Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease.

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.

Pilot investigation of the effect of carvedilol on stress-precipitated smoking-lapse behavior.

INTRODUCTION: Separate α1- and ß-adrenergic antagonists have shown efficacy in reducing nicotine-motivated behaviors in rodents and humans, supporting a role for the noradrenergic system in mediating the reinforcing properties of drugs of abuse. However, the effect of the combined α1- and ß-adrenergic antagonist, carvedilol, on stress-related smoking is unknown. METHODS: Using a well-established human laboratory model of stress-precipitated smoking-lapse behavior, we examined whether carvedilol (0 or 50 mg/day; between subject, n=17 per group), administered to steady-state, would attenuate the ability to resist smoking following stress imagery (vs. neutral imagery) and reduce subsequent smoking self-administration in nicotine-deprived smokers ( n = 34 total). Tobacco craving, withdrawal, and physiologic reactivity were also assessed. RESULTS: Latency to start smoking and number of cigarettes smoked during the self-administration period did not differ by medication condition. Counter to our hypothesis, tobacco craving demonstrated a medication × time effect, with greater craving in the carvedilol condition. Systolic blood pressure and heart rate demonstrated lower values in the carvedilol versus placebo group, consistent with known effects of carvedilol. CONCLUSION: While carvedilol attenuated physiologic reactivity consistent with its clinical indication, beneficial effects on smoking outcomes were absent in this preliminary investigation and may suggest possible worsening. Future work may benefit from discerning the single versus combined effects of α1- and ß-adrenergic antagonism on smoking outcomes.

The effect of labetalol and nifedipine MR on blood pressure in women with chronic hypertension in pregnancy.

AIM: To compare the blood pressure (BP) lowering effects of labetalol and nifedipine modified release (MR) in hypertensive pregnant women. We also investigated the effect on the heart rate (HR) and determined the proportion of time spent in target. METHODS: This was an exploratory study. Women with chronic hypertension taking either labetalol or nifedipine were offered 24-h ambulatory blood pressure monitoring (ABPM). Sleep, wake and drug ingestion times were self-reported. An indirect response model was used to analyse the systolic BP (SBP), diastolic BP (DBP) and HR time-series; the effect of gestation and type of drug was evaluated. RESULTS: Forty-eight women were recruited: 24 in each group. There was no difference in clinical characteristics. In women taking nifedipine there was a positive association between the dose of nifedipine and pre-dose BP p = .002, this was not present in the labetalol group. There was a difference between the drug effects on both the SBP and DBP time-series (p = .014). In comparison to labetalol, there was less variation in day time BP in those women prescribed nifedipine. Women on labetalol spent a larger proportion of time with their DBP below target (<80 mmHg). The HR dynamics were qualitatively different, a stimulatory effect was found with nifedipine compared to an inhibitory effect with labetalol. CONCLUSION: There are significant and important differences between the BP lowering effects of nifedipine and labetalol. A large randomised control trial is required to investigate the relationship between BP variability and time in target on pregnancy outcomes.

Analgesic and anti-inflammatory effects of honey: the involvement of autonomic receptors.

The use of honey for therapeutic purposes is on the increase and many studies have shown that honey has the ability to influence biological systems including pain transmission. Therefore, this study was designed to investigate the analgesic and anti-inflammatory effects of honey and the effects of concurrent administration of autonomic nervous system blocking drugs. Studies on analgesic activities was carried out using hotplate and formalin-induced paw licking models while the anti-inflammatory activity was by the carrageenan paw oedema method. Animals were distributed into six groups consisting of five animals each. They were administered saline, honey (600 mg/kg), indomethacin (5 mg/kg), autonomic blockers (3 µg/kg of tamsulosin, 20 mg/kg (intraperitoneally) of propranolol, 2 ml/kg of atropine or 10 mg/kg (intra muscularly) of hexamethonium) or honey (200 and 600 mg/kg) with one of the blockers. The results showed that honey reduced pain perception especially inflammatory pain and the administration of tamsulosin and propranolol spared the effect of honey. Hexamethonium also spared the effects of honey at the early and late phases of the test while atropine only inhibited the early phase of the test. However, atropine and hexamethonium spared the anti-inflammatory effects of honey but tamsulosin abolished the effects while propranolol only abolished the anti-inflammatory effects at the peak of the inflammation. The results suggest the involvement of autonomic receptors in the anti-nociceptive and anti-inflammatory effects of honey although the level of involvement depends on the different types of the receptors.

Risk factors, pathophysiology, and treatment of hot flashes in cancer.

Hot flashes are prevalent and severe symptoms that can interfere with mood, sleep, and quality of life for women and men with cancer. The purpose of this article is to review existing literature on the risk factors, pathophysiology, and treatment of hot flashes in individuals with cancer. Electronic searches were conducted to identify relevant English-language literature published through June 15, 2012. Results indicated that risk factors for hot flashes in cancer include patient-related factors (eg, age, race/ethnicity, educational level, smoking history, cardiovascular risk including body mass index, and genetics) and disease-related factors (eg, cancer diagnosis and dose/type of treatment). In addition, although the pathophysiology of hot flashes has remained elusive, these symptoms are likely attributable to disruptions in thermoregulation and neurochemicals. Therapies that have been offered or tested fall into 4 broad categories: pharmacological, nutraceutical, surgical, and complementary/behavioral strategies. The evidence base for this broad range of therapies varies, with some treatments not yet having been fully tested or showing equivocal results. The evidence base surrounding all therapies is evaluated to enhance hot flash treatment decision-making by clinicians and patients.

Administration-time differences in effects of hypertension medications on ambulatory blood pressure regulation.

Specific features of the 24-h blood pressure (BP) pattern are linked to progressive injury of target tissues and risk of cardiovascular disease (CVD) events. Several studies have consistently shown an association between blunted asleep BP decline and risk of fatal and nonfatal CVD events. Thus, there is growing focus on ways to properly control BP during nighttime sleep as well as during daytime activity. One strategy, termed chronotherapy, entails the timing of hypertension medications to endogenous circadian rhythm determinants of the 24-h BP pattern. Significant and clinically meaningful treatment-time differences in the beneficial and/or adverse effects of at least six different classes of hypertension medications, and their combinations, are now known. Generally, calcium channel blockers (CCBs) are more effective with bedtime than morning dosing, and for dihydropyridine derivatives bedtime dosing significantly reduces risk of peripheral edema. The renin-angiotensin-aldosterone system is highly circadian rhythmic and activates during nighttime sleep. Accordingly, evening/bedtime ingestion of the angiotensin-converting enzyme inhibitors (ACEIs) benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril exerts more marked effect on the asleep than awake systolic (SBP) and diastolic (DBP) BP means. Likewise, the bedtime, in comparison with morning, ingestion schedule of the angiotensin-II receptor blockers (ARBs irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with the additional benefit, independent of drug terminal half-life, of converting the 24-h BP profile into a more normal dipping pattern. This is the case also for the bedtime versus upon-awakening regimen of combination ARB-CCB, ACEI-CCB, and ARB-diuretic medications. The chronotherapy of conventional hypertension medications constitutes a new and cost-effective strategy for enhancing the control of daytime and nighttime SBP and DBP levels, normalizing the dipping status of their 24-h patterning, and potentially reducing the risk of CVD events and end-organ injury, for example, of the blood vessels and tissues of the heart, brain, kidney, and retina.

Effectiveness of medical and surgical therapies for lower urinary tract symptoms in the community setting.

UNLABELLED: Study Type - Therapy (outcomes research) Level of Evidence 2c. What's known on the subject? and What does the study add? It is known that benign prostatic hyperplasia is a common condition affecting most men by the age of 80 years. There are multiple treatment options available, including both medical and surgical interventions. However, what is not known is how affective the different types of interventions are in the general population. Previous studies have focused on centre-specific data. What is unique about our study is that it is a prospective cross-section analysis of a community cohort of men. Through this study we were able to assess the outcomes in the general population as opposed to in a high-volume surgical centre. Our findings show that in this community medical management was poor at symptomatic improvement, whereas surgical intervention produced the best improvement. OBJECTIVE: • To describe the use and symptomatic outcomes of different therapies for lower urinary tract symptoms (LUTS) in a community-based population of men followed for 17 years. PATIENTS AND METHODS: • Data from a randomly selected cohort of 2184 men, aged 40-79 years in 1990, from Olmsted County, Minnesota, USA were included in the study. Participants completed a questionnaire similar to the American Urological Association Symptom Index (AUASI) and reported on incontinence. • Men were followed biennially through 2007 (median follow-up: 13.7 years; Q1, Q3: 8.8, 15.7). Medical and surgical treatments for LUTS were reported on biennial questionnaires and abstracted from community medical records. RESULTS: • Overall, 610 (28%) men received medical or surgical therapy for treatment of LUTS. Patients undergoing vaporization and transurethral resection of the prostate (TURP) had the highest pre-intervention AUASI scores (P < 0.001) and the most rapid increase in scores over time (P= 0.002) compared with those treated with medications or no therapy. After intervention, symptom progression slowed in all treatment groups. • However, the greatest improvement in AUASI score (median % change) was observed in the TURP group: -27.45%. The TURP group also reported a significant decrease in incontinence after surgery (% change): TURP: -22.58%. CONCLUSION: • All therapies were effective at slowing the progression of LUTS, but only TURP patients reported a significant decrease in both LUTS and incontinence after therapy.

Description of antihypertensive use in patients with resistant hypertension prescribed four or more agents.

Data describing the use of recommended antihypertensive agents in the resistant hypertension population are limited. Treatment recommendations for resistant hypertension include maximizing diuretic therapy by using chlorthalidone and/or adding an aldosterone antagonist. Additional recommendations include combining antihypertensive agents from different drug classes. This retrospective cohort study describes antihypertensive use in patients with resistant hypertension defined as the concurrent use of ≥4 antihypertensive agents. Claims data from the Medstat MarketScan Commercial Claims and Encounter database were used to identify patients with resistant hypertension based on International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes and National Drug Codes between May 1, 2008 and June 30, 2009. Of the 5 442 410 patients with hypertension in the database, 140 126 met study criteria. The most frequently prescribed antihypertensive classes were angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (96.2%), diuretics (93.2%), calcium channel blockers (83.6%), and ß-blockers (80.0%). Only 3.0% and 5.9% of patients were on chlorthalidone or an aldosterone antagonist, respectively. A total of 15.6% of patients were treated with angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker. Our findings demonstrate that frequently prescribed antihypertensive agents for the treatment of resistant hypertension included guideline-recommended first-line agents. However, evidence-based and recommended agents, such as chlorthalidone and aldosterone antagonists, were underused. Moreover, minimally efficacious combinations, such as an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker, were prescribed at higher rates than evidence-based and recommended agents.

Analgesic mechanism of electroacupuncture in an arthritic pain model of rats: a neurotransmitter study.

PURPOSE: We investigated what kinds of neurotransmitters are related with electroacupuncture (EA) analgesia in an arthritic pain model of rats. MATERIALS AND METHODS: One hundred rats were assigned to six groups: control, EA, opioid, adrenergic, serotonin and dopamine group. A standardized model of inflammatory arthritis was produced by injecting 2% carrageenan into the knee joint cavity. EA was applied to an acupoint for 30 min in all groups except fo the control group. In the opioid, adrenergic, serotonin and dopamine groups, each receptor antagonist was injected intraperitoneally to their respective group before initiating EA. RESULTS: In the opioid receptor antagonist group, adrenergic receptor antagonist group, serotonin receptor antagonist group, dopamine receptor antagonist group and the control group weight-bearing force decreased significantly from 30 min to 180 min after EA in comparison with the EA group. CONCLUSION: The analgesic effects of EA are related to opioid, adrenergic, serotonin and dopamine receptors in an arthritic pain model of rats.

Analgesic Mechanism of Electroacupuncture in an Arthritic Pain Model of Rats: A Neurotransmitter Study

PURPOSE: We investigated what kinds of neurotransmitters are related with electroacupuncture (EA) analgesia in an arthritic pain model of rats. MATERIALS AND METHODS: One hundred rats were assigned to six groups: control, EA, opioid, adrenergic, serotonin and dopamine group. A standardized model of inflammatory arthritis was produced by injecting 2% carrageenan into the knee joint cavity. EA was applied to an acupoint for 30 min in all groups except fo the control group. In the opioid, adrenergic, serotonin and dopamine groups, each receptor antagonist was injected intraperitoneally to their respective group before initiating EA. RESULTS: In the opioid receptor antagonist group, adrenergic receptor antagonist group, serotonin receptor antagonist group, dopamine receptor antagonist group and the control group weight-bearing force decreased significantly from 30 min to 180 min after EA in comparison with the EA group. CONCLUSION: The analgesic effects of EA are related to opioid, adrenergic, serotonin and dopamine receptors in an arthritic pain model of rats.

Observational study: Matricaria chamomilla may improve some symptoms of attention-deficit hyperactivity disorder.

OBJECTIVE: Noradrenaline and serotonin reuptake inhibitors have been proven to be effective in some cases of ADHD. In this open trial, Matricaria chamomilla, a serotonin and noradrealine reuptake inhibitor, actually used as an antidepressant, has been checked for this indication. METHOD: Three 14-16-year-old male psychiatric outpatients, diagnosed with attention-deficit disorder (ADHD) have been rated at baseline and while taking Matricaria chamomilla to determine its efficacy as a treatment for ADHD. Improvement was valuated using comparisons of Conners' parent ratings. RESULTS: Patients' mean scores improved for Conners' hyperactivity, inattention and immaturity factors. CONCLUSIONS: Although the sample size is very small and therefore generalization is very difficult, this observation indicates that Matricaria chamomilla might be a slightly effective treatment also for ADHD.

Additional small amounts of diuretics improve blood pressure control at low cost without disadvantages in blood sugar metabolism.

We evaluated our present treatment of hypertension and sought a way to improve it. We studied 164 of outpatients we treated in 2002. Mean systolic blood pressure (SBP)+/-SD was 142.0+/-11.3, and 56% of patients had SBP over 140 mmHg. We used more diuretics in patients with good control of SBP (19% vs. 7% of patients; p=0.012). After observing our hypertensive patients, we changed our treatment in a goal-oriented manner. Our goal was blood pressure below 140/90 mmHg. We used, in principle, additional small amounts of diuretics for inadequately treated patients. We followed 147 of the 164 patients from 2002 to 2006. During this period, mean SBP decreased to 134.7+/-9.1 mmHg (p<0.001), and the frequency of patients with SBP>140 mmHg decreased to 14% (p<0.001). We used more diuretics in 2006 than in 2002 (12% to 46% p<0.001). To estimate the risks and benefits of diuretics, in 2006 we analyzed 510 patients who had been followed for at least 2 years. Potassium supplementation was needed in 28% of diuretic-treated patients and 7% of patients without diuretics. We found a correlation between the use of diuretics and good SBP control in the entire patient group as well as in patients with diabetes. In the control of diabetes mellitus, we found no statistical difference between patients treated with diuretics and those not. We found diuretics had no adverse effects with respect to new-onset diabetes mellitus.

Myth: nephrolithiasis and medical expulsive therapy.

There is a medical myth that ureteral stones larger than 5 mm will not pass spontaneously and require urological intervention for removal. Recent findings indicate that medical expulsive therapy can facilitate spontaneous passage for stones up to 10 mm. For the management of ureteral stones, we recommend administering tamsulosin and a corticosteroid (deflazacort or prednisone) along with the standard therapy of analgesics, antibiotics and hydration.

Treatment options for patients with suboptimal response to surgery for stress urinary incontinence.

BACKGROUND: Many women with stress urinary incontinence (SUI) undergo surgery to relieve their symptoms. Currently, tension-free vaginal tape or transobturator tape sling procedures are the surgical treatments of choice. Although these procedures are often successful, a growing number of women experience suboptimal results ranging from improvement without cure to postoperative failure. Follow-up surgery often improves residual or recurrent symptoms but generally carries lower success rates and higher complication risks. Additionally, many women with suboptimal results are reluctant to undergo further surgery. SCOPE: A PubMed literature search for studies of SUI treatment options published from 1986 to 2006 was performed. FINDINGS: The literature revealed a gap in published studies addressing non-surgical options for patients with failed SUI surgeries. Studies of non-surgical treatments for SUI often exclude women who have had prior surgeries, or do not analyze this subgroup. It is, therefore, difficult to assess non-surgical treatment options for women with failed surgeries. Women whose residual or recurring SUI is attributable to intrinsic sphincter deficiency may instead elect the injection of a bulking agent. Bulking agents are associated with a low rate of complications but frequently require several injections to be successful. Women experiencing suboptimal surgical results whose SUI is attributable to hypermobility may select a new non-surgical treatment, radiofrequency collagen denaturation. This non-invasive procedure has also demonstrated a low rate of complications. CONCLUSIONS: Considering the effect of SUI symptoms on women's quality of life, and with more women experiencing suboptimal results after surgery for SUI, it is important to assess alternatives to further surgery.

Blood pressure management during acute ischaemic stroke.

Control of hypertension is a well-established goal of primary stroke prevention. Management of blood pressure in patients during acute ischaemic stroke, however, is complicated by the need to maintain brain perfusion. Lowering blood pressure in the acute setting may avoid the deleterious effects of high blood pressure but may also lead to cerebral hypoperfusion and worsening of the ischaemic stroke. Little information is available from clinical trials concerning optimal blood pressure management in acute stroke. Current protocols of thrombolytic therapy require strict blood pressure control below certain prescribed limits; however, in most acute stroke patients not treated with thrombolysis, blood pressure reduction is not routinely recommended and guidelines for target blood pressures are difficult to justify. Preliminary studies, in fact, suggest that there may be a role for blood pressure elevation in the treatment of some patients with acute ischaemic stroke.

Tratamiento de la hiperplasia prostática benigna / Treatment of benign prostatic hyperplasia

En el campo de la Urología, una de las causas més frecuentes de consulta la constituye la patología prostática y dentro de ésta, la hiperplasia benigna de la próstata. Esta consiste en un incremento de células en el área periuretral prostática, lo que puede ser debido a una proliferación celular aumentada, a una alteración de la apoptosis, o a una combinación de ambos mecanismos. Entre las principales opciones terapÚuticas actuales para la hiperplasia prostática benigna están: - Tratamiento quirúrgico, que continua siendo la principal alternativa de terapia, representado principalmente por la resección transuretral. Tratamiento farmacológico, utilizado como alternativa y/o complemento a la cirugía y representado por dos grandes grupos de fármacos: los antagonistas adrenÚrgicos y la terapia endocronológica (finasteride). El presente trabajo es una revisión bibliográfica actualizada sobre las distintas opciones de tratamiento disponibles para la hiperplasia prostática benigna y sus respectivas indicaciones.

Innovative drug treatments for viral and autoimmune myocarditis.

Myocarditis has been shown to be a common cause of cardiomyopathy and is believed to account for 25% of all cases in human beings. Unfortunately, the disease is difficult to detect before a myopathic process ensues. Treatment of myocarditis-induced heart failure includes the standard regimen of diuretics, digoxin, angiotensin-converting enzyme inhibitors, and currently, beta-adrenergic blockers. Treatment of myocarditis itself is dependent on the etiology of the illness. Treatments under investigation include immunosuppressants, nonsteroidal antiinflammatory agents, immunoglobulins, immunomodulation, antiadrenergics, calcium-channel blockers, angiotensin-converting enzyme inhibitors, nitric oxide inhibition (e.g., aminoguanidine), and antiviral agents. Despite advances in treatment, more work needs to be done in the early detection of myocarditis. Additionally, better means need to be established for distinguishing between viral and autoimmune forms of the disease, so that appropriate treatment can be instituted.

Cardiovascular activity of A-74283, a 5-hydroxytryptamine 1A agent, in the spontaneously hypertensive rat.

A-74283, (+,-)trans-2-(4-(3a,4,4a,6a,7,7a-hexahydro-4,7-etheno-1 H cyclobut [f] isoindol-1,3-dionyl)-butyl)-9-methoxy-2,2,2a,4,5,9b-hexahydr o-1 H-benz[e]isoindol HC1, was studied in receptor binding assays and in the spontaneously hypertensive rat (SHR). In radioligand binding to rat cortex, A-74283 had high affinity (equipotent to 8-OH-DPAT) and high selectivity for 5HT1A receptors compared to 5HT1B sites. In conscious SHR, A-74283 lowered mean arterial pressure (MAP) in a dose-related fashion with a prolonged effect after oral administration of higher doses, but heart rate (HR) was not changed. In anesthetized SHR, i.v. administration of A-74283 decreased MAP and total peripheral resistance, but not cardiac output. Pretreatment of conscious SHR with the selective 5TH1A receptor antagonists spiroxatrine or BMY 7378 reduced the hypotensive effect of A-74283 significantly, but pretreatment with adrenergic antagonists phenoxybenzamine or idazoxan or the 5HT2 receptor blocker ketanserin did not alter the effect of A-74283. Intracisternal administration of A-74283 also decreased MAP; however, A-74283 had no effect on blood pressure in pithed SHR in which blood pressure was supported with vasopressin, in contrast to nitroprusside. These data demonstrate that A-74283 exerts a potent hypotensive effect in SHR via systemic vasodilation originating from a central 5HT1A receptor mechanism. A-74283 may be useful for studying 5HT1A receptors and cardiovascular function.

Drug management of hypertensive disorders of pregnancy.

Drugs used in the acute and long-term management of hypertension in pregnancy and the preeclampsia-eclampsia syndrome have been reviewed and their therapeutic effects and maternal and fetal adverse effects have been considered. The review also focuses on recent developments in the areas of prevention and management of pre-eclampsia-eclampsia syndrome. Although a number of new drugs have emerged, as potentially useful in the management of hypertension in pregnancy and pre-eclampsia-eclampsia syndrome, some remain at the cornerstone of therapy; for example, methyldopa for long-term treatment of chronic hypertension, hydralazine or nifedipine for rapid reduction of severely elevated blood pressure, and magnesium sulphate for eclampsia. Some of these agents, especially the calcium antagonists, show promise in that their use is associated with fewer side effects. Safety for the fetus, however, has not been adequately evaluated yet. Neither aspirin nor calcium supplements appear to improve the outcome in pregnancy. Currently, the dilemma whether to treat hypertension in pregnancy and pre-eclampsia-eclampsia syndrome with old, established, cost-effective drugs or the promising newer drugs provides an interesting academic challenge.