Search PubMed⌕ Search

Biomedical subjects

R E Ryan

Publications and source records attributed to R E Ryan.

At least 19 recordsLinked to original sources
PubMed2001

Patient treatment preferences and the 5-HT1B/1D agonists.

Migraineurs have specific preferences with regard to migraine therapy. In surveys, they consistently cite several attributes they seek in a migraine medication: rapid pain relief, complete pain relief, ability to return to normal functioning, relief of migraine-associated symptoms, reduction in headache recurrence, and minimal adverse effects. When prescribing medication for patients with migraine, physicians should respect patients' treatment preferences and select drugs that most closely meet patients' needs. As a class, the 5-HT(1B/1D) agonists, or triptans, have many of these attributes, including effectively relieving pain and associated symptoms and allowing patients to return fairly quickly to their normal activities. However, differences have emerged in the ability of specific triptans to satisfy patient preferences. Physicians should consider these differences when prescribing triptans for their patients with migraine.

Humans↗
PubMed2001

Nicotine regulates alpha7 nicotinic receptor subunit mRNA: implications for nicotine dependence.

Recent evidence suggests that alpha7 subunit-containing nicotinic receptors (nAChRs) within the ventral tegmental area (VTA) are involved in the processes underlying nicotine tolerance and withdrawal. The current study used in situ hybridization histochemistry with multiple radiolabelled probes to amplify mRNA signal, to examine the distribution of alpha7 nAChR subunit mRNA both in control brains and following chronic nicotine treatment (1.5 and 30.0 mg/kg/day). Low levels of alpha7 transcript were detected within substantia nigra pars compacta (SNpc), substantia nigra pars reticularis (SNpr) and VTA. Higher levels of alpha7 transcript were found within the cortex and hippocampus. Following chronic nicotine treatment, levels of alpha7 subunit mRNA were significantly elevated in SNpc, SNpr and VTA, but were unchanged in cortex and hippocampus.

Animals↗
PubMed2001

Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knockout mice.

The present study examined the effect of a range of doses of chronic nicotine (0.75, 1.5, 3.0 and 30.0 mg kg(-1) day(-1), s.c., 14 days) upon striatal dopaminergic nerve terminal survival following 6-hydroxydopamine (6-OHDA; 10 microg intrastriatal unilaterally) in rats; and the effects of acute nicotine (1 mg kg(-1), s.c.) pretreatment upon striatal neurodegeneration induced by methamphetamine (5 mg kg(-1), i.p., three doses at 2 h intervals) in wild-type and alpha4 nicotinic receptor (nAChR) subunit knockout mice. In both models of Parkinsonian-like damage, loss of striatal dopaminergic nerve terminals was assessed by [(3)H]-mazindol autoradiography. In rats, chronic nicotine infusion delivered by osmotic minipump implanted subcutaneously 7 days prior to intrastriatal 6-OHDA injection produced significant and dose-related protection against 6-OHDA-induced neurodegeneration. Low (0.75 and 1.5 mg kg(-1) day(-1)) but not high (3.0 and 30.0 mg kg(-1) day(-1)) nicotine doses significantly inhibited 6-OHDA-induced degeneration. In wild-type mice, acute nicotine treatment produced significant inhibition of methamphetamine-induced neurodegeneration. In alpha4 nAChR subunit knockout mice, acute nicotine treatment failed to inhibit methamphetamine-induced neurodegeneration. Nicotine is capable of protecting dopaminergic neurons against Parkinsonian-like neurodegeneration in vivo. In rats, this neuroprotective effect is critically dependent upon nicotine dose and is consistent with the activation of nAChRs, as high, desensitizing doses of nicotine fail to be neuroprotective. Further, neuroprotection is absent in alpha4 nAChR subunit knockout mice. The current results therefore suggest that activation of alpha4 subunit containing nAChRs constitutes a major component of the neuroprotective effect of nicotine upon Parkinsonian-like damage in vivo.

Animals↗
PubMed2001

Lanepitant, an NK-1 antagonist, in migraine prevention.

Lanepitant, a potent non-peptide neurokinin-1 receptor antagonist, inhibits neurogenic dural inflammation, and may have a role in migraine therapy. This study evaluated the effect of lanepitant taken daily for migraine prevention. Patients with migraine headaches with and without aura by International Headache Society classification criteria were enrolled in a 12-week double-blind, parallel design study comparing the effect of 200 mg qd lanepitant (n = 42) and placebo (n = 42) on reduction of migraine frequency. The primary outcome measure was response rate, i.e. the proportion of patients with a 50% reduction in days of headache. Of the 84 patients enrolled, 90.5% were female. The endpoint response rate for lanepitant-treated patients (41.0%) was not statistically significantly (P = 0.065) greater than that for placebo-treated patients (22.0%). No efficacy variables differed significantly between treatments, except for response rates at month 3 (P = 0.045). Higher plasma concentrations were no more effective than lower concentrations. In this study lanepitant was not effective in preventing migraine, but was well tolerated. These results do not support a role for NK-1 antagonism in migraine prevention.

Adult↗
PubMed2000

Nicotinic receptor subunit mRNA in the thalamus of the rat: relevance to schizophrenia?

Recent evidence suggests that aberrant nicotinic receptor (nAChR) expression plays an important role in schizophrenia. The present study sought to examine the distribution of nAChRs within the thalamus and associated cholinergic structures by examining nAChR subunit mRNA expression using in situ hybridization histochemistry. Transcripts for alpha4 and beta2 subunits were found in high levels in all thalamic nuclei and at lower levels in cholinergic nuclei (PPTg and MS/VDB). Distribution of mRNA encoding for additional subunits was restricted; lower alpha3 subunit transcript levels were detected in the anterior thalamic nuclei and portions of the lateral and posterior thalamic nuclei, with alpha7 transcripts being detected in cholinergic nuclei, the IMD and very low levels in the RTN. Low levels of alpha6 and beta3 transcript were found only within the RTN.

Animals↗
PubMed2000

Oral therapy for migraine: comparisons between rizatriptan and sumatriptan. A review of four randomized, double-blind clinical trials.

The introduction in 1991 of sumatriptan succinate, the first approved 5-HT1B/1D receptor agonist, represented a significant advance in the treatment of acute migraine. The approval of three additional 5-HT receptor agonists, including rizatriptan, has further expanded the options for migraine treatment. Four randomized clinical trials have compared the effects of oral sumatriptan with those of oral rizatriptan. Forty mg rizatriptan was more effective than 100 mg sumatriptan but was associated with a high incidence of adverse events. Five mg rizatriptan was comparable to 50 mg sumatriptan. In two trials, rizatriptan 10 mg, the recommended dose in most countries, had a more rapid onset of action than 50 mg (p<0.05) and 100 mg sumatriptan (p=0.075). In addition, 10 mg rizatriptan resulted in more patients being pain-free after 2 hours than 100 mg sumatriptan (p<0.05), and resulted in fewer drug-related adverse events than sumatriptan.

Administration, Oral↗
PubMed1999

Headache diagnosis.

Headache is an extremely common symptom in primary care practice. Despite the ubiquity of the pain, differential diagnosis of headache is not difficult, provided the clinician obtains a comprehensive history. A complete physical examination and specific testing may be required to rule out other underlying causes, but headache itself falls into 3 main classes that are readily identified. Migraine headache occurs most commonly in women, is of moderate to severe intensity, and is often accompanied by nausea and increased sensitivity to light and sound. Cluster headache describes multiple recurrent attacks of severe unilateral pain and occurs most frequently in men. Tension-type headache is the most common form, characterized by mild to moderate dull pain that is often brought on by stress and/or depression. Understanding the triggers and manifestations of these headache types is essential for effective management.

Cluster Headache↗
PubMed1998

Efficacy and safety of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain: three double-blind, randomized, placebo-controlled trials.

OBJECTIVE: To assess the effectiveness of the nonprescription combination of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain. DESIGN: Three double-blind, randomized, parallel-group, single-dose, placebo-controlled studies. SETTING: Private practice, referral centers, and general community. PATIENTS: Migraineurs with moderate or severe headache pain who met International Headache Society diagnostic criteria for migraine with aura or without aura. The most severely disabled segment of migraineurs, including those whose attacks usually required bed rest, or who vomited 20% or more of the time, were excluded. Of the 1357 enrolled patients, 1250 took study medication and 1220 were included in the efficacy-evaluable data set. INTERVENTION: Two tablets of the nonprescription combination of acetaminophen, aspirin, and caffeine or placebo taken orally as a single-dose treatment of 1 eligible acute migraine attack. MAIN OUTCOME MEASURES: Pain intensity difference from baseline; percentage of patients with pain reduced to mild or none. RESULTS: Significantly greater reductions in migraine headache pain intensity 1 to 6 hours after dose were seen in patients taking the acetaminophen, aspirin, and caffeine combination than in those taking placebo in each of the 3 studies. Pain intensity was reduced to mild or none 2 hours after dose in 59.3% of the 602 drug-treated patients compared with 32.8% of the 618 placebo-treated patients (P< .001; 95% confidence interval [CI], 55%-63% for drug, 29%-37% for placebo); at 6 hours after dose, 79% vs 52%, respectively, had pain reduced to mild or none (P<.001; 95% CI, 75%-82% vs 48%-56%). In addition, by 6 hours after dose, 50.8% of the drug-treated patients were pain free compared with 23.5% of the placebo-treated patients (P<.001; 95% CI, 47%-55% for drug, 20%-27% for placebo). Other migraine headache characteristics, such as nausea, photophobia, phonophobia, and functional disability, were significantly improved 2 to 6 hours after treatment with the acetaminophen, aspirin, and caffeine combination compared with placebo (P< or =.01). CONCLUSIONS: The nonprescription combination of acetaminophen, aspirin, and caffeine was highly effective for the treatment of migraine headache pain as well as for alleviating the nausea, photophobia, phonophobia, and functional disability associated with migraine attacks. This drug combination also has an excellent safety profile and is well tolerated.

Acetaminophen↗
PubMed1997

Twenty-four-hour effectiveness of BMS 180048 in the acute treatment of migraine headaches.

The efficacy of BMS 180048, a 5-HT1 agonist in the acute treatment of a migraine headache, was evaluated in 216 patients. Three doses of the study drug were compared to placebo. Patients received a single test dose in the physician's office while being evaluated with a Holter monitor during a headache-free day. They then treated a migraines headache with a single dose of the study drug as an outpatient. The 150 mg- and 200-mg doses of BMS were significantly superior to placebo on change in pain intensity at 2 hours. Patients treated with BMS 180048 had a longer duration of response than placebo-treated patients. At the 24-hour point, only 24% of the 150-mg group and 25% of the 200-mg group had relapsed, compared to placebo which had a 42% relapse rate. It is concluded that BMS 180048 is an effective compound for the treatment of migraine headaches with a prolonged duration of response.

Acute Disease↗
PubMed1995

Microglial cathepsin B: an immunological examination of cellular and secreted species.

The cysteine proteinase cathepsin B (CB) was isolated from immortalized murine BV-2 microglial cells and examined via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting to establish physicochemical properties of CB from what is generally considered the resident CNS macrophage. Microglial proteases have been implicated in several pathological processes occurring in the CNS, including neurodegeneration. Murine microglial CB was observed to consist of two major single-chain species of 32 and 34 kDa, with pls of 5.5-5.2 and 5.1-4.5, respectively. In addition, a minor 24-kDa CB species was also observed in some microglial preparations. The major CB isozymes in microglia differed from those observed in murine liver and brain, which consisted of both single- and double-chain CB variants of 31 and 24-25 kDa/5 kDa, respectively, with pl values of 5.5-4.5. A microglial pro-CB of 37 kDa was also isolated, which could be processed to the 34-kDa single-chain CB species. Cystatin was observed to prevent pro-CB processing, whereas E-64 and leupeptin were only partially inhibitory. The 37-kDa pro-CB species was observed to undergo processing into the 34-kDa CB species when incubated at pH 5.5 but remained stable with respect to molecular mass when incubated at pH 7.0. In contrast, the 34-kDa single-chain CB species was observed to autodegrade when incubated at pH 7.0, whereas incubation at pH 5.5 did not affect the integrity of the species as monitored by immunoblotting. Both pro-CB and 32-kDa single-chain CB species were observed extracellularly following lipopolysaccharide activation of BV-2 microglial cells.

Animals↗
PubMed1989

Cluster headaches.

The patient with cluster headaches will be afflicted with the most severe type of pain that one will encounter. If the physician can do something to help this patient either by symptomatic or, more importantly, prophylactic treatment, he or she will have a most thankful patient. This type of headache is seen most frequently in men, and occurs in a cyclic manner. During an acute cycle, the patient will experience a daily type of pain that may occur many times per day. The pain is usually unilateral and may be accompanied by unilateral lacrimation, conjunctivitis, and clear rhinorrhea. Prednisone is the first treatment we employ. Patients are seen for follow-up approximately twice a week, and their medication is lowered in an appropriate manner, depending on their response to the treatment. Regulation of dosage has to be individualized, and when one reaches the lower dose such as 5 to 10 mg per day, the drug may have to be tapered more slowly, or even maintained at that level for a period of time to prevent further recurrence of symptoms. We frequently will use an intravenous histamine desensitization technique to prevent further attacks. We will give the patient an ergotamine preparation to use for symptomatic relief. As these patients often have headaches during the middle of the night, we will place the patient on a 2-mg ergotamine preparation to take prior to going to bed in the evening. This often works in a prophylactic nature, and prevents the nighttime occurrence of a headache. We believe that following these principles to make the accurate diagnosis and institute the proper therapy will help the practicing otolaryngologist recognize and treat patients suffering from this severe pain.

Calcium Channel Blockers↗
PubMed1987

Properties of a plasma membrane-associated cathepsin B-like cysteine proteinase in metastatic B16 melanoma variants.

Activities of a cathepsin B-like cysteine proteinase have previously been observed to correlate with the malignancy of several animal and human tumors. Plasma membrane fractions of some of these tumors have been found to be enriched in cathepsin B-like activity. We have determined the subcellular distribution of this enzyme and three additional lysosomal hydrolases (cathepsin H, beta-hexosaminidase, and beta-glucuronidase) in normal murine liver and six metastatic variants of the B16 melanoma. The tissues were fractionated initially by differential centrifugation followed by Percoll density gradient centrifugation of the light mitochondrial fraction. Two fractions were obtained: an L-2 fraction enriched in all four lysosomal hydrolases; and an L-1 fraction enriched in a marker enzyme for the plasma membrane. Cathepsin B-like and beta-hexosaminidase activities, but not the other hydrolase activities, were also found to be enriched in the L-1 fractions of the metastatic B16 tumors. We explored the nature of the association of the cathepsin B-like activity with the plasma membrane using fractions from the spontaneously metastatic B16 amelanotic melanoma. Activity could not be dissociated from the plasma membrane fraction by washing with a physiological salt solution suggesting that it was not adsorbed to this fraction nonspecifically, nor could it be displaced by mannose 6-phosphate or other sugars which compete for binding to the known lysosomal receptors. High salt concentrations, low concentrations of the mild detergent saponin, mild acidification, or phosphatidylinositol-specific phospholipase C did not elute the cathepsin B-like activity. However, activity was eluted by exposure to 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a detergent used in the purification of integral membrane proteins. The B16 amelanotic melanoma plasma membrane-associated cathepsin B-like activity had a slightly higher pH optimum and was resistant to inactivation by neutral pH and to inhibition by three low molecular weight inhibitors of cysteine proteinases. The Ki values for inhibition by leupeptin and stefin A were 20-fold higher. The presence of a cathepsin B-like cysteine proteinase at the surface of metastatic tumor cells, particularly in a form which can retain activity at physiological pH and retain activity in the presence of extracellular proteinase inhibitors, may contribute to the focal dissolution of the extracellular matrix observed at sites of contact with invading tumor cells.

Animals↗
PubMed1985

Cathepsin B-like activity in viable tumor cells isolated from rodent tumors.

The cathepsin B-like cysteine proteinase activity which has been implicated in tumor malignancy has been attributed to several cellular sources, including viable tumor cells, necrotic tumor cells, and host-inflammatory cells. We have isolated subpopulations of cells from eight rodent tumors of five histological types, using centrifugal elutriation, and verified the cellular composition of the subpopulations cytologically. Ninety-two % or greater of the cathepsin B-like activity was associated with the isolated fractions containing greater than or equal to 95% tumor cells of 86 +/- 2% (SE) viability (beta fractions). The isolated fractions consisting of necrotic tumor cells and inflammatory cells (alpha fraction) apparently contain a cysteine proteinase inhibitor, since both cathepsin B-like and cathepsin H activities in the beta fraction of B16 amelanotic melanomas could be inhibited by addition of the alpha fraction.

Animals↗
PubMed1984

Comparative study of nadolol and propranolol in prophylactic treatment of migraine.

Forty-eight patients (13 men and 35 women) took part in a double-blind randomized study. All patients received a placebo daily for 4 weeks (period A), at the end of which the frequency and severity of headaches experienced by each patient were assessed. Patients then received an active drug for 12 weeks (period B). Sixteen patients received nadolol, 80 mg/day; 16 received nadolol, 160 mg/day; and 16 received propranolol, 160 mg/day. The frequency and severity of headaches in the three groups were tabulated at the end of period B, as were the side effects. Only three subjects dropped out during the study, and one of these needed abdominal surgery. All three groups reported improvement, the most noticeable being in those patients who received 80 mg of nadolol daily.

Adrenergic beta-Antagonists↗