CHRONIC AND RECURRENT BACTERIAL CYSTITIS (RUTI)

The recurrent bacterial cystitisis an infection that affects at least 6 times a year, while chronic cystitis is a state of continuous disease, (obviously always with presence of bacteria).

Among the risk factors, some researches estimate that 20-30% of women who have had acute infections, develop a recurrent or chronic cystitis, especially those who have in the body fluids (saliva, urethral or vaginal secretion, ect.) a  poor or absent secretion of protective antigens. Researchesmade in USA have shown that 20% of women, do not secrete locally these antigens and therefore are so called not secretive. In addition, in these patients is often poor or absent the Horsfall glycoprotein of Tamm, which is producted by the kidney and released into the urine. This sialo-glycoprotein, is able to neutralize the microcrystal’s formation. As well as the antipathogen Glycoprotein GP51, his binds to Mannose sensitive lectins (Type1) of entero bacteria by preventing the bladder wall adhesion.

Other risk factors associated with RUTI in premenopausal, are the frequency of sexual intercourse, the use of spermicides, age of UTIs (if less than 15 years) and a history of RUTI in mother. In post menopauseinstead the most common risk factors are bladder prolapse, incontinence and urinary postmicturition residue.

Both the recurrent  and the chronic cystitis are treated in the same way and the aim of the treatment is the prevention of reinfection, both with chronic administration of small doses of antibiotics that by administering bladder mucosal protective substances.

PATHOPHYSIOLOGY OF CHRONIC CYSTITIS

(From Lazzeri, Montorsi: Eur. Urol. 60 (2011) 78-80)

Currently, despite the multiplicity of research, it is not entirely clarified the cascade of events that leads to the establishment of chronic cystitis disease, while the many so-called symptomatic therapies, usually fail or do not have that short term effectiveness. In the majority of patients the first cystitis event can be traced back to an acute bacterial infection, although almost all of the researchers concur to maintain (as told before) that this condition is probably resulting from a primary defect of the urothelial lining.

The Urothelium, as mentioned in the overview of Anatomy, is the sheath that from the renal pelvis coats the entire bladder. While in the past it was believed the urothelium as a simple, though very sophisticated barrier, current studies have revealed instead both his sensory function, with the ability to inform the central nervous system of thermal, mechanical, or chemical stimuli that efferent activity through the release of mediators influencing the ability of the smooth muscle cells of the bladder wall to contract.

The ability of such barrrier to maintain its protective features depends on the presence of GAGs(Glucosamminoglicano) covering with a layer “mucinous” its most superficial cells. The GAG has a multiplicity of functions and does not act only as a “physical” barrier, but also functions as a non-stick factor and as a defense mechanism against infections and irritants (e.g. alcohol, chili etc.).

The causes that may lead to the reduction or loss of the GAGs are, as mentioned above, many and not all currently still highlighted. Definitely an important role play the chronic repeated infections, but also particularly aggressive substances or ionizing radiation or chemotherapy administered for therapeutic reasons. Recent research (Rosato and: J BiolRegulHomeost Agents.2009; 23 (3): 173-80.), have made noticed, the possible decrease in bladder defenses with increased urinary infectionsin patients allergic to the nickel. In these patients is statistically significant the co presence of vaginal candidiasis, labial herpes and respiratory infections.

From the above, it is understandable as a decrease or a “hole” in the mucinous barrier of GAGs, triggers the damage to the below bladder wall with chronic neurogenic inflammation.

In this situation the toxic or rather “aggressive”substances, physiologically present in urine, come into contact with an undefended urotelium causing the activation of proinflammatory substances (neuropeptides), such as P substance, the neurokinine the bradikinina, etc. which maintain inflammation and trigger the contraction of bladder muscles.

It turns a vicious cycle in which the relaxation of these neuropeptides causes changes in urination as urgency and very frequent urination associated with pain, which follows a further relaxation of proinflammatory reactive substances (substance P bradikinine etc.), that as well as to regulate the contraction of smooth bladder muscles, result in the migration of immune cells, the degranulation of mast cells (which in turn also release proinflammatory substances). All these mechanisms ultimately cause the beginning of chronic neuritis.

In fact when the defect of GAGs persists or fails its reparative process, the chronic stimulation of suburoteliali tissue causes a hypersensitivity of the bladder with the appearance of the so-called allodinie (i.e. a pain to a stimulus that normally is not able to provoke him).

For example the physiological sensation of bladder filling that is required in normal subject to inform the brain about the need to urinate, it’s transform into a feeling of burning pain, even intense, forcing the patient to very frequent urination, which in turn cause further inflammation.

But in these cases, the injuury produced by chronic inflammation is not only located at the bladder level. In fact, as documented by Carter et al. (1996) and by Doyle et al. (1997) the release of neuropeptides into the bladder, causes in short enough time a selection of specific gene that into the spinal cord increases the number of medullary synapses which, at this point without the need of new painful stimuli, are able to provoke and maintain increased hypersensitivity.

We have to remember  that the painful signal in situations of normality, is brought up to the brain where it is processed by the limbic system which roughly can be regarded as the central management of emotions. The arrival of these pathological messages, physiologically activate behaviors that stop this pain or avoid the repetition. In these caseswe will at first manifest anxiety and then gradually, to continuing pain, anguish until panic accompanied by the radical mood changes up to a state of continuedepression.

Research in animals and humans have shown that our ability to interpret the pain decreases during the depression, resulting in a lowering of the threshold of pain. The patient then putsthe continue and spasmodic attention to his symptoms at the center of his life, which for many of them, in more serious cases, it becomes a “right” of existence.

In fact, when the pain, from a physiological reaction to a nociceptive situation, gets neuropathic, the attention to it becomes an essential component. That’s why this type of pain “inexplicably” decreases until it disappears during the night to increase when the attention of the patient is not necessarily aimed at other important engagments.

From here the common increase of pain on weekends and even more so during any “monotonous”vacation.

In patients most suffering will be gradually lost all social interests with negative impact also on family relationships.

This of course will depend on the sensitivity of potential partners, which, despite all the good will, usually fails even to realizing the drama lived by the partner. The male partners often are unable to understand how they could suddenly lose the intimacy of couple and they live the denial of sexual intercourses (frequent cause of painful stimuli), as an inexplicable and unwarranted guilt to be charged to their partner.

From all the above, it implies the need to occur as soon as possible on local inflammation primitive factors, before they in turn, as explained above, release growth stimulants of the medullary synapses.

 

THERAPY OF CHRONIC CYSTITIS

The therapy for such morbid forms of course is based on the removal of pathological factors mentioned above which can be summarized as follows:

1. sterilization of urine and obstacle to reinfection

2. protection of the bladder mucosa

3. reconstitution of parietal GAGs.

Here follows our therapeutic Protocol which we presented in 2004 World Congress of the American Urological Association, and in the same year, at the Congress of European Urological Association as “Long Lasting Therapy for Recurrent Urinary Tract Infections in Women.

Remember that before starting any treatment protocol, you must of course, try to eliminate or at least minimize, all factors predisposing illness (repeated and risk intercourses, spermicides, alteration of alvo as constipation or diarrhoea, prolapses, etc). You should also abolish lifestyles potentially damaging or predisposing to cystitis. You need drinking at least 1.5 litres of water per day.

The therapeutic Protocol consists of two different phases, of which the first (usually 10 days) is used to restore a situation of bacterial sterility of the base, whereas the second (usually 6 months) serves to keep the situation under control over time. Let us remember how important bacterial sterility is in the first stage, as we have to get in the three areas affected by the disease, i.e. the bladder, especially, but also  the vagina and the rectum.

The recommended treatment is as follows:

In the FIRST 10 days. and after an initial urine culture:

1. Quinolone Antibiotics, full dose (bladder sterilization).

2. Rifamixina, (intestinal sterilization).

3. Lactic acid, humanised and of last generation (restoration of the enteric flora).

4. Vaginal Plugs made of Lactobacillus Doderlein (sterilization and reconstitution of the vaginal flora).

5. Acidifying vaginal Tablets (protection of vaginal flora).

OVER the following 6 months:

1. Quinolone antibiotics minimum dose, administered every 3 days, even an hour before any sexual intercourse.

2. Vaginal Acidifiers to cycles of 7 days/month.

3. Waterfall D-Mannose, see below:

At the end of every month is always repeated, even in situations of perfect affluence, a urine culture with antifungal susceptibility testing in order to highlight the early appearance of asymptomatic bacteriuria resistant!

ANCILLARY THERAPIES

We associate other therapeutic defences in the presence of particularly serious or degenerate over time situations or in all patients more resistant:

1. Hyaluronic Acid & chondroitin sulphate with intra bladder instillations, see below.

2. E. Coli vaccine

3. Amitriptyline, see below.

4. Diets free of proinflammatory substances or Nickel free

5. Local treatment of trigger points (Stanford Protocol).

EXPLANATION OF SOME OF THE SETTED THERAPIES

WATERFALL D-MANNOSE

Mannose is a simple sugar or monosaccharide. It is reabsorbed eight times slower than glucose. Once absorbed, it can not be converted into glycogen and therefore cannot be used as nourishment, but it is delivered the same as in the blood and filtered by the kidneys, reaching high concentrations in the urinary tract.

The Waterfall D-Mannose is an absolutely harmless and natural substance, i.e. a nourishing element normally present in human cells. Moreover, it does not bring about the toxicity of the antibiotics. This kind of mannose is extracted from the bark of larch and is 100% pure. John Bremner and Anna McNamara have discovered that D-Mannose can bind to receptors (lectins) present in the cilia of the bacterium E. Coli (90% of urinary infections) which normally stick to the mucous membranes of the intestinal tract and urinary tract. On the contrary, the bacteria E. Coli by meeting the molecules of free d-Mannose in the urine will bind their receptors and create the complexed form Mannose + pathogen and it remains in urine flow, rather than lurk in the bladder walls. In fact, bacteria, in order to trigger the cystitis should stick to the bladder walls by lectins. This is an essential condition because a cystitis occurs. If bacteria cannot attach themselves to the bladder walls, what we get is exclusively asymptomatic bacteriuria, which should be treated in pregnancy or in recurring cystitis or in pyelonephritis.

The D-Mannose is also especially rich in Tamm Horsfall protein that has the ability to bind to bacterial lectins.

Finally, the D-Mannose inhibits the formation of bacterial biofilms. The biofilms are a prerogative of some bacteria to agglomerate in colonies and produce around these a mucopolysaccharid layer that makes them resistant to the antibiotics. In this state the bacteria lay dormant, even for months, to return to reproduce and therefore to give the disease when defences decrease (end of antibiotic therapy) or when the factors promoting the infection (e.g. mental or physical stress, the intake of irritants, etc.) increase.

HYALURONIC ACID + CHONDROITIN SULFATE (IALURILR)

The instillation into the bladder  of the combination of these two substances in a single product has the ability to significantly reduce the proinflammatory cytokine’s production in order to allow proper repair of urothelial protective layer. It must be remembered that this layer is composed of GAGs that are nothing else that hyaluronic acid and chondroitin sulfate. This layer, when compromised,  has the physiological partial capacity to recover in about 72 hours. The exogenous treatment of GAGs increases both the speed of the amplitude of reparative process, promoting the formation of a “new coat” and blocking the penetration into the walls of potentially damaging molecules.

AMITRIPTYLINE

This high-dose drug is a Tricyclic Antidepressant of older generation. However, we know well by now at least 8 years, that low-dose is a “channel blocker”, i.e. selectively blocks sodium channels (but also those of potassium and also those of calcium) present on peripheral nerve fibers. Sodium channels are responsible for the conduction of the impulse along a nerve fiber. When a nerve fiber inflames sodium channels multiply dramatically. Amitriptyline blocks sodium channels “in excess” and, thus, has on nerve fiber an anti-inflammatory effect easing the painful pulse transmission until it disappears completely. Once trapped the nerve phlogosis (inflammation), the tissue tends to return to normal conditions, since inflammation is no longer being maintained by neuropeptides released from inflamed fiber (substance P, that triggers the mast cells in the first place).

 

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