Treatments for priapism in boys and men with sickle cell disease.

BACKGROUND: Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals. This is an update of a previously published review. OBJECTIVES: To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 September 2019. Date of most recent search of trial registries and of Embase: 01 October 2019. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias of the trials. MAIN RESULTS: Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and a four-arm trial which compared ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence. However, all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome; and from the evidence included in this review, we are uncertain whether stilboestrol, etilefrine or ephedrine reduce the frequency of stuttering priapism as the certainty of the evidence has been assessed as very low. Additionally, we conclude that sildenafil may make little or no difference (low-certainty evidence). Two trials reported on immediate side effects and we are uncertain whether etilefrine or ephedrine reduce the occurrence of these (very low-certainty of evidence) and also conclude that sildenafil may make little or no difference in side effects (low-quality evidence). Given that all of the trials were at risk of bias and all had low participant numbers, we considered the certainty of the evidence to be low to very low. AUTHORS' CONCLUSIONS: There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.

Absorption behavior of etilefrine after buccal administration in rats.

Etilefrine hydrochloride (ET-HCl) is used in the treatment of hypotension. Dosage forms of orally administered tablets and parenteral injections are clinically available, but exhibit unfavorable characteristics, including cardiac toxicity, headaches, and damage at the injection site for the parenteral dosage form, and initially high plasma levels, fast elimination, and first-pass effects for its oral administration. Therefore, the buccal application of ET-HCl was herein investigated as an alternative to conventional administration routes. I.v., intragastric, and buccal administration were performed using rats, and absorption features were compared. Buccal application at open conditions for 1 h exhibited absolute bioavailability of more than 20%, while the intragastric administration gave much lower bioavailability (<10%). The drug residue and drug distribution in the oral mucosa were investigated in order to clarify drug transfer behaviors. In the application of ET-HCl solution using a cotton ball, higher plasma concentrations and their maintenance at higher levels were achieved at 10 mg/kg than at 2.5 mg/kg. In addition, absorption was greater with a longer application (4 h) than with a shorter application (1 h). Etilefrine (ET) was rapidly absorbed using aqueous buffer of pH 9.5 as the solvent. Open application was appropriate for achieving and maintaining higher plasma levels. Thus, in the buccal application of ET-HCl aqueous droplets, a wide distribution throughout the mucosal surface is important for achieving rapid absorption and the maintenance of plasma levels. These findings suggested that the buccal application should be feasible administration of ET-HCl.

Drugs for hypotension: disproportionate harms with etilefrine and heptaminol. .

The French Health Products Agency concluded that etilefrine and heptaminol have an unfavourable harm-benefit balance, and also placed restrictions on the use of midodrine.

Type IV reaction due to phenylephrine administered nasally with cross-reactivity with ethylephrine.

Type IV hypersensitivity eye reactions have been described after the administration of the sympathomimetic agent phenylephrine. We report the case of an atopic woman who developed nasal congestion and discharge, dysphagia, and dyspnea 1 hour after the administration of Stopcold pills and Disneumon Pernasal nasal spray for otitis. The same symptoms reappeared after the accidental administration of Rinobanedif ointment in the nasal mucosa. Skin patch tests were performed with a standard True Test panel, preservatives, Disneumon Pernasal, pseudoephedrine, eyedrops (tropicamide, cyclopentolate, and phenylephrine), and other sympathomimetic agents. The patient also underwent oral, ocular, and nasal controlled challenges with the same drugs. Finally, patch tests were performed in 11 controls with phenylephrine and ethylephrine. Our patient had a positive outcome in patch testing with nickel sulphate, fragrance mix, phenylephrine, and ethylephrine. To our knowledge, this is the first report of a type IV reaction to nasally administered phenylephrine with cross-reactivity with ethylephrine detected by patch testing.

A prospective diary study of stuttering priapism in adolescents and young men with sickle cell anemia: report of an international randomized control trial--the priapism in sickle cell study.

Priapism is defined as a prolonged, persistent, and purposeless penile erection. It is a common (35%) but frequently understated complication in young men and adults with sickle cell disease. We had previously demonstrated an association between stuttering attacks (<4 hours) and an acute catastrophic event with its consequent problems of erectile dysfunction and impotence. We describe a randomized, placebo-controlled, clinical study looking at medical prophylaxis with 2 oral α-adrenergic agonists, etilefrine and ephedrine, in preventing stuttering attacks of priapism. One hundred thirty-one patients were registered into a 2-phase (observational and intervention phase) study, and 86 patients (66%) completed Phase A diary charts. Forty-six patients (59%) completed a 6-month treatment phase (Phase B), and the remaining patients were lost to follow-up despite persistent efforts to contact them. Various reasons are postulated for the high attrition rates. The drugs were well tolerated, and no serious adverse events were reported. There was no significant difference among the 4 treatment groups in the weekly total number of attacks in Phase B (analysis of covariance P = .99) nor among the average pain score per attack after adjusting for attack rates and pain scores in Phase A (analysis of covariance P = .33). None of the patients who completed the study required penile aspiration at study sites while on medical prophylaxis. Young men with sickle cell disease are not comfortable engaging with health care providers about issues relating to their sexual health. The full impact of an improved awareness campaign and early presentation to hospital merits further standardized study. Priapism still contributes seriously to the comorbidity experienced by this previously inaccessible group of patients and medical prophylaxis with oral α-adrenergic agonists is feasible. Future international collaborative efforts using some of the lessons learnt in this study should be undertaken.

[Sickle cell disease priapism: treatment with intracavernous injections of etilefrine]. / Priapisme drépanocytaire: prise en charge par injections intracaverneuses d'étilefrine.

Intracavernous injection (ICI) of adrenergic agonists has recently been proposed for treatment of priapism associated with sickle cell hemoglobinopathy and appears to be effective in cases less than 28 hours old. The purpose of this study was to confirm the usefulness of this technique in a large series of patients. From January 1996 through September 1998, 19 patients with sickle cell disease were treated by ICI of etilefrine for one or several episodes of low-flow priapism lasting between 2 hours and 15 days. A total of 72 consecutive ICI were performed alone in patients with priapism less than 6 hours old or in combination with prior drainage in patients with priapism more than 6 hours old. Results depended mainly on the delay to treatment. Detumescence was achieved in all 10 cases treated within 29 hours as opposed to only 2 of 9 cases treated beyond 29 hours. This finding is in agreement with experimental findings demonstrating histological evidence of necrosis of endothelial cells and cavernous smooth muscle fibers after 24 hours. However based on our experience showing that good results with preservation of erectile function can be achieved after delays longer than 40 hours (42 hours and 5 days in two of our patients), we recommend that treatment by ICI be tried before surgery in sickle cell anemia patients even with long-standing priapism. Untoward side effects including intense pain in the penis and retrosternal pain were observed in 4 patients. ICI of adrenergic agonists is one of the best treatment currently available for management of priapism in patients with sickle cell disease. Surgery should be used only after failure of ICI.

Effect of etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: a double-blind, randomized, placebo-controlled trial. The Vasovagal Syncope International Study.

BACKGROUND: Etilefrine is an alpha-agonist agent with a potent vasoconstrictor effect, which is potentially useful in preventing vasovagal syncope by reducing venous pooling and/or by counteracting reflex arteriolar vasodilatation. The present multicenter, randomized, placebo-controlled study was designed to evaluate the efficacy of this drug for the long-term management of patients with recurrent vasovagal syncope. METHODS AND RESULTS: In the 20 participating centers, 126 patients with recurrent vasovagal syncope (at least 3 episodes in the last 2 years) and a positive baseline head-up tilt response were randomly assigned to placebo (63 patients) or etilefrine at a dosage of 75 mg/d (63 patients) and were followed up for 1 year or until syncope recurred. The primary end-point of the study was the first recurrence of syncope. There were no differences between the 2 study groups in the patients' baseline characteristics. During follow-up, the group treated with etilefrine had a similar incidence of first syncopal recurrence to that of placebo group both in the intention-to-treat analysis (24% versus 24%) and in on- treatment analysis (26% versus 24%). Moreover, the median time to the first syncopal recurrence did not significantly differ between the 2 study groups (106 days in the etilefrine arm and 112 days in the placebo arm). CONCLUSIONS: Oral etilefrine is not superior to placebo in preventing spontaneous episodes of vasovagal syncope. Randomized controlled studies are essential to assess the real usefulness of any proposed therapy for patients with vasovagal syncope.

[Use of etilefrin as local vasoconstrictor in lower gynecologic surgery ]. / Utilisation de l'étiléfrine comme vasoconstricteur local dans la chirurgie gynécologique par voie basse.

In this randomized prospective study the authors have compared the effectiveness and side-effects of two local vasoconstrictor agents, etilefrine (Effortil) and ornithine 8 vasopressin (Por 8) in vaginal gynaecological surgery. Thirty-three patients entered the trial and were divided into two groups: G1 (15 patients) received Effortil, and G2 (18 patients) received Por 8. The products, administered at random, were diluted in saline 40 ml and injected into the cervix through 6 points. A 3-minute interval was allowed between injection and incision. The results were assessed on the basis of trans- and postoperative haemorrhage and haemodynamic variations. Palor of the cervix was achieved after 3 minutes in both groups; moderate bleeding was observed in only one of the G1 patients. Postoperative renewal of packing was necessary in 2 patients in G1 and 4 patients in G2. No electrocardiographic anomaly was recorded in any of the two groups. Diastolic BP was significantly higher in G2 than in G1 (P less than 0.002, Fisher test). Systolic BP was also elevated in that group (P less than 0.03, chi 2 test). Moderate reduction in heart rate was observed in both groups (P less than 0.3, Fischer test), but severe (48 beats/min) bradycardia was noted in one G2 patient.

Long-term effect of etilefrine pivalate on blood pressure in man.

An open and a placebo-controlled double-blind trial were carried out to measure the effect of a long-term treatment (2-6 months) with etilefrine pivalate (K 30 052, Ep) on blood pressure of 60 patients suffering from orthostatic dysregulation. Oral administration of the agent took place once daily, each dose containing 20 mg. While the acute response to a single dose was comparatively weak, long-term administration had a marked and long-lasting effect both on systolic blood pressure (+40.3 mmHg) and blood pressure amplitude (+37.5 mmHg) (p less than 0.01). Steady state values were reached only when duration of therapy was approaching 6 months. The increase in blood pressure amplitude points to an augmentation of stroke volume, whereas heart rate was virtually unaltered. Peripheral resistance appears not to be increased since diastolic pressure was unchanged. The elevation in blood pressure amplitude was fully reversible within 9 weeks of wash-out, thus hinting at functional rather than structural (sclerotic) changes in the cardiovascular system.

Comparison of the oral effectiveness of etilefrine pivalate and etilefrine in a long-term trial in man.

The influence of equimolar oral doses of etilefrine pivalate (K 30 052, Ep) and etilefrine on blood pressure of patients suffering from orthostatic dysregulation was compared. Both drugs augmented the systolic blood pressure in both, the upright and horizontal body posture. Diastolic blood pressure was not influenced. The resulting increase in blood pressure amplitude points to an augmentation of cardiac stroke volume. Ep in equimolar doses was nearly twice as active as etilefrine. This result is in line with the hypothesis that acylation of etilefrine with pivalinic acid inhibits the first-pass inactivation nearly completely.

[Double blind study of migraine therapy with etilefrine pivalate]. / Doppelblindstudie zur Migränetherapie mit Etilefrinpivalat.

In a double-blind trial of 3 months 24 hypotensive patients suffering from migraine were treated with etilefrine pivalate (K 30 052, Ep, 20 mg p.o.) or dihydroergotamine (DHE, 5 mg) or placebo. The number of attacks of migraine was significantly reduced after the 3-month treatment with Ep resp. DHE comparing with placebo. Duration of attacks, intensity and number of additional analgetic drugs were also clearly reduced after medication of Ep and DHE - in contrast to placebo medication. Effectiveness and tolerance of Ep were estimated well and occurring side-effects were only of short duration. Thus the antihypotonics Ep and DHE offer an effective therapeutic scheme for migraine in hypotensive patients. This is in accordance with the fact that hypotension plays an important role in the occurrence of migraine.

[Abnormalities of hypotonic orthostatic regulation: cardiovascular effects of dihydroergotamine, etilefrine and their combination (author's transl)]. / Hypotone orthostatische Regulationsstörungen. Kreislaufwirkung von Dihydroergotamin, Etilefrin und deren Kombination.

In a double-blind inter-individual study of 51 patients with abnormal hypotonic orthostatic regulation, the effect of dihydroergotamine (2 mg), etilefrine (20 mg) or their combination (2 mg and 20 mg, respectively) was studied. Blood pressure, heart rate, dicrotic ratio as well as number and severity of symptoms during standardised orthostasis were studied before and after a week on placebo and after one and two weeks of drug administration. Resting blood pressure after treatment with the two drugs combined rose from 111/73 to 120/77 mm Hg, after etilefrine from 114/74 to 122/79 mm Hg, remaining essentially unchanged after dihydroergotamine. Fall in dicrotic ratio, as a measure of change in mean blood pressure, was 10% during the first minute of standing with the combined drugs, 30-35% with each drug separately. Treatment with the combined drugs was also superior when considering systolic blood pressure, pressure amplitude and heart rate. Similarly, the drugs in combination caused the least number and lowest severity of symptoms: side-effects were less common with the combination than with each drug alone.

[On the action of antihypotensive agents in sympathicotonic orthostatic hypotension in geriartric patients: comparison between placebo and etilefrin (author's transl)]. / Die sympathikotone orthostatosche Dysregulation im Senium. Wirkung von Antithypotonika, ein Placebovergleich mit Etilefrin.

The action of etilefrin (Effortil Depot Perlongets) was compared with placebo in a double-blind study in 24 female geriatric patients with sympathicotonic orthostatic hypotension. After determining the basic values, all patients were treated with the active substance in a titration phase lasting one week (dosage 2-3 Perlongets/day). The decrease in systolic blood pressure and the increase in pulse rate while standing were then statistically significant lower (p less than (p less than 0.001) when compared with the basic values. In 17 out of 21 cases of collapse which occured while standing before therapy was commenced no further collapse occurred (p less than 0.005). Following the titration phase treatment with etilefrin was continued in 12 patients in a double-blind study while the remaining 12 patients were changed over to placebo as a withdrawal study. The effect continued in those patients treated with the active ingredient and the average values and incidence of effects improved further. On the other hand, in the placebo group there was one again a marked decrease in systolic blood pressure and increase in pulse rate as observed in the basic values. The symptomatology, particulary episodes of collapse increased again. There was a statistically significant difference between the action of etilefrin and placebo for all criteria (both objective and subjective parameters). Side-effects were not observed.