PLASMA NEPRILYSIN LEVELS IN PATIENTS WITH POLYCYSTIC OVARY SYNDROME.

Context: Insulin resistance has been detected in a majority of patients with polycystic ovary syndrome (PCOS). Elevated neprilysin levels are associated with insulin resistance. Objective: The present study aims to investigate plasma neprilysin and its relationship with endocrine and metabolic characteristics in patients with PCOS. Subjects and Methods: Thirty-five premenopausal PCOS patients and 35 healthy volunteers of similar age were included in the study. Demographic characteristics, biochemical and hormonal findings and also plasma neprilysin levels were determined in these patients and healthy controls. Results: In our study, HOMA-IR values were significantly higher in PCOS patients (3.3 ± 1.8) compared with the controls [(1.6 ± 1), p<0.01]. Plasma neprilysin levels were significantly higher in the PCOS group compared to the control group (1502.1 ± 1641.2 vs. 764.6 ± 562.6 pg/mL). There was no difference in plasma neprilysin levels when PCOS patients were classified as overweight-obesity (BMI≥25kg/m2) or non-obesity (BMI<25kg/m2). Conclusion: Our findings revealed significantly higher levels for plasma neprilysin and HOMA-IR values in PCOS patients when compared to controls. No significant differences were noted between obese PCOS patients and non-obese PCOS patients in terms of plasma neprilysin levels.

Retrospective analysis of vitamin D status on inflammatory markers and course of the disease in patients with COVID-19 infection.

PURPOSE: The aim of the study was to investigate the association between serum 25-hydroxyvitamin D status within the last 6 months prior to COVID-19 infection and parameters of immune function and clinical outcomes. METHODS: Fifty-six patients, who were admitted to the emergency clinic and diagnosed with COVID-19 infection, were included in the study. Data on clinical characteristics, inflammatory parameters and vitamin D status were recorded for each patient. All the participants had data on 25-hydroxyvitamin D status within the last 6 months prior to COVID-19 infection. RESULTS: The patients were stratified as those with vitamin D status less than 20 ng/mL and higher than 20 ng/mL. A group with vitamin D status less than 20 ng/mL had lower lymphocyte counts and lower haemoglobin levels that was statistically significant (respectively; p = 0.021, p = 0.035). Higher C-reactive protein (CRP) levels were seen in the vitamin D-deficient group (p = 0.013). It was observed that vitamin D status of the patients who required oxygen therapy were lower than those who did not require oxygen therapy, not statistically significant (p = 0.05). Patients who did not use vitamin D supplementation within 6 months prior to COVID-19 infection had more likely to be diagnosed with pneumonia (p = 0.004). CONCLUSION: Cases with lower vitamin D status had increased inflammatory markers and worse clinical outcomes than patients with higher vitamin D status. This study suggests that vitamin D status can be used as a prognostic factor in COVID-19 patients, and vitamin D supplementation can be recommended to improve the clinical outcomes in COVID-19 infection.

Factors influencing Helicobacter Pylori positivity in children.

BACKGROUND: Helicobacter pylori (H. pylori) is a common bacteria all over the world. The factors influencing the acquisition and prevalence of H. pylori infection are still poorly understood. AIMS: The aim of this study was to determine the factors that may affect H. pylori positivity in patients who presented to the pediatric clinic. SUBJECTS AND METHODS: The study included 374 children who attended the pediatric clinic with gastrointestinal complaints. The demographic characteristics of patients were recorded, and fecal samples were examined for H. pylori positivity with a prepared kit procedure. In addition, the samples were examined under microscope for the diagnosis of parasites in stool. The Chi-square analysis and binary logistic regression analysis were used for data analysis. The odds ratio was calculated as an estimate of the relative risk. Results: The study found the incidence of H. pylori positivity to be 18.7%. It was observed that in all H. pylori positive patients had growth retardation. H. pylori positivity had no significant relationship with the presence of parasites in the stool (p = 0.113). The results of the Chi-square test showed that H. pylori positivity was significantly changed age groups and educational levels. Logistic regression analysis showed that "age" and "educational status" are significant predictors of H. pylori positivity (p = 0.023 and 0.017, respectively). The risk of H. pylori positivity in the 11-18 age group patients was found about two times (OR: 2.024) higher than in the 6-10 age group patients. The risk of H. pylori positivity in those with education level of "Middle school and above" were found to be twice as high (OR: 2.126) than those with a primary education level (OR: 2.126). CONCLUSION: In this study, adolescent age and middle school and above level were found to be risk factors for H. pylori. This suggests that there may be other conditions influencing H. pylori positivity. Also, since the frequency of H. pylori is high in those with growth retardation, H. pylori should be considered when evaluating children with growth retardation.

The effect of primary hyperparathyroidism on pancreatic exocrine function.

BACKGROUND: Elastase-1 is a proteolytic enzyme secreted by pancreatic acinar cells, and measurements of the concentration this enzyme are used to evaluate pancreatic exocrine function. We aimed to determine whether pancreatic exocrine function declines due to chronic hypercalcemia by measuring fecal elastase levels. METHODS: 75 patients with primary hyperparathyroidism (18 men and 47 women) and 30 healthy subjects (11 men and 19 women) participated in this study. Renal function tests, lipid parameters, bone mineral density, and serum calcium, phosphorus, vitamin D, parathormone, glucose, and thyroid stimulating hormone levels as well as fecal elastase concentrations, were determined in these patients and controls. RESULTS: The mean fecal elastase level was 335.3 ± 181.4 µg/g in the PHPT group and 317.4 ± 157.3 µg/g in the control group. There was no significant difference in fecal elastase levels between the two groups (p = 0.5). CONCLUSIONS: Chronic hypercalcemia in primary hyperparathyroidism did not decrease the fecal elastase level, which is an indirect indicator of chronic pancreatitis; therefore, chronic hypercalcemia in PHPT may not cause chronic pancreatitis.

Role of anticardiolipin antibodies in the pathogenesis of prosthetic valve thrombosis: An observational study.

BACKGROUND: Prosthetic valve thrombosis (PVT) is serious complication of valvular replacement surgery, and increased levels of anticardiolipin antibodies (aCL) are associated with thrombosis. The aim of this study was to evaluate the role of aCL in the development of PVT. PATIENTS AND METHODS: We studied the aCL IgM and IgG levels in 114 patients with PVT and 80 healthy patients with prosthetic valves without PVT or a history of thrombosis. All patients underwent detailed transthoracic, transesophageal echocardiographic and clinical examinations. Blood samples were obtained after transesophageal echocardiography. Tests were repeated 12 weeks apart in patients with aCL IgM or IgG positivity. RESULTS: The mean age, sex, presence of atrial fibrillation and cardiovascular risk factors, elapsed time after surgery, and prosthetic valve type and location were similar between patients with PVT and those without. Ineffective anticoagulation was significantly higher among patients with PVT (p < 0.001). The aCL IgM values were significantly higher and positive (> 40 MPL) in the PVT group compared with the control group (10.58 ± 15.90 MPL to 3.70 ± 2.30 MPL, p < 0.001; 7.0 to 0 %, p = 0.016, respectively). The aCL IgG values were significantly higher and positive (> 40 GPL) in the PVT group compared with the control group (12.04 ± 17.58 GPL to 3.83 ± 2.56 GPL, p < 0.001 and 7.9 to 0 %, p = 0.01, respectively). According to international consensus documents, 16 patients had antiphospholipid syndrome. Ineffective anticoagulation and aCL IgM and IgG positivity were independent predictors of PVT in logistic regression analysis (multivariate r(2)= 0.648; p < 0.001, OR= 21.405, 95 %CI= 8.201-55.872; p = 0.008, OR= 1.322, % 95CI= 1.076-1.626; p = 0.005, OR= 1.288, 95 %CI= 1.079-1.538). CONCLUSION: Since the presence of aCL IgM and IgG positivity may cause a tendency toward PVT, these values should be examined in all patients with PVT.

Subclinical hypothyroidism and its relationship with therapy failure in patients underwent cardiac resynchronization therapy.

OBJECTIVE: Cardiac resynchronization therapy (CRT) is used in patients with heart failure (HF), an important problem in cardiology practice, with reduced left ventricular systolic dysfunctions and left ventricular dyssynchrony to improve morbidity and mortality. Thyroid diseases have undeniable effects on cardiac functions. So, we aimed to evaluate the effect of subclinical hypothyroidism on CRT response in HF patients in this study. PATIENTS AND METHODS: After the exclusion, 386 consecutive patients who received first-time CRT-defibrillator (CRT-D) or CRT-pacemaker (CRT-P) were retrospectively included. Known overt hypothyroidism or hyperthyroidism patients were excluded. The response of CRT was defined as a relative increase (≥15%) or absolute increase (≥10%) in left ventricular ejection fraction (LVEF) from implantation to one-year after follow-up. RESULTS: Diabetes mellitus, atrial fibrillation and coronary artery disease ratios were similar between responder vs. non-responder groups. Thyroid stimulating hormone (TSH) levels were higher (p <0.005) in non-responder group. Responder group had higher baseline LVEF (p <0.001), and follow-up LVEF (p <0.001) and longer baseline QRS interval (p =0.004), but similar post-implant QRS interval duration (p >0.005) with non-responder group. Baseline QRS interval (p =0.002), baseline LVEF (p <0.001) and the presence of subclinical hypothyroidism (SCH) (p =0.001) were independent predictors of CRT response. Adding SCH as a risk factor to our baseline risk modelling has an independent prognostic impact to predict non-responder patients (p =0.01). CONCLUSIONS: Presence of the SCH may be an important predictor of non-response in patients undergoing CRT. Evaluating the risk factors associated with non-response to CRT may be logical in identifying patients who obtain maximum benefit from CRT treatment.

Preoperative parathyroid hormone levels are correlated with parathyroid adenoma volume and bone mineral density but not serum calcium levels.

AIM: The aim of this study was to determine the relationship between biochemical parameters, parathyroid adenoma volume, and bone mineral density with respect to intact parathyroid hormone (iPTH) levels in patients with primary hyperparathyroidism. METHODS: Data were collected retrospectively from patients with primary hyperparathyroidism who were diagnosed and followed in our clinic between 2005 and 2008. Forty-eight (female/male=42/6) patients with a mean age of 52.8±13.1 years were enrolled into the study. RESULTS: Bone pain was the most common presenting feature, seen in 41.7% of patients, while 29.1% of patients were asymptomatic. The mean serum calcium and iPTH concentrations were 2.9±0.6 mmol/L and 657.1±682 ng/L, respectively. The mean total Z/T scores of dual-energy X-ray absorptiometry (DEXA) scan at the femur and lumbar spine were -0.4±1.6/-1.0±1.7 and -1.4±1.6/-2.2±1.5, respectively. Preoperative iPTH levels were correlated with serum phosphate (r=-0.412, P=0.005), alkaline phosphatase (r=0.698, P=0.0001), and femur (r=-0.402, P=0.020) and lumbar spine total Z scores (r=-0.441, P=0.013), whereas parathyroid adenoma volume was correlated with iPTH (r=0.367, P=0.036) and alkaline phosphatase (r=0.570, P=0.001). There was no correlation between iPTH, serum calcium levels and total T scores at the femur and lumbar spine. After excluding patients with 25-OHD insufficiency, there was still no correlation between serum iPTH and calcium levels. Parathyroid adenoma volume, serum iPTH and calcium levels were also not different between patients with and without 25-OHD insufficiency. CONCLUSION: These results suggest that serum iPTH level may be useful in predicting parathyroid adenoma volume and it is also well correlated with femur and lumbar spine Z scores.

The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome.

Insulin resistance (IR) is one of the common features of the polycystic ovary syndrome (PCOS), and recent studies indicate the possible role of vitamin D in the pathogenesis of IR and glucose metabolism. Aim of this study was aimed to determine the effect of vitamin D replacement therapy on glucose metabolism, insulin, and androgen levels in obese, insulin-resistant women with PCOS. Eleven women with PCOS were included in the study. Mean age of the patients was 23.6+/-5.7 yr, body mass index 33.9+/-5.1 kg/m(2). Six patients (54.5%) had acantosis nigricans and 10 (90.9%) oligoamenorrhea. The mean Ferriman Gallwey score was 14.1+/-4.6. Only 2 women were within the normal limits of vitamin D levels as >20 ng/ml. Three weeks after the administration of the single dose of 300,000 units of vitamin D3 orally, 25-hydroxyvitamin D3 significantly increased from 16.9+/-16 ng/ml to 37.1+/-14.6 ng/ml (p: 0.027) and only 2 women were detected to have vitamin D3 levels <20 ng/ml. Although glucose and insulin levels were decreased non-significantly, homeostasis model assessment (HOMA)-IR significantly decreased from 4.41+/-1.38 to 3.67+/-1.48 (p: 0.043). No significant alterations were witnessed at the levels of DHEAS, total and free testosterone, androstenedione. No correlation was found between vitamin D with HOMA and other hormonal parameters. In conclusion, women with PCOS have mostly insufficient vitamin D levels, and vitamin D replacement therapy may have a beneficial effect on IR in obese women with PCOS.

Effect of levothyroxine treatment on clinical symptoms and serum cytokine levels in euthyroid patients with chronic idiopathic urticaria and thyroid autoimmunity.

BACKGROUND: Screening for thyroid autoimmunity in patients with chronic idiopathic urticaria (CIU) is generally recommended. However, there are not yet sufficient data as to whether levothyroxine treatment is beneficial for the clinical symptoms of CIU in patients with thyroid autoimmunity. AIM: We investigated the effect of levothyroxine treatment on clinical symptoms and serum tumour necrosis factor (TNF)-alpha, interleukin (IL)-10 and interferon (IFN)-gamma levels in euthyroid patients with CIU and thyroid autoimmunity. METHODS: In total, 15 patients with CIU and positive thyroid autoantibodies were randomized to receive either levothyroxine plus 5 mg/day desloratadine (suppression group, n = 8) or 5 mg/day desloratadine alone (control group, n = 7) for 12 weeks. Clinical symptoms of CIU, thyroid hormone levels, thyroid antibodies and serum cytokine levels were assessed at baseline and after the treatment. RESULTS: There were significant improvements in pruritus score and severity of weals in both groups compared with baseline values, but when the two groups were compared, there was no significant difference in the patients' clinical symptoms. Thyroid antibody titres were not different according to intragroup and intergroup analysis. In the suppression group, serum IFN-gamma and TNF-alpha levels were increased after treatment with levothyroxine compared with baseline values and there was a borderline statistical significance (P = 0.05 for both). CONCLUSIONS: These results suggest that levothyroxine treatment is not a reasonable option in euthyroid patients with CIU and thyroid autoimmunity. Augmentation of cytokine production after levothyroxine treatment seems to be related to the immunomodulatory effects of TSH-suppressive treatment.

Association Between Resistance to Cinacalcet and Parathyroid Gland Hyperplasia in Kidney Transplant Recipients with Persistent Hypercalcemia.

BACKGROUND: Persistent hypercalcemia and hyperparathyroidism after successful kidney transplantation can be detrimental in some recipients and should be ameliorated. OBJECTIVE: To point out the concerns regarding resistance to cinacalcet in kidney transplant recipients with persistent hypercalcemia. METHODS: 14 renal transplant recipients who received cinacalcet treatment because of persistent hypercalcemia were included in the study. Serum creatinine, estimated glomerular filtration rate (eGFR), calcium, phosphorus, and intact parathyroid hormone (PTH) levels at the baseline and throughout the treatment, and ultrasonography and parathyroid scintigraphy findings were recorded. RESULTS: Cinacalcet treatment was initiated after a mean±SD of 20.7±19.7 months of transplantation and maintained for 16.9±7.9 months. Serum calcium levels were significantly decreased with the cinacalcet treatment. There were no significant changes in serum creatinine, eGFR, phosphorus, and PTH levels. In all participants, serum calcium levels were increased from 9.8±0.6 to 11.1±0.6 mg/dL (p<0.001) within 1 month of cessation of cinacalcet. 7 recipients with adenoma-like hyperplastic glands underwent parathyroidectomy (PTx) due to failure with cinacalcet. CONCLUSION: Cinacalcet may be an appropriate treatment for a group of recipients with hypercalcemia without adenoma-like hyperplastic glands or who had a contraindication for surgery. Recipients with enlarged parathyroid gland may resist to cinacalcet-induced decrease in serum PTH, although the concomitant hypercalcemia may be corrected.

Production of mouse urinary bladder carcinomas by sodium cyclamate.

Sodium cyclamate was suspended in cholesterol pellets that were surgically implanted in the urinary bladders of mice. In duplicate experiments, incidences of mouse bladder carcinomas observed in animals exposed to these pellets were 78 and 61 percent compared with incidences of 13 and 12 percent in control mice exposed to pellets of pure cholesterol. The exposure of the mouse bladder to sodium cyclamate was very brief, as the time required for 50 percent of the compound to disappear from the pellets was about 1 hour. This experimental technique was found to be highly sensitive, reproducible, and predictive of the bladder carcinogenicity of orally administered cyclamate.

Production of urinary bladder carcinomas in mice by sodium saccharin.

Pellets weighing 20 to 24 milligrams and containing 20 percent sodium saccharin suspended in cholesterol were surgically implanted into the urinary bladder lumens of female Swiss mice (60 to 90 days old) under ether anesthesia. Incidences of mouse bladder carcinomas in animals exposed to these pellets were 47 and 52 percent as compared with incidences of 13 and 12 percent in control mice exposed to pellets of pure cholesterol. The exposure of the mouse bladder to saccharin was very brief, because the time required for 50 percent of the compound to be eluted from the pellets was about 5.5 hours.

The investigation of the efficacy of insulin glargine on glycemic control when combined with either repaglinide or acarbose in obese Type 2 diabetic patients.

Combinations of insulin and oral antidiabetic drugs (OAD) are often prescribed instead of insulin alone. In this study, the effects of insulin glargine (IG) in combination with repaglinide or acarbose on glycemic parameters were investigated. Obese Type 2 diabetic patients with fasting blood glucose (FBG) levels >or= 7.7 mmol/l [corrected] and hemoglobin glycated (A1C) >or=9% under maximal OAD combination therapy were enrolled. Previous therapies were discontinued, and patients were randomized into 2 groups. The combinations of IG and repaglinide were administered to group 1, and of IG and acarbose to group 2 for 13 weeks. Twenty patients in group 1 and 18 patients in group 2 completed the study. A1C levels were significantly decreased from 10.9+/-1.4% to 7.7+/-1.1% in group 1 and 11.0+/-1.4% to 8.1+/-1.4% in group 2. FBG levels were significantly decreased from 11.9+/-2.7 to 7.1+/-2.3 mmol/l in group 1 and 11.1+/-2.5 to 6.8+/-1.4 mmol/l in group 2. Post-prandial glucose levels were significantly decreased from 15.3+/-3.8 to 10.3+/-3.0 mmol/l in group 1 and 14.0+/-3.1 to 8.9+/-2.2 mmol/l in group 2. Intergroup comparisons indicated no significant differences. More weight gain was detected in group 1, compared to the baseline. Symptomatic hypoglycemia incidence was similar in both groups. Severe hypoglycemic attacks were seen in two patients in group 1. Flatulence incidence was higher in acarbose group. Conclusively, repaglinide and acarbose were equally effective when combined with IG for obese Type 2 diabetic patients controlled inadequately with OAD alone. Furthermore, acarbose seems to have advantages over repaglinide concerning weight gain and severe hypoglycemic attacks.

Frequency of atopy and allergic disorders among adults with Type 1 diabetes mellitus in the southern Marmara region of Turkey.

AIM: Autoimmune disorders are considered to be associated with a Th1 immune response whereas allergic diseases with a Th2 response. Studies mainly performed on children revealed conflicting results regarding the association of atopy/allergic disease and autoimmune disorders. Therefore, we aimed to investigate the prevalence of allergic diseases in adult Type 1 diabetic patients. METHODS: Eighty-nine Type 1 diabetic patients and 64 controls were enrolled into the study. Skin-prick test and European Community Respiratory Health Survey questionnaire were performed on all cases. Patients who gave at least one positive answer to questions about asthma in the questionnaire underwent pulmonary function test and methacholine challenge test. RESULTS: Patients' mean age were similar in diabetic patients and controls (28.2+/-8.9 and 28.1+/-5.2 yr; respectively). In skin-prick test, the rate of positive response to at least one allergen was not significantly different in diabetes (29.2%) and in the control group (31.3%). In European Community Respiratory Health Survey questionnaire, diabetic patients waked up by an attack of cough more than controls did. The rate of physician-diagnosed asthma was similar in both groups. There was no difference between the 2 groups based on the answers of other questions about asthma and other allergic diseases such as allergic rhinitis, eczema, and drug allergy. CONCLUSION: We found that atopy frequencies were similar in an adult population of Type 1 diabetic patients and controls. Although asthmatic symptom prevalence is increased in diabetic patients, the incidence of current asthma was similar in both groups.

Antopol-Goldman lesion of the kidney diagnosed by radiology: a case report of observation.

Antopol-Goldman lesions are extremely rare and are characterized by subepithelial hematoma in the renal pelvis. There have been at least 28 case reports in the literature, with all being diagnosed histologically after partial or total nephrectomy for a presumed malignancy. We report the first case in the literature to be diagnosed by radiological imaging and followed on an observatory basis.

Carotid artery disease development after traumatic injury inflicted by a Ram's Horn.

A 36-year-old man presented for treatment of headache, paresthesis, and weakness of his right arm and leg. Examination revealed an atherosclerotic plaque in the left common carotid artery, lying to the left internal carotid artery and resulting in 99% stenosis. The plaque was removed successfully by carotid endarterectomy. Pathological examination of the tissue confirmed the diagnosis of an atherosclerotic plaque. Detailed investigation of risk factors led to the conclusion that the stenosis of the carotid artery was due to blunt trauma caused by an injury that had occurred 30 years previously when the patient was gored by a ram's horn.

Total intravenous anesthesia for evacuation of a hydatidiform mole and termination of pregnancy in a patient with thyrotoxicosis.

Clinical hyperthyroidism is found in approximately 5% of women with a hydatidiform mole, as human chorionic gonadotropin secreted by molar tissue is structurally similar to thyroid-stimulating hormone. A hydatidiform mole occasionally presents with a co-existing viable fetus. Surgical evacuation may be indicated for significant hemorrhage or preeclampsia. Perioperative management in the presence of hyperthyroidism may be complicated by a thyroid storm. We report a case of total intravenous anesthesia with propofol and remifentanil, combined with an esmolol infusion, to control sympathetic hyperactivity during surgery.

Comparative carcinogenicity of 5-nitrothiophenes and 5-nitrofurans in rats.

We investigated the carcinogenicity of five 5-nitrothiophenes with heterocyclic substituents at the 2-position of the thiophene ring by feeding the chemicals to Sprague-Dawley rats and comparing the type and incidence of lesions with those appearing after exposure to two 5-nitrofurans. Benign and malignant mammary tumors and intestinal tract sarcomas were the most frequent lesions induced by 5-nitrothiophenes. 4-Bis(2-hydroxyethyl)amino-2-(5-nitro-2-thienyl)quinazoline caused a 100% incidence of mammary adenocarcinomas in 28 female rats at risk; it induced 3 benign and 5 malignant mammary tumors and 13 small intestine sarcomas in 20 male rats. A high incidence of similar lesions was observed in male and female rats fed the corresponding 5-nitrofuran analogue, 4-bis(2-hydroxyethyl)amino-2-(5-nitro-2-furyl)quinazoline. In marked contrast, 4 of 28 female rats receiving 4-bis(2-hydroxyethyl)amino-2-(2-thienyl)quinazoline, which lacks the nitro group at the 5-position on the thiophene ring, had solitary benign mammary tumors (P greater than 0.2). Additional 5-nitrothiophenes demonstrating significant oncogenic activity for female rats were 4-morpholino-2-(5-nitro-2-thienyl)quinazoline, 4-(2-hydroxyethylamino)-2-(5-nitro-2-thienyl)quinazoline 4-(2,3-dihydroxypropylamino)-2-(5-nitro-2-thienyl)quinazoline, and 1,2-dihydro-2-(5-nitro-2-thienyl)quinazolin-4(3H)-one. Another nitrofuran, 4,6-dimethyl-2-(5-nitro-2-furyl)-pyrimidine, provided the following types of neoplasms in 30 female rats at risk: squamous cell carcinomas of the forestomach (30), sarcomas of the intestine (21), adenocarcinomas of the kidney (2).

Carcinogenicity of 5-nitrofurans and related compounds with amino-heterocyclic substituents.

Carcinogenicity of eight 5-nitrofurans with heterocyclic substituents at the 2-position of the furan ring was investigated by feeding the chemicals to Sprague-Dawley female rats. N-[5-(5-nitro-2-furyl)-1,3,4-thiadiazol-2-yl]acetamide induced in 30 rats the highest incidence of tumors with the greatest number of tissues involved: forestomach squamous cell tumors (22), kidney pelvis transitional cell carcinomas (15), pulmonary alveolar cell carcinomas (16), hemangioendothelialsarcomas (20) of the intestine, mesentery, liver, lung, and pancreas, and a few tumors of other tissues. 2-Amino-5-(5-nitro-2-furyl)-1,3,4-thiadiazole, 2-amino-5-(5-nitro-2furyl)-1,3,4-oxadiazole, and trans-2-[dimethylamino)methylimino]-5-[2-(5-nitro-2-furyl)vinyl]-1,3,4-oxadiazole produced high incidences of mammary tumors. The other four 5-nitrofurans tested: N-[4-(5-NITRO-2-FURYL)-2-THIAZOLYL]ACETAMIDE;2,3,4-TRIFLUORO-N-[4-(5-NITRO-2-furyl)-2-thiazoly]acetamide;5-(5-nitro-2-furyl)-1,3,4-oxadiazol-2-ol; and N-( [3-(5-nitro-2-furyl)-1,2,4-oxadiazol-5-yl]methyl)acetamide were associated with tumor incidences of 40-60%. Two other chemicals were also tested: 2-Amino-5-nitrothiazole caused a low incidence of breast and kidney pelvis tumors, and 2-amino-4-(p-nitrophenyl)thiazole induced a high incidence of breast and salivary gland adenocarcinomas and lymphomas.

Efficacy of antitumor chemotherapy in C3H mice enhanced by the antiangiogenesis steroid, cortisone acetate.

The effect of "antiangiogenesis" therapy using cortisone acetate (CA) with or without heparin on tumor growth as well as in combination with chemotherapy was investigated. C3H mice were implanted intradermally with N-[4-(5-nitro-2-furyl)-thiazolyl]formamide induced undifferentiated transitional cell carcinoma, MBT-2, in the right flank. The treatment was initiated 9 to 10 days after tumor inoculation. Daily injections of CA (250 mg/kg s.c.) suppressed tumor growth significantly in a dose dependent fashion. Administration of heparin (Elkins-Sinn) at the concentration of 200, 400, or 1000 units/ml in drinking water for 3 to 6 days was neither additive nor detrimental to the effect of CA. Chemotherapy was combined with CA; 3 days of administration of 250 mg/kg of CA in tapering doses was used. The chemotherapeutic agent was injected once 24 h before the initial CA. Combinations of chemotherapy (Adriamycin, 2.5-7.5 mg/kg i.v; cisplatin, 3-9 mg/kg i.p.; cyclophosphamide, 50-150 mg/kg i.p.; cis-(diammino)(1,1-cyclobutanedicarboxylate)platinum(II) (JM-8), 60-150 mg/kg i.p.; mitomycin C, 3-4.5 mg/kg i.p.) with CA showed additive suppression of tumor growth. Mice tolerated chemotherapy alone, CA alone, and both in combination. CA combined with JM-8 was not tolerated. Mice tolerated 100 to 150 mg/kg of JM-8, whereas the addition of CA to JM-8 resulted in a 66% (6 of 9) to 89% (8 of 9) mortality rate. CA at a concentration of 5 and 25 micrograms/ml showed no direct cytotoxic activity against MBT-2 cells in vitro. However, 3 days of administration of 250 mg/kg of CA inhibited tumor angiogenesis generated by MBT-2 cells in C3H mice using a dorsal air sac assay. The data suggest that CA alone inhibits tumor angiogenesis in C3H mice and that antiangiogenesis therapy enhances the antitumor efficacy of chemotherapeutic agents without increasing host toxicity (except for JM-8).