Networking Aspects of the Electronic Health Records: Hypertext Transfer Protocol Version 2 (HTTP/2) vs HTTP/3.

The rapid development of the digital healthcare and the electronic health records (EHR) requires smooth networking infrastructure to access data using Hypertext Transfer Protocol (HTTP)-based applications. The new HTTP/3 standard should provide performance and security improvements over HTTP/2. The goal of our work was to test the performance of HTTP/2 and HTTP/3 in the context of the EHRs. We used 45,000 test FHIR Patient resources downloaded and uploaded using 20, 50, 100 and 200 resources per Bundle, which resulted in 2251, 901, 451 and 226 HTTP GET and POST requests respectively. The first test downloading 20 resources per Bundle showed that HTTP/3 outperformed HTTP/2 in the local (mean request time 16.57 ms ± 7.2 standard deviation [SD]) and in the remote network (71.45 ms ± 43.5 SD) which is almost 3 times faster. In the 50 and 100 resources per Bundle test the HTTP/3 protocol demonstrated again more than two times gain in downloading performance for remote requests with mean request time 91.13 ms ± 34.54 SD and 88.09 ms ± 21.66 SD respectively. Furthermore, HTTP/3 outperformed HTTP/2 in the constructed clinical dataset remote transfer. In the upload tests HTTP/3 showed only a slight gain in performance merely in the remote network. The HTTP/3 protocol is a relatively new development and a major improvement for the worldwide web. This new technology is still missing in the digital health and EHRs. Its use could offer a major performance gain in situations where data is gathered from multiple remote locations.

'Exacerbation-free time' to assess the impact of exacerbations in patients with chronic obstructive pulmonary disease (COPD): a prospective observational study.

COPD exacerbations are commonly quantified as rate per year. However, the total amount of time a patient suffers from exacerbations may be stronger related to his or her disease burden than just counting exacerbation episodes. In this study, we examined the relationship between exacerbation frequency and exacerbation-free time, and their associations with baseline characteristics and health-related quality of life. A total of 166 COPD patients reported symptom changes during 12 months. Symptom-defined exacerbation episodes were correlated to the number of exacerbation-free weeks per year. Analysis of covariance was used to examine the effects of baseline characteristics on annual exacerbation frequency and exacerbation-free weeks, Spearman's rank correlations to examine associations between the two methods to express exacerbations and the Chronic Respiratory Questionnaire (CRQ). The correlation between exacerbation frequency and exacerbation-free weeks was -0.71 (p < 0.001). However, among frequent exacerbators (i.e., ≥3 exacerbations/year, n = 113) the correlation was weak (r = -0.25; p < 0.01). Smokers had less exacerbation-free weeks than non-smokers (ß = -5.709, p < 0.05). More exacerbation-free weeks were related to better CRQ Total (r = 0.22, p < 0.05), Mastery (r = 0.22, p < 0.05), and Fatigue (r = 0.23, p < 0.05) scores, whereas no significant associations were found between exacerbation frequency and CRQ scores. In COPD patients with frequent exacerbations, there is substantial variation in exacerbation-free time. Exacerbation-free time may better reflect the burden of exacerbations in patients with COPD than exacerbation frequency does.

Structural transformation with "negative volume expansion": chemical bonding and physical behavior of TiGePt.

The synthesis and a joint experimental and theoretical study of the crystal structure and physical properties of the new ternary intermetallic compound TiGePt are presented. Upon heating, TiGePt exhibits an unusual structural phase transition with a huge volume contraction of about 10 %. The transformation is characterized by a strong change in the physical properties, in particular, by an insulator-metal transition. At temperatures below 885 °C TiGePt crystallizes in the cubic MgAgAs (half-Heusler) type (LT phase, space group F43m, a = 5.9349(2) Å). At elevated temperatures, the crystal structure of TiGePt transforms into the TiNiSi structure type (HT phase, space group Pnma, a = 6.38134(9) Å, b = 3.89081(5) Å, c = 7.5034(1) Å). The reversible, temperature-dependent structural transition was investigated by in-situ neutron powder diffraction and dilatometry measurements. The insulator-metal transition, indicated by resistivity measurements, is in accord with band structure calculations yielding a gap of about 0.9 eV for the LT phase and a metallic HT phase. Detailed analysis of the chemical bonding in both modifications revealed an essential change of the Ti-Pt and Ti-Ge interactions as the origin of the dramatic changes in the physical properties.

The effects of ultrasound on organoclay dispersion in the PP matrix.

PP/MMT nanocomposites were prepared by solution intercalation using sonication and quiescent conditions, and the effects on the morphological, thermal and mechanical properties were evaluated by WAXD, TEM, DMA, TGA and DSC analyses. The present study aims to clarify the effects of ultrasound use on the organoclay surface with different amounts of organic modifiers and on the exfoliation processes. The sonication process decreased around of 200 nm the aspect ratio of C15A organoclay. Besides, the effectiveness of the ultrasound process was only achieved with the C15A system because there is a small energetic barrier between their layers (clay with larger d 001). The sonication process increased the exfoliation and distribution of the C15A platelets in the PP matrix, increasing by 5% its reinforcement capacity. However, for I44P system, the use of ultrasound did not show any significant effect on the morphology and consequently on the final properties of the PP matrix. The T(c) temperature and the thermal stability of the PP nanocomposites were increased, independent of the clay type or of the ultrasound use.

Identification of three CCp genes in Babesia divergens: novel markers for sexual stages parasites.

Babesia divergens, a tick-borne protozoan parasite of red blood cells, is the main agent of bovine and human babesiosis in Europe. Very few data are available concerning its life cycle and sexual reproduction inside the tick vector, Ixodes ricinus. The aim of this study was to define some markers of the B.divergens sexual stage. An in silico post-genomic approach was used to analyze genomic, transcriptomic and proteomic data and to select specific sexual stage proteins of the related apicomplexan genus Plasmodium. Three proteins, based on sequence identity between the available genomes of Plasmodium and Babesia spp., were chosen, as members of a highly conserved and apicomplexan sexual stages specific protein family (CCp) potentially involved in adhesive functions. Degenerate primers were used to amplify and clone three B.divergens orthologs (bdccp1, bdccp2, and bdccp3) corresponding to newly identified genes in this parasite. The opportunities offered by such markers to study parasite development in its vector are discussed.

PDE5 inhibitors beyond erectile dysfunction.

The phosphodiesterase type-5 (PDE5) inhibitors sildenafil, vardenafil and tadalafil are widely used first-line therapy for erectile dysfunction (ED). Since the advent of sildenafil in 1998, more than 40 million men worldwide have been successfully treated with these compounds. The safety and high tolerability of PDE5 inhibitors make them an attractive tool to investigate further physiological functions of PDE5, for example the modulation of intracellular cyclic GMP (cGMP) pools. As cGMP is a key component of intracellular signaling this may provide novel therapeutic opportunities beyond ED even for indications in which chronic administration is necessary. The approval of sildenafil for the treatment of pulmonary hypertension in 2005 was a notable success in this area of research. A number of other potential new indications are currently in various phases of preclinical research and development. In recent years, extensive but very heterogeneous information has been published in this field. The aim of this review is to summarize existing preclinical and clinical knowledge and critically discuss the evidence to support potential future indications for PDE5 inhibitors.

Potency, selectivity, and consequences of nonselectivity of PDE inhibition.

Phosphodiesterases (PDEs) play a decisive role in cyclic nucleotide-mediated intracellular signaling. As PDEs are expressed in a variety of tissues, selectivity is a prerequisite for a therapeutically applicable PDE inhibitor. Sildenafil, vardenafil, and tadalafil are selective for PDE5, with vardenafil exhibiting the highest potency and minimal inhibition of other PDEs, with the exception of PDE6. Tadalafil is extremely selective for PDE5, but also potently inhibits PDE11, an enzyme with unknown physiological function. As PDE1 is expressed in the brain, myocardium, and vascular smooth muscle cells, nonselectivity with respect to this enzyme (selectivity: tadalafil>vardenafil>sildenafil) may result in vasodilation and tachycardia. Inhibition of PDE6 (selectivity: tadalafil>vardenafil congruent with sildenafil), which is expressed only in retina and functions in visual transduction, can transiently disturb vision. PDE5 inhibitors may also indirectly inhibit PDE3 by increasing cyclic guanosine monophospate levels, thereby elevating heart rate and vasodilation while inhibiting platelet aggregation.

Vardenafil preclinical trial data: potency, pharmacodynamics, pharmacokinetics, and adverse events.

Vardenafil potently inhibits human phosphodiesterase 5 (PDE5) with an IC50 of 0.7 nM. Enhancement of nitric oxide (NO)-induced erections in rabbits by 0.1 mg/kg vardenafil is limited by its pharmacokinetic properties (Tmax=1 h; T1/2=1.2 h), although erectile effects have been observed after 7 h. In humans, vardenafil is rapidly absorbed (Tmax approximately 40 min) and more slowly metabolized (T1/2 approximately 4 h), with an absolute bioavailability of 14.5% (vs 40% for sildenafil). Although the consumption of high-fat meals does not affect the drug's relative bioavailability, it retards intestinal absorption. Coadministration of CYP3A4 inhibitors such as ritonavir can affect hepatic metabolism. M1, an active metabolite of vardenafil, is a four-fold-less potent inhibitor of PDE5 than its parent compound, contributing approximately 7% to vardenafil's overall efficacy. The side effects of all selective PDE5 inhibitors commonly include vasodilation, small reductions in blood pressure, headache, and nasal congestion.

The prevalence of allergic sensitisation in immigrant children in The Netherlands.

BACKGROUND: Differences in the prevalence of allergic sensitisation have been reported in immigrant children living in the same urban environment. The purpose of this study is to investigate the prevalence of allergic sensitisation in school children of Dutch, Turkish and Moroccan origin. METHODS: The prevalence of sensitisation to aero-allergens was assessed using the skin prick test in a non-selected sample of 512 children (response rate 54%) living in the same inner city district of Utrecht. In addition, exhaled nitric oxide (FeNO) was determined. RESULTS: The prevalence of allergic sensitisation was dependent on the ethnic origin. As compared with Dutch children (19.1%), a higher prevalence of allergic sensitisation was observed in immigrant children for whom both parents were born in Turkey (23.6%, not significant) or Morocco (30.6%, p<0.05). The prevalence of allergic sensitisation in Dutch children was nearly 2 times lower than the reported prevalence in German children. In all sensitised children, the mean FeNO value was significantly (p<0.05) higher than in non-sensitised children, and the mean FeNO level was highest in Moroccan children sensitised to indoor allergens. CONCLUSION: In The Netherlands, immigrant children show a higher prevalence of allergic sensitisation as compared to Dutch children.

Pro-erectile effect of vardenafil: in vitro experiments in rabbits and in vivo comparison with sildenafil in rats.

OBJECTIVES: To assess pro-erectile responses to vardenafil, a new selective PDE5 inhibitor, in vitro in isolated rabbit corpora cavernosa, and in vivo in anaesthetized rats. METHODS: Rabbit cavernosal strips were precontracted with 10 microM phenylephrine. Dose-response relaxation curves to cumulative dosings of vardenafil (1 nM-10 microM) were constructed alone and in the presence of 10 mM L-NAME. Relaxation responses to electrical field stimulation (EFS) (2 Hz, 2 ms, 10 V) were compared in control preparations and in the presence of vardenafil (1-10 nM). Male Sprague-Dawley rats were anaesthetized with urethane and prepared for measurement of blood pressure and intracavernous pressure. Erectile responses (ICPmax/dBP x 100) to cavernous nerve submaximal stimulation (10 Hz, 1 ms, 0.45-1.6 V) were determined before, and 3, 10 and 23 min after i.v. administration of saline, vardenafil or sildenafil (0.1, 1 mg/kg). RESULTS: Vardenafil was effective in relaxing precontracted rabbit cavernosal strips (IC50 54 +/- 18 nM). This relaxing activity was partially antagonized with 10 mM L-NAME, increasing the IC50 to 620 +/- 81 nM. Vardenafil significantly increased (more than 4 times) relaxation of precontracted rabbit cavernosal strips to EFS at 10 nM. In anaesthetized rats, erectile responses were significantly facilitated 3 and 13 min after 0.1 and 1 mg/kg vardenafil was administered. In contrast, 1 mg/kg sildenafil only significantly increased erectile responses at 3 min post-injection. CONCLUSIONS: Vardenafil relaxes rabbit corpus cavernosum in vitro and is effective at a lower dose than sildenafil in facilitating erectile responses to cavernous nerve stimulation in anaesthetized rats.

Acute effect of air pollution on respiratory complaints, exhaled NO and biomarkers in nasal lavages of allergic children during the pollen season.

During 2 months of the pollen season, the acute and putative adjuvant effect of traffic-related air pollution on respiratory health was investigated in children sensitised to grass pollen or house dust mite (HDM). Respiratory complaints were objectified via measurement of exhaled NO and inflammatory mediators in nasal lavage (NAL). During the study children, skin prick negative (n = 31) or positive to grass pollen (n = 22), HDM (n = 34) or grass pollen + HDM (n = 32), kept a daily diary on respiratory symptoms, and NAL and exhaled air was sampled twice a week. The level of air pollutants and pollen was monitored continuously. Like children sensitised to HDM, those sensitised to pollen reported respiratory complaints (shortness of breath, itchy eyes or blocked nose) more frequently than non-sensitised children during (but not before) the pollen season; the respiratory complaints of sensitised children were independent of the pollen level. In addition, exposure to increased levels of PM(10) induces 'shortness of breath' in pollen- and HDM-sensitised children, whereas ozone induces a blocked nose in HDM-sensitised children. Combined exposure to PM(10) + pollen and O(3) + pollen induces a blocked nose in both HDM-sensitised children and children sensitised to pollen + HDM. Significant positive associations were found between eNO and the levels of NO(2), CO, PM(2.5) and pollen in both sensitised and non-sensitised children. At the start of the pollen season, the NAL concentration of eosinophils and ECP in pollen-sensitised children was increased compared to winter, but their levels were not further affected by increased exposure to pollen or air pollution. In conclusion, during the pollen season, sensitised children continuously report a high prevalence of respiratory complaints which coincides with increased levels of upper and lower airway inflammatory markers. No additional pro-inflammatory effect of air pollution was observed, which indicates that air pollution does not facilitate allergen-induced inflammatory responses.

Vardenafil reverses erectile dysfunction induced by paroxetine in rats.

Selective serotonin reuptake inhibitors (SSRIs) are associated with a high incidence of impotence. Paroxetine is an extensively used SSRI that has been shown to impair erectile function in patients, to induce erectile dysfunction and to inhibit nitric oxide synthase (NOS) activity and NO production in animal models. NO is a key mediator of penile erection. Vardenafil is a type 5 phosphodiesterase inhibitor that potentiates NO-mediated responses in isolated trabecular smooth muscle and penile erection in men in clinical trials. The aim of this study was to evaluate the effects of vardenafil on the impairment of erectile responses produced by paroxetine in the rat model. Application of cavernosal nerve electrical stimulation (CNES) produced frequency-related intracavernosal pressure (ICP) increases, which were inhibited by the NOS inhibitor N(G)-nitro-L-arginine (0.3 mg/kg) and potentiated by vardenafil (0.3 mg/kg). Acute paroxetine treatment (10 mg/kg) significantly reduced ICP-responses to CNES. This inhibition was completely reversed by vardenafil (0.3 mg/kg) administration. The results show that the erectile dysfunction induced by paroxetine in rats can be effectively treated with vardenafil, suggesting that the use of this compound could be a reasonable therapeutic approach to treating erectile dysfunction associated with SSRI administration.

Vardenafil enhances clitoral and vaginal blood flow responses to pelvic nerve stimulation in female dogs.

The relaxation of the smooth muscle in the vagina and clitoris and the increase of blood flow into these organs is thought to be essential in the female sexual response. Vardenafil is a type 5 phosphodiesterase (PDE5) inhibitor that potentiates the nitric oxide (NO)/cGMP pathway facilitating penile smooth muscle relaxation and improving penile erection in men. Although the potentiation of the NO/cGMP pathway through PDE5 inhibitors can clearly enhance blood flow into the penis and is used in the therapy of male sexual dysfunction, there is controversy about the efficacy of these agents in improving female sexual function. The aim of this work was to evaluate the effects of vardenafil on the increase of blood flow into the vagina and clitoris induced by pelvic nerve electrical stimulation (PNES) in a female dog model. Application of PNES produced consistent and frequency-related increased blood flow into the vagina and clitoris of anesthetized female dogs. The magnitude and duration of the blood flow responses to PNES were variable among the different animals but remained stable over time within the same animal. The intravenous administration of vardenafil (1 mg/kg) significantly potentiated the increases in blood flow produced by PNES into the vagina (381.4 and 206.2% of control response at 5 and 10 Hz, respectively, P<0.01, n=6) and clitoris (379.4 and 238.5% of control response at 5 and 10 Hz, respectively, P<0.01, n=6) 20 min after administration. The significant enhancement of PNES-induced responses was maintained 50 min (224.5 and 181.0%, P<0.01 in vagina; 294.8 and 258.9%, P<0.05 in clitoris) and 80 min after vardenafil administration (209.5 and 156.9%, P<0.05 in vagina; 268.9 and 194.9%, P<0.05 in clitoris). Here we present a feasible model for research into female sexual function. Our results show that vardenafil effectively potentiates the blood flow responses to PNES in the genitalia of female dogs. These results emphasize the role of the NO/cGMP pathway in the local vasodilatory response in female sexual organs and provide a rationale for testing PDE5 inhibitors, such as vardenafil, as a treatment for certain forms of female sexual dysfunction.

Exhaled NO level and number of eosinophils in nasal lavage as markers of pollen-induced upper and lower airway inflammation in children sensitive to grass pollen.

OBJECTIVES: This study investigates the upper and lower inflammatory response induced by natural exposure to grass pollen in atopic and non-atopic children. METHODS: After children's atopic profile had been assessed, their nasal lavage fluid (NAL) and exhaled air was sampled once before and once during the pollen season. Level of nitric oxide (NO) was determined in exhaled air, and the following mediators were measured in NAL: ECP, IL-6, IL-8, albumin, uric acid, and urea. The number of eosinophils in NAL was determined after Giemsa staining. During the experiment ozone and pollen levels were measured continuously. RESULTS: During the pollen season the level of grass pollen was 95 pollen grains per cubic metre. At baseline, 8.0% and 5.4% of total cells in NAL of children sensitive to, respectively, house dust mite (HDM) and pollen + HDM were eosinophils, whereas virtually no eosinophils were observed in NAL of non-atopic children. In contrast to the non-atopic and HDM groups, in children sensitive only to grass pollen, grass pollen induced a threefold increase in the percentage of NAL eosinophils and a 2.5-fold increase in the NAL level of ECP ( P<0.05). In all groups, the NAL levels of albumin, uric acid, urea, IL-6 and IL-8 were not significantly increased by pollen exposure. At baseline, children sensitive to HDM showed significantly higher exhaled nitric oxide (eNO) values than non-atopic subjects and children sensitive only to pollen (79 to 141% increase). During pollen exposure eNO of children sensitive only to pollen increased from 35.8 to 64.5 ppb ( P<0.05), whereas no increase in eNO was observed in the other children. CONCLUSION: Pollen-sensitive children show a season-dependent upper and lower airway inflammatory response, resembling the continuous inflammation in HDM-sensitive children.

BAY 41-2272: a stimulator of soluble guanylyl cyclase induces nitric oxide-dependent penile erection in vivo.

OBJECTIVES: To determine the effectiveness of BAY 41-2272 on penile erections in an in vivo rabbit model. The nitric oxide (NO)-dependent increase of intracellular cyclic guanosine monophosphate (cGMP) by cGMP-phosphodiesterase (PDE5) inhibition has been shown to be an effective mechanism in the treatment of erectile dysfunction. Direct, NO-independent stimulation of soluble guanylyl cyclase should also lead to elevated cGMP levels in tissues and could be an attractive alternative therapeutic option for the treatment of erectile dysfunction. BAY 41-2272 is a novel non-NO-based direct stimulator of soluble guanylyl cyclase that activates purified enzyme in a synergistic fashion with NO. METHODS: BAY 41-2272 was administered to conscious rabbits intravenously (IV) and orally (PO). Erection was assessed in a time-dependent manner by measuring the length of the uncovered penile mucosa. Erections were evaluated in the absence and presence of NO (with intravenous sodium nitroprusside [SNP] as the NO donor). RESULTS: BAY 41-2272 only induced weak penile erections in conscious rabbits after IV (1 mg/kg) and PO (10 mg/kg) administration in the absence of an NO donor. However, the efficacy of BAY 41-2272 was potentiated by the simultaneous administration of SNP. Through simultaneous SNP administration, the effective doses of BAY 41-2272 were reduced significantly (minimal effective dose 0.1 mg/kg IV and 1 mg/kg PO). CONCLUSIONS: The results of this study clearly demonstrated the effect of BAY 41-2272 on penile erection in the conscious rabbit model after PO and IV administration. The time-course and onset of erection was concurrent with the stimulation by exogenous NO (SNP), suggesting that this new pharmacologic mechanism of soluble guanylyl cyclase stimulation could be used in the treatment of erectile dysfunction. Because the effect is increased by SNP, it can be expected that BAY 41-2272 would have enhanced activity during sexual arousal, when NO is produced endogenously.

Tumor prevention by 9-cis-retinoic acid in the N-nitroso-N-methylurea model of mammary carcinogenesis is potentiated by the pineal hormone melatonin.

Our laboratory has demonstrated that treatment of MCF-7 breast cancer cells with melatonin (Mlt) followed 24h later with physiological concentrations of all-trans retinoic acid (atRA) results in apoptosis. These studies were extended into trials using the N-nitroso-N-methylurea (NMU)-induced rat mammary tumor model. Initial studies conducted by feeding the animals 9-cis-retinoic acid (9cRA in the chow) and administering melatonin by subcutaneous injection in the late afternoon demonstrated that the combination of Mlt and 9cRA was able to significantly prevent tumor development, and that the combination was more efficacious that either Mlt or 9cRA alone. In this report, we conducted studies to determine if lower doses of 9cRA could be used in combination with Mlt while still maintaining anti-tumor activity and if the route of administration of 9cRA (bolus (gavage) v.s. chronic (chow) routes) affected its interaction with Mlt. The studies presented here demonstrate that significantly reduced doses of 9cRA can be used in combination with Mlt while maintaining anti-tumor efficacy. Furthermore, our studies demonstrate that 9cRA is equally effective when it is administered chronically (chow) or as a bolus (gavage). These data demonstrate that the combined use of Mlt and 9cRA produces additive or synergistic effects, which are more efficacious than 9cRA alone. This combination of Mlt and 9cRA could be a potentially useful clinical treatment regimen for breast cancer since it allows the use of lower doses of retinoic acid, thus, avoiding the toxic side effects associated with the use of high dose retinoids.

Inhibition of cyclic GMP hydrolysis in human corpus cavernosum smooth muscle cells by vardenafil, a novel, selective phosphodiesterase type 5 inhibitor.

One of the key mediators of penile erectile function is nitric oxide (NO), which activates soluble guanylyl cyclase within the smooth muscle of erectile tissue and stimulates the production of cGMP. In addition to synthesis by cyclases, intracellular cGMP concentrations are tightly regulated by phosphodiesterases, which hydrolyze and inactivate cyclic nucleotides. In this study, we compared the inhibition of cGMP hydrolysis by vardenafil and sildenafil; two inhibitors selective for phosphodiesterase type 5 (PDE5). Vardenafil is a novel, high affinity PDE5 inhibitor currently under clinical development. In soluble extracts of human corpus cavernosum smooth muscle cells, vardenafil and sildenafil effectively inhibited cGMP hydrolysis at substrate concentrations of 1, 5 and 10 microM cGMP. The IC50 values for vardenafil were approximately 5-fold lower than for sildenafil at the substrate concentrations tested. Dixon plot analyses of the inhibition data demonstrated that vardenafil had a smaller inhibition constant (Ki = 4.5 nM) than sildenafil (Ki = 14.7 nM) in the same cellular extracts. In intact cells, 10 microM of the nitric oxide donor sodium nitroprusside resulted in a minimal (17%) increase in cGMP, relative to basal levels (321 +/- 65 fmol/mg prot). Treatment of cells with 10, 50 or 100 nM vardenafil, in the presence of 10 microM sodium nitroprusside, elevated cGMP levels in a dose dependent fashion, from 63% to 137% of basal levels. Equimolar concentrations of sildenafil also caused dose dependent increases in intracellular cGMP, but to a lesser extent (27-60%). These observations suggest that vardenafil is a more potent PDE5 inhibitor, than sildenafil in vitro. The more pronounced increase of cGMP in the presence of NO in intact cells suggests that vardenafil will be effective at lower doses than sildenafil under clinical conditions.

Rabbits as models for impotence research.

The anesthetized rabbit model is useful and has many advantages: ability to perform neurophysiological studies; more administration routes, including intracavernous injection; haemodynamic measurements in parallel to measurements of intracavernous pressure or penile volume; and direct measurement of intracavernosal pressure and blood flow. This model has been evaluated with many different types of drugs. The conscious rabbit model is a simple and valid model for the assessment of compounds with potential for treatment of ED. It offers several methodological advantages as a screening model for compounds with erection stimulating properties. It was clearly successful in demonstrating the efficacy and the mechanism of the new potent and selective PDE5 inhibitor vardenafil. The model was also effective in demonstrating erection-generating properties through other mechanisms, eg PDE3 inhibitors and alpha-receptor blockers. In conclusion, both anaesthetized rabbit model and the newly developed conscious-rabbit models are well-suited for studies in impotence research.