Discovery of anti-stroke active substances in Guhong injection based on multi-phenotypic screening of zebrafish.

Ischemic stroke is a leading cause of death worldwide, and it remains an urgent task to develop novel and alternative therapeutic strategies for the disease. We previously reported the positive effects of Guhong injection (GHI), composed of safflower extract and aceglutamide, in promoting functional recovery in ischemic stroke mice. However, the active substances and pharmacological mechanism of GHI is still elusive. Aiming to identify the active anti-stroke components in GHI, here we conducted a multi-phenotypic screening in zebrafish models of phenylhydrazine-induced thrombosis and ponatinib-induced cerebral ischemia. Peripheral and cerebral blood flow was quantified endogenously in erythrocytes fluorescence-labeled thrombosis fish, and baicalein and rutin were identified as major anti-thrombotic substances in GHI. Moreover, using a high-throughput video-tracking system, the effects of locomotion promotion of GHI and its main compounds were analyzed in cerebral ischemia model. Chlorogenic acid and gallic acid showed significant effects in preventing locomotor dyfunctions. Finally, GHI treatment greatly decreased the expression levels of coagulation factors F7 and F2, NF-κB and its mediated proinflammatory cytokines in the fish models. Molecular docking suggested strong affinities between baicalein and F7, and between active substances (baicalein, chlorogenic acid, gallic acid, and rutin) and NF-κB p65. In summary, our findings established a novel drug discovery method based on multi-phenotypic screening of zebrafish, provided endogenous evidences of GHI in preventing thrombus formation and promoting behavioral recovery after cerebral ischemia, and identified baicalein, rutin, chlorogenic acid, and gallic acid as active compounds in the management of ischemic stroke.

Febrile pleuropericarditis, a potentially life-threatening adverse event of balsalazide--case report and literature review of the side effects of 5-aminosalicylates.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disorder that affects the colonic mucosa. One class among the drugs used for its treatment is the 5-aminosalicylates (5-ASAs). While highly efficacious in treating mild-to-moderate UC, 5-ASAs are associated with rare but potentially life-threatening side effects such as pericarditis, myocarditis and pneumonitis. These adverse events appear to be caused by a hypersensitivity reaction and resolve after cessation of 5-ASA drugs. This article presents a case report of febrile pleuropericarditis in a UC patient treated with balsalazide, and provides a thorough literature review of the rare side effects of 5-ASAs, their incidence, clinical presentation, differential diagnosis and treatment. In conclusion, the clinicians should be aware that this type of adverse events to 5-ASA compounds can be easily overlooked but it has significant morbidity if not promptly diagnosed.

Colon-specific prodrugs of 4-aminosalicylic acid for inflammatory bowel disease.

Despite the advent of biological products, such as anti-tumor necrosis factor-α monoclonal antibodies (infliximab and adalimumab), for treatment of moderate to severe cases of inflammatory bowel disease (IBD), most patients depend upon aminosalicylates as the conventional treatment option. In recent years, the increased knowledge of complex pathophysiological processes underlying IBD has resulted in development of a number of newer pharmaceutical agents like low-molecular-weight heparin, omega-3 fatty acids, probiotics and innovative formulations such as high-dose, once-daily multi-matrix mesalamine, which are designed to minimize the inflammatory process through inhibition of different targets. Optimization of delivery of existing drugs to the colon using the prodrug approach is another attractive alternative that has been utilized and commercialized for 5-aminosalicylic acid (ASA) in the form of sulfasalazine, balsalazide, olsalazine and ipsalazine, but rarely for its positional isomer 4-ASA - a well-established antitubercular drug that is twice as potent as 5-ASA against IBD, and more specifically, ulcerative colitis. The present review focuses on the complete profile of 4-ASA and its advantages over 5-ASA and colon-targeting prodrugs reported so far for the management of IBD. The review also emphasizes the need for reappraisal of this promising but unexplored entity as a potential treatment option for IBD.

Alternate endpoints and clinical outcome assessments in pediatric ulcerative colitis registration trials.

OBJECTIVES: Presently, there is no consensus on endpoint measures to assess clinical outcomes for pediatric ulcerative colitis (UC). This study reviewed the endpoints used in the registration trials of approved drugs for pediatric UC. METHODS: The primary efficacy endpoints of all registration trials completed from 1950 to 2008 that led to Food and Drug Administration approval for indications in pediatric and adult UC were reviewed. RESULTS: Colazal and Remicade have been approved for pediatric UC indication, and clinical response was used as a primary endpoint in these registration trials. The clinical response in the adult Colazal trials was defined as a reduction of rectal bleeding and improvement in at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician's global assessment) assessed by the Sutherland UC Activity Index. The pediatric Colazal trial defined clinical response using the Modified Sutherland UC Activity Index, which excluded abdominal pain and functional assessment. Both adult and pediatric Remicade trials used clinical response defined by the Mayo score as the primary endpoint. The Pediatric Ulcerative Colitis Activity Index was used to measure various secondary endpoints in the pediatric Remicade trial. CONCLUSIONS: Pediatric-specific endpoints were used, but outcome measures and definition of clinical response were not consistent in pediatric UC trials. Consensus on the definition of successful treatment outcome (clinical response and/or remission) and collaboration in the development of well-defined and reliable measures of signs and symptoms for use in conjunction with endoscopic parameters of mucosal healing will facilitate pediatric drug development.

Balsalazide: a novel 5-aminosalicylate prodrug for the treatment of active ulcerative colitis.

BACKGROUND: 5-Aminosalicylate (5-ASA) agents are the mainstay of oral therapy for ulcerative colitis (UC). Balsalazide, a prodrug of 5-ASA, has recently been approved for the treatment of UC. OBJECTIVE: To summarize current data on balsalazide and to discuss its impact on management of UC. METHODS: A systematic review of published literature was performed on PubMed using the search terms 'Balsalazide' and 'Colazal(TM)'. The Cochrane database was also reviewed. RESULTS: Balsalzide, a 5-ASA prodrug, ulilizes azoreduction by colonic bacteria to achieve a sustained release of active 5-ASA throughout the colon. A recent clinical trial has demonstrated balsalazide 6.7 g/day to be superior to placebo in inducing remission in symptomatic UC. The drug is well tolerated with a safety profile comparable to other oral 5-ASA agents. The current data suggests that symptomatic remission occurs with both greater swiftness and greater frequency when compared with mesalamine. CONCLUSION: Balsalazide is approved for the treatment of mild-to-moderate active UC. It is efficacious for the induction of remission in mild to moderate UC and has a favorable safety profile, with the added advantages of greater efficacy of remission induction and rapidity of onset.

Chemoprevention of colonic polyps with balsalazide: an exploratory, double-blind, placebo-controlled study.

BACKGROUND: A number of agents, including aspirin, nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, folic acid, calcium, and vitamins, have been evaluated for their potential in chemoprevention of sporadic colorectal adenomas or cancer. Preclinical data suggest that 5-aminosalicylates also may have a chemopreventive effect. AIM: To investigate chemoprevention of colonic polyps with balsalazide, a 5-aminosalicylate prodrug. METHODS: In this randomized, double-blind, placebo-controlled study, adults diagnosed with small polyps in the rectosigmoid colon were treated with either balsalazide 3 g/d or placebo for 6 months. Follow-up lower endoscopy was performed, and all polyps were measured and analyzed histologically. The primary endpoint was reduction in mean size of the largest polyp per subject. RESULTS: Among 241 participants screened, 86 were randomized to treatment, with 75 subjects evaluable. Balsalazide 3 g/d (n = 38) did not significantly reduce the mean size of the largest colonic polyp or the number of polyps compared with placebo (n = 37). Although not significant, post-hoc analysis revealed that total adenoma burden per subject, calculated as the sum of the volumes of all adenomas in mm3, increased by 55% in the balsalazide group compared with 95% in the placebo group. CONCLUSIONS: Although balsalazide did not have significant chemopreventive effects on established colonic polyps, these results can aid in designing future prospective studies.

Balsalazide in treating colonic diseases.

Balsalazide is the newer 5-aminosalicylic acid (5-ASA) prodrug which releases active 5-ASA only into the colon with minimal systemic absorption. The onset of action of this drug is variable, and it may take at least some days to reach clinical effectiveness. Clinical studies found balsalazide faster than mesalazine in the induction of remission, but balsalazide has no benefit compared with mesalazine in preventing relapse in the population selected. However, the high number of pills to take may affect the adherence to the treatment. This 5-ASA prodrug may be effectively used also in patients unable to tolerate other mesalamine compounds for non-hypersensitivity reasons. The costs of balsalazide capsules seem to be lower for the health system, both considering total direct healthcare costs and better outcomes, compared with patients treated with oral mesalazine. Finally, there is also some recent evidence that balsalazide may be effectively used, in combination with probiotics, in treating acute uncomplicated diverticulitis is the colon.

Safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate active ulcerative colitis: results of a randomized, double-blind study.

OBJECTIVES: : A multicenter, double-blind study was conducted to evaluate the safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate ulcerative colitis (UC). PATIENTS AND METHODS: : Sixty-eight patients, 5 to 17 years of age, with mild-to-moderate active UC based on the modified Sutherland UC activity index (MUCAI) were randomized to receive oral balsalazide 2.25 or 6.75 g/day for 8 weeks. The primary endpoint was clinical improvement (reduction of the MUCAI score by > or =3 points from baseline). Clinical remission (MUCAI score of 0 or 1 for stool frequency) and histological improvement after 8 weeks were also assessed. Pharmacokinetic parameters for balsalazide, 5-aminosalicylic acid, and N-acetyl-5-aminosalicylic acid were determined at 2 weeks. Adverse events and laboratory changes were monitored throughout the study. RESULTS: : Clinical improvement was achieved by 45% and 37% of patients and clinical remission by 12% and 9% of patients receiving 6.75 and 2.25 g/day, respectively. Improvement in histologic grade was achieved by 8 of 16 (50%) and 3 of 10 (30%) patients receiving 6.75 and 2.25 g/day, respectively. No significant differences were seen in efficacy. Pharmacokinetics in 12 patients were characterized by large interpatient variability and low systemic exposure. Adverse events were similar between the treatment groups, the most common being headache and abdominal pain. No clinically significant changes were observed in laboratory values, including those indicative of hepatic or renal toxicity. CONCLUSIONS: : Balsalazide is well tolerated and improves the signs and symptoms of mild-to-moderate active UC in pediatric patients 5 to 17 years of age.

[Effect of balsalazide on intestinal mucosal permeability of dextran sulfate sodium-induced colitis in mice].

OBJECTIVE: To investigate the effect of balsalazide on intestinal mucosal permeability of experimental colitis induced by dextran sulfate sodium(DSS) in a mouse model and its possible mechanism. METHODS: Forty-five C57BL/6J mice were randomly divided into five groups. Normal group was only fed with distilled water, DSS group and Balsalazide groups at doses of 42,141,423 mg/kg were fed with 5% DSS. Balsalazide was given by intragastric administration. DAI was evaluated daily. At the end of the experiment, colon tissue was collected for assessment of histological changes, MDA content, MPO, SOD and GSH-PX activity. Small intestinal mucosa was collected for assessment of transmission electron microscope(TEM), and detection of permeability by Evans blue. RESULTS: Compared with normal group, DSS group mice all manifested severe weight loss associated with hematochezia and diarrhea with significant increase of DAI and HI score(P<0.01). MDA content and MPO activity was increased with the reverse result of SOD and GSH-PX(P<0.01) in DSS group. Intestinal mucosa showed a focal reduction in thinning of microvillous carpet and even a total disarrangement of epithelial surface, with decurtated and broaden junctional complex and enlarged intercellular space under TEM observations in DSS group. The amount of Evans blue permeated into intestinal wall was obvious in DSS group. Compared with DSS group, balsalazide improved gross findings, decreased MPO activity and MDA content, but increased the activity of SOD and GSH-PX(P<0.05). The amount of Evans blue permeated into intestinal wall was less(P<0.05). Ileal microvillous carpet was ameliorated in dose-dependent manner by balsalazide. CONCLUSIONS: Intestinal mucosal permeability is increased in DSS group. Balsalazide can significantly ameliorate intestinal mucosal permeability in colitis model.

Comparison of mesalazine and balsalazide in induction and maintenance of remission in patients with ulcerative colitis: a meta-analysis.

BACKGROUND: 5-Aminosalicylates are the standard treatment for induction and maintenance of remission in mild-to-moderate ulcerative colitis. In recent years, the 5-aminosalicylic acid-containing pro-drug balsalazide has been the focus of attention. AIM: To compare the efficacy and tolerance of balsalazide and mesalazine by meta-analysis. METHODS: Pubmed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies comparing the efficacy and/or tolerance of balsalazide with mesalazine in the management of UC. The search terms were: "mesalazine" or "5-aminosalicylic acid" and "balsalazide" and "ulcerative colitis." Data were collected from 1966 to 2007 (up to February). There was no language restriction. "Symptomatic remission," "complete remission," "relapse rate," "total adverse events," and "withdrawals because of adverse events" were the key outcomes of interest. RESULTS: Six randomized placebo-controlled clinical trials met our criteria and were included in the meta-analysis. In these "symptomatic remission," "complete remission," "relapse rate," "total adverse events," and "withdrawals because of adverse events" were evaluated in three, three, two, five, and six of the trials, respectively. They included 653 patients consisting of 55.4% men and 44.6% women randomized to receive either balsalazide or mesalazine. Pooling of three trials for symptomatic remission yielded a significant relative risk (RR) of 1.23 (95% confidence interval of 1.03-1.47, P = 0.02). The summary RR for complete remission in three trials was 1.3 (95% CI of 1.002-1.68, P = 0.048). Pooling of two trials for the outcome of relapse yielded a non-significant RR of 0.77 (95% CI of 0.56-1.07, P = 0.12). Pooling five studies from which data for any adverse events were extracted, yielded a non-significant RR of 0.87 (95% CI of 0.75-1.001, P = 0.53). The summary RR for withdrawals because of adverse events in six trials was 0.69, a non-significant RR (95% CI of 0.37-1.29, P = 0.24). CONCLUSION: Balsalazide is more effective than mesalazine in induction of remission, but balsalazide has no benefit compared with mesalazine in preventing relapse in the population selected. The number of patients with any adverse events and withdrawals because of severe adverse events is similar for mesalazine and balsalazide.

Balsalazide disodium for the treatment of ulcerative colitis.

5-aminosalicylates remain the first-line treatment for patients with ulcerative colitis. A number of formulations are available for the treatment of active ulcerative colitis, including encapsulated mesalazine and mesalazine in combination with other molecules. Balsalazide is an aminosalicylate prodrug that releases mesalazine in the colon, thus exerting its multiple anti-inflammatory effects in areas of colitis. This review will examine the pharmacological and therapeutic features of balsalazide as an anti-inflammatory agent in ulcerative colitis. The introduction of novel aminosalicylate formulations and an appreciation of their molecular mode of action, has renewed interest in these agents in both maintenance of disease remission and cancer prevention.

Balsalazide plus high-potency probiotic preparation (VSL[sharp]3) in the treatment of acute mild-to-moderate ulcerative colitis and uncomplicated diverticulitis of the colon.

Balsalazide is a 5-amino salicylic acid prodrug well-tolerated and effective in treating acute ulcerative colitis. VSL[sharp]3, a high-potency probiotic mixture, has proved to be effective in preventing flare-ups of chronic pouchitis and in obtaining remission of mild-to-moderate ulcerative colitis. Recent studies found the association of low-dose balsalazide/VLS no. 3 effective in treating mild-to-moderate ulcerative colitis and in preventing the recurrence of uncomplicated diverticulitis of the colon. In this paper, the framework for using this association to treat ulcerative colitis or to prevent the recurrence of colonic diverticulitis is reviewed, and 2 studies on this therapeutic approach are briefly summarized.

Balsalazide and/or high-potency probiotic mixture (VSL#3) in maintaining remission after attack of acute, uncomplicated diverticulitis of the colon.

BACKGROUND AND AIMS: The role of probiotics in the treatment of diverticulitis is still not known. The aim of our study was to investigate whether balsalazide and/or VSL#3 is effective in preventing diverticulitis recurrence. MATERIALS AND METHODS: In this pilot study, 30 consecutive patients (19 males, 11 females, mean age 60.1 years, range 47-75 years) affected by uncomplicated diverticulitis of the colon were monitored. After obtaining remission, the patients were randomly assigned to one of the following groups as follows: group A, balsalazide 2.25 g daily for 10 days every month plus VSL#3 450 billions/day for 15 days every month and group B, VSL#3 alone 450 billions/day for 15 days every month. Primary end-point was considered the maintaining of remission throughout a 12-month follow-up. Secondary end-points considered were (1) the assessment of the overall scores at the end of the follow-up and (2) the effects of the two different treatments with regards to every symptom assessed. RESULTS/FINDINGS: One group A patient was withdrawn from the study at the 6th month and one group B patient was lost at the 6th month of follow-up. One group A patient (6.66%) showed relapse of symptoms at the 10th month of follow-up. At the end of follow-up, 11 patients were completely symptom-free (73.33%), whilst 2 patients complained of only mild, recurrent symptoms (13%). Two group B patients (13.33%) showed relapse of the disease at the 5th and 8th month of follow-up, respectively. At the end of follow-up, 8 patients were completely symptom-free (60%), 2 patients complained of mild, recurrent symptoms (13.33%), 1 patient (6.66%) complained of mild but continuous symptoms. No side effects were recorded throughout the follow-up in both groups. INTERPRETATION/CONCLUSIONS: Combination probiotic/anti-inflammatory drug was found better than probiotic treatment in preventing relapse of uncomplicated diverticulitis of the colon, even if without statistical significance.

Lack of cross-reactivity between 5-aminosalicylic acid-based drugs: a case report and review of the literature.

BACKGROUND: 5-Aminosalicylic acid (5-ASA)-containing drugs are the mainstay of therapy in inflammatory bowel disease, but adverse reactions to these medications are relatively common. Because there may be a lack of cross-reactivity among the various 5-ASA formulations, treatment with alternative preparations is sometimes possible even after an apparent allergic reaction to a 5-ASA product. OBJECTIVE: To describe a patient with a possible allergy to 2 different 5-ASA drugs who tolerated a third. METHODS: A 27-year-old man with Crohn disease developed a rash while taking mesalamine (Pentasa and Asacol). Treatment with 5-ASA products was discontinued, and 6-mercaptopurine and prednisone were prescribed. He then experienced multiorgan failure secondary to herpes simplex infection, which required discontinuation of the immunosuppressive therapy. After recovery from the acute infection, he underwent successful graded challenge with balsalazide. RESULTS: The patient continued treatment with balsalazide for 9 months, with good control of his inflammatory bowel disease and no adverse effects. CONCLUSIONS: Adverse reactions to 1 or more 5-ASA medications do not necessarily preclude the use of others in the same class. A treatment algorithm for patients with adverse reactions to 5-ASA is outlined based on the case report and review of the literature.

Treatment of ulcerative colitis with oral mesalamine: advances in drug formulation, efficacy expectations and dose response, compliance, and chemoprevention.

Sulfasalazine, olsalazine, balsalazide, delayed-release mesalamine, controlled-release mesalamine, mesalamine pellets, and Multi-Matrix System mesalamine are effective first-line therapies for the treatment of mildly to moderately active ulcerative colitis and for subsequent maintenance of remission. For induction therapy it is unclear if there is a dose response above 1.5 g, and for maintenance therapy existing data do not support a dose response above 1.5 g. Sulfasalazine has more frequent side effects than olsalazine, balsalazide, and mesalamine formulations. Once-daily dosing with multi-matrix system mesalamine 1.2 g tablets may lead to optimal compliance. Mesalamine >/= 1.2 g and sulfasalazine >/= 2 g reduce the risk of colorectal cancer in patients with ulcerative colitis. Drug formulations, efficacy expectations and dose response, toxicity expectations, compliance considerations, and chemoprevention considerations are reviewed.

Inadequate treatment of excessive erythrocytosis / Tratamiento inadecuado en la eritrocitosis excesiva

Los pacientes con el mal de montaña crónico o eritrocitosis excesiva (EE) son residentes de la altura (3600 m), con mayor o igual 6.5 x 10 a la sexta glóbulos rojos (GR) que presentan cianosis.Esto ocasiona problemas estéticos y psicológicos en su vida ya que las demás personas creen que son alcohólicos. Cuando hay aumento de los GR, ellos buscan una cura milagrosa. De acuerdo a los conceptos evolutivos de la EE, los tratamientos han incluído; sanguijuelas, radioterapia de la médula ósea mediante administración de substancias radiactivas como el fósforo, y más recientemente, flebotomías, infusiuones de té, tabletas de ajo y la más peligrosa la administración de la fenilhidrazina, agente citotóxico prohibido. Encontramos que la mayoría de los pacientes con EE tienen placas radiográficas de tórax anormales. El concepto de los tratamientos es el de disminuir los GR. Sin embargo, la fenilhidrazina es tóxica para la médula ósea, el hígado y otros tejidos, cambiando el color de la piel de cianótica a icterica. Las conjuntivas se tornan ictéricas y la harina de café oscura. Una vez iniciado el tratamiento, la sangre de los pacientes es analizada periódicamente y el recuento de GR disminuyue, con lo que quedan satisfechos. Sin embargo, este medicamento tóxico puede producir la muerte. Al reducir los GR, el contenido arterial de oxígeno (CaO2) en la sangre disminuye. Las pruebas ergométricas en estos pacientes durante el tratamiento producen gran débito de oxígeno. En el paciente descrito, en el 4to nivel del protocolo de Bruce,m el dolor intenso de ambasd pantorrillas se hizo intolerable y requirió oxígeno post ejercicio. Al interrumpirse la fenilhidrazina, el, CaO2 retorna a niveles normales en aproximadamente 60 días, con una elevación de los GR por encima de los valores iniciales, y mejoría de la capacidad de ejercicio. Este y muchos otros casos nos llevan a creer que la EE es un mecanismo de compensación de la enfermedad pulmonar en la altura y que la cantidad de GR no debe ser disminuída.