Inverse agonism and its therapeutic significance

A large number of G-protein-coupled receptors (GPCRs) show varying degrees of basal or constitutive activity. This constitutive activity is usually minimal in natural receptors but is markedly observed in wild type and mutated (naturally or induced) receptors. According to conventional two-state drug receptor interaction model, binding of a ligand may initiate activity (agonist with varying degrees of positive intrinsic activity) or prevent the effect of an agonist (antagonist with zero intrinsic activity). Inverse agonists bind with the constitutively active receptors, stabilize them, and thus reduce the activity (negative intrinsic activity). Receptors of many classes (α-and β-adrenergic, histaminergic, GABAergic, serotoninergic, opiate, and angiotensin receptors) have shown basal activity in suitable in vitro models. Several drugs that have been conventionally classified as antagonists (β-blockers, antihistaminics) have shown inverse agonist effects on corresponding constitutively active receptors. Nearly all H(1) and H(2) antihistaminics (antagonists) have been shown to be inverse agonists. Among the β-blockers, carvedilol and bucindolol demonstrate low level of inverse agonism as compared to propranolol and nadolol. Several antipsychotic drugs (D(2) receptors antagonist), antihypertensive (AT(1) receptor antagonists), antiserotoninergic drugs and opioid antagonists have significant inverse agonistic activity that contributes partly or wholly to their therapeutic value. Inverse agonism may also help explain the underlying mechanism of beneficial effects of carvedilol in congestive failure, naloxone-induced withdrawal syndrome in opioid dependence, clozapine in psychosis, and candesartan in cardiac hypertrophy. Understanding inverse agonisms has paved a way for newer drug development. It is now possible to develop agents, which have only desired therapeutic value and are devoid of unwanted adverse effect. Pimavanserin (ACP-103), a highly selective 5-HT(2A) inverse agonist, attenuates psychosis in patients with Parkinson's disease with psychosis and is devoid of extrapyramidal side effects. This dissociation is also evident from the development of anxioselective benzodiazepines devoid of habit-forming potential. Hemopressin is a peptide ligand that acts as an antagonist as well as inverse agonist. This agent acts as an antinociceptive agent in different in vivo models of pain. Treatment of obesity by drugs having inverse agonist activity at CB(1/2) receptors is also underway. An exciting development is evaluation of β-blockers in chronic bronchial asthma-a condition akin to congestive heart failure where β-blockade has become the standard mode of therapy. Synthesis and evaluation of selective agents is underway. Therefore, inverse agonism is an important aspect of drug-receptor interaction and has immense untapped therapeutic potential.     

Tracing patients on antiretroviral treatment lost-to-follow-up in an urban slum in India

errol l., isaakidis p., zachariah r., ali m., pilankar g., maurya s., geraets c., ladomirska j., patel s. & reid t. (2012)?Tracing patients on antiretroviral treatment lost-to-follow-up in an urban slum in India. Journal of Advanced Nursing68(11), 2399-2409. ABSTRACT: Aim. This article describes a cooperative initiative between an HIV-clinic and non-government organization network providing lost-to-follow-up tracing and delayed appointment follow-up of patients on antiretroviral treatment. Background. Loss-to-follow-up among patients on antiretroviral treatment is a major challenge in resource-constrained settings. A model of cooperation between a Médecins Sans Frontières HIV-clinic and a non-governmental-organization network was piloted in a Mumbai slum. A steady decline in delayed appointments and loss-to-follow-up was observed over 4 years. Design. Mixed method study. Methods. A study conducted in January 2011 explored potential reasons for declining loss-to-follow-up-rates. A retrospective, quantitative analysis of patient data was undertaken complemented by 22 semi-structured interviews, four focus-group discussions to explore patients' and providers' perceptions of tracing activities. Results/findings. The clinic loss-to-follow-up-rate has steadily declined from mid-2008-2011. Thirty-eight (4·6%) of 819 patients registered during the period were lost-to-follow-up with most lost during the first year. Rates of loss-to-follow-up between 0·3-2·4% were observed over the last 2?years. Phoning the day before an appointment was perceived as the most useful intervention to avoid missing appointments. The analysis revealed a widespread fear of forced disclosure by patients during home visits. Conclusions. The low loss-to-follow-up-rate cannot be attributed to the network tracing activities alone. Phoning before appointments may result in fewer delayed appointments and prevent loss-to-follow-up. Home visits should be a last resort method of patient tracing because of the risk of HIV-status disclosure and the opportunity of discrimination from family and neighbours.     

Structured oral examination in pharmacology for undergraduate medical students: Factors influencing its implementation

Objectives:

The study aims to understand the process and factors influencing the implementation of structured oral examination (SOE) for undergraduate medical students; in comparison with conventional oral examination (COE) in pharmacology.

Methods:

In a randomized, parallel group study, 123 students of pharmacology were divided into two groups, SOE (n = 63) and COE (n = 60). Students of each group were subdivided into two, and four examiners took viva voce individually. Three sets of questionnaires from autonomic nervous system were prepared, each having 15 items with increasing difficulty levels and were validated by subject experts and pretested. Ten minutes were allotted for each student for each viva. Feedback of students and faculty about the novel method was obtained.

Results:

SOE yielded significantly lower marks as compared to COE. There were significant inter-examiner variations in marks awarded in SOE and COE. Other factors influencing implementation were difficulty in structuring viva, rigid time limits, lack of flexibility in knowledge content, monotony, and fatigue. The students perceived this format not different from COE but felt that it required in-depth preparation of topic. Faculty opined that SOE led to less drift from main topic and provided uniform coverage of topics in given time.

Conclusion:

Conducting SOE is a resource-intensive exercise. Despite structuring, inter-examiner variability was not completely eliminated. The students’ performance was depended on factors related to examiners such as teaching experience, vernacular language used, and lack of training. Orientation and training of examiners in assessment strategies is necessary. Standardization of questionnaire is necessary before the implementation of SOE for summative assessment.KEY WORDS: Objectivity, pharmacology, reliability, structured oral examination, validity, viva voce     

Evidence of carrier mediated transport of ascorbic acid through mammalian cornea

The purpose of the present study was to evaluate the transport of ascorbic acid, a water soluble molecule, through a predominantly lipophilic cornea. Thus in-vitro permeation of ascorbic acid from aqueous drops through freshly excised mammalian cornea was studied. Aqueous isotonic ophthalmic solutions of ascorbic acid of different concentrations (0.125% w/v to 2% w/v) (pH 5.4) were made. Further 1.0% w/v or 0.5% w/v ascorbic acid solution containing NaCl or dextrose as tonicity modifiers or Na⁺K⁺-ATPase inhibitors were also made. Permeation characteristics of drug were evaluated by putting 1 ml formulation on freshly excised cornea fixed between donor and receptor compartments of an all-glass modified Franz diffusion cell and measuring the drug permeated in the receptor by spectrophotometry at 265 nm, after 120 min. Statistical analysis was done by one-way analysis of variance (ANOVA) followed by Dunnett’s test or paired t-test. Increase in drug concentration in the formulation resulted in an increase in the quantity permeated but after a certain level increase in permeation with increase in concentration was minimal. Aqueous drops made isotonic with dextrose showed decreased permeation through paired cornea compared with aqueous drops made isotonic with NaCl from 1% w/v ascorbic acid solution suggesting likely involvement of Na⁺ co-transporter but there was decreased permeation through 0.5% w/v ascorbic acid solution made isotonic with NaCl as compared to solution made isotonic with dextrose. Further aqueous drops containing Na⁺K⁺-ATPase inhibitor {MAG-Mono Ammonium Glycyrrhizinate (25 μmol)} showed decreased corneal permeation from 0.5% w/v ascorbic acid solution but there was not significant decrease from 1% ascorbic acid solution since MAG is a competitive inhibitor of ascorbic acid. Aqueous drops containing Na⁺K⁺-ATPase inhibitor {MAG (50 μmol) or Ouabain (1 mmol)} showed decreased corneal permeation of ascorbic acid compared with control from 1% ascorbic acid solution confirming the involvement of Na⁺ co-transporter.     

Impact of injection frequency on 5-year real-world visual acuity outcomes of aflibercept therapy for neovascular age-related macular degeneration

BackgroundTo evaluate the impact of injection frequency on yearly visual outcomes of patients treated with intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) over a period of 5 years in a tertiary ophthalmic centre.DesignSingle centre, retrospective cohort study.ParticipantsConsecutive treatment-naive nAMD patients initiated on aflibercept injections 5 years ago.MethodsThe Moorfields OpenEyes database was searched for consecutive patients who were initiated on intravitreal aflibercept for nAMD in 2013–14 and the visual acuity (VA) in Early Diabetic Retinopathy Study (ETDRS) letters and injection records per year were recorded for a period of 5 years. Analyses of the whole cohort and a sub-sample of 5-year completers were done. The cohort was further grouped into Group A (on continuous treatment), Group B (early cessation of treatment) and Group C (interrupted treatment) to evaluate the relation between treatment frequency and visual outcomes.Main outcome measuresThe primary end point was change in VA at 5 years; secondary outcomes included proportion of eyes that gained or maintained VA, number of injections received and the effect of treatment frequency.ResultsData were collected on 468 patients (512 eyes). Sixty-six percent of the patients completed 5-year follow-up. The mean age of the whole cohort was 79.5 ± 8.5 years and the mean baseline VA was 58.3 ± 15.4 letters. Amongst the completers, final VA change was −2.9 (SD 23.4) ETDRS letters and the cumulative number of injections over 5 years was 24.2 (10.6). Group A had three letter gain and received significantly higher cumulative number of injections over 5 years than Group B and C (31.8, 14.6 and 18.4 respectively, p = 0.001). After adjusting for age and baseline VA, on average, final VA was +8.0 letters higher in the ≥20 injections group than the <20 group (p = 0.001).ConclusionsAflibercept therapy results in sustained good visual outcome over 5 years in neovascular AMD eyes when early and persistent treatment is given.Subject terms: Macular degeneration, Vision disorders