Maintained improvement with minocycline of a patient with advanced Huntington's disease

We present the case of a patient with advanced Huntington's disease treated with minocycline. Minocycline (but not tetracycline which does not cross the blood-brain barrier) appears to increase longevity in an animal model for Huntington's disease. The patient has been maintained on minocycline for more than 1 year with positive effects. Cessation of minocyclin for 3 weeks resulted in an exacerbation of symptoms. The animal studies have suggested that minocycline may prevent progression of Huntington's disease and other neurological disorders. By contrast, this present result suggests that minocycline may benefit those with advanced Huntington's disease and can be used safely in these patients.     

Citalopram-induced priapism

Citalopram is a relatively new selective serotonin reuptake inhibitor (SSRI) that is becoming widely administered for the treatment of depression. Selective serotonin reuptake inhibitors generally are associated with mild adverse sexual side effects; however, more serious reactions may occur. A 58-year-old man experienced priapism several hours after inadvertently taking three tablets of citalopram 20 mg, which he had mistaken for aspirin, in addition to his usual dosage of 20 mg twice/day. Three days later, he was hospitalized and treated with intracavernous phenylephrine. He ultimately required surgical intervention. Although the citalopram overdose appears to be largely responsible for the patient developing priapism, he also was taking tamsulosin 0.4 mg/day at bedtime for benign prostatic hyperplasia. As alpha1-blockers have been associated with priapism on rare occasions, tamsulosin may have been a contributing factor. The patient also had a history of priapism associated with trazodone. Health care professionals should vigilantly monitor patients who take citalopram in high dosages or in combination with other drugs associated with priapism. Patients who have a history of priapism with other drugs may be more susceptible to citalopram-associated priapism.     

Lack of effect of nizatidine-induced elevation of gastric pH on the oral bioavailability of dapsone in healthy volunteers

STUDY OBJECTIVE: To investigate the effect of histamine2 (H2)-receptor antagonist-induced elevation of gastric pH on oral bioavailability of a single dose of dapsone 100 mg. DESIGN: Prospective, randomized, crossover, open-label, single-dose pharmacokinetic study. SETTING: Teaching hospital. PATIENTS: Sixteen men were enrolled in the study; data from 11 subjects were evaluable. INTERVENTIONS: Participants received two treatments separated by at least 14 days. Treatment A consisted of a single dose of dapsone 100 mg. Treatment B consisted of a single dose of dapsone 100 mg plus two doses of oral nizatidine 300 mg administered 3-4 hours apart to maintain gastric pH above 6.0. Plasma samples collected before and up to 120 hours after dapsone administration were analyzed for dapsone and monoacetyldapsone (MADDS) by high-performance liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental analysis. MEASUREMENTS AND MAIN RESULTS: Gastric pH in the first 6 hours after dapsone administration was above 6.0 for a mean +/- SD of 1.1% +/- 2.9% of the time in the absence of nizatidine and 69.5% +/- 18.0% of the time during nizatidine therapy. The geometric mean dapsone maximum plasma concentration (Cmax) declined by 13% (p<0.01), and median time to Cmax occurred 2 hours later (p<0.01) with nizatidine coadministration compared with dapsone alone. Inclusion of the 90% confidence interval for the mean Cmax ratio within the equivalence interval of 0.8-1.25 demonstrated the lack of clinical significance for this modest decrease in Cmax. Neither the area under the dapsone plasma concentration-time curve from zero to infinity nor the elimination half-life of dapsone were significantly altered by nizatidine. No clinically significant changes were observed in the pharmacokinetics of MADDS with regard to coadministration of nizatidine. CONCLUSION: Elevation of gastric pH by H2-receptor antagonists, such as nizatidine, does not result in clinically important changes in the rate or extent of oral dapsone absorption.     

Pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso adults and veterans of operation Ranch Hand

A combined analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elimination in Seveso adults and Ranch Hand veterans found a period of fast elimination within the first 0.27 years after exposure in Seveso, followed by a period of slower elimination between 3 and 16.35 years from exposure. The mean TCDD elimination rate within the first 0.27 years after exposure among six adult males in the Seveso cohort was 2.0646 year(-1) (half-life=0.34 years). The mean rate from 3 to 16.35 years was 0.1011 year(-1) (half-life=6.9 years). The mean Ranch Hand elimination rate, 00924 year(-1) (half-life=6.9 years), measured between 9 and 33 years after exposure, was significantly less than the Seveso mean in the first 0.27 years after exposure, but not significantly different from the Seveso mean between 3 and 16.35 years after exposure. The fast elimination within the first 0.27 years followed by a slower rate after 3 years is consistent with the expected pattern in a two-compartment open model, with a distribution phase of rapid elimination followed by a slower elimination phase.     

PF4, a FMRFamide-related peptide,gates low-conductance Cl(-) channels in Ascaris suum

Here we describe the actions of the peptide Lys-Pro-Asn-Phe-Ile-Arg-Phe-NH(2), or PF4, on inside-out membrane patches (n=164), recorded from vesicles derived from Ascaris suum somatic muscle cells. We observed numerous, small-amplitude Cl(-) channels in the membrane patches. The conductance of the Cl(-) channels ranged from 1.09 to 7.07 pS, the open probability (P(open)) ranged from 0.047+/-0.015 (mean+/-S.E.M.) at 0 microM PF4 to 0.156+/-0.026 at 0.1 microM PF4. The channel mean open time was more variable and prolonged at negative potentials than when the membrane patch was clamped at positive potentials: at 0.03 microM PF4, the mean open time (+/-S.E.M) at -80 mV was 522+/-333 ms; at+80 mV, it was 25+/-7 ms. When patches were isolated from the parent vesicle, there were no changes in channel characteristics, suggesting that the channels function without the involvement of cytoplasmic components. Similarly, the channel characteristics were not affected by the G-protein inhibitor, guanosine-5'-O-(2-thiodiphosphate), indicating that the ion channels do not require a G-protein to function. These data indicate that the PF4-activated Cl(-) channels function independently of intracellular signal transducers and are, therefore, directly gated by PF4.     

Characterization of Mycotypha metabolites found to be inhibitors of cell adhesion molecules

Three inhibitors of cell adhesion based on LFA-1/ICAM-1 were isolated from the cultured broth of the fungal strain Mycotypha sp. UMF-006. These compounds were identified by spectroscopy to be cytochalasin E (1), 5,6-dehydro-7-hydroxy derivative of cytochalasin E (2) and delta 6,12-isomer of 2 (3). All these components inhibited adhesion of HL-60 cells to CHO-ICAM-1 cells at IC50 values of 30 micrograms/ml for 1, 75 micrograms/ml for 2, and 90 micrograms/ml for 3.     

Structural basis of RasGRP binding to high-affinity PKC ligands

The Ras guanyl releasing protein RasGRP belongs to the CDC25 class of guanyl nucleotide exchange factors that regulate Ras-related GTPases. These GTPases serve as switches for the propagation and divergence of signaling pathways. One interesting feature of RasGRP is the presence of a C-terminal C1 domain, which has high homology to the PKC C1 domain and binds to diacylglycerol (DAG) and phorbol esters. RasGRP thus represents a novel, non-kinase phorbol ester receptor. In this paper, we investigate the binding of indolactam(V) (ILV), 7-(n-octyl)-ILV, 8-(1-decynyl)benzolactam(V) (benzolactam), and 7-methoxy-8-(1-decynyl)benzolactam(V) (methoxylated benzolactam) to RasGRP through both experimental binding assays and molecular modeling studies. The binding affinities of these lactams to RasGRP are within the nanomolar range. Homology modeling was used to model the structure of the RasGRP C1 domain (C1-RasGRP), which was subsequently used to model the structures of C1-RasGRP in complex with these ligands and phorbol 13-acetate using a computational docking method. The structural model of C1-RasGRP exhibits a folding pattern that is nearly identical to that of C1b-PKCdelta and is comprised of three antiparallel-strand beta-sheets capped against a C-terminal alpha-helix. Two loops A and B comprising residues 8-12 and 21-27 form a binding pocket that has some positive charge character. The ligands phorbol 13-acetate, benzolactam, and ILV are recognized by C1-RasGRP through a number of hydrogen bonds with loops A and B. In the models of C1-RasGRP in complex with phorbol 13-acetate, benzolactam, and ILV, common hydrogen bonds are formed with two residues Thr12 and Leu21, whereas other hydrogen bond interactions are unique for each ligand. Furthermore, our modeling results suggest that the shallower insertion of ligands into the binding pocket of C1-RasGRP compared to C1b-PKCdelta may be due to the presence of Phe rather than Leu at position 20 in C1-RasGRP. Taken together, our experimental and modeling studies provide us with a better understanding of the structural basis of the binding of PKC ligands to the novel phorbol ester receptor RasGRP.     

Selective down-regulation of c-jun gene expression by pentoxifylline and c-jun antisense interrupts platelet-derived growth factor signaling: pentoxifylline inhibits phosphorylation of c-Jun on serine 73

Platelet-derived growth factor (PDGF) signals through several pathways, including mitogen-activated protein (MAP) kinase, Jun kinase, and C kinase, and stimulates proliferation of fibroblasts. Pentoxifylline inhibits PDGF-driven proliferation of fibroblasts. We have reported that pentoxifylline did not inhibit binding of PDGF to its specific cell-surface receptors or PDGF receptor phosphorylation. In this study, we investigated the effect of PDGF on the expression of c-fos and c-jun, because c-fos and c-jun form activator protein-1 complexes that stimulate genes involved in proliferation. We determined whether pentoxifylline would alter the expression of c-fos and c-jun. Our results indicate that PDGF induced the expression of both c-fos and c-jun. Pentoxifylline effectively reduced c-jun gene expression, which had been up-regulated by PDGF, but did not alter c-fos gene expression. The lack of effect on c-fos supports other studies from this laboratory, which indicate that pentoxifylline did not inhibit PDGF activation of MAP kinase. Treatment of fibroblasts with a phosphothioate c-jun antisense oligodeoxynucleotide reduced the levels of c-Jun protein and blocked PDGF-stimulated proliferation, suggesting a critical role for c-jun in PDGF-mediated proliferation. Combination of pentoxifylline and c-jun antisense suggested that they were likely inhibiting PDGF-stimulated proliferation at a single site in the PDGF signaling pathway. These results suggest that pentoxifylline inhibits PDGF-stimulated proliferation by selectively decreasing c-jun expression. To further define the mechanism of action of pentoxifylline, we assessed the effect of pentoxifylline on c-Jun and phosphorylated c-Jun immunoreactivity in cells treated with PDGF and cells that were transfected with wild-type c-jun plasmid using immunocytochemistry and Western blot analyses, and our results indicate that pentoxifylline inhibited phosphorylation of c-Jun on serine 73.     

The community epidemiology work group approach

"Drug abuse" provides many unique challenges to the research community. Some of these involve fundamental epidemiologic issues, such as measuring the extent of the problem, identifying and assessing changes in patterns and trends, detecting emerging "drugs of abuse", characterizing vulnerable populations and determining health and social consequences. A number of research methods are employed to address these issues. This paper describes one of these--a model in which ongoing surveillance of "drug abuse" is maintained through a network of community-based researchers, local officials, academics, and other interested and qualified members of the community. Timely, accurate, and cost-effective data can be generated through systematic collection and analysis of indirect indicators of "drug abuse" that are often routinely produced by a variety of community sources. This information, in turn, can be used to make informed public health policy decisions. The community-based network model has been implemented at the city, state, national, regional, and international levels, and a case is made that this type of program could be useful, as well, in understanding the dynamics of "drug abuse" in rural areas of the country.     

Medical outreach to homeless substance users in New York City: preliminary results

An innovative, experimental, medical out-reach initiative, using a fully-equipped mobile medical van with a staff of 2 part-time physicians, a physician assistant, a social worker, and a driver/medical aid serving the needs of 1048, mostly male, minority group, high-level, homeless New York City substance users with infectious diseases is described. The study sample (N = 250) was divided into experimental S's who received Intensive case management and a control group who could choose to refer themselves to the SW. Biological tests revealed high rates of cocaine use and infectious diseases. Preliminary 4-month outcomes (N = 128) showed reductions in drug use, homelessness and health complaints in both groups; experimental subjects compared with controls received more Public Assistance and had fewer emergency room visits.