------------------------------------------------------------------------- PD AND HORMONES PART TWO OF FIVE ------------------------------------------------------------------------- -----6------------------------------------------------------------------- Date: Tue, 19 Sep 1995 01:21:23 +1000 From: Lloyd Stewart <[log in to unmask]> Subject: diamox ------------------------------------------------------------------------- To John Cottingham Here is some info about diamox / acetazolamide, no controlled trial becoz no funding and the idea seems too radical, and I am not well enough, but see the paper by Factor which made it to Medline. Forgive the translation of Ramos paper. My own comments reflect my early enthusiasm and speculation. Diamox is not a sugar pill so check the package insert if you are tempted. Angel Ramos argues for a buildup of lactate which follows if mitochondria are not working properly, but this occurs in the brain and has only recently been measrable. --------------------------------------------- Acetazolamide in a Case of Parkinson's Disease Case Report --------------------------------------------- The following is extracted from the patients own excellent written account. The author discussed the case in person with the patient, her daughter and her ophthalmologist. TAS1, an active postmenopausal grandmother, developed PD in 1984. In 1987 she was prescribed ACZ 250 mg twice daily after a corneal graft. She continued disipal TDS. Her PD improved, despite missed disipal tablets. By Dec. 1988 she was taking L- Dopa/Carbidopa (L/C) 100/25 TDS. The ACZ was ceased and 'the Parkinson's symptoms came back, in particular the rigidity of the (L) arm plus tremor returned and ..(she)... was quite depressed.....so .. commenced it again....after a short time ...was feeling well again with no sign of a tremor'. Sept 1990 ....'left off ACZ for 6 weeks and ...becoming less able to cope, losing weight.'She was too unwell to visit her neurologist. She restarted ACZ and was 'well again in two or three months.' She regained the lost weight. (1) She is stable on three L/C and ACZ 375 mg per day. She continues 'The effects of ACZ take up to 28 days to wear off...its effect on some symptoms is slow when commencing,.. the aches and stiffness of the arm (are) almost immediately relieved.' 'ACZ does not replace L-dopa ..' (She tried ACZ without L-dopa) She uses less L-dopa with more flexibility. Discussion No improvement was expected by the patient, her medical advisors not being aware of reported benefits of ACZ including less L-dopa; less tremor, aching, seborrhea, weight loss and constipation; fewer fluctuations, slower progression and better quality of life. (1) Two drug withdrawals support causation. She titrated dose, observed onset times, offset times, and L-dopa synergy. She established a window effect. She made excellent handwritten notes. She inspired others to try ACZ. LRS improved in tremor, lethargy, writing, driving and control. NZ1 developed postural hypotension, (60 mm systolic), but his tremor improved. Treatment of Parkinson's disease (PD) with acetazolamide (ACZ) was reported by Ramos (1,2) Stewart, Cuthbert and Whealing, (3) and Factor (4). Ramos supplements ACZ with partial rebreathing. He titrated dose below 125 mg per day in 8 cases. (5) ACZ and ammonium chloride cause metabolic acidosis, which hyperpolarises neurones and stimulates respiration. ACZ points to an hypoxic contribution to PD, and to prevention of some cases of PD by avoiding recurrent hypoxia, a potent source of free radicals. The diaphragm is not immune to stiffness, rigidity, poverty of movement and hyperkinesias. Respiratory control, mitochondria, and Kreb's cycle enzymes have been implicated in PD. (3). Neurones need ATP to make neurotransmitters. The proposed actions of ACZ are independent of neurotransmitter type, consistent with ACZ use in essential tremor, epilepsy,(4), Alzheirmer's Disease and Huntingdon's Chorea. (5) ACZ is used in macular oedema (CME) at 125 mg/day. (6) The mechanism may be the same. Raising pH by hyperventilation leads to neuromuscular hyperexcitability. These principles explain the paresthesiae, Chvostek's and Trousseau's signs of anxiety attacks, and the treatment of neuromuscular hyperexcitability by rebreathing or ACZ to raise carbon dioxide and lower pH. Neuronal hyperexcitability arises from hypocalcemia, calcium channel blockers, hypoparathyroidism, alkalosis, neurotransmitter deficiency or excess, insufficient ATP to drive ion pumps, and hyperventilation. Increasing [H+] causes a stabilising hyperpolarisation, Es, proportional to [H+]. Es =k[H+] Low pH stimulates respiration and cerebral bloodflow. Respiratory stimulants such as theobromine, progesterone, and ammonium chloride may improve PD (1,3) Hyperbaric oxygen is possibly therapeutic. (7) Obstructive hypoxia, (strangulation), anemic hypoxia, (CO), and histotoxic hypoxia (CO via Cytochrome C), cause PD.(3) PD and CME are reported to improve when diuretics such as thiazides, which cause alkalosis and hypoxia, are ceased. (1,8) Hypoxic theory predicts the association of hypoxic free radical damage, Down syndrome, sleep apnea, PD and Alzheimer's disease. (9,10,11) A trial of ACZ 125 mg/day, ACZ 125mg/day plus partial rebreathing, partial rebreathing, and placebo, is worthwhile. Beware of complications of ACZ including allergic, bone marrow, renal, electrolyte, and acid-base problems. Acknowledgments: The author wishes to thank Joyce Carey, Cynthia Carey, Eddie Ross and Marjory Cuthbert. Lloyd R Stewart FRACS 7 Hogan Street Box 608 Wangara tta Victoria 3676 Australia References 1.Ramos, Angel M. Enfermadad de Parkinson. Ciclo alcalosis metabolica -acidosis metabolica - alcalosis respiratoria. La Prensa Medica Argentina 1986; 73:303-307 2.Ramos, Angel M. Enfermadad de Alzheimer. Enfermadad de Parkinson. Ciclo alcalosis metabolica - acidosis metabolica - (acidosis lactica) -alcalosis respiratoria. Orientation therapeutica La Prensa Medica Argentina 1987; 74:313-317 3.Stewart LR, Cuthbert M, Whealing D. Parkinson's disease, hypoxia, lethargy, acetazolamide (diamox), hypoventilation, mitochondria and mountain climbing.In: Conference Papers of the second Australian national multidisciplinary conference on Parkinson's disease. Brisbane: Parkinson's Syndrome Society of Queensland, Box 521 Lutwyche Queensland. 1993; 108-127 4.Factor SA. Acetazolamide therapy of menstrual-related fluctuations in Parkinson's disease. Movement Disorders 1993;8:240-241 5.Ramos Angel M. Central nervous system. Atrophic degenerative syndrome. Metabolic alkalosis - metabolic acidosis (lactic acidosis) - respiratory alkalosis cycle. English draft. Buenos Aires: Angel Ramos Nunez 3649, 5to.Piso, Dpto.B 1430 Capital Federal Buenos Aires Rep Argentina. 6.Gelisken O, Gelisken F, Ozcetin H, Treatment of chronic macular oedema with low dose acetazolamide. Bull Soc Belge Ophthal 1990; 238: 153-160 7.Neretin VYa, Lobov MA, Kotov SV,Cheskidova GF, Molchanova GS, Safronova OG. hyperbaric oxygenation in comprehensive treatment of Parkinsonism. Neurosci. Behav. Physiol. 1990; 6:490-492 8.Stewart, LR. Sleep apnea precedes mild Parkinson's disease by two decades. Poster Presentation, Annual Scientific Congress, Royal Aust. College of Ophthalmologists, Hobart,1993. Unpublished. 9.Brown, P. Rescuing minds from disease and decay. New Scientist 1992; 14 Nov: 2-7 10.Marcus CL, Keens TG, Bautista DB, von Pechman WS, Ward SL. Obstructive sleep apnea in children with Down syndrome. Pediatrics 1991;88 1:132-139. 11.Vieregge P, Ziemans G, Freudenbererg M, Pionski A, Muysers A, Schulze B. Extrapyramidal features in Down's syndrome: clinical evaluation and family history. J. Neurol. Neurosurg. Psychiatry. 1991 1 34-38. 12.Da Costa JL. Chronic hypoventilation due to diminished sensitivity of the respiratory centre assosciated with Parkinsonism. Med. J. Aust, 1972, 1: 373-376. --------------------------------------------- Appendix 1 Paper by Angel Ramos --------------------------------------------- Author: Ramos, Angel Nunez 3649 -p.5o - "B" Cod. 1430 - Buenos Aires Argentina Phone 542 5267 Title: Parkinson's Disease. Cycle Metabolic Alkalosis Metabolic Acidosis Respiratory Alkalosis. Treatment with Acetazolamide Prensa Med. Argent.,73: 303, 1986 Abstract: The study of the arterial blood gases and and electrolytes performed three times a day at 4 hourly intervals in two patients diagnosed with Parkinson's Disease confirmed that the acid base balance and electrolytic equilibrium suffered changing values. Based on these results and with the purpose of interfering with the "metabolic alkalosis - metabolic acidosis - respiratory alkalosis cycle " ( Met Alk - Met Acid - Resp Alk.), the supposed physicopathogenic mechanism, the patients were treated with Acetazolamide. Clinical improvement strongly supported the hypothesis which resulted from treating another patient with ammonium chloride. Introduction The summary of a previous article said "Perhaps the changing acid base state with its inherent metabolic alteration described in the first case, PD stage 3 (pronounced change in the posture, with moderate general motor incapacity) explains the pathophysiology of Parkinson's disease (PD). Also, the pathology results and the clinical findings are in close relation with the time of respiratory alkalosis (Resp Alk), with the reduction of ionic calcium and the consequent neuromuscular hyperexcitability which involves skeletal and smooth muscle." "The fact that clinical tetany does not occur indicates that in the first stages of the disease there is moderate neuromuscular hyperexcitability. The aim is to explain how cyclic acid base changes cause the neuromuscular hyperexcitability. There is no possibility of renal compensation (relief) since renal compensation occurs after 2-3 days of stable acid base changes. (The acid-base changes are not stable so renal compensation does not occur.)" "It has been said that respiratory compensation of metabolic alkalosis is practically non existent." "In considering the second case, stage 5 (complete immobility), it can be said that the clinical spasm and the state of muscular contraction would be explained by a major neuromuscular excitability as a result of the preponderance of the state of metabolic alkalosis." Casuistic 1st case MP 71 years of age. No significant personal or family antecedants (history) The start of her suffering began 1.5 years ago when a tremor was noted on the left hand and a stiffness on the right, also salivary incontinence. Her daughter in law reported that for more than 15 years the patient showed lack of facial expression. She was treated with carbidopa-levodopa 250 mg three times a day, and one tablet of hyperiden chlorhydrate daily. Due to intolerance the carbidopa-levodopa was reduced to 2 times a day. No improvement whatsoever. Clonidine chlorohydrate of 0.075 mg and chlortalidone were prescribed for the treatment of moderate hypertension. The kind of deambulation noted was heavy legs, instability and the need to stop walking every 10 meters. Micturition no change. Constipated, enemas every 3-4 days. But in the last 4-5 months a difficulty in speaking was noted, and increased tremor of both lips. Lost 10 kg weight in two years. Deafness in the left ear. Complains of general weakness and easily tires. Hoarse voice. Physical state leathery, seborrheic skin, less pronounced on the forehead. Present on the eyebrows and the external part of both eyes. Fixed expression. Does not blink. Movements of the lips mimic the mouth of a fish, loss of saliva, tremor in tongue, monotonous voice, low and lacking in intensity. The right hand did not move spontaeneously, tremor of L hand,Tendon reflexes increased. (Tendon hyperreflexia). Respirations 23 per minute, pulse 78. Diagnosis Parkinson's disease between clinical stages 1 and 2. They stopped the clonidina-chlortalidona because the chlortalidone is capable of originating and maintaining a state of metabolic alkalosis. The laboratory results on 21-1- 85 show: complete hemogram, blood chemistry, enzymes, proteinagram, and analysis of urine within normal limits. Results of arterial gases and electrolytes - done at 10:00 hrs, 14:00 hrs and 18:00 hrs of the same day are the following as shown in figure 1- 10:00 hrs pH 7.45, pCO2 29 show Respiratory Alkalosis, the HCO3- 20 and base excess -3 mEq show a state of Metabolic Acidosis compensating mechanism. pO2 95 mmHg. Anion not measured (AG) within normal limits. Lactic acid 16 (normal between 6 - 18 mg%) NA+ 140, K+ 4.6, Cl- 111 Figure 2 pH 7.46 pCO2 33 Resp Alk HCO3- 24 and base excess +0.5. Shows a state of Respiratory Alkalosis, having the relieving Metabolic Acidosis disappeared. The AG and the lactic acid continue within normal limits. pO2 70 mm Hg, K+ 3.2. Hypopotassemia through intracellular migration caused by the uncompensated Respiratory Alkalosis. Figure 3 H 7.45, pCO2 33, HCO3- 24, excess base +0.5 Same as the previous. Respiratory Alkalosis no relief. pO2 60, Na+ 148 , K+ 3.1 Cl- 111. Discrete hypernatraemia and hyperchloraemia with hypopotassemia. The values of pO2 of 95, 70 and 60 showing a decrease into respiratory insufficiency (Respiratory Insufficiency pO2 between 50 and 80 mm Hg ) until now of unknown origin. The lactic acid and AG continue within normal limits. In summary, the results obtained show a state of Respiratory Alkalosis relieved (compensated) which at the end of 4 hours was converted to no relief (compensation), a state which was maintained 4 hours later. It is repeated that the hypopotassemia is the result of the Respiratory Alkalosis; ignoring the origin of respiratory insufficiency. On the basis of the theory confirmed in the publication mentioned, and inasmuch as Respiratory Alkalosis by deviation to the left of the dissociation curve of oxyhaemoglobin is capable of provoking an increase in Lactic Acid, Metabolizing Lactic Acid increases HCO3- with consequent Metabolic Alkalosis and with the deviation to the left of the oxyhaemoglobin curve will provoke in the same way an increase in lactic acid. (The oxygen is bound more tightly to haemoglobin and not available to the tissue. Anaerobic metabolism produces lactic acid. Metabolism of Lactic Acid increases HCO3- and furthur metabolic alkalosis which binds oygen even more tightly to haemoglobin) The use of acetazolamide, strong inhibitor of carbonic anhydrase, is considered a logical attitude or position, which on preventing the reabsorbtion of HCO3- at the level of the renal tubes will impede the Metabolic Alkalosis condition and at the same time compensate for the Respiratory Alkalosis. On May 10 1985 she was prescribed acetazolamide 125 mg twice daily and KCl 12 mEq daily. Followed with carbidopa-levodopa 250 mg twice daily, hyperdino hydrochloride x 1 and clonidone x 1 for her arterial hypertension. On May 22 1985 the patient expressed that she felt more comfortable, enthusiastic and happy, that the stiffness of the right hand lessened, and the left hand trembled less, without things falling from her hands, spoke better, and the tongue trembled less and was softer. The abnormal movement of the upper lip disappeared, the lower lip feeling less hard, her walking was easier and more stable and steps more continuous and not hesitant. She was able to do house chores which she could not do before. The skin lesions on the forehead, eyebrows and on the external angles (corners) of both eyes disappeared as well as the leathery/greasy skin. The bowel movement became practically regular. Her son confirmed the observations, noting that she was more confident and more lively. The physical examination confirmed all the results objectively. The tendon hyperreflexia lessened, patient showed happiness with smiles and laughter, something which was not noted during previous visits. The second dose of 125 mg of acetazolamide was stopped. On May 27 1985 the patient lost the improvement gained before. She was put back to Acetazolamide 125 mg twice daily and with it the improvement was progressively reestablished. On July 5th the improvement was maintained, gaining 7 Kg of the weight previously lost. Respiratory frequency was 18 per minute interval. A third dose was given of Acetazolamide of approximately 60 mg and the KCl was increased to 20 mEqu a day. July 11 1985 the abnormal lip movements totally disappeared. In the publication mentioned it was suggested that the pathophysiology of Parkinson's Disease developed as a result of the unavoidable disequilibrium of acid-base and electrolytes, the installation of the cycle Metabolic Alkalosis- Metabolic Acidosis- (Lactic Acidosis)- Respiratory Alkalosis, more pronounced in the patients in the intervening (or middle) evaluative stage. With regard to the objective of this communication the ionogram and the arterial gases displayed the authentic instability of the acid-base and electrolyte equilibrium. >From the condition of Respiratory Alkalosis with Metabolic Acidosis, in 4 hours converting to uncompensated Respiratory Alkalosis with hypopotassemia and distinct respiratory insufficiency. Four hours later the unrelieved respiratory alkalosis was maintained with hypopotassemia and distinct respiratory insufficiency. Four hours later the unrelieved Respiratory Alkalosis was maintained with hypopotassemia and respiratory insufficiency a little more pronounced. The Respiratory Alkalosis is the cause of the Lactic Acidosis, in Lactic Acidosis by the metabolism of the Lactic Acid, the HCO3- was increased , which in sufficient level produced the Metabolic Alkalosis, giving the conditions for the existence of the previously described cycle. The clinical improvement obtained with Acetazolamide and KCl validated the physicopathogenesis mentioned in the original publication. The worsening occurred with the lessening of the dose of Acetazolamide to half and the reestablishment of the initial treatment improved the condition. There was nothing that disproved it, and the Acid- Base and electrolyte changes are supporting evidence. As a result of this, in regard to the physical area she uses her capacity to demonstrate facial state (expression), of mental concentration, anger and happiness (the patient lost her facial inexpressiveness). In the sensory area greater sensitivity to temperature when the climate changed. (and better temperature regulation ? LS) >From the point of view of the nervous system of the vegetative state the facial greasiness/leatheriness/seborrhea disappeared. The bowel movement also becoming regular. The respiratory frequency was 23 per minute interval, decreasing to 18 per minute interval. >From the point of view of the nervous system the decrease of the hypertonia of the lower extremities permitted ambulation without hesitation and with agility. There was no need to stop the walking movement and then to start again. The lessening of the stiffness of the left hand permitted the performance of manual chores which she could not do before. The loss of the (abnormal) movements of the lips enabled the mouth to be closed, therefore avoiding loss of saliva. The voice lost the monotony apparent at the start of the treatment. From the treatment it can be said that the sick person was capable of improving quickly as mentioned in the results of the prescribed medication on the A-B and electrolyte equilibrium. On the other hand, the dynamic condition controls the clinical condition of these patients, and supposedly the same condition would establish the anatamopathology which in the stage of total disorganisation, the symptoms and signs of the disease for which the injury of the secondary organs needed symptomatic treatment. The hypothetical physiopathology occurs in three movements. In Lactic Acidosis glycolysis in anaerobiosis will terminate by a reduction in the reserves of glycogen. In Respiratory Alkalosis and metabolic alkalosis the deviation to the left of the disassociation curve of the oxyhaemoglobin prevents the release of the O2 at the level of the tissue which will have more effect on the Central Nervous System because of its low reserves of glycogen. It can also be mentioned that the metabolic changes linked to the "imbalance of A-B" in the cycle,generate the physicochemical changes responsible for the emotional changes of the disease e.g. euphoria, insomnia, irritability, emotional instability, changes in personality, depression, and at times with changes at the level of the cerebral cortex, dementia conditions may follow. (It is known that anxiety is produced by Lactate, which supports Ramos' contention. My view is that the psychological changes are a complex interaction of dopamine deficiency, dopamine replacement, hypoxia, neurone loss, and biochemical changes as described by Ramos. LS) With these metabolic changes the Respiratory Alkalosis is considered separately. The known effects over the psyche are worth mentioning. For the effects of Metabolic Alkalosis a brief look at what Ramos, Angel M, has to say is in order. Among other considerations, he discusses how millions of patients are exposed to the risk of suffering mental changes due to Metabolic Alkalosis caused by the use of diuretics (thiazides, furosemide, ethacrinic acid, mercurials, corticosteroids, and ACTH.) The results merit attention because a generalised condition like the cycle Metabolic Alkalosis- Metabolic Acidosis- (Lactic Acidosis)- Respiratory Alkalosis produces the knowm pathophysiology and clinical complexity of the disease including dermatologic, urinary, oesophagus- gastrointestinal conditions, etc. It is difficult to understand and much more difficult to accept that they are a consequence of the classic description of the pathogenesis - the lessening of the nervous cellules to the level of the nucleus of Rolando, cerelious cells and other neurectodermal pigmented cells as well as the lessening of the dopamine in the nervous axons projected over the neo striatum. In brief, the classic description was only a link in a large chain, many or all of (the links) are filled in by the proposed cycle. (The cycle fills in some of the links in the chain of events of which the classic description is but a part. LS) In relation to the evolutive possibilities (possible time related changes) of the cycle there are not two patients with the same or equal clinical evolution to the state of fatal incapacity varying between 10 and 20 years, sometimes 5 years, speculatively it is said that each patient could suffer a cycle of variable intensity which in time would be conditioned to the evolutive state of the disease. In the presented patient, a case of recent diagnosis, it would seem that the component of Respiratory Alkalosis predominated. In the first case of the cited publication, a case of prolonged evolution, the cycle in toto seemed more evident. In the second case of the same publication .....in the terminal stage of the disease the metabolic alkalosis component prevailed without doubt, expressed in a permanent picture of clinical tetany. Second Case (Observation of progress) The summary of a therapeutic communication brought up to date - a patient of 66 years of age, with PD diagnosis, with 19 years of evolution and a clinical course between 4 and 5 evolutive stage. The patient had been surgically treated in both cerebral hemispheres. The electrolyte and A-B instability and the cycle Metabolic Alkalosis- Metabolic Acidosis- (Lactic Acidosis)- Respiratory Alkalosis was confirmed. The acidifying salt NH4Cl, given with the aim of interfering pharmacologically (with) the cycle's most accessible component, the Metabolic Alkalosis, fulfilled its promise. The clinical results up to the present time in their intermittent form (observations made intermittently over a period of time?) and with a variable grade and intensity of disease showed truly positive results. A concomitant clinical worsening and accentuation of the metabolic changes by excessive medication (alkali for gastric pain?) as well as the clinical improvement and the decrease of the metabolic changes by reducing the medication, the A-B instability and the clinical condition would have been directly related. The changes of the vegetative nervous system, physical and sensory areas were of such value that the patient enjoyed real independence, of which she had been deprived for 1.5 years. The patient was treated with NH4Cl 2g twice daily L- Dopa-fenserazida 1/2 tablet twice daily. KCl 20 mEq once daily. The evolution was maintained the same as was mentioned previously. The L-Dopa fenserazida was continued understanding that its action is on the level of organic lesion secondary to the physiopathogenic mechanism. On April 5 1985 a surgical procedure was performed after an accident. Under anaesthetic there was vomiting and gastric intolerance, all medication was stopped. The disease predictably fell back to the initial stage of the treatment. In these circumstances there was an opportunity to start medication with Acetazolamide, suspending the NH4Cl. The patient felt progressively better. In this instance the dose of Acetazolamide was 250 mg per day, with KCl 20 mEq per day. Discussion On continuing the treatment with NH4Cl, the clinical state improved. On stopping NH4Cl, the condition practically regressed to the pretreatment state.. Upon treating with Acetazolamide, the improvement was restabilised, and was probably superior to that obtained with NH4Cl. Once more the medication was appropriate and the truth of the hypothesis was supported Summary Two patients with PD were presented. The study of the electrolytes and blood gases three times in a day at 4 hour intervals demonstrated changes which were valuable in the management of those patients. With the aim of changing the pathophysiology they were treated with Acetazolamide which fulfilled its promise. Clinically there was improvement of the nervous system and the vegetative nervous system as well as the physical and sensory areas. The improvement of the general state of the patients was apparent. It was apparent that the patients were capable of improving in the way mentioned. This was possible on the basis that the A-B and electrolyte values changed state, the changed component prevailed over the static (normal) condition. The dynamic (changed) condition controlled the clinical disease as well as the pathologic anatomy which in time caused the symptoms and signs of the disease. The verification of the hoped for benefit signified the reality of the pathophysiolgical basis of (Acetazolamide) therapy - a therapy capable of suppressing the cause of the disease. These newly emergent diagnostic parameters provide an early diagnosis (of Acid - Base disturbance) and with it an early therapy that prevents the progression of the disease. This new therapy would supplement the present limited symptomatic therapy, limited in its effect to a general benefit only in trembling, stiffness and the complex and wide clinical picture that PD presents. Summary Two patients with PD and showing an unstable Acid Base balance with related electrolyte values were treated with Diamox. Both of them showed frank clinical improvement. Supposedly the drug interfered with the Metabolic Alkalosis - Metabolic Acidosis - Respiratory Alkalosis cycle. Verification of all of the above should signify reality of the described physiopathogenesis, consequently, diagnostic and therapeutic paramaters and with them change from a symptomatic to a more rational therapy. Comment. As a PD person who has observed many of the effects of PD in myself and others I am impressed with Ramos' clinical skill. His observations provide an explanation of hypoxia, lethargy, tremor, aches and pains, exercise intolerance,and response to Acetazolamide, observations made by myself and others independent of Ramos. Improvement of the skin condition is intriguing. The hope of a therapy that slows the progression of PD needs to be further looked at. Ramos goes as far as to suggest that neurone damage is secondary to the Respiratory Alkalosis and hypoxia. Diuretics can cause metabolic alkalosis and diminish the ability of the kidneys to respond to changes in acid base balance. The lungs are only able to compensate for alkalosis by breathing slowly to retain carbon dioxide. The oxygen level suffers in consequence. Recurrent episodes of hypoxia cause brain damage, esoecially when there is incomplete recovery between episodes. PD kidneys may be unable to respond normally to changes in acid base balance because hypothalamic and pituitary control is compromised. ACTH, ADH, and aldosterone may be involved. Aldosterone biosynthesis is inhibited by dopamine; hypoxia also effects aldosterone levels. The hypothalamus is easily damaged by hypoxia. Carbon monoxide, viral infections, mitochondrial damage and organic phosphates cause hypoxia, and the hypoxia can cause PD, as well as damaging critical brain funtions such as memory, movement and hormone funtions. Alteratively the problem may be similar to that seen in mountain climbing. PD with hypoxia, or low energy supply, (low ATP), leads to hyperventilation. Hyperventilation raises oxygen levels, but lowers CO2. Hypoventilation normalizes the CO2, but the oxygen level falls. Recurrent episodes of hypoxia lead to permanent damage, making the PD worse, or causing memory loss. Some PD people are unable to automatically increase pulmonary ventilation with exercise. They may be able to voluntarily increase ventilation and raise oxygen levels. They must remember to breathe in order to exercise. Exercise tests may be needed to diagnose cases where the response to exercise is present but diminished. Acidosis, rather than the alkalosis described by Ramos, suggests diamox be used with caution. Ramos raises the possibility of improvement in PD by paying attention to acid base balance and oxygen levels. 83 Author: Bowen BC; Block RE; Sanchez-Ramos J; Pattany PM; and others Title: Proton MR spectroscopy of the brain in 14 patients with Parkinson disease. Department of Radiology, University of Miami School of Medicine, FL. AJNR Am J Neuroradiol 1995 Jan;16(1):61-8 Unique Identifier: MEDLINE 95208543 Abstract: PURPOSE: To determine whether the proton spectra from patients with clinically diagnosed Parkinson disease differ from the spectra of age-matched healthy subjects with respect to the major cerebral metabolite resonances as well as lactate. METHODS: Fourteen patients with Parkinson disease (38 to 81 years of age) and 13 healthy control subjects (37 to 81 years of age) were studied using image- guided, single-voxel (27-cm3 volume) proton MR spectroscopy of the occipital lobe. RESULTS: The peak area ratios of N-acetyl aspartate to creatine and N-acetyl aspartate to choline for Parkinson patients did not show a statistically significant difference from the corresponding ratios for control subjects. There was a very significant increase in the ratio of lactate to N-acetyl aspartate for patients with Parkinson disease, with the greatest increase (threefold) manifested by the subgroup (n = 4) with dementia. The difference in N-acetyl aspartate to choline between women (n = 7) with Parkinson disease and healthy women (n = 9) approached significance. No dependence of the peak ratios on age, duration of Parkinson disease, or medication (L-dopa) regimen was found. CONCLUSION: Preliminary results indicating an increase in cerebral lactate in patients with Parkinson disease support the hypothesis that Parkinson disease is a systemic disorder characterized by an impairment of oxidative energy metabolism. The larger increases for Parkinson patients with dementia may be diagnostically useful in assessing clinical course and in differentiating Parkinson disease from other causes of dementia. Additional studies are needed, though, to quantitate lactate changes and identify potential contributions from lipid resonances better. ------------------------------------------------------------------------------ [log in to unmask]