Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors.

The dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1H,3H)-dione 2a-g, in addition to the preparation of some new derivatives namely, 3 and 4a-j. Three compounds namely, 2c, 4b, and 4e showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC50 range 0.052-0.084 µM). Both compounds 4b, 4e showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound 4b showed HB with a highly conserved residue Asp1046 in the HB region. Compound 4e showed HB with Glu885 and Asp1046. Moreover, in silico prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1H,3H)-dione derivatives are promising antiproliferative candidates that require further optimisation.HighlightsNew 3-substituted quinazoline-2,4(1H,3H)-dione derivatives were synthesised and characterised.Compounds 4b and 4e showed higher cytotoxic activity than cabozantinib against HCT-116 colorectal cell lines.Both compounds 4b and 4e showed less toxicity to WI38 normal cell line compared to HCT 116 colon cancer cell line.Compound 4b was superior to cabozantinib in VEGFR-2 inhibition while compound 2c was equipotent to cabozantinib.Compounds 4b and 4e showed remarkable c-Met inhibitory activity.Compounds 4b and 4e arrested cell cycle and induced significant levels of apoptosis.In silico ADME prediction revealed high oral bioavailability and enhanced water solubility of target compounds as compared to cabozantinib.Target compounds interacted with both c-Met and VEGFR-2 active site in similar way to cabozantinib.

Proinsulin/insulin ratio as a predictor of insulin resistance in patients with diabetic nephropathy.

Patients with Diabetic nephropathy (DN) have an increase in cardiovascular mortality, and since IR may be a contributing factor. Therefore, the aim of this study was to assess the role of pro insulin/insulin ratio as a predictor of insulin resistance in patients with diabetic nephropathy PATIENTS AND METHODS: A Case-control study was conducted in a total of 50 patients who diagnosed with type 2 diabetes mellitus from July 2017 to March 2018. The patients were divided into 2 groups according to presence of diabetic nephropathy. Demographic and clinical data were collected. RESULTS: There is a significant increase in serum pro insulin/insulin ratio in patients with diabetic nephropathy patients compared to patients without diabetic nephropathy An association was found between increase serum pro insulin/insulin ratio and increase predicting of insulin resistance. Cut-off value of serum pro insulin/insulin ratio ≥0.1145 with sensitivity and specificity of 92.3 and 60.3 respectively as a predictor for insulin resistance CONCLUSION: This study demonstrate a strong relationship between insulin resistance and CKD and this relationship was stronger in the presence of obesity. Pro insulin/insulin ratio was found to be a significant predictor for insulin resistance.

Prevalence of Schistosomiasis and dynamics of its distribution in some villages in Qalyoubia Governorate.

A total of 1535 persons of different age, sex and occupation from 5 villages (Tanan, El-Sad, Sandiun, Kalama and Taha-nob) in Qalyoubia Governorate in Nile Delta were subjected to clinical, stool, urine and intradermal tests accompanied by a questionnaire for 500 of them. Snail vectors of Schistosome parasites were collected from 2 villages (El-Sad and Taha-nob) and snail densities in the waterways as well as the prevalence rate of infection with schistosomal cercariae were recorded. The results revealed that the average prevalence rate of Schistosoma haematobium in the 5 cillages was 4.9% (range 2.3% - 7.1%) and that of S. mansoni was 13.3% (range 11.4-14.4%). The overall prevalence of both types was 18.2% (range 13.7-21.4%). The average density of Biomphalaria alexandrina in the 2 village was 16.47% and that of Bulinus truncatus was 7.5%, the ratio was 2:1. The infectivity with schistosomal cercariae was very low with an average of 2.5% in B. Alexandrina and 1.5% in B. truncatus. Factors responsible for the decreased rates of schistosomiasis and snail infectivity were discussed.

Study of the present status of filariasis in an endemic area in Giza Governorate, Egypt.

In a trial to throw some light on the present status of Filariasis in Giza Governorate, both human and mosquitoes were surveyed in two endemic areas: Kafr-Ghataty and Azizya. In Kafr-Ghataty the clinical cases detected were very rare (0.77%), while no microfilaraemic cases were obtained. The situation was different in Azizya village, where no clinical cases were detected but microfilaraemic cases were relatively higher (8%). The results of the larval survey, carried out only in Kafr-Ghataty, showed that Culex pipiens larvae were predominant (99.57%). They were found in all the breeding places specially canals and seepages, while Theobaldia longiareolata larvae were rare (0.43%) and present only in wells and cesspits. Regarding the adult mosquitoes survey, Culex pipiens was the only species detected in both areas. The results of dissection of adult female mosquitoes showed that individual dissection failed to detect infection among mosquitoes, in contrast to mass dissection which gave positive results (0.27% in Kafr-Ghataty and 2.2% in Azizya). It was also found that infective mosquitoes were 0% in Kafr-Ghataty and 1.1% in Azizya.

Cellular and humoral immunological changes in chronic renal failure associated with schistosomiasis.

The changes that occur in cell mediated and humoral immunity in patients suffering from chronic renal failure associated with schistosomiasis were studied. There was a decrease in T3%, T4% and T4/T8 ratio. IgG, IgM and IgE levels were found to be increased in such cases. It was concluded that there was a reciprocal relationship between cell mediated immunity and IgE levels in cases with chronic renal failure associated with bilharzial hepatosplenomegaly.

Toxoplasma gondii in Saudi blood donors a serological study using three tests.

A total of one hundred and fifty Saudi blood donors were examined for Toxoplasma gondii antibodies (IgG-IgM) by three serological techniques, 50 normal cross matched controls were subjected to the same examination. The number of positive donors for IgG by Indirect Haemagglutination test (IHA) was 36 (24%), by Enzyme Linked Immunosorbent Assay (ELISA) was 70 (46.7%), and by Immunofluorescent test (IFAT) 74 (49.3%). As to IgM the ELISA and IFAT showed 3 positive cases among the blood donors (2%). Rheumatoid factor and antinuclear antibodies were done for positive cases, and showed no significant cross reaction, IgG antibodies were significantly high in donors than in controls. The three tests were more or less dependable. However regarding simplicity, specificity, accuracy and time consumption factor IFAT was recommended for Toxoplasma IgG for all blood donors to avoid the risk of in infection.

Isoenzyme characterization of Leishmania isolates from patients in El Nour Specialized Hospital, Saudi Arabia.

No doubt, the three forms of leishmaniasis (VL, ZCL & ACL) are well documented in Saudi Arabia. The basis of epidemiological studies must be adequate identification of the Leishmania patients. Seven leishmanial strains have been isolated from patients attending El Nour Specialized Hospital, Makka Al Mokarrama. The majority of the patients of this hospital are temporary visitors to Makka Al Mokarrama for "Haj and Omra". Isoenzyme characterization by cellulose acetate electrophores's used nine enzymes was done. The seven isolates were: two L. donovani zymodeme LON 41 (Indian patient) and LON 46 (Sudanese patient); three L. tropica zymodeme LON 71 (2 Yemeri patients) and LON 22 (Egyptian patient) and two L. major zymodeme LON 4 (2 Saudi patients).

Assessment of serum copper and zinc levels in chronic Schistosoma mansoni patients with and without hepatic involvement before and after praziquantel therapy.

Estimation of serum copper and zinc was carried out on 40 Schistosoma mansoni patients with and without hepatosplenic involvement (group A and B respectively) before and after single oral dose of 40 mg praziquantel therapy as well as 20 normal controls (group C). Full clinical examination and assessment of liver function tests was done. HBsAg positive cases were excluded. The results showed a significant increase in the copper level in both groups (A and B) before treatment when compared to normal controls, and a significant reduction in zinc level only in group B. Following praziquantel therapy the copper level decreased with concomitant increase in the serum zinc level.

Otitis media and aural myiasis.

Myiasis is a diseased condition caused by larvae of myiasis producing flies. Still little is known about such an important subject in Egypt. In this paper, the author described three human cases of otitis media associated with aural myiasis. The causative larvae were those of W. magnifica and S. falculata.

Recent study of Hymenolepis nana infection in Egyptian children.

Survey on 1800 children was conducted to detect the prevalence of H. nana infection in Egyptian children, by direct smear and concentration techniques. The incidence of infection was found to be 16%. Two hundred cases of them were subjected to full clinical history, thorough physical examination and anthropometric assessment. Different clinical manifestations were found in 84% of cases. Delayed growth manifested by decrease of the body weight below the third percentile was found in 62% of cases, in addition to marked affection of the body, height, head circumference, midarm circumference and triceps skinfold thickness in 16%, 10%, 32% and 28% of cases respectively. Trials on these 200 cases were carried out to evaluate the efficacy of "Praziquantel" in comparison with "Mebendazole". Praziquantel gave significant higher cure rates, being 91.1% and 97.7% after 2 and 4 weeks respectively, compared to Mebendazole which gave cure rates of 50% and 59%. Both drugs were well tolerated and have no side effects, however Praziquantel was given as a single dose, and so have the advantage of being more effective, easily administered, safe with higher cure rate.

The relation between intestinal troubles and parasitic infection in Cairo.

Stool and urine from 320 subjects in Ain shams region, and 200 subjects in Nasr city were collected and examined for parasites. All these subjects were suffering from abdominal troubles. The results revealed a marked relation between parasitic infection and abdominal troubles, especially in Ain shams region (80%), and to a lesser extent in Nasr City (51%). The commonest parasite in Ain shams was Giardia lamblia (20.3%), and in Nasr city was E. histolytica (13%).

The relation between red cell antigens and the occurrence of filariasis and its complications.

In a trial to assess the role of red cells antigens in pathogenesis of filariasis, 520 individuals from El Korean village were examined clinically to detect clinical filariasis, blood examined by counting chamber to detect microfilaraemic cases and red cell antigens (ABO system, Rh system and MN system) using slide method. The study showed no statistical significance association between filariasis (clinical and microfilaraemic) and red cells antigens.