Drug Safety - Science topic

Well, it incoulds immunofluorescence(IF), hybridization in situ and masson dyeing.

med watch forms in usa pvpi formsissued by cdsc and in clinical trial cioms form

https://www.manufacturingchemist.com/news/article_page/Production_of_pharmaceutical_compounds_through_microbial_fermentation/61614

https://www.biospace.com/article/releases/role-of-microbiology-in-the-pharmaceutical-medical-device-and-cosmetic-industries-/

https://www.omicsonline.org/conferences-list/applications-of-microorganisms-in-the-pharmaceutical-sciences

See attached:

if you are looking for drugs for erectile dusfunction you may be check the fosphodiesterase5 inhibition, if you look to enhance seual responsivenes you should looks to the stimulation of the release of certain sexual hormones.

There could be also a relevant risk linked to hyponatriemia, it is crucial estimate the appropriate rate of the decline of the osmolalities

Preclinical studies in animals are designed to evaluate pharmacodynamic/pharmacokinetic and toxicity profile of a drug. These battery of tests however do not assess clinical efficacy and tolerability. For this, one needs to embark on clinical development studies in human which are usually done in phases:

Phase I - Initial safety/tolerability studies in human volunteers (First in humans). These include human pharmacokinetic studies.

Phase II - Pilot/ Exploratory trials in small number of patients for efficacy and safety. (First in patients) as well as dose-finding studies. These may also include placebo-controlled trials.

Phase III - These are confirmatory trials in a larger number of patients to assess efficacy and safety.

Phase IV - These are post-marketing studies/surveillance undertaken after approval/marketing and are intended to assess efficacy and tolerability in real-life clinical practice situations.

The above phases of clinical trials are so structured that both therapeutic efficacy and clincal safety are evaluated in a step-wise manner backed by clinical expertise.

Thanks Bruce :)

Thank you for the response, Daniel & Michaela

FYI: European Medicines Agency publishes the agendas and minutes of committee meetings. See e.g.

Good question and I must say I am not sure.  For openers, some form of clinical trial data that say that (Q1) and (Q2) have been explored (say in the original NDA or supplements) over sufficient ranges to make it clear that efficacy and /or safety were not affected over wide range.  Say, clinical trials were conducted and the efficacy and safety were shown to be functions of log of dose and the proposed formulation differs by only 10% in concentration.  That would certainly be enough to get a waiver.  

Could be that similar data, showing that log dose was shown in animal experiments would be sufficient evidence (using biomarkers of pharmacological activity) if it the drug is well known from a mechanism of action point of view.

Both clinical (and or animal) data would need to be shown for the active mouthy as well as all of the other inactive components of the new formation.

gets harder from there.

Maybe these links wil help you find the information that you need:

http://www.hra.nhs.uk/research-community/the-review-process/mhra-clinical-trial-authorisation/ and http://www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp/part6.pdf

the attached reference should be helpful

Firstly, you have to ensure your Active Pharmaceutical Ingredient are still in the assay requirements range... for some raw materials that past it's expired date, you have to re-test it... 

If the assay is still in range (see the monograph instead the references such as USP/BP/EP) you may use that raw materials for production/manufacturing process...

There is no standard method of coating plates on an impactor. The coating by reducing re-entrainment of particles aims to reduce variability. But the type of coating largely depend on the type of formulation or in other word on the characteristics of the DPIs. MIcronized lactose or more classical coarse lactose based formulations do not require particular coating. At variance ultrafine powders not requiring deaggregation mechanisms may be "resistant" to any type of coating and the NGI is not the ideal impactor. In these cases Andersen of MSLI are much reliable.

To come to you question you may compare variability without coating and after different coating systems.

At the links below you can some information I hope you will find useful. One of the link is on a paper on this topic I found here on Research Gate.

Thanks Dear Ranjita Santra for answering this question.

Man, I don't know about it, dear John. But seems, our Austrian government is on Meloxicam.

Best, Bernd 

Dear Kanchan Parwani

It depends on the type of extraction.

"i.v." solutions have pH = 7.4 and no need of correction.

In some cases I use phosphate buffer.

Good luck with that

Mihai Ionicã

Jawad M Khan and D Gareth Beevers

Hypertension, currently defined as a blood pressure > 140 mm Hg (systolic) and/or > 90 mm Hg (diastolic), is a common problem. In a western adult population the prevalence of hypertension exceeds 20%.1 The prevalence of hypertension increases with age and is higher in ethnic minority groups in the UK. In the Health Survey for England (2001) the prevalence of hypertension was 3.3% in those aged < 40 years, 27.9% in those aged between 40–79 years, and 49.9% in those aged 80 years and older.2

The two main ethnic origin groups within the UK are the Afro-Caribbean and South Asians. The majority of studies have reported a higher prevalence and significantly higher mean blood pressure levels among both Afro-Caribbean populations and South Asians compared to their white counterparts.3 In a south London community based study, compared with whites, age and sex standardised prevalence ratios for hypertension were 2.6 in people of African descent and 1.8 in those of South Asian origin.4 However, average blood pressure varies between different subgroups of South Asians, being highest in Sikhs, similar to whites in Muslims, and intermediate in Hindus.5 In addition, Indians have higher blood pressures, Pakistanis lower blood pressures, with Bangladeshis having even lower blood pressures than the native white population

Thank you very much Juan! I guess a similar strategy can be used when assessing and comparing efficacy and EC50s or ED50s for different drugs, even if we have drug combinations. Most of what I have read about pertains to dose-response curves and probit analysis in Finney's textbook (1971).  

-David

Actually, Pioglitazone keeps the beta cells of Pancreas under low pressure as it pushes some amount of glucose from the bloodstream into body cells. This means longer life of the beta cells of Pancreas or of Pancreas as a whole , and insulin shots may not be required. Sulfonylureas exert heavy pressure on Pancreas as they  make Pancreas produce insulin unceasingly, often leading to hypoglycemia especially during sleep. Use of Pioglitazone may require less sulfonylurea and thus keep the health of Pancreas good for a longer period of time. 

I am not a Medical Professional, but as a diabetic, I have gathered this information  through studies and from my friends who are doctors. 

Sibaprasad Dutta

Hello Celia,

There is tow methods mathematical  and graphical one. The graphical is as follows: you have to use several groups of animals (mice or rats for example) divided into a control batch receiving only the vehicle (water f eg) and the test batches receiving increasing doses of the drug. each batch receives a single dose. The ratio between tow successive doses must be between [1.2-1.5] (ie: Cn = cn+1 x [1.2-1.5]).

we determine the percentage of the effect corresponding to each dose, draw the dose-response curve: percentage of the response versus the log of the concentration [% response = f (logC)], then EC50 determined graphically, it corresponds to the 50% response.

the presence of antagonist dose may increase the EC50, that is to say the dose-response curve is shifted to the right (50% response is the same but EC50 is greater)

Good luck

Both efficiency and capacity are one or other way same. Based on method adopted, ratio of core-coat, experimental conditions such as stirrer rotation speed, temperature etc., the encapsulation efficiency will vary. But, surely drug content estimation and drug encapsulation efficiency are different.

Mei Liu,1 Yonghui Wu,1 Yukun Chen,1 Jingchun Sun,1 Zhongming Zhao,1 Xue-wen Chen,2,3 Michael Edwin Matheny,1,4,5,6 and Hua Xu 1

Objective

Adverse drug reaction (ADR) is one of the major causes of failure in drug development. Severe ADRs that go undetected until the post-marketing phase of a drug often lead to patient morbidity. Accurate prediction of potential ADRs is required in the entire life cycle of a drug, including early stages of drug design, different phases of clinical trials, and post-marketing surveillance.

Methods

Many studies have utilized either chemical structures or molecular pathways of the drugs to predict ADRs. Here, the authors propose a machine-learning-based approach for ADR prediction by integrating the phenotypic characteristics of a drug, including indications and other known ADRs, with the drug's chemical structures and biological properties, including protein targets and pathway information. A large-scale study was conducted to predict 1385 known ADRs of 832 approved drugs, and five machine-learning algorithms for this task were compared.

Results

This evaluation, based on a fivefold cross-validation, showed that the support vector machine algorithm outperformed the others. Of the three types of information, phenotypic data were the most informative for ADR prediction. When biological and phenotypic features were added to the baseline chemical information, the ADR prediction model achieved significant improvements in area under the curve (from 0.9054 to 0.9524), precision (from 43.37% to 66.17%), and recall (from 49.25% to 63.06%). Most importantly, the proposed model successfully predicted the ADRs associated with withdrawal of rofecoxib and cerivastatin.

Conclusion

The results suggest that phenotypic information on drugs is valuable for ADR prediction. Moreover, they demonstrate that different models that combine chemical, biological, or phenotypic information can be built from approved drugs, and they have the potential to detect clinically important ADRs in both preclinical and post-marketing phases.

Dear Neel,

I have read this report and found it to be a good start to open a discussion on this new issue:

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Postby haidut » Tue Aug 05, 2014 6:39 pm

I posted a study earlier on co-administration of glycine improving the absorption of aspirin. It looks like it also prevents the negative GI symptoms of aspirin intake in some people. The ratio needed is 2:1 in favor of aspirin, which means that if you are taking 1g of aspirin, you need to take 500mg of glycine with it. I have tried it myself, and it not only removed whatever minor GI symptoms aspirin was giving me, but it also removed the insomnia effect that high doses of aspirin had for me when taken before bed. Last night I took 2g of aspirin with 1g of glycine and had the best sleep in months, without waking up even once. Previously, 2g of aspirin before bed would keep me sweating and awake for hours.

"...To determine the tolerability of a glycine (Gly)-containing acetylsalicylic acid (ASA) preparation (Gly-ASA), investigators selected 1135 patients already receiving longterm antiplatelet therapy for a noninterventional trial of Gly-ASA 50 to 300 mg daily. After an average treatment period of 42.6 days, tolerability rating scores and the frequency of 5 gastrointestinal (GI) complaints were compared with those reported for any previous treatment, including plain ASA. After treatment with Gly-ASA, the mean percentage of patients without GI complaints increased more than 2-fold, from 28.2% to 60.6%. Furthermore, the mean percentage of patients reporting any GI symptoms as "always" present decreased from 8.5% to 0.5%. Gly-ASA tolerability was rated "excellent" or "good" by 98% of the patients. "

http://onlinelibrary.wiley.com/doi/10.1 ... x/abstract

"...The relative solubility and rate of dissolution of aspirin in water and glycine solution have been measured. A technique involving a mathematical examination of the front profile of chromatograms has been used to study the extent of the adsorption of glycine from aqueous solution on aspirin.Aspirin is more soluble and more rapidly dissolved in glycine solution than water, and glycine is found to adsorb, in significant amounts, on aspirin crystals. The findings are discussed in an attempt to explain, in physico-chemical terms, differences in taste and adhesion to the oral mucosa that are discernible when aspirin tablets compounded with or without glycine are savoured."

Looks like some countries even sell a packaged combo already:

http://www.ganpatidropshippers.com/gene ... ycine.html

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SQu

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Re: Glycine virtually eliminates adverse GI effects of aspir

Postby SQu » Wed Aug 06, 2014 4:05 am

Thanks for great info! I love aspirin. I've been taking a non prescription cold remedy in the evenings which you add hot water to and drink. It's 800 mg aspirin, 50 mg caffeine, 45 mg ascorbic acid, 2.6 mg menthol and 4254 mg sucrose. I've been adding extra sugar and fructose, and 2 tablespoons gelatin to it just because it's an easy way to get gelatin. At 35% glycine if 2 tbs is 30g that's a bit over 10g of glycine .

According to this it looks like a teaspoon of gelatin would be plenty at about 1.7g but do you think taking more gelatin earlier in the evening might help with later doses of aspirin? I often take aspirin at night when I wake up. It's one of those things that sometimes helps me get back to sleep and stay asleep, but not always. Actually everything I do is like that. It's the staying asleep that's the issue.

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Re: Glycine virtually eliminates adverse GI effects of aspir

Postby haidut » Wed Aug 06, 2014 11:46 am

sueq wrote:Thanks for great info! I love aspirin. I've been taking a non prescription cold remedy in the evenings which you add hot water to and drink. It's 800 mg aspirin, 50 mg caffeine, 45 mg ascorbic acid, 2.6 mg menthol and 4254 mg sucrose. I've been adding extra sugar and fructose, and 2 tablespoons gelatin to it just because it's an easy way to get gelatin. At 35% glycine if 2 tbs is 30g that's a bit over 10g of glycine .

According to this it looks like a teaspoon of gelatin would be plenty at about 1.7g but do you think taking more gelatin earlier in the evening might help with later doses of aspirin? I often take aspirin at night when I wake up. It's one of those things that sometimes helps me get back to sleep and stay asleep, but not always. Actually everything I do is like that. It's the staying asleep that's the issue.

There is a well-done, widely-cited, human study showing 3g glycine at bedtime pretty much eliminated sleep problems.

http://onlinelibrary.wiley.com/doi/10.1 ... 2A8.f01t01

If you take aspirin before bed I'd definitely up my glycine/gelatin intake as well to get even better sleep and protect the stomach from aspirin. I posted another study showing glycine exerts most of its actions at "surprisingly" low doses of 500mg-1,000mg a day. So, your 30g of gelatin is plenty I think.

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Re: Glycine virtually eliminates adverse GI effects of aspir

Postby SQu » Wed Aug 06, 2014 12:22 pm

Ok, going to have it just before bed then. Thanks!

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Re: Glycine virtually eliminates adverse GI effects of aspir

Postby Suikerbuik » Wed Aug 06, 2014 1:14 pm

At the end of the week when you're tired and your sleeping is affected aspirin really helps you sleep like a baby, at least for me. Also the energy is increased, hands warm up immediately - like 5mcg T3 thyroid hormone can do.

However after I have been using it for about 3 days, 500-2000 mg/day tried different doses. I really become fatigued, also feel like it stresses the kidneys (uric acid probably - I've been tested slightly above refenrence for uric acid a few years ago without any aspirin).

Thyroid hormone doesn't introduce any of these issues. I still suspect there's more, maybe something with the antibody response and endotoxin exposure like J. mentioned. I only tried aspirin max. 5 days, but tried this a few times over again but I keep experiencing the same. I am also not convinced that aspirin really is something that's required, so I keep it with thyroid.

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Re: Glycine virtually eliminates adverse GI effects of aspir

Postby schultz » Wed Aug 06, 2014 1:42 pm

I've never heard of this before, but it is really interesting. Thank you for posting these.

Yesterday I stumbled upon an old Chris Masterjohn article in which he says...

"Muscle meats and eggs are very rich in methionine, which increases our need for homocysteine-neutralizing nutrients (vitamins B6, B12, folate, betaine, and choline), and also increases our need for the amino acid glycine..."

and...

"Glycine is depleted in the detoxification of excess methionine"

So would eating a lot of muscle meats - and very little gelatinous meats/gelatin - increase ones sensitivity (in a negative way) to aspirin?

I also wonder if this would also increase - or if glycine would decrease - gut sensitivity to other things such as gluten, dairy or other things that people claim to have issues with?

If the latter is true it would be kind of funny in a way because people who eat a specific paleo diet devoid of glycine would sort of make themselves intolerable to those things. This is speculation of course and I'm in no way trying to hate on the paleo community, just making conversation.

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Peata

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Re: Glycine virtually eliminates adverse GI effects of aspirin

Postby Peata » Thu Jun 25, 2015 5:57 pm

Glycine definitely stops or prevents the GI effect of aspirin for me.

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Greg says

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Re: Glycine virtually eliminates adverse GI effects of aspirin

Postby Greg says » Tue Aug 11, 2015 4:10 pm

haidut wrote:I posted a study earlier on co-administration of glycine improving the absorption of aspirin. It looks like it also prevents the negative GI symptoms of aspirin intake in some people.

I have just been experimenting with 600mg of aspirin a day and immediately felt its positive effects. Warmth, happier, just more healthy. BUT… after a week I could feel the ringing in my ears, gassy, bubbly stomach, brain fog and fatigue and coughing up mucus.

Im now taking glycine hoping for this to pass.

What is the aspirin doing and what is the glycine doing to correct this?

RP says that the stomach will adapt to the aspirin but its a tough decision to carry on with it if its making one sicker. I really want to carry on with the aspirin.

I read haidut saying it depleted glycine but I take tons of glycine. 1 large tbsp a night. [which really helps sleep].

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Re: Glycine virtually eliminates adverse GI effects of aspirin

Postby haidut » Tue Aug 11, 2015 4:19 pm

Greg says wrote:haidut wrote:I posted a study earlier on co-administration of glycine improving the absorption of aspirin. It looks like it also prevents the negative GI symptoms of aspirin intake in some people.

I have just been experimenting with 600mg of aspirin a day and immediately felt its positive effects. Warmth, happier, just more healthy. BUT… after a week I could feel the ringing in my ears, gassy, bubbly stomach, brain fog and fatigue and coughing up mucus.

Im now taking glycine hoping for this to pass.

What is the aspirin doing and what is the glycine doing to correct this?

RP says that the stomach will adapt to the aspirin but its a tough decision to carry on with it if its making one sicker. I really want to carry on with the aspirin.

I read haidut saying it depleted glycine but I take tons of glycine. 1 large tbsp a night. [which really helps sleep].

One possible explanation is that aspirin irritates the gut in some people and Peat said the irritation manifests itself as ear ringing. Glycine is known gastro-protectant, so that could be it. In addition, aspirin depletes glycine since it conjugates with it and forms hippuric acid. That's how it is excreted from the body. So, taking extra aspirin may warrant getting extra glycine to compensate. I don't have specific info on how much aspirin will deplete how much glycine but the glycine:aspirin combo is commonly sold in 1:1 ratio in some European countries, so I guess you can take as much extra glycine as you are taking aspirin.

Drinking Alka-Seltzer, which is aspirin combined with baking soda and citric acid creates sodium acetylsalicylate and that has also been shown to completely eliminate stomach damage by aspirin. Or you can mix your own combo. The ratio is 1:3 aspirin:sodium_bicarbonate.

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Milky

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Glycine virtually eliminates adverse GI effects of aspirin

Postby Milky » Thu Aug 27, 2015 11:30 am

haidut,

What about this study comparing aspirin to aspirin+glycine preparations which mentions that, while those receiving aspirin with glycine did not complain of any side effects, intestinal damage/lesion scores were nearly identical to the non-glycine preparation? This seems to suggest a different cause or mechanism behind symptoms besides simply intestinal irritation/damage.

"In a randomized double-blind study the gastroduodenal tolerability of daily 500 mg acetylsalicylic acid (ASA, CAS 50-78-2) in combination with 250 mg glycine (CAS 56-40-6) (Godamed) and 500 mg ASA without addition of glycine were evaluated in 20 healthy volunteers giving upper GI-endoscopy. Both ASA-preparations have been taken over a period of 4 weeks. Endoscopic controls were performed at entry, and repeated after 7, 14 and 28 days of treatment. Both ASA-preparations induced comparable gastroduodenal damages during the whole test period: The lesions score of both groups on day 7, 14 and day 28 was almost identical. In contrast to plain ASA, where 9 of 10 volunteers reported gastrointestinal side effects, all subjects receiving ASA in combination with glycine did not complain from any dyspeptic symptoms, i.e. epigastric pain etc. "

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haidut

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Glycine virtually eliminates adverse GI effects of aspirin

Postby haidut » Thu Aug 27, 2015 12:27 pm

Milky wrote:Source of the post haidut,

What about this study comparing aspirin to aspirin+glycine preparations which mentions that, while those receiving aspirin with glycine did not complain of any side effects, that intestinal damage/lesion scores were nearly identical to the non-glycine preparation? This seems to suggest a different cause or mechanism behind symptoms besides intestinal irritation/damage.

"In a randomized double-blind study the gastroduodenal tolerability of daily 500 mg acetylsalicylic acid (ASA, CAS 50-78-2) in combination with 250 mg glycine (CAS 56-40-6) (Godamed) and 500 mg ASA without addition of glycine were evaluated in 20 healthy volunteers giving upper GI-endoscopy. Both ASA-preparations have been taken over a period of 4 weeks. Endoscopic controls were performed at entry, and repeated after 7, 14 and 28 days of treatment. Both ASA-preparations induced comparable gastroduodenal damages during the whole test period: The lesions score of both groups on day 7, 14 and day 28 was almost identical. In contrast to plain ASA, where 9 of 10 volunteers reported gastrointestinal side effects, all subjects receiving ASA in combination with glycine did not complain from any dyspeptic symptoms, i.e. epigastric pain etc. "

Yeah, I have seen that study. Not sure what to make of it, as most people that start taking glycine with aspirin report reduction of GI symptoms. I guess if glycine does not work for you you can always try baking soda or caffeine.

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Glycine virtually eliminates adverse GI effects of aspirin

Postby Milky » Thu Aug 27, 2015 12:33 pm

haidut wrote:Source of the post Yeah, I have seen that study. Not sure what to make of it, as most people that start taking glycine with aspirin report reduction of GI symptoms. I guess if glycine does not work for you you can always try baking soda or caffeine.

So far glycine works great...aspirin has always produced ringing/pressure in ears and an anxious/sweaty feeling every time I've tried it orally over the last few years (whole tabs, powder, dissolved in baking soda...doesn't matter), until recently when I tried it again with glycine. I've been taking whole 325mg tablets with nothing but positive benefits. It feels similar to taking ibuprofen in terms of anti-inflammatory effects. I'm just concerned about it still causing damage (as ibuprofen is also known to do), but not being aware of it...especially in the long-term.

My gut feeling is that if it feels good do it so that's what I'll continue to go by, but I'll update if I notice any further effects either way.

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Glycine virtually eliminates adverse GI effects of aspirin

Postby haidut » Thu Aug 27, 2015 1:09 pm

Milky wrote:Source of the posthaidut wrote:Source of the post Yeah, I have seen that study. Not sure what to make of it, as most people that start taking glycine with aspirin report reduction of GI symptoms. I guess if glycine does not work for you you can always try baking soda or caffeine.

So far glycine works great...aspirin has always produced ringing/pressure in ears and an anxious/sweaty feeling every time I've tried it orally over the last few years (whole tabs, powder, dissolved in baking soda...doesn't matter), until recently when I tried it again with glycine. I've been taking whole 325mg tablets with nothing but positive benefits. It feels similar to taking ibuprofen in terms of anti-inflammatory effects. I'm just concerned about it still causing damage (as ibuprofen is also known to do), but not being aware of it...especially in the long-term.

My gut feeling is that if it feels good do it so that's what I'll continue to go by, but I'll update if I notice any further effects either way.

I posted another thread showing that chronic intake of aspirin depletes glycine stores. Given that glycine is the primary inhibitory amino acid in the body, lower levels could explain the anxiety effects you are getting from aspirin. I think the combination of aspirin, glycine and caffeine should be good enough to block GI damage.

Hoping this will contribute positively to the understanding the benefits of using the indicated combination.

Rafik

There is an interesting and applicable commentary in Lancet Infectious Disease this week.

many thanks  for the replies. appreciate the help

I already had it, but thank you very much for thinking of sending it to me.

I understand you prefer not to give us your final opinion on Malet, Faure, Haas, and Lambert's work...And what about Stanley Malamed efforts to prove the inocuity of articaine in paresthesias ( he had a fierce opposition from Dr Haas - from Toronto)

But I would be very interested in your advice : may be by using my email address for privacy ? Or, is the question taboo?

Thierry

Good questions!   Overall, animal experimentation can only be justified when it provides essential information that can improve human health, which cannot be obtained in other ways - when suffering is minimised.  Given a choice, it's always preferable to work with non-animal methods because they are cheaper, quicker and more ethical.

Nevertheless, studies in animals are essential prior to moving new drugs into humans, since they flag up a lot of issues which are not human-specific or individual specific.  Early clinical trialsl are very safe overall because animal studies (plus other focussed studies, such as genetic toxicity testing) protect patients well.

Even so, animal studies are expensive, slow and ethically undesirable.  So they need to be preceded (and ultimately replaced) by non-animal studies which can filter out lots of bad compounds that are unfit for testing in animals.  As it happens, the non-animal methods used for this purpose are also turning out to be much better at detecting bad effects that can lead to infrequent and human specific adverse reactions than animal studies.  This is a hot area of science right now.

Animal studies are of limited use for assessing beneficial disease modifying effects of drugs.  This is especially true for inflammatory diseases and CNS diseases.   We don't really know why that is.  It's likely to be because animal models are unable to reproduce all of the complex processes that cause disease in humans.  Many people have tried and fail to tackle this problem using animals.  Hence my recommendation that we should now focus much more attention on non-animal methods. 

There is a good Review about safety of herbal products in other countries. Please, at Attachment.

After reviewing the USP (2014 edition), there appears to be no concern or required testing regarding glass or plastic containers that  contain alcoholic substances. Containers are only tested for sensitivity to, and reactivity with acid or alkaline solutions.    

Hi Alexander

I suspect it depends upon what you expect to be able to claim for the product.  There are no clear guidelines in relation to "user" trials of cosmetics, although of course you need to have your biological safety assessments and other toxicology data completed before you should consider going ahead.

From a commercial point of view there may be advantages to conducting a properly constructed randomised trial.  Many Advertising Standards authorities now wish to see clear data in support of any claims made, especially if you are planning for marketing in countries like USA where the Federal Trade Commission will follow up on any claims - for example Lornamead were recently fined $500K for not being able to justify claims for a product (http://www.ftc.gov/news-events/press-releases/2014/05/company-settles-ftc-charges-head-lice-prevention-claims-were).

Also if the product is to be advertised through media like QVC they have a really quite strict code for what they want to see in terms of data (see attached).

So my advice is if you are confident of the effectiveness of the product, conducting a properly constructed randomised, controlled trial is not only the best way forward to give the product the best commercial start in life versus the opposition it could also save a lot of grief and money in the long term.

Good luck, Ian

T20, Fuzeon, shows little acceptance by the patients, because it must be injected twice daily and causes local reactions. This problem is expected to remain for T1249.  Increasing the half-life of C-peptide entry inhibitors by conjugation to larger molecules has most likely so far has not been successful because these peptides loose efficacy in conjugated forms. That is at least what we have observed. 

In India, as per regulatory norms, BE studies may be required in the case of subsequent generic versions of  an approved new drug (oral formulation) if it falls within a period of four years of launch of the first product. 

Further, BE studies may pose another dilemma - 'which reference drug?', if several products containing the approved drug are already in the market.

Finally, in addition to 'pharmaceutical equivalence", it is advisable to do "in vitro - in vivo correlation" based on in vitro dissolution and bio-equivalence study data. 

In general for common side-effects pivotal clinical trials will be good places to check, I am not sure where you are looking for the industry supplied information but EPARs for new drug could be one of them. The big issue is estimating incidence rates in rare adverse effects, I do not know of any real repository of reliable knowledge as the way to capture the numerator will be missing. For specific drugs active surveilance systems can give information, but they would be specific and would work best for drugs with relative small exposure, where all are treated in secondary care.

No idea in case of shock. But L-NAME can be used commonly in case of NOS inhibition

Not only we can use them but these are the standard treatment for troublesome urgency and frequency of micturation. The drugs used for this purpose have a relatively selective action on the bladder and trigone. This reduces the risk of unwanted adverse effects.

The benefit is based on the expected efficacy. For exemple, an AE such leucopaenia or sudden death is not acceptable for a drug treating a common cold (negative risk/benefit profile) but could be acceptable, (depending on the incidence), when treating a life-threatening disease. The safety profile is always acceptable or not depending on the treated disease, its treatment options and its expected outcome.

Probably what you have read for marketed products is also aplicable to phase III clinical trials.

Take a look to: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM378422.pdf

You can find other publications and regulations in the web.

I think body surface area should be considered while determining the dose of any drug in humans as well as animals. You can find attached a very good article relating your question which will definitely help you in this matter.

Regards

Dr Tobias Dreischulte has stated that this study was done to evaluate AKI in a cohort group of hypertensive patients to quantify the risk of a certain drug exposure in the community . I shall briefly share my experience on AKI in elderly hypertensive patients . Elderly patients admitted for fractures are assessed by me for fitness for surgery .If a female patient has a serum creatinine of 1.3 mgs% or more & a male patient with serum creatinine of 1.5 mgs% , the surgery is postponed by 48-72 hrs . Most of these patients are hypertensives on ACEI / ARB , who are also taking NSAIDS for osteoarthritis & also pain of fractures . I have to immediately assess whether the rise in creatinine is due AKI or CKD . Since these patients are hypertensives , they would have some record of baseline creatinine done as a routine about 1-2 years ago . The ACEI / ARB are withdrawn & replaced with Calcium Channel Blockers . The NSAIDS are also withdrawn & replaced with Paracetamol . They are adequately hydrated with IV fluids ( 0.9% Saline ) . The serum creatinine is checked daily & a drop of serum creatinine is misleading as John Pickering highlighted , but reassuring ! If there are no complications of AKI , they would undergo surgery & at discharge , the creatinine done would be considered as baseline . The patients are very anxious & it is my duty to explain to them whether it is AKI or CKD . The delay in surgery improves renal function & prevents AKI from progressing stage 1 & 2 to stage 3 .

Generic drugs are required by law to be bioequivalent to the brand name product, however, they can use different excipients, binders and other inert ingredients. The variable adverse reactions could be due to these changes, even though the generic gives the same blood levels.