Accompanying therapy for all types of mitochondrial disorders, and support of cell functions.
(Healthy cell growth and mitochondrial function)
In the following 1st, 4th and 5th cases kanoSAN (100 mg/day) had been used in addition to chemo therapy. The unexpected quick reduction of the tumor in these cases was the reason why it was used only kanoSAN (100 mg/day) in two other patients (refusing chemo therapy).
After treatment with kanoSAN in all cases the tumor was reduced or disappeared completely.
Adeno-Carcinoma of the lung
Male, 69 years old (at the beginning). Initially the patient had been hospitalized for a pulmonary heteroplasia at the left hilus on 07-08-2000. A thorough clinical check revealed: In the brain at the base of dura mater frontal brain at the level of frontal brain left side an egg-like structure with a diameter of 8 mm, being taken as a meningoma. In the thorax at the left hilus a voluminous new structure with an unclear margin, surrounding the main bronchus like a sleeve, reducing its lumen and penetrating lobus inferior.
The apical, lingular and superior segment of lobus superior is surrounded by the sleeve. The parenchyma at the base of the lung is not aerated. There are numerous neoplastic secondary foci in homolateral lobus superior, and in the apical lower segments. Some little nodes could be found subpleuraly in lobus superior and inferior right side. Everywhere in mediastinum lymph-nodes with diameters up to 4.5 cm could be found. In the abdomen liver shows cystic changes in the 6th segment with a wavelike contour up to 4.5 cm. Two nodes with 7 and 15 mm in the 8th and 2nd segments are angiomas or similar to them.
On 12-17-2010 after administration of kanoSAN, a thorax CT with and without contrast agent had been performed. The sleeve-like structure at the left hilus had shrunk to 6 x 3.2 cm. Respiratory difficulties were reduced. Number and size of the nodes in both lungs were reduced. No infiltrations in the pleura. Adenopathy in hilus and mediastinum was reduced with lymph nodes with a maximum diameter of 1 cm at the aortic pulmonary window and of ca. 2 cm at hilus. In the abdomen there were no changes compared to the previous examination.
02-18-2011 showed a further reduction of the tumor at the left hilus. Respiratory complaints improved progressively. Lymph nodes at the right hilus showed a diameter of 24 mm only. The rest of the clinical picture was unchanged, compared to 12-17-2010.
Inoperable Tumor of Pancreas
Female, 61 years old. Anamnesis January 2011. Tumor envelops A. hepatica and V. portae resulting in an occlusion of the portal vein. Bilary stasis and pruritus. Infaust prognosis (six to nine months survival time estimated). Start of treatment 03-08-2011. In the meantime the ductus choleodochus is kept open by a stent.
From May 2011 health improved significantly. Patient works full time in her family business. Only a feeling of pressure in the upper abdomen remained. Because of an improved appetite, weight increased.
Carcinoma of tongue, base of the tongue and epiglottis
Male, 56 years old. The clinical option had been total resection of tongue and larynx with an infaust prognosis. Since it was impossible to swallow, patient had to be nourished with liquids only. After starting treatment on 04-05-2011 health improved steadily. After three weeks onycolysis with a stinking secretion followed a local inflammation. The patient is able now to swallow, while health improved significantly.
Hepatic sigmo carcinoma, metastases
Male, 75 years old. Beginning of treatment 03-21-2011.Partial resection of colon and post-operative pain persisting in the upper abdomen. Appetite and body weight improved as well as depressions. A control check 10-29-2011 showed a significant shrinking of the tumor.
Less differentiated adeno-carcinoma of the lung
Male, 50 years old. Tumor at the right upper lobe with mediastinal infiltration, pulmonal extended lymphatic metastases.
On 12-27-2010 treatment started. In January and April twice per month chemotherapy (Gemeitabine, Avastin, Platinex) was applied, being well tolerated.
The patient can work full-time now, without any complaints.
Primary liver cell carcinoma
Male, 70 years old, G1, ca. 60% of liver afflicted. Urine brown (like beer) Hb 10.5 g/dl, ChE 1,000 U/l. Since chemotherapy (Novardex) was not well tolerated, the patient wanted a complementary treatment.
Beginning July 2011, after eight weeks of treatment, the tumor stayed fixed, without metastases and without ascites. Health improved steadily.
Mode of action:
In all higher cells, eukaryonts, mitochondria can be found. In them the components of the respiratory chain are present. Energy is produced there as ATP and heat by using oxygen (aerobically). Therefore in cells that need a lot of energy there are more mitochondria. In cells of the heart muscle 30% of cell volume are mitochondria.
Mitochondria have their own (short) cyclic DNA. Even being short, often this DNA from all mitochondria is more than the DNA in the nucleus. Spermatocytes get rid of their mitochondria (their motility package) before penetrating the egg cell. Therefore (nearly) all mitochondria are inherited from the mother. Like bacteria and yeast, mitochondria multiply by cell division.
In a largely accepted theory (McFadden 2001) mitochondria had been bacteria 1.5-2 billion years ago (endosymbiotic theory), which invented the way to gain energy by oxygen. In symbiosis with other (anaerobic) cells they transferred this invention to them, a highly efficient way to gain energy. Mitochondria still have some properties in common with bacteria. But they cannot survive outside of their host cell. Mitochondrial DNA (other than DNA of the cell nucleus) is not protected by histones. To avoid detrimental effects, mitochondrial membrane can be closed. This is similar to forming cysts that we know in bacteria.
Energy production is an essential function of cells. Closing of the mitochondrial membrane results in serious effects therefore. Let us have a look at the structure and function of a mitochondrion.
How is a mitochondrion constructed and how does it work?
A mitochondrion is surrounded by two membranes, an outer membrane and an inner one. The inner membrane is folded in many ways with cristae. On them enzymes of citric cycle, respiratory chain and β-oxidation of fatty acids are located. Little bodies rise from the inner membrane into the interior, where ATP is formed. ATP is used for energy transport, necessary for the action of muscles and the formation of substances of the body.
Without mitochondria only an anaerobic degradation of substances is possible (glycolysis). This is performed outside of them in cytoplasm. The end product of glycolysis, pyruvate, is transformed to lactic acid. If muscles are overexerted and the function of mitochondria is not effective enough, this lactic acid may remain and causes aching muscles. They last until lactic acid is oxidized. In mitochondria lactic acid is transported via citric acid cycle to the respiratory chain. Energy efficacy is much less by glycolysis than by the respiratory chain.
In mitochondria pyruvate is transformed into acetyl-CoA and be channeled in this form into the citric acid cycle. By this way energy can be gained from carbohydrates and glucose.
Another important energy source from food, beside of carbohydrates, is fat. Fat and oil (triglycerides) are composed of glycerol and fatty acids. Fatty acids are cleaved in stomach and gut by lipases from the pancreas. After being taken up in the small intestine, fatty acids are bound to glycerol again. Before being taken up in cells, they have to be cleaved. In cell plasma they are bound to L-carnitin and be transported to mitochondria. Via the enzymes of β-oxidation they enter the citric acid cycle as acetyl-CoA. If this is not possible, fat metabolism is seriously inhibited.
The third important food component is protein. It is composed of amino acids and is cleaved already in the gut. After being absorbed, amino acids are mostly recomposed in proteins of the body. But they also can be used as a source of energy. After cleaving amines in the liver the rest is channeled to the mitochondrial citric acid cycle.
By formation of ATP, hydrogen ions (protons) are steadily secreted in to the gap between inner and outer membrane. From this, an electrochemical membrane potential of (normally) 200 mV results. There are many substances being able to decouple the respiratory chain, resulting in a collapse of membrane potential. The consequence is a lack of energy of the body.
The outer membrane bears many pores by which molecules and ions are taken up or released from or to cytoplasm. Very important is the uptake of calcium ions and their release, to control calcium homeostasis of cytoplasm. Normally concentration shall be 100-200 nmol/l in cytoplasm. An increase is a signal and calcium acts as a second messenger. Permeability of cell membranes is controlled additionally. By ion channels and ion pumps, mitochondria are able to take up and release calcium ions.
Cytochrome C can be found in the gap between the two membranes. It is a small molecule transporting electrons in mitochondria. Specific signals cause a release of cytochrome C to cytoplasm. There it starts apoptosis, a type of organized suicide of cells. In this way defective or over mature cells are removed
Nitrosative Stress (Kuklinski 2005; 2008)
The role of nitrogen monoxide (NO) for controlling of the body’s functions is important. Unfortunately it also forms bonds with iron and iron-sulphide containing enzymes of the mitochondrial respiratory chain. Thereby it inhibits ATP synthesis, particularly if manganese lacks. A chronic deficiency of energy results in organs that require a lot of energy, like brain, muscles, retina, gut mucosa and immune system. In this case cells have to switch on their “emergency power generators“, like membrane bound NADH-oxidoreductase and anaerobic glycolysis. This however results in susceptibility for cancer and, in a vicious circle, formation of oxygen radicals. By blocking mitochondrial electron transport, mitochondria become real “free radical guns“.
An important reason for nitrosative stress is cervical-spine–syndrome. An increase of NO by induced NO-synthase (iNOS) can be caused by a lot of environmental contaminants as well (Pall 2007).
At the end, all of them activate NMDA-receptors of cells, causing an influx of Ca++ into cells and activate iNOS. NO being formed, together with an oxygen radical, forms peroxynitrite that activates NMDA-receptors in a vicious circle.
Disease Patterns of Nitrosative Stress
Nitrosative stress results in diseases (Pall 2007) like multi chemical sensitivity (MCS), chronic fatigue (CFS) and fibromyalgia as well as post-traumatic stress disorder (PTS) (formerly Gulf War syndrome). In etiology of other diseases like rheumatism, arteriosclerosis, auto-immune diseases, multiple sclerosis, Morbus Alzheimer and Morbus Parkinson this mechanism plays a role as well.
Inhibition of aconitase in citric acid cycle by NO obstructs acetyl-CoA-channeling. Protein, fat and amino-acids can no longer be utilized. The conversion of cholesterol to bile acids is no longer possible (blocking of 7α-hydroxylase in liver), a diet resistant cholesterolemia results. Blocking of CytP450 at the inner membrane of mitochondria disturbs synthesis of sexual hormones. Every increase in CRP can be a sign of nitrosative stress or mitochondropathy. In many cases of unspecific rheumatic pain of joints, carpal tunnel syndrome, cervico-brachial syndrome, Crohn’s disease or patello-femoral pain nitrosative stress can be in the background.
NO-induced mitochondropathies quickly result in diarrhoea, encephalopathies, myopathies, ataxia, thyroid disorders, visual disorders and disorders of pancreas (exo- and endocrine).
By eating too much carbohydrate, nitrosative stress increases. A lavish meal results in extreme fatigue (gluttony anaesthesia). An increase of lactic acid may result, even in resting periods. The lactate/pyruvate quotient becomes 30:1 to 400:1 (normal value 10:1). 1-4 hours after a meal, the body and mind are exhausted. During the night (when nothing is eaten) rapid heartbeats, an outbreak of sweating and anxiety attacks follow (quasi-hypoglycaemic shock without low blood glucose level). The carbohydrates not being utilized, are stored as fat, especially as abdominal fat, even during reducing diets. A metabolic syndrome may result, since hypoglycaemia can cause an insulin shock.
Severe mitochondropathies can cause extreme emaciation. In cases of nitrosative stress it is wrong to compensate fatigue with more sports. In these cases carbohydrates shall be reduced and fat (oil, butter, cream) are the main source of energy. In cancer, when mitochondria are tight, the so called Budwig diet (oil-protein) (Budwig 1999) is propagated therefore. In general, however, such extreme one-sided diets cannot be recommended.
In nitrosative stress the following medication is contraindicated: long-term nitrates, arginine (more than some grams per day), potency pills and cytostatics. Since in tumor cells few or (in metastases) no mitochondrial activity can be found, healthy tissue will be damaged only. NO leads to carcinogenic nitrosamine. Some antihypertonics increase NO-synthesis as well.
Diagnosis: Nitrosative stress can be measured rather adequately by citrulline (normal value <100 micro=”” mol=”” g=”” creatinin=”” in=”” morning=”” urine=”” or=”” by=”” citrulline=”” out-breath=”” normal=”” value=”” 10=”” l=”” p=””>
Mitochondria and Cancer (Meyer, Mandel, Knapp 2011)
Cells and tissues are steadily renewed by cell division. Some of these divisions are defective resulting in defective cells that have to be removed by the body, especially if these cells are cancer cells. One mechanism is apoptosis, some sort of regular cell-suicide.
In contrast to other cells, cancer cells have lost the ability of apoptosis completely or partially. Apoptosis starts with a release of cytochrom-C from mitochondria to cell plasma, activating caspases there. These enzymes fragment nucleus and then cell plasma to pieces that can be removed by phagocytes.
An important mechanism is recognition of these cells by cellular immune response and to destroy them. Cancer cells, however, have developed a flight mechanism (immune escape mechanism) being promoted by prostaglandines-2 (Cook 2002; Thun et al. 1993; Marnett 1992; Liu et al. 2001). After growing to a size of more than 0.5-2 mm (a tumor can stay in this state for years) and forming of blood vessels (angiogenesis) this mechanism becomes dangerous. In this state cyclooxygenase-2 (COX-2) is over expressed (Subbaramaiha, Dannenberg 2003). It even seems that angiogenesis may be reversed by inhibiting COX (Iniguez et al. 2003). Therefore it is important to inhibit COX-2 and strengthen cellular (TH1-modulated) immunity simultaneously. (Dewson et al. 2001, Maccarone et al. 1997).
This is possible with the bitter of hops (humulone) (Tobe et al. 1997) and with oligomeric procyanidines (OPC) from grape seeds (Sacher 2007)
Ayurvedic spice mixture
In the trials an ayurvedic spice mixture had been used made from chili (katuviru), garlic (lasuna), turmeric (amragandhi), ginger (sunthi) and grapes (draksa). After intensive previous trials humulone had been chosen as a bitter. In classical Ayurveda fenugreek (methi) would have been taken instead.
The blend of spices was prepared in a special, modern process as quantum points (Gradl 2008). This is due to the fact that of the main ingredient chilli, ten chilli husks of the hottest kind (habanero) would have to be taken three times per week, if the effective amount from the animal trials would be converted to humans (10 habanero husks = approx. 2,500 mg capsaicin). This is unreasonable. By means of quantum point technology it is possible to reduce the necessary amount of capsaicine to between 0.25 and 0.75 mg per day, which corresponds to the contents of 40 to 120 g vegetable paprika of the hotter kind. The same applies to garlic, the second most frequently used ingredient. In this way, the smell is hardly detectable any more.
Capsaicin from chillies opens mitochondrial membranes (Mori et al. 2006). In cases of prostate cancer capsaicin reduces expression of PSA (prostate- specific-antigen) as well as AR (androgen –receptor). Diallylsulfide from garlic promotes apoptosis as well (Dorai, Aggarwal 2004). It also prevents prostate and stomach cancer. This had been demonstrated in a big Chinese trial with 5000 men and women for five years. The risk of getting cancer was reduced by 33 percent, for stomach cancer even by 52% (cit. in: You et al. 1988).
Curcumin from turmeric supports apoptosis (Taraphar et al. 2001), while 6-gingerole from ginger is anti-inflammatory and acts as an immuno modulator (Nigam et al. 2009). It is especially effective against skin (Brown et al. 2009), colon and rectum cancers (Bode 2003).
In the case of prostate cancer capsaizine reduces the expression of the PSA (prostate specific antigen) as well as the AR (androgen receptor).
Contrary to other cells, cancer cells have lost partially or completely the ability for apoptosis, the so-called suicide of cells.
Apoptosis starts by releasing cytochrom C from mitochondria to cell plasma activating caspases there. Caspases first fragment cell nuclei and later cell plasma. The fragments can be removed by phagocytes. Humulone as well as OPC play an important role to open membranes of mitochondria (Sacher 2007).
In this stage cyclooxygenase 2 (COX 2) is over-expressed (Subbaramaiha, Dannenberg 2003). Apparently, angiogenesis can be reversed by inhibiting COX (Iniguez et al. 2003).
It is important therefore to inhibit COX-2 strengthening (TH1 modulated) cellular immunity simultaneously. (Dewson et al. 2001; Maccarone et al. 1997). This is possible by using humulone the bitter of hops (Tobe et al. 1997), together with oligomeric procyanidine (OPC) from grape seeds (Fig.15).
Since permeability of mitochondrial membranes is reduces by bcl-2 and mcl-1 (being activated by leukotrienes) (Tong et al. 2002) it is important to inhibit lipoxygenase (LOX) by OPC stopping the formation of leukotrienes from arachidonic acid thereby (Holzhutter et al. 1997).
kanoSAN supports healthy cell growth and mitochondrial function