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Biomedical subjects

A D Dean

Publications and source records attributed to A D Dean.

At least 19 recordsLinked to original sources
PubMed2001

Safety, tolerability, and pharmacokinetics of remacemide in children.

Eleven patients (nine males, two females), 9-14 years of age, received adjunctive therapy with remacemide in an open ascending-dose study at two residential centers in the United Kingdom. Children taking enzyme-inducing drugs were given remacemide twice daily, starting at approximately 4 mg/kg per day and doubling the dose at two weekly intervals to a target dose of approximately 16 mg/kg per day. Children not taking enzyme-inducing drugs (n = 5) received half of these doses. After the dose-escalation phase, remacemide was slowly withdrawn over 2 weeks except in two children who, because of apparent benefit, entered a continuation phase. Remacemide generally was well tolerated in doses up to 13.5 mg/kg per day. Adverse events were similar to those reported in adults, with central nervous system and gastrointestinal events being the most common. One patient died after a suspected seizure, which was unlikely to have been related to remacemide treatment. No adverse effects on neuropsychologic functioning were observed; effects on vital signs and laboratory variables were not clinically significant. The pharmacokinetic profile for remacemide and its desglycinyl metabolite in children is similar to that seen in adult patients. Plasma concentrations of remacemide and the desglycinyl metabolite are reduced in the presence of concomitant antiepileptic drugs with hepatic enzyme-inducing activity.

Acetamides↗
PubMed1997

Low NO concentrations inhibit osteoclast formation in mouse marrow cultures by cGMP-dependent mechanism.

High concentrations of nitric oxide (NO) inhibit bone resorption by mature osteoclasts. We examined the effects of low NO concentrations on osteoclast formation in mouse bone marrow cultures. The NO releasers sodium nitroprusside (SNP) and S-nitroso-N-acetyl-DL-penicillamine inhibited the formation of multinucleated cells expressing tartrate-resistant acid phosphatase (a marker for osteoclasts) when administered during the last 3 days of 6-day cultures (differentiation stage) but not during the first 3 days (proliferation stage). SNP (1 microM) completely inhibited pit formation on dentine wafers when added to cultures during osteoclast formation, but 100 microM SNP was required to inhibit pitting by mature osteoclasts. Conversely, the NO synthase inhibitors aminoguanidine and nitro-L-arginine methyl ester both increased osteoclast formation. Inhibition of osteoclast formation by NO likely was guanosine 3',5'-cyclic monophosphate (cGMP) dependent, as SNP increased cGMP in marrow cultures, and 1 mM 8-bromo-cGMP or dibutyryl-cGMP reduced osteoclast formation when administered during the differentiation stage. The cGMP-specific type V phosphodiesterase inhibitor, zaprinast (M & B 22948) also inhibited osteoclast formation (half-maximal inhibitory constant, 100 microM) only when added during the differentiation stage. We conclude that the differentiation stage of osteoclast formation is inhibited by increases in cGMP levels elicited by NO.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Distribution and regulation of guanylyl cyclase type B in the rat nephron.

C-type natriuretic peptide (CNP) has been localized to the proximal and distal nephron. In this study, we examined the distribution and regulation of the CNP receptor, guanylyl cyclase type B (GC-B), in the rat kidney. GC-B mRNA was detected most frequently in microdissected glomeruli, thin and thick limbs of the loop of Henle, and outer and inner medullary collecting ducts by reverse transcription-polymerase chain reaction (RT-PCR). This pattern of expression is supported by immunofluorescent staining, using anti-GC-B-specific antiserum. Nearly equivalent levels of GC-B and guanylyl cyclase type A (GC-A) mRNAs were found by quantitative RT-PCR (5,662 +/- 1,622 and 5,187 +/- 1,204 molecules of cDNA/microgram total RNA, respectively; means +/- SE, n = 6). Renal inner medulla GC-B mRNA levels, but not renal CNP mRNA levels, were 3.2-fold greater in hypervolemic and 2.3-fold less in hypovolemic rats compared with euvolemic controls. Immunohistochemical staining also supports a greater GC-B expression with increased volume status. These data link hydration status and GC-B expression and suggest an additional and novel mechanism for regulating intravascular volume.

Animals↗
PubMed1995

C-type natriuretic peptide increases bone resorption in 1,25-dihydroxyvitamin D3-stimulated mouse bone marrow cultures.

Most agents that regulate osteoclast bone resorption exert their effects indirectly, through the osteoblast. Nitric oxide, which stimulates soluble guanylyl cyclase, has been reported to inhibit osteoclast bone resorption directly, by a cGMP-independent mechanism (1). In this report, we demonstrate that C-type natriuretic peptide (CNP), an activator of membrane-bound guanylyl cyclase, stimulates bone resorption by osteoclast-containing 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-stimulated mouse bone marrow cultures. Quantitative reverse transcription polymerase chain reaction assays and anti-CNP immunocytochemistry were used to demonstrate that CNP is expressed in mouse marrow cells cultured in the presence, but not the absence, of, 1,25-(OH)2D3. mRNA for guanylyl cyclase type B, the receptor for CNP, was expressed in cultures independent of 1,25-(OH)2D3. CNP (1 and 10 microM) elevated cGMP production in marrow cultures to 350 and 870%, respectively, of control values. 10 microM CNP increased osteoclast bone resorptive activity, measured by the resorption area on whale dentine wafers, or by the NH4Cl-inhibitable release of [3H]proline from radiolabeled bone chips, to 214 and 557% of control, respectively, without affecting osteoclast formation. Bone resorption by the marrow cultures was inhibited by 7F9.1, a monoclonal antibody raised against CNP, but not by control antibodies. These results indicate that CNP is a potent activator of osteoclast activity and may be a novel local regulator of bone remodeling.

Animals↗
PubMed1995

Effects of melanocyte-stimulating hormone on wild-type and white axolotl neural crest cells.

The goals of the current research were twofold: to study the effects of melanocyte-stimulating hormone (MSH) on undifferentiated axolotl (Ambystoma mexicanum) neural crest cells and to determine whether wild-type or white mutant axolotl neural crest cells respond differently to MSH or to either of two agonists of the MSH signal transduction pathway (cholera toxin or N6,O2-dibutyryl adenosine 3',5'-monophosphate (dbcAMP). We found that MSH induces melanophore differentiation in axolotl neural crest cells in a dose-dependent manner; however, white, but not wild-type, neural crest cells are inhibited by the highest concentration of MSH (6 x 10(-6) M) tested. The effects of cholera toxin and dbcAMP indicate that the differentiation of melanophores from white neural crest cells may be more cAMP sensitive than wild-type neural crest cells. These results suggest that MSH is likely to play a regulatory role in the initial pigment pattern formation of wild-type and white axolotls.

Adenylyl Cyclases↗
PubMed1995

Antidepressants and suicide.

OBJECTIVE: To estimate the rate and means of suicide among people taking 10 commonly prescribed antidepressant drugs: dothiepin, amitriptyline, clomipramine, imipramine, flupenthixol, lofepramine, mianserin, fluoxetine, doxepin, and trazodone. DESIGN: Open cohort study with a nested case-control analysis. SETTING: General practices in the United Kingdom that used VAMP computers to maintain their patient records from January 1988 to February 1993. SUBJECTS: 172,598 people who had at least one prescription for one of the 10 antidepressants during the study period. MAIN OUTCOME MEASURE: Suicide confirmed by general practitioner or on death certificate, or both. RESULTS: 143 people committed suicide. The overall rate of suicide was estimated to be 8.5 per 10,000 person years (95% confidence interval 7.2 to 10.0). Rates of suicide were higher in men than women (relative risk 2.8 (95% confidence interval 1.9 to 4.0)), people with a history of feeling suicidal (19.2 (9.5 to 38.7)), and people who had taken several different antidepressants (2.8 (1.8 to 4.3)). People who received high doses of antidepressants and those who had had a prescription in the 30 days before they committed suicide were also at higher risk than those who had received low doses and had had their prescriptions 30 or more days previously (2.3 (1.4 to 3.7) and 2.3 (1.6 to 3.4)) respectively. Rates of suicide were higher in patients who received fluoxetine, but this may be explained by selection biases which were present for those drug users. CONCLUSION: Several factors correlate with the risk of suicide in people taking antidepressants. After controlling for these factors, the risk of suicide was similar among the 10 study antidepressants. Overdose with antidepressants accounted for only 14% of the suicides.

Adult↗
PubMed1995

Natriuretic peptide receptors A and B have different cellular distributions in rat kidney.

The cellular distribution of guanylyl cyclase coupled natriuretic peptide receptors type A (GC-A) and type B (GC-B) was examined by immunocytochemistry in normal rat kidney, and compared with the distribution of the vacuolar H(+)-ATPase. Staining for GC-A was found in glomeruli, thin limbs of Henle's loop, cortical collecting tubule, and inner medullary collecting duct. Staining for GC-B was found in glomeruli and the same nephron sections as GC-A, with the exception of the thin limbs. In the cortical collecting tubule, GC-A was found in both principal and intercalated cells; GC-B was restricted to the apical pole of alpha intercalated cells. In inner medullary collecting duct cells, GC-A was located on the basal membrane, whereas GC-B was found in the apical pole. The different pattern of polarization of natriuretic peptide receptors in the inner medulla provides a plausible basis for the different physiologic effects of atrial natriuretic factor and C-type natriuretic peptide. The results also suggest the possibility that GC-B is involved in the regulation of bicarbonate transport in the cortical collecting tubule.

Animals↗
PubMed1995

Polarized distribution of renal natriuretic peptide receptors in normal physiology and ischemia.

The polarized expression of guanylyl cyclase-coupled natriuretic peptide receptors, types A (GC-A) and B (GC-B), was measured in inner medullary collecting ducts (IMCD) of normal and ischemic rat kidneys, as well as in IMCD cells. Exposure of normal rat kidney medulla to an anti-GC-A antibody demonstrated a propensity of receptor staining on the cellular basal membrane. The polarization of GC-A receptors was lost in the ischemic kidney. The maximal binding capacity of 125I-atrial natriuretic factor (ANF) to the basal membrane of the inner medullary cell line mIMCD-K2 was five times greater than that to the apical membrane. ANF or C-type natriuretic peptide (CNP) added to the basal side of cultured cells resulted in guanosine 3',5'-cyclic monophosphate formation that was greater than when applied to the apical side. Depletion of ATP stores in cultured cells was followed by an increase of 125I-ANF binding to apical cellular membranes. Similar results were obtained when receptor guanylyl cyclase activity was assayed. In conclusion, these results suggest that functional GC-A and GC-B receptors are present predominantly on the basal membrane of IMCD. However, depletion of cellular ATP stores such as in ischemia is followed by a partial loss of polarization.

Animals↗
PubMed1994

Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors.

BACKGROUND: Hospitalizations for acute liver injury in the absence of a viral infection or any other well-defined pathologic finding that could have caused it is rare. In this study, we included both outpatients and hospitalized patients with acute liver injury to estimate the risk of clinically important acute liver injury associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to study the role of certain risk factors. METHODS: This was a retrospective cohort study with secondary case-control analysis. The study included 536 general practitioners' practices in England and Wales for the period October 1987 through August 1991. A total of 625,307 persons who received more than 2 million prescriptions for one of 12 NSAIDs were followed up to estimate the risk of newly diagnosed acute liver injury. RESULTS: There were 23 cases of acute liver injury. The incidence of acute liver injury was 3.7 per 100,000 NSAID users or 1.1 per 100,000 NSAID prescriptions. None of the cases had a fatal outcome. Sulindac was the only NSAID with a substantially greater risk than that for the overall NSAID group. Users of NSAIDs who had rheumatoid arthritis had a 10-fold increased risk of acute liver injury compared with NSAID-treated patients with osteoarthritis. Concomitant exposure to other hepatotoxic medications also increased the risk. Transient minor increases in liver test values were not a useful predictor of diagnosed NSAID-associated acute liver injury. CONCLUSIONS: Although NSAIDs have been found to be associated with acute liver injury in a small number of persons, the risk is sufficiently small as to be of minimal concern for most NSAIDs.

Acute Disease↗
PubMed1994

Synthesis and localization of C-type natriuretic peptide in mammalian kidney.

We have previously demonstrated the synthesis of atrial natriuretic factor (ANF) in the distal cortical nephron of the rat kidney. We now report the synthesis of C-type natriuretic peptide (CNP) in the rat, mouse, and human nephron. CNP mRNA was initially detected in the rat and mouse kidney, as well as in three transformed cell lines isolated from the proximal and distal nephron, using reverse transcription-polymerase chain reaction (RT-PCR). Confirmation of the kidney PCR product was performed by nucleotide sequence analysis and Southern hybridization. Northern hybridization of rat brain CNP cDNA to human kidney polyadenylated RNA detected a 1.4-kb gene transcript. Rat nephron segments were microdissected and subjected to RT-PCR to localize CNP mRNA. CNP mRNA was detected in the proximal convoluted tubule, cortical collecting duct, medullary thick limbs, and inner medullary collecting ducts. CNP, as detected by immunohistochemistry, was found to colocalize with CNP mRNA.

Animals↗
PubMed1993

Cholestatic hepatitis associated with flucloxacillin.

OBJECTIVE: To estimate the frequency of cholestatic hepatitis of uncertain origin occurring among persons who had recently received flucloxacillin, a drug which has recently been reported as causing cholestatic hepatitis, and to compare this frequency with that related to oxytetracycline, a drug which has seldom been reported as causing this disorder. DESIGN: A retrospective cohort study using data automatically recorded on general practitioners' office computers. SETTING: Some 600 general practices in the United Kingdom. SUBJECTS: 132,087 people who received flucloxacillin and 145,844 people who received oxytetracycline. MAIN OUTCOME MEASURE: Clinically documented cholestatic hepatitis of uncertain origin diagnosed 1-45 days after a prescription for flucloxacillin, 46-90 days after a prescription for flucloxacillin and, for comparison, 1-45 days after a prescription for oxytetracycline. RESULTS: There were 10 cases of cholestatic hepatitis of uncertain origin diagnosed within 45 days of receiving flucloxacillin that were either characteristic of or consistent with a syndrome recently described as being associated with this drug; there was one such case 46-90 days after a prescription for flucloxacillin; there were three such cases 1-45 days after a prescription for oxytetracycline. CONCLUSION: Flucloxacillin is a likely cause of cholestatic hepatitis. The risk is estimated to be in the range of 7.6 per 100,000 users (95% confidence interval, 3.6-13.9).

Adolescent↗
PubMed1993

Erythromycin-associated cholestatic hepatitis.

OBJECTIVE: To estimate the risk of cholestatic hepatitis of uncertain origin in patients who had recently received erythromycin, a drug which is known to cause this disorder. DESIGN: A retrospective cohort study using data automatically recorded on general practitioners' office computers. SETTING: Some 600 general practices in the United Kingdom. SUBJECTS: 366,064 people who received erythromycin. MAIN OUTCOME MEASURE: Clinically documented cholestatic hepatitis of uncertain origin diagnosed 1-45 days after a prescription for erythromycin. RESULTS: There were 13 cases of cholestatic hepatitis of uncertain origin diagnosed within 45 days of receiving erythromycin which were either characteristic of or consistent with a syndrome previously described as being associated with this drug. CONCLUSION: The risk of cholestatic jaundice associated with erythromycin is estimated to be in the range of 3.6 per 100,000 users (95% confidence interval, 1.9-6.1).

Adolescent↗
PubMed1992

Urinary tract infections and estrogen use in older women.

OBJECTIVE: To examine the relationship between exogenous estrogen use and risk of clinically diagnosed urinary tract infection (UTI) in older women. DESIGN: A case-control study. SETTING: Two hundred seventy-six general practices. PATIENTS: Cases (n = 3,616) were women, age 50-69 years, with a first recorded UTI in the calendar years 1989 or 1990. Controls (n = 19,162) were matched for age and practice. MAIN OUTCOME MEASURE: Clinical diagnosis of UTI. RESULTS: Women using estrogens for greater than or equal to 1 year had an increased risk of being diagnosed with a UTI compared to non-users, crude odds ratio (OR) 1.9 (95% CI 1.5-2.2). All of this excess risk was observed in women with intact uteri, OR 2.1 (CI 1.7-2.7). Hysterectomized women had no increased risk, OR 1.1 (CI 0.8-1.5). Controlling for diabetes, neurologic deficit, atrophic vaginitis, incontinence, and age did not affect the observed associations. CONCLUSION: Estrogen use is associated with an increased risk of UTI in older women with intact uteri but not in hysterectomized women. This observed differential effect on women with or without uteri may be explained by prescribing biases between these two groups of women, but we lack any evidence to support this conclusion over several alternative possibilities.

Age Factors↗
PubMed1992

Antidepressant drugs and suicide.

The current study provides estimated rates of suicide among users of antidepressant drugs. The data were derived from two population-based data resources: United Kingdom general practitioners using computers provided by Value Added Medical Products, Ltd., and Group Health Cooperative of Puget Sound. The results apply specifically to these populations. The overall rates of suicide in ever users of the study drugs usually used to treat depression were 6.5 x 10(-4) person-years in persons present in the U.K. resource and 5.1 x 10(-4) person-years in members of The Puget Sound group. Rates of suicide among users of particular antidepressant drugs varied somewhat, but the rates were consistent with biologic variability, with the possible exception of rates for mianserin (based on 4 exposed cases), which were higher than rates for other antidepressants. Consistent findings were (1) suicide rates are substantially higher in men than in women, and (2) the use of firearms as a mode of suicide is common in the northwest United States and uncommon in the United Kingdom.

Adult↗
PubMed1992

Antidepressants and convulsions.

We reviewed available computer records and clinical charts in an estimated 42,000 recipients of antidepressant drugs. The study was restricted to persons with no known condition predisposing to convulsions. Only 16 study subjects developed a convulsive disorder that we judged could have been caused by an antidepressant. We conclude that the frequency of convulsions caused by these drugs used at usual prescribed doses in the settings studied is substantially less than one per 1,000 recipients who have no conditions predisposing to convulsions.

Adult↗