Erectile Dysfunction and Current Therapies

 Erectile dysfunction is defined as the inability to produce or maintain a penile erection with rigidity sufficient for intercourse. Risk factors include advanced age, diabetes mellitus, hypertension, obesity, dyslipidemia, pharmacologic side effects and cardiovascular disease. The prevalence increases with age and may affect up
to one third of men over the age of 50, representing a significant source of morbidity in an aging population.

 Currently medical therapies for erectile dysfunction are limited to direct manipulation of cavernosal smooth muscle relaxation. Selective pharmacological inhibition of hosphodiesterase-5 enzyme in penile smooth muscle cells prevents breakdown of cGMP leading to higher intracellular levels of this molecule resulting in increased smooth muscle relaxation and erection. Available PDE-5 inhibitors include sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis). Other pharmacologic options for erectile dysfunction include intracavernosal (Caverject) or intraurethral (MUSE) alprostadil delivery.

 The aforementioned therapies each have drawbacks leading to the search for alternative treatment methods. The PDE-5 inhibitors have been the most successful pharmacotherapy class, however up to 50% of diabetic men with erectile dysfunction remain refractory to such agents.

Importantly, while each of the above therapies addresses the mechanical issue of rigidity necessary for penetration and intercourse, none of the above therapies is known to affect sexual desire/libido, an important component to the overall treatment of erectile dysfunction. Thus, there is an unmet medical need to study alternative pathways and agents, such as the melanocortinergic compounds, which may fill in the gaps left by current forms of treatment.

 Complex interactions between the supraspinal, spinal and peripheral nervous system lead to the highly specific and regulated vasculogenic event of penile erection. Of the many neurotransmitters involved, melanocortins appear to play a significant role in regulation of erection, particularly at the supraspinal and spinal levels. MC agents may regulate physiologic erection, and could also have as yet unexplored effects on sexual motivation and libido.

Much knowledge has been gained of MC receptor sites and MC receptor subtypes involved in erection, particularly through the utilization of  novel compounds which activate and/or inhibit specific MC receptors. However, further detailed studies are necessary, particularly if new therapeutic agents are to be developed. The two superpotent synthetic MC agonists, MT-II and PT-141, have been tested in human subjects, with PT-141 showing promise in early clinical trials for treatment of erectile dysfunction.

Spontaneous erections in rodents

 THIQ is a synthetic small molecule hMC4R agonist with moderate bioavailability (14%), rapid absorption (Tmax = 1hr) and a short T1/2 (0.5hrs). THIQ has a >600 selectivity for the MC4R compared with MC3R. Studies by Martin and Van der Ploeg evaluated the effects of THIQ delivered both systemically and intracerebrally in rodents. Systemic administration (1mg/kg) potentiated electrically stimulated erections as well as decreasing mounting and intromission latency mating behaviors in wild type mice. In an ex copula model using male rats, systemic THIQ dose dependently increased total numbers of erections. This effect was blocked by central administration of the non-specific antagonist, AgRP, as well as the MC4R specific antagonist, MBP-10. ICV delivery of 20kg of THIQ increased reflexive penile erections. There are no studies of THIQ in humans to date. Interestingly, and in contradistinction to MT-II, THIQ has not been reported to initiate spontaneous erections in rodents.

 Endogenous and synthetic antagonists have been used to explore melanocortin signaling. When MCR antagonists bind to the MC receptors they either decrease constitutive levels of cAMP production or prevent agonist induced increases in cAMP production. In studies of penile erection, MCR antagonists have been primarily utilized to identify the mechanisms and location of action of MCR agonists as well as parcel out specific receptor subtype activity. These compounds have not been utilized as therapeutic agents.

 Endogenous melanocortin receptor inhibitors include agouti or agouti-related peptide (AgRP). AgRP is a 132 amino acid peptide which competitively antagonizes both MC3R and MC4R. While AgRP has primarily been studied for its role in energy homeostasis, this peptide is principally expressed in the arcuate nucleus of the hypothalamus, a potential site for regulation of melanocortin mediated erection. As mentioned, intracerebral delivery of AgRP (5.5kg) was shown to block erections in rats induced by the MC4R agonist, THIQ. There have been no studies in humans with regard to erection.

 SHU-9119 is a classical inhibitor of both the MC3R and the MC4R. This synthetic cyclic lactam MSH analogue is closely related in structure to MT-II. SHU-9119 actually has agonist properties at MC1R and MC5R, but for the purposes of discussing erection, this compound is considered primarily an antagonist because of the lack of these receptors in the CNS. In rabbits this highly potent compound readily blocked MT-II induced erections when administered systemically. In rats, SHU-9119 blocked erections and grooming/yawning behaviors stimulated by MT-II both at supraspinal and spinal locations. This compound has not been studied in humans.

 Two other synthetic MC receptor antagonists that have been utilized in studies of erectogenisis include MPB-10 and HS014. Both of these compounds preferentially block the MC4 receptor. Their use in animal studies has primarily been related to determination of receptor specification as described in the following section. These compounds have not been studied in humans.

 Of the 5 melanocortin receptor subtypes, only the MC3R and MC4R have been identified in CNS regions associated with activation of penile erection, particularly the PVN of the hypothalamus. Many of the more commonly studied compounds, such as MT-II and MSH, activate both MC3 and MC4 receptor subtypes to some degree. This lack of receptor specificity has limited our understanding of each receptor’s contribution toward erectile behaviors and has prompted studies utilizing receptor specific agonists and antagonists as well as receptor knock out mouse models. Contrary evidence has pointed to each receptor as the principle subtype mediating erection. Although the weight of evidence leans towards MC4R activation being responsible for activation of erection, the debate remains unresolved.

Evidence of MC3Rs participation in sexual stimulation and erection comes from a series of studies in the late 1990s utilizing an MC4R specific antagonist, HS014. Vergoni et al. administered ACTH and MSH into the lateral ventricle of adult male SpragueDawley rats and showed predictable responses with grooming, stretching, yawning and erections. Co-administration of these compounds with HS014 completely blocked grooming, stretching and yawning behaviors, but only partially reduced erections.

Argiolas  et al. studied this effect further with ACTH,  MSH and HS014 microinjections into regions surrounding the 3rd ventricle of adult rats. The effect was a dose dependent elicitation of yawns, grooms and erections when only ACTH and MSH were administered. Co-administration of these compounds with HS014 significantly blocked yawns and grooms but erections were unaffected. This evidence suggested that the MC4R was not involved in the sexual response to ACTH and MSH. As the only other MC receptor in the region, the MC3R was attributed partial Table 2. Sample of Melanocortin Receptor Binding Agents Studied with Erection Structure Preferential MCR Binding MC3R affinity Ki (nM)* MC4R affinity Ki (nM)* Agonists ACTH 39 amino acid peptide.

Penile Implant

A 58-year-old heterosexual man was referred to our clinic for control visit. He had previously undergone penile implant surgery at 2000, for erectile dysfunction because of arterial vascularisation failure which had developed after transurethral prostatectomy in 1999, and which was unresponsive to medical therapy. He and his partner were satisfied with the penile implant. However, he had begun using home-made herbal remedies in February 2003 to obtain normal physiological erection because he felt himself sentenced to artificial erection evoked by the implant. After 2 months, he perceived that spontaneous full, rigid erections upon sexual arousal, without activation of the implant were adequate for vaginal penetration and satisfying sexual intercourse. He stated that since then, he had been activating the implant only once per month to prevent malfunction of the implant and had been regularly achieving sexual intercourse with spontaneous erection without activation of the implant.

We wanted to confirm radiologically this urological entity by magnetic resonance imaging technique. The images of flaccid penis and artificial erection evoked by the implant were obtained. On the following day, 50 mg sildenafil was given orally to the patient with the inactivated implant, for achievement of penile erection to demonstrate whether the penis still contains erectile tissue. One hour later, rigid penile erection was obtained. The glans and corpus spongiosum are also involved.

However, erection was not resolved spontaneously and semirigid erection persisted with minimal pain. The erection lasted for 6 h and, resolved with oral terbutaline, the application of ice pack to the genitalia and intermittent activation of the implant until detumescence. We did not attempt to stick a needle into cavernous body for diagnostic or therapeutic purposes during prolonged erection, because of the presence of an intracavernous implant. Routine haematological, biochemical and urine tests were normal.

Although the latest pharmacological developments have revolutionised the management of erectile dysfunction, penile implant surgery remains one of the most effective treatments for all types of erectile dysfunction. Nevertheless, it is a common belief that erectile tissue is destroyed utterly during dilatation of corporeal space in penile implant surgery and the penis thus loses its erectile function permanently. Even special penile implants (soft or fenestrated) have been developed with the aim at avoiding this adverse event and the fact remains that spontaneous tumescence or even erection was achieved with these devices in accordance with the expectations. Regular spontaneous tumescence is not surprising in men with specially designed implants, because these devices restore erectile function by the initiation of a new haemodynamic status in the corpora cavernosa which are dilated lesser than that of standard procedure.

The remaining functional cavernous tissue between the cylinder of implant and the tunica albuginea plays a pivotal role in men who experienced spontaneous tumescence, with this special penile implant. However, the same condition was not expected theoretically in men with three-piece hydraulic implants. Surprisingly, Manning et al. reported spontaneous tumescence without activation of the device in 50% of patients with three-piece inflatable device in their retrospective study including 32 patients.

More interestingly, one patient had claimed regular, full, rigid spontaneous erections that were adequate for sexual intercourse in their study. The authors finally stated that the destruction of cavernous tissue during dilatation was incomplete and tumescence, even with three-piece hydraulic implants, was not completely prevented.

Our report includes the complete case history of a penile implant patient who is regularly achieving sexual intercourse with spontaneous erection upon sexual arousal without activation of the three-piece implant. This extremely rare condition becomes more interesting with the occurrence of prolonged drug-induced erection in the patient with penile implant because of arteriogenic erectile dysfunction. The same has not yet been reported in terms of the presence of both spontaneous and prolonged drug-induced erection.

The most important question that needs to be answered in this subject is, how the penis which was unresponsive to medical therapy before penile implant surgery, spontaneously achieves an erection after penile implant. Several hypotheses were proposed to explain the phenomenal aspect. Our case, particularly with the occurrence of prolonged drug-induced erection supports the hypothesis proposed by Goldstein et al. They stated that elevated pre-load of likely compressed rather than destructed cavernous tissue and easier venous compression is the underlying mechanism of spontaneous tumescence with penile implants.

In addition, the herbal remedies used by the patient may have played a role in occurrence of this interesting phenomenon because some naturopathic remedies have significant hormonal content, even though this issue has not yet been clearly elucidated.

PT-141 (Bremelanotide)

 PT-141 (Bremelanotide) is currently the most studied melanocortinergic compound with regard to therapeutic potential for treatment of erectile dysfunction. PT-141 is a synthetic heptapeptide. It is a deaminated derivative and likely metabolite of MT-II. This compound has strong binding to MC receptors 1, 3 and 4, with a higher affinity for MC4R over MC3R. Application of PT-141 to HEK-293 cells expressing MC4R increases cAMP production, indicating that this compound, like MT-II, acts as an agonist.

 Studies with adult male Sprague-Dawley rats indicate pro-erectile responses through multiple modes of delivery. Intranasal injection of 50?g/kg PT-141 produced a significant increase in spontaneous erections compared with saline controls in rats observed over a 30-minute period. As well, 100% of the drug treated rats had at least one erection. In this study the pro-erectile effect of PT-141 was attributed to hypothalamic stimulation of MC3R and/or MC4R. Two hours after PT-141 (50?g/kg IN) administration, immunostaining for FOS, a measure of neural activation, showed increased expression in the paraventricular nucleus compared with rats administered saline.

 Preliminary trials in humans have established both safety and efficacy of PT-141. A phase 1 randomized doubleblind placebo controlled trial involved 24 healthy male subjects without erectile dysfunction. Intranasal doses of 4 to 20mg were delivered to patients in the absence of visual sexual stimulation (VSS). Safety and tolerability were monitored revealing no significant hemodynamic changes or side effects, including priapism. Serum concentration of drug was dose dependent and peaked at 30 minutes in the maximum dose group. Serum half-life was measured at 120 minutes. Rigi-Scan monitoring of erectile response revealed a significantly increased duration of rigid erections of 140 minutes compared to 22 minutes in the placebo group. Time to onset of erection ranged from 34 to 63 minutes.

Erections were considered rigid if they were more than 60% of base rigidity. 

Based on the above results, phase II studies were initiated in patients with mild to moderate ED who showed positive erectile response to PDE-5 inhibitors [44]. RigiScan monitoring in the presence of VSS detected a 3-fold increase in erectile activity with PT-141 (20mg intranasal) administration. The duration of base rigidity was significantly increased utilizing both a 60% and 80% cut-off versus placebo [43]. Timing of erections corresponded well to visual stimulation indicating a potential acilitator mechanism of drug action.

 In a first Phase IIB at home study, PT-141 induced dose dependent improvements in erectile function as assessed by the International Index of Erectile Function (IIEF). Of the patients who completed at least 3 at home attempts (n = 203), the mean IIEF erectile function domain score increased in a dose dependent fashion (p < 0.05 for 10, 15, and 20 mg). Normal erectile function (EF>26) was achieved by 10, 30, 36, 53, and 50% of patients in the placebo, 5, 10, 15, and 20 mg groups respectively.

Improved erections as defined by a global assessment question were reported by 17, 49, 67, 66, and 66% of patients in the placebo, 5, 10, 15, and 20 mg groups respectively. There were no episodes of syncope or hypotension. The only serious adverse event reported in this study occurred in one patient who reported a rolonged erection that was painless and required no treatment. Gastrointestinal side-effects were the primary reasons for discontinuation in the higher two higher dose groups.

 In summary, PT-141 is a potent initiator of erection with minimal side effects, a rapid onset of action and a sufficiently long duration of action. Notably, the recent Phase II studies confirm that the erectile responses are augmented by sexual stimulation. With its central mechanism of action, PT-141 may act independent or synergistically with PDE-5 inhibitors and provide a useful alternative therapy for erectile dysfunction, both from organic and psychogenic origin. A randomized prospective lacebocontrolled study compared treatement of ED with sildenafil alone verses sildenafil with 7.5mg intranasal PT-141. Co-administration of the two agents resulted in significantly prolonged time of increased base rigidity (>60%) compared with sildenafil alone during a 2.5 hour monitoring session. The combination of drugs was well
tolerated with no significantly increased side-effects over either sildenafil or PT-141 alone. The ability of the peptide to safely and effectively induce high quality erections allowed Palatin Technologies to initiate a second Phase IIB study in 2006 and propose Phase III studies in 2007.

Endogenous Receptor Agonists

 ACTH, MSH are the known endogenous agonists of the MC system. Each hormone is a product of posttranslational modification of the POMC gene transcript and
contains the sequence of His-Phe-Arg-Trp, considered to be the “core” of agonist activity. Only ACTH and MSH have shown the ability to generate sexual stimulation and penile erection in various animal species including rats, rabbits, cats, dogs and monkeys. These pro-erectile effects appear to be androgendependent as castration abolishes the aforementioned response.

Notably, many of the synthetic MC agonists contain the “core” sequence present in ACTH and  MSH, particularly the agents MT-II and PT-141.

MT-II is a synthetic cyclic heptapeptide that was initially designed as an artificial tanning agent. Its structure is based on an earlier linear peptide, Melanotan-I, however cyclization was introduced to prevent degradation and allow both N and C terminal truncation of the peptide. The pro-erectile activity of
MT-II was reported as a significant unexpected reaction during a phase-I human trial of human tanning. MT-II contains a seven amino acid sequence with homology to receptor binding portions of MSH and ACTH. The compound is thought to cross the blood brain barrier and has high affinity for the MC1R, MC3R and MC4R. MT-II has a similar affinity for MC4R compared with MC3R and may be considered “superpotent” because of its relatively high affinity for MC4R compared with the endogenous
peptides MSH and ACTH (10-100 fold difference).

 The pro-erectile activity of MT-II appears to be both forebrain and spinally mediated, with little, if any, peripheral effect. Dose dependent increases in spontaneous erections in awake Long-Evans rats were noted with administration of MT-II intracerebrally, intrathecally and intravenously.

Increases in yawning and grooming behaviors paralleled erectile activity with intracerebral administration but not spinal administration. As discussed previously, when the non-selective MCR antagonist SHU-9119 was given spinally, it blocked spinal MT-II induced erections, however intrathecal SHU-9119 failed to block intracerebral MT-II induced erections. This indicates potentially independent sites of melanocortin action along the CNS axis with intracerebral sites activating multiple downstream pathways including those independent of melanocortinergic activation.

 In parallel with the above observations, Vemulapalli et al found that isolated corpus cavernosal strips from rabbits had no relaxation in response to electrical field stimulation in the presence or absence of MT-II. As well, MT-II associated elevations in intracavernosal pressure were abolished when anesthetized rabbits underwent bilateral pudendal nerve ablation. Inhibition of NOsynthase enzymes with L-NAME also blocked the erectile effect of systemic MT-II. These pieces of data indicate that MT-II exerts direct actions through CNS brain and spinal activation, which is then mediated peripherally through established NO vasodilatory pathways.

 A double blind placebo-controlled crossover study by Wessells  et al. demonstrated the safety and pro-erectile activity of subcutaneous MT-II in humans. In the absence of erotic stimulation, 10 men with psychogenic (non-organic) erectile dysfunction received subcutaneous doses ranging from 0.025 to
0.157 mg/kg, while erections were monitored by RigiScan over a 6-hour period. Eight of the 10 men developed clinically apparent erections with greater than 80% rigidity of an average duration of 38 minutes compared with 3 minutes for placebo controls. The time to onset ranged from 15 to 270 minutes. Side effects were dose
dependent included nausea, stretching, yawning and decreased appetite. At the preferred dose of 0.025 mg/kg side effects were mild.

 The above study documented erectogenic effects of MT-II in men with presumed normal underlying physiology. A subsequent study of MT-II was carried out on men with organic ED. In a similar double blind, placebo-controlled crossover study, 10 men received 2 subcutaneous doses of 0.025 mg/kg MT-II and 2 doses of vehicle. MT-II initiated subjectively reported erections following 63% of the drug injection verses 5% of the placebo injections. The mean rigidity score of the responders was 6.9 on a scale of 0 to 10.

 Mean duration of tip rigidity greater than 80% was 45 minutes with Melanotan II compared to two minutes for placebo. There was increased subjective reporting of sexual desire after MT-II administration compared with placebo, although the question used to assess desire was not designed specifically to measure desire in men not engaging in sexual intercourse.

Spinal Cord

 The spinal cord contains neurons which project to the penis and are linked with penile erection. These include thoracolumbar sympathetic, sacral parasympathetic and sacral pudendal pathways. Sensory afferents from the penis project primarily to the lumbosacral spinal cord while some corpus cavernosal afferents have been
traced to the thoracolumbar spinal cord.

 The spinal cord coordinates ascending and descending inputs affecting penile erection utilizing a variety of neurotransmitters. A well-documented pro-erectile pathway involves the aforementioned OT neurons projections from the paraventricular nucleus to the sacral parasympathetic nuclei expressing the OT receptors. These
sacral nuclei directly innervate the corpus cavernosum.
 
 More recently, proerectile functions of spinal melanocortin receptors have been proposed. Spinal MC4R mRNA has been demonstrated in multiple studies. Intrathecal injection of the melanocortin agonist, MT-II, to the lumbar spinal cord dosedependently increased spontaneous erections in male rats. This effect was abolished by intrathecal co-administration of the melanocortin antagonist, SHU-9119. When SHU-9119 was given intracereroventricularly (ICV), it did not block MT-II spinally
induced erections. These results suggest that MC agonists act on independent spinal loci for initiation of erection. Notably, these results are in contrast with a study of intrathecal administration of MSH, which failed to affect intra-cavernosal pressure in anesthetized rats [32]. However, the lack of effect of  MSH may be attributable to its relatively lower affinity for the MC4R and/or its rapid metabolism.

 While MT-II clearly induces erections at the supraspinal level, Giuliano and colleagues have shown both inductive and facilitative effects at the spinal level. In acutely spinally transected rats as well those with bilateral transaction of pelvic or dorsal penile nerves, systemic MT-II facilitated erections induced by cavernous nerve stimulation as measured by increased intercavernous pressures. However, the facilitator effect of MT-II was abolished by removal of the lumbar paravertebral sympathetic chain. These results suggest that the facilitatory effects of MT-II act principally to modulate the sympathetic efferents to the pelvis, with little effect on the parasympathetics. The mechanism by which sympathetic modulation promotes increased cavernosal pressures is unclear, highlighting the need for further studies of spinal melanocortin action.

 Many studies demonstrate pro-erectile effects of melanocortinergic agents after systemic delivery. However, MC agonists have yet to demonstrate modulation of erection through direct action on the cavernosum. One study used in-situ hybridization to localize MC4R mRNA to stretch activated mechanoreceptors and sensory afferent nerves of the penis. However, in anesthetized male rats, MC agonists injected intracavernosally neither increased intracavernous pressure nor augmented neurostimulated erectile responses. Direct application of an MC4R agonist failed to produce relaxation of cavernosal strips in organ bath experiments or alter calcium currents of isolated cavernosal smooth muscle cells in vitro.

 A variety of research modalities have been used to elucidate the action of MC compounds on penile erection. MC compound affinity and activity properties are determined by cell culture and membrane receptor assays. In general, MC agonists bind strongly to subsets of the five G-protein coupled MC receptors
and cause increased intracellular production of cAMP while MC antagonists bind strongly but do not stimulate cAMP production.

Notably MCRs 1, 3, 4 and 5 have high constitutive (ligand-independent) activity enabling antagonists to decrease basal levels of cAMP production.

Normal Penile Erection

Penile erection is the final endpoint of a complex coordination between the central nervous system, peripheral nervous system, endocrine system, voluntary and involuntary pelvic musculature and the highly specialized vascular tissue of the penis.

Supraspinal centers in the brain integrate sensory input and hormonal cues as part of the initiation of sexual desire, arousal and libido. These centrally initiated pro-erectile signals are relayed to sympathetic and parasympathetic centers in the thoracolumbar and sacral spinal cord in order to regulate vascular tone in the penile
tissues. Alternately, direct genital afferents to the lumbosacral spinal cord can initiate a reflexogenic erection independent of supraspinal input. Inhibition of sympathetic vasoconstriction coordinated with vasodilatory parasympathetic activation greatly increases blood flow through the paired cavernosal arteries. As the cavernous spaces within the corpora cavernosa expand, they compress the venous outflow pathways leading to marked increase in intracavernosal pressure with subsequent tissue expansion.

 Voluntary contraction of the bulbocavernosus muscle further increases intracavernous pressures to produce a rigid erection while periurethral and bulbospongiosus muscular contractions assist with seminal ejaculation.

 The most important end-organ neurotransmitter modulating erection is now recognized as nitric oxide (NO). Release of NO from the terminals of non adrenergic non cholinergic parasympathetic nerve fibers results in activation of cavernosal smooth muscle cell guanalyl cyclase (GC). This leads to increased production of the cyclic nucleotide guanosine monophosphate (cGMP), which in turn leads to cellular relaxation through direct calcium regulating mechanisms. Smooth muscle contraction and
penile detumescence is in turn regulated by phosphodiesterase type 5 enzyme degradation of cGMP, as well as sympathetic activation at the moment of ejaculation.

 Neural control of erection results from a complex interaction between the forebrain, midbrain, spinal cord and peripheral nervous system. Although MC agonists are known to induce penile erection, whether or not endogenous melanocortins are necessary for normal physiologic penile erection remains unknown. A broader knowledge of neural erectile pathways, including the nonmelanocortinergic pathways may lead to a greater understanding of areas where the melanocortinergic system may exert influence.

Giuliano and Rampin provide an excellent review of the known pathways and neuropharmacology involved in penile erection.

 Erections occur in many different physiological and behavioral contexts and in response to a variety of stimuli, some of which clearly are relevant to reproduction while others seemingly have little to do with reproduction. Examples of the former may include erections during copulation and genital stimulated erections while examples of the latter include erections observed in-utero, nocturnal erections and “non-contact erections”. The supraspinal CNS is primarily responsible for sexual motivation as related to penile erection. Multiple areas of the forebrain and hindbrain may be responsible for erections in each of these contexts. In particular, based on their projections to the lumbosacral spinal cord, the following forebrain regions have been identified as potential initiators or facilitators of penile erection: the medial preoptic area (MPOA), the parvocellular portion of the paraventricular nucleus (PVN), the nucleus paragigantocellularis (NPGI) and the medial nucleus of the amygdala (MeA).

The MPOA of the hypothalamus is well recognized for its role in male sexual behavior, likely through the integration and redistribution of information to other hypothalamic and brainstem nuclei. Electrical stimulation of this area as well as the PVN elicits complex sexual responses and erection in male monkeys and rats. Neurons of the PVN are activated by dopamine and send oxytocinergic and vasopressinergic projections to the lumbosacral spinal cord. Lesions of this area decrease non-contact erections while having little effect on copulatory erections.

Brainstem NPGI neurons send serotonergic signals to the lumbosacral spinal cord. Lesions of this area remove inhibition of both reflex erections and copulatory erections. PVN projections to the NPGI may be responsible for physiological release of this tonic inhibition of erection. Lesions of the MeA facilitate reflexive erections, depress non-contact erections, and have no effect on copulatory erections.

 Complex circuits involving many neurotransmitters, including oxytocin and dopamine, have been described with potential effects related to erection, most of which are beyond the scope of this article.

 Within this complex neural network, the melanocortinergic system has multiple potential sites for regulation. In male rats exposed to sexual situations, MSH is secreted in the MPOA. The arcuate nucleus (Arc) of the hypothalamus is a primary source of POMC secreting neurons in the CNS with projections to the lateral hypothalamus, dorsal medial nucleus and the PVN.

POMC expression has been documented in regions of the PVN known to send oxytocinergic (OT) projections to the spinal cord, implicating possible regulatory interactions between the OT and MC systems. Male rats show increased expression of the immediate-early gene, Fos, in magnocellular oxytocin neurons in
the PVN when exposed to either intromission or direct  MSH intracerebral exposure. Central administration of an MC4R antagonist attenuated the increased Fos expression in these PVN neurons and inhibited copulatory behaviors.

 Indirect evidence that hindbrain melanocortin signaling may contribute to supraspinal erection may be provided by the localization of POMC neurons in the nucleus tractus solitareus (NTS). An independent caudal brainstem melanocortin receptor trigger for sympathetically stimulated metabolic responses has been reported.

Improvement erectile dysfunction

This study used improvement by 1 erectile dysfunction severity category in the IIEF Erectile Function domain score as the anchor to determine the clinically meaningful improvemen on the quality of erection questionnaire and used the 95% CI of the mean quality of erection questionnaire score to derive the minimal clinically meaningful improvemen. The study results estimated an minimal clinically meaningful improvemen that was corroborated by distribution-based methods.

The slight difference in estimates between the anchor-based approach and the distribution-based approach may be caused, in part, by the different perspectives: group-based differences for the anchor-based approach versus individual-based differences for the s.e.m. and the s.e. of the difference.

Although anchor-based approaches to estimating minimal clinically meaningful improvemen are useful, the validity of such an estimate depends on the strength of the correlation between the disease-related anchor and the patient-reported outcome measure.

As reported previously for these data, improvement in IIEF Erectile Function domain scores showed moderate-to-high correlations with improvement in quality of erection questionnaire item scores (range, 0.52–0.73; Po0.0001) and with the quality of erection questionnaire total score (0.67; Po0.0001).

A limitation to our study is that we made no attempt to investigate clinically meaningful deterioration on the quality of erection questionnaire, which may or may not be of the same magnitude as its clinically meaningful improvemen's.

The quality of erection questionnaire is among an increasing list of patient-reported outcome's for which criteria for meaningful change in scores have been established. Others include the Parkinson’s Disease Questionnaire, the Functional Assessment of Cancer Therapy-Breast, the Functional Assessment of Cancer Therapy-Lung, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, the Overactive Bladder Questionnaire and the Acne-Specific quality of Life Questionnaire.

Erectile dysfunction-specific  patient-reported outcom's, other than the quality of erection questionnaire, for which criteria for meaningful change in scores have been established include the IIEF, the self-esteem and relationship questionnaire and the Erection Hardness Score.

The IIEF provides a broad evaluation of sexual function for use in clinical trial research, the self-esteem and relationship questionnaire evaluates the emotional wellbeing (self-esteem, confidence, sexual satisfaction and overall satisfaction) of men with erectile dysfunction and the Erection Hardness Score is a targeted self-reported measure that classifies erection hardness on a single-item scale.

Each of these concepts is important and provides unique information for assessing erectile dysfunction. A recently published comparative review of seven erectile dysfunction-specific  patient-reported outcom's highlights similarities and differences to aid in choosing the appropriate instrument for a specific clinical situation.

Unlike other erectile dysfunction-specific  patient-reported outcom's, the quality of erection questionnaire is the only psychometrically validated  patient-reported outcom designed to solely and specifically evaluate satisfaction with the quality of erections.

Satisfaction with the quality of erections is a key measure for assessing erectile dysfunction because ‘lack of satisfaction is a prerequisite to concern or bother, the drivers of treatment-seeking behavior’.

Unless a man is dissatisfied with the quality of his erections, he will be unlikely to treat his erectile dysfunction. In the treatment of erectile dysfunction, erection hardness (which can be easily monitored with the Erection Hardness Score) and erection maintenance were the primary attributes sought by patients.

On the basis of the current analyses, we believe that the proposed minimal clinically meaningful improvemen in quality of erection questionnaire scores can be used as an initial guide to interpreting change scores on the quality of erection questionnaire, even accounting for measurement error in individual scores. This is particularly true for populations with moderate or severe erectile dysfunction, given that 70% of the men in the two studies had moderate or severe erectile dysfunction. Repeat testing or corroboration with other psychosocial endpoints (for example, the self-esteem and relationship questionnaire or the Erectile Dysfunction Inventory of Treatment Satisfaction) is encouraged to enhance decision making regarding meaningful improvement or its absence. Further research in this area will only strengthen our understanding of what the minimal clinically meaningful improvemen and clinically meaningful improvemen are for the quality of erection questionnaire. Until such work has been conducted, the proposed minimal clinically meaningful improvemen in quality of erection questionnaire scores could be used for sample size estimations and could assist in interpretation of scores between and within treatment groups.

In conclusion, the quality of erection questionnaire is an easy-to-administer tool that has potential for use in clinical trials and clinical practice for the comprehensive evaluation of satisfaction with erection quality before and after erectile dysfunction therapy. Interpreting quality of erection questionnaire scores and establishing criteria for meaningful improvement in scores are important to understanding the relevance of outcomes on this validated health-status measure.

Improvement of quality of erection in men

The quality of erection questionnaire is a new six-item patient-reported outcome for evaluating the quality of erections in terms of hardness, onset, and duration, as well as for assessing changes in erection quality with successful treatment of erectile dysfunction.

Although the past decade has seen the development of many patient-reported outcome's to evaluate erectile dysfunction, the quality of erection questionnaire is unique in that it is the only psychometrically validated assessment tool designed to solely and specifically evaluate satisfaction with the quality of erections.

The development and validation of the erection questionnaire were described previously.

In prospective trials of flexible-dose sildenafil citrate (25, 50 or 100 mg) for the treatment of men with erectile dysfunction, the mean±s.d. transformed erection questionnaire total score increased by more than 40 points, from baseline values of 22 and 34 points, in men treated with sildenafil. Furthermore, the erection questionnaire had convergent validity with measures of sexual function (International Index of Erectile Function (IIEF), erection hardness (Erection Hardness Score), satisfaction (Erectile Dysfunction Inventory of Treatment Satisfaction) and emotional well-being.

Health-status measures have become a standard and essential part of validated patient-reported outcome's in many different types of diseases. However, to understand the relevance of outcomes on a health-status measure, it is crucial to be able to interpret the scores and have established criteria for determining the meaningfulness of changes in scores. Such an understanding is important, not only in helping complete a psychometric evaluation, but also in designing trials, evaluating interventions, informing consumers and health policy makers, and providing information for formulary and reimbursement decisions.

The importance of determining the minimum important difference threshold is highlighted by the inclusion of a discussion in the US Food and Drug Administration’s draft guidance for industry, ‘Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims’.

For a new patient-reported outcome instrument, clinically meaningful change can be estimated using an anchor-based approach in which change on the new instrument is compared with change in disease status. Assessing change in disease status in some areas such as sexual health must be through self-report by the patient. In this case, a known disease-related measure that has clinical relevance and has an appreciable association with the targeted healthstatus measure can be used.

Another approach relies on the statistical characteristics of a study sample—a distribution-based approach which can be used to attempt to corroborate estimates from an anchor-based approach (and vice versa).

As a clinically meaningful improvement definition is crucial to understanding the relevance of treatment on health-status measures, we estimated the clinically meaningful improvement and the minimal clinically meaningful improvement on the erection questionnaire using an anchor-based approach and a distribution-based approach which can be used to attempt to corroborate estimates from an anchor-based approach (and vice versa).

The clinical trials enrolled 594 men aged 23–65 years (53.8±8.1 years), 558 of whom completed baseline and postbaseline quality of erection questionnaire measurements. Between the two clinical trial populations (n=223 and n=335, respectively), a statistically significant difference was found in the mean duration of erectile dysfunction (5.3 (range, 0.5–31) versus 6.9 (range, 0.7–35) years) at baseline; this was not expected to affect the results. In 542 of the men, erectile dysfunction was categorized according to IIEF Erectile Function domain scores: mild ED (n=44), mild-to-moderate ED (n=119), moderate ED (n=171) and severe ED (n=208). A total of 95 men improved by 1 IIEF Erectile Function domain severity category, and 116 men had no change in IIEF Erectile Function domain severity category.

The mean change from baseline to end of treatment in the quality of erection questionnaire total score for the men who improved by 1 erectile dysfunction severity category (the anchorbased group) was 22.4 (s.d., 2.2)—defined as the clinically meaningful improvemen; the minimal clinically meaningful improvemen, estimated from the lower bound of the 95% CI, was 18.0. Using the difference of this mean score of 22.4 and that from the 116 men who had no change in erectile dysfunction severity (the anchor group minus the no-change group), the clinically meaningful improvemen was 17.7 (s.d., 2.9) and the minimal clinically meaningful improvemen was 12 points.

According to the distribution-based analyses, the baseline 1 s.e.m. was 7.99, the end-of-treatment 1 s.e.m. was 8.22 and the s.e. of the difference was 11.46. Compared with the anchor-based minimal clinically meaningful improvemen estimate of 12 points (based on data from the anchor group minus the no-change group), these s.e.m. values are only slightly lower, and the s.e. of the difference value is approximately equivalent.

Penile erections of rats

Rats in which only chronic guide cannulas were implanted were placed individually in Plexiglas cages. After a 30-min habituation period, oxytocin or vehicle alone was injected into the ventral subiculum or the PMCo in a volume of 0.3 lL over a period of 2 min through the microinjection cannula connected by polyethylene tubing to a 10-lL Hamilton syringe driven by a Stoelting microsyringe pump. When d(CH2)5Tyr(Me)2-Orn8-vasotocin was used, the compound was injected into the ventral subiculum or the PMCo 15 min before oxytocin.

When cis-flupentixol and (+)MK-801 were used, the compounds were injected into the nucleus accumbens or the VTA 15 min before oxytocin. When microdialysis was
performed, the microdialysis probe was connected via polyethylene tubing to a 2500-lL Hamilton syringe driven by a Stoelting microsyringe pump at one end and to the polyethylene collecting loop at the other end.

After a 2-h period of equilibration of the dialysis probe with Ringer’s solution, three dialysate aliquots of 37.5 lL were collected for the determination of basal levels of dopamine and DOPAC, oxytocin or vehicle was injected into the ventral subiculum or the PMCo, and five additional dialysate aliquots were collected.

When d(CH2)5Tyr(Me)2-Orn8-vasotocin was used, this was injected into the ventral subiculum or the PMCo 15 min before oxytocin. In all of the above experimental conditions, after treatments rats were observed for the entire duration of the experiment in order to count penile erection episodes and, in those experiments during which microdialysis was performed, to replace filled loops with empty ones every 15 min. Penile erections were scored when the penis emerged from the penile sheath, which was usually accompanied by penile grooming and hip flexions.


In those experiments in which only microinjections through chronic guide cannulas were performed, one-way anova followed by Tukey’s multiple comparison test was performed in order to show significant differences between groups for penile erection. When microdialysis was performed, the areas under the curves obtained by plotting penile erection, dopamine and DOPAC values vs. time in each animal were first calculated with the classic trapezoidal rule. The AUCs were then statistically compared between groups with one-way anova followed by Tukey’s multiple comparison test, in order to show significant differences between groups. P < 0.025 was considered to be significant.

Effect of oxytocin injected into the dorsal and ventral subiculum or into the PMCo on penile erection: dose–response curves Oxytocin (20, 40, 80 and 100 ng) microinjected into the ventral subiculum or the PMCo, but not into the dorsal subiculum, induced penile erection episodes in a dose-dependent manner. In both cases,
penile erection started about 30 min after the injection and disappeared in about 60 min. In the ventral subiculum, the minimal effective dose was 40 ng, which increased penile erection episodes from 0.35 ± 0.09 to 1.30 ± 0.33 (P < 0.01), and the maximal effective dose was 100 ng, which increased penile erection episodes up to
3.0 ± 0.35 (P < 0.01).

Similar results were found when oxytocin was injected into the PMCo: the minimal effective dose was 40 ng, which increased penile erection episodes from 0.38 ± 0.09 to 1.20 ± 0.21 (P < 0.01), and the maximal effective dose was 100 ng, which increased penile erection episodes up to 2.50 ± 0.31 (P < 0.01). In contrast, oxytocin injected into the dorsal subiculum was ineffective (P > 0.1).

Microinjections for erection

Microinjections into the ventral and dorsal subiculum



For microinjections into the ventral/dorsal subiculum or the PMCo, a stainless-steel chronic guide cannula (22 gauge) aimed at the ventral subiculum, the dorsal subiculum or the PMCo was stereotaxically implanted in the skull of male rats under chloral hydrate anaesthesia. Animals were given 2 days to recover from surgery; each rat was used only once. Oxytocin dissolved in saline or vehicle alone was injected into the dorsal or ventral subiculum or the PMCo in a volume of 0.3 lL over a period of 2 min via an internal cannula, which extended 1.5 mm and 5.3 mm, for the dorsal and ventral subiculum, respectively, and 7.2 mm for the PMCo, below the tip of the guide cannula, and was connected by polyethylene tubing to a 10-lL Hamilton syringe driven by a Stoelting microsyringe pump.

When d(CH2)5Tyr(Me)2-Orn8-vasotocin was used, the oxytocin antagonist was dissolved in saline and injected into the ventral subiculum or the PMCo in a volume of 0.3 lL over a period of 2 min, 15 min before oxytocin. After the injections, the tip of the cannula was left in the injection site for 30 s to allow spread of the injected solution. The injection of 0.3 lL of distilled water coloured with Neutral Red into the ventral subiculum or into the PMCo allowed us to rule out leakage of the injected solutions into the lateral ventricle under the experimental conditions described above.

Microinjections into the ventral subiculum and microdialysis in the nucleus accumbens

For microinjections of oxytocin into the ventral subiculum or the PMCo and microdialysis in the shell of the nucleus accumbens of the same male rat, a stainless-steel chronic guide cannula aimed unilaterally at the ventral subiculum or at the PMCo and a microdialysis probe with a U-shaped dialysis membrane, prepared as previously
described and aimed unilaterally at the ipsilateral nucleus accumbens, were implanted stereotaxically in the skulls of male rats during the same stereotaxic surgery under chloral hydrate anaesthesia. Rats were used 2 days after stereotaxic surgery.

For intracerebral microdialysis, the microdialysis probe aimed at the shell of the nucleus accumbens was perfused with Ringer’s solution containing 147 mm NaCl, 3 mm KCl and 1.2 mm CaCl2, at a constant flow rate of 2.5 lL/min, by using a Stoelting microsyringe pump. After a 2-h equilibration period, the dialysate was collected
every 15 min in aliquots of 37.5 lL in polyethylene tubes kept at 10–15 degrees C for the determination of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations, as described below.

After the collection of three dialysate aliquots, oxytocin dissolved in saline or saline alone was injected into the ventral subiculum or the PMCo in a volume of 0.3 lL over a period of 2 min, as described above. Rats were observed for 75 min, during which time five additional dialysate fractions of 37.5 lL each were collected every 15 min, and penile erection episodes were counted. In those experiments in which d(CH2)5Tyr(Me)2-Orn8-vasotocin was used, the compound was dissolved in saline and microinjected into the ventral subiculum or the PMCo in a volume of 0.3 lL 15 min before oxytocin.


Rats in which only chronic guide cannulas were implanted were placed individually in Plexiglas cages. After a 30-min habituation period, oxytocin or vehicle alone was injected into the ventral subiculum or the PMCo in a volume of 0.3 lL over a period of 2 min through the microinjection cannula connected by polyethylene tubing to a 10-lL Hamilton syringe driven by a Stoelting microsyringe pump.

When d(CH2)5Tyr(Me)2-Orn8-vasotocin was used, the compound was injected into the ventral subiculum or the PMCo 15 min before oxytocin.

When cis-flupentixol and (+)MK-801 were used, the compounds were injected into the nucleus accumbens or the VTA 15 min before oxytocin. When microdialysis was
performed, the microdialysis probe was connected via polyethylene tubing to a 2500-lL Hamilton syringe driven by a Stoelting microsyringe pump at one end and to the polyethylene collecting loop at the other end.

After a 2-h period of equilibration of the dialysis probe with Ringer’s solution, three dialysate aliquots of 37.5 lL were collected for the determination of basal levels of dopamine and DOPAC, oxytocin or vehicle was injected into the ventral subiculum or the PMCo, and ?ve additional dialysate aliquots were collected.

When d(CH2)5Tyr(Me)2-Orn8-vasotocin was used, this was injected into the ventral subiculum or the PMCo 15 min before oxytocin.

In all of the above experimental conditions, after treatments rats were observed for the entire duration of the experiment in order to count penile erection episodes and, in those experiments during which microdialysis was performed, to replace filled loops with empty ones every 15 min. Penile erections were scored when the penis emerged from the penile sheath, which was usually accompanied by penile grooming and hip flexions.

Penile Erection

Oxytocin (20–100 ng) was found to be able to induce penile erection when injected unilaterally into the ventral subiculum or the posteromedial cortical nucleus of the mygdala of male rats. The pro-erectile effect started mostly 30 min after treatment and was abolished by the prior injection of d(CH2)5Tyr(Me)2-Orn8-vasotocin (1–2 lg), an oxytocin receptor antagonist, into the ventral subiculum or posteromedial cortical nucleus. Oxytocin-induced penile erection occurred 15 min after the increase in the concentration of extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the dialysate obtained from the nucleus accumbens, which was also abolished by d(CH2)5Tyr(Me)2-Orn8-vasotocin. The pro-erectile effect of oxytocin was also reduced by cis-flupentixol (2 and 5 lg), a dopamine receptor antagonist, injected into the nucleus accumbens, and by (+)MK-801 (5 lg), a noncompetitive N-methyl-d-aspartate receptor antagonist, injected into the ventral tegmental area, but not into the nucleus accumbens.

Together with studies showing that glutamatergic efferents from the ventral subiculum/posteromedial cortical nucleus of the amygdala to other areas of the limbic system modulate the activity of mesolimbic dopaminergic neurons, these findings suggest that oxytocin injected into these areas increases glutamatergic neurotransmission in the ventral tegmental area. This, in turn, activates mesolimbic dopaminergic neurons, leading to penile erection. These results provide evidence that the ventral subiculum and the posteromedial cortical nucleus of the amygdala participate in a neural circuit that controls not only the consummatory aspects of sexual behaviour (e.g. penile erection and copulatory performance), but also its motivational/reward aspects, con?rming a key role of oxytocin and dopamine in these processes.


Penile erection is the result of a complex interaction between the central and peripheral autonomous nervous systems and plays a key role in male copulatory behaviour and the reproduction of mammals, including humans. Several brain areas involved in male erectile function and copulatory behaviour have been identified. These include
the medial preoptic area, the hypothalamus and its nuclei, mainly the paraventricular nucleus, the hippocampus, the amygdala, the ventral tegmental area, the medulla oblongata, and the spinal cord.

Among these, the PVN is one of the most studied. This nucleus contains the cell bodies of oxytocinergic neurons projecting to extra-hypothalamic brain areas, for example the VTA, the hippocampus, and the spinal cord. These neurons are involved in both the anticipatory and consummatory aspects of sexual behaviour. Accordingly, oxytocinergic neurons projecting to the spinal cord facilitate erectile and copulatory performance, whereas those projecting to the VTA control aspects of the anticipatory phase of sexual behaviour, from arousal to motivation and reward.

The hippocampus and amygdala are two other brain areas that receive a dense oxytocinergic projection from the PVN and are rich in oxytocin receptor mRNA. Both regions belong to the limbic system and play a role in social emotions and social memory, oxytocin being involved in these behaviours. Some of their subdivisions, for example the CA1 field, subiculum, and posteromedial cortical nucleus of the amygdala (PMCo), also have roles in erectile function and sexual behaviour.

Accordingly, oxytocin injected into the CA1 field induces penile erection in male rats; apomorphine, a dopamine agonist that induces penile erection by activating central PVN oxytocinergic neurons, increases oxytocin content in the hippocampus; lesions of the ventral hippocampus, which is functionally connected to the CA1 field, or of the PMCo or of the medial septum, which decrease oxytocin content in the hippocampus, reduce penile erection in rats; and L368,899, a non-peptide oxytocin antagonist, which accumulates not only in the hypothalamus, but also in the amygdala and the ventral hippocampus when given systemically, disrupts male non-human primate sexual behaviour.

Together, the above results suggest that the ventral subiculum and the PMCo may be two other sites in which oxytocin may influence both erectile function and the anticipatory aspects of sexual behaviour, as found for the VTA. In order to verify this hypothesis, we studied the effect of oxytocin injected into the ventral subiculum or the PMCo of male rats on penile erection. As oxytocin was found to be capable of inducing penile erection when injected in these brain areas, we also studied whether this effect was related to the stimulation of dopamine receptors and/or changes in extracellular dopamine concentration in the nucleus accumbens shell. Finally, as both the ventral subiculum and the PMCo play a role in modulating the activity of mesolimbic dopaminergic neurons through direct and indirect (e.g. through the medial prefrontal cortex) glutamatergic efferents reaching the nucleus accumbens and/or the VTA, a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor antagonist, injected into the nucleus accumbens or the VTA, on the pro-erectile effect of oxytocin was also studied.

La santé dans

Paru pour la première fois en 1995, le Rapport sur la santé dans le monde est la publication phare de l'OMS.
Conçu pour fournir aux pays, aux donateurs, aux organisations internationales et autres les informations dont ils ont besoin pour prendre des décisions de politique générale et de financement. Il présente un bilan rigoureux de la santé dans le monde assorti de statistiques sur tous les pays.
Il s'adresse aussi plus largement aux facultés, aux hôpitaux universitaires, aux écoles, ainsi qu'aux journalistes et au grand public, à tous ceux en somme qui, pour des raisons professionnelles ou personnelles, s'intéressent aux questions de santé de portée internationale.

Une bonne santé est essentielle au bien-être humain et au développement économique et social durable. Les États Membres de l’OMS ont pour objectif de développer leurs systèmes de financement de la santé pour garantir à tous l’utilisation des services de santé et la protection contre les difficultés financières associées à leur paiement. Dans ce rapport, l'OMS décrit les mesures que les pays peuvent prendre pour parvenir à une couverture universelle durable.

Dans ces conditions, les services de santé ne peuvent plus continuer comme si de rien n'était. Nombre d'entre eux semblent dériver d'une priorité à court terme à l'autre, d'une manière de plus en plus fragmentée et sans savoir très bien où ils vont.

Heureusement, le contexte international actuel est favorable à un renouveau des SSP. La santé mondiale fait l'objet d'une attention sans précédent. On observe un intérêt croissant pour l'unité d'action et de plus en plus de voix plaident en faveur de soins universels et complets, ainsi que pour que la santé soit présente dans toutes les politiques. Les attentes n'ont jamais été aussi fortes.

En tirant parti de cette dynamique, investir dans les soins de santé primaires peut permettre de transformer les systèmes de santé et d'améliorer partout la santé des individus, de leurs familles et de la collectivité dans son ensemble.
En savoir plus sur la sante d'une personne sur le site Pilules pour la sante

Amoxil - Amoxicillina

Indicazioni terapeutiche

Infezioni da germi sensibili all'amoxicillina a carico di differenti organi ed apparati; infezioni delle alte vie respiratorie (tonsilliti, faringiti, laringiti, sinusiti); infezioni delle basse vie respiratorie (tracheobronchiti, bronchiti acute e croniche, broncopolmoniti, polmoniti, bronchiectasie, ascessi polmonari); infezioni otomastoidee; infezioni dell'apparato uro-genitale ed infezioni venereologiche; infezioni enteriche ed epatobiliari, salmonellosi; altre infezioni, tra cui endocarditi, sepsi, infezioni chirurgiche, infezioni dermatologiche.

Controindicazioni

Ipersensibilita gia note alle penicilline e alle cefalosporine.

Infezioni sostenute da microorganismi produttori di penicillinasi.

Speciali avvertenze e precauzioni per l'uso

L'amoxicillina non offre particolari vantaggi nelle infezioni da germi sensibili alla penicillina G, ne e attivo sui germi resistenti produttori di penicillinasi. Reazioni di ipersensibilita e di anafilassi gravi sono state riportate per lo piu a seguito di impiego parenterale di penicilline, molto raramente a seguito di impiego orale.

L'insorgenza di tali reazioni e, comunque, piu frequente in soggetti con anamnesi di ipersensibilita verso allergeni multipli, di asma, febbre da fieno ed orticaria. E possibile allergia crociata con penicillina G e cefalosporine.

Prima di iniziare una terapia con una penicillina e quindi necessaria un'anamnesi accurata.

In caso di reazione allergica si deve interrompere il trattamento ed istituire un trattamento idoneo. L'uso prolungato di penicilline, cosi come di altri antibiotici, puo favorire lo sviluppo di germi non sensibili e/o infezioni fungine.

In tale evenienza si richiede l'adozione di adeguate misure terapeutiche. E sempre raccomandabile eseguire, durante i trattamenti prolungati con dosi elevate, controlli periodici della crasi ematica e della funzionalita epatica e renale. Tenere fuori dalla portata dei bambini. Non utilizzare il farmaco oltre la data di scadenza riportata sulla confezione.

Interazioni

E possibile allergia crociata con la penicillina G e con le cefalosporine. La contemporanea assunzione di allopurinolo aumenta la frequenza di rash cutanei. La contemporanea assunzione di contraccettivi orali riduce l'assorbimento di questi ultimi. E noto un effetto terapeutico sinergico tra le penicilline semisintetiche e gli aminoglicosidi.Il probenecid somministrato contemporaneamente prolunga i livelli ematici delle penicilline per competizioni con le stesse a livello renale. L'acido acetilsalicilico, il fenilbutazone o altri farmaci antiinfiammatori a forti dosi, somministrati in concomitanza con penicilline, ne aumentano i livelli plasmatici e l'emivita.

Gravidanza e allattamento

Nelle donne in stato di gravidanza il prodotto va somministrato nei casi di effettiva necessita sotto il diretto controllo del medico.

Effetti sulla capacita di guidare veicoli e sull'uso di macchine

Il prodotto non interferisce sulla capacita di guidare e sulla vigilanza di chi attende a macchinari.

Effetti indesiderati

Le eventuali reazioni sfavorevoli con l'impiego delle penicilline in genere sono essenzialmente limitate agli accennati fenomeni di ipersensibilita: eruzioni cutanee a tipo di eritema multiforme o maculopapuloso, prurito, orticaria piu frequentemente.

Altre reazioni sfavorevoli, anche se rare, possono essere:apparato gastrointestinale: glossite, stomatite, nausea, vomito o diarrea, per lo piu a seguito di somministrazione orale.

Eccezionali e di incerto significato le variazioni del tasso delle transaminasi;- apparato emolinfopoietico: altrettanto frequentemente, anemia, trombocitopenia, porpora, eosinofilia, leucopenia ed agranulocitosi di norma reversibili con l'interruzione della terapia e ritenute anch'esse espressione di ipersensibilita. Per ogni altra evenienza che dovesse insorgere durante il trattamento informare il proprio medico.

Sovradosaggio

Finora non sono stati descritti sintomi di sovradosaggio nell'uomo.

Pillole Amoxil

Pillole di Zyban ordine online

Zyban (cloridrato di bupropion) e prodotto da Glaxo-Wellcome ed e stato usato per trattare l'aggiunta del nicotina. E autorizzato negli Stati Uniti, ma non nel Regno Unito. Zyban e un farmaco nicotina-libero che contiene lo stesso ingrediente attivo dell'antideprimente, Wellbutrin di prescrizione. Zyban e differente dalle zone del nicotina o la gomma che sono agenti contro il fumo non-prescription in quanto e non contiene il nicotina. Zyban funziona riducendo craving per il nicotina ad un livello neurologico amplificando i livelli chimici nel cervello. L'ingrediente attivo, bupropion, e un inibitore debole dell'assorbimento di dopamina, di serotonina e del norephinephrine. Di conseguenza, ci e riduzione dei sintomi di ritiro del nicotina e di di meno di uno stimolo a fumare.

Il trattamento con Zyban comincia mentre il paziente ancora sta fumando ed occorre circa una settimana ai livelli efficaci di estensione. Di conseguenza, il paziente non dovrebbe tentare di rinunciare fino alla seconda settimana del trattamento. Zyban dovrebbe continuare ad essere preso per sette - dodici settimane. Se il paziente non ha ridotto fumare livella o rinunciasse entro la settima settimana, esso e improbabile che rinuncino a lungo termine.

Chentix e il farmaco contro il fumo piu recente che e approvato tramite la gestione dell'alimento e della droga degli Stati Uniti nel maggio 2006. Mentre sia Chantix che Zyban riducono craving per il nicotina, il meccanismo di Chantix e differente da Pillole Zyban. Chantix parzialmente attiva i ricevitori del nicotina nel cervello quindi che riduce craving per i sintomi di ritiro e del nicotina. Se fumare e ripreso, gli effetti di nicotina sul cervello sono diminuiti che riducono craving per il nicotina. Zyban amplifica i livelli chimici nel cervello per generare di meno dello stimolo a fumare; Chantix lavora ai ricevitori del nicotina nel cervello per generare di meno di uno stimolo a fumare.

Albenza antiparassitario

Albenza è un antiparassitario. Il farmaco è usato nel trattamento delle infezioni da verme solitario e da altri parassiti.

Speciali avvertenze e precauzioni per l’uso

Prima di iniziare la somministrazione del farmaco avvisare il medico curante se una delle seguenti condizioni è occorsa:

• anemia
• occlusione del tratto biliare
• disfunzioni del sistema immunitario
• malattie epatiche
• se si stanno assumendo altri farmaci per perdere peso
• ipersensibilità o allergie all' albendazolo, altre medicine, cibo, coloranti o conservanti
• gravidanza o intenzione di rimanere incinta
• allattamento

Posologia e modo di somministrazione

Albenza il farmaco per via orale con acqua. Assumere le compresse con cibo. Le compresse possono essere masticate e spezzate. Finire la terapia prescritta anche se le condizioni dovessero migliorare. Non interrompere il trattamento o saltare delle dosi prima della conclusione della cura.

La somministrazione del farmaco ai bambini va preventivamente discussa con il pediatra. Il farmaco può essere somministrato ai bambini dai 2 anni di età, previa prescrizione medica.

Sovradosaggio: In caso di sovradosaggio si consiglia di ricorrere ai normali presidi di pronto soccorso.

Albenza irregolare

Se si dimentica di assumere la medicina all'ora solita, prenderla entro un'ora dai pasti che contengono grassi. Non assumere la dose dimenticata se l'assunzione è ravvicinata alla dose successiva. Non assumere due o più dosi contemporaneamente.

Interazioni

• cimetidina
• dexametasone
• praziquantel
• teofillina

La lista di cui sopra non è esaustiva delle interazioni medicamentose. Contattare il medico curante e indicare i farmaci e medicamenti che si stanno assumendo e se si fuma o si fa consumo di bevande alcoliche, di bevande contenenti caffeina e di droghe. Consultare il medico prima di iniziare con nuovi farmaci.

Speciali avvertenze e precauzioni per l’uso

Sottoporsi a controlli regolari. Avvisare il medico se i sintomi non dovessero migliorare o se si hanno nuovi sintomi. Sono necessarie analisi del sangue ogni due settimane durante il trattamento.

Non rimanere incinta durante il trattamento e nel mese seguente l'interruzione. Consultare il medico per metodi contraccettivi efficaci. Avvisare il medico in caso di gravidanza.

Il farmaco può causare sonnolenza o vertigini. Si consiglia di non guidare, manovrare macchine o eseguire compiti che richiedono attenzione fino a quando non si conoscono gli effetti del farmaco. Non alzarsi o abbassarsi con movimenti bruschi, specialmente in pazienti anziani, per ridurre il rischio di svenimenti e vertigini.

Effetti indesiderati

Consultare il medico curante il prima possibile se uno sei seguenti sintomi si dovesse manifestare:

• reazioni allergiche quali rash cutanei, pruriti o orticaria, gonfiori della faccia, labbra e lingua
• variazioni della vista
• diarrea
• difficoltà respiratorie
• tachicardia
• febbre, brividi, mal di gola
• minzione dolorosa, difficoltà di minzione
• arrossamenti, vesciche, secchezza o perdita di pelle, compreso l'interno della bocca
• crisi convulsive
• malessere, dolori
• emorragie, ecchimosi
• stanchezza, debolezza
• ingiallimento degli occhi e della pelle

Altri effetti indesiderati, che non richiedono l’immediata assistenza del medico, da riportare in caso di prolungato fastidio:

• perdita di capelli
• vertigini
• cefalea
• nausea, vomito
• mal di stomaco

La lista di cui sopra non è esaustiva degli effetti indesiderati. Pillole Albenza