Friday, 7 September 2018

The Stanford Prison Experiment

By now you've probably come across a movie that revisits a fairly extreme research project developed in the 70s by the American Psychologist, Dr. Phillip Zimbardo, where a prison has been recreated and 24 male students were originally placed in to cohabit as guards and inmates (for an intended period of no more than two weeks). Well, a lot has been learned from this quite radical initiative, but above all, this experiment gave everyone a clear sense of how scientific experiments need adequate planning and ample consideration. It is not just because of the psychological atmosphere surrounding every particular aspect of the whole research, something that from the perspective of researchers and subjects would on its own be material for further progressive analysis. But also due to the fact that its originality does not really contradicts a perception of non-applicability, but simultaneously antagonises itself for the lack of primary support.

What I mean with all this jibber-jabber is that when you are the first to lay your brains on analysing something that lacks validity from previous studies, then you're off to something either boring or epic. Boring would be if the construction of the whole scenario and emotional participation of the tested subjects would have been so fake it'd have created a false sense of reality, thus producing false positive/negative results, ergo resulting in makeshift observations. Epic would be, as it was, when the immersing of the subjects (and additional players) into the testing is so naturally achieved, that suddenly there is a sense of hyper reality for a sub-scenario, usually attained when most of ones' strings to the wider reality are cut and the smaller constrained sub-scenario becomes gradually your wider reality.

What do I really mean with all this? I am obviously trying to avoid spoilers as much as possible. As a cinematographic portrait of the actual research experiment that took place in Stanford University, the movie is way to good (in my humble opinion) to be ignored. And the real events that feed it are way too relevant (historically) to be mistaken by just another movie. 

There is a lot more in it for us to interpret that goes far beyond the simplistic plot. There is an intricate boiling of our own self-knowledge, a complex web of uncontrolled behavior in ourselves that can be triggered by external and internal forces when one sees oneself as part of a greater power or as the unfortunate victim of a greater injustice. Fortunately, this movie, as well as the experience that brings up to the wider audience, is not dense in scientific facts or boring jargon and idiosyncrasies. This movie is incredibly good in showing how thin the line is between Victim -> Power <- Repressor. A line that is not straight nor entangled (in my opinion). It is simply a volatile equation telling you that Power makes the oppressor if the victim chooses to be a greater victim than expected, and Injustice makes you the trigger of Great Oppression when you respond to injustice in a reactionary fashion.

Wow, how incredibly hard it is not to bring loads of spoilers here and still try to make any sense.

I don't really enjoy embedding videos as they eventually are taken away from their original sources and I end up with mismatching content. But look at the trailer of this incredible movie and be the judge of this piece of history that shaped important changes in the way Power/Subservience/Research are nowadays considered.


Thursday, 23 August 2018

SciBoard Games is 4 years old!


Tomorrow SciBoard Games will be 4 years old. In 4 years and with a tight budget we managed to release a digital game for the Android system "Adna's Lab" (https://play.google.com/store/apps/details?id=com.sciboardgames.adna), produce a board game, participate in the final of the European Educational Games Competition in Scotland, travel to Dusseldorf-Germany to disseminate our product a bit further and even prepared the demo version of a subsequent game (Crime Grid) . Obviously, as with any other project that is time consuming and lives on a very tight budget we wouldn't be able to achieve what we've achieved without the help of many people that worked alongside our team whether in partnership, under a temporary contract, as benefactors or just freelancing. It would be difficult to name names as there were so many involved whilst working together with very creative and prolific people, but they all know and have already received our uttermost appreciation.

Times are now changing and we must reassess our presence in the serious games market, as we also must reassess the best targets for us to invest our drive and energy, so we not only produce profit for ourselves (as it should be with any other company), but also participate strongly in the education of the young masses that are nowadays so entertained with games and tools and networks that to an extent distract them from the most important educational and human goals.

There is time for everything to be tasted in life: sports, social networks, friends, cinema, music, concerts, gatherings, dating, you name it. However, nothing should be more relevant than education. And that is the reason why, that even for such a small team like ours, a family team with strong family values, the decision to support people in need was mainly focused on two special areas: Education and Health. Through KIVA (https://www.kiva.org/) and GoFundMe, SciBoard Games has been helping financially challenged people with small contributions towards their studies and helping them pay their medical bills. We do it to the extent of our limited capacity, but do not see it as an obligation, rather as a moral value that we will always instill in our children.

The future of SciBoard Games will be decided in the months to come. We might release the demo version of 'Crime Grid' in the virtual tabletop platform Tabletopia (https://tabletopia.com/) where 'Adna's Lab' is already there available for anyone to play with friends all over the world (https://tabletopia.com/games/adna-s-lab). We might try and invest in finding companies interested in purchasing the rights of the digital game 'Adna's Lab' or we can just close doors and move on towards different projects leaving SciBoard Games as a fruitful participation of a family business in the realm of serious/educational games.

Whatever happens we just would like to thank you for being with us throughout these four years. And we ask of you to go spread the message about the different platforms where 'Adna's Lab' has been taken to and distributed completely free to use. If we reach enough people we can therefore consider bringing new games to life and re-energise our small project with big ideas.

Happy Birthday SciBoard Games!

Wednesday, 25 July 2018

The ToxicologistToday just contributed to Ava's Journey, can you also add up?



If you follow this blog you've might  have come across some fundraising and donations I have been involved with to help a young child successfully battle cancer (Stage 4 high risk Neuroblastoma). The little one is the 2-year-old daughter (Ava is her beautiful name) of one of my work colleagues, and even though I haven't met any of the involved personally (it's difficult within a global company of more than two thousand employees) I couldn't help but relate deeply to their story (as a father of two and as a person).

For those who don't know much about her disease I decided to transcribe here the words of those that have been involved in her fundraising from the very beginning, in hope that I can at least find one person who can help her reach the appropriate treatment.

"A neuroblastoma is a very rare, very aggressive form of childhood cancer. Sadly, Ava’s cancer is very aggressive also, and it has spread all across her little body. Ava has a primary tumour in her abdomen, located in the adrenal gland above her left kidney. She also has several other tumours in her bones, her bone marrow, as well as in her blood and lymphatic system.

Ava has already started treatment; but she has a very long way to go (approx. 2 years). The hope is after this point she will go into remission…. However; the rates of relapse following remission are high (approx. 75%). Unfortunately, 75% who then relapse, the survival rates are very low second time. But let’s not focus on the negatives; let’s focus on the hope.

Memorial Sloan Kettering hospital in New York have been trialling a drug which has had brilliant results with keeping children cancer free for years longer than before (https://clinicaltrials.gov/ct2/show/NCT00911560) this drug is used on patients who are in remission with Neuroblastoma. Unfortunately, the cost of the treatment is astronomical.

This means that her family need to raise funds to enable Ava to have this treatment. 

No child should ever have to go through this, so if you would like to help in any way it would be truly appreciated.

How can I help, you ask….


Thank you for taking the time to read this". If you need further information access here

Tuesday, 24 July 2018

Value statements on gouty arthritis and new disease treatments

I was recently asked to produce some value statements on gouty arthritis and new disease treatments for a 'project' that unfortunately did not materialise the way I so wished. Because I believe the research I produced under very restricted availability (in terms of time and resources) can actually be extremely helpful for all those affected by gout, or the relatives/carers of patients battling with gout, I decided to paste hereby my findings on the topic. The compiled information is divided into two main fields, a short value statement and then a brief summary developing the previously stated idea. I honestly hope this can be helpful to any readers who are looking to know more on the subject of gout, the current disease state and the pharmaceutical approaches that are being developed or presently exist in the market. All information can be verified with the scientific literature referred in the bibliography attached. Any questions, be my guest and let me know. I will do my best to help you within my present knowledge on the topic. For medical advice, please seek the help of your healthcare professional (medical doctor, pharmacist, physiotherapist and the like).

Gout, a common arthritis disease defined by inflammatory symptoms as a consequence of the crystallization of uric acid within the joints, is presently a major increasing public health issue. The fundamental anomaly in gout is chronic hyperuricemia, usually resulting from reduced renal uric acid elimination and upsurge of monosodium urate crystals deposition in the joints (Lawrence, 2008). The underlying mechanisms responsible for hyperuricemia in gout patients can be divided into two main origins: a) renal underexcretion of uric acid or b) problems that result in increased secretion of systemic uric acid (Lawrence, 2008). If not treated gout can progress through four phases: a) asymptomatic hyperuricemia, b) acute gout, c) intercritical gout, d) chronic tophaceous gout (Croft, 2008). On the origin of the disease there is a behavioural/societal pattern, such as: accentuated increase in obesity (St-Onge et al., 2003) an aging population (Mikuls et al., 2005), the growing incidence of hypertension and renal failure (Johnson et al., 1999), the generalised use of antihypertensives, e.g., thiazide diuretics and acetylsalicylic acid (Caspi et al., 2000), and a growing intake of beer (Choi et al., 2004). Refractory hyperuricemia and acute flares of gout are a reality for patients and demand early treatment based on previous medication, possible adverse events associated to medication, level of flare onset and site of inflammation (Richette et al., 2016).

An accurate clinically consistent profiling code is deemed crucial for the primary (general medicine) and secondary (specialty) diagnosis and treatment of gout. Gout is usually clinically diagnosed by reassessing past symptoms described by patients in response to an applied treatment (Annemans et al., 2008), however this coding system does not distinguish between different clinical traits (e.g., signs and symptoms of the disease). Health-related quality of life (HRQOL) measurements in gout are difficult to apply due to the sporadic, recurrent and progressive chronic nature of the disease, but after several meetings the American College of Rheumatology (ACR) declared it now as a core area for application in chronic gout clinical trials (Lawrence, 2008) (Kim and Choi, 2009), thus replacing the old 1987 ACR gout classification criteria that missed the identification of cases where very early onset of arthritis later progressed to rheumatic arthritis (Kim and Choi, 2009). In 2010, the ACR provided new classification criteria suggested to clinicians, nevertheless there are still reports that these still make epidemiological counts complicated, lack uniformity (recruitment-wise) across studies and prevent clear comparison of results (Péntek et al., 2014). A recent collaboration between the ACR and the European League against Rheumatism (EULAR) resulted in the new 2015 coding criteria for gout (Tuhina et al., 2015). In addition to considering clinical features, signs, and symptoms, this new coding system also takes into account radiographic and computed tomography imaging, ultrasound, and a biochemical profiling.

Gout is the most common form of inflammatory joint disease in men aged 40 years and older, although postmenopausal women (due to declining oestrogen levels are also at increased risk of developing the disease) at around the age of 45 years. Even though the incidence of gout is quite similar between genders, it is however more prevalent in males, as reported by the Framingham Heart Study as of 1.4 in women and 4.0 in men per each 1000 individuals/year (Roddy and Doherty, 2010) (Weaver, 2008). The aforementioned difference is a natural result of the human physiology where males usually display greater serum uric acid (SUA) levels. This tendency for higher SUA values also intensifies the putative development of hyperuricaemia at a later stage in the lives of these individuals (Weaver, 2008). In fact, age is directly related to the onset of gout for both males and females, although, for males typically reaching a maximum point within the age interval of 75 to 84 years (Doherty, 2009). On the other side of the spectrum, as women approach the age of 45 years old, recognised for the triggering of their endocrine decline (e.g., oestrogen levels decline/menopause) a greater risk of developing hyperuricemia also appears, increasing as women go deeper towards the postmenopausal phase (e.g., ≥60 years old). The recommended age for a patient to initiate uratelowering therapy (ULT) is usually after the first diagnosis in patients respecting certain establishes clinical conditions: a) of age 40 years or younger, b) with an ‘aberrant’ SUA level (>8.0 mg/dL; 480 mmol/L) and/or signs of renal impairment, hypertension, ischaemic heart disease or heart failure (typical comorbidities in gout patients (Richette et al., 2016).

There is a positive correlation between prevalence of comorbidities and increased SUA levels; and the latter is also directly related to the occurrence of gout flares. Hence the importance of periodic monitoring of these indicators. Considering a study focused on two of the major European and Global economies, UK and Germany, distinct scenarios can be drawn in terms of prevalence of comorbidities: in the UK, obesity was the commonest comorbidity observed (27.7%); whereas in Germany a different scenario was verified with diabetes accounting for 25.9% of the reported comorbidities (Annemans et al., 2008). However, for the studied time frames (2000–2005), the tendency indicators concerning gout flares reveal different propensities (when analysing subjects in whom SUA was inferior to 360 mmol/l (less than 6 mg/dl), i.e., odds ratios of 1.33 (UK) and 1.37 (Germany) [SUA between 360–420 mmol/l (6–7 mg/dl)], and 2.15 (UK)and 2.48 (Germany) [SUA over 530 mmol/l ( over 9 mg/dl) (Annemans et al., 2008). Overall, for both markets the results in terms of prevalence of the disease was 1.4%, consequently in agreement with the tendency registered back in the 90s (1990–1999). This study showed that the implementations that led to a stable numerical prevalence, above all reveal the worth and significance of regular monitoring of SUA to address adequate and specific treatments to patients with a range of underlying symptoms. As observed in the analysed subjects, patients with SUA levels over 360 mmol/l (>6 mg/dl) had an increased risk of flaring up (Annemans et al., 2008) and it was projected that for the US adult population, up to 3.0 million would already have had selfreported gout in 2007, against a previous 2.1 million estimate predicted for the year of 1995 (Lawrence, 2008).

Several epidemiological studies originating from multiple geographical areas propose that gout is still increasing in prevalence and incidence over the past decades, however there is still a general lack of data on difficult-to-treat diseases. Based on the NHANES III age/sex prevalence and the 2005 US Census Bureau population estimates, it is expected that up to 6.1 million adults over the age of 20 years old have ever had gout (Kim and Choi, 2009). Additionally, a recent American study from a US managed care population, established that the total prevalence of gout or hyperuricemia where need for gout-directed treatment was observed, grew by 80% in approximately 10 years (from 1990 to 1999) (Wallace et al., 2004). Nevertheless, increased clinical awareness and better treatment approach can be behind this growth (Lawrence, 2008). Studies are still lacking for an adequate evaluation of the frequency and prevalence of occurring difficult-to-treat diseases (Schlesinger, 2010).

The prevalence of gout is highest in rich developed countries and lowest in countries with weaker economies, but the reported prevalence scores lack uniformity between studies, likely due to varying analytical methodologies. In Europe the lowest prevalence of gout was registered in Czech Republic (0.3 %) in opposition to the highest score registered by UK and Germany (1.4%), according to the analytical review of European epidemiological data (Smith et al., 2010). However, these numbers clash with those published by yet another study that consider the overall UK prevalence of gout to be 2.49 % (Kuo et al., 2014). Placed amid both extremes sits Portugal with 1.3%; a country marked by a weak though more buffered economy in comparison to Eastern European countries. However, prevalence scores are affected by differing analytical models (different reporting methods and different definitions) as is suggested by a study that considers that about twothirds of self-reported gout cases lack validity by clinicians (Chen and Schumacher, 2008).

Gouty arthritis is a painful arthritic disorder marked by the likelihood of patients developing comorbidities and/or intolerance/unresponsiveness to treatments. This outcome can substantially impact on the quality of life of the affected individuals. Consequently, it has driven the pharmaceutical industry to reinvest on researching novel molecules has means to take control of what was considered to be a ‘forgotten disease’. Allopurinol (a xanthine oxidase inhibitor), is still the most regularly prescribed ULT pharmaceutical to counteract hyperuricaemia back to standardised levels of 6 mg/dL on the basis of its efficacy, availability, and low cost (Sattui and Gaffo, 2016). Unfortunately, the number of comorbid/uncompliant patients reporting lack of efficacy (no target SUA levels attained) is still relevant, ergo the reporting of recurrent acute flaring (Schlesinger, 2010) (Sattui and Gaffo, 2016). Since the main focus of treatment in chronic gout is to avert crystal formation and stimulate crystal dissolution (Annemans et al., 2008) physicians invest in approaches that address management of hyperuricemia values and related symptoms (Lawrence, 2008). However, many of the affected individuals develop comorbidities to which non-steroidal antiinflammatories respond inefficiently (due to associated NSAIDs and proton pump inhibitors being limited by a considerable number of adverse effects) that have enticed new investments from big pharma (Schlesinger, 2010) (Khanna, 2012) (Jordan et al., 2007) (Zhang et al., 2006). In summary, the new therapies in development (Table 1) that, due to clinical trial results, deserve further attention are:

But above all, it is the approval of febuxostat (a xanthine oxidase inhibitor capable of overcoming the limitations of allopurinol) that finally promises to respond successfully to the biochemical control of gout whilst representing an enticing share-market niche, as it is presented in part 2 of this report.

A gout patient seeking healthcare sustains an incremental annual cost of over $3000 when compared to a healthy individual in the United States, and the associated healthcare investment is similar to major chronic debilitating disorders like migraine or even Parkinson’s disease. Yearly, the bill on gout amounts to more than $3000/patient in the USA where, overall, patients pay tens of billions of dollars per annum regardless of affected gender (Smolen et al., 2016) in associated healthcare. A study concentrating on population costs, analysed the usage of emergency services across the United States of America to draw conclusions on the total bill gout entails to the population (Rohini et al., 2013): a) the burden of gout emergency care is increasing through the many societal layers; b) gout was responsible for 168,410 visits just in 2006, with an overall cost of US$128 million that two years later met an increase by $16 million (due to 174,823 visits that year). Another study evaluated the direct link between gout related costs and achieving the recommended target SUA (represented 58% higher costs for patients with SUA 6–9 mg/dl when compared to patients with SUA inferior to 6 mg/dl) indicating that the financial weight of this disease varies accordingly to SUA levels (Shields and Beard, 2015). 

Since allopurinol was introduced to the markets back in 1964, no developments on low toxicity/high efficacy medication to reduce SUA levels were accomplished; ergo the emergence of febuxostat, represents a new pharmaceutical vision to the rheumatoid arthritis market. Considering the medical approaches available for treating gout, three main options are applied: 1) focusing on the acute flare; 2) focusing on urate-lowering strategies (usually based on uricosuric agents); and, 3) prophylaxis to prevent acute flares (Lawrence, 2008). Febuxostat, developed by Takeda Pharmaceuticals and approved by the Food and Drug Administration (FDA) is a pioneer urate-lowering drug (ULD) since 1964. Contrarily to other rather unsuccessful drugs that only inhibit the oxidation of xanthine to uric acid, long-term studies on Febuxostat show that the drug lowers the SUA levels by increasing the excretion of uric acid, towards the clinical target value of 6 mg/dl (360 mmol/l), more steadily. In many patients, Febuxostat has also efficiently managed tophi. Other clear disadvantage of the uricosuric drugs is its inefficacy on impaired patients (over 60 years of age and/or dealing with renal insufficiency issues) since with this class of drugs creatinine clearance is usually less than 50 ml/min/1.73 m of body surface area) (Bisht and Bist, 2011), thus forcing dose adjustments that affect drug efficacy.

Compared to allopurinol, Febuxostat is a more selective and potent inhibitor of xanthine. Febuxostat research conducted on animals have shown many biochemical advantages when compared to allopurinol: a) Potency: 10 to 30 times more potent (Horiuchi et al., 1999) as revealed by the IC50 for bovine milk xanthine oxidase (20 nmol/l), i.e., 10-fold stronger than allopurinol within the same assay (Takano et al., 2005). b) Action onset: “ADENURIC works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks” (emc, 2018). c) Absorption: only 1 hour from oral administration to peak concentration, bounding to albumin in blood with an efficacy of approximately 99%, and low to medium apparent volume of distribution of about 0.7 l/ kg (Becker et al., 2004). d) Interactions: no know effect on enzymes involved in purine or pyrimidine metabolism (Lawrence, 2008).

The U.S. FDA issued a public safety alert, in November 2017, on a putative link between febuxostat and signs of increased risk of cardiovascular and all-cause mortality (FDA, 2017). Data on the incidence of adverse reactions (e.g., dizziness, nausea, diarrhoea and cephalalgia), available up to 2009, considered risks associated to the use of febuxostat at the same level as with allopurinol (Becker et al., 2004) (Schumacher et al., 2008). Nonetheless, the incidence of cardiovascular side-effects (defined by events of composite of myocardial infarction, stroke death associated to cardiovascular origins) was greater when using febuxostat than with when using allopurinol, even though no significant difference between treatments was observed. Moreover, guidelines febuxostat dosing was not immediately and directly related to cardiovascular distress incidence (Lawrence, 2008). However, febuxostat safety warnings emerged mainly from observations concerning cardiovascular adverse events in two specific studies: the APEX (Febuxostat, Allopurinol and Placebo-Controlled Study in Gout Subjects) (Schumacher et al., 2008) and the FACT study (Febuxostat versus Allopurinol Controlled Trial) (Reza et al., 2008). Presently, there are two major studies being developed in Europe and Japan concerning febuxostat hypothetic relation with cardiovascular events that have the potential to confirm or reject the link the FDA considered to be worth analysing further.

Bibliography 
ANNEMANS, L., SPAEPEN, E., GASKIN, M., BONNEMAIRE, M., MALIER, V., GILBERT, T. & NUKI, G. 2008. Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005. Annals of the Rheumatic Diseases, 67, 960-966. BECKER, M. A., KISICKI, J., KHOSRAVAN, R., WU, J., MULFORD, D., HUNT, B., MACDONALD, P. & JOSEPH‐RIDGE, N. 2004. Febuxostat (TMX‐67), a Novel, Non‐Purine, Selective Inhibitor of Xanthine Oxidase, Is Safe and Decreases Serum Urate in Healthy Volunteers. Nucleosides, Nucleotides and Nucleic Acids, 23, 1111-1116. BISHT, M. & BIST, S. 2011. Febuxostat: A Novel Agent for Management of Hyperuricemia in Gout. CASPI, D., E., L., E., G., B., H., M., Y. & R., S. 2000. The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis & Rheumatism, 43, 103-108. CHEN, L. X. & SCHUMACHER, H. R. 2008. Gout: An Evidence-Based Review. JCR: Journal of Clinical Rheumatology, 14, S55-S62. CHOI, H. K., ATKINSON, K., KARLSON, E. W., WILLETT, W. & CURHAN, G. 2004. Alcohol intake and risk of incident gout in men: a prospective study. The Lancet, 363, 1277-1281. CROFT, J. D. 2008. Clinical Aspects of Gout. Gout ICD-9-CM Coordination and Maintenance Committee Meeting. DOHERTY, M. 2009. New insights into the epidemiology of gout. Rheumatology, 48, ii2-ii8. EMC. 2018. Adenuric 120 mg film-coated tablets summary of product characteristics [Online]. Available: https://www.medicines.org.uk/emc/product/1925/smpc [Accessed 17th of July 2018 2018]. FDA, U. S. F. A. D. A. 2017. FDA Drug Safety Communication: FDA to evaluate increased risk of heart-related death and death from all causes with the gout medicine febuxostat (Uloric) [Online]. Available: https://www.fda.gov/Drugs/DrugSafety/ucm584702.htm [Accessed 17th of July 2018 2018]. HORIUCHI, H., OTA, M., KOBAYASHI, M., KANEKO, H., KASAHARA, Y., NISHIMURA, S. I., KONDO, S. & KOMORIYA, K. 1999. A comparative study on the hypouricemic activity and potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase inhibitors: TEI-6720 and allopurinol in rats. JOHNSON, R. J., KIVLIGHN, S. D., KIM, Y.-G., SUGA, S. & FOGO, A. B. 1999. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. American Journal of Kidney Diseases, 33, 225-234. JORDAN, K. M., ON BEHALF OF THE BRITISH SOCIETY FOR, R., BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY STANDARDS, G., AUDIT WORKING, G., CAMERON, J. S., ON BEHALF OF THE BRITISH SOCIETY FOR, R., BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY STANDARDS, G., AUDIT WORKING, G., SNAITH, M., ON BEHALF OF THE BRITISH SOCIETY FOR, R., BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY STANDARDS, G., AUDIT WORKING, G., ZHANG, W., ON BEHALF OF THE BRITISH SOCIETY FOR, R., BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY STANDARDS, G., AUDIT WORKING, G., DOHERTY, M., ON BEHALF OF THE BRITISH SOCIETY FOR, R., BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY STANDARDS, G., AUDIT WORKING, G., SECKL, J., ON BEHALF OF THE BRITISH SOCIETY FOR, R., BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY STANDARDS, G., AUDIT WORKING, G., HINGORANI, A., ON BEHALF OF THE BRITISH SOCIETY FOR, R., BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY STANDARDS, G., AUDIT WORKING, G., JAQUES, R., ON BEHALF OF THE BRITISH SOCIETY FOR, R., BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY STANDARDS, G., AUDIT WORKING, G., NUKI, G., ON BEHALF OF THE BRITISH SOCIETY FOR, R., BRITISH HEALTH PROFESSIONALS IN RHEUMATOLOGY STANDARDS, G. & AUDIT WORKING, G. 2007. British Society for Rheumatology and British Health Professionals in Rheumatology Guideline for the Management of Gout. Rheumatology, 46, 1372-1374. KHANNA, I. 2012. Drug discovery in pharmaceutical industry: productivity challenges and trends. Drug Discovery Today, 17, 1088-1102. KIM, S. Y. & CHOI, H. K. 2009. Gout and Quality of Life. The Journal of Rheumatology, 36, 865. KUO, C.-F., GRAINGE, M. J., MALLEN, C., ZHANG, W. & DOHERTY, M. 2014. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Annals of the Rheumatic Diseases. LAWRENCE, E. N. 2008. Treatment-failure gout: A moving target. Arthritis & Rheumatism, 58, 2587-2590. MIKULS, T., FARRAR, J., B BILKER, W., FERNANDES, S., R SCHUMACHER, H. & G SAAG, K. 2005. Gout epidemiology: Results from the UK General Practice Research Database, 1990- 1999. NOVECK, R., WANG, Z., FORSTHOEFEL, A., SIGMON, K., HALL, P. & KEOGH, J. 2012. Levotofisopam has uricosuric activity and reduces serum urate levels in patients with gout. Arthritis Rheum, 64, 818. PÉNTEK, M., POÓR, G., WILAND, P., OLEJÁROVÁ, M., BRZOSKO, M., CODREANU, C., BRODSZKY, N. & GULÁCSI, L. 2014. Biological therapy in inflammatory rheumatic diseases: issues in Central and Eastern European countries. The European Journal of Health Economics, 15, 35-43. REZA, K., BRIAN, G., JING-TAO, W., NANCY, J.-R. & LAURENT, V. 2008. Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. British Journal of Clinical Pharmacology, 65, 355-363. RICHETTE, P., DOHERTY, M., PASCUAL, E., BARSKOVA, V., BECCE, F., CASTAÑEDA-SANABRIA, J., COYFISH, M., GUILLO, S., JANSEN, T. L., JANSSENS, H., LIOTÉ, F., MALLEN, C., NUKI, G., PEREZ-RUIZ, F., PIMENTAO, J., PUNZI, L., PYWELL, T., SO, A., TAUSCHE, A. K., UHLIG, T., ZAVADA, J., ZHANG, W., TUBACH, F. & BARDIN, T. 2016. 2016 updated EULAR evidencebased recommendations for the management of gout. Annals of the Rheumatic Diseases. RODDY, E. & DOHERTY, M. 2010. Gout. Epidemiology of gout. Arthritis Research & Therapy, 12, 223. ROHINI, G., R., S. H., FANG, Y., KALEB, M., JASVINDER, S., G., S. K. & R., M. T. 2013. Gout-Related Health Care Utilization in US Emergency Departments, 2006 Through 2008. Arthritis Care & Research, 65, 571-577. SATTUI, S. & GAFFO, A. 2016. Treatment of hyperuricemia in gout: current therapeutic options, latest developments and clinical implications. SCHLESINGER, N. 2010. New Agents for the Treatment of Gout and Hyperuricemia: Febuxostat, Puricase, and Beyond. Current Rheumatology Reports, 12, 130-134. SCHUMACHER, H. R., BECKER, M. A., WORTMANN, R. L., MACDONALD, P. A., HUNT, B., STREIT, J., LADEMACHER, C. & JOSEPH-RIDGE, N. 2008. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: A 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Care & Research, 59, 1540-1548. SHIELDS, G. E. & BEARD, S. M. 2015. A Systematic Review of the Economic and Humanistic Burden of Gout. PharmacoEconomics, 33, 1029-1047. SINGH, J. 2016. Gout: will the “King of Diseases” be the first rheumatic disease to be cured? SMITH, E. U. R., DÍAZ-TORNÉ, C., PEREZ-RUIZ, F. & MARCH, L. M. 2010. Epidemiology of gout: An update. Best Practice & Research Clinical Rheumatology, 24, 811-827. SMOLEN, L. J., GAHN, J. C., MITRI, G. & SHIOZAWA, A. 2016. The Budget Impact of Increased Use of Febuxostat in the Management of Gout: A US Health Plan Managed Care Pharmacy and Medical Costs Perspective. Clinical Therapeutics, 38, 1710-1725. ST-ONGE, M.-P., KELLER, K. L. & HEYMSFIELD, S. B. 2003. Changes in childhood food consumption patterns: a cause for concern in light of increasing body weights. The American Journal of Clinical Nutrition, 78, 1068-1073. TAKANO, Y., HASE-AOKI, K., HORIUCHI, H., ZHAO, L., KASAHARA, Y., KONDO, S. & BECKER, M. A. 2005. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sciences, 76, 1835-1847. TUHINA, N., A., J. T. L. T., NICOLA, D., JAAP, F., RALPH, S. H., DIANNE, B., MELANIE, B., HYON, C., LAWRENCE, E. N., M., J. H. J. E., FRÉDÉRIC, L., P., N. R., GEORGE, N., ALEXIS, O., FERNANDO, P.-R., KENNETH, S., A., S. J., S., S. J., ANNE-KATHRIN, T., JANITZIA, V.-M., A., Y. S. & J., T. W. 2015. 2015 Gout Classification Criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis & Rheumatology, 67, 2557-2568. WALLACE, K., ALTAN, A., JOSEPH-RIDGE, N. & WORTMANN, R. 2004. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. WEAVER, A. 2008. Epidemiology of gout. Cleve Clin J Med, 75, S9-12. ZHANG, W., DOHERTY, M., BARDIN, T., PASCUAL, E., BARSKOVA, V., CONAGHAN, P., GERSTER, J., JACOBS, J., LEEB, B., LIOTÉ, F., MCCARTHY, G., NETTER, P., NUKI, G., PEREZ-RUIZ, F., PIGNONE, A., PIMENTÃO, J., PUNZI, L., RODDY, E., UHLIG, T. & ZIMMERMANN-GÒRSKA, I. 2006. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee For International Clinical Studies Including Therapeutics (ESCISIT). Annals of the Rheumatic Diseases, 65, 1312.  

Monday, 18 June 2018

Can this Devil operate miracles? On the anti-inflammatory potential of the harpagophytum procumbens (Devil's Claw)

The World Cup started a few days ago, Mr Kim has met Mr Trump and apparently we are postponing another global armed conflict. I guess we can say the devil is losing this battle and all because our awareness has been raised lately. We are gradually investing in empathy rather than media displays of vulgar superiority. Just help sort out the plastic epidemics by buying less plastic-wrapped products, by demanding a serious environmental consciousness from your wholesalers and from yourself, and we must have a dandy world to show our grandchildren.

Yeah, the devil must not have the upper hand. Unless, of course, we are talking about autoimmune diseases such as Sjogren's syndrome, Lupus, and the whole rheumatic paraphernalia.... and so on and so forth. When it comes to anti-inflammatory issues we must give the devil a chance. OK, now that those who are crazy religious freaks and do not listen/read 'til the end are already painting banners stating God hates homosexuals and bashing biological evolution theories, let's focus on the devil for a moment. But merely on its claw, the Devil's Claw (known by the botanists as Harpagophytum procumbens).

You know, I got one of those emails that is so paradoxical and disturbing (a bit like when Jesse Lee Peterson goes on TV rebranding racism) - bear in mind I haven't taken a stance here. This is not a political blog and I do not dispute idiosyncrasies unless I am asked my opinion on it. But on such occasion the email I was sent explained that this Devil's Claw was the Father of all Miracles and would really fix any Sjogren's, Lupus, Cushing's etc etc etc patients suffering with pain and inflammation to a degree that Hell would become a vast garden of scented flowers.

I had to search the web for articles that would clarify all my concerns and ease my doubts. I ended up finding a video on YouTube, by a certain Dr. James Meschino, that pretty much throws a flaming scare alarm on the lenient use of this plant. Hence, I decided to review a few articles just to be sure that this product can actually be used for treating certain autoimmune diseases with an inflammatory profile. Huge disclaimer here - please ALWAYS resort to your medical doctor or pharmacist for they are the ones who know about your medical history, and use this information for educational support (Each Case Is a CASE!).

In summary this Dr. Meschino states that in fact this native plant from South West Africa, Angola, Madagascar, Botswana, Zimbabwe, Namibia and Kalahari Desert - Devil's Claw - shows enormous anti-inflammatory potential. He says:

1) one of its active constituents is the harpogaside that is believed to be the agent responsible for counteracting inflammation;

2) due to its bitterness it stimulates acid release in the stomach promoting better protein metabolisation;

3) He advises on a quarter to half a gram, two to three times daily (an amount that will roughly correspond to about 5% in harpagoside content);

4) and that harpagosides are believed to hold powerful anticoagulant effects, and for that matter can reactivate or aggravate ulcers, thus should not be combined with other anti-inflammatories (non-steroidal or steroidal ones), nor with anti-coagulants (even if new generation ones). The risk is simple to understand and serious in its own nature - INTERNAL BLEEDING.



Pharmacological active molecules

Not all molecules show the same anti-inflammatory potential, as shown by Fiebich et al (2001) [1] who conducted a very interesting study using a Devil's claw commercial extract to inhibit lipopolyssacharides of bacterial nature. In fact, McGregor et al (2205) [2] also confirmed such, a few years later, when attesting the pharmacological/therapeutic potential of this plant, especially the role of the iridoid glicosides present in its list of constituents (namely harpagoside, procumbide, harpagide, and the 8-para-coumaroyl-harpagide). But warnings were simultaneously published as to the limitations imposed by the test models used.

Toxicity

Well, in regard to toxicity, al-Harbi et al (2013) [3] subjected mice to different official treatment protocols (as suggested by the World Health Organisation): The chronic toxicity study used 100 mg/Kg/day (representing 1/5 of the pharmacologically active dose) administered for a period of 3 months, and focusing on vital organ weight variation, external general symptoms of toxicity, and body weight changes and mortality (up to the end of the trials and not for long-term periods); and concluded that the subjected cohorts experienced low toxicity.

The same study also covered acute toxicity where the subjects were presented to oral doses (0.5, 1 and 3 g/Kg body weight) of the drug suspended in water. This time the analysis focused on autonomic responses, motor activity and central nervous system excitation. One interesting finding is related to 0.5 g/Kg treatment of Devil's claw that  significantly reduced blood glucose levels when compared to untreated cohorts.  However, these were merely preliminary studies and only point towards general assumptions for future studies to consider.

Applications in rheumatic diseases

The incidence of musculoskeletal disorders responsible for disabling many people's lives is high, and any possible natural treatments with pharmacological potential must be analysed for future remedies. Brien et al (2007) [4] compiled a review on the topic that pointed towards safe use of Devil's claw in comparison to non-steroidal anti-inflammatories in reducing pain associated to this disease. The same positive results were also supported by Warnock et al (2007) [5] that focuses their analysis on a number of rheumatic diseases (including arthritis) and a single group of 259 patients for eight weeks with tolerance, liver tests and blood analysis performed. But the main concern could not be answered to, meaning its safe use is still not guaranteed especially because there are no long-term safety assessments and the populations studied are quite limited in number.

Safety

Because I could not find many articles that supported the allegations of Dr. Meschino (I am not saying there isn't any, I am just saying I couldn't find that many) I am not going to say he isn't right. One think I am certain of is that the jury is pretty much still out there on the safety of this plant. But its pharmacological efficacy and range of applications is very much attested. Nevertheless, what the doctors suggest is almost common sense for when we are unaware of the mechanism of action [MOA], as it is the case for the Devil's claw herb, and the MOA of many other complementary and alternative medical therapies [6]. One thing is certain, because of its bitterness it will indeed affect stomach acidity, ergo affecting drugs like proton pump inhibitors, H2-blockers (also known as H2 receptor antagonists) and the like, used to reduce stomach acidity. This is the reason why it might be involved in the worsening of ulcers. However, the safety assessments I was able to find are limited in numbers of populations studied and even range of observations performed. Having said that, I found a really nice piece of document that is 69-pages long, written by the European Medicines Agency [7] (access here) that I will eventually read and try and summarise for you. Bear in mind this document covers many different aspects like medicinal application of this plant, to clinical and non-clinical data, clinical safety, pharmacovigilance aspects and what interests you the most, being the risk-benefit assessment. Once again, after a very brief reading (not thorough at all) I could only find a drug interaction study [8] supporting the allegations of Dr. Meschino, but I still have to lay my eyes properly on this document. The article by Patel et al (2008) [8] apparently (as I could not pay for it, but if you want me to read it just be my guest and send me the money :DDDD) suggests putative interactions with anticoagulants (e.g. warfarin) leading to gastrointestinal bleeding. There was also another article I found (access here) [9] but with no listed authors or free-PDF available that suggests that, in practice reports and concerning devil's claw roots exposed-patients, some showed up with upper gastrointestinal disorders.

The jury is pretty much out there as I already said, but I am sure I will have to discuss the topic further in the weeks to come. Until then, play it safe.

[1] Fiebich, B. L., Heinrich, M., Hiller, K. O., Kammerer, N. (2001). "Inhibition of TNF-alpha synthesis in LPS-stimulated primary human monocytes by Harpagophytum extract SteiHap 69". Phytomedicine, 8(1), pp. 28-30.

[2] McGregor, G. Fiebich, B., Wartenberg, a., Brien, S., Lewith, G., Wegener, T. (2005). "Devil's Claw (Harpagophytum procumbens): An anti-inflammatory herb with therapeutic potential. Phytochemistry reviews, 4(1), pp. 47-53.

[3] Al-Harbi, N. O., Al-Ashban, R. M., Shah, A. F. (2013). "Toxicity studieson Harpagophytum procumbens (devil's claw) capsules in mice". Journal of Medicinal Plants Research. 7(42), pp.3089-3097.

[4] Brien, S., Lweith, G. T., McGregor, G. (2007). "Devil's Claw (Harpagophytum procumbens) as a treatment for osteoarthritis: a review of efficacy and safety".  The Journal of Alternative and Complimentary Medicine, 12(10).

[5] Warnock, M., McBean, D., Suter, A., Tan, J., Whittaker, P. (2007). "Effectiveness and Safety of Devil's Claw tablets in patients with general rheumatic disorders". Phytotherapy Research, 21(12), pp. 1228-1233.

[6] Setty, A. R., Sigal, L. H. (2005). "Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy and side effects". Seminars in Arthritis and Rheumatism, 34(6)pp. 773-784.

[7] Assessment report of Harpagohytum procumbens DC. and/or Harpagophytum zeyheri Decne, radix. [http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2016/11/WC500216100.pdf]

[8] Patel, J. A., Gohil, K. J. (2008). ""Warfarin-herb interactions: a review ad study based on assessment of  clinical case reporsts in literature". Boletin LatinoAmericano y del Caribe de Plantas Medicinales y Aromaticas, 7(2), pp. pp. 85-99. [https://www.scribd.com/document/293374607/Warfarin-Vitamin-K-Patel-2008]

[9] No authors listed (2013). "Devil's Claw root: Ulcers and gastrointestinal bleeding". Prescrire Int, 22(144), pp. 296. [https://www.ncbi.nlm.nih.gov/pubmed/24600731]

1st image kindly taken from Harpagophytum procumbens - diseases, [http://flipper.diff.org/app/items/6532], last visited on the 18th of June2018.

2nd image kindly taken from Kew, Royal Botanic Gardens, [https://www.kew.org/science/news/plant-story-devils-claw-found-and-collected-from-botswana], last visited on the 18th of June 2018.

Wednesday, 6 June 2018

Pomegranate contamination kills woman in Australia

A cut pomegranate

Image copyrightEPA
Image captionAustralian authorities have linked 24 hepatitis A cases to a frozen pomegranate product
"An Australian woman has died after contracting hepatitis A from a packet of frozen pomegranate.
The 64-year-old died in South Australia last week in a "rare and tragic" case, state health authorities said.
Local officials issued a warning about the Australian-owned Creative Gourmet product in April. It has been linked to 24 cases of hepatitis A nationally.
Australians have been urged to check their freezers and discard packets of the frozen fruit.
About 2,000 packets of the Egyptian-grown pomegranate arils were sold. Fresh pomegranate and locally grown products were not affected, authorities said.
"The woman's death is the only death linked to this recalled product nationally to date," South Australia chief medical officer Prof Paddy Phillips said.
Most other people affected had made a full recovery and no further cases were expected, he said.
Hepatitis A, which attacks the liver, is usually spread through faecal matter, transmitted through sex or by touching contaminated food or objects.
It typically takes between 15 and 50 days to develop symptoms, which include nausea, fever and yellowing of the skin, local health authorities said.
Entyce Food Ingredients has said the contamination was linked to a "a relatively small batch" of its product.
Last year, the company was also forced to pull a selection of its frozen mixed berries products following another hepatitis A outbreak.

Original article on the BBC News website (access here).

The real survival rates to cancer - Part 2 of 3

Following on the first part (see here) where the origins of chemotherapy were briefly discussed, I am here today to present the numbers available on the web and that concern survival rates to cancer. This topic is far from being of a simplistic nature; the disease itself is complicated, multifaceted and generates eruptive emotions. But times have been changing with developments made known that bring new pharmaceuticals to hospitals, better knowledge on disease development and more sensitive predictive technology. Available literature on the matter of survival to cancer is not scarce at all, having said that it is difficult to summarise the enormous lists of sources, references and cited researches that populate the Internet these days.

To better present data in a simplified manner, I decided to generate a summary table where you can find the different categories and the sources used to populate it. Bear in mind that, as expected, this is not an exhaustive compilation of data, but a rough approach to some of the most relevant articles I was able to find with the very limited time I have available these days. I hope that this table can, at least, lead you to the very fine research that is being developed by some important research groups worldwide. Apologies if most of these results are retrospective, but as one can imagine the time it takes for these groups to compile genuine data and make sense of the gathered numbers, discuss these and reproduce meaningful information in the shape of reliable publications, is on its own self-explanatory.

Finally, it would be simpler to just copy-paste incredibly well-put information obtained from websites such as the Cancer Research UK (access here) where a comprehensive and extraordinarily well structured summary of cancer survival rates (for most common cancers) is presented concerning the regions of England and Wales. However, this pool of information comes with many limitations, the first one being the fact that not all countries are represented, and the disease specificity as well as the medical techniques involved are not so well described.

[A]


So to overcome this over generalisation that can be informative to a certain extent, but may lack on a certain identity, I decided to approach this article with a live-table. This table is not amorphous or rigid but a 'tool' that I will be updating whenever I find specific articles that due to their inherent quality and development of a particular treatment analysis represent, in my humble opinion, a good retrospective-or-present indicator of the survival rates associated to a certain population/technique/cancer type/methodology. In addition, this is a nicer method to assess how survival rates have changed through time with the improvements on methodology and technology. And click on the images for better resolution!!!

Please consider this article in constant progression: 



[1] Young, J, L., Ries, L. G., Silverberg, E. et al (1986). "Cancer Incidence, Survival and Mortality for Children Younger than Age 15 Years old". Cancer, 58, pp. 598-602.

[2] Lai, E. C., Tompkins, R. K., Mann, L. L., Roslyn, J. J. (1987). "Proximal Bile Duct Cancer. Quality of Survival". Annals of Surgery, 205(2), pp. 111-118.

[3] Folkesson, J., Birgisson, H., Pahlman, L. et al (2005). "Swedish Rectal Cancer Trial: Long lasting benefits from radiotherapy on survival and local recurrence rate". Journal of Clinical Oncology, 23(24), pp. 5644-5650.

[A] Images kindly taken from Cancer Research UK, Cancer survival for common cancers, [http://www.cancerresearchuk.org/health-professional/cancer-statistics/survival/common-cancers-compared#heading-Two], last visited on the 6th of June 2018, last update unknown.