Involvement of mitogen-activated protein kinase activation in the signal-transduction pathways of the soya bean oxidative burst.

The oxidative burst constitutes one of the most rapid defence responses characterized in the Plant Kingdom. We have observed that four distinct elicitors of the soya bean oxidative burst activate kinases of masses approximately 44 kDa and approximately 47 kDa. Evidence that these kinases regulate production of reactive oxygen species include: (i) their rapid activation by oxidative burst elicitors, (ii) their tight temporal correlation between activation/deactivation of the kinases and activation/deactivation of the oxidative burst, (iii) the identical pharmacological profile of kinase activation and oxidant production for 13 commonly used inhibitors, and (iv) the autologous activation of both kinases and oxidant production by calyculin A and cantharidin, two phosphatase inhibitors. Immunological and biochemical studies reveal that the activated 44 kDa and 47 kDa kinases are mitogen-activated protein (MAP) kinase family members. The kinases prefer myelin basic protein as a substrate, and they phosphorylate primarily on threonine residues. The kinases are themselves phosphorylated on tyrosine residues, and this phosphorylation is required for activity. Finally, both kinases are recognized by an antibody against activated MAP kinase immediately after (but not before) cell stimulation by elicitors. Based on these and other observations, a preliminary sequence of signalling steps linking elicitor stimulation, kinase activation and Ca(2+) entry, to initiation of oxidant production, is proposed.

Improved health-related quality of life with SSRIs and other antidepressants.

STUDY OBJECTIVE: To document the health-related quality of life (HRQOL) of depressed patients receiving antidepressant drugs. DESIGN: Cross-sectional study. SETTING: Community pharmacy-based setting. PATIENTS: Fifty-seven depressed patients. INTERVENTION: Independent pharmacist members of the Community Pharmacists Research Network in Georgia administered the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to subjects. MEASUREMENTS AND MAIN RESULTS: Sixty-one percent of patients were treated with a selective serotonin reuptake inhibitor (SSRI) and 38.6% were treated with a non-SSRI. Those receiving SSRIs scored higher on the mean physical (PCS) and mental (MCS) health summary scores of the SF-36 than those not receiving the drugs. No significant differences were seen in PCS or MCS scores of men and women. CONCLUSION: Community pharmacists documented better HRQOL in patients receiving SSRIs than in those given other antidepressants.

Nature of cysteine-based Re(V)=O(N2S2) radiopharmaceuticals at physiological pH ascertained by investigation of a new complex with a meso N2S2 ligand having carboxyl groups anti to the oxo group.

X-ray structural characterization of a new isomer of ReO(TMECH3) revealed that it is anti-ReO(DL-TMECH3) (1). (DL-TMECH6 is meso-tetramethyl-ethylene-dicysteine prepared from racemic penicillamine (penH4), the subscript on H indicating the number of dissociable protons; anti denotes the geometric isomer having both carboxyl groups anti to the oxo ligand.) In 1, one carboxyl is deprotonated and coordinated trans to the oxo ligand, and the other is protonated and dangling. The 1H NMR spectrum (assigned by 2D methods) of 1 at pH 4 in aqueous solution revealed that the structure of 1 is the same as in the solid state except for deprotonation of the dangling carboxyl group, affording the monoanion. All chelate ring protons and methyl groups are inequivalent and give sharp signals. As the pH was raised above 7, the 1D 1H NMR signals of the monoanion broadened. Broadening was severe for the methyl and ethylene signals of the tridentate half of the monoanion, and these signals were replaced by new signals for the dianion. The changes suggested a rate process that was intermediate on the NMR time scale, such as CO2- ligation/deligation. With increasing pH the dianion signals sharpened up to pH approximately 8 and then broadened up to pH approximately 10. Finally, the spectrum at pH 10.8 showed only half the number of signals. Each signal was at the midpoint shift between two corresponding signals observed at lower pH, indicating a time averaging between the halves of the DL-TMEC ligand, but no change in protonation state. Two Re=O stretching bands (923 and 933 cm-1) with a constant intensity ratio of approximately 1 were observed for the dianion. These results can be explained if the dianion exists detectably only as a NH-deprotonated/carboxyl-deligated form having two conformers. The conformers differ in the N lone pair (NLp) orientation (either endo or exo with respect to the oxo ligand) and thus have slightly different Re=O stretching frequencies. Although they can be detected by resonance Raman spectroscopy, the conformers are indistinguishable by NMR spectroscopy because NLp inversion (and hence conformer interconversion) is very fast. Interchange of the NH and NLp sites affects the NMR spectra. At pH 8.3 the signals of the dianion are sharpest because interchange is slowest. Below and above pH 8.3, the signals are broader because acid and base catalysis, respectively, increase the rate of interchange between the NH and NLp sites.

Re(V) complexes with an open-chain quadridentate ligand containing two amine and two amido donors. Synthesis, characterization, and solution equilibria of Re2O3(dioxo-tetH4)2 and [ReO(H2O)(dioxo-tetH4)]Cl (dioxo-tetH6 = 1,4,8,11-tetraazaundecane-5,7-dione).

We are interested in identifying mononuclear cationic [M(V)=O]3+ (M = Tc, Re) complexes for radiopharmaceutical applications. The open-chain ligand, 1,4,8,11-tetraazaundecane-5,7-dione-(dioxo-tetH6) with two amine and two amide donors, was selected for investigation since the literature led us to expect that a five-coordinate [Re(V)=O(dioxo-tetH4)]+ cation would dominate. Instead, the neutral mu-oxo bridged dinuclear complex, Re2O3(dioxo-tetH4)2 (1), and a salt of the six-coordinate mononuclear cation, [ReO(H2O)(dioxo-tetH4)]+ (2), were isolated; the structure of each was determined by X-ray crystallography. The cation (2) is unusual because it has a trans-oxo/aqua core. Such aqua compounds are rarely isolated, and the Re-OH2 distance is relatively short (2.185 A). The cation has two pKa values, 4.1 and 8.7, determined with visible spectroscopy. Since the Re-OH2 bond is short, the coordinated water is likely to be acidic. Thus the two pKa's are assigned to the stepwise deprotonation of the water ligand to give a trans-oxo/hydroxo neutral form and a trans-dioxo anion. Although 1 was the first product isolated following ligand exchange of ReOCl3(Me2S)(OPPh3) with dioxo-tetH6 under neutral conditions, it probably formed from the hydroxo mononuclear complex. Under concentrated conditions (approximately 300 mM) the dinuclear complex deposited from solution, but the 1H NMR spectra of 2 (approximately 20 mM) were consistent with the presence of only monomeric forms in D2O, pH 3-12. 1H NMR experiments demonstrated that in DMSO-d6 2 converts to 1 upon addition of base, consistent with the proposal that two units of the hydroxo monomer condense to give the dinuclear form. In addition, all spectra of pure 1 dissolved in DMSO-d6 included extra low intensity signals that were characteristic of the monomer. Thus, although 1 is favored over the neutral monomer in DMSO-d6, the two complexes exist as a mixture of equilibrating forms. Our results do not support the previous findings for the Re(V) complex with a macrocyclic diamine-diamide ligand related to dioxo-tetH6. The data indicate that the ability of an amido group to donate electron density to a Re(V) center is moderately greater than the donating ability of a neutral amine group.

Prognostic value of thallium-201 single-photon emission computed tomography for patients with multivessel coronary artery disease after revascularization (the Emory Angioplasty versus Surgery Trial [EAST]).

The aim of this study was to investigate the relation between reversible thallium single-photon emission computed tomography (SPECT) myocardial perfusion defects at 1-year after revascularization and quantitative indexes in Emory Angioplasty versus Surgery Trial (EAST) and outcomes 3 years after revascularization in 336 patients. EAST was a randomized controlled trial assessing cardiac outcomes for angioplasty versus bypass surgery for patients with multivessel coronary artery disease. During this prospective trial, a substudy included the evaluation of the prognostic value of reversible defects on quantitative thallium SPECT. At 1-year after revascularization, 336 patients underwent SPECT thallium-201 stress myocardial perfusion and 3-hour delayed imaging. Subsequent events, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, myocardial infarction, and death, were recorded at 3 years. A stress-induced reversible thallium-201 defect was defined using a quantitative index of a reversibility score >30% and severity score >500. Reversible defects were observed more frequently in the percutaneous transluminal coronary angioplasty than in the coronary artery bypass graft surgery treatment groups (46% vs 27%, p <0.001). A total of 123 patients had stress-induced, reversible thallium defects and more events than patients with other perfusion results (freedom from all events was 81.3% vs 94% [p <0.001], and freedom from myocardial infarction and death 88.3% vs 95.5% [p = 0.031]). Quantitative thallium SPECT at 1 year after revascularization risk stratifies patients as to their likelihood of major cardiac outcomes.

Two-point, timesaving method for measurement of gastric emptying with diagnostic accuracy comparable to that of the conventional method.

Solid-phase gastric emptying is linear. Therefore, the authors calculated gastric-emptying half-time, the time for half of the ingested solids or liquids to leave the stomach, with the conventional multiple-point method and the proposed two-point method (at 0 and 120 minutes) in retrospective and prospective studies of 50 patients each. The results showed excellent correlation. Results with the two-point method were comparable to those with the multiple-point method, and the two-point method substantially reduced technologist and camera times.

Taking the edge off: why patients choose St. John's Wort.

BACKGROUND: The number of visits to alternative medicine practitioners in this country is estimated at 425 million, which is more than the number of visits to allopathic primary care physicians in 1990. Patients' use of St. John's Wort (SJW) has followed this sweeping trend. The purpose of our study was to examine the reasons people choose to self-medicate with SJW instead of seeking care from a conventional health care provider. METHODS: We used open-ended interviews with key questions to elicit information. Twenty-two current users of SJW (21 women; 20 white; mean age = 45 years) in a Southern city participated. All interviews were transcribed, and descriptive participant quotes were extracted by a research assistant. Quotes were reviewed for each key question for similarities and contextual themes. RESULTS: Four dominant decision-making themes were consistently noted. These were: (1) Personal Health Care Values: subjects had a history of alternative medicine use and a belief in the need for personal control of health; (2) Mood: all SJW users reported a depressed mood and occasionally irritability, cognitive difficulties, social isolation, and hormonal mood changes; (3) Perceptions of Seriousness of Disease and Risks of Treatment: SJW users reported the self-diagnosis of "minor" depression, high risks of prescription drugs, and a perception of safety with herbal remedies; and (4) Accessibility Issues: subjects had barriers to and lack of knowledge of traditional health care providers and awareness of the ease of use and popularity of SJW. Also of note was the fact that some SJW users did not inform their primary care providers that they were taking the herb (6 of 22). Users reported moderate effectiveness and few side effects of SJW. CONCLUSIONS: SJW users report depression, ease of access to alternative medicines, and a history of exposure to and belief in the safety of herbal remedies. Users saw little benefit to providing information about SJW to primary care physicians.

Oligogalacturonic acid and chitosan reduce stomatal aperture by inducing the evolution of reactive oxygen species from guard cells of tomato and Commelina communis.

Stomatal opening provides access to inner leaf tissues for many plant pathogens, so narrowing stomatal apertures may be advantageous for plant defense. We investigated how guard cells respond to elicitors that can be generated from cell walls of plants or pathogens during pathogen infection. The effect of oligogalacturonic acid (OGA), a degradation product of the plant cell wall, and chitosan (beta-1,4-linked glucosamine), a component of the fungal cell wall, on stomatal movements were examined in leaf epidermis of tomato (Lycopersicon esculentum L.) and Commelina communis L. These elicitors reduced the size of the stomatal aperture. OGA not only inhibited light-induced stomatal opening, but also accelerated stomatal closing in both species; chitosan inhibited light-induced stomatal opening in tomato epidermis. The effects of OGA and chitosan were suppressed when EGTA, catalase, or ascorbic acid was present in the medium, suggesting that Ca(2+) and H(2)O(2) mediate the elicitor-induced decrease of stomatal apertures. We show that the H(2)O(2) that is involved in this process is produced by guard cells in response to elicitors. Our results suggest that guard cells infected by pathogens may close their stomata via a pathway involving H(2)O(2) production, thus interfering with the continuous invasion of pathogens through the stomatal pores.

Prediction of urinary excretion of technetium-99m-MAG3.

UNLABELLED: The urinary excretion of 99mTc-mercaptotriacetylglycine (MAG3), like that of 131I-orthoiodohippurate (OIH), can be used to identify acute renal transplant rejection and measure its severity. This parameter is often quantitated as the excretory index (observed excretion/predicted excretion). A new method for predicting the urinary excretion of 99mTc-MAG3 is presented. METHODS: The expected excretion was calculated from multisample plasma time-activity curves in 122 subjects, with correction for the first pass of the initial bolus. The resulting formula was tested prospectively against actual urine measurements in an additional 466 subjects. RESULTS: Least-squares fitting led to the following equation: Predicted excretion = 0.79(1-exp(-0.0066CMAG3), with residual s.d. 0.06, where CMAG3 is MAG3 clearance in ml/min and the predicted excretion is expressed as a fraction of the administered dose. Tested prospectively in the additional 466 subjects, the s.d. was 0.09. CONCLUSION: A new formula to predict the urinary excretion of 99mTc-MAG3 has been developed and prospectively validated. Based on our data, the normal range for the excretory index using MAG3 is the same as that of 131I-OIH, 0.8-1.2.

Phospholipase D involvement in the plant oxidative burst.

Pathogen-triggered generation of reactive oxidants, termed the oxidative burst, contributes to disease resistance in both plant and animal kingdoms. Since phospholipase D plays a key role in the neutrophil oxidative burst signaling cascade and is highly abundant in plants, we investigated its participation in the plant oxidative burst. Thin layer chromatography of extracted phospholipids revealed no changes in phosphatidic acid levels in soybean cells undergoing oxidant production, and no changes in phosphatidyl-ethanol biosynthesis could be detected when ethanol was present during elicitation. An inhibitor of phosphatidic acid hydrolase, propranolol, did not modify burst parameters or phosphatidic acid levels during the burst, suggesting our inability to detect phosphatidic acid accumulation was not due to rapid elimination. Furthermore, exogenous phosphatidic acid did not elicit a burst or enhance elicitor-stimulated bursts. Finally, ethanol, a substitute nucleophile, did not abrogate the burst. With data showing the presence of phospholipase D in soybean cells, these data argue that soybean phospholipase D does not participate in signaling the oxidative burst. This constitutes the first major difference between the plant and animal oxidative burst signal transduction pathways.

Lymphoscintigraphy, the sentinel node concept, and the intraoperative gamma probe in melanoma, breast cancer, and other potential cancers.

There is a resurgence of interest in lymphoscintigraphy because of attention to the sentinel node concept and the availability of the surgical gamma probe that can be used in the operating room to localize radiolabeled sentinel nodes. Conventional surgical management of melanoma has been altered for intermediate thickness tumors such that lymph node dissection is performed for a lymph node bed only if the sentinel node is tumor positive on histological exam after gamma probe-guided excision. This approach is cost effective, saving about 80% of these patients (sentinel node tumor negative) the cost and morbidity of unnecessary "elective lymph node dissection." In addition, a biopsy can be performed on all lymph node beds that receive lymphatic drainage from the tumor site thereby improving staging and perhaps survival by providing the most appropriate therapy. Substantial work has been done to develop optimum imaging techniques and the best radiopharmaceutical preparation to achieve accurate, reproducible lymphatic drainage images. Our methodology includes the following intradermal injections of a technetium 99m sulfur colloid (modified preparation) are followed by dynamic imaging (10 seconds per frame); static imaging up to 30 minutes and late imaging at 1 to 2 hours. Images show lymphatic channels that lead to sentinel nodes in 1, 2, 3, or more anatomic locations. Surgical management is altered to include sampling sentinel nodes of nodal beds, many of which would not have been sampled by previous conventional surgical estimates of lymphatic drainage. While clinical success of lymphoscintigraphy and intraoperative probe localization of the sentinel node in melanoma is evident, use of lymphoscintigraphy and the sentinel node concept in breast cancer is investigative, but promising. The radiopharmaceutical is injected around the tumor in the breast followed by imaging to delineate lymphatic drainage to the sentinel node(s). Optimum methodologies for radiopharmaceutical, volume and/or activity of injectate, and imaging have yet to be determined. Breast lymphatic drainage can be to axilla, internal mammary, and/or supraclavicular nodes in any combination.

Technetium-99m-sulfur colloid for lymphoscintigraphy: effects of preparation parameters.

UNLABELLED: There has been a resurgence in the use of lymphoscintigraphy for the external detection of lymph nodes for metastatic melanoma and breast tumors. Technetium-99m-antimony trisulfide colloid was the radiopharmaceutical developed for this procedure and was found to have a narrow distribution of small particles, 0.003-0.03 microns, but it was never approved by the FDA. Technetium-99m-sulfur colloid also forms particles and this article reports on the effects different preparation parameters have on its particle size distribution and stability. METHODS: Four groups of kits were evaluated, kits which utilized: (a) a reduced heating protocol with a new 99mTc-elution, (b) a reduced heating protocol with an old 99mTc-elution, (c) a prolonged heating protocol with a new 99mTc-elution and (d) a prolonged heating protocol with an old 99mTc-elution. The particle size distribution and the stability of the different 99mTc-sulfur colloid kit preparations were evaluated over 6 hr utilizing polycarbonate filters ranging from 0.03 to 10 microns. RESULTS: In vitro studies demonstrated no significant change in the particle size distribution over a 6-hr period and all 99mTc-sulfur colloid preparations had a bimodal particle size distribution pattern. Importantly, heating the kit for shorter periods of times utilizing [99mTc]pertechnetate, which had a longer ingrowth of [99mTc]pertechnetate, produced a formulation which had the largest percentage of particles smaller than 0.03 microns. CONCLUSION: In our clinical setting, 99mTc-sulfur colloid prepared with the reduced heating protocol and utilizing [99mTc]pertechnetate, which has the highest ingrowth of [99mTc]pertechnetate has proved to be an excellent agent for lymphoscintigraphy studies. This preparation has demonstrated rapid movement of the particles from the primary site to the lymph nodes in over 97% (106/109) of the patients we have studied.

The expanding role of pharmacy and therapeutics committees. The 1990s and beyond.

Traditionally, pharmacy and therapeutics (P&T) committees have been responsible for overseeing the drug use process, using formulary systems to control drug costs. Primarily, these committees act in an advisory capacity as policy-recommending bodies within healthcare systems, for the specific purpose of promoting rational drug therapy. Methodologies utilised by these committees include drug use evaluation, medical staff education, continuous quality improvement, formulary restriction and therapeutic interchange. Future roles of P&T committees will include the evaluation of clinical outcomes information, including quality-of-life issues, to establish policies governing the use of drugs at all levels and in all types of healthcare.

Acute management of cancer-related hypercalcemia.

OBJECTIVE: To review the pathogenesis and pharmacologic treatment of acute hypercalcemia associated with malignancy. DATA SOURCES: A MEDLINE search (1966 to 1995) of the English-language literature pertaining to acute hypercalcemia was performed. Additional literature was obtained from reference lists of articles identified through the search. STUDY SELECTION AND DATA EXTRACTION: All articles discussing the etiology and medical management of cancer-related acute hypercalcemia were considered in this review. Clinical trials reporting efficacy and safety of antihypercalcemic agents were also included. Information selected in the review was based on the discretion of the authors. DATA SYNTHESIS: Hypercalcemia is a life-threatening disorder associated with malignancy. It occurs in approximately 10-20% of patients with cancer. A variety of medications have been used in the management of hypercalcemia including bisphosphonates, calcitonin, furosemide, gallium nitrate, glucocorticoids, NaCl 0.9%, and plicamycin. Each of these agents has been reviewed with consideration of pharmacologic mechanism of action, evaluation of clinical trials, recommended dosages, efficacy, safety, cost, and role in treating cancer-related acute hypercalcemia. CONCLUSIONS: Immediate management of cancer-related acute hypercalcemia to prevent death and provide symptomatic relief is warranted. Severity determined by symptoms, calcium concentrations, and the overall status of the patient are important considerations in selecting appropriate therapy. Although the specific role of individual agents may vary, hydration remains the cornerstone of therapy. NaCl 0.9%, calcitonin, and pamidronate disodium have established roles as dominant first-line agents for the management of acute hypercalcemia associated with malignancy.

Measurement of renal function with technetium-99m-MAG3 in children and adults.

UNLABELLED: A single-injection, single-sample procedure for measuring 99mTc-MAG3 clearance is presented that incorporates scaling for patient size and is valid for both children and adults. METHODS: The procedure is based on an empirical formula in which all measurements are expressed in dimensionless combinations. The formula was obtained by fitting data collected from 122 adults and 80 children at several centers. RESULTS: All results were scaled to standard adult surface area and are presented in units of ml/min/1.73 m2. For adult subjects, the residual standard deviation (r.s.d.) calculated from a single sample at 45 min was found to be 23, using the plasma clearance calculated from a multi-sample clearance curve as a reference. This did not differ significantly from the value of 22 obtained with our previous formula, which was valid for adults only. For pediatric subjects, an r.s.d. of 24 was calculated by the new formula from a single sample at 35 min; a comparable value of 33 was found using a pediatric formula previously published. CONCLUSION: The new clearance formula is recommended as a replacement for the formula we previously published, since it is based on a larger and more diverse subject population, and since it now holds for children as well, with no loss of accuracy for adult subjects.

Early stage melanoma: lymphoscintigraphy, reproducibility of sentinel node detection, and effectiveness of the intraoperative gamma probe.

PURPOSE: To assess the influence of lymphoscintigraphic and intraoperative gamma probe findings on the surgical management of melanoma and to test reproducibility of lymphoscintigraphic findings. MATERIALS AND METHODS: After lymphoscintigraphic identification of the sentinel node, intraoperative gamma probe localization and sentinel lymph node excision were performed in 25 patients. To assess reproducibility, 13 patients underwent lymphoscintigraphy twice within 2-17 days. A modified preparation of technetium-99m sulfur colloid with smaller particles than routinely obtained was injected intradermally around the lesion. Dynamic flow images were obtained at 10 seconds per frame followed by a series of static images obtained every 5 minutes for 30 minutes. RESULTS: A sentinel node was identified in all patients. In eight patients, multiple drainage pathways were seen and surgical management was changed. In 11 of the 13 who underwent lymphoscintigraphy twice, sentinel node identification was reproducible. CONCLUSION: Lymphoscintigraphy is reproducible in detection of the sentinel node and with the surgical probe helps effectively guide surgical management.

A single-injection, two-sample method for measuring renal 99mTc-MAG3 clearance in both children and adults.

We present a method for estimating 99mTc-MAG3 clearance from both a single injection and two blood samples that is valid for both adults and children. It was obtained by fitting a scaled two-compartment model (having only two adjustable parameters) to adult and pediatric data from multiple centers.

Continuation of warfarin-nafcillin interaction during dicloxacillin therapy.

Interactions between warfarin and penicillins have been infrequently reported. A case report of a single patient who experienced the effects of a warfarin-nafcillin interaction as well as a warfarin-dicloxacillin interaction is presented. Clinical effects of this interaction were documented primarily through changes in prothrombin time (PT) and the need for higher warfarin dosing. While the patient received nafcillin, warfarin doses were increased to as much as 4.5 times the previous amounts needed to provide adequate anticoagulation. During dicloxacillin therapy, warfarin doses were gradually decreased, but stabilized to a maintenance dose higher than the patient's pre-nafcillin dose. The dicloxacillin-warfarin interaction appears similar to that noted during nafcillin-warfarin combination.

Fluoxetine in family practice patients.

BACKGROUND: Many patients with depression are seen only by family physicians, yet it is unknown how their physicians prescribe newer antidepressants. METHODS: Charts of family practice patients receiving fluoxetine were reviewed using a standardized format. Information reviewed included patient demographics, diagnosis, prescriptions, and course of treatment. RESULTS: Depression was documented in 92.5% of the 40 patients studied. There were significantly more female patients in the fluoxetine sample than in the base sample of depressed patients (P < .04). Fluoxetine patients weighed significantly more than the base sample, with a mean difference of 20.8 pounds (P < .03). Side effects were documented in the charts of 12 (30%) patients. Prescription practice was considered optimal in 43% of patients who were told to take fluoxetine in the morning. No differences in improvement or side effects were found based on optimal prescribing behavior. Improvement was documented in 68% of patients. Fluoxetine was discontinued in 6 (15%) cases because of adverse side effects. CONCLUSIONS: An improvement rate of 68% among patients taking 20 to 40 mg of fluoxetine per day indicates that an adequate response can be achieved without the risk of side effects that typically accompany higher doses. In this study, fluoxetine was prescribed more often to obese patients. This prescribing pattern may indicate that primary care physicians perceive overweight patients as good candidates for fluoxetine regardless of inconclusive evidence about the effectiveness of this drug for weight loss.