I haven't blogged my treatment for a while, as I've been waiting to see if I would stick with a shift in protocol. So far, still with it, so thought it might be time to report in and get other's thoughts. New folks, please read this as informational only. It does help clarify Dr. Stratton's use of the continuous rather than pulsed protocol, but the rest of the hypotheses here are presented as my own speculations, not scientific fact.I've been on the Wheldon (pulsed) CAP for over 2 years now, with the addition a year ago of 1/2 INH and some supplements added by Dr. Powell. Last spring I had really turned a corner on treatment: my pulses became relatively mild; I had recovered about 60% of functioning compared to my starting point where the cliff of disability had been right in front of me, and was able to do physical projects like my kitchen that I hadn't been able to even think about for years. Grateful, grateful, grateful. Thank you Dr.s Stratton, Wheldon and Powell, and your guiding Muses. Summer '06 was a good one for me health wise, the first in years. I hovered around 60-68% level of improvement, with some really bad days scattered in between.But then I seemed to reach a plateau. Through the fall of 2006, and various life stresses and such, I actually seemed to feel gradually worse. Dr. Powell suggested we try Rifampin to gear up treatment. I could tolerate 1/2 dose (150-mg/day) for 2 months, but never got improvements. It too made me feel worse: more brain fog and inflammation. No upside at all. And my pulses suddenly became much harder-- suggesting that the Rifampin addition was kicking more Cpn into Cryptic mode. I stopped the Rifampin at Dr. Powell's review and a bit later added 2000-3000 units of D3. Again, I felt more die-off, and clearly pulses were worse suggesting that D3 was indeed antibacterial for Cpn, but Cpn was converting to Cryptic phase in response or enhancing apoptosis. The similar reports from some others on-site (Red for example) suggested this wasn't just my personal response. This was tolerable, so I stayed with the added D and following pulses began to improve to pre-D levels.I did some thinking about this and came up with a couple of hypothesis. A discussion with Dr. Stratton when I was gathering material for the Chronic Fatigue article for the Handbook also leant some credence to these thoughts.The Two CAP versions- Continuous and PulsedRemember, we have always had two major versions of the CAP protocol (plus Dr. Powell's variations and additions which he individualizes to his patients). The most common one, especially for MS patients, has been Dr. Wheldon's pulsed treatment version of the Vanderbilt protocol. Dr. Wheldon's pulsed flagyl treatment achieves simultaneous use of all agents, but does so every 2-4 weeks. His intention with this protocol, vetted and supported by Dr. Stratton's clinical opinion, is that it mitigates the more brutal reactions to the flagyl, particularly the mass apoptosis which can be so problematic in early treatment and in certain diseases loci like the nervous system. The break in between pulses gives time for cellular clean up and replacement, and tissue repair and reorganization. This approach has been successful clinically for a large number of people, stabilizing their disease process and regaining functioning gradually over time. It is, as David intended, also the safest route for most patients. This is especially helpful when the prescribing doctors are not yet skilled in the nuances of this kind of treatment.The other CAP version is Dr. Stratton's original "continuous" treatment protocol. This is the protocol he has used in all the research done in CFS and MS. Dr. Stratton starts gradually with one of the antichlamydials (usually Azithromycin because of it's low liver toxicity), increasing dosing gradually, one agent at a time as tolerated. He then builds up until all the agents are being taken simultaneously and continuously. He continues this until no reactions are found. This is the protocol he used on his original research, and all the case studies presented. Biologically, this gives no escape route for the Cpn. He calls this putting the Cpn in "a biological conflict." He may, when no reactions are found to the basic CAP agents, then test adding a trial of stronger meds like Rifampin or Rifamycin to the ongoing CAP. The shorter time span of improvement indicated in the case studies (6-12 months) is likely due to this higher intensity protocolWe are often asked here at www.cpnhelp.org "What is the difference between the protocols given in the handbook? Why use one or the other?" We have not answered this question, feeling that the decision on this lies with the medical professional who knows the case and condition of the patient best. Clearly the predominant protocol use is of the Wheldon, pulsed protocol. It is also clear that almost all of us, regardless of disease diagnosis, require quite a period of pulsed treatment anyway, and the thought of continuous use of flagyl/tine is clearly out of the question for quite some time. I could not even entertain the possibility until two+ years into treatment.During my interviews with Dr. Stratton for the recent CFS/CPN article, I discussed these protocol differences with him and some of my own hypotheses. He felt that in a number of cases it will be difficult to completely eradicate Cpn in a pulsed treatment, which is why he has stayed with the continuous protocol for many of his patients. He felt that especially for some diseases like RA, long term CFS/FM, and certain MS cases, the tissues involved may require continuous dosing to get to adequate cryptic kill. He also said that for most patients, due to the severity of early die-off, most treatment was pulsed treatment anyway, and that he was now seeing the time frame for full treatment to be more like 4-5 years, 2-3 years pulsed and another 2 continuous treatment. He has not found ways yet to speed this process up given the toxic nature of the organism involved.Why might there be a place of diminishing returns for some of us on a pulsed treatment? Some observations & hypotheses: a) Cryptic load does is not benign just because it is low metabolizing- Cryptic Cpn have been described as "non-metabolizing" with the implication that in this state they are causing no further harm, and one can then kill them at one's leisure, so to speak, with flagyl pulses. But Cryptic Cpn is not harmless in my view. 1. First, it induces essentially "immortalized host cells." This means that those cells don't go through apoptosis, and don't get replaced with normal, healthy cells. Without this, the host cell's function is impaired and the symptoms for which they are responsible can't actually recover. 2. Additionally, I'm convinced that Cryptic Cpn is harmful. Although low metabolizing, it is not benign. It's effect continues toxic and inflammatory reactions, and degradation of tissue over time. This is completely my own speculation, as there is so little scientific data on this form of the organism. But if the bacterial envelopes of dead Cpn can cause inflammation for up to two weeks after kill (see our research section), than Cryptic Cpn could also do so by mere presence. It's just slower than an active infection, but constant. There is no research literature on this that I've found so far. The idea is based more on personal observation and the thought that the big endotoxin hit many of us get on pulses could be going on, at lower grade, just from bacterial presence in the host cell. Remember, although Cryptic Cpn is in a low metabolizing state, it is still functioning to regulate host cell genes for apoptosis. This means it's secreting something to do this. Could other things be maintaining low grade inflammation from Cryptic infected cells?b) Rate of creating "Immortalized Cells" could exceed rate of Cryptic kill- Now, the whole idea with using the protein synthase inhibitors (like doxy and azith) to block replication is to stop disease progression and create the "stringent" condition which drives Cpn RB's into Cryptic form to survive. It seems obvious from this that the Cryptic load must build up (increase) over time with antibacterial and anti-replicant agents. This means that over long pulsed treatment starting with a high bacterial load, you are creating more and more cryptic, immortalized cells. For different patients these curve ratios would be different. With many, the rate of creating immortalized cryptic loaded cells would be such that pulsing over time diminishes them. If EB's are also cleared, than fewer and fewer RB's are created, and thus fewer Cryptic cells. Episodic pulses would be enough to winnow down the Cryptic load. But, If the load of Cpn has been high to start with, the curve of creating Cryptic cells could be higher than the curve of killing these cells in a spaced out, pulsed regimen.A poor but illustrative schematic:c) TIssue saturation- The pharmacokinetics of drugs is complex. • Standard doses reach blood saturation levels, but local tissues and cells have mechanisms such as efflux pumps which work against this. • Some tissues are not well supplied with blood flow, and so concentrations may vary in different organs and tissues. • Then there is the time factor: how long must a cryptic bacteria within a host cell be exposed to the agent to reach kill? How many of the Cpn must perish in a multiply infected cell to induce apoptosis? Paron discussed this a while ago on-site, hypothesizing why certain pulses can suddenly become more difficult: it takes a couple pulses for a particular host cell to reach the tipping point for apoptosis.So, for some cases, Dr. Stratton suspects this is so in many cases of CFS or FMS particularly, pulsed treatment of flagyl/tinidazole may not be adequate to clear the high and disseminated Cpn load: either to clear the Cryptic load at the rate which it is accumulating from protein synthase inhibitors; or to reach saturation levels long enough for the penetration needed to clear it adequately from certain tissues. Treatment may require much longer constant blood saturation levels, or build up of drug levels in certain tissues to reach this tipping point. This is a matter of pharmacokinetics, i.e.. that it might require reaching tissue saturation of the flagyl/tinidazole for a longer period of time to be able to get to certain tissues (e.g.. poor circulation tissues like joints and extremities), or to overcome cellular efflux pumps, or to simply be at tissue saturation long enough to tip the balance for certain cpn infected host cells.If you look at Dr. Stratton's case reports (in the Handbook) you'll see that treatment appeared relatively short--- for those who were able to stay with it. 6-8 months. What we forget, looking at those figures, is that this was on continuous treatment, not pulsed. Now, how on earth he got patients that sick to do continuous treatment? It is probably a testimony to his persuasive powers as a physician, plus his patients bull headed stubbornness. I can only speculate. Now there's a doctor-patient relationship! No doc could have gotten me to do this at the beginning of this CAP treatment. I could not even think about doing such a thing two years ago, even 6 months ago. Without pulsed treatment I could not have tolerated CAP treatment at all. So pulsed treatment is the essential starting point no matter what.But staying on pulsed treatment might explain why certain of my symptoms were not improving after a fairly long course of pulsed treatment, or even why a gradual worsening (this is my personal evidence that increased cryptic load is not benign). Now, don't everyone go rushing off on this. Lot's of good reasons for pulsed treatment, especially when the cells effected are vital such as liver, central nervous system, heart, and so on. You don't want too fast an apoptosis until the major load is gone.N of 1 experiment-So, having been on the pulsed CAP for two years, I thought I might be ready to switch to continuous treatment with my doctor's consent. I didn't start by simply continuing a full pulse even though I was tolerating a twice a day for 7 days pulse. After all, being on a continuous dose is likely to build up effects over time, so one should take time getting into it-- if one is not an idiot, and I try to be smart from time to time. For a change I actually got smart about it. Yes, yes, amazed looks all around. I actually started February 13th, 2007 with one tinidazole a day until I felt comfortable tolerating that (little reaction). This took about two weeks. Then I added the second dose per day. I was prepared to do this on alternating days at first, but found it generally manageable to do twice a day. I have been on this since then, with one week where, for travel and business reasons, I decided to drop back to one tini per day. Interestingly, I had a distinct improvement on this one per day after 4-5 weeks of twice a day, suggesting that this continuous treatment was getting at some symptoms I had reached diminishing returns on with pulsed treatment. Here are a few specific observations of this 6-7 week trial. I compare my responses to the CAP during early pulsed treatment, pulsed treatment over time, and the current continuous treatment regime:Joints-Early pulses- I would get significant inflammation and pain in certain joints sacro-iliac & hip, knees and wrists, ankles and feet.Pulses Over time- Sacroiliac pain virtually disappeared, knee and ankle pain became diminished, usually flared for first couple days on pulse, then diminished.Over time I no longer had significant joint aching during most pulses, except for mild knee and ankle pain and some sacral twingesContinuous pulse- Joint aching and inflammation flared in knees, wrists & hands, and cervical (C 4) areas. The sacroiliac pain returned, first flaring for a week or so on the left side which then diminished, and then flaring on the right. The right side pain (and sciatic nerve pain) is just starting to diminish.Conclusion- continuous dosing was definitively increasing kill and getting much deeper into those joint tissues I had thought previously cleared. Continuous treatment actually appeared to activate inflammation and kill in one (cervical) area where I had not had significant symptoms in pulsed treatment.Soft tissue (fibromyalgia) painEarly pulses- Significant flares of pain in upper back and trapezius soft tissue, where much of my fibro pain was located.Pulses over time- this gradually diminished. I no longer had this pain between pulses, and during pulses the flare was mild in these areas. I thought it was mostly cleared area of Cpn infection. These had been the most constant areas of pain pre-treatment. Continuous pulse- pain has flared up gradually over course of continuous pulsing, with some days of very big pain/inflam flare up in these areas, and also days of improvement. As I've stayed on it, this locus has diminished so that I'm currently not getting this pain at all here.Conclusions- Again, it seems that tissue saturation is getting to layers in this locus of Cpn infection that had been significantly affected by pulsed treatment, but more recently was almost imperceptibly being winnowed down by pulsing.Cognitive fogging and energy-One of my most stubborn and persistent symptoms. Dr. Stratton assured me years ago that this too would pass with Cpn treatment, but it has held on.Early pulses- The whole CAP including pulses fogged me out more. I stubbornly gutted it out and used ADD meds to maintain adequate mental functioning. Pulses made it even worse. Improvement on these symptoms plateaued during last summer, but actually seemed to grow worse through the fall of 06.Pulses over time- I'd reach a point day 3-5 of pulses where I'd get much clearer mentally and have surges of physical energy. These improvements would diminish between pulses.Continuous pulse- These were initially worse on continuous treatment. Two weeks ago I went from 2 tini a day to 1 tini a day as I was teaching a major presentation and didn't want to fight the full dosing. I had more energy and mental clarity than I'd had for a long time, suggesting that the continuous treatment was doing some real good for this symptom, although it wasn't yet apparent full dose continuous treatment and the subsequent increased, temporary, toxin load.Conclusions- Whether it's over-all lowering of bacterial load, and thus of porphyrins and cytokines, or that continuous treatment is getting into brain areas effected by Cpn, this seems to be reaching these more intractable symptoms.Urinary SymptomsLike the brain fog, these have been one of my earliest (pre CFS, most persistent and intractable symptoms.Early pulses- I would get some flare of these symptoms during pulses.Pulses over time- Again, flares during pulses, but no improvements between pulses. These symptoms had actually gotten worse by fall '06, suggesting to me that the build up of cryptic load was actually increasing symptoms. Of course, it could be that Cpn was simply not the problem here. It doesn't cause everything, does it?Continuous treatment- Actually worsened these symptoms initially. What gives me hope about this is that during my week of single tini dose a day I had noticeable improvement in these symptoms for the first time! So if I hang with it, once the localized inflammation from die-off is cleared, I expect some improvement in urinary symptoms.Conclusions- My guess is that continuous treatment is causing gradual kill of cryptic Cpn, initiating more inflammation in the urinary system and thus worsening symptoms, but is doing so by reaching tissue saturation levels I could not get with pulsed treatment. I would expect very gradual improvement of these symptoms over a number of months if this is true. We'll see.Additional observations: There has been episodic flaring of "bad days" on continuous tini treatment. There is no pattern to this, but generally it seems about every two weeks I have really good days, and similar a difficult day with of inflammatory flares, brain fog, etc. Seems more cytokine/endotoxin than porphyric.Tentative hypotheses: suggestive that there is a build up of effect for certain cells, and that even in a constant saturation model, not all tissues hit kill effect at the same time-- perhaps not all tissues actually saturate, perhaps there is some tipping point (as Paron has suggested) for apoptosis-- killing enough Cpn in the cell before apoptosis occurs-- or perhaps for other metabolic reasons, such as improvement of immune response, stress, etc.Dr. Stratton's emerging views:I'm presenting this in my blog rather than in the Handbook as I'd like to see more comments before editing this into the protocol recommendations.Discussing this with Dr. Stratton while gathering information for the the CFS/FMS article, he noted the following: • Pulsed therapy may be sufficient for a large number of patients, especially where Cpn load is lower or more in focal tissues. • Pulsed therapy is the required actuality anyway even if one is gearing for eventual continuous treatment, as this is the only initial approach tolerable for most patients. He is very appreciative of Dr. Wheldon's perspicacity in developing this approach. • Pulsed therapy is also required where tissue repair and replacement is slower, as with neurological tissues. • He is not yet convinced that ending a pulsed therapy with intermittent is sufficient to clear all the Cpn from tissues, and would expect that after intermittent therapy is finished, patients may require periods of CAP treatment again if they notice any return of symptoms. • Continuous therapy is probably required at some point for patients with higher load, or certain tissues infected, especially in CFS and FMS cases. If symptoms are still dragging after two years of pulsed treatment, then it's time to move to continuous treatment. Dr. Stratton's description of CAP treatment is more like this: 1-2 years of pulsed treatment followed by 1-2 years of continuous treatment. Schematically, It would look like this:Compare this to the pulsed treatment approach:I'll be interested in the ensuing discussion of this blog. Remember, this is an initial report... don't try this at home! The particular versions and timing of CAP treatment have always been individual. There is no "one size fits all." The information given here at www.cpnhelp.org and elsewhere is a starting point, but should not be limiting points for knowledgeable physicians and patients. As for my own treatment, we shall see. I'm never satisfied with my own state of affairs and always push the limits. I like to think I'm tenacious, but "bull headed stubbornness" has also been applied by those who know me well. As a Taurus, I accept the title.