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Background: Propranolol, a non-selective beta-blocker, commonly used to prevent variceal bleed, but might precipitate circulatory dysfunction in severe ascites. Midodrine, an alpha-1 adrenergic agonist improves renal perfusion and systemic hemodynamics. Addition of midodrine might facilitate higher maximum tolerated dose (MTD) of propranolol, thereby less risk of variceal bleed in cirrhosis patients with severe ascites. Methods: 140 patients with cirrhosis and severe/refractory ascites were randomized- propranolol and midodrine (Gr.A,n = 70) or propranolol alone (Gr.B,n = 70). Primary outcome was incidence of bleed at 1 year. Secondary outcomes included ascites control, achievement of target heart rate (THR), HVPG response and adverse effects. Results: Baseline characteristics were comparable between two groups. Cumulative incidence of bleed at 1 year was lower in Gr.A than B (8.5%vs.27.1%,p-0.043). The MTD of propranolol was higher in Gr.A (96.67 ± 36.6 mg vs. 76.52 ± 24.4 mg; p-0.01) and more patients achieved THR (84.2%vs.55.7%,p-0.034). Significantly higher proportion of patients in Gr.A had complete resolution of ascites [17.1%vs.11.4%,p-0.014), diuretic tolerance (80%vs.60%,p-0.047) at higher doses(p-0.02) and lesser need for paracentesis. Patients in Gr.A also had greater reduction in variceal grade (75.7%vs.55.7%;p-0.01), plasma renin activity (54.4% from baseline) (p = 0.02). Mean HVPG reduction was greater in Gr.A than B [4.38 ± 2.81 mmHg(23.5%) vs. 2.61 ± 2.87 mmHg(14.5%),p-0.045]. Complications like post-paracentesis circulatory dysfunction and spontaneous bacterial peritonitis on follow-up were higher in Gr.B than A (22.8%vs.51.4%,p = 0.013 and 10%vs.15.7%, p = 0.03, respectively). Conclusion: Addition of midodrine facilitates effective use of propranolol in higher doses and greater HVPG reduction, thereby preventing first variceal bleed, reduced paracentesis requirements with fewer ascites- related complications in patients with cirrhosis with severe/refractory ascites. [ABSTRACT FROM AUTHOR]

Background: Studies evaluating the role of midodrine as an adjunctive therapy to liberate patients with shock from intravenous (IV) vasopressors have yielded mixed results. The aim of our study was to evaluate the efficacy and safety of midodrine as an adjunctive therapy to liberate patients with shock from IV vasopressors. Methods: Electronic searches of the MEDLINE, EMBASE, and Cochrane databases through April 2022 for randomized controlled trials (RCTs) that evaluated the use of midodrine versus control in patients with shock and a low dose of IV vasopressors. The primary outcome was total IV vasopressor time, while the secondary outcomes included time-to-IV vasopressor discontinuation, IV vasopressor restart, intensive care unit (ICU) length of stay (LOS), hospital LOS, and incidence of bradycardia. Results: The final analysis included four RCTs with a total of 314 patients: 158 in the midodrine group and 156 in the control group, with a weighted mean age of 64 years (54.2% men). There was no significant difference in the total IV vasopressor time between the midodrine and control groups (standardized mean difference [SMD] − 0.53; 95% confidence interval [CI] − 1.38 to 0.32, p = 0.22; I2 = 92%). Also, there were no significant differences between the two groups in the time-to-IV vasopressor discontinuation (SMD − 0.05; 95% CI − 0.57 to 0.47, p = 0.09), IV vasopressor restart (19.3 vs. 28.3%; risk ratio [RR] 0.74; 95% 0.25–2.20, p = 0.59), ICU LOS (SMD − 0.49; 95% CI − 1.30 to 0.33, p = 0.24), and hospital LOS (SMD 0.01; 95% CI − 0.27 to 0.29, p = 0.92). However, compared with the control group, the midodrine group had a higher risk of bradycardia (15.3 vs. 2.1% RR 5.56; 95% CI 1.54–20.05, p = 0.01). Conclusions: Among patients with vasopressor-dependent shock, midodrine was not associated with early liberation of vasopressor support or shorter ICU or hospital length of stay. Adding midodrine increased the risk of bradycardia. Further large RCTs are needed to better evaluate the efficacy and safety of midodrine in liberating patients from IV vasopressors. [ABSTRACT FROM AUTHOR]

Vasovagal syncope (VVS) is the most common cause of transient loss of consciousness. Although not associated with mortality, it causes injuries, reduces quality of life, and is associated with anxiety and depression. The European and North American cardiac societies recently published syncope clinical practice guidelines. Most patients with VVS do well after specialist evaluation, reassurance and education. Adequate hydration, increased salt intake when not contraindicated, and careful withdrawal of diuretics and specific hypotension-inducing drugs are a reasonable initial strategy. Physical counterpressure maneuvers might be helpful but can be of limited efficacy in older patients and those with short or no prodromes. Orthostatic training lacks long term efficacy and is troubled by non-compliance. Yoga might be helpful, although the biomedical mechanism is unknown. Almost a third of VVS patients continue to faint despite these conservative measures. Metoprolol was not helpful in a pivotal randomized clinical trial. Fludrocortisone and midodrine significantly reduce syncope recurrences with tolerable side effects, when titrated to target doses. Pacing therapy with specialized sensors appears promising in carefully selected population who have not responded conservative measures. Cardioneuroablation may be helpful but has not been studied in a formal clinical trial. [ABSTRACT FROM AUTHOR]

Background: Prolonged use of intravenous (IV) vasopressors in patients with septic shock can lead to deleterious effects. Aims: This study assessed the impact of midodrine administration on weaning off IV vasopressors and its economic value. Methods: It is a prospective randomized controlled study of 60 resuscitated patients with septic shock who demonstrated clinical stability on low-dose IV vasopressors for at least 24 h. Participants were randomized into two groups: norepinephrine (IV norepinephrine) and midodrine (IV norepinephrine + oral midodrine 10 mg thrice a day). A cost comparison was applied based on the outcomes of both groups. Results: The median duration of norepinephrine administration in the midodrine and norepinephrine groups was 4 and 6 days, respectively (p = 0.001). Norepinephrine weaning time was significantly less in the midodrine versus norepinephrine groups (26 and 78.5 h, respectively; p < 0.001). Mortality was 43.3% versus 73.3% in the midodrine and norepinephrine groups, respectively (p = 0.018). The mean length of stay was comparable in the two groups. The midodrine group showed cost-saving results versus the norepinephrine group. Conclusion: The use of midodrine in septic shock patients significantly reduced IV norepinephrine duration, weaning period during the septic shock recovery phase, and mortality. Thus, the use of midodrine is dominant with less cost, better outcome and a cost-saving option in terms of budget impact analysis. This study was registered at clinicaltrials.gov (NCT 03,911,817) on April 11, 2019. [ABSTRACT FROM AUTHOR]

The proposed investigation follows a certain methodology to guarantee that the procedure employed is sustainable and green. It is noteworthy to mention that various tools have been implemented as potential indicators of environmental sustainability (greenness and whiteness). From a novelty viewpoint, a new tool, BAGI, for the method's blueness evaluation was applied to the planned method and showed a high applicability score. Fortunately, the WAC concept, which combines ecological and functional variables using the Green/Red/Blue design (RBG 12 tool), identifies the established analytical approach as white. In the planned study, a new, green, simple, nano-trace-sensitive, original fluorimetric methodology was established to analyze and assess midodrine hydrochloride content in different matrices. Midodrine's primary amine moiety reacts with Diacetylmethane/Oxymethylene reagent in an acetate buffer, which leads to generating a fluorescent dihydrolutidine derivative (Hantzsch-named reaction). Consequently, the signal strength of this compound was quantified at 487 nm, with an excitation wavelength of 426 nm. This analysis indicated that the technique exhibited linearity within the range of 0.05 to 1.1 µg mL−1 concentrations, accompanied by remarkably good sensitivity values (LOD and LOQ). The methodology employed in this examination was subjected to validation following the rules recognized by ICH. From the perspective of pharmacy and chemistry, the method presented in this study was successfully employed to analyze commercially available tablets, oral drops, and human fluids. The outcomes obtained demonstrated satisfactory recovery rates without any interference from excipients. Following the USP recommendations, the intended technique was finally implemented to explore the content homogeneity evaluation. [ABSTRACT FROM AUTHOR]

Keywords: Vasovagal; Midodrine; Mechanoreceptors; Nobel Prize, PIEZO, TRPV1; Ampreloxetine; Verdiperstat EN Vasovagal Midodrine Mechanoreceptors Nobel Prize, PIEZO, TRPV1 Ampreloxetine Verdiperstat 655 658 4 12/01/21 20211201 NES 211201 The 2021 Nobel Prize in Medicine and its relevance to the autonomic field The 2021 Nobel Prize in Physiology or Medicine was awarded to David Julius at the University of California San Francisco (UCSF) and Ardem Patapoutian at Scripps Research, La Jolla for their discoveries of the mechanisms related to heat and mechanic perceptions [[13]]. It has been demonstrated that patients with nOH have poor symptom recognition and that the severity of orthostatic blood pressure drops may not correlate with their symptoms particularly if they also have depressive symptoms [[10]]. The M-STAR study enrolled 300 patients with MSA across 30 sites in the U.S. and Europe, and randomized patients to 48 weeks of treatment with 300 mg oral verdiperstat twice daily or placebo. This is, however, the first multicenter, double-blinded, placebo-controlled trial that provides evidence that midodrine is indeed effective in reducing the likelihood of a syncope recurrence in younger patients with frequent syncope in a real-life setting. [Extracted from the article]

Purpose of Review: In autonomic failure, neurogenic orthostatic hypotension (nOH) and neurogenic supine hypertension (nSH) are interrelated conditions characterized by postural blood pressure (BP) dysregulation. nOH results in a sustained BP drop upon standing, which can lead to symptoms that include lightheadedness, orthostatic dizziness, presyncope, and syncope. nSH is characterized by elevated BP when supine and, although often asymptomatic, may increase long-term cardiovascular and cerebrovascular risk. This article reviews the pathophysiology and clinical characteristics of nOH and nSH, and describes the management of patients with both nOH and nSH. Recent Findings: Pressor medications required to treat the symptoms of nOH also increase the risk of nSH. Because nOH and nSH are hemodynamically opposed, therapies to treat one condition may exacerbate the other. The management of patients with nOH who also have nSH can be challenging and requires an individualized approach to balance the short- and long-term risks associated with these conditions. Summary: Approaches to manage neurogenic BP dysregulation include nonpharmacologic approaches and pharmacologic treatments. A stepwise treatment approach is presented to help guide neurologists in managing patients with both nOH and nSH. [ABSTRACT FROM AUTHOR]

Purpose: ICU discharge is often delayed by a requirement for intravenous vasopressor medications to maintain normotension. We hypothesised that the administration of midodrine, an oral α1-adrenergic agonist, as adjunct to standard treatment shortens the duration of intravenous vasopressor requirement. Methods: In this multicentre, randomised, controlled trial including three tertiary referral hospitals in the US and Australia, we enrolled adult patients with hypotension requiring a single-agent intravenous vasopressor for ≥ 24 h. Subjects received oral midodrine (20 mg) or placebo every 8 h in addition to standard care until cessation of intravenous vasopressors, ICU discharge, or occurrence of adverse events. The primary outcome was time to vasopressor discontinuation. Secondary outcomes included time to ICU discharge readiness, ICU and hospital lengths of stay, and ICU readmission rates. Results: Between October 2012 and June 2019, 136 participants were randomised, of whom 132 received the allocated intervention and were included in the analysis (modified intention-to-treat approach). Time to vasopressor discontinuation was not different between midodrine and placebo groups (median [IQR], 23.5 [10–54] vs 22.5 [10.4–40] h; difference, 1 h; 95% CI − 10.4 to 12.3 h; p = 0.62). No differences in secondary endpoints were observed. Bradycardia occurred more often after midodrine administration (5 [7.6%] vs 0 [0%], p = 0.02). Conclusion: Midodrine did not accelerate liberation from intravenous vasopressors and was not effective for the treatment of hypotension in critically ill patients. [ABSTRACT FROM AUTHOR]

Introduction: Type 1 hepatorenal syndrome (HRS) is a fatal complication of cirrhosis. Treatments trend toward HRS reversal, but few show clear mortality benefit. We sought to quantify the progress-or lack thereof-in improving outcomes of type 1 HRS over time.Methods: We performed a systematic review and meta-analysis for randomized controlled trials (RCTs) comparing type 1 HRS outcomes including (a) overall survival (liver transplant-free survival if reported) and (b) HRS reversal. Each study arm was analyzed separately to look at changes in outcomes over time. RCTs published comparing medical treatments for type 1 HRS were searched using several databases through July 31, 2019.Results: Fourteen RCTs (28 arms) involving 778 participants enrolled between 2002 and 2018 were included. Twelve RCTs measured HRS reversal. In conjunction with albumin (or plasma expander), the most common medications used were terlipressin (13 arms), antibiotics (7), norepinephrine (6), dopamine (4), and midodrine/octreotide (3). Pooled survival rate was 34.6% (95% CI 26.4-43.8), and pooled HRS reversal rate was 42.8% (95% CI 34.2-51.9). Regression analyzing the incremental effect of the year the RCT was initiated showed that more recent studies were not associated with improved survival (OR 1.02, 95% CI 0.94-1.11, p = 0.66) or HRS reversal rates (OR 1.03, 95% CI 0.96-1.11, p = 0.41). There was no survival improvement when RCTs with endpoints assessed ≤ or > 1 month were analyzed separately with respective OR of 1.07 (95% CI 0.95-1.20, p = 0.26) and 0.97 (95% CI 0.85-1.12, p = 0.70).Conclusion: Outcomes have not improved for patients with type 1 HRS since 2002. There is a need to improve prevention and treatment of type 1 HRS. [ABSTRACT FROM AUTHOR]

Intradialytic hypotension (IDH) is a common adverse event resulting in premature interruption of hemodialysis, and consequently, inadequate fluid and solute removal. IDH occurs in response to the reduction in blood volume during ultrafiltration and subsequent poor compensatory mechanisms due to abnormal cardiac function or autonomic or baroreceptor failure. Pediatric patients are inherently at risk for IDH due to the added difficulty of determining and attaining an accurate dry weight. While frequent blood pressure monitoring, dialysate sodium profiling, ultrafiltration-guided blood volume monitoring, dialysate cooling, hemodiafiltration, and intradialytic mannitol and midodrine have been used to prevent IDH, they have not been extensively studied in pediatric population. Lack of large-scale studies on IDH in children makes it difficult to develop evidence-based management guidelines. Here, we aim to review IDH preventative strategies in the pediatric population and outlay recommendations from the Pediatric Continuous Renal Replacement Therapy (PCRRT) Workgroup. Without strong evidence in the literature, our recommendations from the expert panel reflect expert opinion and serve as a valuable guide. [ABSTRACT FROM AUTHOR]

An editorial is presented on the risks of developing autonomic neuropathy and cardiovascular diseases in older people. It examines the influence of autonomic neuropathy to cardiovascular syndromes wherein older people shows an increase risks in orthostatic hypotension. It also cites the medications for treating orthostatic hypotension including fludrocortisone, midodrine and pyridostigmine.

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Background: Hepatorenal syndrome (HRS) is a common complication among patients with cirrhosis, primarily attributable to vasodilation of renal vessels. Vasoactive agents are commonly used to treat HRS. The present network meta-analysis compares the vasoactive agents used in HRS.Methods: We searched electronic databases for appropriate randomized controlled clinical trials in patients with HRS, comparing active interventions with either placebo or standard of care. The primary outcome was complete HRS reversal; secondary outcomes included partial HRS reversal, mortality, adverse events, and cardiovascular adverse events. The data were pooled using a random effects model. We also carried out direct comparisons for the primary outcome with trial sequential analysis.Results: A total of 16 studies were included in the systematic review. Rates of complete HRS reversal were significantly higher with terlipressin and noradrenaline combined with albumin than with placebo (OR 6.65, 95% CI: 2.08-21.31 and 6.81, 95% CI: 1.87-24.83, respectively). No significant differences were observed in terms of mortality, partial HRS reversal, or adverse events for any of the interventions. However, cardiovascular adverse events were significantly higher with continuous-infusion terlipressin/albumin (OR 7.07, 95% CI: 1.23-40.62), bolus terlipressin/albumin (OR 7.39, 95% CI: 1.89, 28.94), octreotide/midodrine/albumin (OR 9.85, 95% CI: 1.1, 88.1), and noradrenaline/albumin (OR 15.24, 95% CI: 2.1, 112.6) than with albumin alone. Trial sequential analyses revealed adequate evidence to conclude that terlipressin combined with albumin was effective in achieving complete HRS reversal.Discussion: Terlipressin combined with albumin shows strong evidence of improving short-term survival in patients with type 1 but not type 2 HRS. Through indirect comparison, noradrenaline with albumin was also associated with significant benefits in terms of HRS reversal. [ABSTRACT FROM AUTHOR]

Neurogenic orthostatic hypotension (nOH) is common in patients with neurodegenerative disorders such as Parkinson's disease, multiple system atrophy, pure autonomic failure, dementia with Lewy bodies, and peripheral neuropathies including amyloid or diabetic neuropathy. Due to the frequency of nOH in the aging population, clinicians need to be well informed about its diagnosis and management. To date, studies of nOH have used different outcome measures and various methods of diagnosis, thereby preventing the generation of evidence-based guidelines to direct clinicians towards 'best practices' when treating patients with nOH and associated supine hypertension. To address these issues, the American Autonomic Society and the National Parkinson Foundation initiated a project to develop a statement of recommendations beginning with a consensus panel meeting in Boston on November 7, 2015, with continued communications and contributions to the recommendations through October of 2016. This paper summarizes the panel members' discussions held during the initial meeting along with continued deliberations among the panel members and provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension. [ABSTRACT FROM AUTHOR]

Background: While the effects of rifaximin have been shown to be protective against acute kidney injury (AKI) and hepatorenal syndrome (HRS) in alcohol-induced cirrhosis, its long-term effects on the renal function of other cirrhotic patients are unknown.Aim: To examine the long-term effects of rifaximin on the renal function of patients with cirrhosis from various etiologies.Methods: In a retrospective study, we examined cirrhotic patients at the University of Chicago Liver Clinic from January 1, 2011, to December 31, 2014. The study enrolled patients on rifaximin for ≥90 days, who were then matched by age, gender, and MELD score to a control group. Patients with malignancy and renal replacement therapy (RRT) at baseline were excluded. Data were censored at the last follow-up, termination of rifaximin therapy, initiation of RRT, death, or liver transplant.Results: Eighty-eight rifaximin cases were identified and matched to 88 control cases. Baseline characteristics were similar, with the exceptions of more prevalent long-term midodrine use (≥90 days) (17.0 vs 4.5 %, p = 0.01) and baseline ascites (37.5 vs 23.8 %, p = 0.05) in the rifaximin group. There was no difference in the frequency of infections, deaths, liver transplants, or hospitalizations. After controlling for cofounders, the incidence rate ratio of AKI (IRR 0.71, p = 0.02) and HRS (IRR 0.21, p = 0.02), as well as the risk of requiring RRT (OR 0.23, p = 0.01), was lower in the rifaximin group.Conclusions: Long-term use of rifaximin is associated with a decrease incidence of AKI and HRS and a decrease risk of requiring RRT in a general population of cirrhotic patients. [ABSTRACT FROM AUTHOR]

Liver cirrhosis is a major cause of morbidity and mortality worldwide, mainly due to complications of portal hypertension. In this article, we review the current understanding on the pathophysiology, the diagnostic criteria and the available therapeutic options for patients with emerging hepatic syndromes in cirrhosis, namely the hepatorenal, hepato-adrenal and hepatopulmonary syndrome. The hepatorenal syndrome is a well-recognized complication of advanced cirrhosis and is usually associated with an accelerated course to death unless liver transplantation is performed. The hepatopulmonary syndrome is often missed in the evaluation of patients with cirrhosis; however, early recognition is essential for the efficient management of individual patients. The hepato-adrenal syndrome, although not fully characterized, offers an exciting field for research and potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objective: Midodrine hydrochloride is a short-acting pressor agent that raises blood pressure in the upright position in patients with orthostatic hypotension. The US Food and Drug Administration's Subpart H approval, under which midodrine was initially approved, requires post-marketing studies to confirm midodrine's clinical benefit in this indication. The purpose of this study was to evaluate the clinical benefit of midodrine with regard to symptom response. Methods: This was a double-blind, placebo-controlled, randomized, crossover, multicenter study (NCT01518946). Following screening, patients aged ≥18 years with severe symptomatic orthostatic hypotension and on a stable dose of midodrine for at least 3 months were randomized to treatment with either their previous midodrine dose or placebo on day 1 and the respective alternate treatment on day 2. The primary endpoint measured time to syncopal symptoms or near-syncope using a 45-min tilt-table test at 1 h post-dose. Results: Thirty-three patients were screened for inclusion: 19 received at least one dose of midodrine and had at least one post-dose measurement of the primary endpoint. The least-squares mean time to syncopal symptoms or near-syncope after tilt-table initiation (mean ± standard error) was 1626.6 ± 186.8 s for midodrine and 1105.6 ± 186.8 s for placebo (difference, 521.0 s; 95 % confidence interval 124.2-971.7 s; p = 0.0131). There were 15 adverse events in 10 patients; all of these were mild or moderate in severity, with none considered by the investigators to be related to midodrine. Interpretation: Midodrine is a well-tolerated and clinically effective treatment for symptomatic orthostatic hypotension. [ABSTRACT FROM AUTHOR]

Objective: Midodrine is an α-agonist prodrug of desglymidodrine used for the management of hypotension, and can also be used for hepatorenal syndrome and cirrhotic patients with tense ascites. The objective of the present work was to study the clinical pharmacokinetic parameters of midodrine and its active metabolite desglymidodrine in cirrhotic patients with tense ascites, which may help in dose selection and improve treatment outcome. Method: This was a prospective, open-label, single-dose, parallel-group study. At first, a pilot study was performed on one healthy volunteer by taking serial blood samples at scheduled time intervals to validate the method of analysis and sampling times. The full study was then conducted by selecting 12 cirrhotic patients with tense ascites in one group and taking nine blood samples. We also selected five healthy volunteers as the control group and took 11 blood samples. Results: Statistically significant differences were observed between the healthy volunteer group and the patients group in the area under the concentration versus time curve (AUC) and maximum plasma concentration ( C) values of midodrine and desglymidodrine. Based on the results of the pharmacokinetic analysis, the patient group was further subdivided into those receiving the interacting drug ranitidine (five patients) and those not receiving the interacting drug (seven patients). Conclusions: Pharmacokinetic parameters of midodrine can differ significantly in cirrhotic patients with tense ascites from those in healthy individuals. Drug monitoring, dose adjustments, and drug-drug interactions should all be considered during therapy in this vulnerable patient group. [ABSTRACT FROM AUTHOR]

The article focuses on a study related to use of vasopressors in sepsis when hypotension is assumed to be mainly due to a decreased arterial tone. It mentions that vasopressin did not decrease overall mortality in a large randomized controlled trial (RCT) compared to norepinephrine in septic shock. It also mentions about the Midodrine that was approved in the U.S. in 1996 for orthostatic hypotension.

Patients with rheumatoid arthritis continue to undergo arthroplasty despite widespread use of potent disease-modifying drugs (DMARDs), including the biologic tumor necrosis-α inhibitors. In fact, over 80 % of RA patients are taking DMARDs or biologics at the time of arthroplasty. While many RA-specific factors including disease activity and disability may contribute to the increase in infection in RA patients undergoing arthroplasty, immunosuppressant medications may also play a role. As the age of patients with RA undergoing arthroplasty is rising, and the incidence of arthroplasty among the older population is increasing, optimal perioperative management of DMARDs and biologics in older patients with RA is an increasing challenge. Although evidence is sparse, most evidence supports withholding tumor necrosis-α inhibitors and other biologics prior to surgery based on the dosing interval, and continuing methotrexate and hydroxychloroquine through the perioperative period. There is no consensus regarding leflunomide, and rituximab risk does not appear related to the interval between infusion and surgery. This paper reviews arthroplasty outcomes including complications in patients with RA, and discusses the rationale for strategies for the optimal medication management of DMARDs and biologics in the perioperative period to minimize complications and improve outcomes. [ABSTRACT FROM AUTHOR]

Hypotensive syndromes are common among older adults. Symptomatic drop in blood pressure with standing, eating and head turning is very common in older adults. These conditions cause significant morbidity like dizziness, syncope and falls as well as a resultant decrease in function. Blood pressure dysregulation due to autonomic function abnormalities plays a role in causing these conditions. Non-pharmacological measures should be the first line of management, but it is not always sufficient for subjects with symptomatic hypotensive syndromes. Different medication groups have been shown to be useful. This article focuses mainly on the medication management of these conditions based on efficacy and tolerability evidence in the literature. Standard medication management recommendations based on evidence are lacking for many medications used in treating these hypotensive syndromes. [ABSTRACT FROM AUTHOR]

Background Hyperdynamic circulatory state in liver cirrhosis is characterized by increased splanchnic blood flow and renal vasoconstriction. Aim To evaluate the relationship between renal resistive indices (RI) and HCV liver cirrhosis severity and RI value in predicting 6 month survival of those patients. Also we aimed to assess the effect of midodrine on RI. Patients and methods 120 patients with HCV liver cirrhosis and 40 healthy controls were enrolled in the study. INR, total bilirubin, albumin, creatinine and sodium were measured in all patients. Both patients and controls underwent abdominal ultrasound with duplex Doppler examination of the kidneys with RI calculated. Patients were followed for 6 months. Surviving patients with highest risk underwent renal duplex with RI calculation (RI2). They then received oral midodrine at a dose of 7.5 mg three times daily for 3 months with revaluation of RI (RI3). Results 57 (47.5%) patients had high RI (RI > 0.7) while 63 (52.5%) patients had normal RI. Patients had significantly higher RI than healthy controls ( P < 0.001). There was a significant positive correlation between RI and MELD, MELD-Na, and Child class ( r = 0.859, r = 0.769, rho = 0.56 respectively and P < 0.001). Patients with RI > 0.73 are at higher risk of death within 6 months ( P < 0.001). Administration of midodrine resulted in no significant difference in RI in the 37 surviving patients with baseline RI > 0.73 ( P = 0.1605). Conclusion RI is strongly correlated with liver cirrhosis severity and had comparable prognostic value with MELD score. Midodrine had no significant effect on RI in high risk patients. [ABSTRACT FROM AUTHOR]

The objective of this case is to describe the pharmacokinetics and toxicity of midodrine in overdose. A 20 year old female ingested up to 350 mg midodrine while recovering in hospital from another overdose. She developed vomiting and severe hypertension (blood pressure [BP], 210/100 mmHg). Remarkable findings included a heart rate with a range of 43-60 beats/min, spontaneous respirations (20 breaths/min), and oxygen saturations of >95 % on FiO2 25 %, and a GS of 8. She was admitted to intensive care and had a normal non-contrast CT brain. She was treated with a glyceryl trinitrate patch (5 mg) and observed for 36 h with subsequent BP reduction to 124/81 mmHg and improved in conscious state. Midodrine and desglymidodrine concentrations were measured with liquid chromatography tandem mass spectrometry and were detected with 2-h post-ingestion at concentrations of 158.4 and 169.7 ng/mL, respectively. The parent drug concentrations rapidly decreased with an elimination of half-life of 1.6 h, and the metabolite initially increased and then decreased. The peak in blood pressure appeared to coincide with peak metabolite concentrations. Midodrine in overdose can potentially cause severe hypertension and reflex bradycardia but given its short half-life treatment with vasodilator agents and supportive care is sufficient. [ABSTRACT FROM AUTHOR]

A range of primary or secondary autonomic disorders can cause failure of noradrenergic neurotransmission which can subsequently result in a sustained fall in blood pressure upon standing, known as neurogenic orthostatic hypotension. Non-pharmacological measures are the mainstay of treatment of neurogenic orthostatic hypotension. However, when symptoms are not controlled, pharmacological treatment is required. This is largely empirical, based on short- and long-acting drugs, and relies on the use of a variety of agents which target vasoconstriction and intravascular volume expansion. [ABSTRACT FROM AUTHOR]

Postural orthostatic tachycardia syndrome (POTS) is common, and has a serious impact on children's quality of life. Midodrine hydrochloride, an α1-adrenoreceptor agonist, is an effective treatment. The study was designed to examine the therapeutic efficacy of midodrine hydrochloride by quantifying changes in blood pressure during the head-up test (HUT), in children with POTS. Overall, 104 out of 110 children with POTS were treated with midodrine hydrochloride and successfully followed-up. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes were analyzed during the HUT. In a retrospective analysis, a receiver operating characteristic (ROC) curve was used to analyze the therapeutic predictive value of pre-treatment changes in SBP, DBP, and a combination of both, from the supine position to standing, in the subjects. The increase of SBP and DBP from the supine position to standing in responders were significantly lower than that of the non-responders. The ROC curve showed that midodrine hydrochloride for children with POTS would be predicted to be effective when the pre-treatment increase of SBP was ≤0 mmHg, or when the pre-treatment increase of DBP was ≤6.5 mmHg (from the supine position to standing), yielding a sensitivity of 72 % and specificity of 88 %. The area under the curve was 0.744 and 0.809, respectively. Hence, the results suggested that looking at the changes in blood pressure during the HUT was useful in predicting the response to midodrine hydrochloride in children with POTS. [ABSTRACT FROM AUTHOR]

Hepatorenal syndrome (HRS) is a feared common complication of patients with cirrhosis. This syndrome is mainly characterized by functional renal failure due to renal vasoconstriction in the absence of underlying kidney pathology. The pathogenesis of HRS is complex and a final result of an extreme underfilling of the arterial circulation secondary to an arterial vasodilation located in the splanchnic circulation. This phenomenon leads to a compensatory response with activation of vasoconstrictors that cause intense renal vasoconstriction and kidney failure. The diagnosis of HRS is based on established diagnostic criteria aimed at excluding nonfunctional causes of renal failure. However in recent years the diagnosis of renal failure in patients with cirrhosis has also been adapted to include the acute kidney injury criteria proposed by the acute kidney injury network. The prognosis of patients with HRS is poor, especially in those who have a rapidly progressive course. Liver transplantation is the best option in suitable candidates, but difficult to implement in all patients due to the poor prognosis of many patients. Pharmacological therapies based on the use of vasoconstrictor drugs plus intravenous albumins are the standard first line of therapy. Other treatments such as transjugular intrahepatic portosystemic shunts and renal replacement may be effective but experience is limited. HRS prophylaxisis recommended in patients with spontaneous bacterial peritonitis, advanced cirrhosis and those with severe acute alcoholic hepatitis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To perform a systematic review and meta-analysis of clinical trials evaluating the efficacy and safety of midodrine in orthostatic hypotension (OH). METHODS: We searched major databases and related conference proceedings through June 30, 2012. Two reviewers independently selected studies and extracted data. Random-effects meta-analysis was used to pool the outcome measures across studies. RESULTS: Seven trials were included in the efficacy analysis (enrolling 325 patients, mean age 53 years) and two additional trials were included in the safety analysis. Compared to placebo, the mean change in systolic blood pressure was 4.9 mmHg ( p = 0.65) and the mean change in mean arterial pressure from supine to standing was −1.7 mmHg ( p = 0.45). The change in standing systolic blood pressure before and after giving midodrine was 21.5 mmHg ( p < 0.001). A significant improvement was seen in patients' and investigators' global assessment symptoms scale (a mean difference of 0.70 [95 % CI 0.30-1.09; p < 0.001] and 0.80 [95 % CI 0.76-0.85; p < 0.001], respectively). There was a significant increase in risk of piloerection, scalp pruritis, urinary hesitancy/retention, supine hypertension and scalp paresthesia after giving midodrine. The quality of evidence was limited by imprecision, heterogeneity and increased risk of bias. CONCLUSION: There is insufficient and low quality evidence to support the use of midodrine for OH. [ABSTRACT FROM AUTHOR]

Orthostatic hypotension is a condition commonly affecting the elderly and is often accompanied by disabling presyncopal symptoms, syncope and impaired quality of life. The pathophysiology of orthostatic hypotension is linked to abnormal blood pressure regulatory mechanisms and autonomic insufficiency. As part of its diagnostic evaluation, a comprehensive history and medical examination focused on detecting symptoms and physical findings of autonomic neuropathy should be performed. In individuals with substantial falls in blood pressure upon standing, autonomic function tests are recommended to detect impairment of autonomic reflexes. Treatment should always follow a stepwise approach with initial use of nonpharmacologic interventions including avoidance of hypotensive medications, high-salt diet and physical counter maneuvers. If these measures are not sufficient, medications such as fludrocortisone and midodrine can be added. The goals of treatment are to improve symptoms and to make the patient as ambulatory as possible instead of targeting arbitrary blood pressure values. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Splanchnic arterial vasodilatation and subsequent activation of anti-natriuretic and vasoconstrictive mechanisms have an important role in cirrhotic ascites. The aim of this study was to evaluate the effects of midodrine, clonidine, and their combination on systemic hemodynamics, renal function, and control of ascites in patients with cirrhosis and refractory or recurrent ascites.METHODS:Sixty cirrhotic patients with refractory or recurrent ascites were prospectively studied after long-term administration of clonidine (n=15) or midodrine (n=15), or both (n=15) plus standard medical therapy (SMT), or SMT alone (n=15), in a randomized controlled trial at a tertiary center.RESULTS:A significant increase in urinary volume, urinary sodium excretion, mean arterial pressure, and decrease in plasma renin activity (P<0.05) was noted after 1 month. There was also a significant decrease in cardiac output (P<0.05) and increase in systemic vascular resistance (P<0.05) in all groups, except clonidine. There was no change in glomerular filtration rate and model for end-stage liver disease score. Midodrine and a combination of midodrine and clonidine plus SMT were superior to SMT alone in the control of ascites (P=0.05), and there was a trend towards better control of ascites in the clonidine group (P=0.1). The mortality and frequency of various complications were similar in all groups.CONCLUSIONS:These results suggest that midodrine, clonidine, and their combination plus SMT improves the systemic hemodynamics without any renal or hepatic dysfunction, and is superior to SMT alone for the control of ascites. However, the combination therapy was not superior to midodrine or clonidine alone. [ABSTRACT FROM AUTHOR]

Background: Denys-Drash (DDS) syndrome is a rare genetic syndrome resulting from a mutation in the Wilms' tumor suppressor gene 1 ( WT1), which presents with early onset nephrotic syndrome progressing rapidly to end-stage kidney disease (ESKD), pseudohermaphroditism, and high rates of Wilms' tumor. Case-Diagnosis/Treatment: We present the case of an infant born with DDS and phenylketonuria with neonatal ESKD and dependence on peritoneal dialysis (PD). This patient developed refractory hypotension after elective bilateral nephrectomies at 10 months of age. Despite outpatient management with sodium supplements and changes in PD fluid removal, the patient was hospitalized for refractory post-prandial hypotension with concurrent lactic acidosis. Blood pressure control and feeding tolerance was achieved using intermittent doses of midodrine, an oral alpha-adrenergic agonist. Conclusions: We discuss this case to offer a therapeutic option for the rare occurrence of persistent post-nephrectomy hypotension. [ABSTRACT FROM AUTHOR]

Background: Vasovagal syncope is a common problem associated with a poor quality of life, which improves when the frequency of syncope is reduced. Effective pharmacological therapies for vasovagal syncope have been elusive. Midodrine is a pro-drug whose primary metabolite is an alpha-1 adrenoreceptor agonist. A few studies have suggested that it may be beneficial in syncope, but all have had significant methodological limitations. A placebo-controlled clinical trial of midodrine for the prevention of vasovagal syncope is needed. Structure of study: The prevention of syncope trial IV (POST 4) is a multicenter, international, randomized, placebo-controlled study of midodrine in the prevention of vasovagal syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive midodrine 10-30 mg/day or matching placebo, and followed for 1 year. Secondary end points include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention-to-treat approach, with a secondary on-treatment analysis. Power calculations: A total sample size of 112, split equally between the two groups, achieves 85 % power to detect a 50 % relative risk reduction when the event rates are 55 and 27.5 % in the placebo and midodrine arms. Allowing for 20 % dropout, we propose to enroll 140 patients. Registration: POST 4 is registered with (NCT01456481). Implications: This study will be the first adequately powered trial to determine whether midodrine is effective in preventing vasovagal syncope. If it is effective, then midodrine may become the first-line pharmacological therapy for this condition. [ABSTRACT FROM AUTHOR]

Abstract: Background: Midodrine hydrochloride has been shown to be effective in the management of syncope in adults with reflex syncope, orthostatic hypotension and orthostatic intolerance syndromes; however, its use, tolerability and side effects have not been monitored specifically in the older old, particularly not over a prolonged period of time. Objectives: We aim to document changes in patients’ symptoms, drug dosages employed and adverse drug reactions to midodrine therapy in older adults with a diagnosis of neurocardiogenic syncope assessed and managed at a specialist falls and syncope outpatient unit. Methods: Prospective observational study of 135 consecutive subjects with a mean age of 84 years started on midodrine after comprehensive geriatric assessment, structured falls evaluation, positive tilt table testing (TT) or a mixed/vasodepressor response to carotid sinus massage (CSM). Results: Ninety-seven individuals (71%) commenced on midodrine treatment and followed up for a mean of 2.7 years, reported either significant improvement or abolition of symptoms across all TT/CSM diagnosis. Forty-nine percent of individuals achieved sustained clinical improvement after an initial dosage of 2.5mg three times per day and only four patients required dosages above 7.5mg three times daily. One hundred and one individuals (75%) continued midodrine until the end of the monitoring period, and although 19 subjects developed adverse drug reactions, most were minor and only six resulted in drug withdrawal. Conclusions: Midodrine hydrochloride appears to be safe and well tolerated in older adults and should be considered, independent of age, in the management of patients with symptomatic orthostatic hypotension, vasovagal syncope and vasodepressor or mixed carotid sinus syndrome. This observation requires further confirmation by larger multicenter randomised control studies. [Copyright &y& Elsevier]

Background: There is no widely accepted validated scale to assess the comprehensive symptom burden and severity of neurogenic orthostatic hypotension (NOH). The Orthostatic Hypotension Questionnaire (OHQ) was developed, with two components: the six-item symptoms assessment scale and a four-item daily activity scale to assess the burden of symptoms. Validation analyses were then performed on the two scales and a composite score of the OHQ. Methods: The validation analyses of the OHQ were performed using data from patients with NOH participating in a phase IV, double blind, randomized, cross over, placebo-controlled trial of the alpha agonist midodrine. Convergent validity was assessed by correlating OHQ scores with clinician global impression scores of severity as well as with generic health questionnaire scores. Test-retest reliability was evaluated using intraclass correlation coefficients at baseline and crossover in a subgroup of patients who reported no change in symptoms across visits on a patient global impression scores of change. Responsiveness was examined by determining whether worsening or improvement in the patients' underlying disease status produced an appropriate change in OHQ scores. Results: Baseline data were collected in 137 enrolled patients, follow-up data were collected in 104 patients randomized to treatment arm. Analyses were conducted using all available data. The floor and ceiling effects were minimal. OHQ scores were highly correlated with other patient reported outcome measures, indicating excellent convergent validity. Test-retest reliability was good. OHQ scores could distinguish between patients with severe and patients with less severe symptoms and responded appropriately to midodrine, a pressor agent commonly used to treat NOH. Conclusion: These findings provide empirical evidence that the OHQ can accurately evaluate the severity of symptoms and the functional impact of NOH as well as assess the efficacy of treatment. [ABSTRACT FROM AUTHOR]

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Orthostatic hypotension is a common adverse effect of antipsychotics thatmay delay or prevent titration to a dose necessary to control psychotic symptoms. Complications of orthostatic hypotension include syncope, transient ischaemic attack, stroke, myocardial infarction and death. The risk of orthostatic hypotension associated with antipsychotic therapy is increased in patients with disorders of the autonomic nervous system, fluid imbalance and those taking concomitant drug therapy that affects haemodynamic tone. Prospective monitoring for changes in postural blood pressure is important because patients with psychotic disorders often do not articulate symptoms of orthostasis and the subjective report of dizziness does not correlate well with orthostatic blood pressure changes. Nonpharmacological strategies and patient education, most notably, slowly rising from the supine position, are crucial first steps in the prevention and treatment of both symptomatic and asymptomatic orthostatic hypotension. Pharmacological treatment is only recommended when symptomatic orthostatic hypotension persists despite proper nonpharmacological therapy and there is a compelling indication for antipsychotic treatment. Fludrocortisone is a reasonable first choice for symptomatic orthostatic hypotension. Other agents including desmopressin and midodrine may be considered in patients who do not respond favourably to a trial of fludrocortisone, but safety concerns and lack of evidence limit the utility of these agents. [ABSTRACT FROM AUTHOR]

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One of the most common manifestations of the development of portal hypertension in the patient with cirrhosis is the appearance of ascites. Once ascites develops, the prognosis worsens and the patient becomes susceptible to complications such as bacterial peritonitis, hepatic hydrothorax, hyponatremia, and complications of diuretic therapy. As the liver disease progresses, the ascites becomes more difficult to treat and many patients develop renal failure. Most patients can be managed by diuretics which, when used correctly, will control the ascites. Spontaneous bacterial peritonitis can be treated effectively, but portends a worse prognosis. Once the ascites becomes refractory to diuretics, liver transplantation is the best option, although use of transjugular intrahepatic portosystemic shunts will control the ascites in many patients. Lastly, the development of hepatorenal syndrome indicates the patient's liver disease is advanced, and transplantation again is the best option. However, use of vasoconstrictors may improve renal function in some patients, helping in their management while they await a liver transplant. [ABSTRACT FROM AUTHOR]

The uremic state impairs compensatory responses to ultrafiltration (UF). Intradialytic symptoms and hypotension can result and lead to premature discontinuation of treatment and sub-optimal dialysis. We report the benefits of mannitol, sequential dialysis and midodrine in reducing dialysis failures in those children prone to intradialytic hypotension. Prophylactic mannitol halved the odds of intradialytic symptoms and hypotension and increased UF volumes. Sequential dialysis halved the odds of symptoms but hypotension persisted. In one patient with refractory hypotension, only intradialytic midodrine consistently maintained acceptable intradialytic blood pressures, reduced intradialytic symptoms and increased the UF potential. [ABSTRACT FROM AUTHOR]

Anejaculation is a rare cause of infertility and adversely affects the general sense of well-being and perception of sexual life satisfaction. Evidence to support effective and noninvasive treatment for this ejaculatory disorder is lacking. This study aimed to evaluate the efficacy and safety of midodrine (α1-adrenergic receptor agonist) for the treatment of organic anejaculation but not spinal cord injury (SCI). A total of 128 patients were randomly assigned to oral midodrine 7.5–15 mg per day in a stepwise approach (group 1, n=64), or a similar regimen of placebo (group 2, n=64). They underwent a complete physical examination, echocardiography, 12-lead electrocardiogram, transrectal ultrasonography, complete blood count and blood chemistry. Hormonal assays included serum levels of luteinizing hormone, follicle-stimulating hormone, prolactin and testosterone. To rule out other sexual dysfunction, patients also completed the International Index of Erectile Function questionnaire. Psychiatric disorders were excluded by appropriate tests. Outcome measure was reversal of the anejaculation. None of the patients in the placebo group achieved antegrade or retrograde ejaculation. At the end of study, antegrade, retrograde and antegrade+retrograde ejaculation occurred in 18 (29.5%), 8 (13.1%) and 9 (14.8%) patients in midodrine group, respectively (all P=0.01). The most and least favorable responses were among patients with multiple sclerosis and bilateral sympathectomy, respectively. Midodrine improved ejaculation function in a dose-dependent manner. Four participants (6.3%) in midodrine group discontinued this study for reasons of adverse events. In patients with organic anejaculation but without SCI midodrine can reverse anejaculation in more than 50% of patients. Further studies are needed, however, for the evaluation of different treatment regimens in anejaculation therapy.International Journal of Impotence Research (2009) 21, 213–220; doi:10.1038/ijir.2009.19; published online 28 May 2009 [ABSTRACT FROM AUTHOR]

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The purpose of this study was to determine whether autonomic neuropathy and the postural tachycardia syndrome can be treated with octreotide LAR (Long Acting Release). This was an open-label pilot project. Protocol 1 Patients with autonomic neuropathy (n = 4) were given increasing doses of octreotide LAR once a month for three months. Blood pressure was measured in the sitting posture every two weeks. Pretreatment mean blood pressure averaged 83.8 ± 7.1 mm Hg. After four, six and eight weeks of therapy the blood pressures averaged 96.3 ± 6.4, 98.2 ± 6.1 (p < .025), and 104.1 ± 3.1 (p < .025) respectively. Therapy led to a dramatic improvement in symptoms in one patient but another had an unacceptable elevation in supine blood pressure. Protocol 2 Patients with POTS or orthostatic intolerance were given 10, 20, or 30 mg of octreotide LAR over three months. Seven patients entered and five completed the study. After two months treatment, standing time increased from 36.0 ± 9.2 to 59.2 ± .8 minutes (p < .01). Heart rate in the standing position was suppressed from 106 ± .83 to 93.2 ± .8 beats per minute (p < .05). Orthostatic dizziness and chronic fatigue improved. We conclude that octreotide LAR can be used to treat autonomic neuropathy but there is a risk of an excessive pressor response. Octreotide LAR improved standing time and suppressed tachycardia in patients with orthostatic intolerance. [ABSTRACT FROM AUTHOR]

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Midodrine, a prodrug, is converted after oral administration into its active drug, desglymidodrine, which acts as an α1-adrenoceptor stimulant. Midodrine is prescribed for the treatment of neurogenic orthostatic hypotension in patients with spinal cord injury. By virtue of its α1-adrenergic effects, midodrine causes an increase in the tone of the vesical sphincter, which may silently lead to progressive retention of urine, particularly in patients with spinal cord injury who void urine spontaneously. Further, midodrine may aggravate detrusor-sphincter dyssynergia, which can lead to hydroureteronephrosis. A 68-year-old man with C-4 tetraplegia was voiding urine satisfactorily through reflex detrusor contractions. He was prescribed midodrine (5 mg at 8:00 am, 5 mg at 1:00 pm, and 2.5 mg at 10:00 pm) for postural hypotension. During the next 7 wk, this patient experienced severe leg spasms while passing urine, and the flow of urine became very slow. Intravenous urography showed bilateral hydroureteronephrosis, although an earlier study had revealed normal kidneys. Midodrine therapy was stopped, and intermittent catheterization 4 times a day, along with oral oxybutynin, was started. After midodrine was discontinued, the leg spasms during passage of urine and slowing of the urine stream coincident with the spasms disappeared completely. The patient was able to pursue activities of daily living without taking midodrine. A 40-year-old man with C-7 tetraplegia was passing urine spontaneously with no problem. For postural hypotension, he was prescribed midodrine (5 mg in the morning and 2.5 mg at lunchtime), fludrocortisone (100 μg daily), and ephedrine (15 mg by mouth, taken 10 min before getting up in the morning). Three months later, the patient presented with sweating. During the day, he would pass only small amounts of urine, but from evening onward, he would void large volumes of urine, and the sweating would diminish. Intravenous urography showed vesical diverticula; a postmicturition film revealed moderate residual urine. This patient was able to stop taking the second dose of midodrine, but he required midodrine and ephedrine in the morning to enable him to get up without feeling dizzy. After the noon midodrine dose was stopped, the patient’s sweating diminished by late afternoon. During the morning hours, however, he continued to sweat and had difficulty passing urine. Intermittent catheterization was not possible in the community setting, and the patient remains under close follow-up. These cases illustrate that patients with cervical spinal cord injury who void spontaneously may develop insidious urologic adverse effects after taking midodrine for postural hypotension. When patients with spinal cord injury develop urologic adverse effects while taking midodrine, the drug should be stopped, and other pharmacologic agents (eg, fludrocortisone) and nonpharmacologic methods should be prescribed for management of orthostatic hypotension. If a patient continues to require midodrine to control postural hypotension, intermittent catheterization combined with antimuscarinic therapy (eg, oxybutynin) should be recommended instead of spontaneous voiding. [ABSTRACT FROM AUTHOR]

The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone’s efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisonetreated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to investigate and characterise adverse drug reactions (ADRs) to drugs used in France for orthostatic hypotension (OH). Methods: In this prospective and systematic study, 121 consecutive out-patients suffering from primary (Parkinson's disease, pure autonomic failure, multiple system atrophy, Lewy bodies disease) or secondary (diabetic and non-diabetic peripheral neuropathies) autonomic failure with symptomatic OH requiring pharmacological treatment with at least one drug marketed in France for OH were included together with six patients with refractory neurocardiogenic syncope. Results: Of the patients, 85 received a monotherapy—mainly with midodrine (49.4%)—and 42 received various combinations, the association of midodrine and fludrocortisone being the most frequent (66.6%). Of all the 127 patients, 88 suffered from a total of 141 ADRs (1.60 per patient) with no statistical difference in ADR frequency between monotherapy and drug combinations (P>0.05). Among ADRs, 24 (17.0%) were considered as ''serious'' and 16 (11.3%) were considered as ''unexpected'', most of them observed with heptaminol. Conclusions: This study shows a high frequency of ADRs (especially serious and unexpected ADRs) with antihypotensive drugs. It strongly suggests the need for a better evaluation of the safety profile of antihypotensive drugs and improvement in summary of product characteristics. [ABSTRACT FROM AUTHOR]

Purpose. The purpose of this work was to investigate if fatty acids can increase the iontophoretic delivery of midodrine hydrochloride through human dermatomed skin and to observe the effects of iontophoresis and fatty acids on skin using SEM. Methods. After prehydration for 1 h, human dermatomed skin was treated with 0-0.3 M fatty acids (oleic acid, linoleic acid, decanoic acid, and lauric acid) in propylene glycol (PG) for 1 h. Then the fatty acid solution was replaced by i % midodrine hydrochloride aqueous solution, and 0.1 mA/cm[sup2] constant current was applied. Samples were taken over 24 h and analyzed by HPLC. After the treatments outlined above, the epidermis was separated, fixed with glutaraldehyde, and dehydrated for SEM. Results. SEM studies revealed that only 1 h of treatment with fatty acids opened up the tightly compact stratum corneum cell layer, and the permeation study showed a significant increase of the permeability of skin to midodrine hydrochloride after fatty acid treatment. Conclusions. Using 5% oleic acid pretreatment, with the electrical current offset at 0.1 mA/cm[sup2], the daily delivery of midodrine hydrochloride can provide an adequate clinical application. The enhancement of passive and iontophoretic delivery by fatty acids may be occurring through the same mechanism. [ABSTRACT FROM AUTHOR]