Fibromyalgia dyscognition: concepts and issues.

Fibromyalgia is characterized by widespread pain and tenderness; however, comorbid cognitive difficulties are a common complaint among patients. Known as fibro fog or dyscognition, this symptom comprises difficulties with complex cognitive processes including memory, executive function, concentration and attention. While the mechanisms that initiate and maintain these cognitive deficits are still largely unknown, recent research has increased the understanding of subjective symptoms and objectively-determined deficits in cognitive performance. Treatments have also improved to include complementary cognitive and physical strategies. This review focuses on issues of dyscognition in fibromyalgia. Details of objective testing methods are not within the scope of this paper.

Pharmacokinetics and metabolism of the methyl-branched fatty acid (BMIPP) in animals and humans.

UNLABELLED: The aim of this study was to further characterize the major metabolite of 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP). METHODS: Radioactive components of 131I-BMIPP were evaluated in Langendorff-perfused rat hearts, as well as in blood samples from 20 patients after injection of 123I-BMIPP. Rat hearts were perfused with pH 7.4 Krebs-Henseleit buffer with or without 0.4 mmol/L bovine serum albumin (BSA) or 0.4 mmol/L palmitate. Lipids were Folch extracted and hydrolyzed from samples of the outflow, as well as from homogenized hearts. Radioactive components were determined by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analyses. The major metabolite of BMIPP was then further characterized by electrospray mass spectrometry. RESULTS: The rat heart perfusate showed one major polar metabolite observed by TLC (Rf = 0.35; solvent = benzene-dioxane-acetic acid 80:18:2). The addition of BSA/palmitate to the perfusate buffer significantly increased backdiffusion of BMIPP (Rf = 0.55), as well as reduced BMIPP uptake and metabolism. The major metabolite was identified by mass spectral analysis as 2-(p-iodophenyl)acetic acid (IPC2). From TLC and HPLC analyses of the serum lipids obtained from patients, the same metabolite could be identified with levels increasing over time (0%, 5.2% and 11.8% of the injected dose; 3 min, 20 min and 3 h postinjection, respectively). In addition to the identification of unmetabolized BMIPP (53.9%), the rat heart lipid hydrolysate also contained alpha-methyl-14-(p-iodophenyl)tetradecanoic acid (20.8%), 12-(p-iodophenyl)-substituted-dodecanoic (17.1%), -hexanoic acid (5.2%) and IPC2 (1.1%). CONCLUSION: The animal results show the complexity of uptake, metabolism and release of BMIPP from which a part is metabolized through alpha- and subsequent beta-oxidation to the final IPC2 metabolite as confirmed by mass spectral analysis. The results from patient studies suggest that the slow myocardial washout observed in vivo after intravenous administration of BMIPP may represent a similar process, because both unmetabolized BMIPP and the final metabolite were also identified in serum samples.

Effects of configuration on the myocardial uptake of radioiodinated 3(R)-BMIPP and 3(S)-BMIPP in rats.

UNLABELLED: Radioiodinated 3(R)-(+)- and 3(S)-(-)-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) were prepared and evaluated in rats to investigate the effects of absolute configuration of the 3(beta)-methyl group on myocardial uptake and release kinetics. METHODS: The 3(R)-(+)-BMIPP analog was synthesized by initial acylation of a thiophene template with the acid chloride of ethyl 3(R)-methylglutarate. 3(S)-(-)-BMIPP was obtained by separation from the mixture of diastereomeric amides prepared from reaction of the acid chloride of racemic BMIPP with the S-(-)-alpha-methylbenzylamine. The amide of synthetic 3(R)-BMIPP prepared from S-(-)-alpha-methylbenzylamine was identical to the chromatographically more polar isomer. Free acids were obtained by acid hydrolysis of the amides, fully characterized and then converted to the radioiodinated BMIPP isomers. RESULTS: Biodistribution studies in rats with the dual-labeled [(131)I]-3(S)-BMIPP/[(125)I]-3(R)-BMIPP mixture demonstrated greater myocardial uptake of 3(R)-BMIPP compared with the 3(S)-BMIPP isomer [60 min: 3(R)-BMIPP = 4.37 %ID/g; 3(S)-BMIPP = 3.44; p < 0.05; 180 min, 2.31 and 1.78 %ID/G, respectively, p < 0.01], although both isomers had similar myocardial washout curves (5-180 min). Percent ID/g values for other tissues which were examined (blood, lungs, thyroid) were similar. CONCLUSION: Higher myocardial uptake of the 3(R)-BMIPP isomer observed in these animal studies may suggest differences in carrier-mediated myocyte uptake of the two isomers. These studies suggest that [(123)I]-3(R)-BMIPP is a candidate for clinical evaluation and may show greater myocardial uptake than the 3(S)-BMIPP isomer and may thus require reduced injected dose.

Both total chain length and position of dimethyl-branching effect the myocardial uptake and retention of radioiodinated analogues of 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP).

Introduction of geminal dimethyl-branching into the 3-position of 15-(p-iodophenyl) pentadecanoic acid (IPPA) significantly delays myocardial clearance in rats and dogs following intravenous administration. Several new analogues of DMIPP have been synthesized and evaluated in fasted rats. The effects of both the position of dimethyl-branching and the total chain-length of 3, 3-dimethyl analogues on heart uptake and clearance kinetics have been studied. In the first series of compounds, two methyl groups were introduced into the 3-, 4-, 6-, or 9- position. Tissue distribution studies of the 15-(p-[I-125] iodophenyl)-analogues demonstrated that the position of dimethyl-branching is an important factor affecting both myocardial specificity and retention. The [I-125] labeled 3,3- and 4,4-DMIPP analogues showed higher myocardial uptake and faster blood clearance than the 6,6- and 9,9-DMIPP analogues [heart, % dose/gm heart: blood), 30 min: 3,3-DMIPP = 5.06 (12:1); 4,4-DMIPP = 8.03 (16.7: 1); 6,6-DMIPP = 2.26 (3.1:1); 9,9-DMIPP = 3.06 (2.77)]. In the second series, the effects of total fatty acid chain length were evaluated with 3,3-dimethyl-substituted analogues with C11, C12, C13, C14, C15, and C19 chain lengths. The C14 and C15 chain length analogues showed the best properties [global heart: blood ratios): 30 min: C11, 0.70 (0.82); C12, 1.25 (0.68); C13, 0.47 (0.90); C14, 1.63 (3.54); C15, 5.06 (12); C19. 1.29 (0.82). These detailed studies have demonstrated that both total chain length and the position of geminal dimethyl-branching are important structural parameters which affect myocardial specificity and retention of omega-(p-iodophenyl)-substituted fatty acid analogues and that 3,3-DMIPP and 4,4-DMIPP are the best candidates with optimal properties for further study.

Evaluation of pancreatic lipase activity by simple urine analysis after oral administration of a new iodine-131-labeled triglyceride.

A new iodine-131-labeled triglyceride analogue called "MIPAG" [1,2-dipalmitoyl-3-[(15-p-iodophenyl) pentadecan-1-oyl]rac-glycerol] has been prepared in which 15-(p-iodophenyl)pentadecanoic acid (IPPA) is attached to position-3. MIPAG has been developed for the evaluation of pancreatic exocrine function by simple urine analysis and has been evaluated in rats and humans. After oral administration, IPPA is released from the triglyceride by the action of pancreatic lipases followed by intestinal absorption and the principal IPPA metabolite (p-iodobenzoic acid, IBA) is primarily excreted in the urine. Excretion in the urine and feces was evaluated in rats, as well as the biodistribution in various organs over 21 days. Twenty patients without pancreatic disease (normals) and four patients without pancreatic insufficiency were also investigated. Following oral administration of 30 microCi of MIPAG, urine was collected for two successive 24-h periods. Blood samples were drawn and thin-layer chromatographic (TLC) analysis was performed on the serum lipid extracts. Urine from normals contained 44.9% +/- 7.7% and 61.8% +/- 8.4% of the administered activity after 24 and 48 h, respectively. The patients with pancreatic insufficiency excreted 13.1 +/- 5.6% and 18.9% +/- 6.2%, respectively, which was significantly decreased (P < 0.001) compared with normals. The TLC profiles showed an increasing proportion of IBA with time. Urine analysis after oral administration of MIPAG thus appears to be an attractive new techniques for the evaluation of pancreatic lipase activity by a simple urine analysis.

Site-specific/stable radioiodination of 1,2-Pal-3-IPPA: an agent for the potential clinical evaluation of pancreatic insufficiency by urine analysis.

To measure pancreatic lipase activity, we synthesized a triglyceride containing a radioiodinated fatty acid. The urinary excretion of radioactivity was measured in five rats following administration of the agent by feeding tube. We attached 15-phenylpentadecanoic acid (PPA) to position-3 of 1,2-dipalmitoyl-rac-glycerol (1,2-Pal) to form 1,2-Pal-3-PPA. The 1,2-Pal-3-IPPA (expected lipase substrate) was prepared by the thallation-iodide displacement method. In a dual-label study, the 125I-1,2-Pal-3-IPPA triglyceride was administered with the 131I-IPPA free acid to rats (n = 5) by oral gavage. Urine and feces were collected daily and the tissue distribution of both tracers was evaluated over a five-day period. A significant portion of the administered activity was excreted in 24 hr in the urine (125I, 30.31% + 4.32%; 131I, 35.0% + 7.29%), which cochromatographed with hippuric acid by thin layer chromatography. Release of the acidic components from the conjugated excretory products by acid hydrolysis of the urine provided the radioactive acidic metabolites. Analysis of the Folch extracts of fat samples demonstrated that the radioactive components cochromatographed in the triglyceride region. This agent appears useful for the evaluation of various gastrointestinal diseases.

Incorporation of radioiodinated IPPA and BMIPP fatty acid analogues into complex lipids from isolated rat hearts.

Heart lipids were extracted by the Folch technique from Langendorff-perfused rat hearts after administration of 15-(p-[131I]iodophenyl)pentadecanoic acid and 15-(p-[125I]iodophenyl)-3-R,S-methylpentadecanoic acid. Techniques utilizing successive high performance liquid chromatographic (HPLC) analyses have been developed for the evaluation of the uptake of the tracers into neutral lipids and phospholipids of the rat hearts. Phospholipids were separated on a SiO2 column eluted with a gradient of acetonitrile/water (97.5/2.5) and acetonitrile/water (85/15) followed by separation of the neutral lipids on a C-18 reversed phase column with a gradient consisting of acetonitrile and 2-propanol/hexane (60/40) containing 1 N H2SO4 (5 microL/100 mL). Both tracers show the incorporation into the expected major lipid classes.

Treating exposure to chemical warfare agents: implications for health care providers and community emergency planning.

Current treatment protocols for exposure to nerve and vesicant agents found in the U.S. stockpile of unitary chemical weapons are summarized, and the toxicities of available antidotes are evaluated. The status of the most promising of the new nerve agent antidotes is reviewed. In the U.S. atropine and pralidoxime compose the only approved antidote regimen for organophosphate nerve agent poisoning. Diazepam may also be used if necessary to control convulsions. To avoid death, administration must occur within minutes of substantial exposure together with immediate decontamination. Continuous observation and repeated administration of antidotes are necessary as symptoms warrant. Available antidotes do not necessarily prevent respiratory failure or incapacitation. The toxicity of the antidotes themselves and the individualized nature of medical care preclude recommending that autoinjectors be distributed to the general public. In addition, precautionary administration of protective drugs to the general population would not be feasible or desirable. No antidote exists for poisoning by the vesicant sulfur mustard (H, HD, HT); effective intervention can only be accomplished by rapid decontamination followed by palliative treatment of symptoms. British anti-Lewisite (BAL) (2,3-dimercapto-1-propanolol) is the antidote of choice for treatment of exposure to Lewisite, another potent vesicant. Experimental water-soluble BAL analogues have been developed that are less toxic than BAL. Treatment protocols for each antidote are summarized in tabular form for use by health care providers.

Effect of 3-methyl-branching on the myocardial retention of radioiodinated 19-iodo-18-nonadecenoic acid analogues.

The effect of methyl-branching at the 3(beta-)-position on myocardial uptake and retention of fatty acids where radioiodide has been stabilized as a terminal trans-(E)-vinyl iodide has been evaluated in fasted rats. The syntheses of two new dimethyl-branched fatty acids, 17-iodo-3,3-dimethylheptadecanoic acid (14) and (E)-19-iodo-3,3-dimethyl-18-nonadecenoic acid (19), are described. Tissue distribution studies in fasted rats with [125I]-19 showed significant heart uptake (2 min, 4.56% dose/g), and prolonged retention (60 min 4.10% dose-g). These results suggest that [123I]-19 is a good candidate for further studies of regional myocardial fatty acid uptake patterns by SPECT.

Effects of fasting on the myocardial subcellular distribution and lipid distribution of terminal p-iodophenyl-substituted fatty acids in rats.

The myocardial lipid pool distribution and subcellular distribution of radiolabeled methyl-branched fatty acids in rats was evaluated under conditions of fasting (24 h) and feeding. With the unbranched iodophenyl fatty acid, fasting resulted in increased myocardial extraction and clearance time with a decrease in the incorporation into triglycerides and greater radioactivity in the mitochondrial fraction. With the monomethyl-branched analogue, the effects of fasting on lipid and subcellular distribution were minor except for a decrease in triglyceride incorporation. Like the unbranched analogue, the dimethyl-branched iodophenyl fatty acid showed increased myocardial extraction with fasting, however, this structurally-modified fatty acid showed increased rather than decreased incorporation into triglycerides.

Evaluation of the metabolism in rat hearts of two new radioiodinated 3-methyl-branched fatty acid myocardial imaging agents.

The biological fate of two new radioiodinated 3-methyl-branched fatty acids has been evaluated in rat hearts following intravenous administration. Methyl-branching was introduced in [15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) and 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) to inhibit beta-oxidation. The goals of these studies were to correlate the effects of methyl-branching on the incorporation of these agents into the various fatty acid pools and subcellular distribution profiles, and to relate these data to the myocardial retention properties. The properties of BMIPP and DMIPP were compared with the 15-(p-iodophenyl)pentadecanoic acid straight-chain analogue (IPP). Differences in the heart retention of the analogues after intravenous administration in rats correlated with differences observed in subcellular distribution patterns. The dimethyl DMIPP analogue showed the longest retention and the highest association with the mitochondrial and microsomal fractions (34%, 38%) 30 min after injection. These data are in contrast to the rapid clearance of the straight-chain IPP analogue which showed much lower relative association with the mitochondria and microsomes (18%, 15%). The distribution patterns of each analogue in the various lipid pools appeared consistent with the expected capacity of the analogues to be metabolized by beta-oxidation. In contrast to the rapid oxidation of the straight-chain IPP analogue, the 3-monomethyl BMIPP analogue appeared to undergo slower oxidation and clearance, whereas the dimethyl-branched DMIPP analogue was apparently not catabolized by the myocardium. All three analogues showed some incorporation into triglycerides. The metabolism patterns of the branched analogues reported here may provide useful information in the description of the mechanisms by which BMIPP and DMIPP are retained in rat myocardium.

Effect of 3-methyl-branching on the metabolism in rat hearts of radioiodinated iodovinyl long chain fatty acids.

The metabolism of two new 3-methyl-branched iodovinyl fatty acids in rat hearts was evaluated by determining the subcellular and lipid pool distribution of these radiolabeled analogues after intravenous injection. Methyl branching had been introduced into the straight chain analogue, 19-iodo-18-nonadecenoic acid (IVN), to produce the monomethyl analogue, 19-iodo-3-(R,S)-methyl-18-nonadecenoic acid (BMIVN) and the dimethyl derivative, 19-iodo-3,3-dimethyl-18-nonadecenoic acid (DMIVN) in the hope of inhibiting beta oxidation. Since the presence of 3-methyl branching results in delayed myocardial clearance in rats, differences were sought in the lipid and subcellular distribution of these branched analogues that might correlate with the prolonged retention and reflect differences in metabolism. Hearts of rats injected intravenously with the radiolabeled fatty acids were removed and homogenized and the homogenates partitioned between the chloroform-methanol (organic) fraction and the aqueous fraction. Comparison of the distribution of radioactivity between the organic and aqueous fractions showed that most of the DMIVN and BMIVN activity was in the organic fraction with IVN activity initially divided equally between the two fractions. Identification of the lipid components of these organic fractions showed that there was slow incorporation of DMIVN into the triglyceride and polar lipid fractions with a slow loss from the free fatty acid fraction. With the straight chain IVN analogue which shows rapid washout from rat hearts, there was loss of activity from all 3 lipid components during the 60 min. The monomethyl branched BMIVN analogue demonstrated predominant storage in the polar lipid fraction with some incorporation into triglycerides.(ABSTRACT TRUNCATED AT 250 WORDS)

New radioiodinated methyl-branched fatty acids for cardiac studies.

The effects of 3-methyl substitution on the heart retention and metabolism of 3-R,S-methyl-(BMIPP) and 3,3-dimethyl-(DMIPP) analogues of 15-(p-iodophenyl)-pentadecanoic acid (IPP) were studied in rats. Methyl substitution considerably increased the myocardial half-time values in fasted rats: IPP, 5-10 min; BMIPP, 30-45 min; DMIPP, 6-7 h. Because of the observed differences in the relative myocardial uptake and retention of these agents, an evaluation of the subcellular distribution profiles and the distribution of radioactivity within various lipid pools extracted from cell components was performed. Studies with DMIPP in food-deprived rats have shown high levels of the free fatty acid and only slow conversion to triglycerides. These data are in contrast to the rapid clearance of the straight chain IPP analogue and rapid incorporation into triglycerides, and suggest that the prolonged myocardial retention observed with DMIPP in vivo may result from inhibition of beta oxidation. Subcellular distribution studies have shown predominant association of DMIPP and BMIPP with the mitochondrial and microsomal fractions, while IPP was primarily found in the cytoplasm. Because of the unique "trapping" properties and the high heart:blood ratios, [123I]DMIPP should be useful for evaluation of aberrations in regional myocardial uptake.

Potential tissue-imaging agents: 23-(trimethyl [117mSn]stannyl)-24-nor-5 alpha-cholan-3 beta-ol.

Tin-117m-labeled 23-(trimethylstannyl)-24-nor-5 alpha-cholan-3 beta-ol (2) has been prepared by reaction of trimethyl [117mSn]tin lithium with 3 beta-acetoxy-23-bromo-24-nor-5 alpha-cholane (1). Tin-117m (2) shows pronounced adrenal uptake (2.5% injected dose) in female rats 1 day after injection. Furthermore, the adrenal to liver (9.1:1) and adrenal to blood (33.7:1) ratios are high after this period. The absorbed radiation dose values from [117mSn]2 to human organs have also been estimated by using rat tissue distribution and excretion data. [117mSn]2 is the first reported tissue-specific organic radiopharmaceutical labeled with this nuclide and may have potential as an adrenal imaging agent.

Effect of cis- and trans-dichlorodiammineplatinum(II) on human tumor cell proliferation in diffusion chambers in vivo.

The cis and trans isomers of dichlorodiammineplatinum(II) (DDP) were tested for their ability to inhibit human tumor cell proliferation in vivo. Cell-impermeable diffusion chambers containing KB target cells were surgically implanted in the peritoneal cavities of Fischer rats, which were, 1 day later, given i.p. injections of cis-DDP (0.25 to 8.0 mg/kg), trans-DDP (8.0 mg/kg), or 0.9% NaCl solution. Radiolabeled cis- and trans-[195mPt]DDPs were used to monitor the diffusion of DDP within the chamber fluid and the binding or uptake of DDP by the target cells. Cell counts following injection showed that cis-DDP induced a progressive, dose-dependent loss in cell number so that, by the second day, the chambers of animals receiving cis-DDP (8 mg/kg) contained less than 10% of the cell number found in the control or trans-DDP-treated chambers. Despite the relative lack of biological activity of the transisomer, between 2- and 3-fold greater levels of 195mPt activity were detected in the fluid and target cells in chambers of animals receiving trans-[195mPt[DDP compared to cis-[195mPt]-DDP injected animals. Scanning electron micrographs of target cells from cis-DDP treated rats showed certain morphological features (cell surface blebs and the appearance of giant cells) that were not found in control target cell populations. The diffusion chamber system was shown to be a reproducible, sensitive assay system which differentiated between cis-DDP, a potent antitumor drug, and trans-DDP, a biologically ineffective isomer. In addition, it was possible using 195mPt-labeled DDP in this assay system to quantitate the relative concentrations of the two isomers both surrounding and within the target cells.

Effects of chain length and tellurium position on the myocardial uptake of Te-123m fatty acids.

A series of Te-123m-labeled fatty acids has been synthesized and studied in rats. In the series of compounds studied, the position of the Te-123m heteroatom was not as important as the total chain length, which dramatically affected the heart uptake. Five minutes after injection, significant heart uptake (1.7-2.3% of injected dose) was observed for agents with C15, C17, and C21 chain lengths, in which Te-123m replaced a methylene group in either the 6, 9, 11, or 17 positions, and the heart-to-blood ratios were high. An important observation was the prolonged retention of radioactivity for at least one hour after injection. In contrast, agents with shorter C13 chain lengths, with Te-123m in either the 6 or the 9 position, exhibited only low heart uptake (0.1-0.3% of injected dose).

Potential pancreatic imaging agents. Tellurium-123m labeled DL-alpha-amino-gamma-(phenyltelluro)butyric acid.

This report describes the first successful preparation of a 123mTe-labeled alpha-amino acid as a potential pancreatic imaging agent. Tellurium-123m labeled DL-alpha-amino-gamma-(phenyltelluro)butyric acid was prepared by basic hydrolysis of the radiolabeled 5-[beta-(phenyltelluro)ethyl]hydantoin. The hydantoin was prepared by the reacitron of 123mTe-labeled phenyltellurol, generated by sodium borohydride reduction of diphenyl ditelluride, with 5-(beta-bromoethyl)hydantoin. Tissue distribution studies in rats with the 123mTe-labeled amino acid for periods varying from 30 min to 24 h demonstrated only marginal pancreatic accumulation of radioactivity. The significant result of these studies is that a general synthetic method has been developed for the preparation of 123mTe-labeled amino acids.

Radiation dosimetry of two new tellurium- 123m-labeled adrenal-imaging agents: concise communication.

The absorbed radiation doses to humans from 23-(isopropyl[123mTe]telluro)-24-nor-5 alpha-cholan-3 beta-ol (Te-123m-23-ITC) and 24-(isopropyl[123mTe]telluro)-chol-5-en-3 beta-ol(Te-123m-24-ITC) have been calculated, based on rat biological data, to assess the relative radiation risks to humans from these two new adrenal-imaging agents. The estimated radiation doses to several critical organs have been compared with dose estimates for a variety of other radiolabeled steroids that have been designed as adrenal-imaging agents. Dose estimates to selected organs from Te-123m-23-ITC are as follows (rad/mCi): adrenals 98; ovaries 8.0; liver 1.6. Similar estimated values for Te-123m-24-ITC are: adrenals 210; ovaries 13; liver 2.0. The radiation dose estimates for these two agents are comparable to the calculated radiation doses from 6 beta-[(methyl[75Se]seleno)methyl]-19-nor-cholest-5(10)-en-3 beta-ol (Scintidren) and 19-[131I]iodocholest-5-en-3 beta-ol (NP-59), two agents currently in clinical use for the diagnosis of adrenal disease.