Adult vaccination against tetanus and diphtheria: the European perspective.

Besides immunizations against influenza, Streptococcus pneumoniae and herpes zoster, which are recommended specifically for elderly people, regular booster vaccinations against tetanus, diphtheria and in some cases pertussis and polio are recommended in many European countries for adults, including elderly people. Vaccination recommendations for adults differ greatly between individual countries and coverage data is scarce. Tetanus-specific antibody concentrations are generally higher than diphtheria-specific antibodies, and a substantial proportion of adults, and particularly of elderly people, do not have protective antibody concentrations against diphtheria. Antibody levels increase upon booster vaccination in all age groups, but diphtheria-specific antibody concentrations remain below protective levels in some older individuals, even immediately after vaccination and long-term protection is frequently not achieved. Future vaccination strategies should therefore include regular and well-documented booster shots, e.g. against tetanus and diphtheria, throughout life.

How immunosuppressive therapy affects T cells from kidney transplanted patients of different age: the role of latent cytomegalovirus infection.

The average age of patients receiving renal transplantation is increasing as programmes have been established which support the donation of organs from elderly donors to older recipients. Little is known about the effect of immunosuppressive therapy on the immune system of older patients. In this study, T cell function and the composition of the T cell repertoire were analysed in immunosuppressed renal transplant recipients of different age and cytomegalovirus (CMV) status in comparison to age- and CMV-matched controls. Independent of age and CMV status, the production of interleukin (IL)-2 and interferon (IFN)-γ by T cells was decreased in the patient groups and autologous serum from patients was capable of inhibiting the proliferation of CD3⁺ T cells. CXCR5 expression on T cells was increased in patients versus controls reflecting reduced endogenous IL-2 signalling under immunosuppressive therapy. In CMV-seronegative patients kidney transplantation and immunosuppressive therapy did not induce changes in the CD8⁺ T cell pool, but there was a moderate increase in CD4⁺CD28⁻ effector T cells when compared to age-matched controls. In contrast, latent CMV infection triggered a shift from early to late differentiated CD4⁺ and CD8⁺ T cells in patients and controls. This shift was most pronounced in elderly transplant patients under immunosuppressive therapy. In conclusion, our results demonstrate that immunosuppressive therapy following kidney transplantation is effective in patients older than 65 years. Latent CMV infection, however, accelerates age-related changes in the T cell repertoire in elderly people under immunosuppressive therapy. These patients should therefore be monitored with special care.

Optimizing iron supplementation by monitoring serum ferritin levels in premature infants.

BACKGROUND: Iron (Fe) is essential for growth, but optimal intake is controversial. Our NICU practice was to supplement 2 mg/kg/d Fe for all preterm infants receiving human milk when they achieved full feeding volume. Adjusting Fe supplementation based on ferritin levels is thought to better address physiologic requirements. Our objective was to assess the impact of therapeutic monitoring of ferritin levels on the initiation and dosing of iron supplementation, hematocrit, transfusions, and oxygen radical diseases in preterm infants. METHODS: Preterm infants (< 32 weeks gestation, n = 100) were included. Ferritin was measured when full feeds were achieved, and then every 2 weeks. Fe was started at 2 mg/kg/d or continued at current dose for ferritin 40-300µg/L, increased by 1-2 mg/kg/d for < 40µg/L, or discontinued for > 300µg/L. Outcomes were compared with a historical control group. RESULTS: Ferritin levels were not predictable by dietary or transfusion histories. Using the ferritin protocol, 70% of infants received Fe at the time of full feeds, compared to 100% of controls. In contrast, all infants received Fe 4 weeks later, compared to 87% of controls. Mean age at Fe initiation increased (14.8±6.3 to 21.0±11.76 days). Peak doses were higher, with 32% receiving > 2 mg/kg day by 6 weeks, with fewer transfusions. The incidence of bronchopulmonary dysplasia and necrotizing enterocolitis did not change. CONCLUSION: An iron protocol based on ferritin levels results in later initiation, higher doses, and fewer transfusions, without increasing oxygen radical diseases.

Serum ghrelin is associated with early feeding readiness but not growth in premature infants.

BACKGROUND: Feeding tolerance among premature infants is unpredictable using clinical parameters. Ghrelin, a peptide hormone, acts on the hypothalamus to increase hunger and gut motility. It is present in fetal tissues, promotes intestinal maturation, and is secreted in milk. We hypothesized that higher serum ghrelin levels on days 0-7 are associated with improved feeding tolerance and growth in premature infants. METHODS: Infants (< 1500 g birth weight, n = 36) were recruited on day (D) 0-7. Serum ghrelin was measured by ELISA on D 0-7, D 10-14, and D 24-32, and milk ghrelin in a feeding concurrent with each serum sample. Feeding tolerance was assessed as days to first and full enteral feeds. Growth was quantified as both weight and adipose and muscle deposition by ultrasound. RESULTS: Mean serum ghrelin levels decreased from D 0-7 to D 24-32. Higher ghrelin levels on D 0-7 were correlated with shorter time to first enteral feeding, but not with time to full enteral feeds, rate of weight gain, or rate of accretion of muscle or adipose tissue. Milk ghrelin was not related to serum ghrelin or growth. Abdominal and suprascapular muscle and adipose increased during the first month, but weight gain correlated only with the rate of accretion of abdominal adipose. CONCLUSIONS: Elevated serum ghrelin in the first days of life may contribute to gut motility and readiness to feed. Weight gain in premature infants may primarily indicate abdominal fat accumulation, suggesting that ultrasound measurement of muscle accretion is a better marker for lean body growth.

Exhaled breath condensate nitrite in premature infants with bronchopulmonary dysplasia.

BACKGROUND: Tracheal aspirate is the conventional method to measure biomarkers of inflammation and oxidation from premature infants on mechanical ventilation at risk for bronchopulmonary dysplasia (BPD), but this method is invasive. Exhaled breath condensate (EBC) is a novel, non-invasive method that has been used in older populations. Nitrite, a stable metabolite of nitric oxide (NO), is elevated in inflammatory conditions. We aim to investigate the feasibility of EBC nitrite collection from ventilated premature infants and to quantify EBC nitrite in infants with and without BPD. We hypothesize that EBC nitrite correlates with TA nitrite, and that EBC nitrite in the first week of life is higher in infants who will develop BPD than those without BPD. METHODS: In a pilot prospective cohort study, TA and EBC were collected in the first week of life from mechanically ventilated premature infants. Nitrite levels were measured using chemiluminescence. RESULTS: EBC nitrite significantly correlated with TA nitrite (r = 0.45, p = 0.025). Of 40 infants, 33 (82.5%) developed BPD. EBC and TA nitrite levels collected in the first week of life had a higher trend in infants with BPD than those without BPD (p = 0.23 and 0.38 respectively). CONCLUSIONS: Higher trend of EBC nitrite in the first week of life was associated with the development of BPD. Correlation of nitrite level in EBC with that in TA (conventional method) highlights the utility of EBC as an alternative, non-invasive method to measure inflammation. Further refinement of conditions and timing may optimize the predictive value of EBC nitrite.

Performance of carbon arc-discharge nanotubes to hydrogen energy storage.

Adsorption properties of gram-scale samples of different kind of arc discharge nanotubes were studied, namely: (A) raw collaret collected on the cathode, (B) raw soots collected on the lateral reactor wall, (C) thermally treated soot, and (D) thermally then chemically treated soot. The morphology, structure, and composition of these materials were characterized by SEM, TEM, TGA, and BET. In addition, hydrogen adsorption isotherms were recorded experimentally for A, B, and D samples over the pressure range of 0 to 55 bar at ambient temperature. Our experiments indicated a maximum-yet weak-hydrogen storage at room temperature of approximately 0.13 H2 wt% for the purified product (D).

Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia.

PURPOSE: To determine the maximum-tolerated dose, pharmacokinetic interaction, and activity of PSC 833 compared with daunorubicin (DNR) and cytarabine in patients with poor-risk acute myeloid leukemia. PATIENTS AND METHODS: Patients received ara-C 3 g/m(2)/d on 5 consecutive days, followed by an IV loading dose of PSC 833 (1.5 mg/kg) and an 84-hour continuous infusion escalating from 6, 9, or 10 mg/kg/d. Daunorubicin was administered as a 72-hour continuous infusion at 34 or 45 mg/m2/d [corrected]. Responding patients received consolidation chemotherapy with DNR pharmacokinetics performed without PSC-833 on day 1, and with PSC-833 on day 4. Response was correlated with expression of P-glycoprotein and lung resistance protein (LRP), and in vitro sensitization of leukemia progenitors to DNR cytotoxicity by PSC 833. RESULTS: All 43 patients are assessable for toxicity and response. Grade 3 or greater hyperbilirubinemia (70%) was the only dose-dependent toxicity. Four patients (9%) succumbed to treatment-related complications. Twenty-one patients (49%) achieved a complete remission or restored chronic phase, including 10 of 20 patients treated at the maximum-tolerated dose of 10 mg/kg/d of PSC-833 and 45 mg/m(2) of DNR. The 95% confidence interval for complete response was 33.9% to 63.7%. Administration of PSC 833 did not alter the mean area under the curve for DNR, although clearance decreased approximately two-fold (P =.04). Daunorubicinol clearance decreased 3.3-fold (P =.016). Remission rates were not effected by mdr-1 expression, but LRP overexpression was associated with chemotherapy resistance. CONCLUSION: Combined treatment with infused PSC 833 and DNR is well tolerated and has activity in patients with poor risk acute myeloid leukemia. Administration of PSC 833 delays elimination of daunorubicinol, but yields variable changes in DNR systemic exposure.

Phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer.

PURPOSE: To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer. PATIENTS AND METHODS: Patients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone. RESULTS: Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease. Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%. Eighteen patients have died. The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible. CONCLUSION: The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone. Toxicity was moderate and reversible.

Nitric oxide in the lung: therapeutic and cellular mechanisms of action.

Nitric oxide is produced by many cell types in the lung and plays an important physiologic role in the regulation of pulmonary vasomotor tone by several known mechanisms. Nitric oxide stimulates soluble guanylyl cyclase, resulting in increased levels of cyclic GMP in lung smooth muscle cells. The gating of K+ and Ca2+ channels by cyclic GMP binding is thought to play a role in nitric oxide-mediated vasodilation. Nitric oxide may also regulate pulmonary vasodilation by direct activation of K+ channels or by modulating the expression and activity of angiotensin II receptors. Administration of nitric oxide by inhalation has been shown to acutely improve hypoxemia associated with pulmonary hypertension in humans and animals. This is presumably due to its ability to induce pulmonary vasodilation. Inhaled nitric oxide improves oxygenation and reduces the need for extracorporeal membrane oxygenation in term and near-term infants with persistent pulmonary hypertension. However, long-term benefits to these infants have been difficult to demonstrate. In other pathologic conditions, such as prematurity and acute respiratory distress syndrome, short-term benefits have not been shown conclusively to outweigh potential toxicities. For example, high-dose inhaled nitric oxide decreases surfactant function in the lung. Inhaled nitric oxide also acts as a pulmonary irritant, causing priming of lung macrophages and oxidative damage to lung epithelial cells. Conversely, protective effects of nitric oxide have been described in a number of pathological states, including hyperoxic and ischemia/reperfusion injury. Nitric oxide has also been reported to protect against oxidative damage induced by other reactive intermediates, including superoxide anion and hydroxyl radical. The dose and timing of nitric oxide administration needs to be ascertained in clinical trials before recommendations can be made regarding its optimal use in patients.

Pharmacologic therapy of persistent pulmonary hypertension of the newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is a potentially life-threatening condition characterized by a failure of pulmonary vascular resistance to decrease adequately during the transition to extrauterine life. Inhaled nitric oxide, a vasodilator that acts selectively on the pulmonary circulation, has revolutionized the treatment of this condition. However, inhaled nitric oxide has not proven effective in all patients, particularly those with congenital diaphragmatic hernias or meconium aspiration syndrome. Furthermore, large clinical trials of inhaled nitric oxide have failed to demonstrate significant differences in mortality between nitric oxide-treated and control infants with PPHN. Other therapeutic approaches to PPHN have been limited by a relative lack of specificity for the pulmonary circulation, and have received much less attention. Pharmacologic approaches, including pulmonary surfactants, prostacyclin, endothelin antagonists, Ca(2+)-channel blockers, magnesium sulfate, and tolazoline, have exhibited varying degrees of efficacy in lowering pulmonary vascular pressures in humans and/or animals. A number of these agents are also effective when used in combination. For example, phosphodiesterase inhibitors have been reported to act synergistically with inhaled nitric oxide. Surfactants also appear to be useful in PPHN, particularly in patients with congenital diaphragmatic hernia, when used in combination with other therapies. Surfactant lavage and other novel therapies may also be effective in combination therapy of meconium aspiration syndrome. Further studies should be directed at defining the optimal therapies in specific clinical settings. Validation of multiple therapeutic modalities for PPHN, including inhaled nitric oxide, will allow for rational, combined vasodilator strategies that are specific for the underlying pathophysiology in each patient.

HLA antigens and schizophrenia.

We typed 45 schizophrenic patients for 35 HLA antigens and compared their frequencies with 1,263 population controls. No significant differences between schizophrenics and controls were found. When the schizophrenics were subtyped, a significant (P less than .05) excess of Aw26 was found among the hebephrenics, compared with the population controls. When the published literature on schizophrenia-HLA associations was surveyed, none of the reported associations were found to be consistent across studies. Some possible explanations for the heterogeneity among studies are discussed and it is concluded that an association between schizophrenia and any of the HLA antigens has not yet been demonstrated.

Functional heterogeneity in liver and lung macrophages.

Although initially considered merely "scavenger cells" that participate in immunologic responses only after B and T lymphocytes have performed their biological tasks, more recent evidence suggests that macrophages play a key role in host defense as well as in the maintenance of normal tissue structure and function. For macrophages to perform their biological functions, they must be activated. This involves up-regulation of an array of signaling pathways resulting in altered gene expression and increased biochemical and functional activity. Macrophages have been identified in almost all tissues of the body. However, the basal activity of these cells, as well as their ability to respond to inflammatory mediators, varies considerably with their location. In addition, even within a particular tissue, there is evidence of macrophage heterogeneity. The largest populations of macrophages in the body are located in the liver and lung. Because of the unique attributes of these tissues, hepatic and pulmonary macrophages play essential roles not only in nonspecific host defense but also in the homeostatic responses of these tissues. In this review, the functional and biochemical activities of macrophages localized in the liver and lungs are compared. Evidence suggests that these represent distinct cell populations with unique functions and responsiveness to inflammatory agents.

Mechanisms underlying reduced responsiveness of neonatal neutrophils to distinct chemoattractants.

Potential mechanisms underlying impaired chemotactic responsiveness of neonatal neutrophils were investigated. Two distinct chemoattractants were compared: bacterially derived N-formyl-methionyl-leucyl-phenylalanine (fMLP) and a unique chemotactic monoclonal antibody, designated DL1.2, which binds to a neutrophil antigen with an apparent molecular mass of 120 kDa. Chemotaxis of neutrophils toward fMLP, as well as DL1.2, was reduced in neonates when compared with adult cells. This did not appear to be a result of decreased fMLP receptor or DL1.2 antigen expression by neonatal neutrophils. fMLP, but not DL1.2, induced a rapid increase in intracellular calcium in adult and neonatal cells, which reached a maximum within 30 s. The calcium response of cells from neonates to fMLP was reduced when compared with adult cells, and an unresponsive subpopulation of neonatal neutrophils was identified. NF-kappaB nuclear binding activity induced by fMLP and DL1.2, as well as expression of the p65 NF-kappaB subunit and IkappaB-alpha, was also significantly reduced in neonatal cells, when compared with adult cells. In contrast, although fMLP, but not DL1.2, activated p42/44 and p38 mitogen-activated protein (MAP) kinases in neutrophils, no differences were observed between adults and neonates. Chemotaxis of adult and neonatal neutrophils toward fMLP and DL1.2 was also blocked to a similar extent by inhibitors of phosphatidylinositol 3-kinase, as well as an inhibitor of NF-kappaB. These findings indicate that reduced chemotactic responsiveness in neonatal neutrophils is a result of, at least in part, aberrations in chemoattractant-induced signaling. However, the biochemical pathways mediating this defect appear to be related to the specific chemoattractant.

Autotransplants in men with breast cancer. ABMTR Breast Cancer Working Committee. Autologous Blood and Marrow Transplant Registry.

The purpose of this study was to determine the outcome of high-dose therapy with autologous hematopoietic stem cell support (autotransplants) in men with breast cancer. We studied 13 men receiving autotransplants for breast cancer and reported to the Autologous Blood and Marrow Transplant Registry (ABMTR) by 10 centers. Six men had stage 2 breast cancer, four had stage 3, and three had metastatic breast cancer. Of twelve tumors tested, all were estrogen receptor positive. Median age at transplant was 50 years. The most common conditioning regimen was cyclophosphamide, thiotepa and carboplatin (n = 5); the remaining eight men received other alkylator-based regimens. Three men received bone marrow, eight received blood stem cells, and two received both for hematopoietic support. All patients had hematopoietic recovery. There were no unexpected regimen-related toxicities. Of 10 men receiving autotransplants as adjuvant therapy, three relapsed 3, 5 and 50 months post-transplant and died 16, 19 and 67 months post-transplant. Seven of 10 are disease-free with median follow-up of 23 months (range 6-50 months). Of three men treated for metastatic breast cancer, one had progressive disease and two recurrent disease at 6, 7 and 16 months post-transplant. In conclusion, results of autotransplants for male breast cancer appear similar to those reported for women receiving autotransplants for breast cancer.

Urinary thiobarbituric acid-reacting substances as potential biomarkers of intrauterine hypoxia.

BACKGROUND: Currently available clinical tools cannot accurately identify the extent of perinatal hypoxic injuries. During hypoxia, reactive oxygen species cause lipid peroxidation of cell membranes, yielding oxidation products that constitute thiobarbituric acid-reacting substances (TBARS). OBJECTIVE: To see if the concentrations of TBARS excreted in urine would be elevated during the first day of life in term and preterm infants following chronic hypoxia or acute asphyxia. DESIGN: Thiobarbituric acid-reacting substances levels were measured by a spectrophotometric assay in urine samples collected from term and near-term (>/= 34 weeks gestation, n = 22), and preterm (<34 weeks gestation, n = 52) infants on the first day of life. PATIENTS: Infants were admitted to the St Peter's University Hospital (New Brunswick, NJ) neonatal intensive care unit from July 1997 to January 1999. Acute asphyxia was defined as umbilical cord blood pH values less than 7.05, or Apgar scores of less than 5 at 5 minutes. Chronic hypoxia was defined as intrauterine growth retardation or low birth weight (small for gestational age) associated with pregnancy-induced hypertension or reversal of umbilical arterial blood flow. RESULTS: Among term infants, urinary TBARS levels were significantly increased following acute asphyxia (P =.02). Levels of TBARS also tended to be elevated following chronic hypoxia. Urinary TBARS levels in term infants tended to be increased in those requiring mechanical ventilation (P =.05) or delivery room resuscitation (P =.15), as well as in those passing intrauterine meconium (P =.13) or having clinical evidence of hypoxic-ischemic encephalopathy (P =.24). CONCLUSIONS: The results show a correlation between elevated urinary TBARS levels in term and near-term infants, and perinatal hypoxia (as determined by low Apgar scores or umbilical cord blood acidosis). We speculate that TBARS concentrations may be useful as a biomarker for perinatal hypoxic injury in newborns. Further studies are needed to determine whether elevations in TBARS levels are better predictors of the extent of hypoxic injury than existing markers.

Antecedents and neonatal consequences of low Apgar scores in preterm newborns: a population study.

BACKGROUND: To examine the antenatal and early neonatal correlates of low Apgar scores (<3 and <6 at 1 and 5 minutes) in preterm newborns (23-34 weeks' gestation). OBJECTIVE: The use of Apgar scoring for premature newborns remains widespread, despite controversy regarding its reliability as a measure of morbidity and mortality in the neonatal period. DESIGN: A cohort of 852 preterm newborns born during a 34-month period between 1984 and 1987 was studied. Newborns were stratified into 2 groups by gestational age (23-28 weeks and 29-34 weeks), and data were analyzed, controlling for gestational age in single weeks. SETTING: Two academic and 1 community hospital, which together accounted for 83% of all preterm births in a tri-county area of central New Jersey during the study period. PATIENTS: All premature newborns (birth weight <2000 g and gestational age <35 weeks) born in the participating hospitals during the study period were evaluated. MAIN OUTCOME MEASURES: Antecedents included maternal illness during pregnancy, maternal complications of labor and delivery, and fetal heart rate abnormalities during labor and delivery. Consequences included delivery room resuscitation, abnormal physical findings, diagnoses, and therapeutic interventions in the first 6 to 8 hours of life. RESULTS: Premature newborns with low Apgar scores received more cardiopulmonary resuscitation in the delivery room and in the first 6 to 8 hours of neonatal intensive care. Mortality was significantly increased among newborns with low Apgar scores (54% vs. 26% in the 23- to 28-week stratum, 30% vs 6% in the 29- to 34-week stratum). Newborns with low Apgar scores in the 29- to 34-week stratum more often required intubation, positive pressure ventilation, and umbilical vessel catheterization. Newborns with low Apgar scores had higher rates of bradycardia, pneumothoraces, acidosis, and increased oxygen requirement during the first 6 to 8 hours of life. Maternal illness, complications of labor and delivery;, and fetal heart rate decelerations did not correlate with subsequent Apgar scores of newborns. The presence of severe bradycardia (<90/min) and fetal heart rate accelerations correlated with low Apgar scores in the 29- to 34-week group. CONCLUSION: Low Apgar scores are associated with increased neonatal morbidity and mortality in preterm newborns. Antenatal maternal history, and pregnancy complications are not clearly associated with low Apgar scores. Therefore, the Apgar score is a useful tool in assessing neonatal short-term prognosis and the need for intensive care among preterm newborns.

The toxicology of inhaled nitric oxide.

Inhaled nitric oxide is a targeted pulmonary vasodilator that improves clinical outcomes for newborn patients with persistent pulmonary hypertension of the newborn, and may be effective in treating some premature patients with acute respiratory distress syndrome or lung disease of prematurity. Nitric oxide is now recognized as playing an important role in the regulation of diverse physiological processes. However, the pharmacological properties of inhaled nitric oxide are not easy to separate from its toxicological effects. For example, the intended effect of inhaled nitric oxide, vasodilation in the lung, is mediated, in part, by increased cellular cyclic GMP (cGMP). However, increased cGMP can also interfere with normal cellular proliferation. Nitric oxide has also been shown to cause DNA strand breaks and/or base alterations that are potentially mutagenic. Inhaled nitric oxide can rapidly react with oxygen in the lung to form nitrogen dioxide, which is a potent pulmonary irritant. Nitric oxide also reacts with superoxide anion to form peroxynitrite, a cytotoxic oxidant that can interfere with surfactant functioning. The overall effect of inhaled nitric oxide in potentiating or attenuating inflammation and oxidative damage in diseased lung is dependent on the dose administered. Furthermore, despite rapid inactivation by circulating hemoglobin, inhaled nitric oxide exerts effects outside the lung, including blocking platelet aggregation, causing methemoglobinemia, and possibly inducing extrapulmonary vasodilation. The toxicology of inhaled nitric oxide is not completely understood and must be considered in the design of protocols for its safe and effective clinical use.

A phase II study of bromocriptine in patients with androgen-independent prostate cancer.

Prolactin is an important physiological regulator of prostate development and growth in preclinical models. In prostate cancer there is strong evidence that prolactin exerts a trophic effect independent of testosterone. In addition, patients with prostate cancer that have an elevated prolactin level correlated with a poorer prognosis. Based on these data, we evaluated the clinical effect of prolactin suppression using bromocriptine in patients with androgen-independent prostate cancer. We conducted an open-label phase II trial of bromocriptine in patients with progressive metastatic prostate cancer. Basal and thyrotropin releasing hormone (TRH)-stimulated prolactin levels were utilized as biological endpoints for determining the dose of bromocriptine. All patients continued to receive complete androgen blockade. Thirteen patients were enrolled (median age 69.5 years). There were no complete or partial responses associated with bromocriptine in 11 of the evaluable patients. The mean duration of bromocriptine treatment was 8.2 weeks (2-14 weeks). One patient had a clinically insignificant decrease in prostate-specific antigen (PSA) and another patient had a 19.9% decrease in PSA with progression of a soft tissue mass. The vast majority of patients (10 of 11) had suppression of prolactin with a bromocriptine dose of 2.5 mg three times a day. One patient required a dose adjustment due to inadequate suppression, with a final maintenance dose of bromocriptine 12.5 mg per day resulting in complete suppression. No serious treatment-related toxicities were observed. The most common complications noted were nausea, headaches, dizziness, and fatigue. Our data showed that 2.5 mg three times per day of bromocriptine suppressed prolactin in 90% of the patients. Furthermore, this dose appears to be well tolerated.

Development of the ability to make IgG and IgA in newborns and infants.

An understanding of the ontogeny of the human immune system may provide clues for methods to stimulate the immune response of neonates and young infants at an earlier age than is now possible. Knowledge of normal changes in immune response over time is necessary to evaluate infants for immunodeficiency.