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In this paper, we report the discovery of dual M3antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo(inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro(inhibition of TNFα release). Among the best compounds, compound 92aachieved the goal of demonstrating in vivoefficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.

Supernumerary parathyroid glands (SPGs) are found in 13% of random autopsies. The high incidence of SPGs could explain the persistence or trigger recurrence of renal hyperparathyroidism after surgery. The aim of this study was to assess the frequency and clinical relevance of SPG in patients operated on for renal hyperparathyroidism (HPT). In this retrospective study we reviewed the medical records of 290 patients with renal HPT who were initially treated in our department. We examined the anatomic and pathologic findings during cervical surgical exploration and the outcome of HPT during follow-up. SPGs were identified in 87 patients (30%) during the initial cervicotomy, corresponding to intrathymic parathyroid cell islets (one to four) in 70 cases and to extrathymic SPG in 17 patients. Among 260 patients available for follow-up, 11 experienced persistent HPT (4%), and 34 developed recurrent HPT (13%). A total of 25 patients were reoperated on, and SPGs were responsible for 4 of 8 cases of persistent HPT and 4 of 17 cases of recurrent HPT, representing an overall frequency of 32%. The anatomic distribution of SPGs found during reoperations included thymus, retroesophageal grove, carotid sheath, and mediastinum. SPGs are thus present in 30% of patients with renal HPT and are situated mainly in the thymus. Thymectomy should be performed routinely during the first surgical exploration to prevent recurrences arising from anterior mediastinal glands. SPGs were also responsible for 32% of persistent or recurrent HPT. In that setting, frankly ectopic SPGs are not rare, and preoperative imaging appears highly desirable prior to embarking on surgical reexploration.

Supernumerary parathyroid glands (SPGs) are found in 13% of random autopsies. The high incidence of SPGs could explain the persistence or trigger recurrence of renal hyperparathyroidism after surgery. The aim of this study was to assess the frequency and clinical relevance of SPG in patients operated on for renal hyperparathyroidism (HPT). In this retrospective study we reviewed the medical records of 290 patients with renal HPT who were initially treated in our department. We examined the anatomic and pathologic findings during cervical surgical exploration and the outcome of HPT during follow-up. SPGs were identified in 87 patients (30%) during the initial cervicotomy, corresponding to intrathymic parathyroid cell islets (one to four) in 70 cases and to extrathymic SPG in 17 patients. Among 260 patients available for follow-up, 11 experienced persistent HPT (4%), and 34 developed recurrent HPT (13%). A total of 25 patients were reoperated on, and SPGs were responsible for 4 of 8 cases of persistent HPT and 4 of 17 cases of recurrent HPT, representing an overall frequency of 32%. The anatomic distribution of SPGs found during reoperations included thymus, retroesophageal grove, carotid sheath, and mediastinum. SPGs are thus present in 30% of patients with renal HPT and are situated mainly in the thymus. Thymectomy should be performed routinely during the first surgical exploration to prevent recurrences arising from anterior mediastinal glands. SPGs were also responsible for 32% of persistent or recurrent HPT. In that setting, frankly ectopic SPGs are not rare, and preoperative imaging appears highly desirable prior to embarking on surgical reexploration.

Background:Despite cure of primary aldosteronism by surgical resection, hypertension persists postoperatively in 30% to 50% of patients. The aim of this study was to determine factors influencing long-term outcome of blood pressure after unilateral adrenalectomy for primary aldosteronism. Methods:Records of 100 patients who underwent unilateral adrenalectomy for primary aldosteronism from 1970 through 1997 were reviewed. Patients were distributed in 2 groups according to whether blood pressure was normal (criteria of World Health Organization). Clinical, biochemical, and pathologic data were compared. Results:All patients were biochemically cured. Blood pressure was normal in 56 patients and improved in 44 (mean follow-up, 69 and 59 months). Persistent hypertension correlated with age, known duration and seriousness of preoperative hypertension, family history of hypertension, no preoperative response to spironolactone, and contralateral adrenal hypertrophy. Gender, surgical approach, and pathologic findings were not predictive factors of blood pressure outcome. The prevalence of hypertension was almost the same in these postoperative patients as the prevalence of essential hypertension in a random population of the same age. Conclusions:Early unilateral adrenalectomy allows cure or improvement of hypertension in all patients with primary aldosteronism induced by unilateral excessive source of aldosterone secretion regardless of the pathologic findings. Persistent hypertension suggests that coexisting essential hypertension is present. (Surgery 1998;124:1128-33.)

Abstract. The success of parathyroid surgery is determined by the identification and removal of all parathyroid tumors. Parathyroid tumors accumulate and retain 2-methoxyisobutylisonitrile (MIBI) labeled with technetium-99m. Intravenous injection of this radiopharmacon prior to parathyroid surgery allows identification of parathyroid tumors with a hand-held gamma detector. To assess the value of this technique, a case–control study was performed with 62 patient having nuclear-guided parathyroidectomy and 60 patients having conventional parathyroid explorations. The sensitivity rates of the MIBI probe in single and multiple gland disease were 84.6% and 63.0%, respectively. Rates of success, temporary and permanent hypoparathyroidism, and injury of the recurrent laryngeal nerve were similar in patients who underwent probe-guided surgery and those who had conventional surgery. In conclusion, although the MIBI probe appears to be a valuable tool in parathyroid surgery, its use has not improved the outcome of such surgery at our institution.:

The success of parathyroid surgery is determined by the identification and removal of all parathyroid tumors. Parathyroid tumors accumulate and retain 2-methoxyisobutylisonitrile (MIBI) labeled with technetium-99m. Intravenous injection of this radiopharmacon prior to parathyroid surgery allows identification of parathyroid tumors with a hand-held gamma detector. To assess the value of this technique, a case–control study was performed with 62 patient having nuclear-guided parathyroidectomy and 60 patients having conventional parathyroid explorations. The sensitivity rates of the MIBI probe in single and multiple gland disease were 84.6% and 63.0%, respectively. Rates of success, temporary and permanent hypoparathyroidism, and injury of the recurrent laryngeal nerve were similar in patients who underwent probe-guided surgery and those who had conventional surgery. In conclusion, although the MIBI probe appears to be a valuable tool in parathyroid surgery, its use has not improved the outcome of such surgery at our institution.