ABSTRACT
A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Amides/therapeutic use , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Amides/pharmacology , Anti-Asthmatic Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4 , Humans , Phosphodiesterase Inhibitors/pharmacologyABSTRACT
The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Area Under Curve , Cyclic Nucleotide Phosphodiesterases, Type 4 , Guinea Pigs , Phosphodiesterase Inhibitors/pharmacokinetics , Quinolines/pharmacokinetics , Vomiting/chemically inducedABSTRACT
The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/pharmacology , Furans/chemical synthesis , Furans/pharmacology , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Anti-Asthmatic Agents/pharmacokinetics , Binding Sites , Cyclic Nucleotide Phosphodiesterases, Type 4 , Furans/pharmacokinetics , Guinea Pigs , Indicators and Reagents , Phosphodiesterase Inhibitors/pharmacokinetics , Pyridines/pharmacokinetics , Rolipram/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis of a novel series of guanine analogues is reported. The compounds have been assessed in vitro and some analogues have been found to be inhibitors of phosphodiesterase type 7 (PDE7).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Guanine/chemical synthesis , Guanine/pharmacology , Isoenzymes/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 3 , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cyclic Nucleotide Phosphodiesterases, Type 7 , Enzyme Inhibitors/metabolism , Guanine/analogs & derivatives , Inhibitory Concentration 50 , Structure-Activity RelationshipABSTRACT
BACKGROUND: The role of planned neck dissection after organ preservation therapy with radiotherapy or chemotherapy/radiotherapy for advanced head and neck cancers presenting with clinically positive neck disease is still being elucidated. The aim of this study is to review the outcomes of such patients treated by organ preservation therapy at our institution. METHODS: A retrospective chart review of 33 patients who underwent planned neck dissections after organ preservation therapy for advanced primary head and neck malignancy. Endpoints measured were disease-free survival and local, regional, and distant control. SETTING: Tertiary metropolitan medical center. RESULTS: Two-year actuarial disease-free survival was 61%, and neck control was 92%, with only two failures in the neck. The use of neoadjuvant chemotherapy and total dose of radiotherapy did not correlate with neck control or disease-free survival. The presence of pathologically positive nodal disease at the time of neck dissection did not correlate with recurrent neck disease, but was a predictor of local recurrence (p = .0086). CONCLUSIONS: Our data suggest that for patients undergoing planned neck dissection after organ preservation therapy, neck control is obtained in almost all cases. The presence of pathologically positive nodal disease at the time of surgery may have implications for the incidence of local recurrence.
Subject(s)
Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/therapy , Neck Dissection , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Male , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Benzofurans/chemical synthesis , Benzofurans/pharmacology , Phosphodiesterase Inhibitors/chemical synthesis , Administration, Oral , Animals , Asthma/drug therapy , Benzamides/adverse effects , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzofurans/adverse effects , Cyclic Nucleotide Phosphodiesterases, Type 4 , Eosinophilia/drug therapy , Guinea Pigs , Inhibitory Concentration 50 , Phosphodiesterase Inhibitors/adverse effects , Phosphodiesterase Inhibitors/pharmacology , Pyridines/adverse effects , Pyridines/chemical synthesis , Pyridines/pharmacology , Rolipram/adverse effects , Rolipram/analogs & derivatives , Rolipram/pharmacology , Structure-Activity Relationship , Vomiting/chemically inducedABSTRACT
Ectopic thyroid is rare and occasionally presents suddenly in childhood. Adult patients with thyroid ectopy who develop local symptoms commonly have an enlarged ectopic gland and hypothyroidism. We describe the first case of an adult patient who sudden presented with sudden dysphagia and dyspnea caused by a large lingual thyroid in clinical and biochemical euthyroidism. Treatment consisted of surgical removal of the ectopic gland and thyroid hormone replacement therapy.
Subject(s)
Choristoma/pathology , Thyroid Gland , Tongue Diseases/pathology , Adolescent , Choristoma/diagnostic imaging , Choristoma/surgery , Hormone Replacement Therapy , Humans , Male , Thyroid Hormones/therapeutic use , Tomography, X-Ray Computed , Tongue Diseases/diagnostic imaging , Tongue Diseases/surgeryABSTRACT
OBJECTIVE: To report the complication rate from planned, posttreatment neck dissections in patients who show control of primary squamous cell carcinoma by chemotherapy and radiotherapy or radiotherapy alone. DESIGN: Retrospective review of case series. SETTING: Georgetown University Medical Center, Washington, DC. PATIENTS: Thirty-four patients with clinically positive neck disease treated with organ preservation therapy for squamous cell carcinoma of the head and neck. INTERVENTIONS: Planned neck dissection after treatment with chemotherapy and radiotherapy or radiotherapy alone. MAIN OUTCOME MEASURE: Perioperative complications. RESULTS: Forty-one neck dissections were performed on 34 patients. Complications were seen in 13 (38%) of 34 patients and 15 (37%) of 41 neck dissections. Wound complications occurred in 9 (22%) of 41 dissections. Neck dissection complication rate did not correlate with previous use of chemotherapy or with the use of brachytherapy at the primary site at the time of the neck dissection. Preoperative radiotherapy dose greater than 70 Gy was associated with complications in 58% vs 29% when preoperative dose was less than 70 Gy (P = .09). This trend was reflected primarily in wound complications (42% vs 14%; P = . 10) and reached significance for skin flap necrosis (33% vs 0%; P = .005). Other factors that were associated with increased complications were preoperative albumin level less than 38 g/L and early neck drain removal. CONCLUSIONS: The complication rate associated with planned posttreatment neck dissection is similar to that previously reported for neck dissection. Wound complications are more common when higher preoperative radiotherapy doses are used.
Subject(s)
Carcinoma, Squamous Cell/surgery , Head and Neck Neoplasms/surgery , Lymph Node Excision , Postoperative Complications , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Combined Modality Therapy , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/therapy , Humans , Neck , Neoplasm Staging , Radiotherapy Dosage , Retrospective Studies , Tongue Neoplasms/pathology , Tongue Neoplasms/surgeryABSTRACT
Although the use of carotid artery stents is increasing, the management of recurrent stenosis after their placement is undefined. The authors report on a patient who underwent two left carotid endarterectomies followed by left carotid angioplasty and stent placement for recurrent stenosis. A third symptomatic recurrence was subsequently managed by placement of a saphenous vein interposition graft from the common carotid artery to the distal cervical internal carotid artery. The patient remained without hemispheric or retinal ischemia at his 5-month follow-up visit. Interposition grafting should be considered as a treatment option for carotid restenosis after initial endarterectomy and stent placement.
Subject(s)
Blood Vessel Prosthesis Implantation , Carotid Stenosis/surgery , Endarterectomy , Postoperative Complications , Saphenous Vein/transplantation , Stents , Aged , Carotid Stenosis/diagnostic imaging , Carotid Stenosis/etiology , Cerebral Angiography , Humans , Male , RecurrenceSubject(s)
Graft Survival , Pectoralis Muscles/transplantation , Surgical Flaps/methods , Aged , Carcinoma, Squamous Cell/rehabilitation , Carcinoma, Squamous Cell/surgery , Dissection , Ear Neoplasms/rehabilitation , Ear Neoplasms/surgery , Ear, External/surgery , Female , Humans , Ligation , Male , Mammary Arteries/anatomy & histology , Mammary Arteries/surgery , Middle Aged , Mouth Neoplasms/rehabilitation , Mouth Neoplasms/surgery , Neoplasm Recurrence, Local/rehabilitation , Neoplasm Recurrence, Local/surgery , Pectoralis Muscles/anatomy & histology , Pectoralis Muscles/blood supply , Temporal Bone/surgeryABSTRACT
1. The relative binding affinity of zearalenone, alpha-zearalenol, and beta-zearalenol for estrogen receptors was determined in the pig, rat and chicken. 2. Similar relative binding patterns were observed, with alpha-zearalenol exhibiting greater affinity than zearalenone and beta-zearalenol the least binding affinity in all species. 3. The relative binding affinity of alpha-zearalenol was greater in pig, than in rat and significantly greater than in chicken. 4. Interspecies differences in zearalenone sensitivity may be due to the binding affinity of alpha-zearalenol for estrogen receptors and differences in zearalenone metabolites formed.
Subject(s)
Fallopian Tubes/metabolism , Oviducts/metabolism , Receptors, Estrogen/metabolism , Resorcinols/metabolism , Uterus/metabolism , Zearalenone/metabolism , Zeranol/metabolism , Animals , Chickens , Diethylstilbestrol/metabolism , Female , In Vitro Techniques , Rats , Rats, Inbred Strains , Species Specificity , Swine , Zeranol/analogs & derivativesABSTRACT
Closed mitral commissurotomy (CMC) was performed at the National Heart Institute in 303 patients (73% women, 27% men; mean age 40 years) with acquired isolated mitral stenosis between 1954 and 1980. The average mean mitral valve gradient decreased from 14.2 +/- 0.4 to 5.3 +/- 0.4 mm Hg (p less than 0.001), and mitral valve area index increased from 0.7 +/- 0.03 to 1.4 +/- 0.9 cm2/m2 (p less than 0.001). The perioperative mortality was 2%. Ninety-two percent of patients improved one or more functional classes after CMC. Actuarial survival was 95%, 82% and 70% at 5, 10 and 15 years after CMC, respectively. Fifty-four patients (18%) required mitral valve replacement (MVR) a mean of 9.6 years after commissurotomy (range 1-26 years). Before CMC, factors associated with later MVR included preoperative functional class, calcification of the mitral valve, and the absence of an opening snap. After CMC, poor functional improvement, congestive heart failure, atrial fibrillation, and the necessity for a repeat CMC were associated with late MVR. Catheterization after CMC showed that patients who later required MVR had a smaller decrease in left atrial pressure (p less than 0.001), more mitral regurgitation (p less than 0.001), and were more likely to have pulmonary hypertension (p less than 0.05). The indications for MVR were residual stenosis with or without mild mitral regurgitation in 33 patients (61%), restenosis in 15 (28%), and moderate-to-severe regurgitation in six (11%). Perioperative mortality for valve replacement was 13%. Among survivors, 88% improved at least one functional class after valve replacement. Actuarial survival was estimated to be 95% at 5 years and 74% at 10 years after MVR. This study confirms that CMC provides excellent long-term hemodynamic and clinical improvement in appropriately selected patients. When symptomatic deterioration occurs late after CMC, MVR restores clinical and hemodynamic improvement in many patients. CMC continues to be performed at the National Heart Institute in selected patients with acquired mitral stenosis.