Search

The benzenedisulfonamide derivative clorsulon is a potent fasciolicide which is marketed in fixed combination injectables, typically combined with the macrocyclic lactone ivermectin. In the presented pharmacokinetic study, the plasma profile of clorsulon in 32 healthy, young Brown Swiss cattle was administered a single intravenous dose at 3 mg/kg body weight or subcutaneously at 3, 6 or 12 mg/kg body weight (4 intact male and 4 female animals per treatment) as a 30% w/v clorsulon injection formulation. Serial blood samples were collected up to 24 days after administration to establish the pharmacokinetics, bioavailability and dose proportionality of clorsulon. Following a single intravenous injection of clorsulon at 3 mg/kg body weight, the area under the concentration versus time curve from the start of dose administration to the time of the last quantifiable concentration (AUC last ) was 4830 ± 941 day*ng/mL, and half-live was 2.37 ± 0.98 days. The back extrapolated concentration at time 0 was 38,500 ± 6070 ng/mL. The volume of distribution at steady state and clearance were 685 ± 107 mL/kg and 664 ± 127 mL/day/kg, respectively. In the groups dosed at 3, 6 or 12 mg/kg body weight by subcutaneous injection, clorsulon plasma concentrations rose to maximum within 0.5 day and decreased to the last sample point. For these groups, the maximum plasma clorsulon concentrations were 3100 ± 838, 5250 ± 1220 and 10,800 ± 1730 ng/mL, respectively, and the AUC last was 5330 ± 925, 9630 ± 1300 and 21,500 ± 3320 day*ng/mL, respectively. Half-lives, 2.01 ± 0.62, 3.84 ± 1.42 and 5.36 ± 0.60 days, respectively, increased significantly with dose, likely related to increasing dose volume. Clorsulon was well absorbed and fully bioavailable (103%-114%) after subcutaneous injection. No gender-related difference in systemic exposure was observed. Assessment of C max and AUC last demonstrated a proportional increase in systemic exposure to the clorsulon subcutaneous doses over the range of 3-12 mg/kg body weight., (© 2023 John Wiley & Sons Ltd.)

Torasemide is a loop diuretic with a molecule that is chemically similar to the sulphonamides described as eosinophilic granulomatosis with polyangiitis (EGPA) triggering drugs. The presented case is probably the first description of torasemide-induced vascular purpura in the course of EGPA. Any diagnosis of vasculitis should be followed by an identification of drugs that may aggravate the disease. A 74-year-old patient was admitted to the Department of Dermatology with purpura-like skin lesions on the upper, and lower extremities, including the buttocks. The lesions had appeared around the ankles 7 days before admission to the hospital and then started to progress upwards. The patient complained on lower limb paresthesia and pain. Other comorbidities included bronchial asthma, chronic sinusitis, ischemic heart disease, mild aortic stenosis, arterial hypertension, and degenerative thoracic spine disease. The woman had previously undergone nasal polypectomy twice. She was on a constant regimen of oral rosuvastatin 5 mg per day, spironolactone 50 mg per day, metoprolol 150 mg per day, inhaled formoterol 12 μg per day, and ipratropium bromide 20 μg per day. Ten days prior to admission, she was commenced on torasemide at a dose of 50 mg per day prescribed by a general practitioner due to high blood pressure. Doppler ultrasound upon admission to the hospital excluded deep venal thrombosis. The laboratory tests revealed leukocytosis (17.1 thousand per mm3) with eosinophilia (38.6%), elevated plasma level of C-reactive protein (119 mg per L) and D-dimers (2657 ng per mm3). Indirect immunofluorescent test identified a low titer (1:80) of antinuclear antibodies, but elevated (1:160) antineutrophil cytoplasmic antibodies (ANCA) in the patient's serum. Immunoblot found them to be aimed against myeloperoxidase (pANCA). A chest X-ray showed increased vascular lung markings, while high-resolution computed tomography revealed peribronchial glass-ground opacities. Microscopic evaluation of skin biopsy taken from the lower limbs showed perivascular infiltrates consisting of eosinophils and neutrophils, fragments of neutrophil nuclei, and fibrinous necrosis of small vessels. Electromyography performed in the lower limbs because of their weakness highlighted a loss of response from both sural nerves, as well as slowed conduction velocity of the right tibial nerve and in both common peroneal nerves. Both clinical characteristics of skin lesions and histopathology suggested a diagnosis of EGPA, which was later confirmed by a consultant in rheumatology. The patient was commenced on prednisone at a dose of 0.5 mg per kg of body weight daily and mycophenolate mofetil at a daily dose of 2 g. The antihypertensive therapy was modified, and torasemide was replaced by spironolactone 25 mg per day. The treatment resulted in a gradual regression of skin lesions within a few weeks. The first report of EGPA dates back to 1951. Its authors were Jacob Churg and Lotte Strauss. They described a case series of 13 patients who had severe asthma, fever, peripheral blood eosinophilia, and granulomatous vasculitis in microscopic evaluation of the skin. Three histopathological criteria were then proposed, and Churg-Strauss syndrome was recognized when eosinophilic infiltrates in the tissues, necrotizing inflammation of small and medium vessels, and the presence of extravascular granulomas were observed together in a patient (1). Only 17.4% of patients met all three histopathological criteria, and the diagnosis of the disease was frequently delayed despite of its overt clinical picture (2). In 1984, Lanham et al. proposed new diagnostic criteria which included the presence of bronchial asthma, eosinophilia in a peripheral blood smear >1.5 thousand per mm3, and signs of vasculitis involving at least two organs other than the lungs (3). Lanham's criteria could also delay the recognition of the syndrome before involvement of internal organs, and the American College of Rheumatology therefore established classification criteria in 1990. These included the presence of bronchial asthma, migratory infiltrates in the lungs as assessed by radiographs, the presence of abnormalities in the paranasal sinuses (polyps, allergic rhinitis, chronic inflammation), mono- or polyneuropathy, peripheral blood eosinophilia (>10% of leukocytes must be eosinophils), and extravascular eosinophilic infiltrates in a histopathological examination. Patients who met 4 out of 6 criteria were classified as having Churg-Strauss syndrome (4). The term EGPA was recommended to define patients with Churg-Strauss syndrome in 2012 (5). EGPA is a condition with low incidence (0.11-2.66 cases per million) and morbidity. It usually occurs in the fifth decade of life (6,7), although 65 cases reports of EGPA in people under 18 years of age could be found in the PubMed and Ovid Medline Database at the end of 2020 (8). The etiopathogenesis of the disease has not been fully explained so far. Approximately 40-60% of patients are positive to pANCA (9), but the role of these antibodies in the pathogenesis of EGPA remains unclear. They are suspected to mediate binding of the Fc receptor to MPO exposed on the surface of neutrophils. Subsequently, this may active neutrophils and contribute to a damage of the vascular endothelium (9,10). Glomerulonephritis, neuropathy, and vasculitis are more common in patients with EGPA who have detectable pANCA when compared with seronegative patients. There are at least several drugs which potentially may EGPA. The strongest association with the occurrence of EGPA was found with the use of leukotriene receptor antagonists (montelukast, zafirlukast, pranlukast), although they are commonly used in the treatment of asthma, which is paradoxically one of the complications of the syndrome (13). Although no relationship has been demonstrated so far between the occurrence of EGPA and the intake of drugs from the groups used by the presented patient, a clear time relationship can be observed between the commencement of torasemide and the onset of symptoms in our patient. To date, only three cases of leukocytoclastic vasculitis have been reported after the administration of torasemide. Both of them developed cutaneous symptoms of the disease within 24 hours of the administration of torasemide in patients with no previous history of drug hypersensitivity, but they disappeared quickly within 8-15 days after drug discontinuation (14,15). The chemical structure of torasemide is similar to the molecule of sulfonamides which were previously found to be a triggering factors for EGPA (12). This drug belongs to the group of loop diuretics classified as sulfonamide derivatives. A comparison of the chemical structure of torasemide and sulphanilamide molecules is presented in Figure 1. The clear time relationship between starting the administration of torasemide and the occurrence of purpura-like lesions suggests that it was an aggravating factor for EGPA in our patient. A coexistence of several disorders (asthma, nasal polyps, symptoms of peripheral neuropathy) in our patient suggest EGPA could have developed in her years before oral intake of torasemide. The sudden onset of skin symptoms shows torasemide to be possible inducing factor for the development of vascular purpura in patients suffering from EGPA but without previous cutaneous involvement.

The human ether-à-go-go related gene (HERG) encodes the alpha subunit of Kv11.1, which is a voltage-gated K + channel protein mainly expressed in heart and brain tissue. HERG plays critical role in cardiac repolarization, and mutations in HERG can cause long QT syndrome. More recently, evidence has emerged that HERG channels are aberrantly expressed in many kinds of cancer cells and play important roles in cancer progression. HERG could therefore be a potential biomarker for cancer and a possible molecular target for anticancer drug design. HERG affects a number of cellular processes, including cell proliferation, apoptosis, angiogenesis and migration, any of which could be affected by dysregulation of HERG. This review provides an overview of available information on HERG channel as it relates to cancer, with focus on the mechanism by which HERG influences cancer progression. Molecular docking attempts suggest two possible protein-protein interactions of HERG with the ß1-integrin receptor and the transcription factor STAT-1 as novel HERG-directed therapeutic targeting which avoids possible cardiotoxicity. The role of epigenetics in regulating HERG channel expression and activity in cancer will also be discussed. Finally, given its inherent extracellular accessibility as an ion channel, we discuss regulatory roles of this molecule in cancer physiology and therapeutic potential. Future research should be directed to explore the possibilities of therapeutic interventions targeting HERG channels while minding possible complications., Competing Interests: Declaration of Competing Interest The authors assert that they have no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A long-acting loop diuretic, azosemide, has been shown to improve long-term prognosis in patients with heart failure compared with a short-acting loop diuretic, furosemide. However, the therapeutic advantages of azosemide over furosemide have not been clearly established. In this study, we retrospectively analyzed clinical outcomes and laboratory data in patients with congestive heart failure treated with furosemide or azosemide, and the efficacy of these agents was compared. First, we screened 1900 patients and selected 124 (furosemide group: n = 40; azosemide group: n = 84) as the total study population. From these patients, we next selected 72 patients for the propensity score-matched analysis (furosemide group: n = 36; azosemide group: n = 36). The incidence of all-cause death and rehospitalization due to worsening heart failure during 24 months of follow-up was similar between the furosemide and azosemide groups in both the total study population and the propensity score-matched population. However, in the propensity score-matched analysis, the estimated glomerular filtration rate time-dependently decreased during 36 months of follow-up in the furosemide group (56.5 ± 19.5-43.2 ± 16.3 mL/min/1.73 m), whereas it did not change in the azosemide group (58.6 ± 22.0-50.3 ± 17.8 mL/min/1.73 m) (P = 0.032). Azosemide might have some potential advantage for renal protection over furosemide in patients with congestive heart failure.

Objectives: Diabetic foot ulcers (DFUs) often lead to hospital admissions, amputations and deaths; however, there is no up-to-date information on microbial isolates from DFUs and no mention of utilization of molecular techniques in Sub-Saharan Africa. We conducted a cross-sectional study among 83 adult patients at a tertiary hospital in Kenya over 12 months. The study aimed to isolate, identify bacteria, their antibiotic susceptibility patterns in active DFUs, and to compare standard microbiological methods versus a real-time PCR commercial kit in the detection of Staphylococcus aureus DNA and methicillin-resistant S. aureus (MRSA) DNA., Results: Eighty swabs (94%) were culture-positive; 29% were Gram-positive and 65% were Gram-negative. The main organisms isolated were S. aureus (16%), Escherichia coli (15%), Proteus mirabilis (11%), Klebsiella pneumoniae (7%) and Pseudomonas aeruginosa (7%). The bacterial isolates showed resistance to commonly used antibiotics such as ampicillin, amoxicillin, cefepime, ceftazidime, cefuroxime, clindamycin, erythromycin, piperacillin-tazobactam, tetracycline and trimethoprim-sulphamethoxazole (TMPSMX). Thirty-one percent of the S. aureus isolated and 40% of the Gram-negatives were multi-drug resistant organisms (MDROs). There was a high prevalence of nosocomial bacteria. MRSA were not identified using culture methods but were identified using PCR. PCR was more sensitive but less specific than culture-based methods to identify S. aureus.

A series of potent, selective and long-acting quinoline-based sulfonamide human H 1 histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H 1 receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4. The clinical dose in humans is expected to be low (approximately 0.5mg per day) based on the clinical dose used for azelastine and a comparison of efficacy data from animal models for 33b and azelastine., (Copyright © 2017. Published by Elsevier Ltd.)

Epilepsy is one of the most common neurological diseases, with between 34 and 76 per 100,000 people developing epilepsy annually. Epilepsy therapy for the past 100 + years is based on the use of antiepileptic drugs (AEDs). Despite the availability of more than twenty old and new AEDs, approximately 30% of patients with epilepsy are not seizure-free with the existing medications. In addition, the clinical use of the existing AEDs is restricted by their side-effects, including the teratogenicity associated with valproic acid that restricts its use in women of child-bearing age. Thus, there is an unmet clinical need to develop new, effective AEDs. In the present study, a novel class of carbamates incorporating phenethyl or branched aliphatic chains with 6-9 carbons in their side-chain, and 4-benzenesulfonamide-carbamate moieties were synthesized and evaluated for their anticonvulsant activity, teratogenicity and carbonic anhydrase (CA) inhibition. Three of the ten newly synthesized carbamates showed anticonvulsant activity in the maximal-electroshock (MES) and 6 Hz tests in rodents. In mice, 3-methyl-2-propylpentyl(4-sulfamoylphenyl)carbamate(1), 3-methyl-pentan-2-yl-(4-sulfamoylphenyl)carbamate (9) and 3-methylpentyl, (4-sulfamoylphenyl)carbamate (10) had ED 50 values of 136, 31 and 14 mg/kg (MES) and 74, 53, and 80 mg/kg (6 Hz), respectively. Compound (10) had rat-MES-ED 50  = 13 mg/kg and ED 50 of 59 mg/kg at the mouse-corneal-kindling test. These potent carbamates (1,9,10) induced neural tube defects only at doses markedly exceeding their anticonvuslnat-ED 50 values. None of these compounds were potent inhibitors of CA IV, but inhibited CA isoforms I, II and VII. The anticonvulsant properties of these compounds and particularly compound 10 make them potential candidates for further evaluation and development as new AEDs.

We have previously reported that a long-acting loop diuretic, azosemide, reduces cardiovascular risks in patients with chronic heart failure (CHF) as compared with a short-acting one, furosemide, in Japanese Multicenter Evaluation of LOng- versus short-acting Diuretics In Congestive heart failure (J-MELODIC). However, the mechanisms of the difference have not been elucidated. This study aimed to examine whether there is a difference in the reduction in plasma brain natriuretic peptide (BNP) level and in left ventricular (LV) functional recovery between the CHF patients treated with the long-acting diuretic (the azosemide group) and the short-acting diuretic (the furosemide group). We reviewed changes in plasma BNP level and echo-assessed LV functional parameters from baseline to a year after the entry in 288 CHF patients with New York Heart Association class II or III symptoms that joined J-MELODIC. The decrease in plasma BNP levels was larger in the azosemide group than in the furosemide group (p < 0.01). The changes in echocardiographic parameters were not more favorable in the azosemide group than in the furosemide group. In conclusion, the decrease in plasma BNP levels was larger in the azosemide group than in the furosemide group. These findings may account for the better prognosis in CHF patients treated with azosemide than those with furosemide in J-MELODIC.

Introduction: Carbonic anhydrase inhibitors (CAIs) of the sulfonamide and sulfamate type are clinically used drugs as diuretics, antiglaucoma, antiepileptic, antiobesity and anti-high altitude disease agents. Anticancer agents based on CAIs are also in clinical development for the management of hypoxic, metastatic tumors. Acetazolamide, methazolamide, dichlorophenamide, dorzolamide and brinzolamide are mainly used as antiglaucoma drugs, sulthiame, topiramate and zonisamide as antiepileptic/antiobesity agents, celecoxib and polmacoxib are dual carbonic anhydrase/cycloxygenase inhibitors. Girentuximab, a monoclonal antibody and SLC-0111, a sulfonamide inhibitor, are in clinical trials as anticancer agents., Areas Covered: The drug interactions with many classes of pharmacological agents are reviewed. Some of these drugs, such as acetazolamide, topiramate and celecoxib show a large number of interactions with non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, antiepileptics, immunosupressants, anticholinesterase drugs, β-blockers, anesthetics, oral contraceptives, anticancer agents, antifungals, anti-mycobacterials, lithium, metformin and clopidogrel., Expert Opinion: The multiple drug interactions in which CAIs are involved should be carefully considered when such drugs are used in combination with the drug classes mentioned above, as the risks of developing toxicity and serious side effects if the dosages are not adjusted are high. There are also synergistic effects between CAIs and some NSAIDs, anticancer agents and benzodiazepines for the management of cystoid macular edema, some tumor types and neuropathic pain, respectively.

The emergence of multidrug-resistant (MDR) uropathogens is making the treatment of urinary tract infections (UTIs) more challenging. We sought to evaluate the accuracy of empiric therapy for MDR UTIs and the utility of prior culture data in improving the accuracy of the therapy chosen. The electronic health records from three U.S. Department of Veterans Affairs facilities were retrospectively reviewed for the treatments used for MDR UTIs over 4 years. An MDR UTI was defined as an infection caused by a uropathogen resistant to three or more classes of drugs and identified by a clinician to require therapy. Previous data on culture results, antimicrobial use, and outcomes were captured from records from inpatient and outpatient settings. Among 126 patient episodes of MDR UTIs, the choices of empiric therapy against the index pathogen were accurate in 66 (52%) episodes. For the 95 patient episodes for which prior microbiologic data were available, when empiric therapy was concordant with the prior microbiologic data, the rate of accuracy of the treatment against the uropathogen improved from 32% to 76% (odds ratio, 6.9; 95% confidence interval, 2.7 to 17.1; P < 0.001). Genitourinary tract (GU)-directed agents (nitrofurantoin or sulfa agents) were equally as likely as broad-spectrum agents to be accurate (P = 0.3). Choosing an agent concordant with previous microbiologic data significantly increased the chance of accuracy of therapy for MDR UTIs, even if the previous uropathogen was a different species. Also, GU-directed or broad-spectrum therapy choices were equally likely to be accurate. The accuracy of empiric therapy could be improved by the use of these simple rules., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background/aims: Type 2 diabetic kidney disease (DKD) is frequently accompanied by uncontrollable hypertension due to the sodium sensitivity inherent in DKD and to diuretic-resistant edema. In general, diuretics are effective in treating this condition, but thiazide diuretics are thought to be innocuous in advanced chronic kidney disease (CKD). We examined the renoprotective effects of combination therapy with thiazides and loop diuretics in type 2 DKD patients with CKD stage G4 or G5., Methods: This study included 11 patients with type 2 DKD and an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m(2) who were suffering from severe edema even with loop diuretics. Each patient received additional hydrochlorothiazide (HCTZ) therapy, which was continued for more than 12 months. We examined clinical parameters including blood pressure (BP), proteinuria, and eGFR before and after the addition of HCTZ., Results: Patients received a 13.6 ± 3.8 mg/day dose of HCTZ in addition to loop diuretics (azosemide: 120 mg/day in 6 cases, 60 mg/day in 3 cases and furosemide: 80 mg/day in 1 case, 120 mg/day in 1 case). Side effects of HCTZ were not observed in all patients. After the addition of HCTZ therapy, systolic and diastolic blood pressures (S-BP, D-BP) as well as proteinuria significantly decreased (S-BP: at 6 months, p < 0.05 and 12 months, p < 0.01 vs. 0 month, D-BP: at 12 months, p < 0.05 vs. 0 month, proteinuria: at 6 months, p < 0.05 and 12 months, p < 0.01 vs. 0 month). The annual decline in eGFR was not significantly different before and after HCTZ therapy (-7.7 ± 8.5 and -8.4 ± 4.8 mL/min/1.73 m(2)/year, respectively)., Conclusion: Our findings suggest that the combination of HCTZ and loop diuretics improves BP levels, and decreases proteinuria even in advanced stage type 2 DKD patients with severe edema. The addition of HCTZ therapy was not found to negatively affect the change in eGFR in the present study.

The efficacy and tolerability of combined chondroprotectors Teraflex® in patients with diabetes mellitus type 1 and 2, complicated by arthropathy were investigated. It was established, that Tera- flex® therapy positively influences on the development of diabetic arthropathy (reducing intensity of pain, increasing the range of movements and reduced volume of the affected joints, increasing the functionality of the patient). In addition, an analysis of the impact of chondroprotectors on the level of sugar among patients.It was found, that it is necessary to control blood sugar while taking chondroprotectors and if needed, increasing the dose of hypoglycohaemic drugs during this period.

In the current study, we identified five sheep flocks with fasciolosis in the province of León (northwestern Spain) in order to determine the anthelmintic resistance status to three commonly used anthelmintics, namely albendazole (ABZ), triclabendazole (TCBZ) and clorsulon (CLOR). The identification of one flock resistant to ABZ and CLOR was shown after the faecal egg count reduction test (FECRT). The reductions in eggs per gram values were -17.6% and -68% against immature and adult flukes, respectively, after ABZ treatment; 85.15% and 44.91% against immature and adult flukes, respectively, after CLOR treatment; and 97.06% against both stages, after the administration of TCBZ. As an alternative to control the infection, two combinations of ABZ and CLOR were tested. In the first, both drugs were administered at the recommended dose of each; in this case, the efficiency reached values above 95% against both immature and adult flukes. However, when the combined drugs were administered at half the recommended dose of each, the efficiency of the combination was very low, i.e. 16.67% and -11.11% against mature and immature flukes, respectively. In conclusion, this preliminary report suggests a possible interaction between ABZ and CLOR after their joint administration. However, these results should be confirmed in other flocks., (Copyright © 2014. Published by Elsevier Inc.)

Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the treatment of glaucoma, a disease affecting a large number of people and characterized by an elevated intraocular pressure (IOP). At least three isoforms, CA II, IV and XII are targeted by the sulfonamide inhibitors, some of which are clinically used drugs. Acetazolamide, methazolamide and dichlorophenamide are first generation CA inhibitors (CAIs) still used as systemic drugs for the management of this disease. Dorzolamide and brinzolamide represent the second generation inhibitors, being used topically, as eye drops, with less side effects compared to the first generation drugs. Third generation inhibitors have been developed by using the tail approach, but they did not reach the clinics yet. The most promising such derivatives are the sulfonamides incorporating either tails with nitric oxide releasing moieties or hybrid drugs possessing prostaglandin (PG) F agonist moieties in their molecules. Recently, the dithiocarbamates have also been described as CAIs possessing IOP lowering effects in animal models of glaucoma. CAIs are used alone or in combination with other drugs such as adrenergic agonist/antagonists, or PG analogs, being an important component of the antiglaucoma drugs armamentarium.

Bot fly larvae (Philornis genus) are obligate subcutaneous blood-feeding parasites of Neotropical birds including psittacines. We analyze twelve years of data on scarlet macaw (Ara macao) nestlings in natural and artificial nests in the lowland forests of southeastern Peru and report prevalence and intensity of Philornis parasitism. Bot fly prevalence was 28.9% while mean intensity was 5.0 larvae per infected chick. Prevalence in natural nests (11%, N=90 nestlings) was lower than in wooden nest-boxes (39%, N=57) and PVC boxes (39%, N=109). We describe a new technique of removing Philornis larvae using a reverse syringe design snake bite extractor. We compare this new technique to two other methods for removing bots from macaw chicks and find the new method the most suitable., (Copyright © 2013 Elsevier B.V. All rights reserved.)

More research effort needs to be invested in antimicrobial drug development to address the increasing threat of multidrug-resistant organisms. The enzyme DHPS has been a validated drug target for over 70 years as the target for the highly successful sulfa drugs. The use of sulfa drugs has been compromised by the widespread presence of resistant organisms and the adverse side effects associated with their use. Despite the large amount of structural information available for DHPS, few recent publications address the possibility of using this knowledge for novel drug design. This article reviews the relevant papers and patents that report promising new small-molecule inhibitors of DHPS, and discuss these data in light of new insights into the DHPS catalytic mechanism and recently determined crystal structures of DHPS bound to potent small-molecule inhibitors. This new functional understanding confirms that DHPS deserves further consideration as an antimicrobial drug target.

Efflux transporters belonging to the family of ABC transporters have an important functional role in the maintenance of the intestinal barrier. As efflux transporters they prevent the absorption of toxic substances from feed, while at the same time facilitating the excretion of metabolic waste products as well as drugs from the circulation into the intestinal lumen. As Eimeria tenella infection significantly affects the integrity of caecum, the effects of experimental E. tenella infection on the levels of expression of ABCB1 mRNAs in the intestines and livers of broilers were evaluated. ABCB1 mRNA expression was quantified by qRT-PCR. Its expression levels were significantly down-regulated in the caecum of infected animals. The levels of ABCB1 mRNA were not changed in the duodenum and the liver. After treatment of the animals with sulfapyrazine for three days, not only a significant improvement of the clinical appearance but also a normalization of the P-gp expression was noticed. Although the current study cannot distinguish between the direct effect of the drug on the host and the drug action on the parasite, these results suggest that the treatment of coccidiosis with sulfachlorpyrazine also restored the expression of the investigated efflux transporter in the caecum. This is of clinical significance as P-glycoproteins contribute to the integrity of intestines and their function as important biological barriers, protecting poultry from pathogens and toxic compounds in animal feeds.

Interleukin (IL)-12 and IL-10 are immunoregulatory cytokines with an antagonistic effect on the T-helper (Th)1/Th2 cytokine balance and they provide a functional link between innate resistance and the adaptive immune response. This investigation was conducted to determine the expression of IL-10 and IL-12B mRNA levels in chickens' gut mucosa infected with Eimeria tenella and in sulfachlorpyrazine-sodium treated animals after infection. Broiler chickens were randomly allocated in three groups: healthy untreated control; infected untreated animals and infected, treated with sulfachlorpyrazine sodium chickens 6 days after the challenge with an E. tenella. Quantitative real time PCR analysis was performed using specific primer pairs and probes for IL-10 and IL-12B. The expression of IL-10 mRNA was greater in the duodenum then in the caecum and the liver of healthy chickens. E. tenella infection led to significant up-regulation of IL-10 mRNA in the caecum, followed by mRNA in the liver. A significant down regulation was observed mainly in the caecum after the treatment with sulfachlorpyrazine. In contrast, IL-12B expression in all investigated tissues remained insignificantly affected in the studied groups of animals. Distinct up-regulation of IL-10 mRNA, after the challenge with E. tenella, in the caecum can be attributed to the tissue tropism of Eimeria spp. The production of IL-12 is regulated by negative feedback through IL-10 which explains lack of increase in IL-12B mRNA. Sulfonamide treatment resulted in clinical improvement and restoration of IL-10 mRNA to the levels observed in healthy chickens., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The objective of this study was to evaluate the efficacy of a pour-on solution containing moxidectin plus triclabendazole (MOX plus TCBZ) against immature and adult stages of the liver fluke in cattle and compare the efficacy with other commercially available preparations. To this end, 104 male Holstein-Friesian calves aged between 3 and 4 months, were randomly allocated to 13 groups of eight animals each, and infected with approximately 500 Fasciola hepatica metacercariae. One group remained untreated, four groups were treated with MOX plus TCBZ at a dose rate of 0.1 mL/kg, four other groups were treated with ivermectin (IVM) plus clorsulon injectable at a dose rate of 0.02 mL/kg, and the remaining four groups were treated with IVM plus closantel pour-on at a dose rate of 0.1 mL/kg. Each treatment was applied to one of the groups at 4 weeks, 6 weeks, 8 weeks and 12 weeks after the experimental infection. At necropsy (99-102 days after infection), all untreated animals were infected with a minimum of 30 flukes. The MOX plus TCBZ treated animals had significantly (P<0.0001) lower fluke counts compared to the untreated control animals at all time points after treatment. Efficacy against 8-week old and adult flukes was >99.5%. For 6-week old immature fluke, the efficacy was 98.0% and for 4-week old immature fluke the efficacy was 90.9%. The IVM plus closantel pour-on treated animals had significantly lower fluke counts compared to the untreated control animals for adult and 8-week old flukes (P<0.0001), and for 6-week old flukes (P=0.002). The efficacy was 26.8%, 68.2%, 90.6% and 99.3% against 4-week, 6-week and 8-week old immature flukes, and adult flukes respectively. The IVM plus clorsulon treated animals had significantly lower fluke counts compared to the untreated control animals for adult (P<0.0001) and 8-week old (P<0.05) flukes. The efficacy was 29.7%, 43.4%, 53.2% and 99.2% against 4-week, 6-week and 8-week old immature flukes, and adult flukes respectively. For treatments at 4, 6 and 8 weeks after infection, the fluke counts were significantly (P<0.0001) lower for the MOX plus TCBZ treatment than for IVM plus closantel or IVM plus clorsulon. The results confirm the high efficacy (>90%) of the MOX plus TCBZ pour-on combination against 4-week old to adult liver fluke in cattle. The IVM plus closantel pour-on combination was effective (>90%) against 8-week old and adult flukes, but had low efficacy against 4- and 6-week old fluke. The IVM plus clorsulon injectable combination was effective (>90%) against adult fluke only., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Loop diuretics have two different classes with different duration of activity: short-acting such as furosemide (duration of activity, 6h) and long-acting such as azosemide (duration of activity, 10-12h). We conducted a multicenter, randomized, controlled trial in order to compare the therapeutic effects of azosemide, a long-acting loop diuretic, and furosemide, a short-acting one, on neurohumoral factors and cardiac function in outpatients with chronic heart failure (CHF)., Methods: We enrolled 98 patients with CHF who were receiving furosemide and an angiotensin-converting enzyme inhibitor, and they were randomly divided into furosemide (n=49) and azosemide (n=49) groups. The furosemide group continued furosemide at the same dosage, and the azosemide group switched from furosemide to azosemide. At baseline and after 3 months, we measured body weight, and levels of brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), norepinephrine, active renin, creatinine, blood urea nitrogen, sodium, potassium, and hematocrit. Chest X-ray and echocardiography were also performed., Results: Body weight and plasma levels of BNP and ANP significantly decreased after 3 months in the azosemide group compared to the furosemide group. There were no significant differences in changes of levels of creatinine, blood urea nitrogen, sodium, potassium, hematocrit, norepinephrine, and active renin after 3 months between the furosemide and azosemide groups. Echocardiography and chest X-ray did not demonstrate significant differences between the two groups., Conclusions: Long-acting azosemide is suggested to be useful for the improvement of neurohumoral factors compared with short-acting furosemide in patients with CHF., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Diuretics are the most prescribed drug in heart failure (HF) patients. However, clinical evidence about their long-term effects is lacking. The purpose of this study was to compare the therapeutic effects of furosemide and azosemide, a short- and long-acting loop diuretic, respectively, in patients with chronic heart failure (CHF)., Methods and Results: In this multicenter, prospective, randomized, open, blinded endpoint trial, we compared the effects of azosemide and furosemide in patients with CHF and New York Heart Association class II or III symptoms. 320 patients (160 patients in each group, mean age 71 years) were followed up for a minimum of 2 years. The primary endpoint was a composite of cardiovascular death or unplanned admission to hospital for congestive HF. During a median follow-up of 35.2 months, the primary endpoint occurred in 23 patients in the azosemide group and in 34 patients in the furosemide group (hazard ratio [HR], 0.55, 95% confidence interval [CI] 0.32-0.95: P=0.03). Among the secondary endpoints, unplanned admission to hospital for congestive HF or a need for modification of the treatment for HF were also reduced in the azosemide group compared with the furosemide group (HR, 0.60, 95%CI 0.36-0.99: P=0.048)., Conclusions: Azosemide, compared with furosemide, reduced the risk of cardiovascular death or unplanned admission to hospital for congestive HF.

Among the aetiological agents of treatable sexually transmitted diseases (STDs), Neissseria gonorrhoeae is considered to be most important because of emerging antibiotic resistant strains that compromise the effectiveness of treatment of the disease - gonorrhoea. In most of the developing countries, treatment of gonorrhoea relies mainly on syndromic management rather than the aetiological based therapy. Gonococcal infections are usually treated with single-dose therapy with an agent found to cure > 95 per cent of cases. Unfortunately during the last few decades, N. gonorrhoeae has developed resistance not only to less expensive antimicrobials such as sulphonamides, penicillin and tetracyclines but also to fluoroquinolones. The resistance trend of N. gonorrhoeae towards these antimicrobials can be categorised into pre-quinolone, quinolone and post-quinolone era. Among the antimicrobials available so far, only the third-generation cephalosporins could be safely recommended as first-line therapy for gonorrhoea globally. However, resistance to oral third-generation cephalosporins has also started emerging in some countries. Therefore, it has become imperative to initiate sustained national and international efforts to reduce infection and misuse of antibiotics so as to prevent further emergence and spread of antimicrobial resistance. It is necessary not only to monitor drug resistance and optimise treatment regimens, but also to gain insight into how gonococcus develops drug resistance. Knowledge of mechanism of resistance would help us to devise methods to prevent the occurrence of drug resistance against existing and new drugs. Such studies could also help in finding out new drug targets in N. gonorrhoeae and also a possibility of identification of new drugs for treating gonorrhoea.

Aims: Loop diuretics are essential for the treatment of chronic heart failure (CHF) but short-acting diuretics are reported to induce sympathetic nervous system (SNS) activation. This study was performed to compare therapeutic effects of two loop diuretics, long-acting azosemide and short-acting furosemide, using (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy., Methods and Results: Twenty-two patients with New York Heart Association class II-III heart failure and left ventricular dysfunction, who required treatment with a loop diuretic, were included. In this crossover study, 11 patients were randomized to azosemide treatment first and the remaining 11 patients to furosemide. Treatments were administered for 6 months and then patients were crossed over to the second treatment. (123)I-MIBG scintigraphy was performed before and 6 months after the start of treatment with each loop diuretic. Early and delayed images were obtained 20 min and 4 h after administration of (123)I-MIBG, respectively; and the heart/mediastinum (H/M) ratio and washout rate (WR) were measured. In addition, left ventricular ejection fraction (LVEF), levels of brain natriuretic peptide (BNP), and norepinephrine were measured before and 6 months after the start of treatment. No differences were observed between the two groups in terms of concomitant medication, cause of heart failure, H/M ratio, WR, BNP, norepinephrine, or LVEF. The azosemide group exhibited a significant increase in delayed image H/M ratio, and a significant decrease in WR and norepinephrine after the final administration compared with the furosemide group., Conclusion: This study indicates that azosemide suppresses SNS activation compared with furosemide in patients with CHF, suggesting that long-acting loop diuretics may have more beneficial effects on the prognosis of CHF.

The aim of this study was to assess the prevalence of factors associated with oral colonization by Candida spp. in pediatric patients with AIDS. The sample comprised of 117 children. Clinical status, medicines in use, and laboratory findings were obtained from hospital records; sociodemographic data were given by relatives. A dental examination assessed the prevalence of dental caries. The prevalence of oral colonization by Candida was 62%. Only seven children presented clinical manifestation of oral candidosis despite their high viral load index and low-for-age CD4 count. Candida colonization was directly associated with frequent use of antibiotics (prevalence ratio [PR] = 1.44), sulfa drugs (PR = 1.23), alteration in the oral mucosa (PR = 1.55), and untreated dental caries (PR = 1.93). It was inversely associated with the use of antiretroviral therapies (PR = 0.65). Candida albicans was the most frequently detected species (80%); phenotypic tests did not detect C. dubliniensis strains. This study observed a low prevalence of Candida-related oral lesions in these patients, which is compatible with the hypothesis that antiretroviral medicines may have contributed to reducing oral manifestations from Candida infection. The high prevalence of Candida colonization in HIV+/AIDS children with untreated dental caries reinforces the importance of oral health care in interdisciplinary health units that assist these patients., (© 2010 John Wiley & Sons A/S.)

The objective was to compare the efficacy against artificially induced 2- and 4-week old early immature triclabendazole-susceptible liver flukes (Fasciola hepatica) of an injectable combination of nitroxynil, clorsulon and ivermectin with oral and pour-on combination formulations containing triclabendazole. Groups of yearling Angus or Angus cross cattle were confirmed fluke free before being artificially infected with 500 Sunny Corner strain triclabendazole-susceptible liver fluke metacercariae. Two or four weeks after infection, cattle were treated with the test combination Nitromec (10.2mg/kg nitroxynil, 2.0mg/kg clorsulon, 0.2mg/kg ivermectin), or oral Flukazole C+Se (triclabendazole/oxfendazole/Selenium), oral Fasimec C (triclabendazole/ivermectin) or Genesis Ultra Pour-On (triclabendazole/abamectin). At intervals cattle were weighed, faecal sampled for liver fluke egg counts and blood sampled for liver serum enzyme analysis. Cattle were slaughtered 14 weeks after infection for recovery of adult flukes; fluke egg counts and liver pathology assessment. All cattle increased in body weight by 0.4-0.8kg/day but there were no significant differences between control and treated groups or between the treatment groups. Geometric mean 14-week fluke egg counts and total fluke counts for all treatments, were significantly less (p<0.05) than the control group, except for the group treated with Genesis Ultra Pour-On, 2 weeks after infection. Nitromec treatment of 2-week old flukes was 83% and 95% effective as assessed by 14-week egg and fluke counts, respectively, compared to Flukazole C; 96% and 99%, Fasimec C; 70% and 46%, and Genesis Pour-On, which was ineffective, with egg and fluke count reductions of 0% and 8%, respectively. Against 4-week old flukes, Nitromec treatment was 88% and 99% effective when assessed by 14-week egg and fluke counts, respectively, with Flukazole C; 98% and 99%, Genesis Pour-On; 98% and 82% and Fasimec C; 91% and 61% effective, respectively. Group mean levels of the bile duct-associated enzyme gamma glutamyl transpeptidase (GGT) and the parenchymal associated enzymes, aspartate amino-transferase (AST) and glutamate dehydrogenase (GLDH) increased above the normal range 8 and 11 weeks after infection in the untreated control animals and the group treated 2 weeks after infection with Genesis Pour-On. The groups treated with Fasimec at 2 or 4 weeks after infection, also had elevated enzyme levels. The use of liver-associated enzyme assay is supported as supplementary indicators of fluke-induced pathology.

Loop diuretics could adversely influence prognosis due to activation of neurohumoral mechanism in the long term. Previous study showed torasemide, a loop diuretic with anti-aldosteronergic properties, was associated with lower mortality in patients with chronic heart failure (CHF). We evaluated the effects of torasemide, in comparison with azosemide, in patients with CHF. Patients received oral diuretic therapy with torasemide (8 mg/d, n = 15) or azosemide (60 mg/d, n = 15) for 3 months. Torasemide and azosemide were then switched, and the patients were treated for another 3 months. Torasemide treatment induced significant decreases in left ventricular (LV) systolic wall stress (from 259 +/- 95 to 232 +/- 80 kdyn/cm2) and the plasma level of aldosterone (from 133 +/- 61 to 95 +/- 50 pg/mL) and was not associated with a change in the plasma level of norepinephrine. In contrast, the plasma level of norepinephrine was significantly increased (from 370 +/- 170 to 481 +/- 247 pg/mL), whereas LV systolic wall stress was unchanged after azosemide treatment. This study indicates that torasemide treatment reduced LV systolic wall stress without activation of the sympathetic nervous system in patients with CHF. The anti-aldosteronergic properties of torasemide may contribute to its favorable effects.

In the decade 1935-45 the treatment of lobar pneumonia in the developed and warring world underwent a series of evolutions-anti-sera, specific anti-sera, refinement of sulpha drugs, sulpha and anti-sera, the introduction of penicillin for bacteriology, then ophthalmology, and then for penicillin-sensitive bacterial infections such as lobar pneumonia with its many Cooper types of Streptococcus pneumoniae. Penicillin for civilian use was essentially banned in World War II, a ban that early in 1941 two Musgrave Park physicians tried to circumvent. Strict secrecy on the details of penicillin production was enforced. The treatment option chosen by the Musgrave Park physicians in 1941, and the non-availability of penicillin led to sequelae affecting the post-Belfast careers of both patient and physicians.

We compared the therapeutic effect of three anticoccidial drugs (toltrazuril, sulphadimidine and amprolium) in buffalo (Bubalus bubalis) calves experimentally infected with Eimeria bovis (E. bovis) and E. zuernii oocysts (3 x 104oocyst/calf). Buffalo calves (1.5-4 month old, 70-kg body weight) were randomly allocated into 3 groups (9 calves each). Group T was experimentally infected with oocysts and treated with toltrazuril (20 mg/kg BW twice orally at a 1-week interval). Group S was experimentally infected with oocysts and treated with sulphadimidine (125 mg/kg injected IM followed by half dose for 4 successive days). Group A was experimentally infected with oocysts and treated with amprolium (50 mg/kg orally for 7 successive days). Each group had three subgroups (three calves/subgroup) to represent timing of the drug administration: 1st day of coccidia infection (FD), onset of clinical signs of coccidiosis (CC), and onset of oocyst shedding into the faeces (OS). Clinical signs, body-weight gain (BWG) and number of oocysts per gram feces (OPG) were monitored daily for 35 days post-infection (DPI). The OPG were reduced (but the BWG was not different) in the T calves compared to S and A calves. Within the same group, treatment from the 1st day of infection reduced the OPG and increased the BWG compared to the later treatment timings.

Background: Diuretics are the most prescribed medication for heart failure (HF) patients, but clinical evidence of the long-term effects of diuretics are lacking. The present study was designed to compare the therapeutic effects of furosemide, a short-acting loop diuretic, and azosemide, a long-acting one, in patients with HF to test the hypothesis that long-acting diuretics are superior therapy., Methods and Results: The Japanese Multicenter Evaluation of LOng- vs short-acting Diuretics In Congestive heart failure (J-MELODIC) is a multicenter, prospective, randomized trial enrolling a total of 300 patients (150 patients in each group). The primary outcome is a composite of cardiovascular death and unplanned admission to hospital for congestive HF. Other outcomes include all-cause mortality, worsening of the symptoms of HF, or a need for modification of therapy. Serial assessment of echocardiographic and neurohumoral parameters will be conducted over a minimum follow-up period of 2 years., Conclusions: The study results will provide important evidence for the treatment of chronic HF.

The efficacy of Clorsulon (CLS) against experimental schistosomiasis mansoni, using Praziquantel (PZQ) as a therapeutic control was evaluated. Swiss Albino mice were divided into infected non-treated control, PZQ-treated group given a single dose of 500 mg/kg four weeks post infection (PI), and infected mice treated with single, double, and triple doses of 5 mg/kg CLS per dose, one week apart starting from the 4th week PI. All animals were perfused for adults count. Parts of livers and intestines were examined for granulomata number and sizes. Pathological changes in hepatic parenchyma by H&E and Masson trichrome stains were also examined. Results revealed that a single treatment with PZQ caused a significant percentage reduction (%R) of worm load (92.68%), mean egg count in liver and intestine (91.20 & 94.01% respectively), and mean size of liver granulomata was reduced (92.06%). Regarding CLS, the worm burden was reduced proportionally with number of doses given; 87.80, 96.34 & 97.56% in single, double and triple exposures successively. Egg count in liver was decreased by 85.90, 97.01 & 96.23% respectively in treated mice. Number of intestinal granulomata was decreased by 85.28, 94.24 & 95.49% in a similar way. Size of hepatic granulomata was decreased by 89.02, 94.51 & 95.05% by 1, 2 & 3 doses consecutively. All parameters reflected non significant difference between 2 & 3 dose of CLS. The results were critically discussed.

A study has been carried out to investigate the ultrastructural effects of triclabendazole (TCBZ) at half-normal concentration, clorsulon at half-normal concentration, and a combination of these two drugs against mature Fasciola hepatica. The Cullompton TCBZ-susceptible isolate was used for these experiments. Flukes were incubated for 24 h in vitro in TCBZ sulphoxide (7.5 microg/ml), clorsulon (5 microg/ml), or a combination of the two drugs. For the in vivo experiment, rats were dosed with TCBZ (5 mg/kg body weight), clorsulon (5 mg/kg body weight), or a combination of the two drugs, and flukes recovered after 48 h. Fine structural changes within the tegumental syncytium and tegumental cells were assessed by transmission electron microscopy. Treatment with the combination of drugs produced greater disruption to the flukes than the individual drugs at half-normal concentrations, both in vivo and in vitro; also than TCBZ.SO at normal concentration in vitro. The changes observed aid in the understanding of the gross changes to the tegumental surface described previously (Meaney M, Allister J, McKinstry B, McLaughlin K, Brennan GP, Forbes AB, Fairweather I. Parasitol Res 99:609-621, 2006). The results indicate that there are additive effects between TCBZ and clorsulon and suggest that the use of drug combinations would be of value in the treatment of TCBZ-resistant fluke.

A study has been carried out to investigate the morphological effects of half-strength triclabendazole (TCBZ), half-strength clorsulon, and a combination of these two drugs against mature Fasciola hepatica. The Cullompton TCBZ-susceptible isolate was used for these experiments. Flukes were incubated for 24 h in vitro in TCBZ sulphoxide (7.5 microg/ml), clorsulon (5 microg/ml), or a combination of the two drugs. For the in vivo experiment, rats were dosed with TCBZ (6.25 mg/kg body weight), clorsulon (5 mg/kg body weight), or a combination of the two drugs and flukes recovered after 48 h. Surface changes to the flukes were assessed by scanning electron microscopy. Treatment with the combination of drugs produced greater disruption to the flukes than the individual drugs at half-strength, both in vivo and in vitro. Disruption to the tegument of the flukes induced by the individual drugs at half-strength was relatively minor and less than that caused by the drugs at full-strength. The results suggest that there are additive effects between TCBZ and clorsulon, which may be indicative of synergy: the use of drug combinations would be of value in the treatment of triclabendazole-resistant fluke.

Purpose: Phase II multicenter study investigated the efficacy and toxicity of the novel halogenated derivative of sulfaquixonaline Chloroquinoxaline Sulfonamide (CQS) in metastatic colorectal cancer., Experimental Design: Eligible patients with metastatic or recurrent colorectal cancer received CQS at a dose schedule of 2000 mg/m2 over an hour weekly for 4 weeks every 42 days. Treatment was continued until unexpected toxicity or disease progression., Results: A total of seventeen patients were enrolled on this study. 94% of all patients enrolled had prior treatment. Sixteen patients were evaluable for response with fifteen patients showing evidence of disease progression and one patient with prolonged stable disease. One patient had non-evaluable disease. Following this interim analysis, the drug was considered ineffective and the study was terminated early. The most frequent adverse event was anemia. No patients discontinued the treatment because of toxicity., Conclusion: CQS, when given at a dose of 2000 mg/m2 weekly for 4 weeks every 42 days to patients with metastatic colorectal cancer, does not result in significant tumor regression.

A controlled trial was conducted to evaluate the current efficacy of albendazole (ABZ), rafoxanide (RFX), triclabendazole (TRC) or clorsulon (CLS) against Fasciola hepatica in naturally infected cattle. This trial was conducted in Turkey during the spring, the time of year when liver fluke infection is endemic. Fifty crossbred cattle were selected for inclusion in the trial based on finding eggs of F. hepatica in the feces. The cattle were weighed and randomly allotted into five groups of 10 cattle and treatments were as follows: Group 1 served as non-treated control (CONT), Group 2 was treated orally with ABZ at 12 mg/kg, Group 3 was treated orally with RFX at 10 mg/kg, Group 4 received TRC orally at 12 mg/kg and Group 5 received CLS administered subcutaneously (s.c.) at 2 mg/kg. On day 0 (inclusion day), individual fecal samples were collected on days 0 (inclusion day), 7, 14, 28 and 56, after treatment. The drug efficacy was assessed as a percentage of the egg or fluke reduction and body weight gain relative to the untreated control. The results in the study showed a mean reduction of egg counts by 66.7%, 68.2%, 78% and 84.2% in Groups 2-5, respectively. In conclusion, our results indicate that CLS is a highly effective compound for the treatment of F. hepatica in cattle under these field conditions.

Research on ocular inflammation associated with gonorrhea began in conjunction with the entry of trachoma into Europe during the Napoleonic wars. The initial questions involved the cause of the contagiousness of gonorrhea and how the contagion spreads from the genitalia to other sites. Because efforts to infect animals with gonorrheal matter were unsuccessful, all experiments were conducted on human subjects. Once these two causes of blindness were tentatively differentiated, attempts to restore vision in an eye that had been blinded by a trachomatous membrane over the cornea by instilling gonorrheal pus began to be practiced. In 1841, Joseph Piringer described his use of this method to determine infectiousness decades before the discovery of pathogenic bacteria, as well as ethical concerns about the associated endangerment of patients. Beginning in the 1880s, research focused on the identification of the gonococcus and assessment of its pathogenicity. The ethical dilemma of inducing a disease with an unpredictable outcome persisted until the 1940s, when gonorrhea could be reliably cured by penicillin.

Objectives: We compared therapeutic effects of furosemide, a short-acting loop diuretic, and azosemide, a long-acting one, in hypertensive heart failure rats to test the hypothesis that long-acting diuretics are superior to short-acting types in heart failure., Methods: Dahl salt-sensitive rats fed an 8% NaCl diet from age 8 weeks were divided at age 21 weeks (compensated hypertrophic stage) into three groups: rats treated with furosemide (40 mg/kg/day), those treated with azosemide (80 mg/kg/day) and untreated rats. Rats fed a 0.3% NaCl diet served as controls., Results: Both medications prevented left ventricular systolic dysfunction and enlargement at age 31 weeks, and attenuated macrophage infiltration, reactive oxygen species generation, and gelatinolytic activity to the same degree. Azosemide suppressed left ventricular fibrosis to the control level, but furosemide did not. Azosemide ameliorated myocardial catecholamine depletion and improved survival rate. Furosemide increased plasma norepinephrine levels and did not exert such beneficial effects., Conclusions: Azosemide provided better prognosis in heart failure rats compared with furosemide, partly through attenuation of the reflex increase in cardiac sympathetic neuronal activity caused by the development of heart failure. The current findings suggest a need for clinical trials examining whether long- and short-acting diuretics provide a different prognosis in patients with heart failure.

Objective: To assess the efficacy and safety of azosemide in patients with edema and ascites., Methods: A multicentral, randomized, double-blind, controlled clinical trial was applied. All 223 patients (cardiac edema 92, hepatogenic edema 63, renal edema 68) were randomized to azoesmide and furosemide group, and all patients were treated for 2 weeks. Patients with cardiac or renal edema took azosemide (30 mg/d) or furosemide (20 mg/d); patients with hepatogenic edema took azosemide (60 mg/d) or furosemide (40 mg/d). The dosage were adjusted to azosemide 60 mg/d (cardiac, renal edema), 90 mg (hepatogeic edema); or furosemide 40 mg/d (cardiac, renal edema), 60 mg (hepatogeic edema), if diuretic effects were not obtained at the end of third day., Results: At the end of the study, the weight changes were (2.87+/-3.10) kg and (2.81 +/-2.84) kg; the total effective rate of edema lessen was 89.19% and 89.81%; the total effective rate of heart function improvement was 64.44% and 66.66%; the 24 h urine output increased (321.85 +/-669.52) ml and (273.80 +/-645.72) ml for azosemide and furosemide, respectively. The total effective rate of ascites lessen (tested by B-ultrasound) was 89.28% and 86.66%; abdominal girth decreased (5.20 +/-3.58) cm and (5.03 +/-3.74) cm for azosemide and furosemide, respectively. The adverse event rate was 23.01% in azosemide group and 21.01% in furosemide group; the main adverse effects were hypokalemia, hyperuricemia, hypertriglyceridemia and thirsty., Conclusion: Azosemide could effectively lessen edema, improve heart function and decrease ascitesûit is well tolerated and is particularly useful for the diuretic treatment.

The development and spread of highly drug-resistant parasites pose a central problem in the control of malaria. Understanding mechanisms that regulate genomic stability, such as DNA repair, in drug-resistant parasites and during drug treatment may help determine whether this rapid onset of resistance is due to an increase in the rate at which resistance-causing mutations are generated. This is the first report to demonstrate DNA repair activities from the malaria-causing parasite Plasmodium falciparum that are specific for ultraviolet light-induced DNA damage. The efficiency of DNA repair differs dramatically among P. falciparum strains with varying drug sensitivities. Most notable is the markedly reduced level of repair in the highly drug-resistant W2 isolate, which has been shown to develop resistance to novel drugs at an increased rate when compared to drug-sensitive strains. Additionally, the antimalarial drug chloroquine and other quinoline-like compounds interfered with the DNA synthesis step of the repair process, most likely a result of direct binding to repair substrates. We propose that altered DNA repair, either through defective repair mechanisms or drug-mediated inhibition, may contribute to the accelerated development of drug resistance in the parasite.

Using transmission electron microscopy (TEM), both the tegument and gut of Fasciola hepatica were examined in an effort to identify and characterise the ultrastructural changes induced following treatment with the flukicidal drug clorsulon. Male Sprague-Dawley rats infected with F. hepatica were dosed orally at 8-8.5 weeks post-infection with clorsulon at a concentration of 12.5 mg/kg body weight. After 24, 48 and 72 h, rats were sacrificed by cervical dislocation and mature flukes recovered from the bile ducts. After 24 h treatment in vivo, disruption of the tegumental syncytium was concentrated at the apex of the syncytium where a dark band consisting of numerous secretory bodies was present. Some blebbing of the apex had also occurred, "open" bodies were present in this region and the mitochondria were slightly swollen. In the cell bodies, swelling of the mitochondria and their cristae had also occurred and the Golgi complexes appeared to be smaller than normal. The disruption seen after 48 h treatment in vivo was similar but more severe: the frequency of blebbing had increased, as had the number of "open" bodies and the swelling of the mitochondria. Vacuoles had begun to appear in the syncytium-both autophagic and electron-lucent-and swelling of the mucopolysaccharide masses around the basal infolds had occurred. Lipid droplets were observed occasionally. In the cell bodies, autophagic vacuoles had begun to appear and swelling of the mitochondria had increased in severity. After 72 h treatment in vivo, more severe disruption was seen in the tegumental syncytium in which widespread swelling and blebbing of the apex was apparent. The basal infolds had become very badly swollen in a number of specimens and damage to the spines was evident. The mitochondria remained swollen, as did the mucopolysaccharide masses around the basal infolds. Lipid droplets were more frequently observed in the syncytium. In the tegumental cells, swelling of the mitochondria was greater and an increase in the number of autophagic vacuoles was apparent. The gut showed signs of disruption after 24 h treatment in vivo, in that the surface lamellae were disrupted and a build-up of autophagic vacuoles at the apex of the cells had taken place. Swelling of the mitochondria and the cisternae of granular endoplasmic reticulum (gER) was evident. There was a decrease in the number of secretory bodies. After 48 h treatment in vivo, the number of autophagic vacuoles in the gastrodermal cells had increased, the mitochondria and gER remained swollen and the disruption seen to the lamellae was still evident. In the 72 h-treated specimens, the disruption seen in the gastrodermal cells had increased significantly, with severe vacuolation of the apical cytoplasm. An increase in the number of autophagic vacuoles was evident, the mitochondria and the gER remained swollen and lipid droplets were present in the cells.

Tetracyclines form a group of natural and semisynthetic products that acts inhibiting the bacterial protein synthesis. They are bacteriostatic agents, exhibiting activity against a wide range of organisms, but they are at the present of limited use because of their acquired resistance. Doxycycline is currently the most frequently used tetracycline in human medicine and it is included in the List of Essential Medicines of the World Health Organization. Sulfonamides are synthetic, broad-spectrum bacteriostatic antibiotics. They were the first effective systemic antimicrobial agents. Their mode of action is based on the inhibition of DNA synthesis. Due to their toxicity and high adquired resistance their use is currently very low. Metronidazole is the main compound of 5-nitroimidazole family. It is a very active bactericidal antibiotic against anaerobic and some microaerophilic bacteria and it is still very useful in the treatment of bacterian and parasitic infections.

The efficacy of 5-chloro-2-methylthio-6-(1-napthyloxy)-1H-benzimidazole was evaluated with three commercial fasciolicides in terms of the percentage of egg reduction in cattle. Fifty Swiss cows were selected for inclusion in the trial based on finding eggs of Fasciola hepatica in their feces. On day 0, they were blocked in five groups (G) of ten animals each according to fecal egg counts. G1 received compound alpha at 12 mg/kg p.o.; G2 triclabendazole at 12 mg/kg p.o.; G3.closantel at 3.5 mg/kg s.c.; G4 clorsulon at 2.0 mg/kg s.c. G5 animals served as untreated controls. Fecal analysis was performed on days 0, 7, 14, 21, 28, 60 and 90. Efficacy was measured on days 14 and 21. In addition, the extension and intensity effects were determined on day 60. The percentage efficacy for groups 1-4 was 98.1, 98.7, 98.2 and 97.9 on day 14 and 98.5, 97.9, 97.7 and 97.9 on day 21, respectively. No statistical differences were observed between treated groups.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycemic and antithyroid activity among others. A host of structurally novel sulfonamide derivatives have recently been reported to show substantial antitumor activity in vitro and/or in vivo. Although they have a common chemical motif of aromatic/heterocyclic sulfonamide, there are a variety of mechanisms of their antitumor action, such as carbonic anhydrase inhibition, cell cycle arrest in the G1 phase, disruption of microtubule assembly, functional suppression of the transcriptional activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition among others. Some of these compounds selected via elaborate preclinical screenings or obtained based on computer-aided drug design, are currently being evaluated in clinical trials. This review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed ultimately as effective tumor cell growth inhibitors, or for the treatment of different types of cancer.

Background: Nocturia is one of the major problems of elderly people. The possible causes of nocturia include irritation of lower urinary tract obstruction, disturbance of the fluid balance, and sleep disturbance. In a significant proportion of patients, the mechanism of nocturia is still unclear and a definitive method of treatment has yet to be determined. This study investigated how to treat nocturia., Materials and Methods: We analyzed 51 patients who visited Kobe City General Hospital between January 1998 and June 1999 with nocturia (three or more nocturnal voidings) and no daytime urological problems. Twenty-two of these patients were given daytime diuretic therapy (azosemide 60 mg), while 29 other patients received a minor tranquilizer. The method of treatment was selected randomly. Correlations between the plasma level of atrial natriuretic peptide (hANP) and the effect of treatment were analyzed., Results: Daytime diuretics decreased the nocturnal frequency of voiding in 10 out of 22 patients. The plasma hANP level at the first visit was significantly higher in the patients with improvement (p = 0.0026). Furthermore, the plasma hANP level was significantly decreased after daytime diuretic therapy in patients who showed improvement of nocturia with diuretic therapy (p = 0.0180). Minor tranquilizer administration decreased nocturia in 22 out of 29 patients. The plasma hANP level at the first visit was significantly lower in the patients who improved (p = 0.0021)., Conclusions: These findings suggest that patients with higher plasma hANP levels should be treated as having subclinical heart failure, while nocturia in patients with a normal plasma hANP level might be caused by sleep disturbance.

Five goats naturally infested with Sarcoptes scabiei, Psoroptes ovis and Bovicola caprae were treated with a combination of ivermectin and clorsulon. A subcutaneous injection in a dose of 1 ml/50 kg live weight was given. This provides dose levels of 200 ug ivermectin and 2 mg clorsulon. Four goats were cured from the three ectoparasites within one to two weeks. The last elder goat, which was anaemic and naturally infected with Trichostrongylus colubriformis, was still infested with the two scab mites, but was free from B. caprae. A postal dose of 0.5 ml/50 kg live weight was given one week later (=3 weeks after the 1st injection). This goat was cured within a week, but still passed some T. colibriformis eggs. The result was discussed.

Objective: To compare effects of an injectable doramectin preparation with those of an injectable ivermectin-clorsulon preparation on control of gastrointestinal nematodes and liver flukes and on growth performance in cattle., Design: Randomized complete block design., Animals: 60 crossbred calves., Procedures: Calves (20/treatment group) were treated with doramectin or ivermectin-clorsulon or were not treated. Fecal samples were collected for nematode and Fasciola hepatica egg counts on day 0 and for up to 140 days after treatment. Cattle were weighed before treatment and at 28-day intervals until day 140., Results: From day 7 through day 49, nematode egg counts for calves treated with doramectin or with ivermectin-clorsulon were significantly lower than those for untreated control calves. As the study progressed beyond day 56, the percentages of cattle with fluke eggs in their feces increased, but differences in regard to these percentages were not detected among the 3 groups. Average daily gain for the doramectin-treated cattle (0.79 kg/d [1.74 lb/d]) was significantly greater than that for the cattle treated with ivermectin-clorsuIon (0.71 kg/d [1.56 lb/d]); values for both groups were significantly greater than that for the control cattle (0.62 kg/d [1.37 lb/d])., Conclusions and Clinical Relevance: Results suggest that doramectin had a greater impact on subclinical gastrointestinal tract parasitism in calves, as demonstrated by growth performance, than did ivermectin-clorsulon. In the Gulf Coast region of the United States, spring-born nursing beef calves may have minimal grazing exposure to F hepatica during the peak fluke transmission period; therefore, mature fluke burdens may be negligible at the beginning of the fall season.