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Biomedical subjects

R B Cohen

Publications and source records attributed to R B Cohen.

At least 19 recordsLinked to original sources
PubMed2006

A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors.

BACKGROUND: To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks. PATIENTS AND METHODS: Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined. Peripheral blood mononuclear cells were analyzed for farnesylation of the HDJ2 chaperone protein and FPTase activity. RESULTS: Forty-one patients received 185 courses of treatment. Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib. Capecitabine did not affect the pharmacology of tipifarnib at 100-300 mg b.i.d., although tipifarnib significantly increased the C(max) of 5-FU at 400 mg b.i.d. HDJ2 farnesylation and FPTase activity decreased between 200 and 400 mg b.i.d. doses of tipifarnib, without a dose-response relationship. Five patients demonstrated partial remissions and 11 patients maintained prolonged stable disease. CONCLUSIONS: Tipifarnib and capecitabine are well tolerated at 300 mg/1000 mg/m(2) b.i.d., respectively, resulting in biologically relevant plasma concentrations and antitumor activity. The recommended dose for further disease-focused studies is 300 mg b.i.d. tipifarnib and 1000 mg/m(2) b.i.d. capecitabine, given for 14 days every 3 weeks.

Adult↗
PubMed2006

Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours.

To evaluate the toxicity, pharmacological and biological properties of ATN-161, a five -amino-acid peptide derived from the synergy region of fibronectin, adult patients with advanced solid tumours were enrolled in eight sequential dose cohorts (0.1-16 mg kg(-1)), receiving ATN-161 administered as a 10-min infusion thrice weekly. Pharmacokinetic sampling of blood and urine over 7 h was performed on Day 1. Twenty-six patients received from 1 to 14 4-week cycles of treatment. The total number of cycles administered to all patients was 86, without dose-limiting toxicities. At dose levels above 0.5 mg kg(-1), mean total clearance and volume of distribution showed dose-independent pharmacokinetics (PKs). At 8.0 and 16.0 mg kg(-1), clearance of ATN-161 was reduced, suggesting saturable PKs. Dose escalation was halted at 16 mg kg(-1) when drug exposure (area under the curve) exceeded that associated with efficacy in animal models. There were no objective responses. Six patients received more than four cycles of treatment (>112 days). Three patients received 10 or more cycles (> or =280 days). ATN-161 was well tolerated at all dose levels. Approximately, 1/3 of the patients in the study manifested prolonged stable disease. These findings suggest that ATN-161 should be investigated further as an antiangiogenic and antimetastatic cancer agent alone or with chemotherapy.

Adult↗
PubMed2001

Use of the aromatase inhibitor anastrozole in the treatment of patients with advanced prostate carcinoma.

BACKGROUND: Men with prostate carcinoma initially respond to therapies designed to inhibit androgen secretion or block its action. Later, the tumors in these patients become refractory to androgen-related therapies. Therefore, additional hormonal maneuvers that would benefit these men currently are needed. Reports of androgen receptor mutations and historic clinical observations raised the hypothesis that estrogens might be involved in the proliferation of androgen-refractory prostate carcinoma. METHODS: To explore this hypothesis, 14 men with advanced prostate carcinoma that was refractory to medical or surgical orchiectomy and antiandrogens were entered into a clinical Phase II trial involving suppression of estrogens. After complete evaluation, each patient received 1 mg daily of the third-generation aromatase inhibitor anastrozole until disease progression. Follow-up included serial determinations of prostate specific antigen (PSA), measurements of evaluable lesions, and assessment of intensity of pain. RESULTS: No patient experienced an objective response or disease stabilization as measured by PSA level or the greatest dimension of the lesion. Minimal improvement of bone pain was reported in two patients receiving intensive analgesic medication. CONCLUSIONS: It was concluded that the dependence of androgen-insensitive prostate carcinoma on estrogens for proliferation is uncommon and that aromatase inhibitors may not have a place in the treatment of prostate carcinoma at this stage of the disease.

Aged↗
PubMed2001

Anti-TNF therapy and malignancy - a critical review.

The roles of tumour necrosis factor (TNF) and anti-TNF therapy in malignancy are reviewed, including an overview of baseline risk factors for malignancy in inflammatory diseases and the incidences of malignancies observed in clinical trials of an anti-TNF-a therapy, infliximab. The preclinical data and early clinical experience presented for infliximab do not provide evidence for a causal relationship between TNF-a antagonism and the development of lymphoid or nonlymphoid cancers.

Animals↗
PubMed2000

Causes of failure among cuspal-coverage amalgam restorations: a clinical survey.

BACKGROUND: Investigations of cuspal-coverage amalgam restorations suggest that tooth fracture is the leading cause of failure, while for Class I and II restorations, the leading cause is caries. In this study, the authors evaluated the causes of failure for a large number of cuspal-coverage restorations. METHODS: The causes of failure for 706 cuspal-coverage amalgam restorations were determined through the use of a questionnaire. Dentists from a variety of dental schools; Army, Navy, Air Force, Public Health and Veterans Affairs dental clinics; and private practice were asked to record pertinent information regarding patients and restoration failures from choices provided on a survey form. RESULTS: The survey documented 706 failed restorations. Mandibular first molars accounted for 36.25 percent of all failures. The majority of failures were caused by fractured teeth (24.3 percent), caries (20 percent) and fractured restorations (17.1 percent). Among all of the failed restorations, 82.15 percent were restorable, 9.35 percent were repairable and 8.50 percent were nonrestorable. Among the fractured teeth, 80 percent were restorable, 14.5 percent were nonrestorable and 5.5 percent were repairable. Among the carious teeth, 84 percent were restorable, 8 percent were nonrestorable and 8 percent were repairable. A chi 2 analysis revealed that tooth fracture was more likely to be associated with nonrestorability than either caries (chi 2 = 5.013, P < .05) or restoration fracture (chi 2 = 6.202, P < .05). CONCLUSIONS: The leading cause of failure among the 706 restorations was tooth fracture, which resulted in significantly greater numbers of nonrestorable teeth than either caries or fractured restorations. CLINICAL IMPLICATIONS: Tooth fracture creates a greater risk of nonrestorability than any other cause of failure. Replacement or coverage of fracture-prone cusps is likely to improve the life expectancy of complex amalgam restorations.

Adolescent↗
PubMed2000

Phase I study of weekly vinorelbine in combination with weekly paclitaxel in adult patients with advanced refractory cancer.

Vinorelbine and paclitaxel are highly active antineoplastic agents. Preclinical data indicate a potential for antitumor synergy for a number of common tumor types when they are combined. We investigated a novel weekly schedule of both agents. Eighteen patients with advanced cancer were entered onto this phase I trial. Vinorelbine and paclitaxel were given weekly in combination for 6 consecutive weeks, followed by a 2-week break. Sequential cohorts of patients were treated at two dose levels: vinorelbine 22.5 mg/m2 followed by paclitaxel 40 mg/m2 and vinorelbine 22.5 mg/m2 followed by paclitaxel 60 mg/m2. Ten patients completed at least one 8-week course of therapy. Neutropenic myelosuppression was dose limiting at level II. Neurotoxicity was not dose limiting. Objective responses were seen in patients with esophageal, lung, and breast cancer and suggest that this is an active regimen worthy of further investigation in selected diseases. Phase II trials of this regimen are in progress.

Adult↗
PubMed1999

HIV-specific immunity following immunization with HIV synthetic envelope peptides in asymptomatic HIV-infected patients.

OBJECTIVE: A phase I trial was conducted to evaluate the safety and immunogenicity of an HIV synthetic peptide vaccine in HIV-seropositive individuals. The immunogens used in this study were PCLUS 3-18MN and PCLUS 6.1-18MN envelope peptides. METHODS: Eight HIV-infected patients received six subcutaneous injections of 160 microg PCLUS 3-18MN in Montanide ISA 51 and were followed longitudinally for a year after the first immunization. Peripheral blood mononuclear cells (PBMC) were tested for peptide-specific T helper and cytotoxic T cell (CTL) responses, HIV-1MN neutralizing antibodies and antibodies against HIV PCLUS 3 and P18 MN peptides. RESULTS: PCLUS 3-1 8MN-specific T helper responses were significantly increased at 36 weeks (P < 0.05, after adjustment for multiple comparisons) following initial immunization with PCLUS 3-18MN. A P18MN-specific CTL response, not present prior to vaccination, was observed after immunization in one patient. Serum HIV-1 MN-neutralizing antibody titers increased in each of the three patients who had low titers prior to immunization. Plasma HIV RNA levels and CD4 cell counts did not change appreciably during the study period. CONCLUSIONS: This trial demonstrates that both peptides can be safely administered to HIV-infected individuals and that PCLUS 3-18MN induces increases in HIV peptide-specific immune responses.

AIDS Vaccines↗
PubMed1999

The relationship between infliximab treatment and lymphoma in Crohn's disease.

The relationship between chronic inflammatory conditions and malignancy is complex. We describe the clinical course of 2 patients with Crohn's disease (CD) in whom lymphoma was diagnosed after treatment with infliximab. The first patient was a 61-year-old man with a 30-year history of fistulizing CD in whom B-cell non-Hodgkin's lymphoma was diagnosed 9 months after treatment with infliximab. The second is a 29-year-old man with CD in whom nodular sclerosing Hodgkin's lymphoma was diagnosed 3 weeks after infusion with infliximab. The lymphoma presented with pleural effusions, mediastinal and cervical adenopathy, and no gastrointestinal lesion. We describe the implications of these cases for the use of immunomodulatory therapy in CD and the questionable association between CD and lymphoma.

Adult↗
PubMed1998

Identification of [3H]P1075 binding sites and P1075-activated K+ currents in ovine choroid plexus cells.

This study examined the pharmacological characteristics of binding sites for the potent K+ channel opener [3H]P1075, as well as the functional effects of P1075 on ionic currents and membrane potential, in ovine choroid plexus (OCP) cells. [3H]P1075 bound to OCP cells with a Kd of 26 +/- 4 nM and a Bmax of 10400 +/- 480 sites/cell. Labelled sites were stereoselective and inhibited by potassium channel openers with a rank order of potency: P1075 > BMS-182264, ((4-[[9cyanoimino)[(1,2,2-trimethylpropyl)amino]-methyl]amino]benz onitrile) > pinacidil >> nicorandil > diazoxide. The K(ATP) channel antagonist glyburide inhibited [3H]P1075 binding with a Ki of 2 microM. The presence of K(ATP) channels on OCP cells was examined by patch clamp and fluorescent (membrane-potential sensitive dye) techniques. In some cells, P1075 activated an outward potassium current which was blocked by glyburide. P1075 produced a glyburide-sensitive, concentration-dependent, hyperpolarization of OCP cells. Levcromakalim hyperpolarized more strongly than its 3R,4S enantiomer, BRL 38226 ((3R-trans)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)- 2H-1-benzopyran-6-carbonitrile) indicating a stereoselective interaction. These data indicate that epithelial OCP cells contain glyburide-sensitive K(ATP) channels.

Adenosine Triphosphate↗
PubMed1998

Evidence of acute stress disorder after diagnosis of cancer.

Cancer patients frequently have symptoms of anxiety and depression after diagnosis. Often these symptoms are apparent to the physician. We report the case of a cancer patient who appeared to her physician to be coping relatively well but was actually having psychologic symptoms that met criteria for acute stress disorder (ASD). Cancer patients who have psychologic trauma at diagnosis and meet criteria for ASD may appear to be coping better than they are. Mental health interventions for cancer patients are recommended.

Acute Disease↗
PubMed1998

Impingement syndrome and rotator cuff disease as repetitive motion disorders.

The relationship between repetitive motion and subacromial impingement and rotator cuff disease is controversial and poorly understood. The potential etiology is multifactorial and involves patient related factors (age, supraspinatus outlet anatomy, and preexisting rotator cuff pathology) and worker related factors (arm position, lifting requirements, numbers of repetitions). Radiographic and magnetic resonance imaging abnormalities may represent preexisting disease that could have predisposed the patient to the development of impingement syndrome, but should be interpreted cautiously within the context of the remainder of the clinical picture. Treatment often involves temporary or permanent modifications of the work environment.

Biomechanical Phenomena↗
PubMed1997

Nucleotide regulation and characteristics of potassium channel opener binding to skeletal muscle membranes.

[3H]P1075 binding to membrane preparations of rabbit skeletal muscle were observed in the presence of nucleotide triphosphates or diphosphates but not AMP, cAMP, adenosine, tripolyphosphate, or pyrophosphate. Nonhydrolyzable or poorly hydrolyzable ATP analogs inhibited MgATP-supported binding. The EC50 value for MgATP-supported binding (0.4 mM) was decreased approximately 10-fold in the presence of an ATP-regenerating system, and significant metabolism by membrane nucleotidases was confirmed by high performance liquid chromatographic analysis. [3H]P1075 bound to skeletal muscle with a Kd value of 37 +/- 3 nM and a Bmax value of 280 +/- 14 fmol/mg of protein. [3H]P1075 binding to subcellular fractions was highest in membranes enriched in T tubules. Specific binding was reversible, trypsin-sensitive, maximal at pH 8, and stereoselective for the (3S,4R)-enantiomer of cromakalim. Potassium channel openers exhibited a rank order of potency of P1075 > pinacidil > levcromakalim = BMS-180448 > nicorandil > diazoxide = BRL 38226. Fluorescein analogs (ethyleosin, phloxine B, and rose bengal) were relatively potent inhibitors of binding (Ki = 200-300 nM). The potassium channel openers cromakalim and BMS-180448 were competitive inhibitors of [3H]P1075 binding. In contrast, rose bengal and the ATP-regulated potassium channel antagonist glyburide increased the rate of [3H]P1075 dissociation in a manner consistent with noncompetitive interaction.

Adenosine Triphosphate↗
PubMed1996

Resistance to fracture of teeth with various preparations for amalgam.

OBJECTIVES: Advances in dental instrumentation and materials have allowed for increasingly conservative preparations when treating teeth for dental caries. Research has shown that some materials, properly used, can restore teeth to their pre-prepared strength. At the present time, the longevity of these materials is unknown, requiring clinicians to remain committed to conservative methods of tooth preparation. The purpose of this study is to compare the resistance to fracture of teeth prepared with occlusal, mesio-occlusal-distal (MOD) and mesial/distal slot preparations against unprepared control teeth. METHODS: Thirty-two non-carious, non-restored human maxillary premolar teeth were divided into three experimental groups and a control group with eight teeth in each. After preparation, the teeth were loaded to fracture on an Instron Universal Testing Machine, and the results were compared using an Analysis of Variance (ANOVA) followed by Tukey's Studentized Range Test (P < 0.05). Fracture patterns were compared by chi-square analysis at the 0.1 level of probability. RESULTS: There was no significant difference in fracture resistance among the experimental groups, but all were less resistant to fracture than the unprepared control group. The MOD and occlusal groups demonstrated a tendency towards vertical fracture while the mesial-distal slot and unprepared groups tended to a more limited fracture of a single cusp. CONCLUSIONS: Any preparation appears to decrease a tooth's resistance to fracture. Conservative preparation design may affect fracture pattern and enhance options for subsequent restoration.

Analysis of Variance↗
PubMed1996

Severe restriction in jaw movement after routine injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva.

OBJECTIVE: To determine the relationship of dental procedures to immediate ossification and ankylosis of the jaw in patients who have fibrodysplasia ossificans progressiva. STUDY DESIGN: A mail survey was conducted of the 60 patient-members of the International Fibrodysplasia Ossificans Progressiva Association. All 41 patients (18 males, 23 females) who responded were examined. Instantaneous exact hazard rates for ossification of the jaw were calculated by the Weibull model. RESULTS: Thirty-six patients had dental procedures performed. Twenty-one (58%) patients had received an injection of local anesthetic. Five (24%) patients had an immediate flare-up of fibrodysplasia ossificans progressiva with ossification and permanent ankylosis of the jaw (expected occurrence, 0.031; p < 0.0001). None of the 12 patients who had comparable dental work without injections developed heterotopic ossification (expected occurrence, 0.019; not significant). CONCLUSION: Injections of local anesthetic during dental procedures pose serious and immediate risk for inciting heterotopic ossification and ankylosis of the jaw in patients who have fibrodysplasia ossificans progressiva and should be assiduously avoided.

Adolescent↗