Design and Antiproliferative Evaluation of Novel Sulfanilamide Derivatives as Potential Tubulin Polymerization Inhibitors.

A series of sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, MCF-7 and PC-3). The detailed structure-activity relationships for these sulfanilamide-1,2,3-triazole hybrids were investigated. All these sulfanilamide-1,2,3-triazole hybrids exhibited moderate to potent activity against all cell lines. In particular 4-methyl-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (11f) showed the most potent inhibitory effect against PC-3 cells, with an IC50 value of 4.08 µM. Furthermore, the tubulin polymerization inhibitory activity in vitro of compound 11f was 2.41 µM. These sulfanilamide hybrids might serve as bioactive fragments for developing more potent antiproliferative agents.

Efficacy of an anthelmintic combination in sheep infected with Fasciola hepatica resistant to albendazole and clorsulon.

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.

Physicochemical modulation of skin barrier by microwave for transdermal drug delivery.

PURPOSE: To investigate mechanism of microwave enhancing drug permeation transdermally through its action on skin. METHODS: Hydrophilic pectin-sulphanilamide films, with or without oleic acid (OA), were subjected to drug release and skin permeation studies. The skins were untreated or microwave-treated, and characterized by infrared spectroscopy, Raman spectroscopy, thermal, electron microscopy and histology techniques. RESULTS: Skin treatment by microwave at 2450 MHz for 5 min promoted drug permeation from OA-free film without incurring skin damage. Skin treatment by microwave followed by film loaded with drug and OA resulted in permeation of all drug molecules that were released from film. Microwave exerted spacing of lipid architecture of stratum corneum into structureless domains which was unattainable by OA. It allowed OA to permeate stratum corneum and accumulate in dermis at a greater ease, and synergistically inducing lipid/keratin fluidization at hydrophobic C-H and hydrophilic O-H, N-H, C-O, C=O, C-N regimes of skin, and promoting drug permeation. CONCLUSION: The microwave technology is evidently feasible for use in promotion of drug permeation across the skin barrier. It represents a new approach in transdermal drug delivery.

Electric field-controlled benzoic acid and sulphanilamide delivery from poly(vinyl alcohol) hydrogel.

The controlled release of benzoic acid (3.31 Å) and sulphanilamide (3.47 Å) from poly(vinyl alcohol), PVA, hydrogels fabricated by solution casting at various cross-linking ratios, were investigated. The PVA hydrogels were characterized in terms of the degree of swelling, the molecular weight between cross-links, and the mesh size. The drug release experiment was carried out using a modified Franz diffusion cell, at a pH value of 5.5 and at temperature of 37°C. The amount of drug release and the diffusion coefficients of the drugs from the PVA hydrogels increased with decreasing cross-linking ratio, as a larger mesh size was obtained with lower cross-linking ratios. With the application of an electric field, the amount of drug release and the diffusion coefficient increased monotonically with increasing electric field strength, since the resultant electrostatic force drove the ionic drugs from the PVA matrix. The drug size, matrix pore size, electrode polarity, and applied electric field were shown to be influential controlling factors for the drug release rate.

Effects of the NKCC1 inhibitors bumetanide, azosemide, and torasemide alone or in combination with phenobarbital on seizure threshold in epileptic and nonepileptic mice.

The sodium-potassium-chloride (Na-K-Cl) cotransporter NKCC1 is found in the plasma membrane of a wide variety of cell types, including neurons, glia and endothelial cells in the brain. Increased expression of neuronal NKCC1 has been implicated in several brain disorders, including neonatal seizures and epilepsy. The loop diuretic and NKCC inhibitor bumetanide has been evaluated as an antiseizure agent alone or together with approved antiseizure drugs such as phenobarbital (PB) in pre-clinical and clinical studies with varying results. The equivocal efficacy of bumetanide may be a result of its poor brain penetration. We recently reported that the loop diuretic azosemide is more potent to inhibit NKCC1 than bumetanide. In contrast to bumetanide, azosemide is not acidic, which should favor its brain penetration. Thus, azosemide may be a promising alternative to bumetanide for treatment of brain disorders such as epilepsy. In the present study, we determined the effect of azosemide and bumetanide on seizure threshold in adult epileptic mice. A structurally related non-acidic loop diuretic, torasemide, which also blocks NKCC1, was included in the experiments. The drug effects were assessed by determing the maximal electroshock seizure threshold (MEST) in epileptic vs. nonepileptic mice. Epilepsy was induced by pilocarpine, which was shown to produce long-lasting increases in NKCC1 in the hippocampus, whereas MEST did not alter NKCC1 mRNA in this region. None of the three loop diuretics increased MEST or the effect of PB on MEST in nonepileptic mice. In epileptic mice, all three diuretics significantly increased PB's seizure threshold increasing efficacy, but the effect was variable upon repeated MEST determinations and not correlated with the drugs' diuretic potency. These data may indicate that inhibition of NKCC1 by loop diuretics is not an effective means of increasing seizure threshold in adult epilepsy.

Sulfachlorpyrazine residues depletion in turkey edible tissues.

Sulfachlorpyrazine (SCP) is currently used to treat coccidian infections in turkeys; however, there is no information available about the withdrawal period necessary for the turkey to be safe for human consumption. A high performance liquid chromatography method with ultraviolet-visible light detection was adapted and validated for the determination of SCP in turkey tissues. The procedure is based on isolation of the (SCP sodium) compound from edible turkey tissues (muscles, liver, kidneys, and fat with skin) with satisfactory recovery (72.80 +/- 1.40) and specificity. The residue depletion of SCP in turkeys was conducted after a dose of 50 mg/kg body weight/day had been administrated orally for 3 days. After treatment has been discontinued residue concentrations were detected in tissues on the 7th day. The highest SCP concentrations were measured in muscles. Based on the results presented in this study, it could be assumed that a withdrawal period of 21 days, before medicated turkeys could be slaughtered, would be sufficient to ensure consumer safety.

Efficacy of an injectable combination anthelmintic (nitroxynil+clorsulon+ivermectin) against early immature Fasciola hepatica compared to triclabendazole combination flukicides given orally or topically to cattle.

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.

Comparative therapeutic effect of toltrazuril, sulphadimidine and amprolium on Eimeria bovis and Eimeria zuernii given at different times following infection in buffalo calves (Bubalus bubalis).

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.

Assessment of diuretic effects and changes in plasma aldosterone concentration following oral administration of a single dose of furosemide or azosemide in healthy dogs.

OBJECTIVE: To determine the diuretic effects and changes in plasma aldosterone concentration (PAC) following oral administration of a single dose of furosemide or azosemide in healthy dogs. ANIMALS: 8 mixed-breed dogs. PROCEDURES: A single dose of furosemide (2 mg/kg), azosemide (1, 5, or 10 mg/kg), or placebo (bifidobacterium [1 mg/kg]) was administered orally (in random order at 7-day intervals) to each dog (5 treatments/dog). Urine and blood samples were collected before (2 hours after evacuation of the urinary bladder; baseline) and at intervals for 24 hours after drug treatment to assess urine volume and plasma and urine biochemical variables. RESULTS: Compared with baseline values, treatment with furosemide and azosemide (5 and 10 mg/kg) increased urine output for 1 to 2 hours and 2 to 4 hours, respectively. The 24-hour urine volume and urinary sodium excretion were significantly increased following furosemide and azosemide (5 and 10 mg/kg) treatments, compared with effects of placebo; these increases were dose dependent for azosemide, and increases were similar for furosemide and the 5 mg/kg dose of azosemide. Compared with other treatments, 24-hour urinary potassium excretion was significantly increased with azosemide at 10 mg/kg. Azosemide (5 and 10 mg/kg) significantly increased plasma total protein concentration and decreased plasma potassium concentration, compared with baseline values. Compared with the effect of placebo, PAC was significantly increased by furosemide and the 10 mg/kg dose of azosemide. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy dogs, a moderate dose of azosemide caused sufficient diuretic action and increased PAC to a lesser extent than furosemide.

The prognostic value of brain natriuretic peptide in patients with heart failure and left ventricular ejection fraction higher than 60%: a sub-analysis of the J-MELODIC study.

AIMS: Cardiac function varies in the population of patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF; HFpEF). This study investigated the heterogeneity of clinical features associated with HF and the prognostic value of BNP levels in patients with HFpEF. METHODS AND RESULTS: The study enrolled 288 patients with stable HF and serum creatinine <1.5 mg/dL who were part of the original J-MELODIC study cohort. They were categorized as having HF with reduced LVEF (HFrEF; EF ≤ 40%, n = 83) or as having HFpEF (EF > 40%, n = 205). Patients with HFpEF were further categorized as having relatively low LVEF (HFrlEF; EF 40-60%, n = 107) or as having relatively high LVEF (HFrhEF; EF ≥ 60%, n = 98). We defined cardiovascular death and hospitalization for HF as adverse events and evaluated the prognostic value of the BNP levels in each group. There was no significant difference in event-free survival between HFpEF and HFrEF patients or between HFrhEF and HFrlEF patients. A multivariate Cox proportional hazards model revealed that the BNP level was an independent predictor of adverse events in HFrEF patients (hazard ratio: 4.088, 95% confidence interval: 1.178-14.179, P = 0.027) and in HFrlEF patients (hazard ratio: 14.888, 95% confidence interval: 4.969-44.608, P < 0.001) but not in HFrhEF patients (P = 0.767). CONCLUSIONS: The BNP level has prognostic value in HFrlEF but not in HFrhEF. This indicates that HFrhEF and HFrlEF are distinct entities that may require different approaches for the management of HF.

Accelerated titration designs for phase I clinical trials in oncology.

BACKGROUND: Many cancer patients in phase I clinical trials are treated at doses of chemotherapeutic agents that are below the biologically active level, thus reducing their chances for therapeutic benefit. Current phase I trials often take a long time to complete and provide little information about interpatient variability or cumulative toxicity. PURPOSE: Our objective was to develop alternative designs for phase I trials so that fewer patients are treated at subtherapeutic dose levels, trials are of reduced duration, and important information (i.e., cumulative toxicity and maximum tolerated dose) needed to plan phase II trials is obtained. METHODS: We fit a stochastic model to data from 20 phase I trials involving the study of nine different drugs. We then simulated new data from the model with the parameters estimated from the actual trials and evaluated the performance of alternative phase I designs on this simulated data. Four designs were evaluated. Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40% dose-step increments and no intrapatient dose escalation. Designs 2 through 4 included only one patient per cohort until one patient experienced dose-limiting toxic effects or two patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100% dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resorted to standard cohorts of three to six patients, with 40% dose-step increments. Designs 2 through 4 used intrapatient dose escalation if the worst toxicity is grade 0-1 in the previous course for that patient. RESULTS: Only three of the actual trials demonstrated cumulative toxic effects of the chemotherapeutic agents in patients. The average number of patients required for a phase I trial was reduced from 39.9 for design 1 to 24.4, 20.7, and 21.2 for designs 2, 3, and 4, respectively. The average number of patients who would be expected to have grade 0-1 toxicity as their worst toxicity over three cycles of treatment is 23.3 for design 1, but only 7.9, 3.9, and 4.8 for designs 2, 3, and 4, respectively. The average number of patients with grade 3 toxicity as their worst toxicity increases from 5.5 for design 1 to 6.2, 6.8, and 6.2 for designs 2, 3, and 4, respectively. The average number of patients with grade 4 toxicity as their worst toxicity increases from 1.9 for design 1 to 3.0, 4.3, and 3.2 for designs 2, 3, and 4, respectively. CONCLUSION: Accelerated titration (i.e., rapid intrapatient drug dose escalation) designs appear to effectively reduce the number of patients who are under-treated, speed the completion of phase I trials, and provide a substantial increase in the information obtained.

Oral absorption profiles of sulfonamides in Shiba goats: a comparison among sulfadimidine, sulfadiazine and sulfanilamide.

The oral pharmacokinetics of three sulfonamides, sulfadimidine (pKa 7.5), sulfadiazine (pKa 6.5) and sulfanilamide (pKa 10.5), with different rates of unionization in rumen juice, were compared in Shiba goats to clarify the relationship between drug absorption profiles after their oral administration as well as their degree of unionization in the rumen. Sulfonamides were administered either into the left jugular vein or orally to five male goats at doses of 10 mg/kg body weight, using a crossover design with at least a 3-week washout period. The Tmax of sulfadimidine, sulfadiazine and sulfanilamide reached 2.0 ± 1.2, 6.0 ± 0.0, and 7.8 ± 1.6 hr, respectively, after their oral administration, and this was followed by their slow elimination due to a slow rate of drug absorption from the gastrointestinal tract. The MAT and t1/2ka of sulfadiazine (13.2 ± 2.0 and 10.9 ± 1.08 hr) were significantly longer than those of sulfanilamide (9.09 ± 1.67 and 7.46 ± 1.70 hr) and sulfadimidine (7.52 ± 0.85 and 5.17 ± 0.66 hr). These results suggest that the absorption rates of highly unionized drugs (such as sulfanilamide and sulfadimidine) from the forestomach of goats may be markedly higher than less unionized ones (such as sulfadiazine). The mean oral bioavailability of sulfadiazine was high (83.9 ± 17.0%), whereas those of sulfadimidine and sulfanilamide were low (44.9 ± 16.4% and 49.2 ± 2.11%, respectively).

Determination of sulphachloropyrazine-diaveridine residues by high performance liquid chromatography in broiler edible tissues.

Diaveridine (DVD) is used in combination with sulphachloropyrazine (SPZ) as an effective antibacterial agent and antiprotozoal agent, respectively, in humans and animals. To gain a better understanding of the metabolism of SPZ and DVD in the food-producing animals, a high performance liquid chromatography (HPLC) method to determine and quantify sulphachloropyrazine (SPZ) and diaveridine (DVD) suspension residues from broilers is reported. Thirty healthy chickens were orally administered with sulphachloropyrazine-diaveridine (SPZ-DVD) suspension in water of 300 mg/l (SPZ) per day for seven successive days. Six chickens per day were slaughtered at 0, 1, 3, 5 and 7 days after the last administration. This procedure permitted SPZ and DVD to be separated from muscle tissue, liver, kidneys and skin with fat after extraction with acetonitrile and acetone under slightly acidic conditions. From the detected residuals in different tissues, we found that SPZ was quickly eliminated in liver and muscle, and slowly eliminated in kidney and skin with fat. DVD was quickly eliminated in liver and slowly eliminated in kidney. The withdrawal period of SPZ was 3.26, 3.72, 4.39 and 5.43 days in muscle, liver, kidney and skin with fat, respectively. The withdrawal period of DVD was 4.77, 4.94, 6.74 and 4.58 days in muscle, liver, kidney and skin with fat, respectively. Therefore, the suggested withdrawal period for SPZ-DVD suspension should be 7 days after dosing for seven successive days.

Análise ultraestrutural do colágeno de feridas cutâneas de coelhos tratadas com plasma rico em plaquetas de equino / Ultrastructural analysis of the collagen of rabbit skin wounds treated with platelet-rich equine plasma

O colágeno é sintetizado e segregado no espaço extracelular e organizados em fibrilas estriadas de acordo com o tipo de tecido. Utilizaram-se 24 coelhos brancos da raça Nova Zelândia, com idade de 12 meses e com 3,0kg de peso corporal, para avaliar a porcentagem de colágeno das feridas cutâneas tratadas com plasma rico em plaquetas de equino e pomada contendo gentamicina, sulfanilamida, sulfadiazina, ureia e vitamina A. Os animais foram separados em quatro grupos de igual número e submetidos à remoção de pele na região das linhas médias dorsal torácica (feridas tratadas) e lombar (feridas controle). As feridas torácicas foram tratadas com plasma rico em plaqueta de equino e pomada contendo gentamicina, sulfanilamida, sulfadiazina, ureia e vitamina A, e as do grupo controle somente com a pomada. Dos animais do grupo I, foi coletado tecido cutâneo, para a avaliação histológica e a ultraestrutural, com três dias de pós-operatório; dos animais do grupo II, com sete dias; do grupo III, com 14 dias; e do grupo IV, com 21 dias. Decorrido o período de avaliação de cada grupo, foi coletado fragmento de pele para avaliação da porcentagem de colágeno, bem como do diâmetro e da densidade da fibrila de colágeno por microscopia eletrônica de transmissão. O tratamento com PRP de equino associado à aplicação tópica da pomada mostrou-se eficaz na maturação das fibrilas colágenas e na antecipação do processo cicatricial.(AU)

Collagen is synthesized and secreted into the extracellular space and organized into striated fibrils according to the tissue type. This study evaluated the concentration of collagen in rabbit skin wounds treated with equine platelet-rich plasma (PRP) and ointment containing gentamicin, sulfanilamide, sulfadiazine, urea, and vitamin A. Twenty-four New Zealand white rabbits aged 2 to 12 months and weighing 3.0kg were included. The animals were allocated equally into four groups and the skin was removed from the thoracic dorsal midline (treated wound) and lumbar (control wound) regions. The thoracic wounds were treated with equine PRP and ointment containing gentamicin, sulfanilamide, sulfadiazine, urea, and vitamin A, and the control group was treated with the ointment alone. For histological and ultrastructural assessment, cutaneous tissue was collected on postoperative days 3 (group I), 7 (group II), 14 (group III), and 21 (group IV). After the evaluation period, in each group, a skin fragment was collected for analysis of the collagen concentration, as well as the collagen fibril diameter and density by transmission electron microscopy. The results indicated that treatment with equine PRP combined with topical application of the ointment was effective in facilitating the maturation of collagen fibrils and the wound healing process.(AU)

Spiramycin/cotrimoxazole versus pyrimethamine/sulfonamide and spiramycin alone for the treatment of toxoplasmosis in pregnancy.

OBJECTIVE: To compare the effectiviness of spiramycin/cotrimoxazole (Sp/C) versus pyrimethamine/sulfonamide (Pyr/Sul) and spiramycin alone (Spy) on mother-to-child transmission of toxoplasmosis infection in pregnancy. STUDY DESIGN: Retrospective study of pregnant women evaluated for suspected toxoplasmosis between 1992 and 2011. RESULT: A total of 120 mothers and their 123 newborns were included. Prenatal treatment consisted of spiramycin in 43 mothers (35%), spiramycin/cotrimoxazole in 70 (56.9%) and pyrimethamine/sulfonamide in 10 (8.1%). A trend toward reduction in toxoplasmosis transmission was found when Sp/C was compared with Pyr/Sul and particularly with Spy alone (P=0.014). In particular, Spy increased the risk of congenital infection when compared with Sp/C (odds ratio (OR) 4.368; 95% CI: 1.253 to 15.219), but there was no significant reduction when Sp/C was compared with Pyr/Sul (OR 1.83; 95% CI: 0.184 to 18.274). CONCLUSION: The treatment based on Sp/C has significant efficacy in reducing maternal-fetal transmission of Toxoplasma gondii when compared with Pyr/Sul and particularly to Spy. Randomized controlled trials would be required.

Experimental photoallergy to systemic drugs.

We have induced photoallergy in mice to systemically administered drugs, specifically sulfanilamide and chlorpromazine. Mice were photosensitized to systemic sulfanilamide or chlorpromazine by i.p. administration of drug followed by UVB and UVA irradiation of shaved flank skin, on two consecutive days. Control mice received i.p. drug with no irradiation. In some experiments cyclophosphamide pretreatment, or intradermal Corynebacterium parvum (Propionibacterium acnes), was administered as an immunoadjuvant. All animals were photochallenged on day 5 with i.p. drug followed by UVA irradiation of one ear. Mice that had been previously immunized with drug and UV radiation developed ear swelling and erythema, evident 24 h after photochallenge, but not at 4 h. Control animals showed no reactions. In a typical experiment of photosensitization to systemic sulfanilamide, the experimental group had a mean increase in ear thickness of 6.0 X 10(-2) mm 24 h after photochallenge, while unsensitized control animals showed a mean change of -0.8 X 10(-2) mm. The histopathology of the positive challenge reaction was characteristic of a delayed type hypersensitivity. Adoptive transfer of photoallergy to systemic sulfanilamide to naive recipients was accomplished by i.v. injection of lymph node cells (5 X 10(7) harvested from actively photosensitized donors. Clinical reports have suggested that exposure to systemic medications followed by sunlight can induce an eruption having a photoallergic basis. We now report the first experimental proof of that hypothesis. The murine model should facilitate exploration of photoallergic mechanisms and, in addition, it provides the basis for a prospective test of systemic drugs for their photoallergenicity.

Azosemide kinetics and dynamics.

Azosemide is a loop diuretic that may also affect sodium reabsorption at the proximal tubule. We gave intravenous and oral doses of the drug to normal subjects to examine its kinetic and dynamic parameters. In the fasting state a lag time of absorption of approximately 1 hr was followed by absorption t 1/2s and elimination t 1/2s of approximately 0.75 and 2 2.5 hr. Only 2% of an oral dose was excreted unchanged in the urine. After intravenous dosing the elimination t 1/2 was approximately 2 hr; 20% of a dose was recovered unchanged. Thus azosemide has an estimated bioavailability of 10%. The relationship between urinary azosemide excretion rate ("dose") and natriuretic response follows a sigmoid-shaped curve with a dose inducing half-maximal response of 9.3 +/- 2.6 micrograms/min, whereas it is 69.8, 12.1 and 1 microgram/min for furosemide, piretanide, and bumetanide respectively.

Effects in normal subjects of long-term administration of azosemide.

Azosemide is a new loop diuretic which has been shown to affect solute transport proximal to the diluting segment. We assessed the effects of chronic administration of azosemide in normal subjects on low and normal salt diets. In both, there was compensatory renin release and aldosterone secretion, but the subjects on the low sodium diet developed striking hyperuricemia and metabolic alkalosis and were symptomatic, whereas those on the normal diet compensated to the extent that there were only minor changes.

Comparative studies on the efficacy of sulphachlorpyrazine and toltrazuril for the treatment of caecal coccidiosis in chickens.

The therapeutic efficacy of sulphachlorpyrazine and toltrazuril against experimentally induced Eimeria tenella infection was compared in battery and floor pen raised broiler chickens. In the battery studies, both drugs prevented coccidiosis-related mortality and decrease of weight gain to a similar degree, but toltrazuril was more effective in reducing intestinal lesions and faecal scores, when treatments were initiated 24 h postinfection. When medication was delayed until 72 h after inoculation, the sulphonamide proved to be more effective in preventing reduction of weight gain and intestinal lesions caused by the parasites. Under simulated use conditions both drugs showed an appropriate anticoccidial efficacy without major differences between them.

Transient eosinophilic pneumonia secondary to use of a vaginal cream.

Various drugs have been implicated in the development of transient eosinophilic pneumonia or Loeffler's syndrome. We present such a case occurring in a woman who had been using a sulfanilamide-containing vaginal cream.