Perspectives for combination therapy to overcome drug-resistant multiple myeloma.

The introduction of melphalan and prednisone 40 years ago was a significant advance in the treatment of multiple myeloma (MM). In the following decades, significant advances were few, but included landmarks, such as the introduction of VAD and autologous transplantation during the 1980s and bisphosphonates in the 1990s. Although response rates to therapy were increased, overall survival was not significantly improved. In 1999, the treatment of myeloma was revolutionized by the introduction of thalidomide. Subsequently, the development of the immunomodulatory thalidomide analogues and the proteasome inhibitor bortezomib have impacted on response rates to therapy in relapsed and refractory myeloma and are currently being evaluated as primary therapy for myeloma. Early results suggest activity in combination with standard therapy to overcome drug resistance in patients with early stage disease and are changing treatment strategies in multiple myeloma. As an increasing number of other novel therapeutics is identified and mechanisms of resistance are elucidated, combinations of these drugs will be developed to optimize new therapeutic regimens.     

Cyclodextrins: application in different routes of drug administration

The objective of this review article is to explain the use of cyclodextrin in the different routes of drug administration. The article gives the chemistry of cyclodextrins and addresses the issue of the mechanism of drug release from cyclodextrin complexes. Dilution, competitive displacement, protein binding, change in ionic strength and temperature and drug uptake by tissues are the different release mechanisms of the drug from the drug-cyclodextrin complex discussed here. Use and its limitations in the different drug delivery systems like nasal, ophthalmic, transdermal and rectal drug delivery are explained. The application of the cyclodextrins in the oral drug delivery is detailed in this review. Many studies have shown that cyclodextrins are useful additives in the different routes of drug administration because of increased aqueous solubility, stability, bioavailability and reduced drug irritation.     

A study on the extracts of Cuscuta reflexa Roxb. in treatment of cyclophosphamide induced alopecia

Background

Alopecia is a dermatological disorder with psychosocial implications on patients with hair loss. Hair loss is one of the most feared side effects of chemotherapy. Plants have been widely used for hair growth promotion since ancient times in Ayurveda, Chinese and Unani systems of medicine. The effect of extracts of Cuscuta reflexa Roxb. in testosterone induced alopecia was reported.

Objective

In the present study, the efficacies of the extracts of Cuscuta reflexa in promoting hair growth in cyclophosphamide-induced hair loss have been determined.

Materials and methods

The study was performed by treated with petroleum ether and ethanolic extract of Cuscuta reflexa at the dose 250 mg/kg in male swiss albino rats. Cyclophosphamide (125 mg/kg) was used to induce alopecia.

Results

Groups treated with extracts of plant showed hair regrowth. Histopathology and gross morphologic observations for hair regrowth at shaved sites revealed active follicular proliferation.

Conclusions

It concluded that extracts of Cuscuta reflexa shown to be capable of promoting follicular proliferation or preventing hair loss in cyclophosphamide-induced hair fall.     

Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant <Emphasis Type="Italic">Mycobacterium Tuberculosis</Emphasis>

Purpose

First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF.

Methods

HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and ¹H–NMR spectroscopy. Later on RIF loaded HPMA-PLA-INH co-polymeric micelles (PMRI) were formulated and characterized for size, zeta potential and surface morphology (SEM, TEM) as well as critical micellar concentration. The safety was assessed through RBC’s interaction study. The prepared PMRI were evaluated through MABA assay against sensitive and resistant strains of M. Tuberculosis.

Results

Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, ?19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p < 0.01, INH Vs PMRI; p < 0.0001, RIF Vs PMRI), respectively. MABA assay (cytotoxicity) based MIC values of PMRI formulation was observed as ≥0.0625 and ≥0.50 μg/mL (for sensitive and resistant strain). The microscopic analysis further confirmed that the delivery approach was effective than pure drugs.

Conclusions

RIF loaded and INH conjugated HPMA-PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.

     

Contraceptive Use and Unintended Pregnancies Among HIV-Infected Women in Mumbai

Background:

Access to reproductive health services in Human Immunodeficiency Virus (HIV) programs can greatly enhance program''s potential to limit the spread of disease, reduce unintended pregnancies and safeguard the health of infected people.

Objectives:

To assess (i) knowledge, attitude, and use regarding contraceptives; safe sex and dual protection; (ii) fertility desires and unintended pregnancies post HIV and (iii) symptoms of reproductive tract infection/sexually transmitted infection (RTI/STI) among women infected with HIV.

Materials and Methods:

A cross-sectional study among 300 currently married HIV-positive women who had not undergone permanent sterilization with no immediate desire for pregnancy. Study site was Integrated Counseling and Testing Centers (ICTC) in tertiary hospitals of Mumbai and women were interviewed using a semistructured questionnaire.

Results:

In spite of good awareness about modern methods, 42.7 felt that contraceptives other than condoms were harmful to use due to their HIV status. Knowledge on dual protection was limited to condom (75%). Condom use increased from 5.7% pre-HIV to 71.7% post-HIV, with 89.6% reporting regular use. Future fertility desire was expressed by 8.7% women. Induced abortions post-HIV was reported by16.6% women, as pregnancies were unintended. About 69% wished to use dual contraceptive methods for effective protection if it was not harmful to be used by people living with HIV (PLHIV).

Conclusion:

Data reveals a need to promote modern contraceptive methods along with regular condom use to prevent unintended pregnancies and improve health-seeking behavior for contraception. Health system models that converge or link HIV services with other reproductive health services need to be tested to provide comprehensive reproductive healthcare to infected women in India.     

Potentiation of antimicrobial activity of ciprofloxacin by Pelargonium graveolens essential oil against selected uropathogens

The recent approach of using herbs and antibiotics in combination constitutes a strategy to overcome the problems of resistance and side effects associated with conventional antibiotics. In the present study, the antimicrobial effect of Pelargonium graveolens L' Hér essential oil in combination with ciprofloxacin was evaluated on uropathogens, namely, Klebsiella pneumoniae KT2, Proteus mirabilis PRT3 and Staphylococcus aureus ST2. Minimum inhibitory concentrations of P. graveolens essential oil and ciprofloxacin were determined by the microbroth dilution method and further, the interaction between these two agents was studied by a checkerboard method. The fractional inhibitory concentration index (FICI) was calculated to be 0.375 for both K. pneumoniae KT2 and P. mirabilis PRT3, while for S. aureus ST2 it was found to be 0.5. The values of FICI for the tested microorganisms were found to be ≤0.5, which indicates synergism between P. graveolens essential oil and ciprofloxacin. The concave shaped curve in the isobolograms also depicted a synergistic effect of P. graveolens essential oil and ciprofloxacin against the tested microorganisms. Hence, the synergistic action of P. graveolens essential oil and ciprofloxacin may be applied for the treatment of UTIs, which have hitherto been treated by using only synthetic drugs.     

Late presenters to HIV care and treatment,identification of associated risk factors in HIV-1 infected Indian population

Background  

Timely access to antiretroviral therapy is a key to controlling HIV infection. Late diagnosis and presentation to care diminish the benefits of antiretrovirals and increase risk of transmission. We aimed to identify late presenters in patients sent for first CD4 T cell count after HIV diagnosis, for therapy initiation evaluation. Further we aimed at identifying patient factors associated with higher risk of late presentation.     

Design of curcumin loaded cellulose nanoparticles for prostate cancer

Prostate cancer (PC) is the most frequently diagnosed disease in men in the United States. Curcumin (CUR), a natural diphenol, has shown potent anti-cancer efficacy in various types of cancers. However, suboptimal pharmacokinetics and poor bioavailability limit its effective use in cancer therapeutics. Several successful CUR nanoformulations have recently been reported which improve upon these features; however, there is no personalized safe nanoformulation for prostate cancer. This study contributes two important scientific aspects of prostate cancer therapeutics. The first objective was to investigate the comparative cellular uptake and cytotoxicity evaluation of β-cyclodextrin (CD), hydroxypropyl methylcellulose (cellulose), poly(lactic-co-glycolic acid) (PLGA), magnetic nanoparticles (MNP), and dendrimer based CUR nanoformulations in prostate cancer cells. Curcumin loaded cellulose nanoparticles (cellulose-CUR) formulation exhibited the highest cellular uptake and caused maximum ultrastructural changes related to apoptosis (presence of vacuoles) in prostate cancer cells. Secondly, the anti-cancer potential of the cellulose-CUR formulation was evaluated in cell culture models using cell proliferation, colony formation and apoptosis (7-AAD staining) assays. In these assays, the cellulose-CUR formulation showed improved anti-cancer efficacy compared to free curcumin. Our study shows, for the first time, the feasibility of cellulose-CUR formulation and its potential use in prostate cancer therapy.     

Neuroimaging, biochemical and cellular evidence of protection by mycophenolate mofetil on middle cerebral artery occlusion induced injury in rats

Stroke is a major cause of mortality and disability worldwide. Presently, recombinant tissue plasminogen activator is the only approved drug for the management of acute ischemic stroke. However, it has limitations like narrow therapeutic window and increased risk of intracranial hemorrhage. In previous studies, immunosuppressive agents such as cyclosporine A and tacrolimus have shown neuroprotection by improving neurological functions and infarct volume in models of ischemic stroke. Therefore, the present study was designed to evaluate the effect of mycophenolate mofetil (MMF) on the cerebral ischemic injury in the middle cerebral artery occlusion (MCAo) model in rats. MCAo was carried out in male Wistar rats by inserting an intraluminal thread. One hour after MCAo, the animals were treated with MMF (50, 100, 200mg/kg, i.p.). Reperfusion was done after 2h of occlusion. Thirty minutes after reperfusion, animals were subjected to diffusion-weighted magnetic resonance imaging for assessment of neuroprotective effect of MMF. Twenty four hours after MCAo, motor performance was assessed and the animals were euthanized for estimation of brain malondialdehyde, glutathione, myeloperoxidase and nitric oxide levels. The effect of MMF on apoptosis was also evaluated. MMF significantly attenuated the percent infarct area, apparent diffusion coefficient and signal intensity as compared to a vehicle treated group. Treatment with MMF prevented the motor impairment and significantly reversed the changes in levels of malondialdehyde, glutathione, myeloperoxidase and nitric oxide. MMF treatment significantly reduced the apoptosis. Data of the present study indicate neuroprotective effect of MMF in the experimental model of ischemic stroke.