Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.     

Double flap from amputated opposite lower limb for cover of plantar and dorsal surfaces of a crushed foot

Bilateral limb trauma poses many possibilities for management. In a situation of bilateral amputation, if the amputated limb is not salvageable or replantation is not advisable, the amputated limb can be used to harvest tissue for free tissue transfer to cover the amputation stump. We describe a case here in which we have used these principles.KEY WORDS: Double free flap, free tissue transfer, microsurgery, non-replantable amputation, spare parts surgery     

Evaluation of DNA damage in mice topically exposed to total particulate matter from mainstream and sidestream smoke from cigarettes and bidis

The genotoxic potential of total particulate matter (TPM) from mainstream smoke (MS) and sidestream smoke (SS) of Indian smoking products, namely cigarettes and bidis, as well as a brand of US cigarettes, was studied by determining the levels of bulky aromatic DNA adducts in mouse tissues. TPM from MS or SS of various smoking products [equal weights (2.5 mg) or the amount derived from equal (0.25) cigarette/bidi] was applied topically to mouse skin once a day for four consecutive days and adduct levels were determined in DNA from skin and lung by (32)P-post-labelling analysis. Relatively higher levels of bulky aromatic DNA adducts were noted in mouse skin treated with MS from a single Indian non-filter (INF) cigarette when compared with MS of a single bidi (with about half the product weight and one-quarter the tobacco compared with a cigarette), while comparable adduct levels were noted with SS from these two products. Considering the differences in the yields of constituents of tobacco smoke from the different products analyzed, the genotoxic potential of INF, Indian filter king (IFK) and American filter (AF) cigarettes as well as bidis was determined by topically applying an equal amount of TPM (rather than equal product-derived TPM). SS-derived TPM from all the products showed relatively higher levels of total polycyclic aromatic hydrocarbons and induced relatively higher levels of bulky aromatic DNA adducts than those derived from MS. The data indicate that TPM (MS + SS) from cigarettes appears to be more genotoxic than that from bidis and the contribution of tendu leaf (a non-tobacco bidi wrapper) to the generation of bulky aromatic DNA adducts appears to be significant, particularly in SS of bidis. Topical pretreatment with curcumin decreased the levels of TPM-derived adducts while pretreatment with dietary turmeric failed to show such protection.     

The fatty ridge and fatty cushion of the human pulmonary trunk

Presence of a ridge of fatty tissue running obliquely upwards and backwards over the left aspect of the pulmonary trunk was observed. It started from the left end of the infundibulo-truncal junction and after running parallel adjacent to free anterior border of the left auricle, terminated into an expanded, oval and discoid structure, a little above the level of the tip of the left auricle. The structure was found to be of constant occurrence, position and form. A comparison between similar structure reported in relation with the aorta and the right auricle was attempted.     

Role of red cell distribution width in classifying microcytic hypochromic anaemia

Red cell distribution width (RDW) is an automated laboratory determination of red cell anisocytosis. The aim of the study was to analyse the role of RDW in differentiating iron deficiency anaemia (IDA) from thalassaemia trait. There were 500 patients who were screened for the study. Selection criteria of microcytic anaemia were Hb < 13 g/dl in males, Hb < 12 g/dl in females with mean corpuscular volume (MCV) < 80fl. These cases were subjected to complete iron profile and haemoglobin chromatography for definite diagnosis. The values of RDW were analysed in all these cases to see the utility of RDW in classifying microcytic anaemia; especially differentiating iron deficiency anaemia from thalassaemia minor cases. There were 133 out of 500 cases anaemic; 105/133 cases had microcytic anaemia, of which 53 had iron deficiency anaemia, 39 were thalassaemia traits, 6 were thalassaemia major, and 7 had other haemoglobinopathies. Thirty-six cases (67.92%) out of 53 iron deficiency anaemia had increased RDW, 32.08% (n = 17) had normal RDW; 71.79% (n = 28) of thalassaemia trait had increased RDW, 28.21% (n =11) had normal RDW. Evaluation of RDW as screening test to detect microcytic anaemia had sensitivity of 71.42% and specificity of 40%, Evaluation of RDW as a screening test for IDA had sensitivity of 67.9% and specificity 25%. It was found uniform increase in RDW in all cases of microcytosis. It is concluded that RDW adds useful but limited information in classifying microcytic anaemia.     

Evaluation of effect of allopurinol and febuxostat in behavioral model of depression in mice

Objective:

To evaluate the effects of allopurinol and febuxostat on depression using Forced Swim Test (FST) in mice.

Materials and Methods:

Allopurinol (39 mg/kg p. o) and febuxostat (15.6 mg/kg p. o) were administered once daily for 21 successive days to Swiss Albino mice. On the 21^st day, the effect of the drug on locomotion was tested using photo-actometer followed by the recording of immobility period in the FST and the results were compared with the standard drug fluoxetine (10 mg/kg p. o).

Results:

Allopurinol and febuxostat expressed significant antidepressant like effect as indicated by reduction in the immobility period of mice in the FST as compared to control group. The effects of allopurinol and febuxostat were found to be comparable to that of fluoxetine.

Conclusion:

The results of the present study indicate that allopurinol and febuxostat possess significant antidepressant like activity.KEY WORDS: Forced swim test, photo-actometer, serotonin, tryptophan     

Promotional literature: how do we critically appraise?

There has been a tremendous increase in the number of new and generic drugs coming into the market. The busy practitioner obtains the information from various sources, of which promotional literature forms an important source. The promotional literature provided by the pharmaceutical companies cannot be entirely relied upon; moreover, very few physicians are equipped with the skills of critically appraising it. The new drug should be relevant to the clinician's practice in terms of population studied, the disease and the need for new treatment. The methodology of the study should be carefully judged to determine the authenticity of the evidence. The new drug should be preferred over the existing one if it offers clear advantages in terms of safety, tolerability, efficacy and price. Critical appraisal of promotional literature can provide valuable information to the busy physician to practice evidence-based medicine.