A comprehensive history of injection therapy for erectile dysfunction, 1982-2023.

INTRODUCTION: Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection therapy with vasoactive drugs remains a viable alternative for all those who are not reacting or cannot tolerate oral drug therapy. This current injection therapy has an interesting history beginning in 1982. OBJECTIVES: To provide a comprehensive history of self-injection therapy from the very beginnings in 1982 by contemporary witnesses and some members of the International Society for Sexual Medicine's History Committee, a complete history of injection therapy is prepared from eyewitness accounts and review of the published literature on the subject, as well as an update of the current status of self-injection therapy. METHODS: Published data on injection therapy, as a diagnostic and therapeutic tool for ED, were reviewed thoroughly by PubMed and Medline research from 1982 until June 2023. Early pioneers and witnesses added firsthand details to this historical review. Therapeutic reports of injection therapy were reviewed, and results of side effects and complications were thoroughly reviewed. RESULTS: The pioneers of the first hours were Ronal Virag (1982) for papaverine, Giles Brindley (1983) for cavernosal alpha-blockade (phentolamine and phenoxybenzamine), Adrian Zorgniotti (1985) for papaverine/phentolamine, and Ganesan Adaikan and N. Ishii (1986) for prostaglandin E1. Moxisylyte (thymoxamine) was originally marketed but later withdrawn. The most common side effect is priapism, with the greatest risk of this from papaverine, which has modified its use for therapy. Currently, prostaglandin E1 and trimixes continue to be the agents of choice for diagnostic and therapeutic use in ED. A recent agent is a mixture of a vasoactive intestinal polypeptide (aviptadil) and phentolamine. CONCLUSIONS: After 40 years, self-injection therapy represents the medication with the highest efficacy and reliability rates and remains a viable option for many couples with ED. The history of this therapy is rich.

Adrenaline auto-injector injuries: Practical considerations in emergency management in a tertiary hand surgery unit.

Adrenaline auto-injectors are the first line treatment for anaphylaxis in the community setting. Both anaphylaxis and auto-injector carriage are increasing in prevalence. Adrenaline auto-injector injuries are common and most often involve the hand or digits. Such injuries carry a risk of ischemic necrosis due to profound vasoconstriction, especially if there is undying vascular pathology such as Raynaud's disease. The effects can be readily reversed with local infiltration of phentolamine. A survey was circulated to 40 clinicians working in the emergency and hand surgery departments of a major urban center. Knowledge of adrenaline duration of action and its reversal (agent, dose and location in the hospital) was assessed. All clinicians working within the two departments were eligible for participation. Only 25% of clinicians surveyed were aware of the duration of action of adrenaline. Half were aware of the correct reversal agent and only 20% knew the correct dose. Only one person was aware of phentolamine's location within the hospital. There is relatively poor clinician knowledge surrounding adrenaline reversal and a lack of easily accessible information available about dosing and drug location within the hospital. Given the time dependent nature of adrenaline auto-injector injuries Emergency Departments should consider stocking phentolamine in an emergency drugs fridge within the department along with a dosing guide. This is likely to greatly reduce time from presentation to treatment and thus the chances of digital ischemia progressing to necrosis.

A randomized phase 2 clinical trial of phentolamine mesylate eye drops in patients with severe night vision disturbances.

PURPOSE: Dim light vision disturbances (DLD) comprise a wide range of symptoms affecting the quality of vision at low illumination including glare, halos, and starbursts. This exploratory study investigated 1.0% phentolamine mesylate ophthalmic solution (PMOS) as a treatment to improve vision and image quality for patients with DLD. METHODS: In this placebo-controlled, randomized, double-masked clinical trial, 24 adult patients with severe DLD were randomized in a 2:1 ratio to receive either one dose of PMOS or placebo. Subjects were eligible if they reported experiencing severe night vision difficulty that was not eliminated by distance spectacle correction and scored ≥0.3 log units below the normal range of contrast sensitivity assessed under mesopic conditions with glare at ≥2 spatial frequencies. Key efficacy outcomes were change from baseline in pupil diameter, contrast sensitivity, and visual acuity. Safety measures including intraocular pressure, conjunctival hyperemia, and systemic effects were also assessed. RESULTS: Eight subjects were randomized to placebo (63% female; mean age 47 years) and 16 were randomized to PMOS (75% female; mean age 42 years). Mean (SD) pupil diameter of PMOS-treated subjects decreased significantly - 1.3 mm (0 to - 2.8 mm) with p < 0.0001. Mean contrast sensitivity with glare in PMOS-treated subjects improved significantly post-treatment at spatial frequencies 3, 6, 12, and 18 cycles per degree (p ≤ 0.03). PMOS also demonstrated improvements in the numbers of letters read for mesopic and photopic, high- and low-contrast visual acuity (LCVA). Importantly, a statistically greater proportion of PMOS-treated eyes registered mesopic LCVA 5 letter (69% vs. 31%, p = 0.029) and 10 letter (34% vs. 6%, p = 0.04) improvement, with a trend at 15 letters (19% vs. 0%, p = 0.16). PMOS was well tolerated with the only reported side effect being a mild increase in conjunctival hyperemia. CONCLUSION: PMOS was well tolerated and effectively reduced pupil size with improvements in contrast sensitivity and visual acuity in adults with severe DLD. Future Phase 3 studies should be conducted to further evaluate its potential to treat DLD. TRIAL REGISTRATION: The trial registration number is NCT04004507 (02/07/2019). Retrospectively registered.

Effects of Kisspeptin Administration in Women With Hypoactive Sexual Desire Disorder: A Randomized Clinical Trial.

Importance: Despite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their safety and effectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonal axis with additional emerging roles in sexual and emotional behavior; however, its effects in women with HSDD are unknown. Objective: To test the hypothesis that kisspeptin enhances sexual and attraction brain processing in women with HSDD. Design, Setting, and Participants: This randomized clinical trial was double-masked and placebo controlled with a 2-way crossover. The trial was conducted in a university research setting in the UK from October 2020 to April 2021. Eligible participants were premenopausal women with HSDD. Functional neuroimaging, psychometric, and hormonal analyses were employed to investigate the effects of kisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Data were analyzed from May to December 2021. Interventions: A 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rate placebo infusion. Main Outcomes and Measures: Blood oxygen level-dependent responses across the whole brain and regions of interest during kisspeptin vs placebo administration in response to erotic and facial attraction stimuli. Results: Of the 40 participants who were randomized, 32 women completed both kisspeptin and placebo visits, with a mean (SE) age of 29.2 (1.2) years. Kisspeptin administration resulted in modulations in sexual and facial attraction brain processing (deactivation of the left inferior frontal gyrus: Z max, 3.76; P = .01; activation of the right postcentral and supramarginal gyrus: Z max, 3.73; P < .001; deactivation of the right temporoparietal junction: Z max 4.08; P = .02). Furthermore, positive correlations were observed between kisspeptin-enhanced hippocampal activity in response to erotic videos, and baseline distress relating to sexual function (r = 0.469; P = .007). Kisspeptin's enhancement of posterior cingulate cortex activity in response to attractive male faces also correlated with reduced sexual aversion, providing additional functional significance (r = 0.476, P = .005). Kisspeptin was well-tolerated with no reported adverse effects. Conclusions and Relevance: These findings lay the foundations for clinical applications for kisspeptin in women with HSDD. Trial Registration: ISRCTN trial registry identifier: ISRCTN17271094.

Efficacy Assessment of Phentolamine Accompanied by Lidocaine Subcutaneously under Ultrasound Guidance on Radial Artery Catheterization in Pediatric Patients.

Objective: Pediatric patients are facing greater difficulties in radial catheterization for anatomic variation and smaller diameter. This study is to investigate the efficacy of phentolamine accompanied by lidocaine subcutaneously under ultrasound guidance on radial catheterization in pediatric patients. Methods: 66 pediatric patients were enrolled and randomly divided into saline group, phentolamine group, and phentolamine+lidocaine group. Baseline characteristics and surgical types were collected. Relevant solutions were subcutaneously injected, and catheterization was subsequently conducted under ultrasound guidance. Radial artery diameter and depth were measured, the success rate of catheterization and procedure time were calculated, and the complications were evaluated with ultrasonography. Results: No significant differences were observed in age, sex, weight, American Society of Anesthesiologists' classification, systolic blood pressure, diastolic blood pressure, heart rate, hemoglobin, and surgical types among three groups. Subcutaneously, the diameter in phentolamine and phentolamine+lidocaine groups increased significantly compared with the saline group. Moreover, the diameter also increased significantly after injection compared with that before injection both in the phentolamine and phentolamine+lidocaine groups. The first-attempt success rates were significantly higher while the procedure times of cannulation were shorter in the phentolamine and phentolamine+lidocaine groups than that in the saline group. Kaplan-Meier analysis showed that the overall procedure time was shorter in the phentolamine and phentolamine+lidocaine groups than the saline group. Overall complications and vasospasm incidence were lower in the phentolamine and phentolamine+lidocaine groups than the saline group. Conclusion: Phentolamine accompanied by lidocaine subcutaneous injection under ultrasound guidance improved the first-attempt success rate and reduced the complication of radial artery catheterization in pediatric patients.

Novel roles of phentolamine in protecting axon myelination, muscle atrophy, and functional recovery following nerve injury.

Incomplete functional recovery after peripheral nerve injury (PNI) often results in devastating physical disabilities in human patients. Despite improved progress in surgical and non-surgical approaches, achieving complete functional recovery following PNI remains a challenge. This study demonstrates that phentolamine may hold a significant promise in treating nerve injuries and denervation induced muscle atrophy following PNI. In a sciatic nerve crush injury mouse model, we found that phentolamine treatment enhanced motor and functional recovery, protected axon myelination, and attenuated injury-induced muscle atrophy in mice at 14 days post-injury (dpi) compared to saline treatment. In the soleus of phentolamine treated animals, we observed the downregulation of phosphorylated signal transducer and activator of transcription factor 3 (p-STAT3) as well as muscle atrophy-related genes Myogenin, muscle ring finger 1 (MuRF-1), and Forkhead box O proteins (FoxO1, FoxO3). Our results show that both nerve and muscle recovery are integral components of phentolamine treatment-induced global functional recovery in mice at 14 dpi. Moreover, phentolamine treatment improved locomotor functional recovery in the mice after spinal cord crush (SCC) injury. The fact that phentolamine is an FDA approved non-selective alpha-adrenergic blocker, clinically prescribed for oral anesthesia reversal, hypertension, and erectile dysfunction makes this drug a promising candidate for repurposing in restoring behavioral recovery following PNI and SCC injuries, axonal neuropathy, and muscle wasting disorders.

WALANT: Perceptions, approaches, and contraindications in a tertiary hand surgery unit.

Wide awake local anesthetic no tourniquet (WALANT) is gaining popularity amongst hand surgeons. Digital adrenaline use has been shown to be safe in multiple studies and the misconception forbidding it is receding. Phentolamine has been shown to safely reverse the effects of adrenaline should the feared complication of digital ischemia occur. A survey was circulated to 40 specialist practitioners who regularly perform hand procedures at a major tertiary plastic and hand surgery unit. Knowledge and understanding of WALANT, onset and duration of adrenaline effects and reversal was assessed. Whilst the majority of respondents (80%) recognized digital adrenaline use as safe, only 65% were aware of the delay until adrenaline takes full effect. Similarly, only 25% of respondents were aware of the duration of effect of adrenaline. Half of respondents were aware that phentolamine is the established reversal agent for adrenaline with only 20% knowing the correct dose. Given the lack of clinician knowledge surrounding adrenaline and its reversal, we feel that to safely undertake WALANT surgery at our Unit a WALANT protocol must be implemented. Drawing on the successes in the airline industry, a variety of safety frameworks have been established to deliver targeted education for prevention and eventual management of predictable risks. We plan to develop a checklist style protocol targeting the knowledge gaps raised in the survey. This will educate and equip all practitioners working with adrenaline with the knowledge to safely manage complications should they occur. LEVEL OF EVIDENCE: Level 5 (UK Oxford Centre for Evidence based Medicine (CEBM) Levels of Evidence).

Reversal of Digital Ischemia with Phentolamine After Accidental Epinephrine Injection.

BACKGROUND Accidental finger-stick injuries have been reported with epinephrine autoinjectors, such as EpiPen and EpiPen Jr, and can result in necrosis and digital ischemia. However, long-term adverse effects are very rare. The treatment for accidental finger-stick injuries is controversial and includes intra-arterial injections of vasodilating agents, topical vasodilators, and supportive management as needed. CASE REPORT Here, we report a case of a 26-year-old pharmacist who injected herself accidentally with an EpiPen on the tip of her index finger. Warm water and nitroglycerine gel did not alleviate her symptoms. After three hours, phentolamine was injected around the necrotic area, and the skin normalized. CONCLUSIONS All health professionals should be trained in how to handle epinephrine autoinjectors safely. Phentolamine may be efficacious in treating accidental finger-stick injuries from epinephrine autoinjectors.

[Efficacy and prognosis of phentolamine in the treatment of patients with myocardial injury due to sepsis].

Objective: To explore the effect of phenolamine on the outcome and prognosis of patients with myocardial injury due to sepsis. Methods: From January 2015 to December 2017, 62 septic patients with myocardial injury were randomly divided into study group (n=32) and control group (n=30). Two groups were given conventional treatment, while the study group was treated with phentolamine. The NT-pro brain natriuretic pepitide (NT-proBNP), cardiac troponin I (cTnI), lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB) and tumor necrosis factor (TNF)-α, high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-1ß, IL-6 were detected at 0,12, 24, 48, 72 h and 7 d after hospitalization. And left ventricular ejection fraction (LVEF), e', E and A in each time period were observed. The 28 d survival rate and length of ICU stay were observed in both groups. The data were compared with single sample t test between the two groups. Results: After 12, 24, 48, 72 h and 7 d, NT-proBNP, cTnI, LDH, CK-MB, TNF-α, hs-CRP, IL-1ß, IL-6 in the study group were all significantly lower than those in the control group (all P<0.05). The cardiac function indexes of LVEF, E/A and E/e' in the study group were all significantly improved when compared with those in the control group (all P<0.05). The length of ICU stay and 28-day mortality in the study group were significantly lower than those in the control group ((9.8±3.6) d vs (13.0±4.1) d, t=3.152, P=0.004; 21.9% vs 36.7%, χ(2)=5.078, P=0.021). Conclusion: Combined application of phentolamine can significantly improve the outcome of sepsis patients with myocardial injury and improve the survival rate.

Avances en anestesia local y su utilidad en el ámbito de la odontología militar: mesilato de fentolamina / New advances in local anesthetics and their applications in military dentistry: phentolamine Mesylate

Objetivo: Describir el mecanismo de acción del mesilato de fentolamina (MF), que es un producto poco conocido en España, capaz de revertir el efecto de los anestésicos locales empleados en odontología, enumerar sus indicaciones y analizar su efectividad y seguridad. Fuentes de datos: se ha realizado una revisión bibliográfica en las principales bases de datos médicas así como en buscadores genéricos. Selección de estudios: Se ha seleccionado los estudios clínicos, llevados a cabo desde su aprobación como medicamento de uso en el campo odontológico, que han sido realizados en los países donde se comercializa con la misma formulación que en España. Recopilación de datos: Se han obtenido datos sobre el tiempo medio de reducción del efecto anestésico y sobre la incidencia de efectos adversos. Síntesis de datos: Todos los estudios muestran una eficacia y presencia de reacciones adversas similares, en relación con la administración del MF y de un placebo, independientemente de la forma en que se ha llevado el estudio. Discusión: El uso del MF en la actuación clínica diaria, debe ser una decisión del profesional basada en la evidencia científica y en el coste-beneficio de su administración, debiendo seleccionar que pacientes son susceptibles de su administración. Conclusiones: El MF es un medicamento eficaz y seguro en la reducción del efecto anestésico y con indicaciones tanto en el ámbito de la odontología civil como militar

Objective: Describing the mechanism of action of the Phentolamine Mesylate (PM), which is not a so well known product in Spain, capable of reversing the effect of local anesthetics used in dentistry, highlighting its indications and analizing its effectiveness and safety. Data sources: A literature review has been carried out in the main medical databases as well as in generic search engines. Selection of studies: Clinical studies have been selected, carried out since its approval as a medicine for use in the dental field, which have been tested in the countries where it is marketed with the same formula as in Spain. Data collection: Data was obtained on the average time of reduction of the anesthetic effect and on the incidence of adverse reactions. Data synthesis: All studies show an efficacy and presence of similar adverse reactions, related to the administration of PM and of a placebo, regardless of the way in which the study was conducted. Discussion: The use of the PM in the daily practice, should be a decision that must be taken by the professional based on the scientific evidence and the cost-benefit of its administration, having to select which patients are susceptible to its administration. Conclusions: PM is an effective and safe medicine in the reduction of the anesthetic effect and with indications both in the field of civil and as in military dentistry

Effect of Magnesium Sulfate Combined with Phentolamine and Nifedipine for Gestational Hypertension and Serum Levels of LIF and Apelin.

OBJECTIVE: To investigate the effect of magnesium sulfate combined with phentolamine and nifedipine for the treatment of gestational hypertension and on the levels of serum LIF and Apelin. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Obstetrics and Gynecology Clinics, The Affiliated Hospital North China University of Science and Technology, China, from September 2016 to February 2018. METHODOLOGY: One hundred and sixty patients with gestational hypertension were randomly divided into a control group and an observation group, 80 patients in each group. Control group was given magnesium sulfate alone, while observation group was added with phentolamine and nifedipine on the basis of the treatment in control group. Curative effects, pregnancy outcomes, and levels of serum LIF and Apelin were compared. RESULTS: The total effective rate of treatment in the observation group was higher than that in the control group (p=0.005). After treatment, level of serum LIF in the observation group was higher than that in the control group (p<0.001), and level of serum Apelin in the observation group was lower than that in the control group (p<0.001). Incidence of premature birth, cesarean section and neonatal asphyxia in the observation group were all lower than those in the control group (p=0.005, p<0.001 and p=0.005, respectively), while there was no significant difference in the incidence of neonatal death between the two groups (p=0.316). CONCLUSION: Magnesium sulfate combined with phentolamine and nifedipine has a better therapeutic effect on gestational hypertension, which can effectively regulate the levels of serum LIF and Apelin and improve pregnancy outcomes.

Inyección accidental de adrenalina en un dedo / Accidental injection of adrenaline into a finger

Presentamos un caso de inyección accidental en un dedo de la mano en personal sanitario resuelto con inmersión del dedo en agua caliente y aplicación tópica de pomada nitroglicerina. Los síntomas más habituales son el dolor, palidez y frialdad a nivel local, aunque se han descrito complicaciones graves por vasoconstricción severa como la necrosis isquémica, que obliga a tratamientos más agresivos como la administración de fentolamina. El uso cada vez más extendido de autoinyectores de adrenalina para el tratamiento de reacciones anafilácticas severas ha hecho que aumenten los casos de inyección accidental de estos dispositivos, siendo recomendable el conocimiento del manejo de estas situaciones por los profesionales de Atención Primaria y de los Servicios de Urgencia (AU)

We present the case of an accidental injection of adrenaline into a digital finger in health personnel, solved by immersion of the finger in warm water and topical application of nitroglycerine intment. Most common symptoms are local pain, pallor and coldness, although some cases may present serious complications due to severe vasoconstriction, such as ischemic necrosis, which requires more aggressive treatments, including administration of phentolamine. The increased use of adrenaline auto-injectors for the treatment of severe anaphylactic reactions has caused an increasing incidence of accidental injection from these devices. It is therefore advisable that Primary Care and Emergency Department professionals are knowledgeable about the management of these situation (AU)

Delayed-Onset Digital Ischemia After Local Anesthetic With Epinephrine Injection Requiring Phentolamine Reversal.

The use of low-dose epinephrine in hand surgery has made it possible to perform a wide range of surgical procedures in the office setting. Low-dose epinephrine use is safe, and its vasoconstrictive effects are reversible with phentolamine. In this report, we present late-onset finger ischemia beginning 3 hours after an ipsilateral carpal tunnel and A1 pulley release of the middle finger anesthetized with local anesthetic and low-dose epinephrine (1:100,000). Finger ischemia lasted 14 hours until rescued with phentolamine injection.

Phase Four, Randomized, Double-Blinded, Controlled Trial of Phentolamine Mesylate in Two- to Five-year-old Dental Patients.

PURPOSE: The purpose of this study was to evaluate, using a randomized, double-blind methodology: (1) the safety of phentolamine mesylate (Oraverse) in accelerating the recovery of soft tissue anesthesia following the injection of two percent lidocaine plus 1:100,000 epinephrine in two- to five-year-olds; and (2) efficacy in four- to five-year-olds only. METHODS: One hundred fifty pediatric dental patients underwent routine dental restorative procedures with two percent lidocaine plus 1:100,000 epinephrine with doses based on body weight. Phentolamine mesylate or a sham injection (two to one ratio) was then administered. Subjects were monitored for safety and, in four- to five-year-olds, for efficacy during the two-hour evaluation period. RESULTS: There were no significant differences in adverse events between the phentolamine and sham injections. Compared to sham, phentolamine was not associated with nerve injury, increased analgesic use, or abnormalities of the oral cavity. Phentolamine was associated with transient decreased blood pressure in some children. In four- and five-year-olds, phentolamine induced more rapid recovery of lip anesthesia by 48 minutes (P<0.0001). CONCLUSIONS: Phentolamine was well tolerated and safe in three- to five-year-olds; in four- to five-year-olds, a statistically significant more rapid recovery of lip sensation compared to sham injections was determined.

Effectiveness and safety of phentolamine mesylate in routine dental care.

BACKGROUND: Phentolamine mesylate (PM) is widely used to reverse local anesthesia after dental procedures. Limited knowledge is available regarding effectiveness and safety in routine dental practice. METHODS: The authors conducted 2 national, prospective, noninterventional, postauthorization effectiveness studies (OraVerse Post-Authorization Efficacy Study [ORAPAES] controlled, OraVerse Non-Interventional Study [ORANIS] uncontrolled) in patients receiving a local anesthetic as part of their dental treatment. They investigated time to recovery of normal sensation and function and the frequency of adverse events (AEs). The authors used Kaplan-Meier methods to analyze times to recovery; in ORAPAES, they used hazard ratios based on Cox models using the control group as a reference. RESULTS: In ORAPAES (n = 856), PM reduced the time to recovery of normal sensation and function with a difference in the median time of 70 and 79 minutes, respectively, with similar results observed in ORANIS (n = 445). In ORAPAES, patients in the PM group had, at any time point, a 2.77-fold higher chance of recovery to normal sensation (hazard ratio, 2.77; 95% confidence interval [CI], 2.35-3.26; P < .001) and for normal function 2.94-fold higher chance of recovery to normal sensation (95% CI, 2.49-3.47; P < .001) than in the control group. The observed incidence of AEs with PM treatment was 8.4% in ORAPAES (95% CI, 6.2-10.9) and 9.7% (95% CI, 7.1-12.7) in ORANIS. No serious AEs occurred. CONCLUSIONS: PM substantially reduced the time to recovery of normal sensation and function after local anesthesia in routine dental treatment. The results confirm the effectiveness, safety, and tolerability of PM used in patients with routine dental conditions in Germany, and that PM augments the safety of dental treatments. PRACTICAL IMPLICATIONS: The authors determined that PM is well suited to reverse local anesthesia after routine dental procedures.

Phentolamine inhibits angiogenesis in vitro: Suppression of proliferation migration and differentiation of human endothelial cells.

It is widely known that the ß-adrenergic receptor (AR) blocker (propranolol) inhibits human endothelial cell (EC) angiogenesis in vitro, but how the α-AR antagonist (phentolamine) affects human EC angiogenesis has not yet been studied. Here, we show for the first time that both human dermal microvascular ECs (HDMECs) and human brain microvascular ECs (HBMECs) express α-ARs. Moreover, our results indicate that phentolamine inhibits the proliferation, migration, and tubulogenesis of HDMECs and HBMECs. Finally, VEGFR-2 and Ang1/2 expression of HDMECs was suppressed by phentolamine. Together, these results indicate that phentolamine impairs several critical events of neovascularization, and α-ARs, as well as the VEGF/VEGFR-2 and Ang/Tie-2 signaling pathways, may be involved in these processes. Our results suggest a novel therapeutic strategy for the use of α-blockers in the treatment of human angiogenesis-dependent diseases.

O estresse crônico e a via de sinalização adrenérgica no desenvolvimento da lesão periapical / Chronic stress and the adrenergic signaling pathway on the development of periapical lesion

Os objetivos deste estudo são: 1) Esclarecer a possível associação entre o estresse crônico e a estimulação do Sistema Nervoso Simpático (SNS) e investigar sua interferência no desenvolvimento e progressão da lesão periapical; 2) Avaliar a quantidade de receptores para os neurotransmissores na região periapical; 3) Elucidar uma via farmacológica de modulação inflamatória através do uso de bloqueadores adrenérgicos. Trinta e dois ratos Wistar foram submetidos à modelo animal de lesão periapical através da exposição da cavidade pulpar e em seguida foram aleatoriamente divididos em 4 grupos: sem estresse (NS); estresse + solução salina (SS); estresse + ß-bloqueador (Sß); estresse + α-bloqueador (Sα). Os grupos SS, Sß e Sα foram submetidos à modelo animal de estresse crônico durante 28 dias e receberam injeções diárias de solução salina, propranolol (ß bloqueador adrenérgico) e fentolamina (α bloqueador adrenérgico), respectivamente. Após 28 dias os animais foram eutanasiados e procedeu-se as seguintes análises: a) dos níveis séricos de corticosterona através de Radioimunoensaio; b) histomorfométrica por coloração com hematoxilina e eosina; c) da estrutura óssea periapical através de microtomografia computadorizada (micro-CT); d) expressão de receptores ß e α adrenérgicos; e) da atividade osteoclástica através de histoquímica para fosfatase ácida resistente ao tartarato (TRAP). Os resultados obtidos mostram um aumento do nível sérico de corticosterona dos animais do grupo SS sendo estatisticamente significante comparados aos animais do grupo NS (sem estresse) (p<.05). Nenhuma diferença estatística foi observada a nível histológico uma vez que todos os animais apresentaram infiltrado inflamatório moderado e área de lesão periapical similares. A análise por micro-CT também mostrou similaridade da área e volume da lesão periapical em todos grupos. Através da histoquímica para TRAP verificou-se uma quantidade significativamente menor de osteoclastos nos grupos que receberam bloqueadores adrenérgicos (Sß e Sα) (p<.05). Conclui-se que não houve influência significativa do estresse crônico no desenvolvimento e progressão da lesão periapical e a administração de bloqueadores adrenérgicos apesar de não ter sido capaz de modular a resposta inflamatória, diminuiu significativamente o número de osteoclastos na região periapical(AU)

The objectives of this study are: 1) To clarify the possible association between chronic stress (CS) and stimulation of the Sympathetic Nervous System (SNS) and to investigate its interference in the development and progression of periapical lesion; 2) To evaluate the amount of receptors for neurotransmitters in the periapical region; 3) To elucidate a pharmacological pathway of inflammatory modulation through the use of adrenergic blockers. Thirty- two Wistar rats were submitted to animal model of periapical lesion through exposure of the pulp cavity and were then randomly divided into 4 groups: no stress (NS); stress + saline solution (SS); stress + ß-blocker (Sß); stress + α-blocker (Sα). The SS, Sß and Sα groups were submitted to animal model of CS for 28 days and received daily injections of saline solution, propranolol (ß blocker adrenergic) and phentolamine (α adrenergic blocker), respectively. After 28 days the animals were euthanized and the following analysis were carried out: a) serum corticosterone levels through Radioimmunoassay; b) histomorphometric by staining with hematoxylin and eosin; c) periapical bone structure through micro computed tomography; d) expression of ß and α adrenergic receptors; e) osteoclast activity by histochemistry for tartrate resistant acid phosphatase (TRAP). The results obtained show an increase in the seric corticosterone level of the animals of the SS group being statistically significant compared to the NS group animals (without stress). No statistical difference was observed histologically since all animals had moderate inflammatory infiltrate and similar periapical lesion area. Micro-CT analysis also showed similarity of the area and volume of the periapical lesion in all groups. Through histochemistry for TRAP, a significantly lower amount of osteoclasts was observed in the groups receiving adrenergic blockers (Sß and Sα). It was concluded that there was no significant influence of chronic stress on the development and progression of the periapical lesion and the administration of adrenergic blockers despite not being able to modulate the inflammatory response, significantly decreased the number of osteoclasts in the periapical region(AU)

Pharmacological Reversal Agents in Dental Practice: Keys to Patient Safety.

Though uncommon, medical emergencies in the dental office are harrowing occurrences that can be the result of adverse drug reactions. Pharmacological antagonists have been developed for administration as reversal agents in emergency situations in which patients may have an untoward effect, typically caused by too much medication. Dental practitioners should be familiar with these agents to keep patients safe and help mitigate drug-induced medical emergencies. This article reviews the pharmacokinetic and pharmacodynamic principles of pharmacological antagonists; it emphasizes six specific reversal agents as they relate to the clinical practice of dentistry: naloxone, flumazenil, epinephrine, diphenhydramine, phentolamine, and atropine. Outside of emergency situations, the pharmacological antagonist phentolamine has been developed to reverse the effects of the vasoconstrictor in dental local anesthesia preparations when the effects of the agonist medication are no longer required. Such newer reversal agents are being considered for more routine use once the dental procedure is complete. This article is intended to assist dental practitioners who are familiar with pharmacological antagonists to be better able to help mitigate drug-induced medical emergencies should they occur.