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

UPLC-MS/MS determination of phentolamine in human plasma and its application to a pharmacokinetic study.

A sensitive and rapid ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed to determine phentolamine in human plasma. Sample preparation was accomplished through a simple liquid-liquid extraction with ethyl acetate. Chromatographic separation was carried out on an Acquity UPLC BEH C18 column using an isocratic mobile phase system composed of acetonitrile and 1% formic acid in water (33:67, v/v) at a flow rate of 0.45 mL/min. Mass spectrometric analysis was performed using a QTrap5500 mass spectrometer coupled with an electro-spray ionization (ESI) source in the positive ion mode. The MRM transitions of m/z 282.1 → 212.0 and m/z 237.1 → 194.2 were used to quantify for phentolamine and carbamazepine (internal standard, IS), respectively. The linearity of this method was found to be within the concentration range of 0.5-100.0 ng/mL with a lower limit of quantification of 0.5 ng/mL. Only 1.0 min was needed for an analytical run. This fully validated method was successfully applied to the pharmacokinetic study after oral administration of 60 mg phentolamine to 20 Chinese healthy male volunteers.

Sex differences in the systemic response to adrenoreceptor antagonists during sympathetic activation.

BACKGROUND: Sex differences in sensitivity to adrenergic agonists have been described in forearm plethysmography studies. The attenuation in noradrenaline-mediated vasoconstriction is because of enhanced ß(2)-adrenergic stimulation in women. The systemic relevance of these observations is unknown. The aim of this study was to determine sex inequalities in the systemic haemodynamic response to sympathetic activation by isometric forearm contraction in the presence of adrenoreceptor blockade. MATERIALS AND METHODS: Isometric forearm contraction was performed in the presence of isotonic saline, esmolol and phentolamine, respectively, in six men and six premenopausal women. RESULTS: Isometric forearm contraction increased heart rate by 9·5% ± 4·8 CI(95%), P = 0·00001 in both sexes. Mean arterial pressure was also increased in both sexes 13·9% ± 3·2 CI(95%), P = 0·002. Esmolol attenuated the rise in mean arterial pressure in men (5·9% ± 3·6 CI(95%), P = 0·6) but not in women (14·3% ± 3·2 CI(95%), P = 0·007). CONCLUSIONS: This study supports previous findings of sex differences in adrenergic responsiveness and suggests that its consequences are systemically relevant.

Pharmacologic modulation of alveolar liquid clearance in transplanted lungs by phentolamine and FK506.

BACKGROUND: The lung's capacity to clear alveolar fluid can determine the severity of the edema seen after transplantation. We recently observed that alveolar liquid clearance was decreased in transplanted lungs. This study evaluates the ability of phentolamine and FK506 to modulate the severity of lung injury and the decline in alveolar liquid clearance after transplantation. METHODS: A canine orthotopic single-lung transplantation model was used. The lungs were preserved with a low-potassium-dextran solution (50 mL/kg) and transplanted after 3 hours of cold ischemia. The experimental protocol included a control group, a phentolamine group, in which donor lungs were infused with phentolamine (2 mg/kg), and a FK506 group, in which the animals received FK506 (25 mg/kg per hour) intravenously during reperfusion. After 4 hours of reperfusion, alveolar liquid clearance, wet-to-dry ratios, lung epithelial Na(+) channel expression, and the response to beta-adrenergic stimulation were measured. RESULTS: The increase in wet-to-dry ratios of transplanted lungs was less pronounced in the phentolamine and FK506 groups. The FK506 treatment led to improvement of alveolar liquid clearance. Neither phentolamine nor FK506 influenced lung epithelial Na(+) channel expression in transplanted lungs or preserved alveolar cell ability to respond to beta-adrenergic stimulation. CONCLUSIONS: Phentolamine or FK506 treatment during reperfusion improves alveolar liquid clearance and decreases the severity of lung injury.

Pharmacokinetics of lidocaine with epinephrine following local anesthesia reversal with phentolamine mesylate.

Phentolamine mesylate accelerates recovery from oral soft tissue anesthesia in patients who have received local anesthetic injections containing a vasoconstrictor. The proposed mechanism is that phentolamine, an alpha-adrenergic antagonist, blocks the vasoconstriction associated with the epinephrine used in dental anesthetic formulations, thus enhancing the systemic absorption of the local anesthetic from the injection site. Assessments of the pharmacokinetics of lidocaine and phentolamine, and the impact of phentolamine on the pharmacokinetics of lidocaine with epinephrine were performed to characterize this potentially valuable strategy. The blood levels of phentolamine were determined following its administration intraorally and intravenously. Additionally, the effects of phentolamine mesylate on the pharmacokinetics of intraoral injections of lidocaine with epinephrine were evaluated. Sixteen subjects were enrolled in this phase 1 trial, each receiving 4 drug treatments: 1 cartridge lidocaine/epinephrine followed after 30 minutes by 1 cartridge phentolamine (1L1P), 1 cartridge phentolamine administered intravenously (1Piv), 4 cartridges lidocaine/epinephrine followed after 30 minutes by 2 cartridges phentolamine (4L2P), and 4 cartridges lidocaine/epinephrine followed by no phentolamine (4L). Pharmacokinetic parameters estimated for phentolamine, lidocaine, and epinephrine included peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve from 0 to the last time point (AUClast) or from time 0 to infinity (AUCinf), elimination half-life (t1/2), clearance (CL), and volume of distribution (Vd). The phentolamine Tmax occurred earlier following the intravenous administration of 1Piv (7 minutes than following its submucosal administration in treatment 1L1P (15 minutes) or 4L2P (11 minutes). The phentolamine t1/2, CL, and Vd values were similar for 1L1P, 1Piv, and 4L2P. The Tmax for lidocaine occurred later and the Cmax for lidocaine was slightly higher when comparing the 4L2P treatment and the 4L treatment. The phentolamine-induced delay of the lidocaine Tmax likely represents phentolamine's ability to accelerate the systemic absorption of lidocaine from oral tissues into the systemic circulation.

Catecholamine clearance from alveolar spaces of rat and human lungs.

BACKGROUND: Although aerosolized beta-adrenergic agonists have been used as a therapy for the resolution of pulmonary edema, the mechanisms of catecholamine clearance from the alveolar spaces of the lung are not well known. OBJECTIVE: To determine whether catecholamine clearance from the alveolar spaces is correlated with the fluid transport capacity of the lung. METHODS: Albumin solution containing epinephrine (10(-7)M) or norepinephrine (10(-7)M) was instilled into the alveolar spaces of isolated rat and human lungs. Alveolar fluid clearance rate was estimated by the progressive increase in the albumin concentration over 1 h. Catecholamine clearance rate was estimated by the changes in catecholamine concentration and alveolar fluid volume over 1 h. RESULTS: The norepinephrine clearance rate was faster than the epinephrine clearance rate in the rat and human lungs. In the rat lungs, amiloride (a sodium channel blocker) caused a greater decrease in alveolar fluid clearance and epinephrine clearance rate than propranolol (a nonselective beta-adrenergic antagonist). Although propranolol and phentolamine (an alpha-adrenergic antagonist), and 5-(N-ethyl-N-isoprophyl)amiloride (a Na+/H+ antiport blocker) changed neither the alveolar fluid clearance nor the norepinephrine clearance rate, amiloride and benzamil (a sodium channel blocker) decreased both clearance rates. As in the rat lungs, amiloride decreased alveolar fluid and norepinephrine clearance rates in the human lungs. CONCLUSION: These results indicate that the catecholamine clearance rate from the alveolar spaces is correlated with alveolar fluid clearance in rat and human lungs.

Phentolamine bioequivalence study.

OBJECTIVE: To assess the bioequivalence of 2 tablet formulations of phentolamine (Regitine phentolamine 40 mg tablet formulation by Novartis, Brazil, as test formulation, and Vasomax, phentolamine 40 mg tablet formulation by Schering Plough S.A., Brazil, as reference formulation). METHODS: A single 40 mg oral dose of each formulation was administered to 36 male healthy volunteers. The study was conducted after screening, using an open, randomized, 2-period crossover design, a 7-day interval between doses, and wash-out period of at least 4 weeks. Plasma samples for determination of phentolamine were obtained predose and at intervals over 720 min postdose. Plasma concentrations were quantified by reversed-phase liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM) method. Precision of the method was evaluated using calibration curves and plasma quality control samples. The subjects were monitored throughout the study. Systolic and diastolic blood pressure and pulse rate measurement were taken predose and at intervals up to 720 min. Tolerance of both products was good. No serious adverse reactions were reported. The pharmacokinetic parameters calculated for both compounds included: AUC(0-720 min), AUC(0-infinity), C(max), Ca and k(e). RESULTS: The maximum concentrations reached (C(max)) were compared. Regitine 40 mg formulation C(max) geometric mean ratio was 108.29% (90% CI = 98.58-118.96) of Vasomax 40 mg formulation. The areas under the curve (AUC(0-720 min)) were compared. Regitine 40 formulation (AUC(0-720 min)) geometric mean ratio was 102.33% (90% CI = 97.21-107.72) of Vasomax 40 mg formulation. CONCLUSION: Since the 90% CI for both C(max) and AUC ratio where inside the 80 to 125% interval proposed by the Food and Drug Administration, it is concluded that Regitine 40 mg tablet is bioequivalent to Vasomax for the rate and extent of absorption.

Functional characterization of alpha-adrenoceptors mediating pupillary dilation in rats.

Previously, we reported that the alpha(1A)-adrenoceptor, but not the alpha(1D)-adrenoceptor, mediates pupillary dilation elicited by sympathetic nerve stimulation in rats. This study was undertaken to further characterize the alpha-adrenoceptor subtypes mediating pupillary dilation in response to both neural and agonist activation. Pupillary dilator response curves were generated by intravenous injection of norepinephrine in pentobarbital-anesthetized rats. Involvement of alpha(1)-adrenoceptors was established as mydriatic responses were inhibited by systemic administration of nonselective alpha-adrenoceptor antagonists, phentolamine (0.3-3 mg/kg) and phenoxybenzamine (0.03-0.3 mg/kg), as well as by the selective alpha(1)-adrenoceptor antagonist, prazosin (0.3 mg/kg). The alpha(2)-adrenoceptor antagonist, rauwolscine (0.5 mg/kg), was without antagonistic effects. alpha(1A)-Adrenoceptor selective antagonists, 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB-4101; 0.1-1 mg/kg) and 5-methylurapidil (0.1-1 mg/kg), the alpha(1B)-adrenoceptor selective antagonist, 4-amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6,7-dimethoxyquinazoline (L-765314; 0.3-1 mg/kg), as well as the alpha(1D)-adrenoceptor selective antagonist, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY-7378; 1 mg/kg), were used to delineate the adrenoceptor subtypes involved. Mydriatic responses to norepinephrine were significantly antagonized by intravenous administration of both WB-4101 and 5-methylurapidil, but neither by L-765314 nor by BMY-7378. L-765314 (0.3-3 mg/kg, i.v.) was also ineffective in inhibiting the mydriasis evoked by cervical sympathetic nerve stimulation. These results suggest that alpha(1B)-adrenoceptors do not mediate sympathetic mydriasis in rats, and that the alpha(1A)-adrenoceptor is the exclusive subtype mediating mydriatic responses in this species.

Effects of castration and of testosterone replacement on alpha(1)-adrenoceptor subtypes in the rat vas deferens.

The contractions of the rat vas deferens in response to noradrenaline are mediated through alpha(1A)-adrenoceptors. We observed participation of alpha(1B)-adrenoceptors in these contractions after castration. We now investigated the time course of this plasticity and the effects of testosterone by determining the actions of competitive antagonists on noradrenaline-induced contractions after 7, 14, 21 and 30 days of castration. BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride) antagonised noradrenaline-induced contractions in control and castrated rats with low pA(2) values (approximately = 6.8). In control vas deferens, WB 4101 (2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride) had a slope in the Schild plot no different from 1.0, while slopes lower than 1.0 (approximately 0.6) were observed for vas deferens from castrated rats. Chloroethylclonidine was ineffective in the control vas while it inhibited noradrenaline-induced contractions in vasa from castrated rats and converted the complex antagonism by WB 4101 into simple competitive antagonism. Treatment of castrated rats with testosterone prevented the effects of castration. The results suggest that alpha(1B)-adrenoceptors are detectable in vas deferens from at least the 7th through the 30th day after castration and that testosterone prevents this plasticity.

Influence of the stimulation of central chemoreceptors on the gastric mucosal blood flow in artificially ventilated and spontaneously breathing rats.

Respiratory failure coincides frequently with the occurrence of gastric ulceration. In advanced respiratory insufficiency hypoxemia is often accompanied by hypercapnia, which is the stimulus for central chemoreceptors as well as for carotid body chemoreceptors. The purpose of the work was to investigate the reflex effect of stimulation of central chemoreceptors on gastric mucosal blood flow (GMBF) in the rat. Central chemoreceptors were stimulated by a gas mixture composed of 10% carbon dioxide, 50% oxide and 40% nitrogen. In artificially ventilated and spontaneously breathing animals, the stimulation of central chemoreceptors caused a significant increase in gastric mucosal vascular resistance, accompanied by a marked decline in blood flow. We hypothesize that in patients with respiratory insufficiency accompanied by hypercapnia, the reflex impairment of GMBF may contribute to gastric ulceration.

Erectile dysfunction: oral pharmacotherapy options.

Erectile dysfunction (ED) (impotence) is a widespread, age-related problem, which affects 52% of men between 40 and 70 years of age. It is classified as psychogenic, organic, or mixed psychogenic and organic. ED is not a problem only of men, because the relationship between partners can also be disturbed. Therefore, adequate treatment of ED is needed and the most convenient and simplest way is oral drug therapy. Sildenafil, phosphodiesterase-(PDE)-5-selective inhibitor has been the drug of choice for patients with ED since it has been launched in March 1998. The results of various studies have confirmed the efficacy of the drug in men with ED of various etiologies, as well as the positive effect of sildenafil on the quality of a partnership. The most frequent adverse effects documented with sildenafil usage are headache, flushes, dyspepsia, visual disturbances and nasal congestion/rhinitis. These adverse effects are dose-related, usually transient and mild, with low withdrawal rate. Several studies performed recently have shown that sildenafil is a safe and effective treatment of ED in patients with cardiovascular disease, who do not take nitrates or nitrate donors concomitantly. Other oral medications for ED include apomorphine, phentolamine, yohimbine, trazodone, testosterone and new PDE-5 inhibitors in Phase III clinical trials, such as vardenafil and tadalafil. It is obvious, according to recent data, that the concept of PDE-5 inhibition has a central position in oral pharmacotherapy of ED. However, larger clinical studies of efficacy and safety should be carried out using most of the other above-mentioned oral agents and these may also gain a place in the therapy of ED. There are no studies directly comparing sildenafil and other treatments of ED or assessing its role in combination with other therapies. According to the present knowledge, the quality of life, not only of patients but also of their sexual partners, will be improved significantly with sildenafil usage and this is an important precondition for overall health ofboth. Sildenafil is thus a highly effective peroral treatment for ED in patients without contraindications for its use, which can be considered as the firstline therapy with an acceptable risk-benefit ratio.

Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction.

Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment. Biochemical and physiological studies in human erectile tissue have revealed a high affinity of phentolamine for alpha-1 and alpha-2 adrenergic receptors. Based on pharmacokinetic studies, it is suggested that 30-40 min following oral ingestion of 40 or 80 mg of phentolamine (Vasomax), the mean plasma phentolamine concentrations are sufficient to occupy the alpha-1 and -2 adrenergic receptors in erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity. In large multi-center, placebo-controlled pivotal phase III clinical trials, the mean change in the erectile function domain of the International Index of Erectile Function scores (Questions 1-5 and 15) from screening to the end of treatment was significantly higher following use of active drug (40 mg and 80 mg) compared to placebo. Three to four times as many patients receiving phentolamine reported being satisfied or very satisfied compared with those receiving placebo. At doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration with 51% and 53% achieving penetration on 75% of attempts. The correction of erectile dysfunction or improvement to a less severe category of dysfunction was experienced by 53% of men with the 80 mg dose and 40% with the 40 mg dose of phentolamine. All trends of response were the same regardless of any concomitant medication. There were no severe adverse events. At 40 mg, 7.7% experienced rhinitis and fewer than 3.1% experienced any other side effect of treatment. Phentolamine is safe, well tolerated and efficacious for the treatment of erectile dysfunction.

Pharmacokinetics of vasoactive substances administered into the human corpus cavernosum.

The pharmacokinetics of vasoactive substances injected into the corpus cavernosum for the treatment of erectile dysfunction have not been investigated to date. We measured the local intracavernous and peripheral venous concentration curves of papaverine and prostaglandin E1, and its primary metabolite 15-keto-13,14-dihydro-prostaglandin E1 in an intra-individual comparison after intracavernous injection. Papaverine was measured with high performance liquid chromatography and prostaglandin E1 was measured with a specially adapted radioimmunoassay. The results demonstrate that papaverine is slowly draining into the systemic circulation, showing slightly elevated levels in the peripheral blood 30 and 60 minutes after injection. Prostaglandin E1 shows a much faster decrease in local concentrations with no measurable increase in the periphery, probably due to the short half-time after lung passage. Measurement of the primary metabolite proves a local degradation of prostaglandin E1 in the corpus cavernosum into the biologically inactive 15-keto-13,14-dihydro-prostaglandin E1, which also shows a slight increase in the peripheral circulation due to the longer half-time of approximately 8 minutes. The data provide good explanation for the clinical finding of a markedly decreased incidence of priapism with the use of prostaglandin E1, which can be shown to be locally metabolized, compared to papaverine, which is retained in the corpus cavernosum in cases of nonvenogenic impotence.

Kinetics of [3H]-prazosin binding to the rat cortex during aging.

Kinetics (Bmax, KD, k on, k off) of [3H]-prazosin binding to the rat cortex was measured at different ages of animals (2-4, 13-15, 20-24 months old). Additionally, an agonist (phenylephrine) and an antagonist (phentolamine) inhibition of [3H]-prazosin binding was performed at two different rat ages (2-4 and 20-24 months old). The number of cortical alpha 1-adrenoceptors was significantly reduced in 20-24-month-old rats, when compared with 2-4-month ones. Association (k on) and dissociation (k off) rate constants were also reduced in the oldest group, but the dissociation constant (KD) was similar in all the age groups tested. Affinity of phenylephrine, but not of phentolamine, was reduced in the oldest group (20-24 months old). The obtained data suggest that changes in the brain alpha 1-adrenoceptors, correlated with the animal age, are connected to the number of binding sites, rate constants and the affinity of an agonist.

Neuropharmacologic control of cerebral capillary permeability: current implications for therapy of vasogenic brain edema.

Vasogenic brain edema occurs as a result of a diverse spectrum of central nervous system pathology. The fundamental physiologic abnormality of vasogenic brain edema is an increase in cerebral capillary permeability. It is hypothesized that the recent development of new, potent, synthetic vasopressin antagonists will make it possible to impede the formation of vasogenic brain edema by the intraventricular administration of such agents with the subsequent inhibition of the neural control of brain capillary permeability by the locus ceruleus. The action of the vasopressin antagonists should be synergistic with the anti-edema effects of central alpha-adrenergic blockade produced by phentolamine. The combination of these two modes of therapy is expected to produce an increase in intracranial pressure which will require additional forms of medical therapy to control, in spite of the overall decrease of brain parenchymal water content.

An assay for phentolamine using high performance liquid chromatography with electrochemical detection.

A new method is presented for the detection of phentolamine by high performance liquid chromatography with electrochemical detection. The electrochemical detector was used in the oxidative mode at +900 mV potential versus Ag/AgCl reference. The on-column detection limit for phentolamine using this method was 3 ng, and detector response was linear for 3-1000 ng injected on column. The coefficient of variation for replicate injections was 2.4%. The measurement of phentolamine in biological samples was accomplished using yohimbime as the internal standard; retention time for yohimbine was 3.0 min while phentolamine eluted at 4.75 min. Biological samples were buffered to pH 9.2 and extracted with diethyl ether, followed by back extraction into 0.1 N HCl. The extraction efficiency for this method was 99.4% for phentolamine in serum and 59.3% in liver tissue. The detection limit for phentolamine was 5 ng/ml for 1.0-ml serum samples, and was 10 ng/ml for 1.0-ml liver homogenate samples. The disappearance of phentolamine from serum and liver after administration of a single ip dose of phentolamine to mice was determined using this method. Absorption from the ip route was rapid, with peak phentolamine concentrations achieved in 15 min or less. The elimination half-life of phentolamine in serum was approximately 50 min and was paralleled by disappearance of phentolamine in the liver.