Effects of sulfamethazine on induction of precocious puberty in Japanese quails (Coturnix japonica) assessed through monitoring the hormonal changes and gonadal development.

To investigate the effect of dietary supplementation of sulfamethazine (SMZ) on growth performance, gonadal development and hormonal changes, male and female Japanese quails (Coturnix japonica) were fed a control diet with or without SMZ (0.2%) from one day post hatching until 6 weeks of age. In male quail, the deviation in growth performance between SMZ and control chicks started at the 3rd week, and the disparity was significant at the 5th and 6th weeks. Hormonal analysis revealed a substantial increase in the pituitary and circulating LH (at the 5th and 6th weeks), testicular and circulating testosterone (at the 6th week) and plasma ir-inhibin (at 5th week) levels following feeding of the diet containing SMZ. The testicular size and weights were significantly larger at the 5th week, and histological analysis demonstrated an enlargement of seminiferous tubules, filling of the luminal fluid with spermatozoa and a number of interstitial cells. In female quail, the body and ovarian weights were considerably increased at the 6th week. The SMZ supplemented group showed a significant elevation in pituitary LH content (from the 4th week), plasma LH (at the 5th and 6th weeks), ir-inhibin (at the 3rd and 6th week) and progesterone (at the 2nd, 5th and 6th weeks) as compared with control chicks. These results indicated that SMZ was able to stimulate the secretion of gonadotropins and accordingly the gonadal hormones and that was associated with an early gonadal function in male (at the 5th week) and female (at the 6th week) Japanese quail.

A landmark contribution to poultry science--a possible mode of action of sulfamethazine on the reproductive system of Leghorn cockerels.

The paper "The effect of sulfamethazine feeding on the thyroids, combs and testes of Single Comb White Leghorn cockerels" was published early in the career of Ari van Tienhoven when he was an assistant professor. The current manuscript pays tribute to that study submitted to the journal, Poultry Science, over 5 decades ago. In addition, the review examines the academic lineage of van Tienhoven to show that his line of descent produced several scientists who have contributed significantly to the success of the Poultry Science Association in the discipline of neuroendocrinology and avian physiology during most of its first 100 yr. In a quiet, unassuming manner, van Tienhoven has had a major effect on basic research addressing reproductive endocrinology in vertebrates, particularly in the domestic fowl, Gallus gallus. Biographical information, his academic pedigree, students produced, research areas pursued, and the landmark contribution selected for review are highlighted. A link to an electronic archive of a recorded interview with van Tienhoven in preparation for the symposium can be accessed using the link given in the first footnote.

The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study.

OBJECTIVE: To study human teratogenic potential of two trimethoprim-sulfonamide combinations: trimethoprim-sulfamethoxazole (cotrimoxazole) and trimethoprim-sulfamethazine during pregnancy. These agents have antifolate effects and other antifolate agents can induce multiple congenital abnormalities, neural-tube defects, cardiovascular, and other malformations in animal experiments and in humans. DESIGN: Pair analysis of cases with congenital abnormalities and matched healthy controls in the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. PARTICIPANTS: 38,151 pregnant women who had newborn infants without any congenital abnormalities (control group) and 22,865 case pregnant women who had newborns or fetuses with congenital abnormalities. MAIN OUTCOME: Prevalence of drug use in matched case-control pairs to study the possible association with congenital abnormalities. RESULTS: In the case group 351 (1.5%) and in the control group 443 (1.2%) pregnant women were treated with cotrimoxazole (crude OR 1.3 with 95% CI 1.1-1.5). In addition 45 (0.2%) case and 39 (0.1%) control pregnant women had trimethoprim-sulfamethazine treatment (crude OR 1.9 with 95% CI 1.3-3.0). A higher rate of multiple congenital abnormalities (including mainly urinary tract and cardiovascular abnormalities) was found in case infants born to mothers with cotrimoxazole treatment during the second-third months of pregnancy. In addition, a higher rate of cardiovascular malformations occurred in cases born to mothers with cotrimoxazole treatment and trimethoprim-sulfamethazine treatment during the second-third months of pregnancy, respectively. CONCLUSION: Treatment with cotrimoxazole during pregnancy may increase the risk of cardiovascular malformations, and particularly multiple congenital abnormalities including defects of the urinary tract and cardiovascular system. A higher rate of cardiovascular malformations was also found after treatment with trimethoprim-sulfamethazine in the second-third months of pregnancy.

An FDA review of sulfamethazine toxicity.

Recently, changes have been proposed in the criteria historically used in the evaluation of the applicability to humans of some of the results obtained from the rodent carcinogenicity bioassay data. These questions center on the suitability of the rodent model for agents that exert their toxic effects via specific enzyme interactions and endocrine mechanisms which appear to be inoperative within humans. Within the U.S. Food and Drug Administration (FDA), this issue has been brought to the forefront of concern with the recent application for a New Animal Drug Application for sulfamethazine (SMZ). A panel of FDA experts from the National Center for Toxicological Research (NCTR), the Center for Veterinary Medicine (CVM), and the Center for Food Safety and Applied Nutrition has reviewed the sum of the scientific evidence available on the toxicology of SMZ. They noted that, in previous feeding studies at NCTR, high doses of SMZ were associated with significant incidences of thyroid tumors in mice and rats. The panel also notes that the tumorigenic activity of SMZ in rodents was due to its goitrogenic activity, resulting in constant stimulation of the thyroid by TSH. Humans, on the other hand, were found to be insensitive to the SMZ-like inhibition of thyroid function. Further, apart from X-irradiation and radioactive iodine, there are no other physical or chemical agents known to cause thyroid tumors in humans. Thus, the expert panel concludes that the best scientific information available indicates that elevated levels of TSH and the consequent thyroid tumors would not be produced under approved use conditions of SMZ. This conclusion is in agreement with recommendations made by three other panels, viz. the World Health Organization, the U.S. Environmental Protection Agency, and CVM, which also evaluated the public health risk of SMZ.

Quadruple therapy for ocular toxoplasmosis.

Between Dec. 1, 1973, and May 30, 1989, 36 patients (37 eyes) with ocular toxoplasmosis seen at a uveitis clinic received quadruple therapy (pyrimethamine, trisulfapyrimidines, clindamycin and prednisone). The criteria for quadruple therapy were active lesions involving or threatening the macula or the optic disc, or a visual acuity of 20/70 or worse due to vitreous opacification caused by active inflammation. All but four of the cases showed improved vision. A total of 54% of the cases responded favourably within 2 weeks after the start of treatment, and 81% responded within 3 weeks. Patients took pyrimethamine for 1 to 2 weeks and received trisulfapyrimidines and clindamycin for 3 weeks, with a tapering course of orally given prednisone. The only complication was skin rash secondary to trisulfapyrimidine therapy, in four cases. None of the patients manifested diarrhea, pseudomembranous colitis or bone marrow suppression. The length of follow-up ranged from 1 month to 15.5 years. There were seven recurrences in five patients, five of which responded to a second course of quadruple therapy.

Pharmacokinetics, safety and tissue residues of sustained-release sulfamethazine in sheep.

Concentration-time profiles and the rates of absorption, extent of distribution and half-lives of sulfamethazine (SMZ), administered intravenously, orally as a water solution and as a sustained-release formulation (CalfSpan) were determined in 10 healthy sheep. The geometric mean half-life of elimination of i.v. SMZ was 10.8 h, compared to 14.3 h for the sustained-release preparation (CalfSpan) and 4.3 h for the oral water solution. Blood levels of SMZ were at or above 50 micrograms/ml for more than 48 h for CalfSpan, for 24 h after i.v. SMZ (100 mg/kg body wt), and for less than 24 h after p.o. SMZ (100 mg/kg body wt). The mean bioavailability of the oral SMZ solution was 58.3% (AUCp.o./AUCi.v.). The estimated bioavailability of the CalfSpan preparation was 52.5%. The safety of the sustained-release preparation was tested by dosing sheep with multiples (one, three and five times) of the recommended dose (one tablet, 8 g SMZ, per 20 kg body wt), once a day for 3 days. Clinical blood chemistries showed a significant increase in serum iron, and a decrease in serum phosphorus in animals treated at the 3x and 5x dose levels. Necropsies of the 5x dose animals did not show any gross signs that could be attributed to SMZ, and histological examination of tissues from the 5x animals revealed no organ pathology. Residues of SMZ in liver, fat, kidney and skeletal muscle were measured in 20 animals that received one bolus per 20 kg body wt. The results indicate that SMZ residues are cleared rapidly, and are at or below the tolerance level of 0.1 mg/kg within 8 days after dosing so that the 18-day withdrawal time used in cattle would provide an appropriate margin of safety if used in sheep.

[Toxicological considerations in the evaluation of veterinary drugs]. / Toxicologische overwegingen bij de beoordeling van diergeneesmiddelen.

Interactions between veterinary pharmacotherapy, toxicology of residues, prevention of residues of veterinary drugs and the evaluation of veterinary drug files are discussed on the basis of a number of examples. Sulphadimidine is used to treat atrophic rhinitis in medicated feeds which do not benefit the animal but are the cause of persistent sulphonamide residues in feed mills and husbandry. Carbadox is a potentially effective prophylactic feed additive for the prevention of swine dysentery, but is mostly used in high dosages which are almost toxic for the animals, and used during unnecessary prolonged periods. It is also prescribed as a therapeutic agent in which case a symptom of poisoning, dry faeces, is mistaken for a sign of recovery. Carbadox and/or its metabolites are carcinogenic and its use should be restricted to a bare minimum. Furazolidone is an example of an effective veterinary drug, the use of which should be limited by the fact that detoxification mechanisms of the animals, may result in the appearance of reactive metabolites which are available in the gastro-intestinal tract of the consumer. The central issue in a 'minimal residue' policy regarding the use of veterinary drugs should be the selection of effective drugs. Such a selection could result in a significant reduction of the incidence of veterinary drug residues. Second to this issue is the question of the extent to which residue toxicology should modulate the use of veterinary drugs.

Acetylation polymorphism and leprosy.

The sulfones are the drug of choice in the treatment of leprosy, with dapsone as the clear favorite. The major route for dapsone metabolism leading to its inactivation and excretion is via acetylation by hepatic N-acetyl transferase (NAT), as is the case with isoniazid (INH) and sulfamethazine (SMZ). The enzyme is known to exhibit genetic polymorphism. The object of the present study is mainly to determine the incidence of acetylator phenotype in a population of leprosy patients with a view to evaluating the degree of association, if any, between phenotype and the disease. Obviously a knowledge of the incidence of the phenotypes may provide a valuable contribution to the institution of more rational and successful therapy. In the normal or control subjects, as well as in the leprosy patients, the frequency distribution histograms of the percentage acetylsulfamethazine in urine and serum samples are bimodal, and this indicates the existence of a genetic polymorphism. Based on the bimodality, individuals were classified as either "rapid" or "slow" acetylators, and the incidence of the slow acetylator phenotype of about 51% was observed in the leprosy population. This gives a relatively high incidence of the allele controlling the slow acetylator (q = 0.73). Although there is evidence that the mean percentage of SMZ acetylated in leprosy patients of the slow acetylator phenotype is significantly higher than that observed for the same phenotype in the controls (t = 4.86, P less than 0.02), statistical analyses show that there is no association between the slow acetylator phenotype and the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of tick-borne fever on metabolism and renal clearance of sulfadimidine in goats.

The tick-borne fever (TBF) model was used to study the effect of fever on the metabolism of sulfadimidine in goats. During TBF the elimination half-lives were prolonged, and the renal clearance values of sulfadimidine and the majority of its metabolites were markedly diminished compared with those in the uninfected state. During TBF the steady-state levels of the hydroxy metabolites were markedly increased. TBF reduced the extent of hydroxymethylation of the pyrimidine side chain; TBF did not affect acetylation of sulfadimidine. In one goat a progressive accumulation of the metabolites was noticed.

Single-dose antimicrobial therapy for urinary tract infections in women.

Single-dose antimicrobial therapy for uncomplicated urinary tract inductions in women has been reported and evaluated by several investigators. A review of the results of these studies suggest that amoxicillin, sulfisoxazole, and trimethoprim-sulfamethoxazole are effective single-dose regimens in this setting. These results should not be extrapolated to other populations, such as pregnant women or children, or to other antimicrobial agents. The limited data available suggest that cephalosporins are less effective than the regimens recommended. When the infecting organism is sensitive, failure to eradicate bacteriuria with one of these single-dose regimens may be indicative of a more invasive infection, perhaps in the kidney.

[Blood concentrations of sulfadimidine after the internal use of depot sulfadimezine granules in sheep]. / Kruvni kontsentratsii na sulfadimidin sled vutreshno prilagane na sulfadimezin-depo-granuli, pri ovtse.

A granular premixed form, called sulphadimesin-depot-granules, was produced, containing 40% of sulphadimine inserted into a hydrophobic matrix of hydrogeneric sunflower oil. After a single internal insertion into sheep by means of a stomach-tube or of a bottle on an empty stomach in a dose of 0.5 g/kg t, they caused bacteriostatic concentrations in blood plasma during 78 hours, and in a dose of 1.0 g/kg t--during 96 hours, whereas the sulphadimesin in tablets, applied in a dose of 0.2g/kg t, kept up a therapeutic concentration for 24 hours. The duration of the bacteriostatic level of sulphadimesin after the taking of the granules in a dose of 0.5 g/kg t and after the feeding, was 12 hours; after two treatment with a stomach-tube or of a bottle, on an empty stomach, in an initial dose of 1.0 g/kg t and a following one of 0.5 g/kg t, applied after a period of 96 hours--it was 174 hours. No side phenomena were observed, besides a temporary (for 12-24 h) slight slow-down of belly movements. For a prophylactic treatment of sheep it is recommended that the granules should be applied in the fodder and on an empty stomach, in an initial dose of 1.0 g/kg t, and 72 hours later in a dose of 0.5 g/kg t. For a curative treatment an internal insertion is recommended by means of a stomach-tube or of a bottle, on an empty stomach, in the same doses, at an interval of 96 hours.

[Drug-induced bullous dermatitis - Lyell's syndrome]. / Medikamentoznyi bulleznyi dermatit - sindrom Laiella.

Three section observations of drug dermatitis which had developed against the background of treatment of acute respiratory diseases (Lyiell's syndrome) with sulphamides, antibiotics, and aspirin are presented.