Lupine Publishers| The ins and outs of elimination

 Lupine Publishers| Journal of Medical Sciences

Abstract

The interdependence of all living things affects human health. Food is more than energy alone. There are varieties of minerals that are balanced by the body according to its needs and what it does not need is expelled. If they remain, they cause problems.

Introduction

Animals and plants are hosts for bacteria. The sun is the source of all energy that is converted into reproduceable life and the forms that the life takes change continuously by mutation. Common to all life is nutrition going in, being absorbed and then something coming out. That absorption is done mostly by bacteria. Let it perform as it prefers and the result is called healthy. Most medical understanding is about what goes in. Equally important is what comes out. If waste does not emerge, there will be illness.

Our health depends on the health of all forms of life around us because the exchange of nutrients and bacteria is all-embracing. No part of the mix can survive in isolation. Feel unwell, consult a doctor and you will most likely be given something to take, something to put into your body. There will be an assumption that either something breeding inside you needs to be killed or that the nutrients necessary for sustaining your energy are inadequate. Seldom is the output mechanism questioned.

Bladder

The bowel and bladder are two of the main emitting organs. With a healthy diet and exercise [1], constipation should never occur. Elimination of urine is evidence of the kidneys working. Note that they are not the only exit route. By perspiration, the skin releases a lot of liquid and it is seldom realised how essential it is to sweat. Sweat a lot leaving nothing for the kidneys and the result can be dire. Without flushing, the kidneys accumulate particles which can solidify to stone and grow in size. The northern and southern flanks of the Mediterranean Sea and further into the Middle East are described by urologists as The Stone Belt. This is where kidney stones frequently form. People sweat a lot, do not drink enough and the kidneys are not irrigated. Suffers claim that kidney stones inflict the worst of all types of pain. Removing kidney stones used to be a major surgical operation and patients would avoid surgery and suffer the pain until large deposits called stag horn stones formed and surgery was unavoidable. Thankfully, lithotripters were developed to break the stones into tiny particles that would flush out with the urine [2]. The history of the development of lithotripters is one of the most important accounts in the evolution of medicine because it leads to the healing of diabetic ulcers rendering amputation unnecessary [3] and eventually to discovering how to stop cancer cells replicating further mutant cells [4].

Kidney Failure

The importance of the kidney is evident for we have two. Would it help if we had more than one heart? Dialysis three times a week occupies three days and still leaves the patient encumbered.

a) Physical improvements

b) increase of urine output

c) improved appetite

d) dry skin tone turning to normal

e) reduced skin irritation

f) less gain of dry weight

g) reduced leg swelling

Overall improvement in health & relief from depression, anxiety & other problems

I was introduced to the patient at Professor Chouhan’s clinic. She was with her son who spoke English and he confirmed that his mother looked forward to the CellSonic treatments because they always left her feeling much better and she was now seeing that they would restore her kidneys to normal. More patients have been added to the CellSonic kidney treatment programme and good progress is reported for all of them. It is not an instant cure because new tissues take time to grow and have to be stimulated to grow. It is interesting that no drug can cause these changes. Only the effect of the VIPP (very intense pressure pulse) technology works. Quite apart from the benefit to the patient, the cost and time savings are enormous (Figure 1) and (Table 1).

Figure 1: Here we see a treatment in progress with CellSonic VIPP

Table 1: Physico-chemical parameters at refrigerator temperature (2 °C-8 °C/40% Rh).

Flexible plumbing

If the skeleton is the chassis, the organs and tubes are the plumbing. There has to be constant flow through the pipes. Blood must circulate carrying oxygen and platelets to all parts of the body. If blood is not present, tissues die. To maintain flow, the body must move. Exercise is a term we have started to use in recent years since it became possible to sit and lie for hour after hour. We now know that we must move to keep the contents of the flexible pipes travelling along. Think of the body as a factory in which raw materials come in to be processed into energy with unwanted side products ejected. Without the body moving, only the heart is beating and that too slows down until it is unable to push anymore. Idleness kills.

I remember almost fifty years ago, a friend in the cycling club, remarking that the colour of urine on a Monday was darker than later in the week. We were cycling up to a hundred miles at the weekends. That exercise flushed from our bodies rubbish that showed in the urine as dark brown. During the week, riding fewer miles, the elimination process was less vigorous and the urine became almost colourless. Not scientific measurement, of course, but evidence nevertheless and I believe that friend went on to a distinguished academic career in science. Note that all investigations begin with a simple observation. It was later realised when on a long cycle tour lasting more than two weeks that the urine colour remained almost colourless. The conclusion was that all the impurities were being flushed through continuously with regular exercise and by drinking more water than usual.

Sweat

A further observation when cycling in the heat is that the skin is dry. Don’t let that fool you into thinking you are not sweating. Come to a stop and within a minute you are covered in sweat. Whilst riding with air blowing over you, the sweat is dried as soon as it emerges. Only when you stop and lose the cooling effect of the draught do you realise the amount of water being lost. This volume is not available to the kidneys and has to be replenished to avoid dehydration. Interestingly, the sit-up posture on a bicycle is more efficient than the recumbent, lying down, position because the body acts as an air-cooled engine [5]. Overheating reduces efficiency. Although the upright rider creates more wind resistance, the air draught aids cooling. A streamlined cocoon that makes the recumbent bicycle look like a torpedo is only efficient over short distances during which high speeds can be attained and then the rider emerges lathered in sweat.

When exercising, an average person can sweat 1.4 litres an hour. [6] This is mostly water because the prime function of sweat is cooling by evaporation. With the water comes sodium plus minerals, lactic acid and urea, potassium, calcium and magnesium. Some trace elements are also found of zinc, copper, iron, chromium, nickel and lead. The significance of sweating can best be understood by thinking of the consequences of not sweating; all those chemicals and minerals would remain and accumulate in the body. Without sweating, would they filter out through the bladder and bowel? It is doubtful because we see in the body an operating system to maintain health dependant on exercise [7] without which health fails. Sweating is therefore as necessary as all the other bodily functions. Unfortunately, there was a social attitude that deplored women sweating. Gone are those attitudes of previous years when skirts had to be long enough to hide an ankle and waists squeezed so tight that the stomach failed.

Alcohol

The chemical name for alcohol is ethanol (CH₃ CH₂ OH). Medically, it is a poison. Socially, it is a lubricant. That people like to detach their minds is observable everywhere. Governments cannot ban it and have tried. Some religions succeed in banning it and others support it. The medical consequences of imbibing ethanol are serious. This is not just something that goes in and will flow out. When it is in, metabolic changes are made before the residues come out. A paper by Laura A. Stokowski, RN, MS entitled “No Amount of Alcohol Is Safe” should be compulsory reading for anyone over the age of twelve [8]. An earlier report from 2007 by the United States Department of Health and Human Services, Alcohol Alert, is not sanctimonious and the warning is clear [9].

Chemicals called enzymes help to break apart the ethanol molecule into other compounds (or metabolites), which can be processed more easily by the body. Some of these intermediate metabolites can have harmful effects on the body. Most of the ethanol in the body is broken down in the liver by an enzyme called alcohol dehydrogenase (ADH), which transforms ethanol into a toxic compound called acetaldehyde (CH₃CHO), a known carcinogen. However, acetaldehyde is generally short-lived; it is quickly broken down to a less toxic compound called acetate (CH₃COO–) by another enzyme called aldehyde dehydrogenase (ALDH). Acetate then is broken down to carbon dioxide and water, mainly in tissues other than the liver.

Although acetaldehyde is short lived, usually existing in the body only for a brief time before it is further broken down into acetate, it has the potential to cause significant damage. This is particularly evident in the liver, where the metabolism takes place. Some alcohol metabolism also occurs in other tissues, including the pancreas and the brain, causing damage to cells and tissues. Additionally, small amounts of alcohol are metabolized to acetaldehyde in the gastrointestinal tract, exposing these tissues to acetaldehyde’s damaging effects.

You should read the Alcohol Alert paper and if it leaves you in need of a drink, be sure it is spring water.

The notion that alcohol can flush out of the body is nonsense. Like all poisons, it does damage. It may be possible to repair that damage over time and abstinence. The frustration, medically, is that the patient voluntarily swallowed the poison and usually paid a lot of money for it. This desire to detach the brain and ignore the consequences is a feature unique to humans. Our brain distinguishes us from other animals, is supposed to be clever and yet fails in many cases to protect the individual. We cannot help those who do not want to be helped.

In addition to alcohol which has been distilled from ancient times even before agriculture, humans also like ingesting anything else that leaves them disoriented or worse. Magic mushrooms are celebrated. Narcotics are big business. Their addictive quality strengthens demand to the level of prioritising its consumption above all else, even to accepting a longer stay in prison (which confirms that for this problem prison is useless).

There appear to be more people eager to endanger their health than to preserve it. Cancer and diabetes are not infectious diseases and are now seen as avoidable. As Laura Stokowski points out, the role alcohol plays in preventing the immune system from intercepting and destroying mutant cells is denied when the patient is asked about their drinking habits. Prosperity allows many families to have wine with every meal. Do they think it is healthy and full of vitamin C from grapes?

Since I developed the means of stopping cancer more than two years ago, I have become acquainted with nutritional cures for cancer which have the merit of supporting the immune system and thereby killing incipient cancer cells. In all cases, the nutrients and food supplements contain minerals and vitamins which do not store in the body and if they did they may become as much a danger as the problem they are trying to solve. For the cure to work, what goes in, must come out. This means that all exits have to be open, not just the bowel and bladder. Eyes wash with water when we blink, saliva glands wet the mouth, the nose runs and wax forms in the ears. As well as oiling the skin to protect against constant water and at other times the baking of the sun, our pores release chemicals that should come out after they have fulfilled their role in maintaining balances.

The Microbiome Balance

One way to understand the balance is to think not just of the balance of the body’s nutrition but the requirements of our microbiome, the masses of bacteria that collectively support our health. It can be argued that the microbiome is not there to support us but that we are living to host the microbiome. There is a constant balancing programme running to keep the bacteria fed so that it can reproduce without harming its host. The behaviour of gut bacteria is controlled through the vagus nerve, the 10th cranial nerve that runs from the brain stem down to the abdomen [10]. Dr Mercola reports that the makeup of gut microbiome can have a tremendous influence over psychological health and well-being affecting both the general mood and a risk of more serious mental health dysfunction (Figure 2).

Figure 2: The bowel

The black, hard pieces of gravel in the tube in this photo were for many years in the bowel of a patient who was being treated for cancer. Thankfully, the doctor took a holistic approach and by a thorough examination found what had been causing pain. That was a problem; some of the pain was from cancer and some was from other failings such as this bowel detritus. That the immune system had been unable to support the patient is obvious. The doctor succeeded in returning the health to where it had been twenty years earlier and hoped that the patient had learned what to do to stay healthy.

Opening the valves

Figure 3: The source of this cross-section diagram is unknown. It was found on the internet.

It may seem unnecessary to advise a man how to urinate but what is obvious to a child is more difficult as he ages. The ladies have problems of a different kind. As the urology student soon learns, the old men have difficulty opening the valve whilst the ladies may have trouble keeping it closed. The main difference is that the female urethra is short and the male urethra more than four times longer. The source of this cross-section diagram is unknown (Figure 3). It was found on the internet. There is a lot of publicity advising men to have their prostate checked if they are frequently needing to urinate. If the prostate gland compresses the urethra, the flow of urine is restricted. The frequency of urination and the amount passed is measured with a uroflow meter [11]. The importance of the prostate inspection is to check if a cancer growth is causing the obstruction.

A problem seldom admitted by the elderly is reduced elasticity. This can be see easily in wrinkled skin. It is also happening internally. A young bladder would fill and then empty powerfully squeezing the contents. As the elasticity of the bladder deteriorates, it lacks the pressure to expel the urine. It could be this, not just an expanding prostate gland, that is the problem.

As you get older, you learn where the toilets are. When you go to a new place, identify the toilets in readiness and the rule is never miss an opportunity to use the toilet because you don’t know when you will find the next one. When you urinate and think the bladder has emptied, wait, maybe thirty seconds, and then a few more drops will come out. That delay has given the bladder time to shrink. Removing the last few dregs is important because if they are left inside they can cause infection leading to further problems. The usual cure is to drink an excessive amount of water and flush out the infection. The body protects itself from dehydration. When it senses aridity from dry air which can be the weather or air conditioning, it will retain water. The stomach can be bloated. Ankles and wrists swell. Move to a cooler, humid environment and quickly the bladder will be back in action. Opening the bowel is assumed to be a matter of squeezing. That is sometimes easier said than done. Toilet seats are a recent invention in the evolution of humans and always too high. The natural posture for defecating is to squat. This positions the bowel and anus ideally to release the contents.

Food and soil

Food intake is fundamental. If the food lacks nutrients, the body suffers. The nutrients come from soil either into plants eaten directly or by the plants to animals that are eaten. Either way, soil quality is essential for human health. The industrialisation of agriculture has leached soils. Yields are sustained by fertiliser that does not lead to better nutrition. Crops are sold by weight, not by nutritional quality. Fifty years ago, the strong man, cartoon character, Popeye ate spinach for strength. Now he would need to consume fifty times more spinach to ingest the same amount of iron that he got fifty years ago. The crops may look and weigh the same but what is needed in them is not there. Just as the pharmaceutical industry has replaced natural foods with synthetic additives so too has the fertiliser industry ignored the benefits of natural methods of recycling bacteria back into the soil [12,13]. An interesting company is CBX based in Arizona in the USA and known in Europe as Envirom Green based in Norway. CBX discovered Leonardite, an ancient geological deposit of plant material that has not turned to coal and decomposed slowly over millions of years until only the mineral elements remain. Their websites show with and without photos of crops treated with and without CBX and the differences are startling [12a]. Follow the link to what CBX call the 5th element. There is life in soil.

Soil

In 1 teaspoon of soil there can be the following numbers of microbes:

a) 1 to 600 million individual bacteria

b) 5 to 60,000 yards of Fungal Hyphae

c) 100 to 100,000 Protozoa

d) 5 to 500 beneficial nematodes

e) few to several hundred thousand Microarthropods

These organisms help convert organic matter and soil minerals into the vitamins, hormones, disease-suppressing compounds and nutrients that plants need to grow. Healthy soil makes healthy plants and promotes the health of those who eat the plants. The concept of what goes in, must come out is displayed in the soil enrichment company called Bat Master [14] They have found an inexhaustible supply of bat guano (dung) in deep caves that rebalances and replenishes exhausted soils so successfully that it rids plants of disease better than any pesticide. They call their product a plant food. Apparently, there would be legal complications if it were called fertiliser. Bats eat insects. Ingesting the variety of foods from many types of insects delivers to the bat’s faeces a bountiful range of minerals and decayed bacteria. This is what Popeye needs at the start of his food chain.

Conclusion

We are scared. We do not know where the food and drink we put into ourselves comes from. We have to trust the suppliers because we have no choice. Even farmers buy food in the shops. In this modern world, hardly anyone grows everything they need for every day of the year. The best we can do is be careful and hope that what goes in will come out without doing harm whilst inside us.

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Lupine Publishers| Cefpodoxime Proxetil and its By-Products: A Comparative Study as Per EP-7

 Lupine Publishers| Journal of Medical Sciences

Abstract

Cephalosporins are the highly used Broad-spectrum antibiotics, belong to β-lactam class. Cephalosporins resemble penicillin in that they have a β-lactam structure, but the five-member thiazolidine ring characteristic of the penicillin is replaced by a sixmember dihydrothiazine ring. The bactericidal action of beta lactam antibiotics is directly attributable to their ability to react with PBP’s. The research work relates to a by-products during process for the industrial manufacture of Cefpodoxime Proxetil. The drug is registered in USP and belongs to 3rd generation drug. It was discovered by Brotzu in fungus Cephalosporium Acremonium which produces a chemical which show antimicrobial activity. Abraham isolated the three fragmentation patterns of cefpodoxime proxetil. Data from this systematic study will help improve the safety and quality of cefpodoxime proxetil types of cephalosporin antibiotics cephalosporin P, cephalosporin N, cephalosporin C.7-ACA is widely used as the substrate for synthesizing cephalosporin antibiotics. Modification of the 7-ACA side-chains resulted in the development of useful antibiotic agents, and the first agent is Cephalothin (cefalotin) was launched by. Eli Lilly Company in 1964 There are many patents which gives the procedure of Synthesis of Cefpodoxime ProxetilStability of three Cefpodoxime proxetil products available in indian market at fridge temperatures (2-8 °C), room temperature (25 °C) and elevated temperature (42 °C). Flow properties, rheological and the physicochemical parameters of both powder and reconstituted powder were used to evaluate the stability of different brands of Cefpodoxime proxetil available in india. The powder of stability samples was eluted through a C18 column with formic acid-methanol-water as the mobile phase. In total, 15 impurities were characterized in commercial samples, including 7 known impurities and 8 new impurities. The structures of these unknown compounds were deduced via comparison.

Introduction

Scheme 1: Synthesis of cefpodoxime proxetil [1].

Cefpodoxime proxetil1 is chemically known as 1-(isopropoxycarbonyloxy) ethyl (6R,7R)-7-[(Z)-2--(2-amino-4- thiazolyl)-2- (methoxyimino)acetamido]-3-methoxymethyl-3- cephem-4-carboxylate. Cefpodoxime proxetil is a potent antibiotic and is of great therapeutic interest in the treatment of acute bronchitis, exacerbations, pneumonia, sinusitis, recurrence of chronic tonisillitis, pharyngitis and acute otitis media. Several methods have been reported in the literature2-4 for the synthesis of cefpodoxime proxetil [1]. Cefpodoxime acid (6) is treated with 1-iodoethyl isopropyl carbonate (5) to produce cefpodoxime proxetil 1, as shown in scheme 1. 1-iodoethyl isopropyl carbonate (5) is prepared5-7 from 1-chloroethyl chloroformte 2, as shown in scheme 1. 1-chloroethyl chloroformate (2) is reacted with isopropanol in presence of a base to produce 1-chloroethyl isoprpopyl carbonate (4). 1-chloroethyl isoprpopyl carbonate (4) on further treatment with sodium iodide results 1-iodoethyl isopropyl carbonate (5).

Cefpodoxime proxtil is a cephalosporin class of antibiotic used for the treatment of bacterial infection. It consists of eight steps namely Methoxilation, condensation side chain formation, work up charcolisation, crystallization and drying [2]. Stage 1: Methoxylation of 7-ACA is carried out with methanol and BF3 complex at low temperature. filter and pH of the filtrate is adjusted with TEA to get 7-AMCA (Stage-I). Stage 2: 7-AMCA is condensed with MAEM in presence of methanol and TEA. By product is removed by filtration. Filtered mass is treated with activated carbon. Product is isolated by adjusting its pH with sulphuric acid. It is centrifuged, washed with acetone and dried at 45 °C to get Cefpodoxime acid. Stage 3 1-Iodoethyl isopropyl carbonate is further subjected to condensation with the Cefpodoxime Acid in the presence of dimethyl acetamide using the 1,8- Diazabicyclo [5,4,0] unde-7-ene (DBU) as a catalyst which on further workup with water & washing with sodium thiosulfate & sodium chloride ethyl acetate, cyclo hexane and treatment with Methanol & EDTA & its further crystallization using the ammonia solution for pH adjustment yields the Cefpodoxime Proxetil 10.

Cefpodoxime proxetil an oral, broad-spectrum third generation cephalosporin antibiotic. It has in vitro activity against many common Gram-positive and Gram-negative pathogens associated with common pediatric infections, so it is a useful option for empirical therapy. It is listed in the United States Pharmacopeia 36th Edition, the European Pharmacopeia 7.0 Edition and the Japanese Pharmacopeia 15^th Edition. Different analysis methods have been developed and compared to measure impurities and degradation products. Fukutsu et al. identified three degradation products of cefpodoxime proxetil by high-performance liquid chromatography-hyphenated techniques. However, ICH guidelines Q3A require that all impurities (from processing and degradation) be identified above a certain threshold. Yet, currently, a systematic study for identifying cefpodoxime proxetil impurities is not available11-12. Hence, we focused on identifying unknown process impurities and degradation products in cefpodoxime proxetil using a chromatographic system from the European Pharmacopeia 7.0 Edition using liquid chromatography with diode array detection (LC-DAD), multiple stage mass spectrometry (MSn), and liquid chromatography-high-resolution mass spectrometry (LC-HRMS) methods along with stress degradation tests, degradation and mass fragmentation mechanisms of cephalosporins, and related synthesis processes. These studies will inform future quality control and safety of cefpodoxime proxetil products. We characterized 15 impurities including 4 new degradation products and 4 new process impurities, along with 7 known impurities as identified in the European Pharmacopeia. We would discuss these as well as the most likely cause of their appearance and the mass fragmentation pathways of the impurities.

Stability of a pharmaceutical product may be defined as the capability of a formulation in a specific container/closure system to remain within its physical, chemical, microbiological, toxicological, protective and informational specifications [3]. Although there are exceptions, 90% of the labelled potency is generally recognized as the maximum acceptable potency level [4]. Thus, stability study maintains the product quality, safety and efficacy throughout the product shelf-life [3]. The stability of pharmaceutical products depends on many factors, such as stability of the active pharmaceutical ingredient, the potential interaction between the active ingredient and the excipient, the dosage form, the storage condition, handling and length of time between manufacture and final usage. Although factors like environmental influence like light, moisture and heat are important in stability study of pharmaceutical products [5]. Dry powders for oral suspension are powder mixtures which require reconstitution at the time of administration mostly for paediatric use [6]. We therefore investigated the effect of temperature on the physicochemical characteristics of some oral re constitutable Cefpodoxime proxetil dry powder and suspension available in Nigerian pharmaceutical market and also to be able to select and recommend the best from the series of possible choices. This study specifically aimed to achieve these objectives by applying a simple, accurate and less time-consuming validated UV spectroscopic method for the quantification of Cefpodoxime proxetil in samples subject to variable storage conditions, thus their physicochemical stability assessment over a period of time. Three brands of Cefpodoxime (40mg/5mL, 50 mg/5mLl and 40 mg/5mLl) containing 800 mg, 1000 mg and 800 mg respectively for reconstitution in water for oral use were used in this study. The brands used (A: Innovator product, B: Generic product-Indian origin, and C: Generic product Indian origin) [7-10].

Physical properties determination18-19 The samples (reconstituted and non-reconstituted) were evaluated for physical stability by determining the aesthetic appeal (odour, taste, colour and texture), sedimentation volume, ease of re-dispersion, viscosity, particle size, flow rate, angle of repose, bulk density, tapped density, compressibility index and Hausner’s ratio as applicable. All parameters were performed in triplicate 13-15. Powder material and degradation products under different forced degradation conditions: 60 °C water bath degradation; high-temperature degradation; oxidative degradation, UV degradation; and, UV+ oxidative degradation). Acetonitrile was purchased from Thermo Fisher Scientific. Formic acid (98.0%) was supplied by Sigma- Aldrich Co. Ltd. and analytical-grade hydrochloric acid (HCl), NaOH and (H₂O₂, 30%) Merck A milli-Q (Millipore, Billerica, MA) was used to further purify glass-distilled water. RS (Batch17-201802, containing 95.9% of cefpodoxime, India.

Reference standard and sample solutions preparation

Approximately 3mg of cefpodoxime proxetil systematic RS was transferred to a 10mL volumetric flask, and dissolved in 10mL of a mixture of water, acetonitrile and acetic acid (99:99:1, v/v/v). This was the systematic RS solution. Next, 3mg of cefpodoxime proxetil impurity H RS was added to a 10mL volumetric flask and dissolved in 10mL of a mixture of water, acetonitrile and acetic acid (99:99:1, v/v/v). This was the impurity H RS solution. Then, cefpodoxime proxetil capsule contents (50mg) were dissolved in 50mL of a mixture of water, acetonitrile and acetic acid (100%) (99:99:1, v/v/v) [11-13]. This was the sample solution. Cefpodoxime proxetil bulk material (50mg) was dissolved in 50mL of a mixture of water, acetonitrile and acetic acid (99:99:1, v/v/v). This was the forced degradation stock solution.

Instrumentation

The LC/MS system consisted of a 3201 S1-2 binary pump, a 3202 S1-2 vacuum degasser, a 3014 S1-2 column heater, a 3012 S1-2 column switch system, a 3133 S1-2 sampler from SHISEIDO (Tokyo, Japan), an Accela PDA detector (Thermo Fisher Scientific Inc., Waltham, MA) and a 3200Q TRAP mass detector (Applied Biosystem Inc., California), controlled by Analyst® software (version 1.5.1).

Forced degradation study

The forced degradation stock solution was transferred and degraded under acidic, basic, 60 °C water bath, oxidative, UV and high-temperature conditions, separately.

Acid degradation solution

About 5mL of stock solution was transferred into a 25mL volumetric flask. Then, 2mL of 0.1mol/L hydrochloric acid was added. This mixture could stand for 2h, and then the acidic solution was neutralized with 2mL of 0.1 mol/L sodium hydroxide. Base degradation solution: About 5mL of stock solution was transferred into a 25mL volumetric flask and 2mL of 0.1mol/L sodium hydroxide was added and maintained for 2h. The basic solution was then neutralized with 2mL of 0.1mol/L hydrochloric acid16. Oxidative degradation solution: About 5mL of stock solution was transferred into a 25mL volumetric flask. Then, 1.0 mL of 10% hydrogen peroxide solution was added. This mixture was maintained for 2 h. Water bath degradation solution: About 5mL of stock solution was transferred into a 25mL volumetric flask. This solution was kept in a 60 °C water bath for 45min, and the solution could cool to room temperature. UV degradation solution: About 10 mL of stock solution was placed under UV light (254nm) for 12h. Hightemperature degradation solution: About 100mg of cefpodoxime proxetil bulk material was placed in an oven at 60 °C for 2h. Then 10mg of the above sample was transferred into a 10mL volumetric flask. The sample was dissolved and diluted with a mixture of water, acetonitrile and acetic acid (99:99:1, v/v/v).

Chromatographic Conditions

The analysis was carried out on a Kromasil 100-5 C18 column (4.6 mm×150 mm, 5 μm-particle diameter). Mobile phase A contained formic acid-methanol-water (1:400:600, v/v/v). Mobile phase B contained formic acid-methanol-water (1:50:950, v/v/v). UV detection was at 254nm and the flow rate was kept at 0.6mL/ min. Column oven temperature was 25 °C and the data acquisition time was 165min. The pump mode was gradient, and the program was as follows, time (min)/A (v/v): B (v/v); T0.01/95:5, T65.0/95:5, T145.0/15:85, T155.0/15:85, T155.1/95:5, and T165.0/95:5.

Mass Spectrometry

Tuning and MSn investigation of cefpodoxime proxetil and impurities was carried out using the following optimized MS conditions16 ,17:

a) Electro spray ionization: (EPI) positive ionisation mode, decluster potential (DP) 50 V, entrance potential (EP) 10 V, collision energy (CE) 40 V, curtain gas: 20.0 L/h. Ion source gas 1: 65.0 L/h, ion source gas 2: 60.0L/h, ion spray voltage (IS): 5500 V, temperature (TEM): 500.0 °C, and Interface heater. Enhanced MS (EMS) and enhanced product ion (EPI) spectra were acquired from m/z 50 to m/z 1200 in 0.1 amu steps with dwell time of 2.0 s. Analyst software (version 1.5.1) was used for data acquisition and processing. Molecular weights of each component were deduced using protonated.

b) Molecular ions- ([M+H]+) and were confirmed using minor adduct ions of [M+Na]+ and [M+K]+ peaks: High resolution-mass spectrum (HR-MS) investigation was accomplished with a dual gradient Ultimate 3000 HPLC system (Dionex Inc., Sunnyvale, CA) equipped with a LTQ Orbit trap XL high resolution mass spectrometer (Thermo Fisher Scientific Inc.) with the following MS conditions: positive ionization mode, FT cell recording window from m/z 100 to 1200, and resolution 60,000. Data processing was performed using Perl script (Quant Merge) software.

Results and Discussion

Impurity analysis by HPLC- Bulk materials were analyzed using the HPLC-DAD FIG a and b) and 15 impurity peaks were detected from the two samples. All 15 impurities originated from cefpodoxime proxetil bulk material. To determine the source of impurities, cefpodoxime proxetil bulk material was degraded under alkaline, acidic, 60 °C water bath, oxidation, hightemperature, and UV irradiation conditions, based on published cephalosporin degradation conditions. Typical chromatograms for the different forced degradation conditions are shown. Mass fragmentation pathway of cefpodoxime proxetil Understanding cefpodoxime proxetil fragmentation pathways can help identify impurity structures. Cefpodoxime proxetil was analyzed in positive ion mode firstly by direct flow injection using a methanol/water (1:1) mixture as the solvent through MSn. Mass spectra and the cefpodoxime proxetil mass fragmentation pathway are shown in Figures 1-3. The primary reason why drugs are formulated as a suspension for reconstitution is inadequate chemical stability of the drug in aqueous vehicle [14]. In this study we investigated the effect of temperature on the physicochemical characteristics of some brands of oral re constitutable Cefpodoxime proxetil to determine their stability profile. All the samples were within the expiry period and registered with appropriate drug regulatory agency in India. The colours of the un reconstituted product varies from off white to cream colour (sample “A”) and yellow to brown (sample “B’’) in spite of the fact that sample “C” maintaining its cream colour all through the duration of the study. The colours of individual sample depend on other formulation excipients. The reconstituted samples were banana flavoured, sweet with smooth texture. Chemical stability was analyzed through the drug content assay and by chromatography for possible degradation product of active drug (Cefpodoxime proxetil). The percentage of the labelled claim of the non-reconstituted samples decreased with time, across the different samples and at different storage conditions. Product “B” had the least percentage content across all storage conditions used (Figures 4-6).

Figure 1: structure of cefpodoxime proxetil [1].

Figure 2:

Figure 3:

Figure 4:

Figure 5:

Figure 6:

The drug content of samples in the refrigerator were within the USP specification for the duration of the study, except Product “B” whose drug content could not meet the specification on day 90 at room temperature [15]. Degradation of Cefpodoxime occurs either acidic, alkaline, oxidative, photolytic stabilities or combination thereof, but in this study as a result of the type of dissolution medium and the ester functional group present in the drug one is tempted to say hydrolysis must have play an important role in the degradation of Cefpodoxime proxetil [16]. The decrease in drug content of the samples as the sample ages for the non-reconstituted samples were reversed on day 60, across all brands and storage conditions. The chromatographic analysis of the reconstituted products showed two distinct retention factor values on days 60 and 90 (Tables 1 and 2). The implication of this is that before/on day 60 another product (possibly the degradation product) has been formed which possibly might have a similar wavelength of maximum absorption close to that of the pure Cefpodoxime proxetil, thereby increasing the absorbance value obtained and therefore the corresponding increase in the calculated amount of the Cefpodoxime present in the samples (Further research is ongoing in our laboratory to characterize the product that gave the second Rf value) (Figures 7-10). Changes in concentration may be caused by the mechanisms associated with hydrolytic decomposition and higher temperatures during the long period of storage [17].

Figure 7:

Figure 8:

Figure 9:

Figure 10:

Table 1: Physico-chemical parameters at refrigerator temperature (2 °C-8 °C/40% Rh).

Table 2: Physico-chemical parameters at room temperature (25 °C/60% Rh).

Weakly acidic or basic drugs show good solubility because of ionization and thus their degradation rate is faster. For the reconstituted samples, the pH decreases as the suspension ages across all the storage conditions and brands (Tables 3). The decrease in pH value is expected Cefpodoxime being an ester which readily hydrolysed in water to form carboxylic acid, though the acid produced is either poorly soluble or it exceed its solubility product thereby leading to product colour change or cloudiness [18]. This explains the colour changes earlier discussed. Most disperse systems are stable over a pH range of 4-8. The pH of the sample decreases as the samples ages. Products “A” and “C” have similar pH variation, although the pH of product “B” (3.00) deviate from the standard pH range stated above as early as day 14 at elevated temperature while, the pH values of products “A” and “C” only deviated from the standard range on day 60 across the storage conditions. The three brands evaluated were banana flavoured and sweet to taste throughout the duration of the study for refrigerated and room temperature conditions while the taste turned sour on the 30th day for all the brands at elevated temperature. Sour tastes rely on ion current to conduct the taste signal, thus stronger ionic taste. Recall that hydrolysis of Cefpodoxime lead to more ionic degradation products. Particle size has profound effect on the dissolution of a formulation. The bigger the particle size the lower the dissolution rate and the less intense the taste of the particle. The particle sizes for products “A” and “C” were similar and significantly smaller than that of product “B”. Within the first 30 days of this study all the reconstituted samples were of smooth and sticky texture except for those kept in the refrigerator which is smooth. The increase in temperature at both room and elevated temperature might have increase the kinetic energy of the individual particles of the molecules, thereby leading to an increase in their rate of collision which resulted in the samples being sticky.

Table 3:

Conclusion

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, and it enables us to predict the storage condition, predict the period in which the product should be re-tested and finally determine the product shelf life. This research studied three brands of Cefpodoxime proxetil poeder (Products A, B and C) at potential temperature of exposures, which shows that the refrigerator temperature condition (2 °C -8 °C/40% Rh) is best for storing the reconstituted suspensions and the non-reconstituted samples is best stored at room temperature condition (25 °C/60% Rh). Product A showed a very good chemical, physicochemical and physical stability profile over time when compared with Product B and Product C. Thin layer chromatography show the presence of the degradation product after prolonged storage which underscores the importance of manufacturer instruction for storage and disposal of the product after usage. The increase in the absorbance of the reconstituted suspension after day 30. The impurities in commercial cefpodoxime proxetil samples were characterized based on MS/MS fragmentation pathways and chromatographic behaviours. In total, 15 impurities were detected in the sample. Based on published cephalosporin degradation mechanisms, stress tests were designed and performed. The data showed that four impurities were degradation products and 11 impurities originated from the synthesis process. In addition, five impurities were potential degradation products. Seven known impurities were accurately elucidated by comparison with the mass spectra of the systematic RS and impurity H RS. Eight new impurities were elucidated for the first time based on the synthesis process and the mass fragmentation pathway of cefpodoxime proxetil. The remaining five synthetic impurities were not characterized by MS/ MS methods because they were in very low concentrations. This systematic study to identify impurities in cefpodoxime proxetil samples will assist us to improve its quality and safety. Note: These impurities are reported in European Pharmacopeia 7.0.b-These unknown impurities are characterized for the first time.

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Lupine Publishers| Doctors should be paid more

 Lupine Publishers| Journal of Medical Sciences

Abstract

Only by increasing productivity can earnings be increased. This applies to doctors as much as all trades. Better techniques enable diseases to be cured that have hitherto been impossible by traditional methods. By these means, a doctor can heal more patients more easily. Thus, a doctor can earn more, and patients be charged less.

Introduction

In every country, a medical doctor is highly respected and usually paid double the average wage and often much more especially if they can be self-employed and charge the patients directly. Governments and insurance companies always control the medical providers. Doctors are seen as having the power of life and death over people and this is feared by politicians who seldom understand medicine. So long as students continue to apply to medical schools, the renumeration is settled by supply and demand. If there are enough doctors, the pay must be enough. If doctors left the profession and fewer students enrolled, the pay would be increased to attract more.

All this assumes that a doctor is able to restore health and postpone death. Longevity has increased, so doctors and the medical industry claim to be earning their keep. But is living longer a result of what a doctor can do when called upon to stop an illness? What about the improvements in sanitation that happened over a hundred years ago in the modernised countries and are being installed now in emerging countries. Soap does more to maintain health than aspirin. It has to be said that a headache is never the result of an aspirin deficiency [1]. Plumbers contribute more to health than doctors. Some can earn as much as doctors by working hard and taking on unpleasant jobs. To become a doctor requires more study and expense than ever faces an apprentice plumber and the skills are different.

The makings of a doctor

Think back to school days. Those who passed exams all had good memories. They may have lacked imagination but when it came to remembering names and dates, they had total recall and that is all an exam tested. Medical students are similarly tested on their memory [2]. Now ask whether a good memory is more important than an instinct for asking the right questions when it comes to puzzling out what the cause of an illness is. Having learned a lot of case histories, a doctor may remember that what he sees in the clinic is the same as reported in a text book and on that basis prescribes drugs which should help. That, unfortunately, is not good practice and usually supplied with the advice, “If you don’t feel better in a few days, come back and we’ll try something else.” Whether the medicine works or not, the doctor gets paid. By contrast, if the new toilet did not flush, the plumber would not be paid until it worked properly.

A doctor’s priority

The doctor will have provided the patient with a medicine that can be justified as correct by reference to existing practice. It will have been used before and tested. Whether the circumstances are the same, one can never be sure but at least the uncertainties are limited if the drug, and it usually is a drug, has been around long enough to be well tested. This is all about legalities. The doctor’s first responsibility is to protect himself and his colleagues. It is not about doing the best for the patient.

A patient who has not been treated by a doctor, cannot sue that doctor. This is now the first rule of medicine.

The language of medicine is deliberately non-conventional. It will be argued that it eliminates misunderstandings and can be more precise. So, who misunderstands? It is always the patient. Who dares to argue with a doctor? His rebuttal will be to let you seek a second opinion. Go for an operation and you will have to sign a disclaimer. Only another doctor would understand the legal clauses. Dentists are the same. As you sit in the waiting room two minutes before the appointment, the nurse presents you with a tenpage document and asks you to sign it; you do, so that if anything goes wrong, it is your fault and you still have to pay.

Where’s the money?

The whole procedure should be changed to put the patient first. In every other business, the customer comes first. Ask any doctor about their pay and they will tell you they do not do it for the money, they do it for the satisfaction of helping people. Does that mean they would work for less pay? No way! It means they know what to say to maintain their status. The world’s first welfare state was created by Aneurin Bevan [3] in Britain after the tragedy of the second world war. He wanted all hospitals to be government owned and all doctors to work for the government. The doctors’ unions protested. They were self-employed and could charge whatever the patients would stand. Eventually Bevan had to compromise and allowed the doctors to work for others as well as the government. In other trades, this is known as moonlighting and is generally frowned upon but for doctors it is regarded as the step up to the high earnings. Private medicine was allowed to run alongside the National Health Service and gave the surgeons and those at the top of the NHS an opportunity to put in a few extra hours in private hospitals so that they can bring their total earnings to about five times more than they would get from the NHS alone. Usually insurance companies were covering the costs of treatment in the private hospitals. The doctors were the same whether the patient was in private care or the NHS. The difference being that the floors in the private hospitals are carpeted and patients had individual rooms with a television. The patient would also jump the queue. The NHS would keep the patient waiting and that wait would be longer if the surgeon was not available due to commitments in the private hospital. Bevan’s socialist ambitions were thwarted, not by the patients who are the electorate, but by the doctors. Nevertheless, the NHS, now in its 70th year grumbles along with almost daily complaints about insufficient money. The assumption that spending more on health care will improve health is false and based on pleas from the medical profession. Never having worked in any other job, they think they work harder than anyone else and have higher responsibilities. How often does a doctor say, Unfortunately, you are not responding to the medication? It is the patient’s fault.

Payment by results

Pay doctors and their support staff according to results and their attitude will change. All other workers are paid on this basis. Productivity is the measure of efficiency and performance. No longer should the medical profession be allowed to hide behind their failure to apply better means of healing. If a doctor is unable to cure a disease, let him sue his medical school or employers for keeping him ignorant.

Patients should complain

There are many examples where failure to cure or heal should not be tolerated. The belief that it is better to let a patient die than treat them with something that has not been proven over many years on thousands of patients is a scam perpetrated for profit by corrupt regulators supported by existing suppliers. Despite asking for innovation, the obstacles to innovation in medicine are colossal. The complaints should be aimed by patients at their politicians who control the laws and regulators governing medical practice.

Non-healing wounds

In Britain there are 140 amputations a week, mostly because diabetic ulcers cannot be healed. This figure is rising, having doubled in the last few years. An amputation costs £25,000 plus the cost of equipping the patient with a prosthesis and their rehabilitation. Twenty years ago, the ability of low powered lithotripters to heal non-healing wounds was announced by orthopaedic surgeons who had observed the effect when treating wounds; they healed better than expected. Roll forward to the present day and NICE, National Institute of Clinical Excellence, in Britain states that the technology is still experimental [4]. That statement was made by a lawyer, not a doctor. In Germany, treatments are paid for (reimbursed) by insurance companies, so they only pay for approved treatments. CellSonic VIPP was being used successfully by Dr Christian Busch [5] at Tübingen University and following a complaint by a patient to her insurer for not getting adequate treatment and knowing that Busch with his CellSonic machine could help she informed the insurer and a director then telephoned Dr Busch. He agreed that CellSonic is the best of all methods for wound healing and criticised the insurance company for reimbursing the negative pressure machine which does not work. The company director agreed and asked for €400,000 for further trials. With adequate trials already done, why should the insurance company want more money?

In 2017, the total cost of wound care in Britain was £5.3 billion. The number of wounds in a year is 2.2 million so the cost to the NHS of each wound is £2,409. As these wounds never heal, the costs run on until the patient dies or has an amputation. Even an amputation often fails to intercept the infection preventing the wound closing, so the crisis continues [6]. The cost of healing a wound with CellSonic VIPP including labour and the machine is £130.00 plus 30% for cleaning and dressings totalling £169.00. This gives a saving of £2,240 per wound (£2,409 - £169) which spread over 2.2 million patients would be a saving of almost £5 billion a year. This amount is of no interest to the politicians or the NHS management. They think that the answer is to have more to spend on methods that do not work. The refusal of doctors to try machines offered to them free of charge confirms a major failure in the system. They have no incentive to improve.

Pain

One of the main reasons for absenteeism from work is lower back pain. The nurse at the local clinic will prescribe a pain killer. This will numb the brain making the pain tolerable, not cure the cause of the pain and not make the person able to perform better at work. Over many years, CellSonic VIPP has been found to cure all types of back pain and even succeeded in growing new nerves in cases of severed spinal cord. The treatment does not use drugs so there are no side effects [7]. For lower back pain, the treatment takes a few minutes and can be done by a nurse. Severed spinal cord takes longer and repeat treatments have to be carried out for a few months but given the fact that this is bringing a patient back from paralysis it is a breakthrough that restores life to a patient. I met a young girl in India who had been treated and asked her if she could now tell when she needed to go to the toilet. She smiled and realised I appreciated the enormity of her predicament. Her nerves from the waist downwards were working again. She was now getting back her dignity and independence. Only Cellsonic VIPP is able to bring about this transformation [8].

Cancer

A third of the world’s population is affected by cancer at some stage in their life and it remains a major killer. There is a general belief that cancer is caused by a bio-chemical failure and the cure has to be a drug. The aim is to selectively kill cancer cells with a deadly poison called chemotherapy (banned in warfare where is it known as mustard gas) but it also kills all cells, not just mutating cells. Radiation is more dangerous and causes cancer, yet it is used to burn away cancer cells whilst trying to avoid harming adjacent healthy cells. The cure rates from chemo and radiation are miserably low and during the treatment the patient is tortured.

CellSonic VIPP has been described by Dr Steve Halti wanger [9]

When you educated me on the fact that CellSonic not only produced sound waves but also CellSonic produces a short duration, high powered electrical field it looks more likely that you have created a nonsurgical form of irreversible electroporation using a combination of sound waves PLUS a high-powered electric field. The combination of VIPP sound and high-powered electrical fields have never been combined before to my knowledge to treat cancer. Noble prize work if you can live to collect it. This is a paradigmbreaking disruptive technology. WOW!

I think we now have a good working theory to explain why VIPP works in cancer

In my opinion, it is the combined effect of sound and electric field that produces the unique effects of VIPP which is why your technology is different from your competitors. So, if I can hang around, I may get a Nobel prize for medicine. Great! The real reward will be to know that deaths and pain have been halted. It surprises me that the medical establishment does not want a cancer cure. In Britain, the 1939 Cancer Act forbids advertising anything to do with cancer. The purpose is to prevent people being given false hope. Why that act was used to threaten a company selling a bright light to help a woman check if there are lumps in her breast only the woman at the Advertising Standards Agency knows. The breast light had been approved by a renowned doctor [10]. Their website now refers to cancer, so I hope they are not now legally threatened.

The opioid crisis

In the USA, the opioid crisis is killing and costing. The Financial Times article [11] says that pharmaceutical companies will be sued just as tobacco companies were sued for the damage their products inflicted on the innocent public [12]. The US Department of Health and Human Services reports [13] that in the late 1990s, pharmaceutical companies reassured the medical community that patients would not become addicted to opioid pain relievers and healthcare providers began to prescribe them at greater rates. Increased prescription of opioid medications led to widespread misuse of both prescription and non-prescription opioids before it became clear that these medications could indeed be highly addictive.

At the core of this problem is pain and mostly the pain of cancer. CellSonic VIPP has now been approved in the USA to treat pain in Stages III & IV Cancer and chronic disease Patients. The CIRBI link is Pro0002913 and the submission was written by Annie Brandt of the Best Answer for Cancer Foundation [14]. CellSonic does not use drugs so there are no side effects and the results are apparent within three days. The procedure works on all types of cancers. Big Pharma is in a self-inflicted crisis. CellSonic can help them as well as patients. Cancer is an electrical fault as explained by the researchers at Bradford University in England [15]. Pharmaceuticals will not resolve an electrical fault.

The value of life

With the title of this article suggesting that doctors should be paid more, the question should now be that if CellSonic can save the life of a cancer patient, what could the doctor charge? To help answer this, we have the value of a life. In August 2018, a jury in California awarded $289 million to a school’s ground-keeper with cancer after finding that the weed killer he used had not adequately described the risks to human health. The weed killer contained glyphosate and was made by Monsanto, a chemicals company that was recently taken over by Bayer. The German company’s share price plunged after the jury’s decision [16].

Does this mean that CellSonic should approach the victim and offer to clear his cancer for $289 million less a sum to pay for the legal costs he has suffered? The idea is fanciful, but the amount of money is real. This is what a court places on the value of the man’s shortened life and discomfort. There are millions of people suffering as is this man and their cancers are the results of all things such as tobacco, pollution, electrical powerlines, smartphones and the stress of divorce. The cost of treating cancer with CellSonic is about the same as healing a wound. It is not even as much as one night’s board in a private hospital. Therefore, the profit margin could be astronomical. It won’t be because I will not allow it and it will cost considerably less than the useless cancer treatments now inflicted. In the USA, a cancer patient incurs a spend of $200,000 a year either personally or from an insurance company and they die in the fifth year.

Conclusion

With doctors paid by results, they would increase their incomes by providing a better service. Only by changing the terms of remuneration will doctors be lifted out of their complacency and be taken back to the basics; by the best means available, to save their patients from pain and death. Like any other tradesman, they need the right tools to do the job and that equipment is readily available and affordable.

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Lupine Publishers| The World Politics of Dominique Moisi

 Lupine Publishers| Journal of Medical Science

Mini Review

In his recent (2009) book, The Geopolitics of Emotion, D. Moisi, a French political scientist, took a still somewhat unusual approach; emotions can be causal in political relationships. The book argues indeed that they may be causes of both peace and war between and within nations. He focuses on three emotions: hope, fear, and humiliation. Surprisingly, the book has received a torrent of praise from reviewers. The overwhelmingly positive response to the book is surprising because modern societies play down emotions as unimportant, even between individuals, much less nations. Most persons, even many researchers, take a materialistic stance: emotions are unimportant because both individuals and nations guide their actions toward owning money, land, resources, and other clearly visible materials. It might be that in order to write persuasively about a specific emotion, the readers must first be dissuaded from their fixed idea: emotions are unimportant [1-4].

How did Moisi deal with this idea? There are three parts to his solution. First, rather than focusing on a single emotion, as most emotion researchers do, he considered three: fear, hope, and humiliation. Since one of the three, hope, is positive, the reader probably feels somewhat reassured by its inclusion, even if she or he has an inclination to reject emotions in general. The second emotion, fear, is not positive, but there is less confusion about it than with the emotion discussed below. The third step is more complex. In choosing the word humiliation, Moisi avoids a substantial difficulty that has long ruled the response to one particular emotion. The term humiliation usually refers to the emotion of shame, without using the term that is frequently avoided; people seem ashamed of shame. Just as research on sexual act avoids the f-word, acceptable conversation and most talk and writing about shame avoid the s-word.

The psychologist Gershen Kaufman [5] is one of several who have argued that shame is taboo in modern societies:

American society is a shame-based culture, but …shame remains hidden. Since there is shame about shame, it remains under taboo …The taboo on shame is so strict …that we behave as if shame does not exist. Shame, or the anticipation of shame, is virtually omnipresent for most people, especially secret shame. The idea that people spend much of their time and energy involved in or avoiding shame, if possible, and managing it if not successful, was central to the best known of Erving Goffman’s books:

“…there is no interaction in which participants do not take an appreciable chance of being slightly embarrassed or a slight chance of being deeply humiliated.” (1959, p. 243, emphasis added).

If this sentence is taken literally, it means that shame and/or the anticipation of shame haunts all social interaction. Avoidance of shame/embarrassment/humiliation is the driving force behind Goffman’s phrase “impression management”, which at first sight seems to be the central concept thru-out the book: everyone constantly worries about how they are seen by others. At first I wondered why his sentence about humiliation was virtually hidden in the last chapter of the book. But now I believe that he was aware of the distaste of most readers for shame. If he had flaunted the idea in the first chapter, the book might not have been a bestseller. The idea that shame issues are a virtually continuous presence in human affairs seems unthinkable in modern societies; modernity fosters the doctrine of individualism. We are taught that each person is a sovereign entity, self-reliant, standing alone. This emphasis is just a pipedream, since flourishing and even, to a large extent, surviving is dependent upon recognition and help from others. Individualism, and many other doctrines in modern societies, make it very difficult to deal directly with shame [5-12].

A) Shame and Violence

The psychiatrist James Gilligan (1997) proposed that most violence is caused by hidden shame. A prison psychiatrist for many years, he asked the prisoners convicted of murder why they did it. Their answers were surprisingly similar: “What did you expect me to do: he dissed me.”

Gilligan’s initial explanation of the way in which secret shame leads to violence is largely metaphorical:

The degree of shame that a man needs to be experiencing in order to become homicidal is so intense and so painful that it threatens to overwhelm him and bring about the death of the self, cause him to lose his mind, his soul, or his sacred honor. (p. 110- 111). A more realistic model might be the building up of painful feeling by another of Gilligan’s ideas, the spiraling of shame loops: I am ashamed that I am ashamed , toward infinity. The model of recursive loops proposed here explains how laminations and spirals of shame could lead to pain that feels unbearable.

Recently several historians and political scientists have at least hinted that humiliation might be a cause of war, in that revenge is driven by hidden shame. But most are cautious about an outright statement. In Hall’s (2017) study, for example, the word shame is not used at all, but humiliation is mentioned 8 times. But not in the summaries at the beginning and end of the article, nor in the title. There are several writers in this area, but only a few take a stronger stance than Hall (See, for example, Löwenheim & Heimann 2008 and Saurette 2006.) But even these more advanced studies don’t take the step of relating humiliation to the shame literature.

Vengeance against the nation that defeated it has been considered one of the causes of war. During the last century this idea was often expressed in terms of the French word for revenge, Revanche. A recent example can be found in the book by Schivelbusch (2001) who uses the term frequently in his review of consequences of defeat (there 51 pages of discussion of revanche). My own book (1994) and recent article (with Daniel and Loe-Sterphone (2018) follow the same thread, suggesting that revenge is usually caused by the acting out unbearable shame. This theory is illustrated by an analysis of what seems to be the emotional origins of WWI and WWII. Judging from the success of Moisi’s book, I am guessing that my earlier book and the other revenge studies are ignored because they dealt with a the single emotion of shame without first solving most reader’s rejection of all emotions as causal. Moisi’s book may take a crucial step in an extraordinarily important direction: changing our understanding of the causes of most wars. Perhaps it would be a step toward reducing the number and size of war in our time.

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Lupine Publishers| Shockwave Therapy in Atherosclerosis

 Lupine Publishers| Journal of Medical Science

Abstract

In this mini review recent developments in extracorporeal shockwave therapy (ESWT) within the field of atherosclerosis are discussed. Increased ecpression of growth factors such as endothelial nitric oxide (eNOS) and vascular endothelial growth factors (VGEFs) are induced by ESWT. IKL, integrin linked kinase, plays a key factor in this process of angiogenesis, believed to be responsible for the beneficial effects of ESWT. Both cardiac shock wave therapy (CWST) in chronic refractory angina pectoris patients as well as ESWT in patients with peripheral arterial disease (PAD) show a uniformly, consistent, beneficial effect in all studies available until now. International standardization of dose-response curves, doses applied, number of sessions and duration of treatment should be established at first, before starting large RCTs. With that knowledge the future of shockwave therapy in CAD and PAD seems bright.

Introduction

The medical use of high energy extracorporeal shockwaves started in the 1980’s, when they were targeted to fragment urinary stones (lithotripsy, ESWL) and gallstones [1,2]. In addition ESWT has been used in orthopedics for musculoskeletal disorders, wound and non-union healing of fractures and the stimulation of bone growth [3-8]. The exact mechanism of action of ESWT on soft tissue is not fully understood, although the principle of mechano transduction is thought to be responsible for the biological changes that take place, Mechano transduction transfers mechanical stimuli into chemical signals at the cellular level, which activates gene expression of growth factors and cytokines as well as cell proliferation and differentiation [9]. Increased expression of growth factors such as endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factors (VGEFs) in soft tissue has been observed in animal studies [10-13]. Due to these findings further applications of ESWT are explored such as in atherosclerosis. One such application included the use of ESWT in ischaemic heart disease and in claudication in peripheral arterial disease. In this mini-review the recent developments in the application of ESWT in the field of atherosclerosis are discussed.

Cardiac Shockwave Therapy (CSWT)

The anti -anginal efficacy of cardiac shock wave therapy was investigated in a Cochrane analysis by Burneikaite et al. [14]. In total 39 studies evaluating the efficacy of CSWT in patients with stable angina were identified including single arm, non- and randomized trials. Totally,1189 patients were included in 39 reviewed studies with 1006 patients treated with CSWT. The largest patient sample consisted of 111 patients. All selected studies demonstrated significant improvement in subjective measures of angina pectoris and or quality of life. In the majority of studies left ventricular function and myocardial perfusion improved. In 12 controlled studies with 483 patients included (183 controls) angina class, Seattle Angina Questionnaire (SAQ) score and nitrate consumption were significantly improved after the treatment. In 593 participants across 22 studies the exercise capacity was significantly improved after CSWT, as compared with the baseline values (in meta-analysis standardized mean difference SMD=;-0,74;95 CI:-0.97 to-0,5; p<0,001).The authors conclude that CSWT in stable coronary artery disease (CAD) demonstrated consistent improvements of clinical variables. Meta-analysis showed a moderate improvement of exercise capacity. Overall, CSWT is a promising non-invasive option for patients with end-stage CAD but evidence is limited to small sample, single center studies [14].

Yang showed in a rat model of acute myocardial infarction (AMI) that CSWT improves myocardial perfusion and ameliorates cardiac remodeling [15]. They demonstrated the arteriogenesis of coronary microangium and protein expression change in ischaemic myocardium after CSWT. Four weeks after CSWT, the fractioning of rats was improved greatly and the cardiomyocyte apoptosis index was significantly lower than in the AMI group (p<0,05). Besides, the fibrotic area was markedly decreased in the CSWT group. In the infarction borderzone, the thickness of smooth muscle layer was expanded apparently after CSWT. Label-free quantitative proteomic analysis and bioinformatics analysis revealed that the differentially exposed proteins were largely enriched in the focal adhesion signalling pathway. Integrin linked kinase (ILK) may be a key factor contributing to arteriogenesis of coronary micrangium during CSWT [15]. Vainer studied 33 patients with chronic refractory angina pectoris and reverible ischaemia on myocardial scintigraphy. CSWT was applied to the ischaemic zones (3-7 spots,100 impulses/ spot,0,09 mJ/square mm) in an echocardiography -guided and ECG- triggered fashion [16]. The protocol included a total of 9 treatment sessions (3 sessions within 1 week at baseline, and after 1 and 2 months. Clinical measurement was performed using exercise testing,angina score (CCS class), nitrate use,myocardial scintigraphy, and cardiac magnetic resonance (CMR) 1 and 4 months after the last treatment session. One and 4 months after CSWT, sublingual nitrate use decreased from 10/week to 2/week (p<0,01) and the angina symptoms diminished from CCS class 3 to CCS class 2 (p<0,01). This clinical improvement was accompanied by an improved myocardial uptake on stress myocardial scintigraphy (54,2 plus/minus7,7%, to 56,4+9,4 %; p=o,016) and by increased exercise tolerance at 4-month follow-up (from 7,4 plus minus 2,8 to 8,8 plus minus 3,6 min:P=0,015). No clinically relevant side effects were observed [16].

Shkollink designed a model for a randomized, triple blind, sham procedure, controlled study to reach a better quality evidence of CSWT in patients with refractory angina pectoris despite optimal medical treatment, responsible for 20% of cardiac deaths in Europe [17]. The new study protocol aims to extend the widespread use of CSWT that is not based on the results of imaging tests or coronary angiography,which are unavailable sometimes. Until now CSWT is applied to the ischaemic segments of the Left Ventricle (LV). This new study design foresees in application of CSWT to all segments of LV which may provide beneficial therapeutic effects by not only reducing ischaemia but also attenuating inflammation and suppressing oxidative stress and fibrosis in non-ischaemic segments, as well potentially preventing LV remodeling [17]. More multicenter trials of CSWT are underway [18].

ESWT and Peripheral Arterial Disease (PAD)

PAD has a prevalence of 4,6% and of 20 % in people older than 60 years with intermittent claudication (IC) as one of the earliest and most common symptoms. PAD has detrimental effects on patients’ walking ability in terms of maximum walking distance (MWD) and pain-free walking distance (PFWD). Research has suggested that ESWT may induce angiogenesis in treated tissue. PAD sufferers experience a cramping pain in the affected muscles, most commonly the calves, which occurs after a short walking distance, until the patient stops, where the pain then gradually subsides. PAD can be limiting and occasionally debilitating and has been shown to have considerable effects on patients ’quality of life [19]. To date 4 studies have investigated ESWT in claudication. In a randomized trial of 22 patients (12 patients treated,10 controls) Ciccone and Notarnicola targeted ESWT at a stenotic plaque lesion within lower limb arteries and demonstrated significant reduction in degree of arterial stenosis,significant improvement in PFWD and reduction in pain severity. These findings were also coupled with a significant reduction in Fontaine staging, In this study ESWT was applied in 4 sessions at 1 weekly interval (2000 impulses,0,03mJ/square mm)- [20]. Tara and Miyamota performed a small prospective non-randomized study (n=10) which aimed to prove safety and its primary end-point was observation of adverse events [21]. The study found no adverse events secondary to shockwave therapy. The secondary end -point was a measure of tissue perfusion using scintigraphy, laser Doppler and measurement of transcutaneous oxygen tension (TcPO2). The use of scintigraphy improved tissue perfusion in the dorsum of the foot. However, perfusion was unchanged in the lower leg region. Moreover, TcPO2 increased significantly in both the calf region and dorsum of the foot. Skin perfusion pressure using laser Doppler showed increases in both regions, but neither was significant [21]. Belcaro and Cesarone studied 32 patients undergoing ESWT for critical limb ischaemia with both rest pain and localized distal necrosis [22]. Outcome included PFWD, visual analogue scale (VAS) for pain, laser Doppler skin perfusion, partial pressure of oxygen and partial pressure of carbon dioxide. All outcomes demonstrated significantly improved measurements [22]. Serizawa et al performed two prospective nonrandomized trials with a total of 6 patients and then 12 patients with Fontaine stage 2 PAD who were treated with ESWT. Patients demonstrated significantly maximum walking distance (MWD), shorter recovery time and improved walking questionnaire scores [23].

Studies in PAD not caused by atherosclerosis as e.g.in patients with thromboangiitis obliterans (Buerger’s disease are not known yet. As dose response curves and standardization are nearly lacking ESWT regimen differ enormously in doses apllied, number of sessions and duration of treatment. New trials such as the Shockwave1 trial are enrolling patients now to meet some of the shortcomings in present available data [24].

Conclusion

It is obvious that extracorporeal shockwave therapy will be a promising treatment modality in end-stage coronary artery diseases (CAD) and in peripheral arterial disease (PAD) Patients with chronic refractory angina pectoris, not amenable to bypass surgery or catheter intervention therapy seem to benefit from cardiac shock wave therapy (CSWT). The same picture is seen in PAD patients, especially those with crural artery disease of the lower limbs. The results of bypass surgery or catheter interventional therapy for infrapoplitial lesions are still unsatisfactory and recurrence rates are high in these patients.

Until now study samples are small and large RCTs should be performed in the future. Nevertheless, all these available studies show a consistent uniformly beneficial picture, even in a Cochrane analysis of CSWT. It is clear that the first goal should be establishing international standardization of dose-response- curves, doses applied, number of sessions and duration of treatment. With that knowledge extracorporeal shock wave therapy will have a bright future in CAD and PAD.

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Lupine Publishers| How to Evaluate Pancreaticoduodenectomy Specimens after Pancreatic Surgery? A Review

Lupine Publishers| Journal of Medical Sciences

Abstract

Pancreaticoduodenectomy (Whipple procedure) is a complicated surgical procedure that is preferred in conditions such as malignancies and traumas of the pancreatic head, duodenum, bulb and choledoch or in case of pancreatitis. Careful attention should be paid to accurately determine the pathological and clinical stage of the disease in patients undergoing oncologic therapies that have changed over the years. This procedure, which is surgically troublesome, requires pathological sampling and care. During sampling, a pathologist must macroscopically analyse the pancreaticoduodenectomy specimens and carefully perform sampling.

Keywords: Whipple Procedure; Pancreas Pathology; Pancreas Gross Examination; Pancreaticoduodenectomy

Introduction

Pancreaticoduodenectomy (Whipple procedure) is a complicated surgical procedure that is preferred in conditions such as malignancies and traumas of the pancreatic head, duodenum, bulb and choledoch or in case of pancreatitis [1]. This procedure was first described by Allan Whipple in 1935 for periampullary tumours and was subsequently preferred for many other indications [2,3]. In recent years, this procedure has been highly preferred because of significant reduction in morbidity and mortality rates associated with it [4]. However, careful attention should be paid to accurately determine the pathological and clinical stage of the disease in patients undergoing oncologic therapies that have changed over the years. This procedure, which is surgically troublesome, requires pathological sampling and care. During sampling, a pathologist must macroscopically analyse the pancreaticoduodenectomy specimens and carefully perform sampling only after completely understanding the anatomical landmarks of the specimen. This will ensure that parameters essentially affecting survival, such as tumour type and lymph node status, will be evaluated more accurately [5,6] (Figures 1-4).

As reported by Adsay [7] macroscopic sampling is very important in the examination of pancreatic resection specimens. Particularly, it is necessary to sample the entire surface of the specimen by peeling it like an orange to mark the surgical margins and obtain maximum number of lymph nodes [7]. We routinely employ this method to perform macroscopic sampling. When pancreaticoduodenectomy specimens are macroscopically examined, the pancreatic head, duodenum, distal bile duct and occasionally the distal part of the stomach and gall bladder are observed. After anatomically understanding the right, left, anterior and posterior parts of the resected specimen, the length and threedimensional measurements of all organs should be obtained. Next, surgical margins of the pancreas should be marked with ink. The surgical margins of the choledoch should be defined and sampled with a block. The duodenum should then be carefully opened from the antimesenteric border (to avoid damage to the ampulla of Vater). If there is a duodenal lesion, it should be described and measured. It is then necessary to open the main pancreatic duct and bile duct longitudinally, preferably using a stylet. The presence of enlargement/stenosis or other lesions in these areas should be reported. Then, if the stomach and gall bladder are present in the specimen, they must be opened using conventional methods, and all specimens should then be fixed in formaldehyde, preferably for 1 day, followed by macroscopic sampling.

Figure 1: Mass localized in the ampulla of Vater, choledochal enlargement.

Figure 2: Mass localized in the ampulla of Vater (stile in choledoch).

Figure 3: Pancreatitis case, stone localized in distal choledoch.

Figure 4: Mass localized in the distal choledoch and thickening of the choledoch wall.

Figure 5: Mass localized in the pancreas head and tumor infiltrates the duodenum.

In pancreaticoduodenectomy specimens, the region where the tumour or lesion is present should be carefully analysed, and sampling should be performed accordingly because the behaviour and stage of tumours located in the ampulla of Vater, choledoch or pancreatic head may vary according to the area invaded by the tumours. The macroscopy report should include the association of the tumour with the duodenum, choledoch, pancreatic head, ampulla of Vater and duct of Santorini. One of the most important points in macroscopic sampling is that the distal, retroperitoneal (posterior), anterior, inferior and superior surgical margins of the pancreas should be marked and accurately sampled. In addition, after sampling all the surgical margins, the entire pancreas should be peeled like an orange and sampled after marking the margins using the method described by Adsay [7]. In addition to the surgical margins of pancreas, surgical margins of the choledoch, proximal stomach and distal duodenum should be marked and sampled [7,8].

Conclusion

In conclusion, the following points should be considered in the macroscopic examination of pancreaticoduodenectomy specimens:

The specimen should be anatomically analysed.

The duodenum should be opened from the antimesenteric border; if the stomach is included, it should be opened using the conventional method.

All surgical margins of the pancreas [distal, retroperitoneal (posterior), anterior, inferior and superior], choledoch, proximal stomach and distal duodenum should be accurately marked with ink and then sampled.

The choledoch and pancreatic duct should be opened using a stylet. The region should be described in terms of the presence of obstruction/dilation and tumour involvement.

The size of the tumour, its relation with anatomical structures and distance from surgical margins must be accurately described and marked, followed by tumour sampling.

All structures should be sampled even if there is no tumour involvement.

Lymph nodes dissected from the fat tissue around the stomach, duodenum and pancreas must be sampled.

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