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They examined retrospective data on 25 patients surgically treated for a pituitary lesion weight loss pills doctor buy alli 60 mg otc, with all procedures performed by the same senior neurosurgeon who was initially unfamiliar with the endoscopic endonasal approach. Internal view of the sella after removal of the pituitary Outcomes Senior et al20 examined the mortality rate in their series of 176 consecutive patients and found a mortality rate of 0. Most mortality reported in the literature is because of medical complications such as pulmonary embolus or cardiac events. Mortality related to the surgery itself is most often secondary to incomplete resection of large, suprasellar tumors that develop significant edema and irreversible neurological insult. The wide range is likely because of the small numbers of patients in some of the other series. The rate of vascular complications including intracranial hemorrhage, cerebral vascular accident, epistaxis, and intraoperative hemorrhage was 5. Epistaxis controlled with pressure, cauterization, or anterior packing occurred in six resections (3. One patient with a conchal sphenoid early in the series had significant cavernous bleeding from an anterior communicating sinus that resulted in aborting the procedure. Another patient taking an antiplatelet medication (clopidogrel) perioperatively had 900 mL of blood loss and required blood transfusion. There were no episodes of massive epistaxis, cavernous sinus thrombosis, carotid injury, subdural, or subarachnoid hematoma in any of the 193 procedures. Of the patients who had pre- and postoperative imaging studies, 14 (66%) of 21 endoscopically treated patients had gross total resection; 4 patients had two or more operations, and 10 (66%) of 15 patients reported complete symptom resolution at followup. The first nine patients who were treated endoscopically had a mean surgical time of 3. The difference in length of operation between the first nine and the last eight patients treated endoscopically was significantly different. They estimated that the learning curve for endoscopic resection should be 17 or less procedures. Other factors examined included intraoperative blood loss, length of stay, and tumor histology and were similar between the three groups. Kabil et al23 performed a retrospective study of 300 patients who underwent fully endoscopic endonasal pituitary adenoma resection during a 6-year period. Data on outcomes were collected and compared with mean values calculated from several transseptal transsphenoidal reports. From a total of 300 pituitary adenomas treated endoscopically, 139 (46%) were hormonally active, whereas 161 (54%) were nonfunctioning. Remission, being defined as no hormonal or radiologic evidence of recurrence within the time frame of the followup, was demonstrated in 127/134 (95%) of enclosed and 144/166 (87%) of invasive adenomas. A comparison of fully endoscopic endonasal versus transseptal transsphenoidal remission results revealed an improved outcome using the fully endoscopic endonasal technique for all hormonesecreting tumor types: adrenocorticotropic hormone (86 vs. The authors also noted a marked reduction in complications related to the endoscopic procedure, indicating that the fully endoscopic endonasal technique is a safe and effective method for the removal of pituitary adenomas providing more complete tumor removal and reducing complications. The use of the natural ostium preserves a functional sphenoid cavity that can be easily monitored postoperatively. The use of this minimally invasive approach has been shown to decrease the length of patient hospital stay, and the two-team approach using an otolaryngological team working in conjunction with a neurosurgical team has a short learning curve and has been shown to have a low rate of postoperative complications. Pioneers in the development of transsphenoidal surgery: Theodor Kocher, Oskar Hirsch, and Norman Dott. The Pituitary Body and Its Disorders: Clinical States Produced by Disorders of the Hypophysis Cerebri. Harvey Cushing and Oskar Hirsch: early forefathers of modern transsphenoidal surgery. Partial Hypophysectomy for acromegaly: with remarks on the function of the hypophysis. Computerassisted neurosurgical navigational system for transsphenoidal surgery-technical note.

A similarity in response also was noted between muscarine and nerve stimulation in those organs innervated by the craniosacral divisions of the autonomic nervous system weight loss plans discount alli on line. The functional consequences of these effects are hyperpolarization and inhibition of excitable membranes. In addition, heterologous systems may produce different receptor-transducer-effector interactions (Nathanson, 2008). Drugs affecting these endogenous amines and their actions are used in the treatment of hypertension, mental disorders, and a variety of other conditions. The basic physiological, biochemical, and pharmacological features are presented here. The final step occurs only in the adrenal medulla and in a few epinephrine-containing neuronal pathways in the brainstem. These enzymes are not completely specific; consequently, other endogenous substances, as well as certain drugs, are also substrates. These mechanisms serve to maintain the content of catecholamines in response to increased transmitter release. Tyrosinase may be an alternate source for catecholamines, although tyrosinasederived catecholamines are clearly not sufficient for survival (Carson and Robertson, 2002). Our understanding of the cellular sites and mechanisms of synthesis, storage, and release of catecholamines derives from studies of sympathetically innervated organs and the adrenal medulla. In the adrenal medulla, catecholamines are stored in chromaffin granules (Aunis, 1998). Vasostatin 1, the N-terminal fragment of chromogranin A, has been found to have antibacterial and antifungal activity (Lugardon et al. This family of proteins transports amino acids and their derivatives into cells using cotransport of extracellular Na+ as a driving force for substrate translocation against chemical gradients (see Chapter 5). One hypothesis is that the pool of neurotransmitter available for displacement by these drugs is small relative to the total amount stored in the sympathetic nerve ending. The 2A and 2C adrenergic receptors are the principal prejunctional receptors that inhibit sympathetic neurotransmitter release, whereas the 2B adrenergic receptors also may inhibit transmitter release at selected sites. The importance of neuronal reuptake of catecholamines is shown by observations that inhibitors of uptake. As a consequence, most metabolism of catecholamines takes place in the same cells where the amines are synthesized and stored. Thus, Ahlquist proposed the designations and for receptors on smooth muscle where catecholamines produce excitatory and inhibitory responses, respectively (an exception was the gut, which generally is relaxed by activation of either or receptors). This initial classification was corroborated by the finding that certain antagonists produced selective blockade of the effects of adrenergic nerve impulses and sympathomimetic agents at receptors. Animals treated with 3 receptor agonists exhibit a vigorous thermogenic response as well as lipolysis (Robidoux et al. The existence of a fourth adrenergic receptor, 4 was proposed but no such receptor has been cloned; rather, the "4 receptor" seems to be an affinity state of the 1 adrenergic receptor rather than a distinct new protein (Gherbi et al. Although there is little evidence to suggest that 1 adrenergic receptors function presynaptically in the autonomic nervous system, 2 receptors are present at postjunctional or nonjunctional sites in several tissues. Cloning revealed additional heterogeneity of both 1 and 2 adrenergic receptors (Bylund, 1992). Elucidation of the characteristics of these receptors and the biochemical and physiological pathways they regulate has increased our understanding of the seemingly contradictory and variable effects of catecholamines on various organ systems. Although structurally related (discussed further in the chapter), different receptors regulate distinct physiological processes by controlling the synthesis or mobilization of a variety of second messengers. It was known that adrenergic agents could cause either contraction or relaxation of smooth Raymond Ahlquist and the Functional Definition of and Receptors.

Drug X is more efficacious than drug Y; their asymptotic fractional responses are 100% for drug X and 50% for drug Y weight loss pills without caffeine alli 60mg with visa. The advantage of using maxima is that this property depends solely on efficacy, whereas drug potency is a mixed function of both affinity and efficacy. One is straightforward competitive antagonism, whereby a drug with affinity for a receptor but lacking intrinsic efficacy. The magnitude of the rightward shift of the curve depends on the concentration of the antagonist and its affinity for the receptor (Schild, 1957). For example, varenicline is a nicotinic receptor partial agonist used in smoking cessation therapy. In each set of curves, the green curve represents the effect of orthosteric agonist, unmodulated by any antagonist or potentiator. Competitive antagonism occurs when the agonist A and antagonist I compete for the same binding site on the receptor. If the antagonist binds to the same site as the agonist but does so irreversibly or pseudoirreversibly (slow dissociation but no covalent bond), it causes a shift of the dose-response curve to the right, with progressive depression of the maximal response as [I] increases. Allosteric effects occur when an allosteric ligand I or P binds to a different site on the receptor to either inhibit (I) the response (panel C. This allosteric effect is saturable; inhibition or potentiation reaches a limiting value when the allosteric site is fully occupied. Noncompetitive antagonism can be produced by an allosteric or allotopic antagonist, which binds to a site on the receptor distinct from that of the primary agonist, thereby changing the affinity of the receptor for the agonist. Such positive interactions of two agents may permit use of reduced concentrations of each drug, thereby reducing concentration-dependent adverse effects. Drugs used in combination can also demonstrate negative synergism or subadditive effects, where the efficacy of the drug combination is less than would be expected if the effects were additive. If A and B are superadditive (positive synergism), the relative concentrations of A and B needed to achieve a given response will fall below the additive response line. The basis for the use of isobolograms in characterizing the effects of drug combinations has been developed and reviewed by Tallarida (2006, 2012). Drug responsiveness may change because of disease, age, or previous drug administration. Receptors are dynamic, and their concentrations and functions may be up- or downregulated by endogenous and exogenous factors. Data on the correlation of drug levels with efficacy and toxicity must be interpreted in the context of the pharmacodynamic variability in the population. The isobologram shows the line of additivity for a 50% effect obtained with a combination of two drugs (concentrations of drug A are on the x axis, concentrations of drug B are on the y axis) that have similar effects but different mechanisms of action. The isobologram can be used to estimate the concentrations of two drugs needed to obtain a given effect when used in combination. For a full explanation of the concept and utility of isoboles, consult Tallarida (2006, 2012). An experiment was performed on 100 subjects, and the effective plasma concentration that produced a quantal response was determined for each individual. The number of subjects who required each dose was plotted, giving a log-normal frequency distribution (purple bars). The normal frequency distribution, when summated, yields the cumulative frequency distribution-a sigmoidal curve that is a quantal concentration-effect curve (red bars, red line). Therefore, use of the population therapeutic window to optimize the dosage of a drug should be complemented by monitoring appropriate clinical and surrogate markers for drug effect(s) in a given patient. The effects of these factors on variability of drug pharmacokinetics are described more thoroughly in Chapters 2, 5, 6, and 7. Drug Interactions and Combination Therapy Drugs are commonly used in combination with other drugs, sometimes to achieve an additive or synergistic effect, but more often because two or more drugs are needed to treat multiple conditions. Marked alterations in the effects of some drugs can result from coadministration with other agents, including prescription and nonprescription drugs, supplements, and nutraceuticals. Understanding the mechanisms of drug interactions provides a framework for preventing them. Examples of pharmacokinetic interactions that can enhance or diminish the delivery of drug to its site of action are provided in Chapter 2.

Multidisciplinary operative teams are typically needed with the involvement of otolaryngology weight loss pills hcg order alli 60mg fast delivery, neurosurgery, ophthalmology, and others. While there are single-surgeon techniques, two-surgeon techniques are more often employed in the setting of complicated malignancies. This allows a greater ability for surgical manipulation, with one surgeon providing visualization and another performing bimanual surgical dissection. For endoscopic-assisted methods, tumors may be approached through multiple approaches, including combining endonasal and open transcranial approaches if needed. A way to consider endoscopic surgery is to view the approach and resection as defined by approach corridors. This has been well described in the open literature, with the paradigm shifted because of the use of endoscopic methods; in contrast with open techniques, a wide lateral corridor is not needed to reach deep in the skull base. The surgeon can choose a more direct path to a lesion and use the endoscope to reach it. The limits of endoscopic resection continue to expand with the improvement in techniques and equipment. Tumors that preclude a completely endoscopic approach include those with involvement of superficial structures such as skin and subcutaneous fat. Furthermore, invasion of the anterior orbit or globe, or lesions superior or lateral to the optic nerve can be difficult to access endoscopically. In cases of highly aggressive local growth such as tumors that encase the carotid artery or invade the cavernous sinus, surgical excision has a high morbidity and mortality. It is often reserved for salvage after neoadjuvant chemotherapy with or without radiation. For tumors, such as adenoid cystic carcinomas, however, even procedures with curative intent often cannot remove the entirety of the lesion because of the potential for extensive perineural spread into the skull base and intracranial cavity. The goal is to remove as much tumor as possible with as little damage to the cranial nerves, orbit, and other vital structures in preparation for adjuvant therapies. For patient with metastatic disease or those medically unfit for lengthy surgeries, palliative resection is performed to relieve symptoms such as mass effect and pressure, epistaxis, nasal obstruction, and pain. The ease of access to the endonasal corridor makes repeat palliative debulking procedures a possibility. Different technologies have enabled resection of malignancies through an endoscopic route. A key technology is image guidance, with the ability to fuse computed tomography scan, magnetic resonance imaging, and positron emission tomography images. Image shows an endoscopic view of a sarcoma extending into the infratemporal fossa, localized with image guidance, to allow for intraoperative navigation. Much of the hesitation to accept the endoscopic or some endoscopic-assisted approaches is centered on the likely inability to preserve the en bloc excision of a tumor. The classic en bloc resection may not be possible because of the size of the lesion relative to the operative portal. As such, it is often necessary to debulk the tumor to gain full access of the lesion, with acquisition of the same margins as one would in an open procedure. However, in the case of sinonasal lesion, the debulking reduces the volume of tumor growing into the air-filled cavities of the sinuses and does not violate or manipulate normal tissue planes. Piecemeal excisions have proven successful in various other scenarios including treatment of cutaneous malignancy. Image shows a sinonasal undifferentiated carcinoma undergoing carbon dioxide laser-assisted resection. Note the cut below the level of the tumor along the nasal septum to provide a wide margin for resection. An advantage of endoscopic approaches is the reduced surgical corridor aperture required to reach anatomic areas. Image shows an example of (A) the endoscopic corridor versus (B) the analogous open corridor to reach the same anatomic area. This is underscored by the association of local recurrence and decreased survival with positive surgical margins. It is important to note that there is no head-to-head study on reconstruction methods or postoperative management.

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