0 1941

At present, the treatment of human diseases with the former drug is a very wide phenomenon in the pharmaceutical industry. The former drug, also known as the prodrug, is first introduced by the drug chemist Albert in 1958, describing the prodrug as a compound that undergoes biological transformation before presenting a pharmacological action “. It can overcome some undesirable properties, such as poor absorption, biodegradation and preparation of some bioactive compounds. However, it should also be noted that a large number of new difficulties, especially in the evaluation of pharmacological, toxicological and clinical properties, will produce, such as the problem of prodrug bioequivalence.

We intend to discuss the following aspects.

Determination of the prodrug is preferred

The prodrug, although metabolites have the pharmacological activity, but if prodrug is released from the preparation and absorbed. At the same time, the determination method is reliable, then the best way shall still is the bioequivalence with the prototype drug (prodrug) to evaluate the two drugs.

Simultaneous determination of the prodrug and its metabolites

It is rarely considered the simultaneous determination of prototype drug and metabolite levels to evaluate the bioequivalence, but in some cases, for example, the drug itself is inactive prodrug, which in vivo can quickly transforms into active metabolites, and efficacy or toxicity mainly relates to the metabolites. So, metabolite determination also has important reference value in the bioequvalence decision making, and it can reduce the risk of consumers to replace the use of drugs by increasing the bioequvalence characteristic parameters of the metabolites.

Determination of metabolites

In some cases, some of the drug themselves are inactive prodrugs. But due to some reasons, for example, prodrug is not stable in a biological matrix; rapid metabolism and analysis method studies have difficulties; we can not determine the prototype drug in biological samples. Or when pharmaceutical active metabolites are closely related to drug efficacy and safety, it is generally thought to use the method for the determination of biological samples in the corresponding active metabolites to do bioequivalence trial.

Problems should be paid attention to in the detection

Consideration of the prodrug or metabolite as the detection index

Quality control of reference materials

0 2012

ADME/Tox test and obesity
Researchers need to build a more humanized mouse model to evaluate the absorption, distribution, metabolism, and excretion of newly developed drugs in preclinical toxicity testing. These mouse models in vivo experiments are able to clear the important link among drug dosage, concentration, toxicity and so on.
A good mouse model, not only at the level of genes, but also in histology and phenotype is similar to human disease. It is the only way to reduce the risk of drug failure in expensive clinical trials.

Behavioral and developmental disorders(like Autism spectrum disorders)
ASDs is difficult to use the model to simulate, partly because in the human body it is very difficult to find the cause of the disease itself. Recently, scientists have found a gene that is associated with an increased risk of ASDs disease, which could lead to new animal models. On the other hand, the Patient Derived Xenograft (PDX) model has great potential for the development of personalized therapeutic drugs, and the full human source of the mouse immune system will drive a lot of possibilities in this field. This model can be used to study the immune regulation related diseases, and to provide a platform for evaluating the effectiveness of stem cell therapy.New animal models

In tumor treatment, many still do not meet the actual needs of the medical. The clinical trial success rate of cancer treatment is only about 5%. We still need a new model to develop new effective drugs and treatment programs to save the lives of thousands of patients.

Rare disease
There are hundreds of thousands of rare diseases in the world, but the number of patients with these rare diseases adds up, the total number is no longer rare. Because the funds invested in these diseases are limited, so the relevant model and the development of the drug rate themselves are very slow.
The development of gene sequencing technology has allowed researchers to discover a number of rare and even unique mutations. At the same time, the emergence of CRISPR technology allows scientists to edit these human mutations in mouse models faster, easier, and cheaper.

0 1999

A drug used in the treatment of leukemia can improve the cognition, physical activity and non action function in patients with Parkinson’s disease and Lewy. In addition, the drug may also cause significant changes in the toxic proteins associated with disease progression. The researchers introduced the results on the pharmacology conference.

The drug’s name is nilotinib. In 6 months study, the researchers conducted a dose escalation study of 12 patients. The results showed that the drug could benefit all patients who completed the study, including 10 patients who reported that they had a meaningful clinical improvement. Some good changes were also shown in the cerebrospinal fluid of the patients with Parkinson’s disease. The researchers explained that the changes in Tau, p-Tau, a-synuclein and Abeta-40 in the cerebrospinal fluid of the patient showed a clear change in the brain of the patient.

However, the study did not set up a reasonable control study group. People should be cautious in interpreting the results of this study.pharmacology

The researchers noted that the study’s main goal is to test the safety of drug use. The drug concentrations used in the study were much lower than the drug concentrations used in cancer treatment, and the patient did not show a serious side effect.

The use of this is very significant drug for the treatment of many patients, including the body’s ability to act and non action improvement. The researchers reported that one of the patients in a wheelchair could even walk again, while the other three patients who lose their ability to speak also could talk with others.

The researchers also explained the possible mechanism, “when using high dose drug for the treatment of CML, the drug can force the cancer cells to have autophagy, and promote cancer cell to death. In this study, a small dose of drug treatment will also open 4 to 8 hours autophagy a day, helping cells to remove toxic proteins without causing cell death. ”
This study is a new hope for patients with Parkinson’s disease and other neurodegenerative diseases.

0 2001

Recently, a promising HIV experimental vaccine failed to prevent experiment participants from infection. And it’s reported that gut microbiome interfere with the effect of the vaccine. Another important finding for the reasons of failure is that protein-binding antibodies were found in the blood that had not been injected with the experimental vaccine.

The vaccine is HVTN 505, the most promising one in recent years, but the development process stopped in 2013 for that, it was found failed to protect experiment participant from infecting with HIV in the trial period.

Good news is that scientists have found the main reason, which will give direction to the new successful HIV vaccine R&D.

It’s the first time that scientists found microbiome played an interfering role in the process when a vaccine took effect. At present scientists propose a hypothesis that microbiome is the origin of the failure, and the hypothesis will lead new studies on the influence of microbiome on immune system.

By tracking the reason of why the vaccine failed to work, scientists found after the injection of the vaccine, a type of antibody will be produced. The antibody is also produce at very young age after the child is given to birth, but there won’t be such antibody made when the human body goes into maturity in adulthood.

Scientists also found the antibody on people that were naturally infected with HIV virus. And when they test the people who received the experimental vaccine, they found similar situation. The vaccine would boost the production of antibodies that bound with HIV protein and other bacteria. Antibodies protein binding with virus and microbiome in the blood of participant before the vaccine injection were also found, which showed that the vaccine driven antibodies were produced by B cells in bodies.

And now scientists think that the HIV protein mimic helpful gut bacteria by binding with other bacteria, and then escape from the attack of immune system. But all is in the stage of brave guess, more researches are needed to find out the real reason of the failure, and lay a better foundation for the R&D of new HIV vaccine.

0 2219

Protein binding assay is used to test the protein binding extent. In other words, it’s to measure the binding level of a protein. Before finding out what protein binding assay is, the definition of protein binding should be clearly understood.

Generally, protein binding determines a drug’s efficacy in human bodies. It can both strengthen and weaken the effect of drugs, but in different ways. Protein binding, as it means literally, refers to protein making bond with other substances, which in the pharmacological context is the bond that drugs make to the molecules in blood, like red blood cells and membrane.

Protein binding level can be used to describe the drug efficiency. The drugs bound with other molecules won’t perform its medical properties, whilst the unbound drug will take the responsibility and carry out the tasks it shoulder. If 90% percent of a drug bond to other substance and become bound drugs, the rest 10% unbound drug will keep in the blood stream and take medical effect. That’s how protein binding determines drug efficacy. The bound drugs still can take effect but the ability will be detracted. The more bonds they make, the lower medical property level will be performed. Fewer bonds directly lead to smaller size, meaning better ability of passing through tissues.

How does the binding be made? That’s a kind of complicated question to answer. Proteins combine with other molecules including proteins at binding sites, a protein may contain several such sites, which are always in the form of indentations. The binding will be made when a molecule fit into the indentation. Thus more indentations a protein has, the bigger the protein will be after being bound. Protein binding will change with its surrounding alteration, like stress and pregnancy.

However, the indentation is not available for a fixed type of molecule; it can be filled by any molecules that fit to it chemically, which pose danger to bodies. If two drugs are taken by a patient at the same time, and both of them bond to a same type of molecule, but one is with stronger ability to combine with the targeted molecule, thus the other drug will remain more unbound and effective protein in the blood and take effect. In this way overdose situation may appear.

Protein binding assay

Protein binding assay is designed to identify the tendency of a protein to combine with other molecules. In the assay, plasma or tissue will be employed. With these substances, protein will be incubated for a certain period, and then they will pass through a very accurate filter. The unbound proteins can successfully pass the filter, however the bound ones can’t for that they are enlarged by the binding with other molecules.

Drug that are newly developed will be tested with protein binding assay to roughly determine the amount of free drug will be existed in blood stream and take effects, which is a must-have process before a newly invented drug can be put into market.