bluuebunny/crossref_metadata_2025 huggingface dataset:
Placebo-Controlled Comparison of Effervescent Acetylsalicylic Acid, Sumatriptan and Ibuprofen in the Treatment of Migraine Attacks
Authors: EMSASI The , Diener HC , Bussone G , de Liano H , Eikermann A , Englert R , Floeter T , Gallai V , Göbel H , Hartung E , Jimenez MD , Lange R , Manzoni GC , Mueller-Schwefe G , Nappi G , Pinessi L , Prat J , Puca FM , Titus F , Voelker M
Published: October 2004

Acetylsalicylic acid (ASA) in combination with metoclopramide has been frequently used in clinical trials in the acute treatment of migraine attacks. Recently the efficacy of a new high buffered formulation of 1000 mg effervescent ASA without metoclopramide compared to placebo has been shown. To further confirm the efficacy of this new formulation in comparison with a triptan and a nonsteroidal anti-inflammatory drug (ibuprofen) a three-fold crossover, double-blind, randomized trial with 312 patients was conducted in Germany, Italy and Spain. Effervescent ASA (1000 mg) was compared to encapsulated sumatriptan (50 mg), ibuprofen (400 mg) and placebo. The percentage of patients with reduction in headache severity from moderate or severe to mild or no pain (primary endpoint) was 52.5% for ASA, 60.2% for ibuprofen, 55.8% for sumatriptan and 30.6% for placebo. All active treatments were superior to placebo ( P < 0.0001), whereas active treatments were not statistically different. The number of patients who were pain-free at 2 h was 27.1%, 33.2%, 37.1% and 12.6% for those treated with ASA, ibuprofen, sumatriptan or placebo, respectively. The difference between ASA and sumatriptan was statistically significant ( P = 0.025). With respect to other secondary efficacy criteria and accompanying symptoms no statistically significant differences between ASA and ibuprofen or sumatriptan were found. Drug-related adverse events were reported in 4.1%, 5.7%, 6.6% and 4.5% of patients treated with ASA, ibuprofen sumatriptan or placebo. This study showed that 1000 mg effervescent ASA is as effective as 50 mg sumatriptan and 400 mg ibuprofen in the treatment of migraine attacks regarding headache relief from moderate/severe to mild/no pain at 2 h. Regarding pain-free at 2 h sumatriptan was most effective.
Prevalence of Primary Headaches in People with Multiple Sclerosis
Authors: D'Amico D , La Mantia L , Rigamonti A , Usai S , Mascoli N , Milanese C , Bussone G , Besta C.
Published: October 2004

The aim was to investigate the lifetime prevalence of headache and primary headache (diagnoses according to International Headache Society criteria) in multiple sclerosis (MS). The relationships between headache and clinical features of MS and MS therapy were also investigated. We studied 137 patients with clinically definite MS; 88 reported headache, 21 of whom developed headache after the initiation of interferon. The prevalence of all headaches in the remaining 116 patients was 57.7%. Migraine was found in 25.0%, tension-type headache in 31.9%, and cluster headache in one patient. A significant correlation ( P = 0.007, Fisher's exact test) between migraine and relapsing-remitting MS was found. Primary headaches are common in MS patients. Further studies are needed to clarify the mechanisms underlying this association, particularly the association between migraine and relapsing-remitting MS, and the role of interferon in the development of new headache.
Early Treatment of a Migraine Attack while Pain is Still Mild Increases the Efficacy of Sumatriptan
Authors: Scholpp J , Schellenberg R , Moeckesch B , Banik N
Published: October 2004

To investigate the hypothesis that early treatment of a migraine attack with sumatriptan, while pain is still mild, results in higher pain free rates in comparison to delayed treatment, when pain is at least moderate, we performed a prospective, controlled and open label study. Migraineurs with or without aura who fulfilled the diagnostic criteria recommended by the International Headache Society were enrolled in the study and randomly assigned to either ‘early’ or ‘late’ treatment with sumatriptan 100 mg tablets. In the early treatment group significantly more patients were pain free at all times measured during two hours after dosing than in the late treatment group. Furthermore, patients in the early treatment group became pain free significantly sooner after dosing than patients who delayed treatment. It is concluded that migraineurs, who are able to differentiate between a migraine attack and other forms of headache, benefit from early intervention with sumatriptan 100 mg tablets.
Fish oils in the care of coronary heart disease patients: a meta‐analysis of randomized controlled trials
Authors: Yzebe Delphine , Lievre Michel
Published: October 2004

What is the place of fish oils in the care of coronary heart disease (CHD) patients? As several clinical trials have already addressed this question without giving definitive answers, we did a meta‐analysis of trials regarding the efficacy of omega‐3 fatty acids in preventing cardiovascular mortality and morbidity. We searched the MEDLINE (1966–2003), EMBASE databases, proceedings abstracts and references of reviewed articles. Randomized controlled trials (RCTs) of the efficacy of omega‐3 fatty acids among adults with recent or acute myocardial infarction (MI), or angina were selected. Two reviewers abstracted data independently. Five relevant outcomes, mortality from all causes, fatal and non‐fatal MI, non‐fatal stroke and angina, were measured. Data were synthesized using a fixed effect model. Ten RCTs with 14 727 patients were included. No significant heterogeneity was detected. Daily intake of omega‐3 fatty acids for a mean duration of 37 months decreased all causes of mortality by 16% (relative risk 0.84, 95% confidence interval [0.76; 0.94]) and the incidence of death due to MI by 24% (0.76, [0.66; 0.88]). No significant effect was found for the other outcomes. Because of the suboptimal quality of the studies included into the meta‐analysis and the absence of data in patients receiving statins, these results do not justify adding fish oils systematically to the heavy pharmaceutical assortment already recommended in CHD patients.
Current guidelines applicable for the approval of topically applied dermatological drugs in the EU
Authors: Straube Myrjam Dorothea , Zesch Achim
Published: October 2004

Dermatologicals 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

Apoptosis 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

The 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

This 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

Recent 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

Introduction

Data concerning the physiology of desire, arousal, and orgasm in women are limited because of ethical constraints.

Aim

To gain knowledge of physiology of female sexual function through animal models.

Methods

To 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 Measure

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

Results

Sexual 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.

Conclusion

More 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

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

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

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

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 (<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

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 < 0.001) and from on-demand tadalafil, respectively (P < 0.001). Fifty-eight percent of intercourse attempts (Sexual Encounter Profile question 3) were successfully completed (P < 0.001 vs. pretreatment baseline, P < 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

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

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 >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 < 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 < 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.
Review of Phosphodiesterases in the Urogenital System: New Directions for Therapeutic Intervention
Authors: Montorsi Francesco , Corbin Jackie , Phillips Stephen
Published: October 2004

Introduction

With the success of Phosphodiesterase (PDE) type 5 inhibitors (i.e., sildenafil, tadalafil, vardenafil) in the treatment of erectile dysfunction (ED), PDEs are considered attractive targets for drug intervention in the urogenital tract.

Aim

To review the role of PDEs, which exist as a superfamily of enzymes comprising 11 distinct families, in the urogenital system, focusing on anatomical locations, functions and dysfunctions, potential disorders that could be treated, and any promising new selective PDE inhibitors under development.

Methods

Included are (i) abstracts from 2001, 2002, and 2003; (ii) a MEDLINE search from 1996 through December 2003; and (iii) a pipeline search for therapeutics in development. Data from animal experiments are presented when there is a paucity of human data, but with the caveat that the distribution of PDE isozymes in a specific tissue can vary between species.

Results

PDE mRNA and protein have been localized throughout the normal human urogenital tract. Double-blind, placebo-controlled studies suggest possible new clinical roles for sildenafil, including prophylaxis to preserve penile smooth muscle and erectile function after radical prostatectomy, and treatment of ejaculatory delay secondary to serotonergic reuptake inhibitor antidepressant therapy. Open-label studies suggest a potential clinical role for: vinpocetine (a PDE1 inhibitor) in the treatment of incontinence and low-compliance bladder; and sildenafil in the treatment of premature ejaculation, prostate-related lower urinary tract symptoms, and in women who have had unsuccessful in vitro fertilization. Several new orally administered PDE5 inhibitors are in early clinical development for the treatment of ED. Potential indications for PDE inhibitors that are suggested by preclinical data include Peyronie's disease, ureteral colic, male and female birth control, and prevention of preterm labor.

Conclusion

Drug selectivity and differential PDE tissue distribution allow for potential targeted intervention for numerous disorders related to the urogenital tract.
Possible Correlation Between Type 1 Diabetes Mellitus and Female Sexual Dysfunction: Case Report and Literature Review
Authors: Bultrini Antonella , Carosa Eleonora , Colpi Elisabetta M. , Poccia Gianfranco , Iannarelli Rossella , Lembo Danilo , Lenzi Andrea , Jannini Emmanuele A.
Published: October 2004

Introduction

Sexual dysfunction in diabetic women has received less attention in clinical research than the sexual symptoms of diabetic men. Although conflicting results have been reported, several studies suggest an increased prevalence of deficient vaginal lubrication in women with diabetes mellitus. As support to the hypothesis of a potential diabetes-related arousal dysfunction caused by a decrease in vaginal lubrication of women with Type 1 diabetes mellitus, we describe the following case report.

Methods

A 29-year-old white woman was found with a sexual arousal disorder of sudden onset, complicated by loss of orgasm and sexual desire, in absence of any marital, relational, psychological, or gynecological cause.

Results

One month later she was diagnosed with severe Type 1 diabetes. With the correction of diabetes and without other treatment of the sexual dysfunction, she experienced a full recovery of her sexual complaints.

Conclusion

The case illustrates the importance of being aware of female sexual dysfunction as an early symptom of diabetes mellitus and suggests that a good glycemic control would be fundamental to restore a normal sexual activity in diabetic women. It also demonstrates the need to take into account, not only in males, a sexual history in the management of diabetes mellitus.
MicC, a Second Small-RNA Regulator of Omp Protein Expression inEscherichia coli
Authors: Chen Shuo , Zhang Aixia , Blyn Lawrence B. , Storz Gisela
Published: October 2004

In a previous bioinformatics-based search for novel small-RNA genes encoded by theEscherichia coligenome, we identified a region, IS063, located between theompNandydbKgenes, that encodes an ∼100-nucleotide small-RNA transcript. Here we show that the expression of this small RNA is increased at a low temperature and in minimal medium. Twenty-two nucleotides at the 5′ end of this transcript have the potential to form base pairs with the leader sequence of the mRNA encoding the outer membrane protein OmpC. The deletion of IS063 increased the expression of anompC-luctranslational fusion 1.5- to 2-fold, and a 10-fold overexpression of the small RNA led to a 2- to 3-fold repression of the fusion. Deletion and overexpression of the IS063 RNA also resulted in increases and decreases, respectively, in OmpC protein levels. Taken together, these results suggest that IS063is a regulator of OmpC expression; thus, the small RNA has been renamed MicC. The antisense regulation was further demonstrated by the finding thatmicCmutations were suppressed by compensatory mutations in theompCmRNA. MicC was also shown to inhibit ribosome binding to theompCmRNA leader in vitro and to require the Hfq RNA chaperone for its function. We suggest that the MicF and MicC RNAs act in conjunction with the EnvZ-OmpR two-component system to control the OmpF/OmpC protein ratio in response to a variety of environmental stimuli.
GadY, a Small-RNA Regulator of Acid Response Genes inEscherichia coli
Authors: Opdyke Jason A. , Kang Ju-Gyeong , Storz Gisela
Published: October 2004

A previous bioinformatics-based search for small RNAs inEscherichia coliidentified a novel RNA named IS183. The gene encoding this small RNA is located between and on the opposite strand of genes encoding two transcriptional regulators of the acid response,gadX(yhiX) andgadW(yhiW). Given that IS183 is encoded in thegadgene cluster and because of its role in regulating acid response genes reported here, this RNA has been renamed GadY. We show that GadY exists in three forms, a long form consisting of 105 nucleotides and two processed forms, consisting of 90 and 59 nucleotides. The expression of this small RNA is highly induced during stationary phase in a manner that is dependent on the alternative sigma factor σS. Overexpression of the three GadY RNA forms resulted in increased levels of the mRNA encoding the GadX transcriptional activator, which in turn caused increased levels of the GadA and GadB glutamate decarboxylases. A promoter mutation which abolishedgadYexpression resulted in a reduction in the amount ofgadXmRNA during stationary phase. ThegadYgene was shown to overlap the 3′ end of thegadXgene, and this overlap region was found to be necessary for the GadY-dependent accumulation ofgadXmRNA. We suggest that during stationary phase, GadY forms base pairs with the 3′-untranslated region of thegadXmRNA and confers increased stability, allowing forgadXmRNA accumulation and the increased expression of downstream acid resistance genes.
Identification of a Staphylococcal AgrB Segment(s) Responsible for Group-Specific Processing of AgrD by Gene Swapping
Authors: Zhang Linsheng , Ji Guangyong
Published: October 2004

The four gene products of the accessory gene regulator (
agr
) P2 operon of
Staphylococcus aureus
assemble a quorum-sensing system: AgrA and AgrC resemble a two-component signal transduction system, and AgrB and AgrD are required to produce an autoinducing peptide. Upon activation, this quorum-sensing system positively regulates the transcription of the P2 operon as well as the P3 operon, whose transcript, RNAIII, regulates the expression of virulence genes. Four groups of
S. aureus
have been identified based on the
agr
sequences and the group-specific interaction between the autoinducing peptide and AgrC. AgrB is a transmembrane protein involved in the processing of AgrD propeptide, and its interaction with AgrD is also group specific. In this study, a series of chimeric AgrBs were constructed by swapping between group I and group II AgrBs, and these mutants were used to analyze the group-specific segment(s) in AgrB that was responsible for AgrD processing. Our results revealed that the first transmembrane α-helix and the extracellular loop 1 of group I AgrB were decisive in the specific processing of group I AgrD. In contrast, two hydrophilic segments of group II AgrB played a crucial role in the group-specific processing of group II AgrD. We also found that several chimeric AgrBs were capable of processing AgrD from both groups, suggesting that all AgrB homologues may utilize the same or a similar mechanism in the processing of AgrDs.
Global Transcriptional Effects of a Suppressor tRNA and the Inactivation of the Regulator
frmR
Authors: Herring Christopher D. , Blattner Frederick R.
Published: October 2004

Expression of an amber suppressor tRNA should result in read-through of the 326 open reading frames (ORFs) that terminate with amber stop codons in the
Escherichia coli
genome, including six pseudogenes. Abnormal extension of an ORF might alter the activities of the protein and have effects on cellular physiology, while suppression of a pseudogene could lead to a gain of function. We used oligonucleotide microarrays to determine if any effects were apparent at the level of transcription in glucose minimal medium. Surprisingly, only eight genes had significantly different expression in the presence of the suppressor. Among these were the genes
yaiN
,
adhC
, and
yaiM
, forming a single putative operon whose likely function is the degradation of formaldehyde. Expression of wild-type
yaiN
was shown to result in repression of the operon, while a suppression-mimicking allele lacking the amber stop codon and extended 7 amino acids did not. The operon was shown to be induced by formaldehyde, and the genes have been renamed
frmR
,
frmA
, and
frmB
, respectively.
TheEscherichia coli dnaN159Mutant Displays Altered DNA Polymerase Usage and Chronic SOS Induction
Authors: Sutton Mark D.
Published: October 2004

TheEscherichia coliβ sliding clamp, which is encoded by thednaNgene, is reported to interact with a variety of proteins involved in different aspects of DNA metabolism. Recent findings indicate that many of these partner proteins interact with a common surface on the β clamp, suggesting that competition between these partners for binding to the clamp might help to coordinate both the nature and order of the events that take place at a replication fork. The purpose of the experiments discussed in this report was to test a prediction of this model, namely, that a mutant β clamp protein impaired for interactions with the replicative DNA polymerase (polymerase III [Pol III]) would likewise have impaired interactions with other partner proteins and hence would display pleiotropic phenotypes. Results discussed herein indicate that thednaN159-encoded mutant β clamp protein (β159) is impaired for interactions with the α catalytic subunit of Pol III. Moreover, thednaN159mutant strain displayed multiple replication and repair phenotypes, including sensitivity to UV light, an absolute dependence on the polymerase activity of Pol I for viability, enhanced Pol V-dependent mutagenesis, and altered induction of the global SOS response. Furthermore, epistasis analyses indicated that the UV sensitivity of thednaN159mutant was suppressed by (not epistatic with) inactivation of Pol IV (dinBgene product). Taken together, these findings suggest that in thednaN159mutant, DNA polymerase usage, and hence DNA replication, repair, and translesion synthesis, are altered. These findings are discussed in terms of a model to describe how the β clamp might help to coordinate protein traffic at the replication fork.
Functional and Structural Analysis of HrcA Repressor Protein from
Caulobacter crescentus
Authors: Susin Michelle F. , Perez Humberto R. , Baldini Regina L. , Gomes Suely L.
Published: October 2004

A large number of bacteria regulate chaperone gene expression during heat shock by the HrcA-CIRCE system, in which the DNA element called CIRCE serves as binding site for the repressor protein HrcA under nonstress conditions. In
Caulobacter crescentus
, the
groESL
operon presents a dual type of control. Heat shock induction is controlled by a σ
32
-dependent promoter and the HrcA-CIRCE system plays a role in regulation of
groESL
expression under physiological temperatures. To study the activity of HrcA in vitro, we purified a histidine-tagged version of the protein, and specific binding to the CIRCE element was obtained by gel shift assays. The amount of retarded DNA increased significantly in the presence of GroES/GroEL, suggesting that the GroE chaperonin machine modulates HrcA activity. Further evidence of this modulation was obtained using
lacZ
transcription fusions with the
groESL
regulatory region in
C. crescentus
cells, producing different amounts of GroES/GroEL. In addition, we identified the putative DNA-binding domain of HrcA through extensive protein sequence comparison and constructed various HrcA mutant proteins containing single amino acid substitutions in or near this region. In vitro and in vivo experiments with these mutated proteins indicated several amino acids important for repressor activity.
Modulation of Monomer Conformation of the BglG Transcriptional Antiterminator from
Escherichia coli
Authors: Fux Liat , Nussbaum-Shochat Anat , Lopian Livnat , Amster-Choder Orna
Published: October 2004

The BglG protein positively regulates expression of the
bgl
operon in
Escherichia coli
by binding as a dimer to the
bgl
transcript and preventing premature termination of transcription in the presence of β-glucosides. BglG activity is negatively controlled by BglF, the β-glucoside phosphotransferase, which reversibly phosphorylates BglG according to β-glucoside availability, thus modulating its dimeric state. BglG consists of an RNA-binding domain and two homologous domains, PRD1 and PRD2. Based on structural studies of a BglG homologue, the two PRDs fold similarly, and the interactions within the dimer are PRD1-PRD1 and PRD2-PRD2. We have recently shown that the affinity between PRD1 and PRD2 of BglG is high, and a fraction of the BglG monomers folds in the cell into a compact conformation, in which PRD1 and PRD2 are in close proximity. We show here that both BglG forms, the compact and noncompact, bind to the active site-containing domain of BglF, IIB
bgl
, in vitro. The interaction of BglG with IIB
bgl
or BglF is mediated by PRD2. Both BglG forms are detected as phosphorylated proteins after in vitro phosphorylation with IIB
bgl
and are dephosphorylated by BglF in vitro in the presence of β-glucosides. Nevertheless, genetic evidence indicates that the interaction of IIB
bgl
and BglF with the compact form is seemingly less favorable. Using in vivo cross-linking, we show that BglF enhances folding of BglG into a compact conformation, whereas the addition of β-glucosides reduces the amount of this form. Based on these results we suggest a model for the modulation of BglG conformation and activity by BglF.
The Glutathione-Glutaredoxin System inRhodobacter capsulatus: Part of a Complex Regulatory Network Controlling Defense against Oxidative Stress
Authors: Li Kuanyu , Hein Silke , Zou Wenxin , Klug Gabriele
Published: October 2004

Mutants with defects in components of the glutathione-glutaredoxin (GSH/Grx) system ofRhodobacter capsulatuswere constructed to study its role in defense against oxidative stress and the redox-dependent formation of photosynthetic complexes. The lack of the glutaredoxin 3 gene (grxC) or the glutathione synthetase B gene (gshB) resulted in lower growth rates under aerobic conditions and higher sensitivity to oxidative stress, confirming the role of the GSH/Grx system in oxidative stress defense. Both mutants are highly sensitive to disulfide stress, indicating a major contribution of the GSH/Grx system to the thiol-disulfide redox buffer in the cytoplasm. Like mutations in the thioredoxin system, mutations in the GSH/Grx system affected the formation of photosynthetic complexes, which is redox dependent inR. capsulatus. Expression of the genesgrxC,gshB,grxAfor glutaredoxin 1, andgorAfor glutathione reductase, all encoding components of the GSH/Grx system, was not induced by oxidative stress. Other genes, for which a role in oxidative stress was established inEscherichia coli,acnA,fpr,fur, andkatG, were strongly induced by oxidative stress inR. capsulatus. Mutations in thegrxC, and/orgshB, and/ortrxC(thioredoxin 2) genes affected expression of these genes, indicating an interplay of the different defense systems against oxidative stress. The OxyR and the SoxRS regulons control the expression of many genes involved in oxidative stress defense inE. coliin response to H2O2and superoxide, respectively. Our data and the available genome sequence ofR. capsulatussuggest that a SoxRS system is lacking but an alternative superoxide specific regulator exists inR. capsulatus.While the expression ofgorAandgrxAis regulated by H2O2inE. colithis is not the case inR. capsulatus, indicating that the OxyR regulons of these two species are significantly different.