Role of norepinephrine in the rabbit ganglionectomy response

Superior cervical ganglionectomy (SCG) produced delayed mydriasis and ocular hypotension in rabbits. Norepinephrine (NE) was lost from the iris-ciliary body exponentially with onset of about 11 h. NE in aqueous humor peaked at twice control levels (from 7 to 14 ng/ml) at 16.5 h and subsequently declined to below control levels by 24 h. Intracameral administration of radiolabeled NE (150 ng) to control eyes resulted in a calculated outflow of 1.6 microliter/min, comparable to that seen with fluorescein (1.7 microliter/min). NE administered to ganglionectomized eyes (26 h after surgery) resulted in a calculated outflow of 3.1 microliter/min. These results suggest that mydriasis following SCG may be due to NE released from degenerating sympathetic nerve endings. However, NE concentration in the aqueous humor appears inadequate to produce the delayed increase in outflow observed in rabbits after SCG.     

Ocular effects of dipivalyl esters of epinephrine and alpha-methylepinephrine

The intraocular pressure (IOP) and pupillary effects of dipivalyl esters of epinephrine and alpha-methylepinephrine were compared after topical application in conscious rabbits. Both dipivalyl-alpha-methylepinephrine (DP alpha meE) and dipivalylepinephrine (DPE) produced a dose-dependent pupillary dilation (PD) and decrease in IOP. The onset of PD was approximately 30 min for both agents and reached maximal plateau within 1 and 2 hr for DPE and DP alpha meE, respectively. Duration of mydriatic effect was also dose-related, although more prolonged with DP alpha meE. This probably reflects differences in rate of inactivation of these compounds. The onset of IOP lowering effect of DP alpha meE was more rapid (35-45 min) when compared with DPE (1.5-2 hr) which may be due to the initial ocular hypertensive response seen with DPE. The initial rise in IOP was prevented by transection of three rectus muscles. DP alpha meE produced initial ocular hypertension only at the highest doses. The decrease of IOP lasted more than 6 hr for both drugs, returning to normal by 24 hr. No pupillary or IOP effects were seen in the contralateral eye. Denervation supersensitivity to both the pupillary and IOP responses to DP alpha meE was seen after superior cervical ganglionectomy. These findings are consistent with the hypothesis that the pupillary and IOP responses to DP alpha meE do not require intact adrenergic innervation to the eye, and that these effects are mediated by activation of postjunctional alpha-adrenoceptors. It is concluded that DP alpha meE is a potent adrenergic ocular hypotensive agent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ineffectiveness of a purine analogue,EMD 28422, in two animal tests of anxiolytic action

EMD 28422 was compared to chlordiazepoxide for antianxiety activity in two behavioral tests known to predict the anxiolytic action of drugs. In the conflict test, male rats were trained to respond for food reinforcement in which some of the reinforced responses also resulted in the delivery of footshock. Treatment of these rats with chlordiazepoxide but not with EMD 28422 antagonized the foot-shock-induced suppression of responding. In the drug discrimination test, male hooded rats were trained to discriminate the anxiogenic action of pentylenetetrazol from saline by responding for food reinforcement on one of two levers after pentylenetetrazol treatment (subconvulsant dose) and on the other lever after saline injection. Pretreatment with chlordiazepoxide and not with EMD 28422 antagonized the pentylenetetrazol stimulus. Ineffectiveness of EMD 28422 in both tests sensitive to chlordiazepoxide action suggests lack of anxiolytic efficacy of this drug, despite its reported enhancement of benzodiazepine binding in the brain.     

Pharmacological characterization of alpha-adrenoceptors involved in nictitating membrane and pupillary responses to sympathetic nerve stimulation in cats

Summary Electrical stimulation of the preganglionic cervical sympathetic nerve produced frequency-related contraction of the nictitating membrane (NM) and dilation of the pupil in anesthetized cats. Observations of the effects of alpha-adrenoceptor blockade on these effectors were made simultaneously from the same preparations. All of the alpha₁ -adrenoceptor antagonists tested produced a doserelated blockade of the NM with the relative potencies being prazosin > WB-4101 > phentolamine > phenoxybenzamine. In contrast, the iris dilator response was blocked by WB-4101 and phenoxybenzamine but was almost totally refractory to antagonism by doses of prazosin and phentolamine that reduced the evoked NM responses by more than 75% in these same preparations. Neither alpha₂-adrenoceptor (yohimbine or rauwolscine) nor beta-adrenoceptor (propranolol) antagonism produced significant inhibition of the activation of either organ. These results suggest that: 1) neural activation of the nictitating membrane is solely due to stimulation of alpha₁ -adrenoceptors; 2) neither beta- nor alpha₂-adrenoceptors contribute significantly to nerve activation of either the nictitating membrane or iris dilator muscle in vivo; 3) the alpha-adrenoceptors on the dilator muscle that are activated neurally can not be classified pharmacologically as either alpha₁ or alpha₂ receptors.This work was supported by Grant OK 8710676 from the National Science Foundation and by Research to Prevent Blindness, Inc. Send offprint requests to M. C. Koss     

α-Adrenoceptor activation of nictitating membrane and iris in cats

Summary Intra-arterial administration of (+)- and (–)isomers of adrenaline and noradrenaline produced doserelated contraction of the nictitating membrane (NM) and dilation of the pupil in anesthetized cats. The relative potencies were (–)-adrenaline > (+)-adrenaline = (–)-noradrenaline > (+)-noradrenaline. Observations of the effects of -adrenoceptor antagonists on (–)-noradrenaline activation of these two effectors were made simultaneously. All of the ₁-adrenoceptor antagonists tested produced a doserelated blockade of the NM with the relative potencies being prazosin > WB-4101 > phentolamine > phenoxybenzamine. In contrast, the iris dilator was blocked by WB-4101 and phenoxybenzamine but was refractory to antagonism by doses of prazosin and phentolamine that reduced the (–)-noradrenaline evoked NM response by 75–80% in the same animals. The ₂-adrenoceptor antagonist, yohimbine, produced significant inhibition of the NM only at high dose (1 mg/kg) but even at this level had no effect on pupil diameter. These results suggest that activation of the NM by exogenous noradrenaline is due solely to stimulation of ₁-adrenoceptors. ₂-adrenoceptors do not seem to significantly contribute to noradrenaline induced activation of either the NM or iris dilator muscle in vivo. In contrast, the -adrenoceptors on the iris dilator muscle that are stimulated by exogenous noradrenaline can not easily be classified pharmacologically as either ₁- or ₂-adrenoceptors.This work was supported by Grant OK8710676 from the National Science Foundation and by Research to Prevent Blindness, Inc     

Assessment of Knowledge and Attitude towards Palliative Care and Associated Factors among Nurses Working in North Wollo Hospitals

BackgroundPalliative care improves the quality of life of patients facing a life-threatening illness. Nurses should improve their caregiving capacity. In Ethiopia, palliative care is underestimated. The availability of data regarding the knowledge and attitude of nurses towards palliative care is critically important. Thus, this study aimed to assess the level of knowledge and attitude of nurses towards palliative care.MethodsInstitution-based, cross-sectional study was conducted in North Wollo hospitals. A simple random sampling technique was used. The data was collected using structured self-administered questionnaires from February to March 2019. The analysis was done using a binary logistic regression model. P-value < 0.05 was considered as statistically significant.ResultsThe result revealed that 59.7% of the respondents had good knowledge and 44.2% had a favorable attitude towards palliative care. Level of education, experience in caring for chronically ill patients, and experience in caring for dying family members within the last 6 months had a significant association with the knowledge of nurses. Monthly income, experience in caring for chronically ill patients, formal palliative care education, and knowledge were found statistically significant with the attitude of nurses towards palliative care.ConclusionMore than half of the nurses had good knowledge, but less than half of the respondents had a favorable attitude towards palliative care. Attention should be given towards palliative care by the health policy and needs to be incorporated into the national curriculum of nursing education.     

Selective estrogen receptor modulator (SERM) lasofoxifene forms reactive quinones similar to estradiol

The bioactivation of both endogenous and equine estrogens to electrophilic quinoid metabolites has been postulated as a contributing factor in carcinogenic initiation and/or promotion in hormone sensitive tissues. Bearing structural resemblance to estrogens, extensive studies have shown that many selective estrogen receptor modulators (SERMs) are subject to similar bioactivation pathways. Lasofoxifene (LAS), a third generation SERM which has completed phase III clinical trials for the prevention and treatment of osteoporosis, is currently approved in the European Union for this indication. Previously, Prakash et al. (Drug Metab. Dispos. (2008) 36, 1218-1226) reported that similar to estradiol, two catechol regioisomers of LAS are formed as primary oxidative metabolites, accounting for roughly half of the total LAS metabolism. However, the potential for further oxidation of these catechols to electrophilic o-quinones has not been reported. In the present study, LAS was synthesized and its oxidative metabolism investigated in vitro under various conditions. Incubation of LAS with tyrosinase, human liver microsomes, or rat liver microsomes in the presence of GSH as a trapping reagent resulted in the formation of two mono-GSH and two di-GSH catechol conjugates which were characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Similar conjugates were also detected in incubations with P450 3A4, P450 2D6, and P450 1B1 supersomes. Interestingly, these conjugates were also detected as major metabolites when compared to competing detoxification pathways such as glucuronidation and methylation. The 7-hydroxylasofoxifene (7-OHLAS) catechol regioisomer was also synthesized and oxidized either chemically or enzymatically to an o-quinone that was shown to form depurinating adducts with DNA. Collectively, these data show that analogous to estrogens, LAS is oxidized to catechols and o-quinones which could potentially contribute to in vivo toxicity for this SERM.     

Inosine and N6-substituted adenosine analogs lack anxiolytic activity in the pentylenetetrazol discrimination model of anxiety

Although some in vitro studies have raised the possibility that endogenous purines mediate the therapeutic effects of the benzodiazepines, no behavioral studies have been performed to confirm or reject this hypothesis. Consequently, inosine and the adenosine A1 receptor agonists N6- (L-phenylisopropyl) adenosine (L-PIA) and 2-chloroadenosine (2CA) were evaluated for diazepam-like anxiolytic activity in the pentylenetrazol-saline discrimination model of anxiety. Rats were trained to press one of two levers for food reward after pentylenetetrazol (PTZ) injection (20 mg/kg) and to press the other after saline injection. During testing in these rats, diazepam (10 mg/kg) blocked the PTZ-induced selection of the PTZ-appropriate lever (i.e., rats selected the saline-correct lever). Inosine, L-PIA, and 2CA neither blocked selection of the PTZ-appropriate lever after PTZ administration nor did they reverse the diazepam blockade. It is suggested that adenosine or inosine may not act endogenously to mediate the anxiolytic effects of benzodiazepines.