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Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is indicated to improve glycaemic control in adults of type 2 diabetes. In nonclinical studies, dapagliflozin was neither genotoxic nor carcinogenic. However, in some clinical studies, an increased incidence of bladder cancer was observed in the dapagliflozin group vs. the placebo. Therefore, this study was undertaken to determine if dapagliflozin can act as a promoter in a 2-stage bladder cancer model in rats induced with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Rats given BBN (100 or 400 mg/kg, po) twice weekly for 6 weeks in Phase 1 were assigned in Phase 2 to receive daily dose of vehicle, dapagliflozin (0.5 mg/kg, po) or uracil (positive control, 3% in diet) from weeks 8-34. All bladders were evaluated by histopathology. Verifying the validity of the model, uracil increased the incidence of bladder cancer, while dapagliflozin had no effect on the incidence or invasiveness of transitional cell carcinoma. The exposure of dapagliflozin at 0.5 mg/kg/day in rats was 7 times the clinical exposure at maximal therapeutic dose (10 mg). In conclusion, dapagliflozin does not act as promoter or progressor of bladder cancer in a validated bladder cancer model in rats., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to establish a 2-stage model of urinary bladder carcinogenesis in male Sprague-Dawley rats to identify tumor promoters. In phase 1 of the study, rats ( n = 170) were administered 100 mg/kg of the tumor initiator, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), twice weekly by oral gavage (po) for a period of 6 weeks. Phase 2 consisted of dividing rats into 4 groups ( n = 40 per group) and administering one of the following for 26 weeks to identify putative tumor promoters: (1) vehicle po, (2) 25 mg/kg/day rosiglitazone po, (3) 5% dietary sodium l-ascorbate, and (4) 3% dietary uracil. Rats were necropsied after 7.5 months, and urinary bladders were evaluated by histopathology. BBN/vehicle treatments induced the development of urothelial hyperplasia (83%) and papillomas (15%) but no transitional cell carcinomas (TCCs). Rosiglitazone increased the incidence and severity of papillomas (93%) and resulted in TCC in 10% of treated rats. Uracil was the most effective tumor promoter in our study and increased the incidence of papillomas (90%) and TCC (74%). Sodium ascorbate decreased the incidence of urothelial hyperplasia (63%) and did not increase the incidence of urothelial papillomas or TCC. These data confirm the capacity of our 2-stage model to identify urinary bladder tumor promoters.

Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 μg/kg or 30 μg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 μg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The principal objective was to investigate the association between periodontal diseases and sickle cell anaemia (SCA)., Materials and Methods: A group of 59 children with SCA (ages 12 to 16 years) were examined and compared to 54 healthy controls, matched by age and gender. Oral clinical examination included: plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment loss (CAL), presence of calculus and tooth mobility. Clinical severity of SCA and oral hygiene habits were also assessed., Results: There was no statistically significant difference between cases and controls in terms of PI, PD, CAL and tooth mobility at the 5% significance level. However, there was a statistically significant association between GI and SCA (P = 0.002). The mean gingival index of SCA patients was 1.35 ± 0.19 compared to 1.18 ± 0.16 for the controls (P = 0.00001). There was a probability of 76.1% that the GI of SCA patients was greater than the GI of controls. The percentage of teeth with PD = 4 mm was greater in SCA patients compared to controls (2.5% vs 0.6%). Moreover, SCA patients had a higher percentage of teeth with CAL= 3 mm (0.7% vs 0.3%). There was a statistically significant association between having mild, moderate or severe gingival inflammation and the severity of sickle cell anemia (P = 0.028)., Conclusions: The results showed a statistically significantly higher prevalence of inflammed periodontium in children with SCA compared to a similar healthy population.

The presence of a geographical pattern in the distribution of the sickle cell gene (S gene) and its association with malaria is well documented. To study the distribution of the S gene among various ethnic and linguistic groups in the Sudan we analyzed a hospital-based sample of 189 sickle cell anemia (SCA) patients who reported to the Khartoum Teaching Hospital between June 1996 and March 2000 and 118 controls with other complaints, against their ethnic and linguistic affiliations and geographic origin. Electrophoresis for hemoglobin S and sickling tests were carried out on all patients and controls as a prerequisite for inclusion. The majority of patients (93.7%) belonged to families of single ethnic descent, indicating the high degree of within-group marriages and thus the higher risk of augmenting the gene. SCA was found to be predominant among the Afro-Asiatic-speaking groups (68.4%) including nomadic groups of Arab and non- Arab descent that migrated to the Sudan in various historical epochs. Those patients clustered in western Sudan (Kordofan and Darfur) from where 73% of all cases originate. The proportion of patients reporting from other geographic areas like the south (3.1%), which is primarily inhabited by Nilo-Saharan-speaking groups (19% of the whole sample) who populated the country in previous times, is disproportionate to their total population in the country (chi(2) = 71.6; p = 0.0001). Analysis of the haplotypes associated with the S gene indicated that the most abundant haplotypes are the Cameroon, Benin, Bantu and Senegal haplotypes, respectively. No relationship was seen between haplotypes and the various hematological parameters in the sub-sample analyzed for such association. These results provide an insight into the distribution of the sickle cell gene in the Sudan, and highlight the strong link of the middle Nile Valley with West Africa through the open plateau of the Sahel and the nomadic cattle herders and also probably the relatively young age of the S gene.