Lapatinib nano-delivery systems: a promising future for breast cancer treatment

Introduction: Breast cancer stands the second prominent cause of death among women. For its efficient treatment, Lapatinib (LAPA) was developed as a selective tyrosine kinase inhibitor of receptors, overexpressed by breast cancer cells. Various explored delivery strategies for LAPA indicated its controlled release with enhanced aqueous solubility, improved bioavailability, decreased plasma protein binding, reduced dose and toxicity to the other organs with maximized clinical efficacy, compared to its marketed tablet formulation.

Areas covered: This comprehensive review deals with the survey, performed through different electronic databases, regarding various challenges and their solutions attained by fabricating delivery systems like nanoparticles, micelle, nanocapsules, nanochannels, and liposomes. It also covers the synthesis of novel LAPA-conjugates for diagnostic purpose.

Expert opinion: Unfortunately, clinical use of LAPA is restricted because of its extensive albumin binding capacity, poor oral bioavailability, and poor aqueous solubility. LAPA is marketed as the oral tablet only. Therefore, it becomes imperative to formulate alternate efficient multiparticulate or nano-delivery systems for administration through non-oral routes, for active/passive targeting, and to scale-up by pharmaceutical scientists followed by their clinical trials by clinical experts. LAPA combinations with capecitabine and letrozole should also be tried for breast cancer treatment.     

Existential neuroscience: effects of mortality salience on the neurocognitive processing of attractive opposite-sex faces

Being reminded of the inherently finite nature of human existence has been demonstrated to elicit strivings for sexual reproduction and the formation and maintenance of intimate relationships. Recently, it has been proposed that the perception of potential mating partners is influenced by mortality salience. Using functional magnetic resonance imaging, we investigated the neurocognitive processing of attractive opposite-sex faces after priming with death-related words for heterosexual men and women. Significant modulations of behavioral and neural responses were found when participants were requested to decide whether they would like to meet the presented person. Men were more in favor of meeting attractive women after being primed with death-related words compared to a no-prime condition. Increased neural activation could be found under mortality salience in the left anterior insula and the adjacent lateral prefrontal cortex (lPFC) for both men and women. As previously suggested, we believe that the lPFC activation reflects an approach-motivated defense mechanism to overcome concerns that are induced by being reminded of death and dying. Our results provide insight on a neurocognitive level that approach motivation in general, and mating motivation in particular is modulated by mortality salience.     

CD8dim but not CD8bright cells positive to CD56 dominantly express KIR and are cytotoxic during visceral leishmaniasis

This study reports a structural and functional heterogeneity of CD8⁺CD56⁺NKT cells, which usually decrease quantitatively during visceral leishmaniasis. Based on fluorescence intensity of CD8 receptors on CD56⁺NKT cells, two populations of CD8⁺CD56⁺NKT cells have been identified. These cells were recognized as CD8^dimCD56⁺NKT and CD8^brightCD56⁺NKT cells. We further analyzed the functional nature of CD8^dim and CD8^bright positive CD56⁺NKT cells. In comparison to CD8^brightCD56⁺NKT cells, a significantly higher percentage of CD8^dimCD56⁺NKT cells expressed KIR during VL. The percentage of CD8^dimCD56⁺NKT cells expressing KIR was found 4 fold higher in VL as compared to healthy subjects. But, the difference was insignificant in case of CD8^brightCD56⁺NKT cells. CD8⁺CD56⁺NKT cells release granzyme B to kill the infected cells. A categorical difference was also observed in the function of CD8^dimCD56⁺NKT and CD8^brightCD56⁺NKT cells during visceral leishmaniasis. The percentage of granzyme B expressing CD8^dimCD56⁺NKT cells was 2.83 fold higher in VL compared to healthy subjects. But, there was no significant difference in granzyme B expressing CD8^brightCD56⁺NKT cells in samples from healthy and VL subjects. However, within VL subject, the percentage of granzyme B expressing CD8^dimCD56⁺NKT cells was 5.7 fold higher in comparison to CD8^brightCD56⁺NKT cells. This study concludes that CD8^dimCD56⁺NKT cells are more cytotoxic than CD8^brightCD56⁺NKT cells during VL.     

Drug reaction with eosinophilia and systemic symptoms without skin rash

Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug hypersensitivity syndrome is considered as a severe cutaneous adverse drug reaction which is most commonly precipitated by aromatic anticonvulsants, lamotrigine, dapsone, allopurinol, minocycline, and salazopyrin. Its clinical manifestations are often variable. On rare occasions, it can present with only systemic involvement without any cutaneous features. A complete drug history is of paramount importance in making an early diagnosis. We report the case of a male patient who presented with fever, lymphadenopathy, hepatosplenomegaly, and hepatitis, 2 weeks after starting salazopyrin. The presence of atypical lymphocytes in the peripheral smear was indicative of a viral infection or a hematological dyscrasia. Bone marrow examination revealed a normocellular marrow with an increase in eosinophil precursors. Investigations for the common causes for fever and hepatitis were negative. The presence of eosinophilia, the temporal relationship of the symptoms with the initiation of treatment with salazopyrin, and the marked improvement on withdrawal of the drug along with the administration of systemic corticosteroids, were features consistent with the diagnosis of DRESS. With the incidence of this condition showing a rising trend, it is important for the clinician to be aware of its variable manifestations, as a delay in diagnosis and treatment can be fatal.KEY WORDS: Absence of skin lesions, drug reaction with eosinophilia and systemic symptoms, salazopyrin     

Novel vascular endothelial growth factor blocker improves cellular viability and reduces hypobaric hypoxia‐induced vascular leakage and oedema in rat brain

Vascular endothelial growth factor (VEGF) is an important cerebral angiogenic and permeability factor under hypoxia. There is a need to find effective molecules that may ameliorate hypoxia‐induced cerebral oedema. In silico identification of novel candidate molecules that block VEGF‐A site were identified and validated with a Ramachandran plot. The active site residues of VEGF‐A were detected by Pocketfinder, CASTp, and DogSiteScorer. Based on in silico data, three VEGF‐A blocker (VAB) candidate molecules (VAB1, VAB2, and VAB3) were checked for improvement in cellular viability and regulation of VEGF levels in N2a cells under hypoxia (0.5% O₂). Additionally, the best candidate molecule's efficacy was assessed in male Sprague‐Dawley rats for its ameliorative effect on cerebral oedema and vascular leakage under hypobaric hypoxia 7260 m. All experimental results were compared with the commercially available VEGF blocker sunitinib. Vascular endothelial growth factor‐A blocker 1 was found most effective in increasing cellular viability and maintaining normal VEGF levels under hypoxia (0.5% oxygen) in N2a cells. Vascular endothelial growth factor‐A blocker 1 effectively restored VEGF levels, decreased cerebral oedema, and reduced vascular leakage under hypobaric hypoxia when compared to sunitinib‐treated rats. Vascular endothelial growth factor‐A blocker 1 may be a promising candidate molecule for ameliorating hypobaric hypoxia‐induced vasogenic oedema by regulating VEGF levels.