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Biomedical subjects

P Finley

Publications and source records attributed to P Finley.

At least 19 recordsLinked to original sources
PubMed2000

Biodistribution of [18F] SR144385 and [18F] SR147963: selective radioligands for positron emission tomographic studies of brain cannabinoid receptors.

ABSTRACT. [(18)F] SR144385 and [(18)F] SR147963 were synthesized in a multistep reaction in which fluorine-18 was introduced by nucleophilic halogen displacement on a bromo precursor. The fluorine-18-labeled intermediate was deprotected and coupled with the appropriate alkyl amine to give the final products. Both radioligands had appropriate regional brain distribution for cannabinoid receptors with a target to nontarget ratio of 1.7 for [(18)F] SR147963 and 2.5 for [(18)F] SR144385 at 60 and 90 min postinjection, respectively. The uptake of both tracers was blocked with a 1 mg/kg dose of SR141716A.

Administration, Inhalation↗
PubMed1999

[11C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1- piperazinecarboxylate ([11C]GR89696): synthesis and in vivo binding to kappa opiate receptors.

GR89696, racemic methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate, a kappa opioid receptor ligand, was labeled with [11C]methyl chloroformate. The radiochemical yield was 20% with an observed specific radioactivity of 75.5 GBq/micromol at end of synthesis (2,040 mCi/micromol). Five minutes after intravenous administration, 5.4% of the injected dose accumulated in mouse whole brain. Brain region to cerebellar ratios increased over time with ratios at 90 min of 7.8, 5.6, and 4.5 for the hypothalamus, olfactory tubercle, and striatum, respectively. The uptake of [11C]GR89696 correlated with known kappa opioid receptor densities and was inhibited by kappa opioid selective drugs.

Animals↗
PubMed1998

Nicotine induced up-regulation of nicotinic receptors in CD-1 mice demonstrated with an in vivo radiotracer: gender differences.

Up-regulation of brain nicotinic receptors (nAChRs) by chronic nicotine treatment has chiefly been demonstrated by in vitro binding assays. Here, we report that up-regulation of nAChRs in CD-1 mice can be detected using a specific in vivo radioligand for nAChRs, [125I]IPH. After 10 days of (-)-nicotine administration, male and female mice demonstrated a significant elevation of [125I]IPH binding in all brain regions studied. [125I]IPH uptake also displayed significant gender differences with male animals showing a more pronounced increase in [125I]IPH accumulation.

Animals↗
PubMed1997

[125/123I]IPH: a radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors.

Tomographic imaging of central nicotinic acetylcholine receptors (nAChRs) via single photon emission computed tomography (SPECT) has been hampered by the lack of a radioligand with suitable in vivo binding characteristics. Therefore, a novel analog of epibatidine, (+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), labeled with [(125)I] or [(123)I] was evaluated as an in vivo marker of central nicotinic acetylcholine receptors (nAChRs). [(125)I]IPH showed substantial brain penetration (4.2% of the injected dose at 30 min) and a cerebral biodistribution in mice consistent with the in vivo labeling of nAChRs (% injected dose/gram of thalamus, superior colliculi >> cerebellum). [(125)I]IPH binding sites were shown to be saturable with unlabeled IPH (ED50 approximately 1 microg/kg). The uptake of [(125)I]IPH was blocked significantly by the nicotinic agonists, cytisine, lobeline, and (-)-nicotine, but not by the noncompetitive nAChR antagonist, mecamylamine. Antagonists of muscarinic (scopolamine), serotonin (ketanserin), and opioid (naloxone) receptors had no significant effect on [(125)I]IPH binding. A preliminary SPECT imaging study with [(123)I]IPH in a baboon showed [(123)I]IPH to localize in nAChR-rich areas of brain (thalamus > frontal cortex > cerebellum). [(123)I]IPH binding in baboon brain was also displaced (35-45% displacement) by a challenge dose of cytisine showing that a well-characterized nicotinic agonist effectively competes for [(123)I]IPH binding sites. [(123)I]IPH seems well suited for imaging studies of nAChRs and, to our knowledge, is the first SPECT agent that has allowed for the visualization of nAChRs in primate brain.

Animals↗
PubMed1997

Fluorine-18-FPH for PET imaging of nicotinic acetylcholine receptors.

UNLABELLED: Visualization of central nicotinic acetylcholine receptors (nAChRs) with modern PET or SPECT imaging techniques has been hampered by the lack of a radioligand with suitable in vivo binding characteristics (i.e., high target-to-nontarget ratios and kinetics appropriate for the half-life of the tracer and imaging modality used). This paper describes in vivo binding, kinetics and pharmacology of a highly potent 18F-labeled analog of epibatidine, (+/-)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([18F]FPH), in the mouse brain with the view towards application of this tracer for PET imaging of nAChR in human brain. METHODS: Fluorine-18-FPH was administered intravenously to mice, and time-activity curves were determined for several regions in the brain and other organs. Saturation and pharmacology of [18F]FPH binding was demonstrated in vivo by preinjecting unlabeled FPH or other drugs with known pharmacological action before [18F]FPH was injected. The effect of the drugs on [18F]FPH accumulation was evaluated. RESULTS: [18F]FPH was rapidly incorporated into the mouse brain; peak activity (2.4% of the injected dose) was measured at 5 min after intravenous administration, followed by washout to 1.1% injected dose (ID) at 60 min. Highest concentrations of 18F occurred at 15 min in areas known to contain high densities of nAChR ¿e.g., thalamus [9.7% of injected dose per gram tissue (ID/g¿] and superior colliculus (8.3% ID/g)]. Accumulation of the 18F tracer in hippocampus, striatum, hypothalamus and cortical areas was intermediate (5.0, 5.6, 4.2 and 5.6% ID/g, respectively) and low in the cerebellum (2.8% ID/g). The distribution of [18F]FPH in the mouse brain matched that of other in vivo nAChR probes such as 3H-labeled epibatidine or norchloroepibatidine, [3H](-)-nicotine and [3H]cytisine and that of nAChR densities determined in postmortem autoradiographic studies in rodents. Preinjection of blocking doses of unlabeled epibatidine, (-)-nicotine, lobeline and cytisine significantly inhibited [18F]FPH binding in thalamus and superior colliculus, but not in cerebellum, whereas drugs that interact with binding sites other than acetylcholine recognition sites of nAChR (e.g., mecamylamine, scopolamine, N-methylspiperone and ketanserin) had no effect on [18F]FPH accumulation in any of the brain regions examined. CONCLUSION: Fluorine-18-FPH labels nAChR in vivo in the mouse brain. Because of its high uptake into the brain and high ratios of specific-to-nonspecific binding, this radioligand appears to be ideally suited for PET imaging of nAChR in the mammalian brain.

Animals↗
PubMed1997

Imaging nicotinic acetylcholine receptors with fluorine-18-FPH, an epibatidine analog.

UNLABELLED: Nicotinic acetylcholine receptors (nAChRs) have been implicated in a variety of central processes, such as learning and memory and analgesia. These receptors also mediate the reinforcing properties of nicotine in tobacco products and are increased in postmortem samples of brains of smokers. On the other hand, brains of individuals who have died from dementia of the Alzheimer type show abnormally low densities of nAChRs. In this study, the distribution and kinetics of [(+/-)-exo-2-(2-[18F] fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (18F-FPH), a high-affinity nAChR agonist, was evaluated in a baboon using PET. METHODS: After intravenous injection of 5 mCi [185 MBq] 18F-FPH into a 25-kg anesthetized baboon, sequential quantitative tomographic data were acquired over a period of 150 min. Regions of interest were placed and time-activity curves were generated. Brain kinetics of the radiotracer were calculated, and the in vivo regional binding in the baboon brain was compared with the known in vitro regional distribution of nAChRs in the rat and human brain. RESULTS: Brain activity reached a plateau within 60 min after injection of the tracer, and the binding was reversible. Elimination of 18F-FPH was relatively rapid from the cerebellum (clearance t[1/2] = 3 hr), intermediate from the hypothalamus/midbrain (t[1/2] = 7 hr) and slow from the thalamus (t[1/2] = 16 hr). Radioactivity due to 18F-FPH at 130 min postinjection was highest in the thalamus and hypothalamus/midbrain, intermediate in the neocortex and hippocampus and lowest in the cerebellum. Subcutaneous injection of 1 mg/kg cytisine 45 min after injection of the radiotracer reduced brain activity at 130 min by 67%, 64%, 56% and 52% of control values in the thalamus, hypothalamus/midbrain, hippocampus and cerebellum, respectively. The regional binding of 18F-FPH at 130 min was highly correlated with the known densities of nAChR measured in vitro in human (r = 0.81) and rat brain (r = 0.90). CONCLUSION: These results demonstrate the feasibility of imaging nAChRs in vivo. Fluorine-18-FPH appears to be a suitable tracer to study nAChRs in the human brain.

Animals↗
PubMed1994

Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: a Southwest Oncology Group study.

PURPOSE: Standard therapy for multiple myeloma consists of cytotoxic chemotherapy plus glucocorticoids. Interferon (IFN) alfa maintenance is reported to prolong chemotherapy-induced remissions and survival. This study evaluates induction chemotherapy, glucocorticoids, and interferon maintenance in myeloma. PATIENTS AND METHODS: Five hundred twenty-two previously untreated myeloma patients were randomized to three chemotherapy regimens with differing glucocorticoid intensities. Patients who achieved remission were randomized to receive IFN or observation until relapse. Patients who failed to respond to chemotherapy received IFN alfa plus dexamethasone (DEX). RESULTS: Five hundred nine patients were eligible for induction chemotherapy. Chemotherapy with higher dose-intensity glucocorticoids yielded higher response rates and improved survival (P = .02 for the three-group comparison; P < .05 for each higher glucocorticoid arm v vincristine, melphalan, cyclophosphamide, and prednisone alternating with vincristine, carmustine [BCNU], doxorubicin, and prednisone [VMCP/VBAP]). One hundred ninety-three patients who achieved remission were randomized to receive IFN alfa 3 MU three times weekly or observation. IFN was not superior to observation for relapse-free (P = .95) or overall survival (P = .39) from start of maintenance. Eighty-eight induction failures received 5 MU of IFN three times weekly plus DEX. Patients who received IFN/DEX had a median survival duration of 48 months from start of IFN/DEX. CONCLUSION: Higher-dose glucocorticoids increases frequency of response to chemotherapy and prolong survival in myeloma. IFN maintenance with the dose schedule used in this trial did not prolong relapse-free or overall survival. We cannot exclude a small effect of IFN, as most individual trials do not have sufficient statistical power. Meta-analysis of randomized trials evaluating IFN maintenance in myeloma might be of value. While IFN appeared ineffective, addition of higher-dose glucocorticoids improved outcome in myeloma.

Adult↗
PubMed1993

An in vivo model of human multidrug-resistant multiple myeloma in SCID mice.

We have established a reproducible in vivo model of human multiple myeloma in the severe combined immunodeficient (SCID) mouse using both the RPMI 8226 human myeloma cell line and the P-glycoprotein-expressing multidrug-resistant 8226/C1N subline. SCID mice 5 to 8 weeks of age were injected intraperitoneally with either 8226 drug-sensitive or P-glycoprotein-expressing multidrug-resistant myeloma cells (8226/C1N). Tumors were detected within 5 days after injection by the presence of human lambda light chain excretion in the mouse urine. Growth of the tumor was observed primarily in the abdominal cavity with spread to the abdominal organs. The anti-neoplastic agent doxorubicin was effective in treating the drug-sensitive 8226 human-SCID xenografts but had no effect on the multi-drug-resistant 8226/C1N human-SCID xenografts. In the 8226-sensitive xenografts, treatment with doxorubicin resulted in a sharp decline in the concentration of human lambda light chain being excreted in the mouse urine. This correlated with an increased survival of the drug-treated animals. This mouse model offers an in vivo means of evaluating efficacy and toxicity of new therapeutic approaches, including development of chemosensitizers directed against P-glycoprotein in multidrug-resistant myelomas.

Animals↗
PubMed1992

Chyle leakage after blunt trauma.

Three patients developed chylous leakage after major blunt trauma. In one patient with non-remitting right-sided chylothorax, lymphangioscintigraphy as well as conventional oil contrast lymphography demonstrated disruption of the thoracic duct at the aortic hiatus which eventually required transpleural mediastinal ductal ligation proximal to the fistula. The other two patients had chylous retroperitoneum and/or chylous peritoneum which was self-limited although one patient (a three-year-old boy) died of multiorgan failure from associated pulmonary contusions and cervical spine injuries. Chylous leak after non-penetrating trauma is usually attributed to hyperflexion-extension of the vertebral column with shearing of tethered lymphatics. Alternatively, sudden compression of lipemic and engorged mesenteric lymphatics, adjacent nodes and the lower thoracic duct aggravated by deformations associated with stretching and tearing motions may also directly disrupt chyle-containing lymphatics.

Adolescent↗
PubMed1991

Characterization of ascites present at cesarean section.

Ascites has been reported at cesarean section delivery in pregnancies complicated by preeclampsia. The frequency and composition of peritoneal fluid collections in pregnancy have not previously been described. This descriptive study evaluated presence, composition, and characteristics of ascites present in 41 women undergoing cesarean delivery for a variety of indications. Twenty-six women had sufficient quantities of peritoneal fluid to be collected immediately after opening the parietal peritoneum. The protein content of the fluid was analyzed. The presence of fluid was not related to labor preceding delivery. All preeclamptic women in this study had fluid obtainable at cesarean section. Large volume ascites was noted in five preeclamptic women whose fluid had low total protein content, consistent with a transudate. Intrahepatic portal hypertension is one possible explanation of the large volume and low protein ascites in some preeclamptic patients. Ultrasonic measurements in preeclamptic patients and normotensive pregnant women showed uniform portal vein diameters and Doppler-derived portal vein flow velocities in all patients. The physiology of peritoneal fluid production in complicated and normal pregnancy remains unexplained.

Adult↗
PubMed1990

Prognostic value of pretreatment serum beta 2 microglobulin in myeloma: a Southwest Oncology Group Study.

Six hundred twelve eligible, previously untreated patients with active multiple myeloma and at least some data available for analysis were entered into a randomized trial (Southwest Oncology Group [SWOG] Phase III myeloma study 8229/30), in which the prognostic significance of pretreatment serum beta 2 microglobulin levels was evaluated. Because there was no statistically significant survival difference between the alternating and syncopating VMCP/VBAP regimens, it was possible to evaluate serum beta 2 microglobulin for the total population all together. The serum beta 2 microglobulin measurements showed the highest significance of any prognostic factor, both in the bivariate and multivariate regression analyses. The median survival was 36 months for the 322 patients with pretreatment serum beta 2 microglobulin values of less than 6 micrograms/mL, as compared with a median survival of 23 months for the 225 patients with a beta 2 level of greater than or equal to 6 mcg/mL (P less than .0001). The stepwise multiple regression model first contained serum beta 2 microglobulin, followed by serum albumin, serum calcium, age, and serum creatinine. Serum beta 2 microglobulin was highly correlated with stage: median values ranged from 3.7 micrograms/mL for stage IA, to 10.1 for stage IIIB. It was possible to stratify myeloma patients based on combinations of serum beta 2 microglobulin with both albumin and age, producing excellent separation of patients into low-, intermediate-, and high-risk categories. It is concluded that serum beta 2 microglobulin is the most powerful prognostic factor currently available for multiple myeloma and that it can be used alone or in combination with other variables for pretreatment stratification.

Age Factors↗
PubMed1990

Chemotherapy is superior to sequential hemibody irradiation for remission consolidation in multiple myeloma: a Southwest Oncology Group study.

Six hundred fourteen previously untreated patients with multiple myeloma were evaluated on this phase III Southwest Oncology Group (SWOG) trial. For remission induction, two noncross-resistant drug combinations (vincristine, melphalan, cyclophosphamide, and prednisone [VMCP] and vincristine, carmustine [BCNU], Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], and prednisone [VBAP]) were administered with either a direct alternating or a syncopated schedule. Pretreatment serum beta-2 microglobulin (beta 2M) was the single most important prognostic factor for survival (P less than .0001). There was no difference in toxicity, response, or survival by induction chemotherapy schedule (P greater than .7). For consolidation, 180 eligible and responsive patients were randomized to receive either an additional year of VMCP or sequential hemibody radiation (HBI) with vincristine and prednisone (VP) administered between the two HBI courses. Relapse-free survival (26 months) and overall survival (median, 36 months) were better with VMCP than with HBI (median, 20 months and 28 months; P = .04 and .018, respectively). HBI was also evaluated on a nonrandomized basis in 66 patients who achieved either a partial response (PR) or who were nonresponders to induction therapy. While HBI converted 24% of the PR patients to remission status, this effect was only seen in 5% of nonresponding patients. The survival of responsive and nonresponding patients receiving HBI was similar. All HBI groups had an inferior outcome to those receiving VMCP consolidation. Myelosuppression was also significantly worse after HBI. Survival from the time of relapse did not differ between patients randomized to receive VMCP or HBI. Thus HBI induced less durable remissions, but did not render patients less amenable to postrelapse chemotherapy. Our findings do not support the use of HBI in either chemotherapy responsive or nonresponding patients with multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Influence of ascites on tobramycin pharmacokinetics.

The influence of ascites on the disposition of tobramycin was examined in eight subjects with cirrhosis of the liver. Five of these subjects had resolution of ascites so they could be used as their own controls. While there was no significant effect of ascites on the clearance and half-life of tobramycin, the volume of distribution of tobramycin was significantly larger when ascites was present, 0.32 versus 0.26 liter/kg (P less than 0.01). There was a trend for the volume of distribution to be larger in those patients with larger ascitic fluid volume.

Adult↗
PubMed1984

Serum beta 2-microglobulin in the initial staging and subsequent monitoring of monoclonal plasma cell disorders.

Serum beta 2-microglobulin (beta 2-M) measurements were carried out in 97 patients with monoclonal plasma cell disorders. Twenty-six (87%) of 30 patients with monoclonal gammopathy of undetermined significance (MGUS) had increased beta 2-M levels and serial follow-up in seven patients showed a progressive increase with time. Of the 63 patients with active myeloma, pretreatment serum beta 2-M values were available in 25 for correlation with pretreatment stage. Stage III beta 2-M levels were significantly higher than stages I and II (p less than 0.001). Four patients with smoldering myeloma had beta 2-M values similar to stage I disease. There was, therefore, excellent correlation between beta 2-M and myeloma tumor burden. Levels of beta 2-M decreased with response to chemotherapy induction and low levels in stable remission (plateau phase) were associated with unusually good prognosis. Median survival for stage III patients in stable remission with low serum beta 2-M was greater than 48 months. Conversely, at relapse very high beta 2-M levels were associated with a very fulminant and refractory course. Serum beta 2-M, therefore, appears to be an extremely useful marker in initial stratification and follow-up of myeloma patients.

Adult↗
PubMed1982

Rheumatoid factor activity by rate nephelometry correlated with clinical activity in rheumatoid arthritis.

The purpose of this study was to evaluate, prospectively, the clinical usefulness of the rate nephelometric method for determining rheumatoid factor (RF) activity, measured in International Units (IU), in patients with rheumatoid arthritis. These results were compared with those of standard latex agglutination titration. The overall correlation between clinical activity and RF activity measured by rate nephelometry and serologic titration are similar, i.e., r = 0.47 (P less than 0.001) and r = 0.43 (p less than 0.001), respectively. However, on an individual patient basis, the nephelometric determination appears to correlate better with disease activity and response to therapy than do titers. The RF activity measured in IU would give the clinician a more sensitive and precise tool with which to follow RF activity in individual patients with active disease.

Arthritis, Rheumatoid↗