The past decade has seen several effective anti-HIV-1 agent discoveries, yet microbicides continue to disappoint clinically. Our review expounds the view that unsatisfactory microbicide failures may be a result of inefficient delivery systems employed.
Microbicide delivery devices will be critical in ensuring safe and effective use of microbicide products. The device impacts the product’s overall safety (relationship with product purity and stability, avoidance of local trauma associated with insertion or use), efficacy (consistent delivery of the required amount of product in the intended location), and acceptability (comfort, ease of use, disposability).
Several novel microbicide delivery methods to help reduce cost, ensure microbicide efficacy, and increase user acceptability. Methods include:
• Diaphragm: This combination of barrier method and microbicide could enable prevention of both pregnancy and disease. Two studies were recently completed. One study assessed gel retention and distribution in the vagina comparing Diaphragm single-sided and double-sided gel delivery to a
vaginal applicator. The second study used the same three gel application modes and evaluated couples’ use acceptability.
• Paper applicator with dosage stop: This user-filled applicator is low cost, easily disposed of, and prevents over-filling, making it an important option for microbicide gel delivery in low-resource settings.
• Rectal applicator: This applicator has been designed specifically for the rectal delivery of microbicide products.
Intravaginal targeting of HIV-1 increases the chances of microbicide success, wherein vaginal micro environmental factors including pH should be maintained at HIV-1 prohibitive acidic levels simultaneously to ward off other sexually transmitted diseases, which compromise vaginal epithelial barrier properties.
Furthermore, choice of receptors to target both on HIV-1 and on target cells is vital in deterring transmission. Appropriate modeling of virus–target cell interactions as well as targeting early stages of the HIV-1 infection accompanied by computation and delivery of appropriate microbicide quantities could revolutionize microbicide research, ultimately delivering a female-controlled HIV-1 prevention modality appropriately.
(Qualitative and quantitative intravaginal targeting: Key to anti-HIV-1 microbicide delivery from test tube to In Vivo success; Viness Pillay,*, Felix Mashingaidze, Yahya E. Choonara, Lisa C. Du Toit, Eckhart Buchmann, Vinesh Maharaj, Valence M. K. Ndesendo, Pradeep Kumar)
The first delivery system was designed to promote uniform distribution and retention of the antivirals in the vaginal lumen, and provide semen triggered delivery into semen—the carrier of HIV in male-to-female sexual transmission.
The delivery system consisted of a temperature and pH sensitive gel composed of a terpolymer of N-isopropylacrylamide, acrylic acid and butyl methacrylate. The neutralization of acidic pH in the vagina upon exposure to semen was used as the trigger to release the active agents from the terpolymer gel.
The thermosensitive design employed was such that the delivery vehicle is applied as a liquid at room temperature to allow uniform coating, and gels post-application to promote retention. In vitro characterizations under simulated physiological conditions confirmed that the designed system was liquid at room temperature, gels as the temperature is increased from room to body temperature, and
provides burst release of active agents upon exposure to semen fluid simulant.
The second and third systems were intravaginal rings (IVRs) for sustained delivery of dapivirine, a potent inhibitor of HIV replication after the virus has entered the host cells.
A sustained delivery of replication inhibitors is pursued to allow enough time for antiviral drugs to diffuse into the vaginal epithelium and ensure that inhibitory concentrations are established before the viral attack.
Monolithic IVRs were fabricated from biomedical grade polyurethanes and degradable polyurethanes synthesized with hydrolytically labile ester groups in the polymer backbone. The ability of the utilized polyurethane matrix to provide a zero-order delivery of dapivirine enabled a monolithic design that can be
manufactured using a cost-effective melt extrusion procedure. The inexpensive IVR design loaded with a potent drug and with the high user adherence associated with IVRs offer a promising solution for an effective microbicide.
Conceival, a novel noncontraceptive vaginal vehicle for lipophilic microbicides
By Osmond J. D'Cruz, Peter Samuel , Fatih M. Uckun
The objective of this study was to develop a nontoxic and noncontraceptive vaginal drug delivery vehicle for lipophilic anti-human immunodeficiency virus (HIV) microbicides.
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Based on their solubility profiles, a novel non-spermicidal self-emulsifying gel (viz Conceival) composed of pharmaceutical excipients, sorbitol, polyethylene glycol 400, polysorbate 80, microcrystalline cellulose, xanthan gum, and water was optimized.
Conceival was evaluated in vivo in the New Zealand white rabbit model for the preservation of sperm function based on pregnancy outcome and the potential for vaginal irritation following single and multiple intravaginal applications, respectively.
Conceival administered intravaginally immediately prior to artificial insemination with semen had no adverse effects on subsequent reproductive performance, neonatal survival, or pup development when compared with untreated control group.
Histologic evaluation of vaginal tissues of rabbits exposed intravaginally to Conceival for 14 consecutive days revealed lack of epithelial, submucosal, and vascular changes at the gel application site (total irritation score <3 out of a possible 16). These findings indicate that Conceival has potential to become a clinically useful, safe noncontraceptive vaginal vehicle for lipophilic microbicides.
Yes yes & yes many cancers & like diseases like HIV/AIDS, HSV/HERPES, and many organ related diseases are cured this days with herbal remedies & more herbal treatments are being discovered all the time. More anticancer & antiviral herbal drugs are in clinical trials this days than ever before and promising herbalist like Dr Utu all thanks to him. I do hear of many people he has helped cured their diseases using African natural Herbs & Roots. I'm Paul G. From Australia a father of four which include 3 girls and a boy. My boss is more than a father to me, he assist my family even financially. He completely lost himself when he was diagnosed of kidney stone & to make matter worst he started noticing his first outbreak. Ever since his kidney stone issues, he keep having herpes outbreak on any little fever. He's my boss and the only way I can pay him is to help his situation. At first I doubted Dr Utu, but in a case of life & death as this am left with only a choice. I contacted Dr Utu to give him a try. He sent herbal meds to my boss that completely flushed out the stone in his kidney. He completely cured my boss of kidney stone and herpes virus using African herbs. I also prescribed this herbal cure for a colleague with HIV and he was completely cured. Dr Utu is health future. Through me Dr Utu have completely cured; herpes, hiv, cancers, kidney stone. I think it pays to be good because you never know who might pay you back in future. So my knowledge on this is what I share. For the sick, trying herbal meds will tell you the different. Reach Dr Utu on his email; drutuherbalcure@gmail.com
ReplyDeleteIt took almost one year for my first real outbreak but it was the hardest thing in the world to get along with. I felt so unwanted and dirty. I tried many formulas, suggestions, methods to get rid of it permanently. Booked appointment with many doctors, professionals, even religiously until I started getting away spiritually and still it won't go. The worst is my outbreaks occurs within short period and take as long as even weeks to go away. I was at last placed on antiviral treatment which is a good treatment but for how long? I prayed every four times a day for God to cure me miraculously or direct me to cure because I know there is. During outbreaks I thought it's the end of the world but it's not, with time I will become normal again. I started trying fruits and herbs, take herbal produced, and with time became very interested in herbs. I read blogs, websites, and comments on herbs and built a stronger hope. I saw comments and decided to try Dr Utu African Traditional Herbal meds. I know of one mr Brown who was HIV and now brags he was cured of HIV with Dr Utu traditional meds but never give it a thought because I believed HIV already has a cure and never think it through or make a research. And for herpes my doctor told me that there is no known cure. When I saw testimonies of his Herpes cure on sites. I copied his contact d r u t u h e r b a l c u r e @ g m a i l . c o m.
ReplyDeleteI showed it to brown who confirmed it was Dr Utu contact. I contacted him immediately and he also prepared and sent me herbal herpes meds through DHL. Right after getting this traditional meds I followed the prescription cautiously and withing days I started noticing rapid change and I know within me it's the cure. I used it for up to two weeks and when my test result was out not only did this herbal meds cure me but boost my immune and I feel real and free. Dr Utu African Traditional meds have successfully cured Herpes, Warts, HIV, Cancers, Kidney Stone, Asthma, most importantly this traditional meds boost immune and have no after effect.
I am deeply concerned about the still increase in population of people living with HSV, HIV, CANCERS, HEPATITIS, STROKES in our society today because of ignorance, to be Frank all this big names are grammars. I saw comments of people DR UTU helped get rid of their diseases, with the increase in population of people living with various diseases and myself as a beneficiary to DR UTU traditional cure I thought I too should reach the world via comment. Many People believed traditional herbs are so primitive and some are even shy to purchase it in public. Some went as far as trashing the legendary name of herbal medicine hiding its numerous advantages and let publicly it disadvantage and yet makes it look big, all this are just for pharmaceutical gain. All pharmaceutical cure are derived from existing traditional herbal cure from ages.
ReplyDeleteYes! I'm here to tell the world the actual FACT! which is; there is herbal cure for herpes, Ebola, HIV, cancers, hepatitis, ulcers, asthma, pile, diabetes and many big names of diseases. all my career I've lived my life believing and making research on this, till I confirmed it four years ago. Since four years ago and till today I still say yes! That among many real traditional herbalist Dr Nze Utu Njoku @ (drutuherbalcure) cures this diseases using African traditional herbs. After he cured me four years ago of genital herpes, ever since then I worked with him distance never a barrier, I'm a living witness to this. And I have directed both genital and oral herpes patients to him and they are permanently cured. I'm Ethan Oliver from Australia and also a herbal dealer and lover. I'm also a researcher on herbs for good health. Which also include Africa traditional herbal treatment, I support Herbal treatment, cure and vaccines. My view is based on my extensive research over a very long period of time, and my conclusion is, there is cure to all natural diseases including HSV, HIV, CANCERS, DIABETES, using the right medications with the right herbalist. Are you herpes positive and permanently want get rid of this disease or any of this big name diseases don't be scared to save yourself, contact Dr Utu for permanent herbal cure. Be bold and smart Don't be fooled by selfish people who say, cure is impossible.
Dr UTU e-mail , 'drutuherbalcure@gmail.com'
My boyfriend and I met three years ago on herpes dating site so we discovered we are +ve from the beginning of our relationship, that we both had genital herpes. My first outbreak was the ABSOLUTE worst experience, I was so sick. We suffered for one year plus, had constant outbreaks and then finally we decided to both respectively take Dr Utu African Traditional Herbs as advised by friends. His herb is Not much bitter or sour taste.
ReplyDeleteDosage two times daily every day for four weeks, and honest to goodness it was a miraculous herbs. We were on it for not more than two weeks when we noticed total change. 'couldn't wait for four weeks. It was third week and five days we used the herbs. Then we went for test and was already hsv2 negative, the both of us. Neither of us have had any lesion, outbreak or symptoms till date.
For traditional and permanent hsv cure, Contact him on drutuherbalcure@gmail.com or direct WhatsApp or phone +2347032718477