Cardiovascular adverse events of antineoplastic monoclonal antibodies among cancer patients: real-world evidence from a tertiary healthcare system.

BACKGROUND: Antineoplastic monoclonal antibodies (mAbs), such as trastuzumab, bevacizumab, and pertuzumab have been the mainstay of therapy in cancer patients. Despite proven efficacy of the monoclonal antibodies, cardiovascular-induced adverse events such as heart failure, hypertension, ischemic heart disease, arrhythmias, thromboembolic events, and hemorrhage remain a major complication. The European society of cardiology address that concern with antineoplastic monoclonal antibodies issuing a guideline to manage and monitor chemotherapy-induced cardiotoxicity. There is limited evidence of the real-world prevalence of cardiovascular (CV) events induced by monoclonal antibodies among patients with cancer in Saudi Arabia. OBJECTIVE: To evaluate the prevalence of cardiovascular adverse events among patients with cancer treated with monoclonal antibodies in Saudi Arabia. METHODS: This is a retrospective study conducted in a tertiary care hospital, Riyadh, Saudi Arabia. Data were obtained from an electronic medical record of patients with cancer treated with one of the selected monoclonal antibodies, who met the inclusion criteria between January 2005 until June 2015 and have been followed up for at least one year. Patients were stratified into groups according to monoclonal antibodies treatment: trastuzumab, bevacizumab, pertuzumab, and combined mAbs. RESULTS: A total of 1067 patient were included in the study, within the pre-determined study period. The prevalence of cardiovascular disease among patients with cancer treated with monoclonal antibodies was 16.3%. The prevalence of heart failure was relatively higher in the trastuzumab group (46/626 patients, 7.3%). Among 418 patients treated with bevacizumab, hypertension was the most frequent adverse event, reported in 38 patients (9.1%), followed by thromboembolism reported in 27 patients (6.5%). Treatment discontinuation owing to cardiovascular adverse events was reported in 42/1,067 patients (3.9%). CONCLUSION AND RELEVANCE: Prevalence of antineoplastic monoclonal antibody induced cardiovascular adverse events among patients with cancer is substantially high in Saudi Arabia. There is an urgent need to streamline the practice for identifying high risk patients and flexible referral system for cardio-oncology care.

Effects of potassium channel modulators on the responses of mammalian slowly adapting mechanoreceptors.

Introduction: slowly adapting mechanoreceptors in the skin provide vital tactile information to animals. The ionic channels that underlie their functioning is the subject of intense research. Previous work suggests that potassium channels may play particular roles in the activation and firing of these mechanoreceptors. Objective: We used a range of potassium channel blockers and openers to observe their effects on different phases of mechanoreceptor responses. Methods: Extracellular recording of neural activity of slowly adapting mechanoreceptors was carried out in an in vitro preparation of the sinus hair follicles taken from rat whisker pads. A range of potassium (K+) channel modulators were tested on these mechanoreceptor responses. The channel blockers tested were: tetraethylammonium (TEA), barium chloride (BaCl2), dequalinium, 4-aminopyridine (4-AP), paxilline, XE 991, apamin, and charybdotoxin. Results: Except for charybdotoxin and apamin, these drugs increased the activity of both types of slowly adapting units, St I and St II. Generally, both spontaneous and evoked (dynamic and static) activities increased. The channel opener NS1619 was also tested. NS1619 clearly decreased evoked activity (both dynamic and static) while leaving spontaneous activity relatively unaffected, with no clear discrimination of effects on the two types of St receptor. Conclusion: These findings are consistent with the targets of the drugs suggesting that K+ channels play an important role in the maintenance of spontaneous firing and in the production of and persistence of mechanoreceptor activity.

Effects of camphor and related compounds on slowly adapting mechanoreceptors in the rat sinus hair follicle.

Introduction: Camphor is a popular compound for therapeutic and cosmetic use with a distinctive odour, and somatosensory warming and cooling properties. The mechanisms for its action remain unclear. Objective: The current study examined the effects of two enantiomers of camphor and related monoterpenoid compounds on mechanoreceptors. Methods: Extracellular recordings were made in an in vitro bath preparation. Camphor, borneol, eugenol, carveol, and thymol were tested on the neural activity of St I and St II slowly adapting mechanoreceptors in the rat vibrissal hair follicle preparation. Results: All compounds tested (0.5 - 2 mM bath concentrations) resulted in dose-dependent depression of spontaneous and mechanically evoked firing (dynamic and static phases). The mean latency of responses also increased. Both St I and St II were similarly affected, although (-)-camphor had a greater depressant effect on St II than on St I units. Differences were found across the different compounds for their effect on the dynamic and static phases. Thymol was found to have the greatest depressant effect on these phases. The broad spectrum TRP blocker ruthenium red did not reverse the depressant effects of camphor. The depressant effects of the compounds appeared similar to those obtained using the local anaesthetic lignocaine. The depressant effects of camphor and of lignocaine were partially reversed by the K+ channel blocker tetraethylammonium. Conclusions: The results question whether the depressant effects of camphor and related compounds act through TRP channels. Perhaps the use of more selective blockers may reveal the molecular mechanisms through which these compounds act.

Evaluation of COVID-19 myths in Saudi Arabia.

OBJECTIVES: To examine the awareness level of COVID-19 and to highlight the frequency of myths and misconceptions among Saudi Arabia's population. METHODS: We conducted a cross-sectional study from June 13 to 20, 2020 by distributing a 16-item online Google forms questionnaire among adults (18-65 years old) living in Saudi Arabia. We utilized the convenience sampling. Data analysis was performed using Chi-square and multiple regression analysis on Jamovi. RESULTS: A total of 1436 responses were analyzed with 43.5% males and 56.5% females. Most respondents (89.1%) thought that only the elderly above 60 years old are considered at high risk of contracting COVID-19. Most respondents (86.5%) agreed that people with other health conditions could be more affected by COVID-19. Approximately 97.2% agreed that wearing a mask and avoiding touching eyes, nose, and mouth with unwashed hands was the leading preventive action. Most participants (99.4%) chose fever as an associated symptom. Respondents from the healthcare sector presented statistically higher scores than those in non-healthcare sectors (p<0.001). Higher education and higher salary were important predictors of better COVID-19 knowledge. CONCLUSION: Public health officials need to increase awareness measures on COVID-19 to limit myths and misconceptions and reduce psychological distress associated with it.

Does Hyaluronidase Enhance Drug Penetration to Mechanoreceptors?

BACKGROUND: The pharmacological study of mechanoreceptors embedded within tissue is hampered by tissue barriers to applied research drugs. METHODS: Hyaluronidase increases the permeability of tissues and is used clinically to facilitate the distribution of injected drugs. An in vitro rat sinus hair preparation was used to determine whether hyaluronidase (1,500 or 3,000 IU/10 mL) had an effect on drug access to receptor sites on slowly adapting St I and St II mechanoreceptors. Electrical recordings were made from single mechanoreceptor units that were activated by trapezoid ramp stimuli. Cinnamaldehyde (500-1,500 µM) and capsazepine (100 µM) were used as test drugs. Changes in onset time and degree of depression of firing due to test drugs were compared to control experiments not employing hyaluronidase. RESULTS: There were no statistical effects on any of the observed measures. Often the effects were opposite to those predicted. Using a likelihood approach, it was calculated that there was strong evidence (log-likelihood ratios from -0.5 to -6.5) to support a null effect over a facilitatory effect. There was no evidence of loss of integrity of mechanoreceptor mechanotransduction mechanisms following hyaluronidase applications. Comparison with Existing Method: The use of hyaluronidase does not facilitate drug access to receptors. CONCLUSIONS: In the in vitro sinus hair preparation, the addition of hyaluronidase does not allow easier access to slowly adapting mechanoreceptors within the follicle.

Comparative Analysis of Prescription Drug Prices in South Asian Association for Regional Cooperation Countries.

OBJECTIVES: The SAARC (South Asian Association for Regional Cooperation) is a geopolitical organization composed of 8 neighboring countries: Afghanistan, Bangladesh, Bhutan, India, the Maldives, Nepal, Pakistan, and Sri Lanka. The objective of this study was to compare the prices of some selected drugs in SAARC countries. METHODS: A list of 24 drugs was prepared based on certain inclusion and exclusion criteria. The retail prices of the drugs were determined from different sources and verified manually in the open market. The prices obtained in local currencies were converted into US dollars for comparison purposes. In another analysis, the gross domestic product (GDP) of each country was factored for comparative analysis. RESULTS: Out of the 23 drugs, 17 comparisons across countries were statistically different at P < .05. These analyses revealed large differences in drug prices among SAARC countries. The GDP-adjusted median drug prices revealed a more polarized picture, with Nepal generally having the highest prices (19 out of 24 drugs) and Sri Lanka having the lowest (19 out of 24 drugs). For example, the widely used antipsychotic drug risperidone was 7 times more expensive in Pakistan ($0.316) compared with Sri Lanka ($0.045). Adjusting for GDP made risperidone more than 18 times more expensive ($21.90 and $1.20) across the same 2 countries. CONCLUSION: Prices of selected drugs varied markedly in SAARC countries. After adjusting for GDP, drug prices became more polarized across countries, with Nepal featuring the highest prices. In determining drug prices, the country's GDP and the population's purchasing power need to be taken into account.

Selective decline in the prevalence of slowly adapting type I mechanoreceptors during development.

Merkel nerve endings are identified physiologically as slowly adapting type I mechanoreceptor units. They are important for fine acuity tactile perception. We examined the effect of age on the electrophysiological availability of different types of slowly adapting mechanoreceptor units. Using 6-50 week old rats, we observed an obvious decline with age in the probability of recording from St I units of the deep vibrissal nerve. The precipitous decline occurred between ages 6-14 weeks and then stabilized. By contrast, the prevalence of St II units, the other type of slowly adapting mechanoreceptor, remained constant over the age range studied. These observations correlate with anatomical findings reported elsewhere.

Use of beta blockers is associated with hearing loss.

OBJECTIVE: This study was conducted to investigate the hypothesis that patients using ß-blockers will develop hearing loss. DESIGN: A cross-sectional study. STUDY SAMPLE: A total of 125 patients completed the study. A total of 63 patients were on ß-blockers and 62 were not on ß-blockers. RESULTS: Carvedilol was significantly associated with hearing loss. Other beta-blockers including metoprolol and atenolol showed no association with hearing loss. Linear multiple regression analysis was run including variables of gender, age, ischaemic heart disease, cardiac failure/dilated cardiomyopathy, frusemide and carvedilol use as predictors for total hearing loss severity at all frequencies. Age and gender, as well as carvedilol, were found to be the only statistically significant predictors for hearing loss severity. CONCLUSION: Chronic use of carvedilol was associated with significant hearing loss. This may need to be taken into account when prescribing the drug. Further randomised controlled studies with baseline audiometric hearing tests before starting treatment, and periodic follow-up tests, would provide a better assessment of the effect of carvedilol on hearing.

Combined Recording of Mechanically Stimulated Afferent Output and Nerve Terminal Labelling in Mouse Hair Follicle Lanceolate Endings.

A novel dissection and recording technique is described for monitoring afferent firing evoked by mechanical displacement of hairs in the mouse pinna. The technique is very cost-effective and easily undertaken with materials commonly found in most electrophysiology laboratories, or easily purchased. The dissection is simple and fast, with the mechanical displacement provided by a generic electroceramic wafer controlled by proprietary software. The same software also records and analyses the electroneurogram output. The recording of the evoked nerve activity is through a commercial differential amplifier connected to fire-polished standard glass microelectrodes. Helpful tips are given for improving the quality of the preparation, the stimulation and the recording conditions to optimize recording quality. The system is suitable for assaying the electrophysiological and optical properties of lanceolate terminals of palisade endings of hair follicles, as well as the outcomes from their pharmacological and/or genetic manipulation. An example of combining electrical recording with mechanical stimulation and labeling with a styryl pyridinium vital dye is given.

Glutamatergic modulation of synaptic-like vesicle recycling in mechanosensory lanceolate nerve terminals of mammalian hair follicles.

Our aim in the present study was to determine whether a glutamatergic modulatory system involving synaptic-like vesicles (SLVs) is present in the lanceolate ending of the mouse and rat hair follicle and, if so, to assess its similarity to that of the rat muscle spindle annulospiral ending we have described previously. Both types of endings are formed by the peripheral sensory terminals of primary mechanosensory dorsal root ganglion cells, so the presence of such a system in the lanceolate ending would provide support for our hypothesis that it is a general property of fundamental importance to the regulation of the responsiveness of the broad class of primary mechanosensory endings. We show not only that an SLV-based system is present in lanceolate endings, but also that there are clear parallels between its operation in the two types of mechanosensory endings. In particular, we demonstrate that, as in the muscle spindle: (i) FM1-43 labels the sensory terminals of the lanceolate ending, rather than the closely associated accessory (glial) cells; (ii) the dye enters and leaves the terminals primarily by SLV recycling; (iii) the dye does not block the electrical response to mechanical stimulation, in contrast to its effect on the hair cell and dorsal root ganglion cells in culture; (iv) SLV recycling is Ca(2+) sensitive; and (v) the sensory terminals are enriched in glutamate. Thus, in the lanceolate sensory ending SLV recycling is itself regulated, at least in part, by glutamate acting through a phospholipase D-coupled metabotropic glutamate receptor.

Effects of transient receptor potential (TRP) channel agonists and antagonists on slowly adapting type II mechanoreceptors in the rat sinus hair follicle.

The possible functional role of transient receptor potential (TRP) channels was investigated by testing various TRP agonists and antagonists in an isolated rat sinus hair follicle preparation. Extracellular recordings from slowly adapting type II mechanoreceptor units were made. The antagonist capsazepine depressed spontaneous and mechanically evoked activity, with an IC(50) of 82 microM. In one-third of units, capsazepine caused a selective depression of mechanically evoked firing, such that the existing spontaneous firing was interrupted by an absence of activity during the mechanical stimulus. The broad spectrum TRP blocker ruthenium red (30 microM) had inconsistent effects, although in some units a delayed onset (following wash) bursting and paroxysmal firing ensued. The agonist icilin (50-100 microM) had an excitatory effect on spontaneous firing, and (-)-menthol (200 microM) had inconsistent effects. Cinnamaldehyde (1-2 mM) depressed all types of activity equally, mechanically evoked and spontaneous. Camphor (0.5-2 mM) also depressed all types of activity, although it had a preferential effect on spontaneous activity. Capsaicin (1-10 microM) and allyl isothiocyanate (50-100 microM) had no clear effects. These results rule out any role for TRPA1 and TRPV1 channels in mechanotransduction processes of slowly adapting type II mechanoreceptors.

Behavioural lateralization of tactile performance in the rat.

Ten rats were assessed for behavioural lateralization using two different tests: paw preference and tail-suspension test. It was found that animals, at an individual level, tended to have a behavioural preference which was polarized either to the left side or the right side. Animals were then randomly assigned to two groups. One group had whiskers trimmed ipsilateral, and the other group had whisker trimmed contralateral, to their lateralized behavioural preference. Over 10 days the rats were trained on a roughness discrimination task. It was found that animals with whiskers trimmed on the contralateral side performed better (p<.05) than those with whiskers trimmed on the ipsilateral side. This finding was associated with a large effect size (partial eta(2)) of .474. The side of whisker trimming (right versus left) per se had no effect on performance (p=.26). These results indicate that motor lateralization at the individual level is associated with lateralization in the efficacy of whisker use.

Enhanced short-latency responses in the ventral posterior medial (VPM) thalamic nucleus following whisker trimming in the adult rat.

This study examined the effects of whisker trimming on the functional organization of the adult somatosensory thalamus. In vivo extracellular unit recordings were made on ventral posterior medial (VPM) thalamic neurons in urethane anaesthetised adult rats. Neuronal response properties to controlled whisker deflection were recorded in untrimmed control animals and in animals where one row of whiskers had been trimmed for a median of 18 days. Trimming significantly increased short-latency responses to stimulation of the centre receptive field whisker (mean increase of 36%, p<.001). Longer latency responses to surround receptive field whiskers were unaffected. Spontaneous firing was significantly decreased in trimmed animals. A condition-test paradigm indicated that thalamic inhibition was reduced following whisker trimming, although this effect failed to reach statistical significance. These results demonstrate a capacity of the adult somatosensory thalamus to undergo functional reorganization in response to non-traumatic and innocuous whisker trimming.

Decreased sensitivity to self-inflicted pain.

There is anecdotal and incidental research evidence suggesting that self-inflicted injury is experienced as less painful than when the same injury is applied by another person. We tested the hypothesis that the sensitivity and the ability to tolerate pain differs depending on the person applying the painful stimulus. Self-selected healthy undergraduate students were obtained from the University of Stirling participant panel. None were suffering chronic pain or taking any form of analgesic drug. The participants applied a pressure algometer to themselves and to other participants. Depending on the type of trial, each was terminated when the participant experienced the algometer as either "painful" (for threshold reading) or "unbearable" (for tolerance reading). Both measures of pain, threshold and tolerance, were significantly higher when the algometer had been self-applied compared with when it was applied by another person. The mean difference for pain thresholds was 0.27MPa (95% confidence interval 0.10-0.44, P=0.002), and the mean difference for pain tolerance readings was 0.25MPa (95% confidence interval 0.03-0.48, P=0.028). An unexpected finding was that the mean tolerance score was less when females applied the algometer (P<0.01). When a painful stimulus was self-inflicted this resulted in significantly less pain and a greater ability to tolerate the pain compared with when the same stimulus was applied by another person. If the findings generalized to a clinical context, certain painful or discomforting procedures, such as mammography, removal of wound dressings and lancet withdrawal of blood, should be adapted for self-application by patients.

Metabotropic glutamate receptor antagonists selectively enhance responses of slowly adapting type I mechanoreceptors.

There is evidence that glutamate may participate as a transmitter at the junction between Merkel cells and the nerve terminals of slowly adapting type I (St I) units. We recorded extracellularly from the deep vibrissal nerve of an isolated rat vibrissa preparation in vitro. Five second trapezoid stimulus ramp deflections of the hair shaft were used to evoke responses. We bath-applied two compounds, which we planned would interfere with glutamatergic transmission. (2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495) was used at concentrations up to 100 microM to block all known metabotropic glutamate (mGlu) receptors. The racemic mixture (RS)-4-carboxy-3-hydroxyphenylglycine ((RS)-4C3HPG) was used up to 100 microM to block ionotropic and Group I metabotropic glutamate receptors, and as an agonist at Group II mGlu receptors. Unexpectedly, both compounds had rapid onset excitatory effects on mechanically-evoked responses. (RS)-4C3HPG increased responses, with a mean 146% of control (P < 0.05) in a concentration-dependent manner. LY341495 increased responses, with a mean 128% of control (P < 0.05). With (RS)-4C3HPG in particular, it was noted that the static component (the firing during the last 1 s plateau) was preferentially enhanced relative to the dynamic component (firing during the first 0.5 s). Rapid recovery was seen after wash. Slowly adapting type II units, which have no junctional transmission, were completely unaffected by these compounds up to 200 microM. These results suggest that mGlu receptors play a role in Merkel cell-neurite complex mechanotransduction, although other explanations are considered.

Essential components for a glutamatergic synapse between Merkel cell and nerve terminal in rats.

The exact role of Merkel cells and their possible involvement in mechanosensation is unclear. The aim of this study was to determine, in the adult rat sinus hair follicle, the expression pattern of a number of vesicular proteins involved in neurotransmitter release to provide a clearer understanding of Merkel cell signalling mechanisms. We identified prominent expression and co-localization of the glutamatergic vesicle loading proteins VGLUT1 and VGLUT2 at the site of the sinus hair follicle known to be densely populated with Merkel cells. We also found expression of the vesicle recycling proteins synaptogyrin and syntaxin-6 in the same region of the hair follicle. Our data suggest that glutamate signalling is involved in Merkel cell mechanosensation and that vesicular trafficking is commonplace in the Merkel cell-neurite complex.