Propranolol and verapamil inhibit mRNA expression of RyR2 and SERCA in L-thyroxin-induced rat ventricular hypertrophy

INTRODUCTION An important mechanism contributing to the highmortality and sudden death in patients with cardiac hy-pertrophy is ventricular arrhythmias[1]. The most con-sistently observed abnormalities are: 1) prolongation ofthe action potential duration and refractoriness; 2) non-uniform prolongation of the action potential; 3) the im-paired ability to handle intracellular calcium due tochanges in ryanodine receptor (RyR) and sarco-endo-plasmic reticulum Ca2 -ATPase (SERCA)[2,3]. Rya…     

Iontophoretic in Vivo Transdermal Delivery of β-Blockers in Hairless Rats and Reduced Skin Irritation by Liposomal Formulation

Purpose. To demonstrate the in vivo transdermal delivery and establish the comparative pharmacokinetics of five -blockers in hairless rat. Methods. Intravenous dosing was initially done via jugular cannula. For iontophoretic delivery, current (0.1 mA/cm²) was applied for 2 h through a drug reservoir patch containing the -blocker (10 mg/ml). Blood samples were collected and analyzed by stereoselective HPLC assays. Any irritation resulting from patch application was quantified by a chromameter. Multilamellar liposomal formulation was prepared by the thin-film hydration method and converted to unilamellar liposomes by extrusion. Results. With transdermal iontophoresis, therapeutically relevant amounts of propranolol (83.78 ± 7.4 ng/ml) were delivered within an hour and lasted for up to 4 h. C_max (185.1 ± 56.8 ng/ml) was reached at hour 3. A significantly higher amount (p < 0.05) of sotalol HCl was delivered compared to other -blockers. There was no significant difference in the S/R ratio of AUC_0-t for enantiomers after both intravenous and transdermal delivery. Skin irritation was significantly reduced (p < 0.05) when a liposomal formulation of the propranolol base was used rather than the base itself. Conclusions. The comparative pharmacokinetics of intravenous and transdermal iontophoretic delivery of five -blockers in hairless rats was established. It was shown that there is no stereoselective permeation.     

Blockade of noradrenergic receptors in the basolateral amygdala impairs taste memory

In conditioned taste aversion (CTA), a subject learns to associate a novel taste (conditioned stimulus, CS) with visceral malaise (unconditioned stimulus, US). Considerable evidence indicates that the noradrenergic system in the amygdala plays an important role in memory consolidation for emotionally arousing experiences. The specific aim of the present set of experiments was to determine the involvement of noradrenergic activity in the basolateral amygdala (BLA) during the US presentation and consolidation of CTA as well as during the consolidation of a nonaversive/incidental gustatory memory. Selective bilateral microinfusions of the beta-adrenergic antagonist propranolol administered into the BLA immediately before intraperitoneal (i.p.) lithium chloride (LiCl) injections disrupted CTA memory. Additionally, propranolol infused into the BLA immediately after a pre-exposure to the saccharin (CS) significantly attenuated latent inhibition. The present findings indicating that alterations in noradrenergic function in the BLA affect taste memory formation, provide additional evidence that the BLA plays a critical role in modulating the consolidation of memory and that the influence is mediated by interactions with other brain regions that support memory for different kinds of experiences.     

Time-Dependent Oral Absorption Models

The plasma concentration–time profiles following oral administration of drugs are often irregular and cannot be interpreted easily with conventional models based on first- or zero-order absorption kinetics and lag time. Six new models were developed using a time-dependent absorption rate coefficient, k_a(t), wherein the time dependency was varied to account for the dynamic processes such as changes in fluid absorption or secretion, in absorption surface area, and in motility with time, in the gastrointestinal tract. In the present study, the plasma concentration profiles of propranolol obtained in human subjects following oral dosing were analyzed using the newly derived models based on mass balance and compared with the conventional models. Nonlinear regression analysis indicated that the conventional compartment model including lag time (CLAG model) could not predict the rapid initial increase in plasma concentration after dosing and the predicted C_max values were much lower than that observed. On the other hand, all models with the time-dependent absorption rate coefficient, k_a(t), were superior to the CLAG model in predicting plasma concentration profiles. Based on Akaike's Information Criterion (AIC), the fluid absorption model without lag time (FA model) exhibited the best overall fit to the data. The two-phase model including lag time, TPLAG model was also found to be a good model judging from the values of sum of squares. This model also described the irregular profiles of plasma concentration with time and frequently predicted C_max values satisfactorily. A comparison of the absorption rate profiles also suggested that the TPLAG model is better at prediction of irregular absorption kinetics than the FA model. In conclusion, the incorporation of a time-dependent absorption rate coefficient k_a(t) allows the prediction of nonlinear absorption characteristics in a more reliable manner.     

Severe acne as a side effect of propranolol and nadolol in a migraineur

Beta-blockers have proven effective in the treatment of migraine. Dermatologic side effects are extremely rare. We report a patient with migraine who developed an acnelike dermatitis with two different beta-blockers with complete resolution of the acne upon discontinuation of each drug.     

盐酸普萘洛尔微球剂的制备及其质量评价

 目的:对盐酸普萘洛尔白蛋白微球的制备工艺进行考察,并评价其质量?方法:采用乳化-热固化法制备微球,并对其形态学、载药量、体外释药等性质进行了研究,同时用在体蟾蜍上腭模型评价了其鼻纤毛毒性?结果:微球形态圆整,大小较均匀,粒径1～10μm,载药量4.05%,24h累计释药达85.5%?给予微球4h后,蟾蜍上腭70%纤毛活动剧烈,而溶液剂给药5min,纤毛全部死亡?结论:微球剂的制备工艺对其质量有较大影响,制备良好的微球剂能有效降低盐酸普萘洛尔的鼻纤毛毒性?     

Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region

Propranolol has been used successfully in a limited number of children with infantile hemangiomas (IHs). This study describes the efficacy and adverse effects of propranolol in IH. Seventy-one infants with IHs were treated with oral propranolol, administered at a dose of 2 mg/kg/day, for at least 12 weeks. A photograph-based severity scoring assessment was performed by five observers to evaluate efficacy, utilizing a score of 10 as the original IHs before treatment and 0 as completely normal skin. The mean of the five independent measurements was used in the analysis. Propranolol was a rapid and effective treatment for IHs at 4 weeks (P < 0.001), at 8 weeks (P < 0.001 compared with the value at 4 weeks), at 12 weeks (P < 0.05 compared with the value at 8 weeks), and thereafter up to 32 weeks (P < 0.01 compared with the value at 16 weeks). The response of IHs to propranolol was similar regardless of gender, age at the onset of treatment, type of involvement (local and extended), facial segments affected, special locations (eyelid, nasal tip, and parotid regions), ulceration, and depth of IHs. In the series of patients in this study, oral propranolol at a dosage of 2 mg/kg/day was a well-tolerated and effective treatment for IHs.     

A Comparison of the Effects of Medial Preoptic Electrical Versus Electrochemical Stimulation on Luteinizing Hormone-Releasing Hormone Neuronal Responsiveness to Norepinephrine

Recently, we reported that luteinizing hormone-releasing hormone (LHRH) neurons of estrogen-treated, ovariectomized rats have only limited responsiveness to norepinephrine (NE). These conclusions were based upon observations that NE, when infused intracerebroventricularly, produced only minor increases in plasma luteinizing hormone (LH), whereas, similar infusions following preliminary medial preoptic area (MPOA) electrochemical stimulation (ECS) markedly amplified LH secretion. One difficulty with this approach is that ECS produces an irritative lesion and deposits iron within the tissue, whereas, electrical stimulation (ES) does not have such effects. Accordingly, in the present study, we compared the effects of MPOA–ECS versus –ES on LHRH neuronal responsiveness to NE. While equivalent peak LH concentrations occurred within 15 min after MPOA–ECS or –ES, in the ECS group, LH release was sustained, whereas, it abruptly ceased upon termination of ES (at 15 min). The intracerebroventricular pulse infusion of NE at the time of peak LH secretion (30 min) in MPOA–ECS animals markedly amplified LH release. In these animals, plasma LH remained significantly elevated for 75 min before a decline was observed. In contrast, an infusion of NE at the time of maximal LH release in ES rats (16 min) did not augment LH secretion. The second series of studies examined the effects of MPOA infusions of NE in animals receiving preoptic ES. A single infusion of NE 16 min after ES (i.e. one min after termination of ES) did not amplify LH release, but when two NE pulses were given at 5 and 16 min after beginning preoptic ES, peak plasma LH levels were maintained for an additional 30 min before a decline occurred. Pretreatment of rats with a yS-adrenoreceptor antagonist (propranolol) or a monoamine oxidase inhibitor did not affect peak LH responses obtained after either MPOA–ES alone or combined with two pulses of NE infused into the MPOA at 5 and 16 min. We conclude that following cessation of MPOA–ES, LHRH neurons rapidly lose their responsiveness to NE, whereas, rats which received MPOA–ECS retain such responsiveness possibly due to the stimulative properties of the iron deposited by the ECS. Presumably, for NE to trigger an LH surge requires prior removal of some intrinsic inhibitory control which regulates LHRH neuronal responsiveness to NE.     

Comparative efficacy of behavioral stress management versus propranolol in reducing psychophysiological reactivity in post-myocardial infarction patients

The present study compared the relative efficacy of a behavioral stressmanagement procedure versus a pharmacologic method (the beta-blocker propranolol) in reducing psychophysiological reactivity in post-myocardial infarction (MI) patients. A pretreatment-posttreatment assessment design was used, with 10 patients participating in six separate sessions. The first session involved evaluating psychophysiological reactivity to an emotional stressor (a public-speaking task). The subsequent five sessions involved the administration of the respective treatments, either stress management or drug. The patients were randomly assigned to each treatment group. The public-speaking stressor was readministered after the last treatment session. Results demonstrated that behavioral stress management reduced psychophysiological reactivity to public speaking to the same level seen with propranolol. The findings suggest that this nonpharmacological approach could be of use when beta-blocker therapy is not desired, not practical, or medically contraindicated.This research was supported by a grant to the first author from the American Heart Association, Texas Affiliate.     

葛根素对大鼠离体工作心脏冠状动脉结扎后再灌流损伤的保护作用

用改良K—H液灌流的大鼠离体工作心脏能在90min内保持稳定,120min时心肌收缩力和心输出量明显下降。结扎冠状动脉后心脏做功能力迅速下降,肌酸磷酸激酶释放量明显增加。结扎冠状动脉30min再灌流15min时心脏功能无明显恢复,而肌酸磷酸激酶释放量则进一步增加。1.4×10~(-4)M葛根素对正常大鼠离休工作心脏无明显抑制作用,能增加其冠脉流量。1.4×10(-4)M葛根素和10~(-5)M普萘洛尔均能明显降低冠脉结扎与再灌流时心肌肌酸磷酸激酶释放量,促进再灌流时心脏功能恢复,这是药物对心脏的直接保护作用。