product was well tolerated.

Introduction Tobacco harm reduction aims to provide reduced risk alternatives to adult smokers who would otherwise continue smoking combustible cigarettes (CCs). This randomized, open-label, three-arm, parallel-group, single-center, short-term confinement study aimed to investigate the effects of exposure to selected harmful and potentially harmful constituents (HPHCs) of cigarette smoke in adult smokers who switched to a carbon-heated tobacco product (CHTP) compared with adult smokers who continued to smoke CCs and those who abstained from smoking for 5 days. Methods Biomarkers of exposure to HPHCs, including nicotine and urinary excretion of mutagenic material, were measured in 24-hour urine and blood samples in 112 male and female Caucasian smokers switching from CCs to the CHTP ad libitum use. Puffing topography was assessed during product use. Results Switching to the CHTP or smoking abstinence (SA) resulted in marked decreases from baseline to Day 5 in all biomarkers of exposure measured, including carboxyhemoglobin (43% and 55% decrease in the CHTP and SA groups, respectively). The urinary excretion of mutagenic material was also markedly decreased on Day 5 compared with baseline (89% and 87% decrease in the CHTP and SA groups, respectively). No changes in biomarkers of exposure to HPHCs or urinary mutagenic material were observed between baseline and Day 5 in the CC group. Conclusions Our results provide clear evidence supporting a reduction in the level of exposure to HPHCs of tobacco smoke in smokers who switch to CHTP under controlled conditions, similar to that observed in SA. Implications The reductions observed in biomarkers of exposure to HPHCs of tobacco smoke in this short-term study could potentially also reduce the incidence of cancer, cardiovascular and respiratory diseases in those smokers who switch to a heated tobacco product.

Background Making tobacco products associated with lower risks available to smokers who would otherwise continue smoking is recognized as an important strategy towards addressing smoking-related harm. Predicting use behavior is an important major component of product risk assessment. In this context, risk perception is a possible factor driving tobacco product uptake and use. As prior to market launch real-world actual product use cannot be observed, assessing risk perception can provide predictive information. Considering the lack of suitable validated self-report instruments, the development of a new instrument was undertaken to quantify perceived risks of tobacco and nicotine-containing products by adult smokers, former smokers and never-smokers. Methods Initial items were constructed based on a literature review, focus groups and expert opinion. Data for scale formation and assessment were obtained through two successive US-based web surveys (n = 2020 and 1640 completers, respectively). Psychometric evaluation was based on Rasch Measurement Theory and Classical Test Theory. Results Psychometric evaluation supported the formation of an 18-item Perceived Health Risk scale and a 7-item Perceived Addiction Risk scale: item response option thresholds were ordered correctly for all items; item locations in each scale were spread out (coverage range 75–87%); scale reliability was supported by high person separation indices > 0.93, Cronbach’s alpha > 0.98 and Corrected Item-Total Correlations > 0.88; and no differential item functioning was present. Construct validity evaluations met expectations through inter-scale correlations and findings from known-group comparisons. Conclusions The Perceived Risk Instrument is a psychometrically robust instrument applicable for general and personal risk perception measurement, for use in different types of products (including cigarettes, nicotine replacement therapy, potential Modified Risk Tobacco Products), and for different smoking status groups (i.e., current smokers with and without intention to quit, former smokers, never smokers).

Reduced Risk Products (RRPs) do not burn tobacco and produce lower levels of toxicants than in cigarette smoke. The long-term effects of using RRPs on health are difficult to assess in a pre-market setting and a modeling approach is required to quantify harm reduction. The Population Health Impact Model (Weitkunat et al., 2015) follows a hypothetical population of individuals over time, creating their tobacco use histories and, based on these, estimating relative and absolute risks of lung cancer, ischemic heart disease, stroke and chronic obstructive pulmonary disease. Linking the tobacco use to the risk profile allow us to assess how the relative and absolute risks of these diseases vary between individuals aged 20, 30, 40 or 50 at baseline who have never smoked or who initiated smoking at 19 years old and either continued to smoke, quit smoking, or switched to RRPs with varying degrees of harm reduction. The simulations suggest that, for smokers in their 20s-30s quitting, or switching to RRP primarily prevents the accrual of risk, while in their 40s-50s it reduces risk. Though tobacco prevention has been the primary approach to limit smoking-related diseases, RRPs can also substantially reduce risks in individuals who do not quit.

Introduction: We aimed to compare the pharmacokinetics of nicotine between the heat-not-burn Tobacco Heating System 2.1 (THS 2.1) and combustible cigarettes (CCs). We also examined whether the subjective urge to smoke was associated with the pharmacokinetics of nicotine. Methods: This open-label, randomized, two-period, two-sequence crossover study conducted in 28 healthy smokers assessed the pharmacokinetics of nicotine after single and ad libitum use of the THS 2.1 or CCs. During the 7-day confinement period, blood samples were drawn for pharmacokinetic analysis. Subjective effects related to THS 2.1 or CC use were assessed using the Questionnaire of Smoking Urges (QSU-Brief). Results: The nicotine delivery rate was similar with the THS 2.1 and CCs after single and ad libitum use. The time to the maximum nicotine concentration was 8 minutes after single use of the THS 2.1 and CCs. The time to the peak concentration following ad libitum use was similar between the THS 2.1 and CCs. The maximum plasma nicotine concentration after single use of the THS 2.1 was 8.4ng/mL, 70.3% of that obtained with CCs. A transient reduction from baseline in the urge to smoke of 40% was observed 15 minutes after the single use of both the THS 2.1 and CCs. The mean QSU-Brief total scores following single and ad libitum use were similar for the THS 2.1 and CCs. Conclusions: These results suggest that the THS 2.1 effectively delivers nicotine and achieves similar pharmacokinetic profiles to CCs. The THS 2.1 also reduced the urge to smoke similarly to CCs. Implications: Reducing exposure to toxicants and safer delivery of nicotine are among the strategies that may reduce the harm of smoking-related diseases. In the present study, we investigated the pharmacokinetics of nicotine and their effects on the urge to smoke using the THS 2.1. It was developed to replicate the ritual of smoking as closely as possible by providing nicotine in a way that mimics CC smoking, but limits pyrolysis and combustion by heating tobacco at a much lower temperature than CCs (heat-not-burn).

We performed a cross-sectional, multicentre study in Japan to detect the differences in biomarkers of exposure and cardiovascular biomarkers between smokers and non-smokers. Several clinically relevant cardiovascular biomarkers differed significantly between smokers and non-smokers, including lipid metabolism (high-density lipoprotein cholesterol concentrations – lower in smokers), inflammation (fibrinogen and white blood cell count – both higher in smokers), oxidative stress (8-epi-prostaglandin F2α – higher in smokers) and platelet activation (11-dehydro-thromboxane B2 – higher in smokers) (p ≤ 0.0001). These results provide further evidence showing that cardiovascular biomarkers can discriminate smokers from non-smokers, and could be used to evaluate the risks associated with tobacco products.

Introduction The menthol Tobacco Heating System 2.2 (mTHS) is a newly developed candidate modified-risk tobacco product intended to reduce exposure to the harmful and potentially harmful constituents (HPHCs) of conventional cigarette (CC) smoke. This study examined the impact of switching to mTHS on biomarkers of exposure to HPHCs relative to menthol CCs (mCCs) and smoking abstinence (SA). Methods In this three-arm, parallel-group study, 160 Japanese adult smokers (23–65 years; smoking ≥10 mCCs per day) were randomized to mTHS (n = 78), mCC (n = 42), or SA (n = 40) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to HPHCs, human puffing topography, safety, and subjective effects of smoking measures. Results After 5 days of product use, the concentrations of carboxyhemoglobin, 3-hydroxypropylmercapturic acid, monohydroxybutenyl mercapturic acid, and S-phenylmercapturic acid were 55%, 49%, 87%, and 89% lower (p < .001), respectively, in the mTHS group than in the mCC group. Other biomarkers of exposure (measured as secondary endpoints) were 50%–94% lower in the mTHS group than in the mCC group on day 5. These reductions in the mTHS group were maintained at day 90, similar to the SA group. Switching to mTHS was associated with changes in human puffing topography (shorter puff intervals and more frequent puffs). The urge-to-smoke and smoking satisfaction levels on day 90 were similar in the mTHS and the mCC groups. Conclusion Switching from mCCs to mTHS significantly reduced exposure to HPHCs relative to continuing smoking mCCs with concentrations similar to those observed following SA in Japanese adult smokers. Implications This randomized study compared the impact of switching to a modified-risk tobacco product candidate mTHS on biomarkers of exposure to HPHCs of cigarette smoke relative to continuing smoking cigarettes or abstaining from smoking in sequential confinement and ambulatory settings. The study showed that switching to mTHS was associated with significant biomarker reductions within 5 days in confinement, these reductions being maintained throughout the ambulatory setting up to day 90. The results provide evidence that switching to mTHS reduces real-life exposure to HPHCs in adult smokers.

Background and Objective: Filgrastim is a human granulocyte-colony stimulating factor (G-CSF). The biological activity of filgrastim is identical to that of endogenous G-CSF. It controls neutrophil production within the bone marrow by stimulating the proliferation, differentiation and survival of myeloid progenitor cells and some end-cell function activation. The purpose of this work is to propose a target-mediated drug disposition pharmacokinetic model of filgrastim. Methods: A mechanism-based population pharmacokinetic model was developed to account for receptormediated endocytosis as a mechanism for nonlinear disposition of G-CSF. Time profiles of serum filgrastim concentrations following subcutaneous doses of 2.5, 5 and 10 μg/kg and intravenous infusion of 5 μg/kg over 0.5 hour were studied. The pharmacokinetic model included first-order elimination from the serum, receptor binding, turnover of free receptors and internalization of drug-receptor complexes. The proposed targetmediated drug disposition models served as a tool to study drug absorption and the impact of receptor binding on filgrastim clearance. Results: Filgrastim was found to exhibit parallel absorption with first- and zero-order kinetics and bioavailability of 69.1%. The majority of the drug (58.6%) was absorbed by zero-order processes, presumably through the lymphatic system. The equilibrium dissociation constant (Kd) was estimated as 16.38 pM. Conclusion: The proposed model predicts that clearance is initially mostly governed by the binding of filgrastim to G-CSF receptors. Subsequently, the clearance slows down because of the saturation of binding sites, and occurs mostly via the linear (renal) pathway. Finally, for G-CSF concentrations lower than the Kd, target-mediated clearance dominates. The presented receptor-mediated model adequately describes filgrastim serum concentrations and quantifies the role of receptor binding in G-CSF clearance.

This study is part of a larger prospective research program focusing on termination of pregnancy (TOP). One hundred and three women requesting TOP were interviewed before the intervention and 6 months later using open and closed questions and psychological tests. This paper focuses on contraceptive practices before and after abortion. The analysis took into account specific aspects of contraceptive practices and patients' behaviors. The aims were to assess: the level of women's knowledge and practice of contraception at the time of request for a TOP; the behavioral modifications following professional counseling 6 months after TOP; the influence of psychological and sexual factors, and those linked to the women's use of contraception. Most women (n = 101) had already used recommended contraception. During the cycle that had resulted in pregnancy, more than half (n = 58) had used recommended contraception and one third had not used any contraception. Six months later, 86 women used recommended contraception, and 17 did not. The majority of women reported changes in their contraceptive methods (n = 82). Most changes were within recommended methods. The women (n = 10) who continued to practice unprotected intercourse post-TOP were slightly older, satisfied with their sexual relations with their partner, often involved in a long-term and good relationship. During post-TOP period, it is essential to take into account the psychological dynamics involved in the choice of contraceptive methods. Counseling should emphasize not only protection against an unwanted pregnancy but also protection against sexually transmitted diseases, which is often perceived as a less important issue following TOP.

Objective: Our study was designed to investigate 5-aminolevulinic acid (ALA) as a candidate for intraperitoneal photodynamic therapy (IP-PDT). The toxicity of IP-PDT and the effects of IP-PDT on abdominal and pelvic organs, particularly the small intestine, were investigated after ALA administration and illumination with violet laser light. Study design and results: The toxicity of IP-PDT was evaluated in Fischer 344 rats in two ways. In the first part of the study local PDT effects on the intestine were analyzed histologically. Violet laser light (lambda: 406-415 nm) was applied as a 2 cm diameter spot on the intestine 3 h after intraperitoneal (i.p.) administration of 50 mg/kg ALA. (A) Histological tissue samples were taken 0 min, 6 h and 1, 2 and 3 days after treatment (optical dose 3.2 J/cm(2)). Immediately after local PDT (3.2 J/cm(2), 50 mg/kg ALA) showed no effect on the intestine. However, 6 h post PDT there was complete destruction of the mesothelial lining and the outer (longitudinal) smooth muscle. Ganglion cells of the myenteric (Auerbach) plexus were also destroyed. The inner circular smooth muscle, the muscularis mucosa and the lamina propria were unharmed. Marked lymphectasia was present at this time. (B) To determine the threshold light dose of tissue destruction caused by PDT, different optical doses (1.6, 3.2, 6.4 J/cm(2)) were administered and histologic analysis of tissue samples were obtained I day post treatment. Destruction of the entire external musculature, submucosal structures and muscularis mucosa of the intestine at the illumination site could be observed above 1.6 J/cm(2) (50 mg/ka ALA). In the second part of the study whole peritoneal cavity PDT (WPC-PDT) was performed by illumination of the whole peritoneal cavity with 1.6 j/cm(2) Violet light 3 h after ALA administration using different drug doses (200, 100 and 50 mg/kg). WPC-PDT showed lethal toxicity with a drug dose above 50 mg/kg ALA at 1.6 j/cm(2). The probable cause of death in the first 3 days after IP-PDT was rhabdomyolysis, whereas when death occurred at longer time intervals, megaintestine associated with significant damage could be observed; however, without perforation of the intestinal wall. Conclusion: In rats WPC-PDT with 50 mg/kg ALA, 1.6 J/cm2 at lambda=415 nm was the maximum tolerable light dose. This dose is likely to be above the threshold of destruction of ovarian cancer micrometastasis. (C) 2002 Elsevier Science BY All rights reserved

Objective: This study examined the influence of weather conditions on the incidence of outpatient emergency consultations at the Department of Obstetrics and Gynecology at the Regional Hospital in Lugano, Switzerland. Study Design: The medical records of all women who attended the outpatient emergency unit at the Department for Obstetrics and Gynecology over the 1-year study period were reviewed. The final diagnosis was pelvic pain of unidentified origin in 180 cases, menorrhagia and/or metrorrhagia in 95 cases, threatened abortion in 56 cases and spontaneous abortion in 54 cases. The meteorological factors considered were atmospheric pressure, temperature, humidity and global radiation. A logistic regression model was used to correlate the occurrence of symptoms with the chosen weather factors. Results: High mean daily temperature was found to be a significant predictor of pelvic pain (p < 0.001). A rise in barometric pressure compared to the previous day increased the probability of menorrhagia and/or metrorrhagia (p = 0.001). Higher minimal temperature (p = 0.011) and an increase in atmospheric pressure (p = 0.006) were identified as positive predictors of threatened abortion. None of the meteorological factors considered seemed to influence the frequency of spontaneous abortions. Conclusion: Meteorological factors such as temperature and barometric change appear to affect the probability of emergency admissions for gynecological symptoms including uterine bleeding, threatened abortion and pelvic pain.

The objective of the study was to determine the suppressive effect on ovarian activity of 20 micrograms ethinylestradiol plus 75 micrograms gestodene administered for 21 or 23 days. The study was designed as a double-blind, randomized, multicenter trial in 60 women. A pre-treatment cycle, three treatment cycles and a post-treatment period were monitored by ovarian ultrasound and by LH, FSH, 17 beta-estradiol and progesterone measurements every other day. No ovulation and no luteinized, unruptured follicle were observed. Suppression of ovarian activity was more pronounced by the 23-day regimen. 17 beta-Estradiol serum levels during the last six days of a cycle and during the first six days of the next cycle were significantly less (p0.05) in the 23-day regimen. The superiority of the 23-day regimen in comparison to the 21-day regimen with regard to the suppression of ovarian activity was shown in this study. The observed differences in the 17 beta-estradiol levels and follicular development between a 21-day and 23-day preparation combine to suggest that shortening the pill-free interval in combined oral contraceptives may increase the contraceptive safety margin in women on low-dose formulations.The objective of a double-blind randomized multicenter trial enrolling 60 women was to determine the suppressive effect on ovarian activity of 20 mcg ethinyl estradiol plus 75 mcg gestodene administered for 21 or 23 days. The sites were at the Department of Obstetrics and Gynecology, University of Manchester, UK, and the Institute for Sterility Treatment, Vienna, Austria. The 60 women were healthy volunteers 19-35 years old, and they were randomized with 30 subjects each entering the treatment phase for either the 21-day regimen or the 23-day regimen. A pre-treatment cycle, 3 treatment cycles, and a post-treatment period were monitored by ovarian ultrasound and by measurements of luteinizing hormone (LH), follicle stimulating hormone (FSH), 17-beta-estradiol, and progesterone every other day. Two women on the 21-day regimen forgot to take 1 pill each. Side effects were minor including breast tension, vomiting, nausea, acne, and weight loss or weight gain. Withdrawal bleeding commenced in the 23-day group 2 days later than in the 21-day group. The frequency of intracyclic bleeding decreased when progressing from treatment cycle 1 to 3. No ovulation and no luteinized, unruptured follicle were observed. After stopping the medication, spontaneous ovulations were observed in all volunteers in the 23-day regimen. Suppression of ovarian activity was more pronounced in the 23-day regimen. 17-beta-estradiol serum levels during the last 6 days of a cycle and during the first 6 days of the next cycle were significantly less (p 0.05) in the 23-day regimen. The superiority of the 23-day regimen in comparison to the 21-day regimen with regard to the suppression of ovarian activity was shown. The observed differences in the 17-beta-estradiol levels and follicular development between the 21-day and 23-day preparations suggest that shortening the pill-free interval in combined oral contraceptives may increase the contraceptive safety margin in women on low-dose formulations.

Since the fall of the Berlin Wall, fundamental political changes in eastern Europe have affected the Soviet-style health care systems that formerly provided basic care for everyone. Many of these systems have collapsed, and the new systems of social insurance that have replaced them often are inadequate. Advanced Training in Reproductive Health in Romania aimed to create an authority in family planning and reproductive health in selected Romanian university centers and to improve training and research capabilities. Initially, the project had 2 main goals: to provide advanced training in reproductive health and family planning to Romanian obstetrics–gynecology specialists from the main university centers—which would allow them to train other physicians (obstetricians, gynecologists, and general practitioners) and medical students—and to develop, test, and finalize specific training materials in Romanian to be used by the new trainers.

A 51-year-old woman referred herself to the Obstetric Unit in February 2001 demanding urgent attention on the grounds that she was about to give birth. Following an initial pregnancy test at home that she reported as positive (September 2000), the woman had visited two gynaecologists in September and November 2000 who repeated the pregnancy test, both with negative results. There were no clinical signs of pregnancy and two pelvic ultrasound examinations confirmed the absence of pregnancy. Furthermore, tubal ligation had been performed some 10 years earlier. The patient was a housewife who had been married since 1975. The couple had one child, a daughter aged 17. No abnormalities in the patient’s medical history were noted, and she was not on any hormone substitution therapy. The gynecological examination was normal, with no clinical signs of pregnancy. Her last menstrual period had been about 1 year previously and she had experienced hot flushes over the last 2 years.

This study compared the impact on carbohydrate metabolism of two combinedoral contraceptives (COCs). This open-label, single-center trial enrolled participants for a total of 15 cycles. Thirty-six women were randomized to receive either 20 microg ethinyl estradiol (EE) and 75 microg gestodene (GSD) or 20 microg ethinyl estradiol and 150 microg desogestrel (DSG) daily for 21 days out of 28. A glucose tolerance test was performed at baseline and cycles 6 and 13. The area under the curve (AUC) for glucose increased in both study groups. The change was statistically significant (p = 0.036) for the 20 EE/75 GSD group at cycle 6 versus baseline. Fasting blood glucose at cycle 13 was significantly (p0.01) higher for both treatment groups compared to baseline. No changes were found for fasting insulin and fasting C-peptide levels or for the AUCs of insulin or C-peptide. Both regimens were well tolerated. Gestodene and desogestrel in combination with 20-microg ethinyl estradiol induce similar changes in carbohydrate metabolism which are smaller than those described earlier for COCs containing higher estrogen doses or more androgenic progestins such as levonorgestrel.

Objective: Premenstrual dysphoric disorder (PMDD), also referred to as premenstrual syndrome (PMS), is a recurrent luteal-phase condition involving regular occurrence, prior to the onset of menstrual bleeding, of a cluster of symptoms of sufficient severity to result in the deterioration of interpersonal relationships and normal activity. Several treatment options for PMDD with varying degrees of efficacy have been proposed. The literature is reviewed and treatments of proven efficacy are reported. Study design and methods: A MEDLINE/ Cochrane Library search for all studies on PMS and PMDD published between 1983 and 2001 was performed. Only randomised trials were included. Results: Several treatments appear to be effective. Among these are increased physical activity, dietary change, mineral salt supplementation and ovulation inhibitors. The most effective seems to be administration of selective inhibitors of serotonin reuptake (SSRIs). Conclusion: Therapy should begin with non-medicated approaches and pharmacological treatment should only be envisaged if symptoms persist.

The majority of menopausal women suffer from climacteric symptoms. The purpose of this study was to assess the effects of acupuncture on the quality of life and reproductive hormones secretion in menopausal women. Eleven (11) menopausal women with climacteric symptoms entered this prospective study. The Menopause Specific Quality of life Questionnaire was filled out by the patients before the first acupuncture session, after the last one (5 weeks later), and 3 months after the last acupuncture session. Reproductive hormones including follicular-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, and prolactin were measured before and after treatment. Acupuncture significantly improved menopausal vasomotor symptoms (p = 0.001 and p = 0.003 for the end of treatment and 3 months later, respectively) and physical symptoms (p = 0.014 at the end of treatment and p = 0.046 3 months later). It did not change psychosocial or sexual symptoms, nor did it change the measured reproductive hormones. In conclusion, acupuncture is shown to be effective in relieving vasomotor and physical disturbances of menopausal women with effects lasting at least up to 3 months after termination of the treatment. Acupuncture may be a useful treatment alternative for women who are unable or do not want to receive hormone replacement therapy. A prospective study with larger sample sizes will be needed to define the role of acupuncture in the management of menopausal symptoms.

Objective: To determine the influence of termination of pregnancy (TOP) on women’s sexuality. Design: Prospective qualitative and quantitative study. Subjects: 103 women undergoing induced abortion by vacuum aspiration, interviewed 1–3 weeks before surgery and 6 months later. Results: After TOP, patients described symptoms of fatigue (39%), feelings of guilt (35%), sadness (34%) and anxiety (29%). Thirty-one percent of women presented at least one sexual dysfunction, 18% a decrease in sexual desire, 17% orgasmic disorders, 12% vaginal dryness and 11% dyspareunia. These sexual dysfunctions were correlated with anxiety and symptoms of depression following TOP. Six months after TOP, 57% of the women reported no change in their sexual satisfaction, 17% were ‘more satisfied’ and 7% ‘less satisfied’. Lessening of sexual satisfaction after TOP was correlated with diminished partner satisfaction (p < 0.00001), fatigue (p < 0.0009), feelings of guilt (p < 0.01), low frequency of sexual relations (p < 0.01) and anxiety over sexual relations (p < 0.02). Conclusions: Six months after TOP some women presented persisting sexual dysfunction. This sexual dysfunction may be explained essentially by the appearance of symptoms of anxiety and depression following TOP. When the quality of the relationship was satisfying, women could cope more easily with the appearance of a sexual dysfunction.

An open label, non-comparative study was carried out in 22 women over a total of five cycles. After an untreated cycle, oral administration of 20 microg ethinyl estradiol (EE) with 50 microg gestodene (GST) (tablets taken daily for 21 days with a break of 7 days) was commenced, and three treatment cycles were followed by an untreated follow-up control cycle. The ability of this formulation to inhibit ovulation and suppress ovarian activity was assessed by using hormonal parameters and ultrasound. One ovulation occurred during treatment. Luteinized unruptured follicles were observed in three cases in the second treatment cycle and in one case during the third treatment cycle. Follicle-like structures larger than 13 mm associated with a serum estradiol level of more than 30 pg/mL were noted in 19% of the women in the first treatment cycle. The rate of active follicle-like structures was 43% in the second treatment cycle and 28% in the third treatment cycle. The results were compared with previously reported findings of a preparation containing 20 microg EE and 75 microg GST. With regard to ovarian grading and endogenous hormone secretion, considerably more residual ovarian activity, with all parameters examined, was found in the 20 microg EE and 50 microg GST preparation compared to the 20 microg EE and 75 microg GST preparation. It was concluded that the 20 microg EE and 50 microg GST preparation administered for 21 days does not meet the requirements of a combined oral contraceptive with respect to ovulation inhibition.

Study Objective: To determine the prevalence of high- and intermediate-risk type human papillomavirus (HPV) infection and cervical dysplasia in an urban Swiss adolescent population attending the local Adolescent Clinic, using a liquid-based Pap test combined with risk type HPV DNA testing. To determine the prevalence of Chlamydia trachomatis in the same study population. Design: Observational study. Setting: The Adolescent Clinic of the Department of Obstetrics and Gynaecology at the University Clinic, Geneva, Switzerland. Participants: 134 women between 14 and 20 years of age were enrolled in the study. Main Outcome Measures: A standardized patient file on demographic and sexual history information was compiled and completed by physical examination, including a Pap test with adjunct high- and intermediate-risk type HPV DNA detection. Results: Of the 134 specimens analyzed for HPV, 115 patients were negative and 19 (14.2%) were positive for HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, or 68. A significant association between HPV infection and having had more than one lifetime sexual partner was found (P < .05). Six (31.6%) of the HPV-positive and three (2.6%) of the HPV-negative specimens had a low-grade squamous intraepithelial lesion (SIL) by cytology. Abnormal Pap test was related to HPV infection (odds ratio, 46.2; 95% confidence interval, 7.4 to 287.4) and, inversely, to age at first sexual intercourse (odds ratio, 0.98; 95% confidence interval, .97 to 1.0). Conclusion: High- and intermediate-risk type HPV infection is a frequent finding in our study group and is linked to having had more than one lifetime sexual partner. No association was found between HPV infection and other potential risk factors such as patient's age, age at first intercourse, frequency of intercourse during the three months prior to the investigation, smoking habits, or alcohol consumption.

The aim of this study was to determine the impact of termination of pregnancy (TOP) on women's sexual well-being, the couple and contraceptive practice. In a prospective qualitative and quantitative study, 103 women undergoing induced abortion by vacuum aspiration were interviewed before the abortion and 6 months later. The interview was performed by means of a questionnaire including open and closed questions, and two psychological tests (Locke-Wallace and Horowitz). After TOP, the majority of women did not report changes in their sexual behavior and satisfaction. Eighteen per cent of women reported a decrease in sexual desire and 17% reported orgasmic disorders. About one-third of women described psychosomatic symptoms, but a minority were traumatized by the event. Ninety-eight per cent of the women were informed about, and had practiced, contraception in the past; 69% had actually used some kind of contraception during the menstrual cycle that had resulted in pregnancy (31% had had unprotected intercourse). Six months later, 83% practiced contraception, and only 17% did not. Fourteen out of 84 couples separated after TOP (one in six). Six months after TOP, the large majority of women interviewed seemed able to cope with TOP. A minority presented some persisting sexual dysfunction and/or some psychosomatic symptoms.

In conclusion we can draw some practical advice for family planning providers from our survey: (a) the term—still frequently used—‘morning after pill’ should be avoided and more publicity should concentrate on the timing of its use; (b) counseling on emergency contraception (EC) should state that the method is not 100% effective; (c) the family planning services and other providers of EC may consider producing and providing short information leaflets on EC. (excerpt)

Background and Objective Characterizing nicotine pharmacokinetics is challenging in the presence of background exposure. We performed a combined retrospective population pharmacokinetic analysis of 8 trials, including exposure to Tobacco Heating System and cigarettes (both inhaled), nicotine nasal spray and oral nicotine gum. Method Data from 4 single product use trials were used to develop a population pharmacokinetic model with Phoenix® NLME™ and to derive exposure parameters. Data from 4 separate ad libitum use studies were used for external validation. A total of 702 healthy adult smokers (54% males; 21–66 years of age; smoking ≥10 cigarettes/day; from US, Europe and Japan) were eligible for participation. Results Two-compartment linear disposition combined with zero-order absorption model was adequate to describe nicotine pharmacokinetics, and a mono-exponentially decreasing background component was utilized to account for nicotine carry-over effects. Apparent nicotine clearance was typically 0.407 L/min in males and 26% higher in females (68% inter-individual variability). Bioavailability was product-specific, decreased with increasing nicotine ISO yield, and increased with increasing body weight. Absorption duration was apparently prolonged with nicotine gum. The typical initial and terminal half-lives were 1.35 and 17 h, respectively. The presence of menthol did not impact the determinants of the area under the curve. The model adequately described the external validation data. Conclusions The population model was able to describe in different populations the nicotine pharmacokinetics after single product use and after 4 days of ad libitum use of Tobacco Heating System, cigarettes, and of different nicotine replacement therapies with various routes of administration. Electronic supplementary material The online version of this article (doi:10.1007/s13318-017-0405-2) contains supplementary material, which is available to authorized users.