The Influence of Low Salivary Flow Rates on the Absorption of a Sublingual Fentanyl Citrate Formulation for Breakthrough Cancer Pain.

CONTEXT: Salivary gland hypofunction may affect the absorption of drugs through the oral mucosa, which in turn may affect their clinical efficacy (e.g., onset of action). OBJECTIVES: The aim of this study was to assess the pharmacokinetics of a sublingual fentanyl orally disintegrating tablet (Abstral, Prostrakan Inc.) in a group of cancer patients with salivary gland hypofunction. METHODS: Nine cancer patients with salivary gland hypofunction underwent a series of three pharmacokinetic studies with the sublingual fentanyl orally disintegrating tablet. In the first phase, the patients received no pretreatment; in the second phase, the patients were allowed to moisten the oral cavity before dosing; in the third phase, the patients were given pilocarpine hydrochloride (saliva stimulant) before dosing. Fentanyl concentrations were measured using a method of high-performance liquid chromatography with validated tandem mass spectrometric detection. RESULTS: The Tmax was longer, the Cmax was lower, the AUC0-30 lower, and the AUClast lower in the phase involving no pretreatment; the Tmax/Cmax/AUC0-30/AUClast were similar in the phase involving moistening of the oral cavity and the phase involving giving pilocarpine hydrochloride. CONCLUSION: The pharmacokinetics of the sublingual fentanyl orally disintegrating tablet appear to be negatively affected by the presence of salivary gland hypofunction, although the moistening of the oral cavity before dosing results in a pharmacokinetic profile similar to that seen with the giving of pilocarpine hydrochloride.

Centrally administered isoproterenol induces sympathetic outflow via brain prostaglandin E2-mediated mechanisms in rats.

Brain ß-adrenoceptor stimulation can induce elevations of plasma levels of noradrenaline. However, there have been no detailed studies related to signaling pathways downstream of ß-adrenoceptors responsible for central sympathetic outflow. In the present study, we pharmacologically examined the possibility that centrally administered isoproterenol can induce elevations of plasma noradrenaline levels in a brain prostaglandin-dependent manner. In addition, we also examined whether or not intracerebroventricular administration of isoproterenol could release endogenously synthesized prostaglandin (PG) E2 in the hypothalamic paraventricular nucleus (PVN) by using the brain microdialysis technique combined with liquid chromatography-ion trap tandem mass spectrometry (LC-ITMS(n)). Under urethane anesthesia, a femoral venous line was inserted for infusion of saline and a femoral arterial line was inserted for collecting blood samples. Next, animals were placed in a stereotaxic apparatus for application of test agents. Catecholamines in the plasma were extracted by alumina absorption and were assayed by high-performance liquid chromatography with electrochemical detection. Quantification of PGE2 in rat PVN microdialysates was performed by the LC-ITMS(n) method. We demonstrated that centrally administered isoproterenol-induced elevations of plasma noradrenaline could be mediated via activation of ß-adrenoceptors and the downstream phospholipase A2-cyclooxygenase pathway. Furthermore, PGE2 in the PVN and the PGE2 receptor EP3 subtype appear to play an important role in the process. Our results suggest that central isoproterenol-induced sympathetic outflow is mediated via brain PGE2 in a PGE2 receptor EP3 subtype-dependent manner.

Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.

OBJECTIVE: To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). METHODS: Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. RESULTS: From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. CONCLUSIONS: In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.

Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs.

Effects of ranolazine alone and in the presence of phenylephrine (PE) or isoproterenol (ISO) on hemodynamics, coronary blood flow and heart rate (HR) in the absence and presence of hexamethonium (a ganglionic blocker) were studied in conscious dogs. Ranolazine (0.4, 1.2, 3.6, and 6 mg/kg, intravenous) alone caused transient (<1 minute) and reversible hemodynamic changes. PE (0.3-10 µg/kg) caused a dose-dependent increase in blood pressure and decrease in HR. ISO (0.01-0.3 µg/kg) caused a dose-dependent decrease in blood pressure and an increase in HR. Ranolazine at high (11-13 mM), but not at moderate (4-5 mM) concentrations partially attenuated changes in mean arterial blood pressure and HR caused by either PE or ISO in normal conscious dogs. However, in dogs treated with hexamethonium (20 mg/kg) to cause autonomic blockade, ranolazine (both 4-5 and 11-13 µM) significantly attenuated both the PE- and ISO-induced changes in mean arterial blood pressure. The results suggest that a potential antiadrenergic effect of ranolazine was masked by autonomic control mechanisms in conscious dogs but could be observed when these mechanisms were inhibited (eg, in the hexamethonium-treated dog). Ranolazine, at plasma concentrations <10 µM and in conscious dogs with intact autonomic regulation, had minimal antiadrenergic (α and ß) effects.

Autonomic drugs and the accommodative system in rhesus monkeys.

Accommodation and pupil constriction result from parasympathetic stimulation from the Edinger-Westphal (EW) nucleus of the midbrain resulting in release of acetylcholine at the neuromuscular junctions of the ciliary muscle and iris. Cholinergic and adrenergic drugs can be applied topically to evaluate the effects on the pupil and accommodative system without input from the EW nucleus. This study is directed at characterizing how topical low dose echothiophate, an anti-cholinesterase inhibitor (i.e., an indirect cholinergic agonist), epinephrine, an adrenergic agonist, and timolol maleate, a beta adrenergic antagonist, affect pupil diameter, resting refraction and accommodative amplitude and dynamics in rhesus monkeys. The effects of 0.015% echothiophate, 2% epinephrine, 0.5% timolol maleate and saline on pupil diameter and resting refraction were measured in one eye each of four normal rhesus monkeys for 60-90 min following topical instillation. Pupil diameter was measured with infrared videography and refraction was measured with a Hartinger coincidence refractometer. Effects on static and dynamic EW stimulated accommodation were studied in three iridectomized monkeys (ages 5, 6 and 12 years) with permanent indwelling stimulating electrodes in the EW nucleus. Dynamic accommodative responses were measured with infrared photorefraction for increasing current amplitudes before and during the course of action of the pharmacological agents. Echothiophate caused a significant decrease in pupil diameter of 3.07 +/- 0.65 mm (mean +/- SEM, p < 0.01), and a myopic shift in resting refraction of 1.30 +/- 0.39 D (p < 0.05) 90 min after instillation. Epinephrine caused a 2.76 +/- 0.38 mm (p < 0.01) increase in pupil diameter with no change in resting refraction 60 min after instillation. Timolol maleate resulted in no significant change in either pupil diameter or resting refraction 60 min after instillation. There was no significant change in maximum EW stimulated accommodative amplitude after any agent tested. The amplitude vs. peak velocity relationship for accommodation was significantly different after echothiophate and timolol maleate, and for disaccommodation after echothiophate, epinephrine and timolol maleate. In conclusion, when tested objectively in anesthetized monkeys, epinephrine and timolol maleate did not alter resting refraction or accommodative amplitude, but did have small, significant affects on accommodative dynamics. This suggests that there is an adrenergic component to the accommodative system. Low dose echothiophate had significant effects on pupil diameter and resting refraction, with only small effects on the dynamics of the accommodative response.

Age and gender difference in ST height at rest and after double autonomic blockade in normal adults.

BACKGROUND: ST elevation is commonly seen in young, healthy men. The exact mechanisms that cause ST height to be greater in young men are not yet completely understood. The purpose of the present study was to determine whether autonomic tone is responsible for age and gender differences in ST height. METHODS: Gender and age differences in ST height were studied at rest and after double autonomic blockade (DAB) with atropine and propranolol. Fifty healthy men and women were included (16 men, 14 women, age 23-32 years; 9 men, 11 women, age 65-79 years). Twelve-lead ECGs were registered at rest and after DAB. Leads II and V(1)-V(4) were chosen for analysis. ST height (in mm) was measured manually at the J-point, and 40 ms and 80 ms after the J-point. Values were corrected for QRS amplitude. RESULTS: Gender and age differences in ST height were seen in both rest and DAB data. Men had greater ST height compared to women at J-point, 40 and 80 ms after the J-point (P < or = 0.0001), and younger subjects had greater ST height than older subjects at J-point (P = 0.0140), 40 and 80 ms after the J-point (P < or = 0.0001). DAB did not change ST height at J-point or at 40 ms, but increased ST height at 80 ms. Women had less of an increase in ST height following DAB than men did. CONCLUSIONS: ST elevation in the absence of structural or electrical heart disease is mainly seen in young men. Age and gender difference persist after DAB and thus are not due to differences in autonomic tone.

Effects of saw palmetto extract on micturition reflex of rats and its autonomic receptor binding activity.

PURPOSE: We examined the effects of saw palmetto extract (SPE) on the rat micturition reflex and on autonomic receptors in the lower urinary tract. MATERIALS AND METHODS: The effect of SPE was examined on cystometrograms of anesthetized rats induced by intravesical infusion of saline or 0.1% acetic acid. SHR/NDmc-cp (cp/cp) rats received repeat oral administration of SPE and nighttime urodynamic function was determined. The autonomic receptor binding activity of SPE in the rat bladder and prostate was examined by radioligand binding assay. RESULTS: Intraduodenal administration of SPE (60 mg/kg) in anesthetized rat cystometry caused a significant increase in the micturition interval, micturition volume and bladder capacity during intravesical saline infusion. Also, similar administration of SPE at doses of 12 and 20 mg/kg significantly reversed the shortened micturition interval as well as the decreased micturition volume and bladder capacity due to 0.1% acetic acid infusion in a dose dependent manner. In conscious SHR/NDmc-cp (cp/cp) rats repeat oral administration of SPE (6 mg/kg daily) constantly increased the micturition interval and concomitantly decreased voiding frequency. SPE inhibited specific binding of [H]NMS ([N-methyl-H]scopolamine methyl chloride) (bladder) and [H]prazosin (prostate) with IC50 values of 46.1 and 183 microg/ml, respectively. CONCLUSIONS: SPE significantly alleviates urodynamic symptoms in hyperactive rat bladders by increasing bladder capacity and subsequently prolonging the micturition interval. Our data may support the clinical efficacy of SPE for the treatment of lower urinary tract symptoms.

Nonhypotensive autonomic agents in veterinary ophthalmology.

The parasympathetic and sympathetic divisions of the autonomic nervous system are involved in homeostatic control of a wide variety of ocular functions, including accommodation, pupillomotor control, lacrimation, eyelid position, and aqueous humor production. Familiarity with the functional anatomy of the autonomic nervous system is paramount to the understanding and application of the large number of autonomic drugs used in veterinary ophthalmology. The cholinergic and adrenergic agents discussed in this article are commonly employed to facilitate routine ophthalmic examination, in the diagnosis of autonomic dysfunction, and in the treatment of a variety of ocular diseases.

The autonomic control of accommodation and implications for human myopia development: a review.

Prolonged nearwork has long been associated with myopia development, however, there is no well described linking mechanism. One theory suggests that if accommodation accuracy during nearwork is not maintained, the defocused retinal image leads to myopia development. Here we review the findings of research aimed at determining whether the autonomic inputs to the ciliary smooth muscle are involved in this type of environmental myopia. We examine whether an autonomic imbalance could be a precursor to axial elongation and the resulting myopia. Accommodation responses, such as tonic accommodation and nearwork-induced accommodative adaptation, as a function of refractive error, are described in relation to an autonomic imbalance model. The collective results of this research point to anomalous accommodation responses, possibly as a result of underlying anomalous autonomic input to the ciliary muscle, being involved in myopia development and progression.

Autonomic nervous responses according to preference for the odor of jasmine tea.

The effect of jasmine tea odor on the autonomic nervous system was investigated by a power spectral analysis of the heart rate variability. We assigned eight volunteers to two groups with either a predilection for or antipathy toward the jasmine tea odor. We tested both high- and low-intensity jasmine tea odors. The low-intensity odor was produced by diluting 20-fold the jasmine tea used for the high-intensity odor test. The low-intensity odor produced an increase in parasympathetic nervous activity in both the predilection and antipathy groups. The high-intensity odor produced an increase in parasympathetic nervous activity in the predilection group, but an increase in sympathetic nervous activity in the antipathy group. The odor of Chinese green tea, a basic ingredient of jasmine tea, produced no effects similar to those of the jasmine tea odor. These results suggest that the jasmine tea odor activated the parasympathetic nerve, whereas the higher-intensity odor activated the sympathetic nerve in those subjects who disliked the odor.

[Neuropharmacological reactivity of the body exposed to extreme factors: the effect of radiation]. / Neirofarmakologicheskaia reaktivnost' organizma pri vozdeistvii ékstremal'nykh faktorov: vliianie oblucheniia.

The functional state of neurochemical structures of male mice was investigated after their gamma-irradiation with 137Cs (1.9 Gy/min) at a dose of 100 Gy. The animals were treated with the following drugs that produce selective effects on specific receptors: galanthamine (0.5 mg/kg), amizyl (30 and 60 mg/kg), arpenal (30 mg/kg), phenamine (3, 6 and 10 mg/kg) phentolamine and obsidan (1 mg/kg), haloperidol (0.5 and 1 mg/kg), apomorphine (2 mg/kg), phenazepam (0.05 and 2 mg/kg), phenibut (200 mg/kg), and strychnin (0.1 and 0.2 mg/kg). The physical performance of the animals was measured with the aid of a swimming test applied 2 and 6 hours after irradiation. The results point to the development of heterologous desensibilization of receptors at early post-irradiation periods. The high effectiveness of agonists and antagonists of CNS transmitters in the nonirradiated animals and their low effectiveness in the irradiated animals may be considered as an indicator of post-radiation injury of specific receptors. This seems to be responsible for partial or total resistance of irradiated animals to the regulatory effects of neurotransmitters. These neuropharmacological interactions may obviously be modified in response to the combined effects of space flight factors.

[Intracavernous injections of vasoactive drugs. Contribution to the study of their value in erectile impotence]. / Les injections intracaverneuses de drogues vasoactives. Contribution à l'étude de leur valeur dans l'impuissance érectile.

The obtention of an artificial erection with a single intracavernous injection (ICI) of vasoactive drugs, has upset our conceptions about erection and the approach for erectile failure. If this pharmacologic stimulation increases the reliability of some erection tests, their diagnosis value is still questioned. The complexity of both erection and vasomotricity pharmacology, make difficult the understanding of the mechanisms of these ICI. Their therapeutic value is reduced to the method by self injections, new treatment for impotence, even if it concerns only few impotent patients. Finally, the experimental feature and the unquestionable morbidity of these ICI, mainly priapism, impede their large diffusion. However, in spite of these doubts, this intracavernous pharmacology is a real progress for erection and its troubles.

[Study on the functional development of the sympathetic nervous system of fetal heart in rats].

The drugs acting on the autonomic nervous system were administered intravenously to dams or intraperitoneally to the 20-day-old fetuses maintained by umbilical and placental circulation. The fetal heart rates were accelerated by the administration of isoproterenol, epinephrine, norepinephrine, tyramine and dopamine to fetuses, and they were decelecated by the injection of propranolol and methacholine to fetuses. However, the tachycardia caused by the fetal injection of isoproterenol and the bradycardia by methacholine were inhibited by the pretreatment of propranolol and atropine. The fetal bradycardia and hypoxia caused by the administration of epinephrine under the pretreatment of propranolol to fetuses were inhibited by the injection of alpha-adrenergic receptor blockers such as phentolamine and yohimbine. Furthermore, the tyramine treatment to fetuses produced significant acceleration of the fetal heart rate on day 19-20 of gestation, but not on day 18. These findings suggest that fetal cardiac beta-adrenergic, muscarine-cholinergic receptors and vascular postsynaptic alpha-adrenergic receptor may be sensitive enough to respond to sympathomimetic and sympatholytic drugs, and the fetal cardiac sympathetic innervation between the adrenergic nerve terminal and synapse effector cells may be developed on day 18-19 of gestation.

Systemic effects of topical ophthalmic medications.

Ophthalmic drugs topically applied have significant systemic absorption, which may result in widespread adverse side effects. All physicians involved in the care of patients receiving these drugs should be cognizant of such actions, interactions, and toxic effects. They should also be familiar with the prevention, diagnosis, and treatment of these effects, as well as the mechanisms of systemic drug absorption.

Effects of vasodilators on microcirculation of the rat cremaster muscle: a microscopic method for screening drugs.

Effects of vasodilating drugs on microcirculation of the rat cremaster muscle were investigated microscopically. Topical application and intravenous injection of papaverine produced dilatation of arterioles. Cyclandelate applied topically dilated the arterioles to a considerable extent. Topical application of bamethan induced arteriolar dilatation while bamethan given intravenously constricted the arterioles. Kallikrein applied topically induced a slight dilatation of arterioles, and intravenous administration of kallikrein produced an appreciable vasodilatation. Topical administration of bradykinin produced a vasodilatation of arterioles of the rat cremaster muscle. These results indicate that direct action of a drug on the microcirculation can be properly evaluated by the microscopic method in the rat cremater muscle, if the drug is applied topically, in the vicinity of small vessels under study.

Changes in rat hind limb vascular resistance following intracerebroventricular drug administration.

The right hind limbs of rats (which had previously implanted intraventricular guide cannulae) were isolated from the systemic circulation, but with the nerves to the limb remaining intact, and perfused using a constant output blood pump. Using this preparation, changes in vascular resistance, blood pressure and heart rate were monitored following injection of noradrenaline, phentolamine and propranolol into the lateral cerebral ventricles (i.c.v.) of rats anaesthetised with alpha-chloralose. All three drugs lowered blood pressure. Noradrenaline administered i.c.v. induced a nervously mediated vasocilatation and an insignificant fall in heart rate whereas i.c.v. phentolamine administration was followed by a nervously mediated vasoconstriction in the isolated hind limb and a gradual rise in heart rate. After i.c.v. administration of propranolol there was no evidence of an immediate nervously mediated vasodilatation but heart rate fell significantly. Following i.c.v. phentolamine or propranolol vasodilatation did not occur in the hind limb until after the time taken for circulating blood ro reach the isolated vascular bed. The vasodilatatory and hypotensive responses to i.c.v. noradrenaline were not evident following prior i.c.v. injection of phentolamine. These results indicate the suitability of this preparation for investigations of central actions of other drugs.