Overcoming pharmacokinetic problems in the treatment of Parkinson's disease.
Explore the source record for details and available documents.
Antiparkinson Agents↗
Biomedical subjects
M Rodriguez
Publications and source records attributed to M Rodriguez.
Algal partner regulates fungal urease in the lichen Evernia prunastri by producing a protein which inhibits urease synthesis.
Occurrence of a protein controlling urease synthesis (PIUS) at the transcriptional level in the lichen Evernia prunastri has been previously reported (Perez-Urria & Vicente, Physiol Plant 65: 433-438, 1985; id. Endocyt C Res 3: 311-316, 1986). In this work it was found that 0.1 mM cycloheximide seems to inhibit PIUS synthesis when lichen thalli are incubated on PIUS inducer, L-arginine. PIUS has been purified and characterized by PAGE, electrofocusing and amino acid analysis. It is a glycoprotein containing a homopolymer of fructose bound to the protein. PIUS has been located in whole thallus and lichenized mycobiont but remains undetectable in cultured fungi. PIUS is only detected in photobiont cells when they are axenically cultured on arginine. Thus, it is postulated that PIUS could be synthesized by lichenized photobionts from which it moves to mycobionts where it inhibits the production of fungal urease.
Amino Acids↗
Neurophysiological follow-up in a case of chronic progressive epilepsia partialis continua of childhood.
We report the waking and sleeping polygraphic and evoked potential data recorded during the follow-up of a child with chronic progressive epilepsia partialis continua of childhood (Bancaud's type II). The findings that emerged from these investigations coupled with the clinical pattern enabled us to delineate the course of this rare condition and provided clues for a tentative interpretation of the pathogenesis of the repetitive myoclonic jerks typical of epilepsia partialis continua, on which there is as yet no consensus. In our case involvement of cortico-subcortical systems seems probable.
Child↗
Gonadal influences on behavioral deterioration with aging of male rats.
There is much evidence that gonadal steroids modulate brain and behavioral development. However their possible influence on age-related deteroriation of brain and behavior has received little attention. We now present evidence that neonatal castration reduces the decline in locomotion, motor coordination, and circadian activity rhythms that normally accompanies old age in male rats. Three behavioral tests (open field, Rota-Rod, and wheel running) were conducted with aged male rats (24 months). Those castrated in the first 24 hr of postnatal life were more active in the open field (P less than 0.001) than aged rats that were sham-operated neonatally. The sham-operated aged males showed a more marked deterioration of motor coordination in the Rota-Rod (P less than 0.01) and greater disorganization of circadian wheel-running (P less than 0.05) than the neonatal castrates or than young rats neonatally sham-operated.
Aging↗
Anti-mu treatment suppresses immunoglobulin light-chain gene expression and Peyer's patch development.
Anti-mu treated mice have been used extensively as a model for suppressed B-cell development [Murgita R. A., Mattioli C. A. and Tomasi T. B., Jr. (1973) J. exp. Med. 138, 209; Manning D. D. (1975) J. Reticuloendothel. Soc. 18, 63; Manning D. D. and Jutila J. W. (1972) J. Immun. 108, 282; Janeway C. A., Jr., Murgita R. A., Weinbaum F. I., Asofsky R. and Wigzell H. (1977) Proc. natn. Acad. Sci. U.S.A. 74, 4582; Hayglass K. T., Naides S. J., Benacerraf B. and Sy M.-S. (1985) J. Molec. Cell. Immun. 2, 107; Manning D. D. (1972) J. Immun. 109, 1152; Cooper M. D., Kearney J. F., Gathings W. E. and Lawton A. R. (1980) Immun. Rev. 52, 29; Burrows P. D., Kearney J. F., Lawton A. R. and Cooper M. D. (1978) J. Immun. 120, 1526]. However, little molecular evaluation has been performed on these animals to determine the level at which B-lineage cells are arrested. Experiments reported here were designed to determine the effects of anti-mu treatment of newborn mice on Ig-specific mRNA expression in lymphocyte populations. Newborn CBA/J mice received i.p. injections of goat anti-mu IgG or non-immune goat IgG, every 2 days, from birth until age 4 weeks. The degree of B-cell suppression in anti-mu treated mice was evident by low serum Ig levels and lack of surface Ig+ cells in splenic lymphocytes. Morphologically, spleens of B-cell depleted mice were slightly reduced or normal size, while the total area of Peyer's patches (PP) was three-fold less than control mice. Spleen cells from anti-mu suppressed mice contained high levels of mu-mRNA, but markedly reduced levels of mRNA specific for other Ig heavy-chain isotypes, as determined by DNA excess dot blot and Northern blot hybridizations. RNA specific for other sequences (actin or IL-2 receptor) was not affected and hybridization to parent plasmid (pACYC) was not detected. In addition, suppression of kappa- and lambda-mRNA accumulation was evident. This was surprising, since the target for anti-mu treatment appears to be a B-cell population expressing intact surface IgM, a stage in B-cell development in which both mu- and light-chain-specific mRNA accumulation should be detected. Our results suggest one of the following models: (1) anti-mu treatment deletes all Ig+ cells from the animal, so that only mu expressing pre-B-cells remain; or (2) anti-mu suppresses B-cell development by inhibiting kappa and lambda transcription, perhaps by some feedback mechanism in which the presence of surface Ig is required to maintain light-chain transcription.
Animals↗
Update on the epidemiology of multiple sclerosis.
Neuroepidemiology has been important in providing clues about the cause and pathogenesis of multiple sclerosis. In this review, we update the incidence and prevalence rates of multiple sclerosis in Olmsted County, Minnesota, and examine the potential role of viruses, exposure to animals, toxins, trauma, and diet in the development of this disease. Diseases of probable autoimmune nature have also been linked to multiple sclerosis. These descriptive data may contribute to the formulation of testable specific hypotheses about the pathogenesis and treatment of multiple sclerosis and other demyelinating diseases.
Age Factors↗
Immunosuppressive treatment of multiple sclerosis.
Multiple sclerosis is thought, by many investigators, to be an immunologic disease. Therefore, a rationale exists for treating this disease by immunosuppressive therapy. In exacerbating-remitting multiple sclerosis, corticosteroids and adrenocorticotropic hormone are the most widely used drugs; high doses of intravenously administered methylprednisolone have recently gained favor. Chronic progressive multiple sclerosis has been treated with a number of immunosuppressive regimens, several of which have shown promise to date. Cyclophosphamide and azathioprine have been used most often and are reviewed in this report, as are other agents currently under investigation. No firm guidelines for the treatment of chronic progressive multiple sclerosis can be offered, but an approach to immunosuppressive therapy is suggested in this review.
Adrenal Cortex Hormones↗
Multiple sclerosis: basic concepts and hypothesis.
Multiple sclerosis, an inflammatory disease of the central nervous system, is characterized by primary destruction of myelin. This review covers recent advances in neuropathology, immunogenetics, neuroimmunology, and neurovirology that have provided insights regarding its pathogenesis. Three hypotheses are discussed: (1) autoimmunity, (2) "bystander" demyelination, and (3) immune destruction of persistently infected oligodendrocytes. A paradigm for induction of primary demyelination is proposed in which immune cells recognize "foreign" antigens on the surface of oligodendrocytes in the context of major histocompatibility complex gene products. The final result of this scheme may be "dying-back gliopathy," the alteration being noted first in the most distal extension of the oligodendrocyte--that is, the myelin sheaths.
Animals↗
Tubulointerstitial nephritis due to vancomycin.
Vancomycin was used to treat a patient with Staphylococcus aureus endocarditis. After 3 weeks of therapy, the patient developed a diffuse maculopapular rash, which resolved upon stopping the drug. Rechallenge with vancomycin several days later resulted in reappearance of the rash and rapid onset of acute anuric renal failure. Renal biopsy revealed acute granulomatous interstitial nephritis. This is the first report of biopsy-proven vancomycin-induced acute interstitial nephritis. Renal function should be monitored closely in patients receiving vancomycin therapy.
Aged↗
Synthesis of gastrin antagonists, analogues of the C-terminal tetrapeptide of gastrin, by introduction of a beta-homo residue.
A series of analogues of Boc-Trp-Leu-Asp-Phe-NH2, a potent gastrin agonist, were synthesized by introducing a beta-homo residue in the sequence. These compounds were tested in vivo on acid secretion, in the anesthetized rat, and for their ability to inhibit binding of labeled gastrin to its receptors on gastric mucosal cells. These analogues behaved as gastrin antagonists. The most potent compounds in this series were Boc-Trp-Leu-beta-homo-Asp-NHCH2C6H5 (10) (IC50 = 1 microM, ED50 = 0.2 mg/kg), Boc-Trp-Leu-beta-homo-Asp-NHCH2CH2C6H5 (11) (IC50 = 0.75 microM, ED50 = 0.5 mg/kg), Boc-Trp-Leu-beta-homo-Asp-Phe-NH2 (12) (IC50 = 1.5 microM, ED50 = 0.1 mg/kg), and Boc-Trp-Leu-beta-homo-Asp-D-Phe-NH2 (13) (IC50 = 2 microM, ED50 = 0.1 mg/kg). We could demonstrate the importance of the region of the peptide bond between leucine and aspartic acid and of the structure of the C-terminal dipeptide Asp-Phe-NH2, for exhibiting biological activity on acid secretion.
Animals↗
Synthesis and biological activity of some partially modified retro-inverso analogues of cholecystokinin.
Syntheses of some partially modified retro-inverso analogues of the C-terminal octa- or heptapeptide of cholecystokinin are described. These analogues (in which the C-terminal carboxamide was deleted or not) were obtained by reverting one or several peptide bonds in the parent molecule. All these compounds were able to inhibit binding of labeled CCK-8 to rat pancreatic acini and guinea pig brain membranes and to stimulate amylase release from rat pancreatic acini with various potencies. Some of these derivatives reproduce only part of the biological response of CCK on amylase release.
Amino Acid Sequence↗
Behavioral lateralization in rats and dopaminergic system: individual and population laterality.
Recently, we reported that practice facilitates the expression of the behavioral asymmetry in rats at individual and population levels. In the present study we investigated the side preference in the performance of four different tasks during 10 successive days. The practice increased individual laterality and internal consistency in all tasks. In addition, practice facilitated the expression of marked population laterality in two tasks (78.1% and 63.3% for right bias). The influence of dopaminergic systems on these behaviors was evaluated with apomorphine and with 6-hydroxydopamine lesions ipsi- and contralateral to the side preference. The results suggest that there is a presynaptic dominance contralateral to the side preference in the four tests. However, as influences of dopaminergic systems were different in each task and because the tests were unrelated, the results suggest that the behavioral laterality in rats, as in humans, is a phenomenon caused by different and relatively independent systems.
Animals↗
Desferrioxamine therapy in hemodialysis patients with aluminum-associated bone disease.
Aluminum toxicity in dialysis patients is associated with decreased bone turnover and a relative parathyroid hormone (PTH) deficiency. Desferrioxamine (DFO), a chelating agent, has been reported to improve bone histology in aluminum associated, low turnover bone disease in dialysis patients not subjected to parathyroidectomy. Information on the effect of DFO therapy on parathyroid gland function is lacking. In the present study, in addition to changes in bone histology, parathyroid gland function was evaluated in 18 hemodialysis patients with aluminum associated, low turnover bone disease (osteomalacia and aplastic bone disease) before and after one year of DFO treatment (1 to 6 g/week). Parathyroid gland function was assessed by using a calcium free and high calcium (3.5 to 4 mEq/liter) hemodialysis bath.(ABSTRACT TRUNCATED AT 250 WORDS)
Aluminum↗
Direct inhibitory effect of calcitriol on parathyroid function (sigmoidal curve) in dialysis.
The effect of intravenous calcitriol on parathyroid function was evaluated in nine chronic hemodialysis patients with secondary hyperparathyroidism. Two micrograms of calcitriol were administered intravenously after dialysis thrice weekly for ten weeks. Parathyroid function was assessed by inducing hypo- and hypercalcemia with low calcium (1.0 mEq/liter) and high calcium (4.0 mEq/liter) dialyses before and after ten weeks of intravenous calcitriol therapy. To avoid hypercalcemia during calcitriol administration, the dialysate calcium was reduced to 2.5 mEq/liter. Parathyroid hormone (PTH) values (pg/ml) from dialysis-induced hypo- and hypercalcemia were plotted against serum ionized calcium, and the sigmoidal relationship between PTH and calcium was evaluated. Basal PTH levels fell from 902 +/- 126 pg/ml to 466 +/- 152 pg/ml (P less than 0.01) after therapy without a significant change in the serum total calcium concentration. The ionized calcium-PTH sigmoidal curve shifted to the left and downward after calcitriol therapy. The maximal PTH response during hypocalcemia decreased after calcitriol from 1661 +/- 485 pg/ml before calcitriol to 1031 +/- 280 pg/ml afterward (P less than 0.05). The PTH level at maximal inhibition due to hypercalcemia decreased from 281 +/- 76 pg/ml before calcitriol to 192 +/- 48 pg/ml afterward (P less than 0.05). The slope of the sigmoidal curve changed from -2125 +/- 487 to -1563 +/- 385 (P less than 0.05). The set point of ionized calcium (4.60 +/- .11 mg/dl before vs. 4.44 +/- .07 mg/dl after) did not change significantly with calcitriol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Calcitriol↗
Silent genes in the mouse major urinary protein gene family.
To date, two classes of mouse major urinary protein (MUP)-encoding genes have been described, the expressed genes and the intervening-sequence-containing pseudogenes. The data presented in this paper define a third class, the silent Mup genes, which are potentially functional but appear not to be expressed under normal circumstances. We describe a MUP subfamily (Mup-1.5) containing two genes, Mup-1.5a and Mup-1.5b, that are nearly identical, differing at only three positions (greater than 99.9% identity) over the entire 4-kilobase (kb) transcription unit and approximately 1 kb of flanking DNA. The similarity between these two genes extends over greater than 35 kb. Using specific oligonucleotides, we have shown that the 5a gene is expressed in BALB/cByJ mice, primarily in the submaxillary gland, whereas the 5b gene is not expressed. However, we found that when a 9.4-kb DNA fragment containing the Mup-1.5b gene was introduced into the mouse germ line, mice in two of the four transgenic lines expressed this gene at a high level and with the tissue-specificity characteristic of the Mup-1.5a gene. These results suggest that the inactivity of the endogenous Mup-1.5b gene is due not to a lack of functional positive regulatory elements, but to long-range, inhibitory position effects.
Animals↗
Ultrastructural, morphometric, and immunocytochemical study of anterior horn cells in mice with "wasted" mutation.
Mice with the autosomal recessive gene "wasted" (wst/wst) manifest hindlimb paralysis and tremulousness, develop reduced secretory immune responses, and have abnormal DNA repair mechanisms. There is prominent vacuolar degeneration of neurons within anterior horns of the spinal cord and motor nuclei of the brainstem. A morphometric analysis of motor neurons in the spinal cord was performed on 2-hydroxyethyl methacrylate-embedded tissue from ten wst/wst mice, ten littermates (wst/+, +/+) without clinical deficits, and ten parental (+/+) control mice. Vacuolated neurons were present only in wst/wst mice (p = 0.0008). Fibrillary neurons were more numerous in the wst/wst mice than in littermates (p = 0.01) or controls (p = 0.007). The number of total or normal neurons did not differ significantly among the three groups. Volume measurements for normal, fibrillary, vacuolated, and total neurons were greater in wst/wst mice (p less than 0.008). Electron microscopic studies revealed vacuolar degeneration exclusively within neurons of wst/wst mice with the prominent accumulation of neurofilaments. Immunocytochemical staining of Araldite-embedded sections with monoclonal antibodies (MAb) to 68 kDa, 160 kDa, and 200 kDa neurofilament proteins showed prominent staining of vacuolated and fibrillary neurons in wst/wst mice exclusively with the MAb to 200 kDa neurofilaments. Dephosphorylation of tissue reduced the staining of 200 kDa neurofilaments in wst/wst mice. These studies suggest that phosphorylated neurofilaments may be important in events producing neuronal dysfunction. Therefore the "wasted" mutation may be an excellent model for the study of motor neuron disease.
Animals↗
Clinical pharmacokinetics of intravenous flecainide in critically ill patients.
Plasma flecainide (FLC) levels versus time were measured in a group of 10 acute myocardial infarction (AMI) patients at our Intensive Care Unit. These patients were treated with single doses of 150 mg FLC as a 30-min intravenous infusion. Mean FLC plasma concentration values at 0, 1, 2, 4, and 8 h following administration were 562 +/- 271, 342 +/- 129, 270 +/- 90m, 240 +/- 80 and 210 +/- 60 ng/ml, respectively. Flecainide pharmacokinetics fitted an open two-compartment model, with a rapid distribution phase and a slow elimination phase. Mean values for the terminal plasma half-life (t1/2 beta) was 22.0 +/- 9.7 h and the volume of distribution (V beta) was 7.99 +/- 3.02 1/kg. FLC is different to other i.v. antiarrhythmics in having a prolonged plasma half-life which is a decided advantage. In contrast to lidocaine, FLC has a pharmacokinetic profile that enables it to be used for treating ventricular arrhythmia without constant-rate i.v. infusion and without the need for complicated loading dosages in order to avoid a 'pharmacokinetic dip' over the first hour of treatment.
Acute Disease↗
Synthesis and biological activities of some cholecystokinin analogues substituted in position 29 by a beta-alanine.
Syntheses of analogues of the C-terminal heptapeptide of cholecystokinin are described. These analogues were obtained by replacing glycine 29 by a beta-alanine. The C-terminal phenylalanine amide was in some cases substituted by 2-phenylethyl alcohol and/or residues of the C-terminal tetrapeptide by their D-enantiomers. These compounds were tested for their action on stimulation of amylase release from rat pancreatic acini and for their ability to inhibit binding of labeled CCK to rat pancreatic acini and guinea pig brain membranes. Some of these derivatives behaved as CCK receptor antagonists.
Alanine↗