Alan G. Harris

Cytokine Dysregulation, Inflammation and Well-Being

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic ‘overshooting’ with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-α and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the ‘systemic anti-inflammatory feedback’ and/or ‘hyperactivity’ of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.

Acromegaly. Clinical and biochemical features in 500 patients.

This prospective study defines the clinical and biochemical features of acromegaly in a large cohort of patients. There was no difference in sex distribution, and for men and women the mean ages at diagnosis (40 +/- 12 and 40 +/- 14 yr, respectively) were similar. Nearly three-quarters of patients were overweight and some 12% severely overweight; the frequency and severity of obesity also was not different between the sexes. Half of patients were hypertensive or were taking anti-hypertensive drugs. Neither GH nor insulin levels were significantly different between normotensive and hypertensive patients. Acral growth and facial coarsening, soft tissue swelling, and excessive perspiration were present in the majority (98%) of patients. Mean serum GH, Sm-C, and PRL levels did not differ between the sexes. Sm-C levels correlated with mean GH concentration (r = 0.31, p < 0.001), both variables inversely related to age. With each decade of life, mean GH and Sm-C levels declined by 7.6 +/- 0.2 ng/mL and 0.5 +/- 0.2 U/mL, respectively. Impaired glucose tolerance was diagnosed in 36% and frank diabetes mellitus in 30% of patients. Hyperprolactinemia was noted in 18% of patients. Galactorrhea was noted in 43 (9%) patients, most of whom were female; the mean GH levels of patients with galactorrhea (60.1 +/- 13 ng/mL) were higher than those of patients without (35.4 +/- 2.6 ng/mL, p = 0.02). Acromegaly appears to afflict men and women equally with a preponderance of presentation in the fourth decade of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Octreotide Therapy for Thyroid-Stimulating Hormone-Secreting Pituitary Adenomas: A Follow-up of 52 Patients

Table. SI Units, Drug, and Abbreviation Thyroid-stimulating hormone (TSH)-secreting adenomas are rare, constituting fewer than 1% of all pituitary adenomas in large neurosurgical series [1-3]. The inappropriate secretion of TSH by these tumors can result in hyperthyroidism [1-5], but diagnosis may be delayed because symptoms are often attributed to more common causes of thyrotoxicosis. This delay, coupled with the usually aggressive nature of these tumors, allows tumors to become large and invasive. In most cases, surgical removal is incomplete, and, even after additional pituitary irradiation, only about 40% of patients can be cured [1, 6]. The use of dopamine agonists has proved to be generally unsuccessful [1, 4, 5]. Because native somatostatin inhibits TSH secretion in healthy persons [7, 8] and in patients with TSH-secreting adenomas [9], treatment with the long-acting somatostatin analog octreotide has been proposed for such patients. Studies of octreotide in a limited number of patients with TSH-secreting adenomas have shown a favorable effect of this drug on TSH secretion, thyroid function, and, in rare cases, pituitary adenoma size [2,10-36]. To assess the efficacy of octreotide therapy in patients with TSH-secreting adenomas, we reviewed outcomes in 15 new cases and 37 previously reported cases. Methods Patients Twenty-seven men and 25 women who were 16 to 84 years old (median age, 44 years) and had a TSH-secreting adenoma were evaluated. Studies were done at 24 medical centers in nine countries (Appendix). Data were collected from reports published in the English or French language between 1987 and 1991 [2,10-36]. The list of published articles and abstracts of papers presented at various national and international meetings was provided by the Centre de Documentation of Laboratoires Sandoz, Rueil-Malmaison, France. The authors of these studies were asked to provide us, when possible, with follow-up information on their patients [2, 10-36]. In 6 of these patients (patients 30 to 35), available data were too imprecise or incomplete, particularly regarding TSH levels, to allow pertinent evaluation [29-32]. However, some data on these patients were analyzed. Data on 15 additional patients (patients 38 to 52) whose studies were done in various centers (see Appendix) and not previously reported were included in the final analysis. In all patients, the diagnosis of thyrotropinoma had been made on the basis of an inappropriate secretion of TSH (that is, the coexistence of increased serum thyroid hormone levels and an increased or normal [but at least unsuppressed] TSH serum level [3]. In all but 5 patients, who had surgically proven microadenoma, macroadenoma generally associated with suprasellar or laterosellar extension was shown by computed tomographic (CT) scan or magnetic resonance imaging (MRI). Before octreotide therapy, 23 patients had undergone pituitary adenomectomy; 9 of these patients had also had radiotherapy of the pituitary area without resolution of hyperthyroidism. At the time octreotide therapy was initiated, some patients were receiving antithyroid medication because of hyperthyroidism or thyroid hormone replacement because of previous thyroidectomy or radioiodine treatments, and only fragmentary information could be obtained in these cases. In all but 4 of the remaining patients (90%), hyperthyroidism was present before treatment. Basal serum TSH levels were increased (5.2 to 129 mU/L) in 23 of 49 patients and normal (but inappropriately unsuppressed in the presence of high thyroid hormone levels) in the remaining patients. Thirty patients had increased serum levels (1.5 to 311 g/L) of free -subunitthe uncombined subunit of glycoprotein hormones often secreted in excess together with TSH by TSH-secreting adenomas [3]whereas 4 of the 37 patients studied had normal levels. Nine of the patients had mixed growth hormone-TSH-secreting adenoma and also had the classic features of acromegaly. Treatment Regimen The initial dose of octreotide (Sandostatin, Sandoz Pharma, Ltd., Basel, Switzerland) ranged from 50 to 100 g subcutaneously two or three times per day. The dosage was increased according to individual biochemical responses to a maximum level of 500 g three times per day. The median octreotide dose at the final evaluation was 300 g/d. In 25 patients, treatment was extended beyond 3 months (range, 3 to 61 months; mean, 20 17 months). Evaluation Patients were evaluated at various intervals determined by the protocol of the medical center at which they were treated. Data from the pretherapeutic evaluation were available in 49 patients. The response to the first injection of octreotide (50 or 100 g), although assessed in 40 patients, was provided in 35. Evaluation of TSH levels was done after 1 to 2 weeks of octreotide therapy in 33 patients. Evaluation was done again after 1 month of therapy in 23 patients. In the 25 patients receiving long-term therapy (> 3 months), evaluation was done at 3-month intervals during the first year and thereafter at 6-month intervals. For each evaluation, we attempted to retrieve measurements of serum TSH, free -subunit, and thyroid hormone levels done on blood samples collected in the morning or, when available, hourly during a 3- to 12-hour profile; mean values were used for analysis. Levels of TSH, -subunit and thyroid hormone (generally as free thyroxine, free triiodothyronine, or both) were measured by immunoradiometric assay or radioimmunoassay using commercially available kits at the individual study centers. In consideration of the different assays used, the normal ranges for TSH and free thyroxine levels were set at 0.1 to 5 mU/L and 10 to 20 pmol/L, respectively. Methods of serum free -subunit determination were too heterogeneous to allow within-group comparison. Thus, the individual course of -subunit was assessed according to the normal reference range indicated by the individual medical center. In general, hormonal responses are indicated as a percentage decrease in hormone levels or expressed in terms of whether they returned to within the normal range (as defined by the investigators). Serial anatomic evaluation of the pituitary gland by either CT scan or MRI was available in 26 patients. In 7 patients, the percentage change in tumor volume was calculated. Abdominal ultrasound examinations were done at regular intervals and at the final evaluation in 19 of the 25 patients receiving long-term therapy. Statistical Analysis Statistical analysis was done using a Wilcoxon test for paired data. Results are expressed as mean SD. Results Hormonal Effects The acute response of serum TSH levels to the first injection of octreotide (50 to 100 g) was evaluated in 35 patients (Figure 1). The TSH level decreased in all but 2 of these patients (mean decrease for the whole group, 55.8% 27%), the nadir occurring between 3 and 6 hours after injection. The -subunit level decreased in 15 of the 19 patients assessed (mean decrease, 37.5% 24%). Figure 1. Individual levels of thyroid-stimulating hormone (TSH) and free -subunit during single-dose octreotide studies in patients with TSH-secreting adenomas. Thirty-three patients were evaluated for the short-term effect of octreotide (Figure 2). The mean pretreatment TSH concentration was 14.7 25.9 mU/L. Reduction of TSH levels after 1 to 2 weeks of octreotide therapy (50 or 100 g two or three times daily) was observed in 30 patients (mean decrease for the whole group, 74.1%). Serum TSH levels decreased to a mean level of 3.8 7.4 mU/L (P < 0.01). Among patients whose basal serum TSH levels were supranormal, 88% showed a reduction of more than 50% in the TSH level; in 72%, the TSH level returned to normal. The -subunit levels, assessed in 19 patients, showed a similar pattern, with a mean reduction of 64.3% (24%). In about two thirds of the patients, the TSH response after 1 to 2 weeks was better than after the first dose; this analysis included 5 patients who did not respond to acute injection with a reduction in TSH level of more than 50%. Thyroid hormone levels decreased in all patients and returned to normal in 73% of patients. Patients had similar TSH and thyroid hormone responses to octreotide, regardless of whether they had a pure TSH-secreting adenoma or a mixed growth hormone-TSH-secreting adenoma. After 1 month of treatment, serum TSH (n = 23) and -subunit (n = 11) levels were similar to those seen after 1 week of treatment (data not shown). In 3 patients, despite the lack of normalization of serum TSH levels, thyroid hormone levels returned to normal after 1 week of therapy [10, 17]. The relation between individual dosage and the hormonal response was impossible to assess because of the different octreotide doses used (ranging from 100 to 300 g/d). Although 2 of the patients studied showed persistently suppressed TSH levels, thyroid hormone levels that initially returned to normal demonstrated an escapedefined as the re-increase in serum levels despite increasing dosageearly between weeks 2 and 4 of treatment. This led to the discontinuation of treatment in these two patients. Figure 2. Individual levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) during short-term (1 to 2 weeks) octreotide therapy in patients with TSH-secreting adenomas. Octreotide therapy was continued beyond 3 months (range, 3 to 61 months; mean, 20 17 months) in 25 patients, with daily doses ranging from 100 to 1500 g. Overall, the response to treatment, as assessed by TSH and -subunit levels, was better than or similar to that after short-term treatment. Based on the persistence of normal thyroid hormone levels, efficacy was maintained in 21 of the 25 patients (84%) as long as the treatment was continued. Tachyphylaxisdefined as the necessity to increase doses to maintain normal TSH levelswas observed in 5 of the 21 patients. Thyroid hormone levels did not increase, however, and, in fact, remained normal in 4 of these pati

Cardiovascular Effects of the Somatostatin Analog Octreotide in Acromegaly

OBJECTIVE To determine the cardiovascular effects of the somatostatin analog octreotide in patients with acromegaly. DESIGN Prospective nonrandomized study. SETTING Referral-based endocrinology clinic. PATIENTS Seven patients with active acromegaly, three of whom had refractory congestive heart failure. The other four patients were free of symptoms associated with heart failure. INTERVENTIONS All patients were treated with octreotide, 100 to 500 micrograms subcutaneously three times daily. The three patients with heart failure continued to receive cardiovascular therapy (angiotensin converting enzyme inhibitors, digitalis, diuretics). MEASUREMENTS AND MAIN RESULTS During octreotide therapy, patients showed a rapid decrease in growth hormone and insulin-like growth factor 1 (IGF-1): Mean levels (+/- SD) fell from 28.1 +/- 32.7 micrograms/L to 5.2 +/- 8.3 micrograms/L and 740 +/- 126 micrograms/L to 372 +/- 64 micrograms/L, respectively (P less than 0.025). Plasma volume returned to normal and heart rate decreased significantly. In the four patients without heart failure, right-heart catheterization done before and after 3 months of octreotide therapy showed an 18.3% +/- 11% reduction in stroke volume and a return to normal of the cardiac index. The three patients with congestive heart failure, evaluated before and after 40 days and up to 2 years of therapy, showed a dramatic clinical improvement that was associated with an increase in stroke volume (by 24% to 51%). In these patients, the cardiac index remained in the normal range, filling pressures were markedly decreased, and pulmonary wedge pressure returned to normal. This improvement was sustained for up to 3 years in the two patients with heart failure who were receiving long-term treatment. CONCLUSION The rapid and sustained cardiac improvement seen in our patients shows that octreotide therapy for patients with acromegaly may be highly beneficial, even in those patients with advanced cardiac failure.

Subjective and objective assessments in patients with seasonal allergic rhinitis: Effects of therapy with mometasone furoate nasal spray

BACKGROUND Efficacy of topical nasal steroid therapy for allergic rhinitis is usually evaluated by patient and clinician assessments of subjective symptom changes in diaries and at clinical interviews. OBJECTIVE We sought to complement the subjective measures with objective measures of nasal cytology, biochemistry, and function. METHODS In this double-blind, randomized study patients with seasonal allergic rhinitis (SAR) 12 years of age or older received 200 microg mometasone furoate nasal spray (n = 80) or placebo spray (n = 41) once daily for 2 weeks. Subjective assessments by clinician and patient comprised symptom/sign scores and overall therapeutic response evaluations. Objective measures included nasal cytology, nasal biochemistry, nasal airway resistance (NAR), mucociliary clearance, and olfactory functions. RESULTS Mometasone furoate produced a significantly greater decrease than placebo in subjective measures of SAR for total symptom score (-46% vs -30%, p < 0.05), total nasal score (-47% vs -30%, p < 0.024), individual nasal symptom scores, and overall therapeutic response. The objective measures of eosinophil, basophil, and neutrophil counts and mucociliary clearance were significantly better in mometasone furoate- than in placebo-treated patients. Similarly, within-treatment statistically significant improvements were produced by mometasone furoate but not by placebo sprays for levels of eosinophilic cationic protein, tryptase and albumin, NAR, and odor identification. Significant positive correlations were found between NAR and nasal stuffiness and between eosinophils, basophils, and neutrophils and both eosinophilic cationic protein and albumin. CONCLUSION Subjective measures of SAR were significantly improved in the mometasone furoate group by comparison with placebo-treated patients. Objective assessments supported the subjective findings because within-treatment measures were frequently significantly improved after mometasone furoate treatment but not after placebo treatment.

Comparison of the effects of desloratadine 5-mg daily and placebo on nasal airflow and seasonal allergic rhinitis symptoms induced by grass pollen exposure.

Background: Nasal congestion is a chronic symptom of seasonal allergic rhinitis (SAR) that is often difficult to treat with antihistamines. Desloratadine, a new, potent, H1‐receptor antagonist has been shown to decrease nasal congestion in clinical trials and to maintain nasal airflow in response to grass pollen exposure. We compared the effects of desloratadine 5 mg and placebo on nasal airflow, nasal secretion weights and SAR symptoms, including nasal congestion, in patients exposed to grass pollen in an environmental exposure unit.

Characteristics of patients with seasonal allergic rhinitis and concomitant asthma

Background Allergic rhinitis and asthma often co‐exist and appear to produce a continuum of airway disease, but whether the clinical characteristics of asthma in patients with seasonal rhinitis differ from those of persistent asthma has not been examined.

Hypothalamic-Pituitary-Adrenal Axis Suppression and Inhaled Corticosteroid Therapy

The safety of long-term inhaled corticosteroid therapy at commonly prescribed doses is an issue of growing concern to physicians and international regulatory bodies. This is so because long-term use of these drugs has become the mainstay of chronic asthma management and their introduction now is widely recommended in official treatment guidelines at the ‘mild persistent’ stage of asthma, where regular daily therapy is first begun. In addition to more frequent use of inhaled corticosteroids, there is a further trend to use higher doses of existing inhaler therapies and to use the newer and more potent compounds that have recently become available. At the same time as these developments have been taking place, there has not been a concurrent move to a more rigorous examination of the safety profile of these inhaled corticosteroid treatments – especially to assess their effects on the hypothalamic-pituitary-adrenal (HPA) axis. Most safety data with respect to HPA axis effects have been derived from testing methods that are limited in their ability to detect HPA system impairment and, more seriously, that can give the impression of functional integrity in the HPA axis when there may be moderate (or even greater) impairment. In this first part of a two-part review of the HPA axis effects of inhaled corticosteroids and of how these effects should be assessed, we examine the currently used and the currently available testing methodologies and also review the present state of knowledge concerning the structure and function of the HPA axis and the effects of its suppression. It is clear that there are state-of-the-art tests to assess in a discriminating manner the safety profile of inhaled corticosteroids. These tests have been insufficiently employed, including during the drug development process, yet they are readily available, relatively inexpensive and can detect adrenal suppression before the appearance of clinical effects. In part 2 of this review we examine what can be learned about the effects of inhaled corticosteroid therapy on the HPA axis from the limited amount of reliable published information from clinical and pharmacological studies describing their use and safety.

Effect of desloratadine therapy on symptom scores and measures of nasal patency in seasonal allergic rhinitis: results of a single-center, placebo-controlled trial

BACKGROUND Desloratadine reduces symptoms and maintains nasal airflow in patients with seasonal allergic rhinitis (SAR) during experimental allergen exposure. OBJECTIVE To compare the effects of desloratadine and placebo on symptom scores, quality of life (QOL), and nasal airway patency in patients with SAR during the allergy season. METHODS Adults with symptomatic SAR were randomized in a double-blind manner to receive desloratadine, 5 mg, or placebo for 14 days. Patient-rated SAR symptoms were recorded twice daily (morning and evening). On days 1 and 15, SAR symptoms were scored jointly (investigator and patient), nasal airflow was measured using 4-phase rhinomanometry, and QOL and the overall condition of SAR were rated. Overall treatment response was scored on day 15. Adverse events were recorded. RESULTS At day 15, total symptom (P = .03) and total nasal symptom (P = .02) scores and patient morning-rated individual nasal symptom scores (except nasal stuffiness) (P < or = .04) decreased significantly from baseline with desloratadine vs placebo. Flow in the descending expiratory nasal airflow phase was significantly greater (P = .046) and the percentage increase in total inspiratory nasal airway resistance was less (P = .03) in the desloratadine group vs the placebo group. The overall condition of SAR was less severe (P = .045), the therapeutic response was greater (P = .004), and the nasal symptom domain of the QOL score was significantly better (P = .03) in the desloratadine group. Adverse event rates were similar in both groups. CONCLUSION Desloratadine treatment for 14 days improved nasal airflow and resistance as well as symptom and QOL scores in patients with symptomatic SAR during the allergy season.

Efficacy and tolerability of loratadine versus fexofenadine in the treatment of seasonal allergic rhinitis: A double-blind comparison with crossover treatment of nonresponders

BACKGROUND Nonsedating antihistamines are well-established treatment for seasonal allergic rhinitis (SAR), but patients do not always respond to the first antihistamine prescribed. OBJECTIVE This double-blind, double-dummy, randomized, 2-phase, multicenter study was designed primarily to compare the therapeutic responses to loratadine and fexofenadine in patients who failed initial therapy with the other drug. METHODS Male and female patients aged 12 to 60 years received loratadine 10 mg once daily (n = 331) or fexofenadine 60 mg twice daily (n = 328) for 14 days (phase 1); nonresponders (ie, those who had <25% reduction in the sum of 5 SAR symptoms rated by the investigator on a 4-point scale) subsequently received the alternate medication for 14 days (phase 2). The investigators rating of relief (complete, marked, moderate, or slight relief of symptoms or treatment failure) at the end of phase 2 was the primary efficacy measure; changes in total symptom severity (TSS) assessed by the investigator (4-point scale) and the patient (11-point visual analog scale) were secondary measures. RESULTS Mean decreases in TSS were significantly greater with loratadine than with fexofenadine for the 659 patients who completed phase 1 (-12.7 vs -10.2, respectively; P = 0.019; patient assessment) and for the 389 patients who responded to initial therapy (-6.6 vs -6.1, respectively; P = 0.037; investigator assessment). Of the 389 patients who responded to initial therapy, 61.0% had received loratadine and 57.0% had received fexofenadine. More nonresponders to initial therapy had moderate, marked, or complete relief of symptoms after switching to loratadine than after switching to fexofenadine (62.4% vs 51.2%, respectively; P = 0.005) and treatment failure in 10.6% vs 21.7%, respectively (P = 0.011). CONCLUSION Overall, ioratadine provided significantly better therapeutic response than fexofenadine in patients who failed to respond to initial therapy with the other drug.