bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current guidelines applicable for the approval of topically applied dermatological drugs in the EU
Authors: Straube Myrjam Dorothea , Zesch Achim 
Published: October 2004

AbstractDermatologicals as well as other medicinal products are submitted to the rules governing medicinal products in the European Union (EU) (Directive 2001/83/EC). With appreciation of the EU enlargement those regulatories deserve a recent consideration with special regard to the peculiarities of external dermatological therapy, recently passed novel and future guidelines. As regards the criteria for authorization of a medicinal product it is set out in Regulation (EEC) 2309/93 Article 11(1) that a marketing authorization shall be refused if it appears that the quality, the safety or efficacy of the medicinal product have not been adequately or sufficiently demonstrated by the applicant. Article 26(1) of Council Directive 2001/83/EC is worded a little differently but the criteria are the same irrespective of the procedure for the marketing authorization. For the final evaluation of the benefit/risk profile of a topically applied dermatological medicinal product not only the active agent but the whole galenic formulation as well has to be taken into account as the extent of penetration of the active compound might be influenced by changing the non‐active substances. Furthermore the vehicle itself – independent of the active agent – influence the dermatological disorder, often in dependence on the stage of the dermatopathy. With special concern to safety/tolerability the (photo)toxic and (photo)allergic potential of the dermatological drug have to be taken into consideration too. In case of total body therapy in children the differing percutaneous resorption due to another body surface/body weight relation deserves special concern. The following review gives a survey of the current most important EU‐guidelines for the evaluation of the benefit/risk profile of topically applied dermatological medicinal drugs and an outlook on further developments. As systemically applied dermatological medicinal products are assessed like other systemically applied drugs they are not treated in the following contribution.
Volume‐sensitive chloride channels (ICl,vol) mediate doxorubicin‐induced apoptosis through apoptotic volume decrease in cardiomyocytes
Authors: D'Anglemont De Tassigny Alexandra , Souktani Rachid , Henry Patrick , Ghaleh Bijan , Berdeaux Alain 
Published: October 2004

AbstractApoptosis is associated with early changes in cell volume through a mechanism called apoptotic volume decrease (AVD). As volume‐sensitive chloride channels (ICl,vol) are known to play a key role in the regulation of cell volume, this study investigated the role of ICl,vol and AVD in doxorubicin‐induced apoptotic cell death in adult rabbit ventricular cardiomyocytes. Exposure of cardiomyocytes to 1 μm doxorubicin induced a rapid and significant reduction in cell volume of cardiomyocytes (average of 15%), i.e. AVD as well as increases in the early markers of apoptosis, annexin V labeling and caspase‐3 activity. Doxorubicin also induced the activation of a current characterized as ICl,vol on the basis of the external chloride sensitivity and pharmacological properties with the patch clamp technique. Doxorubicin‐induced AVD and apoptosis were both abolished when cardiomyocytes were exposed to the ICl,vol inhibitors 5‐nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB) (0.1 mm) or indanyloxyacetic acid 94 (IAA‐94) (10 μm). The crucial role of ICl,vol during AVD and apoptosis was confirmed using C2‐ceramide, another pro‐apoptotic compound. These results demonstrate that activation of ICl,vol plays a major role in the mechanism leading to cell shrinkage and apoptosis‐induced AVD by agents such as doxorubicin or C2‐ceramide in adult cardiomyocytes.
Influence of a thiazole derivative on ethanol and thermally oxidized sunflower oil‐induced oxidative stress
Authors: Kode Aruna , Rajagopalan Rukkumani , Penumathsa Suresh Varma , Menon Venugopal P. 
Published: October 2004

AbstractThe present work describes the protective influence of the dendrodoine analogue (DA) [4‐amino‐5‐benzoyl‐2‐(4‐methoxy phenylamino) thiazole] on thermally oxidized sunflower oil and ethanol‐induced oxidative stress. Ethanol was fed to animals at a level of 20% [(7.9 g/kg body weight (bw)] and thermally oxidized sunflower oil at a level of 15% (15 mL/100 g feed). Hepatotoxicity was assessed by measuring the activity of plasma aspartate transaminase (AST), alkaline phosphatase (ALP) and γ‐glutamyl transferase (GGT), which were elevated in thermally oxidized oil, and ethanol fed rats when compared with normal control rats. Tissue damage was associated with increased lipid peroxidation and disruption in the antioxidant defence mechanism in thermally oxidized oil‐ and ethanol‐fed groups when compared with normal control group. The activity of liver marker enzymes (AST, ALP and GGT) and the level of lipid peroxidation decreased when DA was administered along with ethanol and thermally oxidized oil. The antioxidant status was near normal in DA‐administered groups. Thus we propose that DA exerts antioxidant properties by modulating the activity of hepatic marker enzymes, level of lipid peroxidation and antioxidant status.
17 β‐Estradiol prevents focal cerebral ischemic damages via activation of Akt and CREB in association with reduced PTEN phosphorylation in rats
Authors: Choi Yeoung Cheul , Lee Jeong Hyun , Hong Ki Whan , Lee Kyu Sup 
Published: October 2004

AbstractThis study aimed to assess the signaling pathway of the neuroprotective action of estrogen in the cerebral ischemic injury evoked by subjecting rats to 2‐h occlusion of the middle cerebral artery (MCA) followed by 24‐h reperfusion. Rats received 17 β‐estradiol (1, 4 and 10 mg/kg, i.p.) 24 h before and 5 min after the completion of 2‐h MCA occlusion. The cerebral infarct area was consistently observed in the cortex and striatum of the left hemisphere. Increased terminal deoxynucleotidyl transferase‐mediated deoxyuridine–biotin nick‐end labeling (TUNEL)‐positive cells and DNA fragmentation in the penumbral zone were significantly reduced by 17 β‐estradiol. In line with these results, 17 β‐estradiol significantly increased Akt and cyclic AMP response element binding protein (CREB) with increased Bcl‐2 protein in the ischemic area, whereas the elevated the phosphatase and tensin homolog deleted from chromosome10 (PTEN) phosphorylation was significantly reduced with decreased Bax protein and cytochrome c release. Inhibition of DNA fragmentation, PTEN phosphorylation, and Akt activation by 17 β‐estradiol were antagonized by iberiotoxin, a maxi‐K channel blocker. Taken together, it is suggested that suppression of cerebral ischemic injury by 17 β‐estradiol may be ascribed to the maxi‐K channel opening‐coupled downregulation of PTEN phosphorylation and upregulation of Akt and CREB phosphorylation with resultant increase in Bcl‐2 protein and decrease in Bax protein and cytochrome c release.
Interactions between aspirin and COX‐2 inhibitors or NSAIDs in a rat thrombosis model
Authors: Umar Anwar , Boisseau Michel , Yusup Abdiryim , Upur Halmurat , Bégaud Bernard , Moore Nicholas 
Published: October 2004

AbstractRecent in vitro studies, clinical trials and epidemiological studies have suggested possible interactions between aspirin and other cyclo‐oxygenase (COX) inhibitors, such as ibuprofen of the COX‐2 inhibitors celecoxib and rofecoxib. The objective of this study was to test the effects of aspirin (1, 2.5 and 5 mg/kg), and ibuprofen (4 and 15 mg/kg), diclofenac (2.5 mg/kg), flurbiprofen (2 mg/kg), celecoxib (7.5 mg/kg), and rofecoxib (1 mg/kg), alone or combined on a rat model of arterial thrombosis. Drugs were given orally daily for 7 days, before insertion of an arterio‐venous shunt thrombosis system, left in place for 15 min. Main parameter was thrombus weight. Five to 12 rats were used per experiment, and 35 controls overall. Aspirin inhibited thrombus formation in a dose‐dependent manner. All NSAIDS given alone also inhibited thrombus formation to approximately the same level as aspirin 1 mg/kg/day. Ibuprofen, celecoxib and rofecoxib inhibited the effects of aspirin, but not diclofenac or flurbiprofen. The interactions with aspirin do not seem to affect all NSAIDs to equal levels. The clinical impact of this needs to be confirmed in adequately powered clinical trials or pharmaco‐epidemiological studies.
Physiology of Female Sexual Function: Animal Models
Authors: Giraldi Annamaria , Marson Lesley , Nappi Rossella , Pfaus James , Traish Abdulmaged M. , Vardi Yoram , Goldstein Irwin 
Published: October 2004

ABSTRACTIntroductionData concerning the physiology of desire, arousal, and orgasm in women are limited because of ethical constraints.AimTo gain knowledge of physiology of female sexual function through animal models.MethodsTo provide state-of-the-art knowledge concerning female sexual function in animal models, representing the opinions of seven experts from five countries developed in a consensus process over a 2-year period.Main Outcome MeasureExpert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate.ResultsSexual desire may be considered as the presence of desire for, and fantasy about, sexual activity. Desire in animals can be inferred from certain appetitive behaviors that occur during copulation and from certain unconditioned copulatory measures. Proceptive behaviors are dependent in part on estrogen, progesterone, and drugs that bind to D1 dopamine receptors, adrenergic receptors, oxytocin receptors, opioid receptors, or gamma-amino butyric acid receptors. Peripheral arousal states are dependent on regulation of genital smooth muscle tone. Multiple neurotransmitters/mediators are involved including adrenergic, and nonadrenergic, noncholinergic agents such as vasoactive intestinal polypeptide, nitric oxide, neuropeptide Y, calcitonin gene-related peptide, and substance P. Sex steroid hormones, estrogens and androgens, are critical for structure and function of genital tissues including modulation of genital blood flow, lubrication, neurotransmitter function, smooth muscle contractility, mucification, and sex steroid receptor expression in genital tissues. Orgasm may be investigated by urethrogenital (UG) reflex, in which genital stimulation results in rhythmic contractions of striated perineal muscles and contractions of vagina, anus, and uterine smooth muscle. The UG reflex is generated by a multisegmental spinal pattern generator involving the coordination of sympathetic, parasympathetic, and somatic efferents innervating the genital organs. Serotonin and dopamine may modulate UG reflex activity.ConclusionMore research is needed in animal models in the physiology of female sexual function.
Physiology of Erectile Function
Authors: Sáenz de Tejada Iñigo , Angulo Javier , Cellek Selim , González-Cadavid Nestor , Heaton Jeremy , Pickard Robert , Simonsen Ulf 
Published: October 2004

ABSTRACT

Introduction
There are numerous investigations concerning the balance and interactions between relaxant and contractile factors regulating penile smooth muscle (arterial and trabecular) tone, the determinant of penile flaccidity or erection. Enhanced knowledge of erectile physiology may improve management of men with erectile dysfunction.

Aim
To provide state-of-the-art knowledge on the physiology of erectile function.

Methods
An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a two-year period. Concerning the physiology of erectile function and pathophysiology of erectile dysfunction committee, there were seven experts from five countries.

Main Outcome Measure
Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate.

Results
Key roles in the mechanism determining the tone of penile smooth muscle are played by the rise of the intracellular concentration of free calcium and the sensitivity of the contractile machinery to calcium, endothelial health, endothelium-derived nitric oxide, endothelium-derived hyperpolarizing factor (EDHF), neuronal nitric oxide, cyclic guanosine monophosphate-dependent protein kinase and phosphodiesterase type 5.

Conclusion
A number of new mechanisms have been identified for the local regulation of penile smooth muscle contractility and therefore penile erection. Molecules participating in these pathways can be considered targets for the development of new treatments to treat erectile dysfunction.
Psychophysiological Assessment in Premenopausal Sexual Arousal Disorder
Authors: Brotto Lori A. , Basson Rosemary , Gorzalka Boris B. 
Published: October 2004

ABSTRACT

Introduction
Female sexual arousal disorder (FSAD) is a complex diagnostic category whose definition continues to evolve.

Aim
The purpose of this study was to explore the physiological patterns of genital arousal in 31 women with and 30 women without sexual arousal difficulties using a vaginal photoplethysmograph. In addition, subtypes of FSAD, based on a recently proposed redefinition, were explored on measures of sexual arousal.

Results
Whereas there were no psychophysiological or subjective sexual arousal differences when the entire group of women with arousal complaints was compared to a control group, significant differences emerged when subtypes of arousal disorder were compared. Only women fitting the description of “Genital Arousal Disorder” showed evidence of impaired psychophysiological arousal, whereas those characterized with “Subjective Sexual Arousal Disorder” and “Combined Genital and Subjective Sexual Arousal Disorder” did not differ from the control group. These subgroups also differed in the correlation between psychophysiological and subjective arousal.

Conclusion
Overall, there is evidence for diagnostic heterogeneity in FSAD which supports the recent redefinition of this disorder into subtypes.
A Swedish Telephone Help-Line for Sexual Problems: A 5-Year Survey
Authors: Fugl-Meyer Kerstin S. , Arrhult Helene , Pharmanson Helena , Bäckman Ann-Charlotte , Fugl-Meyer Ann Mirjam , Fugl-Meyer Axel R. 
Published: October 2004

ABSTRACT

Introduction
Telephone help-lines for people with sexual problems have been established in many European countries during the late decade. They, however, have very different modes of operation, and very few reports focusing on the way they function have been published internationally.

Aim
To describe the methods and activities of a Swedish help-line for sexual problems.

Methods
In the 5 years, from 1999 to 2003, 27,387 persons called the Swedish toll-free help-line for “impotence and sexual problems” that operates around the clock. The majority of callers appeared to be looking for information on erectile dysfunction. A counseling option staffed by experts in sexual medicine counseled 2,817 (men 73%, women 27%). A further 478 callers were professionals wanting information or advice.

Results
Among a wide spectrum of problems associated with the callers’ sexual life, sexual dysfunctions were the most frequent. Calls about sexual abuse, sexual preference, paraphilias, and other subjects were also received. Among those with sexual dysfunction, 33% of men and 41% of women had more than one sexual dysfunction. These were often concomitant with a frequently drug-treated, medical condition. In addition to counseling, the majority of callers were advised to contact physicians or specialists in sexology/sexual medicine for further help.

Conclusion
Competent person-to-person telephone counseling in the multifaceted bio–psycho–social field of sexual problems requires broad knowledge on sexual medicine.
Prevalence of Erectile Dysfunction Among Young Adults: Results of a Large-Scale Survey
Authors: Heruti Rafi , Shochat Tzipi , Tekes-Manova Dorit , Ashkenazi Itshak , Justo Dan 
Published: October 2004

ABSTRACT

Introduction
Erectile dysfunction (ED) can be an early and first sign of an underlying systemic disease. A screening program is offered by the Medical services of the Israel Defense Force for career servicemen at the Staff Periodic Examination Center (SPEC) aimed at early detection of morbidity. The Sexual Human Inventory for Males (SHIM) questionnaire was introduced to these men in order to identify ED, to offer men with ED suitable treatment options, and to investigate underlying systemic diseases.

Aim
To provide epidemiological data regarding the prevalence of ED among a large-scale young adult population.

Methods
Subjects aged 25–50 years are undergoing a routine check-up at SPEC. Blood samples, physiological measures, demographic variables, information on health status and smoking habits are recorded and documented. The SHIM self-administrated questionnaire was used to characterize ED.

Results
During 2001–2003, 11,914 males reported to SPEC (average age 34.8 ± 7.1 years). Five thousand eight hundred thirty-six of them chose to answer the SHIM questionnaire (compliance of 48.9%). According to the SHIM scores, at least one out of three men (26.9%) suffered from ED (19%, 7%, and 1% had mild, moderate, and severe ED, respectively). ED was prevalent also among young adults: 22.1% of males under-40 had low SHIM scores (&lt;21). Severity of ED correlated with age and diabetes mellitus.

Conclusion
In light of these results, we conclude that ED is a major health concern among young men as well. Incorporating questions regarding sexual health in a routine check-up may encourage more men to seek treatment, not only for ED, but also for underlying diseases.
Efficacy and Safety of Daily Tadalafil in Men with Erectile Dysfunction Previously Unresponsive to On-Demand Tadalafil
Authors: McMahon Chris 
Published: October 2004

ABSTRACT

Objective
To assess the efficacy and safety of daily tadalafil, a potent selective phosphodiesterase 5 inhibitor, for the treatment of erectile dysfunction (ED) in men previously unresponsive to on-demand tadalafil.

Materials and Methods
A total of 112 men with a mean age of 63 (range 21–79) and moderate to severe ED of various aetiologies were treated with tadalafil, taken on a daily basis at flexible daily doses of 10 and 20 mg for 12 weeks. The three primary outcomes were changes from the pretreatment and on-demand tadalafil baseline in the erectile function domain of the International Index of Erectile Function and the proportion of yes responses to questions 2 and 3 of the Sexual Encounter Profile. Additional efficacy instruments included a Global Assessment Question administered at completion of the study.

Results
Compared with pretreatment and on-demand tadalafil baseline, daily dosed tadalafil significantly enhanced all efficacy outcome variables. Patients receiving daily tadalafil (10 mg) experienced a significant mean improvement of 12.8 and 8.2 in the International Index of Erectile Function erectile function domain score from baseline (P &lt; 0.001) and from on-demand tadalafil, respectively (P &lt; 0.001). Fifty-eight percent of intercourse attempts (Sexual Encounter Profile question 3) were successfully completed (P &lt; 0.001 vs. pretreatment baseline, P &lt; 0.001 vs. on-demand tadalafil). Improved erections at end point were reported by 69% of men compared with 42% of men with on-demand tadalafil. Daily tadalafil was well tolerated with headache, dyspepsia, and facial flushing as the most frequent adverse events.

Conclusion
Daily tadalafil (10/20 mg) was effective and well tolerated in this study population and is an effective salvage for previous on-demand tadalafil nonresponders.
Intracavernous Chlorpromazine Versus Phentolamine: A Double-Blind Clinical Comparative Study
Authors: Shamloul Rany , El-Dakhly Mohamed , Ghanem Hussein , Gadallah Amr , Mokhtar Hany 
Published: October 2004

ABSTRACT

Introduction
Intracavernous pharmacotherapy is one of the most common treatment modalities of erectile dysfunction (ED). There are different drugs that are used for intracavernous injection including papaverine, phentolamine, prostaglandins E1, phenoxybenzamine, and moxisylate.

Aim
The aim of this study is to evaluate the efficacy of chlorpromazine as an intracavernous vasoactive agent alone or with other drugs.

Methods
This study was performed on 50 patients presenting to our department complaining of ED. Patients were divided into three groups according to the type of intracavernous drug injected. Group A included 20 patients who received an intracavernous injection of 1 mL bimix (30 mg papaverine + 1 mg phentolamine) followed a week later by intracavernous test dose using a 1 mL mixture of papaverine and chlorpromazine (30 mg papaverine + 2.5 mg chlorpromazine). Group B included 20 patients who received an intracavernous injection of 1 mL trimix (30 mg papaverine + 1 mg phentolamine + 10 µg PGE1). A week later they received another intracavernous test dose using a 1 mL mixture of papaverine, PGE1, and chlorpromazine (30 mg papaverine + 2.5 mg chlorpromazine + 10 µg PGE1). Group C included 10 patients who received various intracavernous injections of chlorpromazine in doses 1 mg, 2 mg, 5 mg, and 10 mg.

Results
There was no significant difference in erection response and erection duration between phentolamine and chlorpromazine. Prolonged erection occurred in two patients of group B and postural hypotension occurred in three patients of group C.

Conclusion
Chlorpromazine can be used as an intracavernous vasoactive agent; it is similar to phentolamine in efficacy and short-term side effect profile.
Does Sildenafil Enhance Quality of Nocturnal Erections in Healthy Young Men? A NPT-RigiScan™ Study
Authors: Greenstein Alexander , Chen Juza , Salonia Andrea , Sofer Mario , Matzkin Haim , Montorsi Francesco 
Published: October 2004

ABSTRACT

Objective
To assess the effect of sildenafil on nocturnal erectile function (EF) in young healthy volunteers with normal sexual function (SF) according to the International Index of Erectile Function (IIEF) questionnaire.

Methods
Thirty-three young (mean age 21 ± 0.3 years; range 18–25) healthy volunteers not taking any medications who had normal SF and an EF domain &gt;26 on the IIEF questionnaire were evaluated. Erectile function was assessed using the RigiScan™ (Dacomed Corp., MN, USA) during three nights: night 1 = adaptation to the NPT-Rigiscan apparatus, night 2 = baseline recording of eight parameters, and night 3 = recordings after ingestion of sildenafil 100 mg. Data on the number of erections, erection duration, minimal and maximal base tumescence, minimal and maximal tip tumescence, and base and tip rigidity were analysed usinganova with repeated measures.

Results
A statistically significant improvement in all eight parameters was observed as a result of sildenafil administration: number of erections from 3.1 ± 0.7 to 4.0 ± 0.7 (P &lt; 0.05), erection time 22 ± 3.5 to 34.2 ± 5.9, minimal base tumescence 8.2 ± 0.8 to 8.7 ± 0.8, maximal base tumescence 12.1 ± 0.7 to 14.2 ± 0.7, base rigidity 75.6 ± 3.1 to 81.6 ± 3.6, tip rigidity 70.6 ± 1.5 to 75.9 ± 3.1, minimal tip tumescence 5.9 ± 0.5 to 6.5 ± 0.6, and maximal tip tumescence 8.6 ± 0.6 to 11.7 ± 0.7 (P &lt; 0.0001 for each of the last seven parameters). The mean sleep duration, 7.3 hours (range 6.30–9.20 hours), was similar for both nights of recording.

Conclusion
Sildenafil increases the quality and number of nocturnal erections as tested by the NPT-RigiScan™ in young healthy volunteers with normal EF.