Involvement of Cardiorespiratory Capacity on the Acute Effects of Caffeine on Autonomic Recovery.

Background and objectives: As a result of ergogenic properties, caffeine has been increasingly taken prior to physical exercise, yet its effects on post-exercise recovery, considering the differences in the cardiorespiratory capacity of the individuals, has not yet been studied or fully elucidated. Optimizing the post-exercise recovery can convey advantages to physical activity practitioners. We evaluated the acute effects of caffeine on heart rate (HR) autonomic control recovery following moderate aerobic exercise in males with different cardiorespiratory capacities. Materials and Methods: We split young adult men into two groups based on their various oxygen consumption peaks (VO2 peak): (1) Higher VO2 (HO): Sixteen volunteers, peak VO2 > 42.46 mL/kg/min and (2) Low VO2 (LO): Sixteen individuals, VO2 < 42.46 mL/kg/min). The volunteers were submitted to placebo and caffeine protocols, which entailed 300 mg of caffeine or placebo (starch) in capsules, followed by 15 min of rest, 30 min of moderate exercise on a treadmill at 60% of the VO2 peak, followed by 60 min of supine recovery. Heart rate variability (HRV) indexes in the time and frequency domains were examined. Results: Effect of time for RMSSD (square root of the average of the square of the differences between normal adjacent RR intervals) and SDNN (standard deviation of all normal RR intervals recorded in a time interval) was achieved (p < 0.001). Significant adjustments were observed (rest versus recovery) at the 0 to 5th min of recovery from exercise for the LO during the placebo protocol and at the 5th at 10th min of recovery for the caffeine protocol. For the HO in both procedures we found significant alterations only at the 0 to 5th min of recovery. Conclusion: Caffeine delayed parasympathetic recovery from exercise in individuals with lower cardiorespiratory capacity.

Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers.

STUDY DESIGN: Single centre, single ascending dose study. OBJECTIVES: To compare the pharmacokinetics and assess the safety of capromorelin, a compound that has potential to treat constipation following spinal cord injury (SCI), in groups of able-bodied and SCI volunteers. SETTING: Local population from Victoria, Australia. METHODS: Following initial screening and baseline blood collections, participants received ascending oral doses (20, 50 and then 100 mg at least 1-week apart) of capromorelin after pre-dose blood collection, followed by blood collections over the following 12 h for pharmacokinetic analysis and 1-week and 4-week follow-up blood collections for safety evaluations. Blood pressure and heart rate were monitored. RESULTS: No serious adverse events were recorded following any dose in either the able-bodied group or the SCI group. There were no abnormal blood pressure or heart rate changes. Minor adverse events resolved quickly without the need for treatment. Pharmacokinetic behaviour was broadly similar between groups, with both exhibiting dose-dependent increases in Cmax and AUC0-∞. The SCI participants showed greater variance in pharmacokinetic parameters and had a slightly delayed Tmax and half-life. CONCLUSION: Capromorelin at the doses tested was safe and well tolerated in both SCI and able-bodied participants and also showed similar pharmacokinetics with dose-dependent increases in concentration and drug exposure.

Effects of MDMA alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin on pupillary light reflex.

RATIONALE: Pupillometry can be used to characterize autonomic drug effects. OBJECTIVE: This study was conducted to determine the autonomic effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), administered alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin, on pupillary function. METHODS: Infrared pupillometry was performed in five placebo-controlled randomized studies. Each study included 16 healthy subjects (eight men, eight women) who received placebo-MDMA (125 mg), placebo-placebo, pretreatment-placebo, or pretreatment-MDMA using a crossover design. RESULTS: MDMA produced mydriasis, prolonged the latency, reduced the response to light, and shortened the recovery time. The impaired reflex response was associated with subjective, cardiostimulant, and hyperthermic drug effects and returned to normal within 6 h after MDMA administration when plasma MDMA levels were still high. Mydriasis was associated with changes in plasma MDMA concentration over time and longer-lasting. Both reboxetine and duloxetine interacted with the effects of MDMA on pupillary function. Clonidine did not significantly reduce the mydriatic effects of MDMA, although it produced miosis when administered alone. Carvedilol and doxazosin did not alter the effects of MDMA on pupillary function. CONCLUSIONS: The MDMA-induced prolongation of the latency to and reduction of light-induced miosis indicate indirect central parasympathetic inhibition, and the faster recovery time reflects an increased sympathomimetic action. Both norepinephrine and serotonin mediate the effects of MDMA on pupillary function. Although mydriasis is lasting and mirrors the plasma concentration-time curve of MDMA, the impairment in the reaction to light is associated with the subjective and other autonomic effects of MDMA and exhibits acute tolerance.

Microdialysis for pharmacokinetic-pharmacodynamic studies.

Microdialysis (MD) has become one of the major tools to sample endogenous and exogenous substances in extracellular spaces. It is more suitable for pharmacokinetic-pharmacodynamic (PK-PD) studies than other techniques. This review aims to give an overview of MD for PK-PD (MD/PK-PD) studies, including PK-PD studies, three aspects (principles, recovery, advantages) of MD/PK-PD, and application examples of MD/PK-PD organized by types of drugs and information collected. It can be concluded that MD offers an unique opportunity, to study simultaneously pharmacokinetic (PK) behavior of a drug and its effect on the extracellular levels of endogenous compounds, which may facilitate proof-of-concept demonstrations for target modulation, enhance the rational selection of an optimal drug dose and schedule. In addition, MD/PK-PD can also minimize uncertainties associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development.

Placental and blood-brain barrier transfer following prenatal and postnatal exposures to neuroactive drugs: relationship with partition coefficient and behavioral teratogenesis.

In order to determine the neurotoxicity of prenatal and postnatal exposures to neuroactive drugs in developing rats, we examined placental and blood-brain barrier (BBB) transfers of these radiolabeled drugs when they were administered sc to pregnant rats on Day 19 of gestation, and to pups on Days 2, 7, and 14 after birth. The logarithms of partition coefficients (log Pcorr), used as indices of the lipid solubility of the drugs, decreased in the order propranolol greater than chlorpromazine greater than haloperidol greater than atropine greater than reserpine greater than dopamine greater than epinephrine greater than norepinephrine. The coefficients of correlation between log Pcorr and BBB transfer were statistically significant in all dams, fetuses, and pups. Propranolol, chlorpromazine, and haloperidol, having high lipid solubility, passed rapidly into fetuses. Behavioral teratogenesis occurred to a greater extent with postnatal than with prenatal exposures. All moderately and poorly lipophilic drugs transferred into fetuses, although at lower plasma concentrations than in dams. BBB transfer was low in dams, fetuses, and pups. The behavioral teratogenic potential of these drugs was relatively weaker than that of highly lipophilic drugs. Our results suggest that BBB transfer of drugs, which varies according to lipid solubility, is a major factor in behavioral teratogenesis. Highly lipid-soluble drugs were readily incorporated into developing rat brains, becoming strongly behaviorally teratogenetic by impairing postnatal functional maturation.