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PubMed2002

Influence of type and level of water-soluble additives on drug release and surface and mechanical properties of Surelease films.

Ethylcellulose in combination with water-soluble additives has been used in the development of microporous membrane-coated dosage forms. In the present study, application of three types of water-soluble additives, namely polyethylene glycols (PEG 400, 3350, and 8000), maltodextrins (Maltrin M150, M100, and M040 in the order of lower to higher average polymer size and molecular weight; dextrose equivalence 16.9, 11.1, and 4.8, respectively), and xylitol, as porosity modifiers in the films of a commercially available aqueous ethylcellulose dispersion (Surelease/E-7-7060 plasticized with glyceryl tricaprylate/caprate) was investigated. The effect of type and level of these additives on drug release characteristics and surface and mechanical properties of the polymeric films was studied. Each additive was incorporated at 20 and 30% levels in the polymeric dispersion based on its solids content. Ibuprofen tablets were coated using the polymeric dispersion with and without additive at 3% w/w coat level in a fluid-bed equipment. The coated tablets were evaluated for their drug release rate, coat reflectivity (gloss), Brinell hardness, and elastic modulus. Differential scanning calorimetric analysis of the films was performed to determine the physico-chemical changes in the applied film-coats. The rate of drug release, hence film porosity, was observed to be dependent on the type and level of the additive added. The molecular weight of the additive and its concentration in the polymeric dispersion had significant influence on the rate of drug release, hardness, and elasticity of the film-coats.

Cellulose↗
PubMed2006

Impact of additional extracranial injuries on outcome after mild traumatic brain injury.

Many patients with mild traumatic brain injury (MTBI) concurrently sustain extracranial injuries; however, little is known about the impact of these additional injuries on outcome. We assessed the impact of additional injuries on the severity of postconcussional symptoms (PCS) and functional outcome 6 months post-injury. A questionnaire (including the Rivermead Post-Concussion Questionnaire and SF-36) was sent to consecutive MTBI patients (hospital admission Glasgow Coma Score 13-15; age range 18-60 years) admitted to the emergency department of a level-I trauma center, and, to serve as a baseline for PCS, a control group of minor-injury patients (ankle or wrist distortion). Of the 299 MTBI respondents (response rate 52%), 89 had suffered additional injuries (mean Injury Severity Score [ISS] of 14.5 +/- 7.4). After 6 months, 44% of the patients with additional injuries were still in some form of treatment, compared to 14% of patients with isolated MTBI and 5% of the controls. Compared to patients with isolated injury, MTBI patients with additional injuries had resumed work less frequently and reported more limitations in physical functioning. Overall, they did not report higher levels of PCS, despite somewhat more severe head injury. Regardless of the presence of additional injuries, patients that were still in treatment reported significantly more severe PCS, with highest rates in patients with isolated MTBI. In conclusion, many patients with additional extracranial injuries are still in the process of recovery at 6 months after injury. However, despite more severe impact to the head and inferior functional outcomes, these patients do not report more severe PCS.

Adult↗
PubMed2005

Non-additivity in protein-DNA binding.

MOTIVATION: Localizing protein binding sites within genomic DNA is of considerable importance, but remains difficult for protein families, such as transcription factors, which have loosely defined target sequences. It is generally assumed that protein affinity for DNA involves additive contributions from successive nucleotide pairs within the target sequence. This is not necessarily true, and non-additive effects have already been experimentally demonstrated in a small number of cases. The principal origin of non-additivity involves the so-called indirect component of protein-DNA recognition which is related to the sequence dependence of DNA deformation induced during complex formation. Non-additive effects are difficult to study because they require the identification of many more binding sequences than are normally necessary for describing additive specificity (typically via the construction of weight matrices). RESULTS: In the present work we will use theoretically estimated binding energies as a basis for overcoming this problem. Our approach enables us to study the full combinatorial set of sequences for a variety of DNA-binding proteins, make a detailed analysis of non-additive effects and exploit this information to improve binding site predictions using either weight matrices or support vector machines. The results underline the fact that, even in the presence of significant deformation, non-additive effects may involve only a limited number of dinucleotide steps. This information helps to reduce the number of binding sites which need to be identified for successful predictions and to avoid problems of over-fitting. AVAILABILITY: The SVM software is available upon request from the authors.

Algorithms↗
PubMed1998

Addition of clonidine or fentanyl to local anaesthetics prolongs the duration of surgical analgesia after single shot caudal block in children.

Caudal anaesthesia is indicated for surgical procedures lasting less than 90 min. Fentanyl and clonidine are known to prolong postoperative caudal analgesia, but there are no data on their effect on duration of surgical analgesia. We evaluated if the addition of clonidine or fentanyl to local anaesthetics prolonged the duration of surgical analgesia after single shot caudal block in children in a randomized, double-blind study. We studied 64 children, aged 6-108 months, undergoing bilateral correction of vesicoureteral reflux which was expected to last more than 90 min. Patients were allocated to one of four groups: group O received 1 ml kg-1 of a mixture of 0.25% bupivacaine with epinephrine and 1% lidocaine in equal parts; group F received the same mixture of local anaesthetics in addition to fentanyl 1 microgram kg-1; group C received the same mixture of local anaesthetics in addition to clonidine 1.5 micrograms kg-1; and group C + F received the same mixture of local anaesthetics in addition to fentanyl 0.5 microgram kg-1 and clonidine 0.75 microgram kg-1. Single shot caudal block was sufficient in only 57% of children in group O compared with 93% in groups C and F and 86% in group C + F (P = 0.035). Global assessment of anaesthesia, defined as the time from caudal injection to the first administration of analgesic (either during or after surgery), was significantly longer in the three groups of children who received additives compared with local anaesthetics alone (P = 0.035), but there were no differences between the three additive groups. Vomiting was observed only in children who received fentanyl. Addition of clonidine or fentanyl to local anaesthetics prolonged the duration of surgical analgesia of caudal block, allowing single shot caudal anaesthesia to be recommended for surgery lasting 90-150 minutes. Clonidine had some advantages over fentanyl as it did not produce clinically significant side effects.

Adrenergic alpha-Agonists↗
PubMed2002

Polymer-additive extraction via pressurized fluids and organic solvents of variously cross-linked poly(methylmethacrylates).

Variously cross-linked poly(methylmethacrylates) (PMMAs) are synthesized with three additives incorporated at theoretically 1000 microg of the additive per gram of prepared polymer. The additives are Irganox 1010, Irganox 1076, and Irgafos 168. The in-house" synthesized polyacrylates are then subjected to supercritical fluid extraction (SFE) to determine if additive recovery is a function of percent cross-linking. Although considerable work in this regard has been performed with non-cross-linked polyolefins, the literature is lacking regarding polyacrylates. Some additive degradation apparently occurs during the synthesis, as judged by the increased complexity of the extract high-performance liquid chromatographic trace and the low percent recoveries observed especially for the Irganoxes. For low polymer cross-linking (1%), it appears that both PMMA synthetic reproducibility and readily observed polymer swelling during SFE are serious issues that adversely affect additive percent recovery and precision of results. Higher percent cross-linking yields more consistent analytical data than low percent cross-linking, even though the amount of additive extracted in all PMMA samples (regardless of cross-linking percentage) is essentially the same whether the extraction is via SFE or liquid-solid extraction with methylene chloride. Results for comparably cross-linked poly(ethylmethacrylate) and poly(butylmethacrylate) are similar to PMMA.

Journal Article↗
PubMed1999

A clinical trial for adolescent depression: predictors of additional treatment in the acute and follow-up phases of the trial.

OBJECTIVE: To examine the predictors of additional service use among participants in a clinical trial for depression. METHOD: 107 adolescents with DSM-III-R depression were randomly assigned to receive either cognitive-behavioral therapy, systemic behavioral family therapy, or nondirective supportive therapy for 12 to 16 weeks of acute treatment and followed up periodically for 24 months after the termination of acute treatment. RESULTS: More than half (53.3%) of the 107 randomized adolescents received additional treatment beyond that provided in the clinical trial, with a median time to additional treatment from intake of 7.2 months. The rates and times to additional treatment were similar in the 3 treatment groups, despite the superior efficacy of cognitive-behavioral therapy in the acute phase. The severity of the index depressive episode and comorbid dysthymia were a predictor of additional treatment in the acute phase, whereas in the follow-up period the severity of depressive symptomatology, the presence of disruptive disorders, and family problems predicted additional treatment. CONCLUSIONS: Subsequent clinical trials for early-onset depression must focus on the entire depressive episode, rather than just the acute phase, to prevent depressive relapse. In addition, attendant family difficulties and comorbid behavioral problems must be addressed.

Acute Disease↗
PubMed1989

Amelioration of chronic renal allograft dysfunction in cyclosporine-treated patients by addition of azathioprine.

Management of chronic renal allograft dysfunction in cyclosporine-prednisone treated renal allograft recipients remains problematic. We therefore initiated a protocol of azathioprine addition (1.0-1.5 mg/kg/day) to ongoing CsA/Pred therapy. Three groups were treated. Group A (n = 21) had chronic progressive renal dysfunction (serum creatinine greater than or equal to 2.5 mg/dl or more than 15% above baseline) four or more months after transplantation. Group B (n = 8) had frequent or severe rejection episodes occurring despite adequate CsA levels. Group C (n = 7) had constitutional side effects of CsA with or without renal dysfunction persisting despite drug taper or financial difficulty in affording CsA. Aza was initiated 17.8 +/- 2.8 months after transplantation in group A, the mean serum creatinine having risen from 2.55 +/- 27 mg/dl to 3.04 +/- .20 mg/dl (P = .07) over the six months preceding Aza initiation, despite stable and low therapeutic range HPLC whole-blood CsA levels (118 +/- 10 ng/ml vs. 133 +/- 11 ng/ml, P = NS). Renal function declined at a rate of -0.20 +/- .06 Cr1/year in the six-month period before addition of Aza, and then improved at a rate of 0.09 +/- .04 Cr-1/year after addition of Aza (P = .002). These changes in renal function occurred without a decrease in CsA levels (118 +/- 10 six months before Aza vs. 126 +/- 26 six months after Aza, P = NS). In group B Aza was initiated at 58 +/- 8 days after transplantation when mean sCr was 3.56 +/- .29 mg/dl and mean CsA level was 222 +/- 17 ng/ml. At least follow-up 12.7 +/- 2.0 months after addition of Aza, all group B grafts were functioning, mean sCr was 2.69 +/- .31 mg/dl (P = .09 compared with baseline), and mean CsA level was 128 +/- 34 ng/ml (P = .07 compared with baseline). Group C patients had addition of Aza at 43 +/- 19 months after transplantation when mean sCr was 2.97 +/- .60 and mean CsA level was 125 +/- 30 ng/ml; addition of Aza had no influence on the rate of decline in renal function in this group. Of these 36 patients, 6 received therapy for acute rejection over the entire follow-up period of 12.3 +/- 1.4 months after addition of Aza; 4 of these retain graft function. Infectious complications consisted of 2 urinary tract infections, 1 bacterial pneumonia, and one case of otitis media.(ABSTRACT TRUNCATED AT 400 WORDS)

Actuarial Analysis↗
PubMed2006

Additive effect of dorzolamide or carteolol to latanoprost in primary open-angle glaucoma: a prospective randomized crossover trial.

PURPOSE: To compare the additive effect of dorzolamide or carteolol to latanoprost on intraocular pressure (IOP) in glaucoma patients. DESIGN: Prospective open-label randomized crossover clinical study. METHODS: A total of 64 patients with primary open-angle glaucoma were treated with latanoprost 0.005% once daily for 3 months then randomized to receive latanoprost plus dorzolamide 1% 3 times daily (dorzolamide preceding group; n=32) or carteolol hydrochloride 2% twice daily (carteolol preceding group; n=32) for a further 3 months. Then, all patients were crossed over to the opposite treatment arm for a further 3 months. IOP was recorded each month at around the time same as on the baseline day. RESULTS: Sixty-one patients (95%) completed this trial. In the dorzolamide preceding group, mean (+/-SD) IOP was 19.0+/-2.1 mm Hg at baseline and 16.0+/-2.1 mm Hg at the end of latanoprost monotherapy (P<0.01). Addition of dorzolamide reduced IOP to 15.0+/-1.3 mm Hg and this was not changed by switching to carteolol (15.1+/-1.7 mm Hg). In the carteolol preceding group, IOP was 19.1+/-1.9 mm Hg at baseline and 16.2+/-1.2 mm Hg at the end of latanoprost monotherapy (P<0.01). Addition of carteolol reduced IOP to 14.9+/-1.5 mm Hg, and after switching to dorzolamide IOP was 15.2+/-1.5 mm Hg. Mean additional IOP reduction was 0.9+/-1.2 mm Hg (5.6%) for the latanoprost-dorzolamide combination and 1.1+/-1.5 mm Hg (6.8%) for the latanoprost-carteolol combination. Hence, IOP reduction by carteolol and dorzolamide additionally to latanoprost was not different. CONCLUSIONS: Both dorzolamide and carteolol reduce IOP additively when used in combination with latanoprost, and the additive effect of these drugs is equal.

Antihypertensive Agents↗
PubMed2006

Fracture strain and stability with additional locking screws in intramedullary nailing: a biomechanical study.

BACKGROUND: We studied the effect of additional locking screws on fracture strain and stability in tibial intramedullary nailing. METHODS: We drilled an additional diaphyseal locking hole into 8-mm solid tibial nails 185 mm from the proximal end of the nail, and locked it proximally and distally. An osteotomy was produced 4.5 cm distal to the additional hole, and the construct loaded axially, in flexion, extension, and torsion. The nails were also tested for their fatigue strength. RESULTS: With the additional locking screw, strain increased proximally during loading in neutral and flexion. Strain decreased on loading in extension. The extra locking screw decreased strain close to the osteotomy site in all loading positions. A significant reduction in angular motion at the osteotomy site occurred with the addition of the extra locking screw. The nails survived the fatigue test, although the stress increased around the additional locking hole CONCLUSIONS: Nails with additional locking options, by altering strain and motion at the fracture site, may have the clinical potential to affect fracture healing.

Biomechanical Phenomena↗
PubMed1988

Multiple factors are required for poly(A) addition to a mRNA 3' end.

Polyadenylation of pre-mRNAs in the nucleus involves a specific endonucleolytic cleavage, followed by the addition of approximately 200 adenylic acid residues. We have assayed HeLa nuclear extracts for the activity that catalyzes the poly(A) addition reaction. The authenticity of the in vitro assay was indicated by the observation that the poly(A) tract added in vitro is approximately 200 nucleotides in length. We have fractionated nuclear extracts in order to define components involved in specific poly(A) addition. No single fraction from DEAE-Sephacel chromatography of a HeLa nuclear extract possessed the specific poly(A) addition activity. However, if the various fractions were recombined, activity was restored, indicating the presence of multiple components. Further fractionation revealed the presence of at least two factors necessary for the poly(A) addition reaction. The reconstituted system retains the characteristics and specificity seen in the crude extract. Additional purification of one of the factors strongly suggests it to be a previously characterized poly(A) polymerase which, when assayed in the absence of the other factor, can add AMP to an RNA terminus but without specificity. Thus, the other component of the reaction may provide specificity to the process. In contrast to the 3' cleavage reaction, the poly(A) addition machinery does not possess an essential RNA component, as assayed by micrococcal nuclease digestion, nor do anti-Sm sera inhibit the reaction. Thus, the total process of formation of a polyadenylated mRNA 3' end is complex and requires the concerted action of distinct nuclear components.

Catalysis↗
PubMed2006

Vitrification of in vitro-produced bovine embryos by addition of ethylene glycol in one-step.

The objective of this study was to simplify two-step addition of cryoprotectant for vitrification of bovine embryos by developing a one-step procedure. Survival was calculated as a percentage of non-vitrified controls developed from the same batch of oocytes. In experiment 1, bovine blastocysts were vitrified following one- or two-step addition of cryoprotectant. Exposure of embryos to cryoprotectant in one-step resulted in survival rates not significantly lower (p > 0.1) than those obtained by two-step addition (85% vs 98%, respectively). Based on these results, experiments 2-4 were designed to test one-step addition of cryoprotectant more rigorously. Experiment 2 exposed day 7 blastocysts to 6, 7 or 8 M ethylene glycol for 2.5 or 3.5 min. At 24 h post-vitrification, survival of embryos was similar, irrespective of ethylene glycol concentration or exposure time (6 M 38%, 7 M 51%, 8 M 59%; 2.5 min 54%, 3.5 min 45%). In experiment 3, blastocysts were exposed to 7 M ethylene glycol for shorter times (30 or 60 s); 30 s exposure resulted in decreased survival (8% vs 31%, p < 0.05). Experiment 4 concerned one-step addition of cryoprotectant to day 6 bovine morulae, exposed to 7 M ethylene glycol for 1 or 1.5 min. There was no difference in survival between exposure times of 1 or 1.5 min (28% vs 45%, respectively; p > 0.1). It is unclear why many embryos survive vitrification with one-step addition of cryoprotectant, but others do not. Although, one-step addition of cryoprotectant simplifies the vitrification procedure, survival rates were inadequate for routine cryopreservation of in vitro-produced bovine embryos.

Animals↗
PubMed1993

Decimal assay for additivity of drugs permits delineation of synergy and antagonism.

Although there are many in vitro tests for drug interactions, few possess a linear, predictable dose-dependent end point or have a precise definition for additivity. Therefore, a new test with both of these features, the decimal assay for additivity, was developed. This test is based on a disk diffusion assay and the strict linear relationship between drug mass and size of the inhibition zone. When the decimal assay for additivity was applied to combinations known on a mechanistic basis to be additive, synergistic, or antagonistic, results of the new test always reflected the expected drug interaction. For example, synergy between trimethoprim and sulfamethoxazole was detected in tests with Escherichia coli and Haemophilus influenzae, as was antagonism between cefoxitin and cefotaxime in tests with Enterobacter cloacae. Quinolones plus chloramphenicol appeared to be antagonistic. In addition to correctly identifying the drug interaction, the decimal assay for additivity identified the drug ratio producing the maximal drug interaction. These results suggest that the decimal assay for additivity should prove very useful in future studies of drug interactions.

4-Quinolones↗
PubMed1970

Bacteriophage receptor development and synthesis of O-specific side chains after addition of D-galactose to the uridine diphosphate-galactose-4-epimeraseless mutant Salmonella typhimurium LT2-M1.

The formation of complete cell wall core lipopolysaccharide (LPS) and O-antigenic side chains after addition of d-galactose to the uridine diphosphate-galactose-4-epimeraseless mutant, Salmonella typhimurium LT2-M1, has been studied by (i) determination of adsorption rates of smooth and rough specific bacteriophages, (ii) passive hemagglutination inhibition, and (iii) qualitative and quantitative determination of the polysaccharide composition and structure. A rapid synthesis of the complete core LPS and O side chains occurred in bacteria in the log phase and the early stationary phase. Phage C21, which attaches to unsubstituted Rc structures, was adsorbed by the bacteria for only 10 min after the addition of d-galactose. Unsubstituted Rc structures, however, could still be detected after 160 min by immunological and chemical assays. Attachment of the P22 phage, which requires O-specific side chains with more than one repeating unit for adsorption, was demonstrated 10 min after the addition of d-galactose. Attachment of the Felix O-1 phage, which requires a complete core, was observed between 20 and 80 min after the addition of d-galactose. The rough specific phages 6SR and Br2 did not adsorb to the bacteria at any time after the addition of d-galactose. By passive hemagglutination inhibition, the presence of O-specific structures could be demonstrated after 10 min. No antigenic activity of the Ra and Rb structures was observed in the LPS preparations isolated at any time after the addition of d-galactose. Methylation analysis of LPS preparations isolated at 10 and 160 min after the addition of d-galactose showed that the O-specific side chains contained an average of 11 and 15 repeating units, respectively. In the 10-min sample, every 25th "Rc structure" carried a side chain, compared to every 3rd residue in the 160-min sample.

Adsorption↗
PubMed1998

Use of three additional mid biopsies to improve local assessment of prostate cancer in patients with one positive sextant biopsy.

OBJECTIVES: Routine sextant biopsies have proven useful in the diagnosis and local staging of prostate cancer. A single positive biopsy is more frequently associated with a smaller tumor and a low risk of positive margins. Nevertheless, the risk of positive margins in patients with 1 positive sextant biopsy remains high (20%). A better assessment of local invasion is therefore needed. In addition to standard sextant biopsies, we routinely obtain 3 additional mid biopsies from the apex to the base of the prostate. The aim of this study is to analyze the contribution of these 3 additional mid biopsies to local staging. METHODS: From 1988 to 1996, 177 men underwent sextant biopsies plus 3 additional mid biopsies prior to radical prostatectomy; 59 men had 1 positive sextant biopsy, and 13 also had 1-3 positive mid biopsies. The pathological results of the prostatectomy specimens from these 13 men (group A) were compared with those of the 46 men with only 1 positive sextant biopsy (group B), by means of the Fisher and Mann-Whitney tests. RESULTS: The two groups were similar in terms of age, preoperative prostate-specific antigen, the Gleason score of positive biopsies, the weight of the specimen, the Gleason specimen score, tumor volume and pathological stage. Positive surgical margins were found in 53.8% of group A and 19.4% of group B patients (p = 0.002). The location of the positive additional biopsies matched that of the positive surgical margins. CONCLUSIONS: Additional mid biopsies improve the local assessment of prostate cancer in patients with a single positive sextant biopsy, identifying significantly more positive margins when these additional mid biopsies are positive and indicating the location of the positive surgical margins. These informations could be helpful to avoid positive surgical margins during radical prostatectomy.

Aged↗
PubMed2004

Additional collection devices used in conjunction with the SurePath Liquid-Based Pap Test broom device do not enhance diagnostic utility.

BACKGROUND: We have previously shown that use of an EC brush device in combination with the Rovers Cervex-Brush (SurePath broom) offered no significant improvement in EC recovery. Here we determine if use of additional collection devices enhance the diagnostic utility of the SurePath Pap for gynecologic cytology. METHODS: After informed consent, 37 women ages 18-56 receiving their routine cervical examinations were randomized into four experimental groups. Each group was first sampled with the SurePath broom then immediately re-sampled with an additional collection device or devices. Group 1: Rover endocervix brush (n = 8). Group 2: Medscand CytoBrush Plus GT (n = 7). Group 3: Rover spatula + endocervix brush (n = 11). Group 4: Medscand spatula + CytoBrush Plus GT (n = 11). RESULTS: Examination of SurePath broom-collected cytology yielded the following abnormal diagnoses: atypia (n = 2), LSIL (n = 5) and HSIL (n = 3). Comparison of these diagnoses to those obtained from paired samples using the additional collection devices showed that use of a second and or third device yielded no additional abnormal diagnoses. Importantly, use of additional devices did not improve upon the abnormal cell recovery of the SurePath broom and in 4/10 cases under-predicted or did not detect the SurePath broom-collected lesion as confirmed by cervical biopsy. Finally, in 36/37 cases, the SurePath broom successfully recovered ECs. Use of additional devices, in Group 3, augmented EC recovery to 37/37. CONCLUSIONS: Use of additional collection devices in conjunction with the SurePath broom did not enhance diagnostic utility of the SurePath Pap. A potential but not significant improvement in EC recovery might be seen with the use of three devices.

Journal Article↗
PubMed2006

Measuring additive interaction using odds ratios.

Interaction measured on the additive scale has been argued to be better correlated with biologic interaction than when measured on the multiplicative scale. Measures of interaction on the additive scale have been developed using risk ratios. However, in studies that use odds ratios as the sole measure of effect, the calculation of these measures of additive interaction is usually performed by directly substituting odds ratios for risk ratios. Yet assessing additive interaction based on replacing risk ratios by odds ratios in formulas that were derived using the former may be erroneous. In this paper, we evaluate the extent to which three measures of additive interaction - the interaction contrast ratio (ICR), the attributable proportion due to interaction (AP), and the synergy index (S), estimated using odds ratios versus using risk ratios differ as the incidence of the outcome of interest increases in the source population and/or as the magnitude of interaction increases. Our analysis shows that the difference between the two depends on the measure of interaction used, the type of interaction present, and the baseline incidence of the outcome. Substituting odds ratios for risk ratios, when calculating measures of additive interaction, may result in misleading conclusions. Of the three measures, AP appears to be the most robust to this direct substitution. Formulas that use stratum specific odds and odds ratios to accurately calculate measures of additive interaction are presented.

Journal Article↗
PubMed2004

Triiodothyronine addition to paroxetine in the treatment of major depressive disorder.

There is evidence that thyroid hormone T3 increases serotonergic neurotransmission. Therefore, T3 addition to antidepressants may improve treatment response in major depression. In nonrefractory depression, T3 addition to tricyclic antidepressants indeed accelerates treatment response. Current therapeutic practice favors selective serotonin reuptake inhibitors. This is the first study to investigate the efficacy of T3 addition to paroxetine in major depression. One hundred thirteen patients with major depressive disorder were randomly assigned to 8 wk of double-blind outpatient treatment with low-dose T3 (25 microg), high-dose T3 (25 microg twice daily), or placebo in addition to paroxetine 30 mg daily. A total of 106 patients started treatment and were included in the outcome analysis. Response rate after 8 wk (reduction of Hamilton Rating Scale for Depression score > or = 50%) was 46% in all three treatment arms (P = 0.99). T3 addition did not accelerate clinical response to paroxetine, nor was an effect of T3 found when only women were analyzed. Patients on T3 addition reported more adverse events than patients on placebo comedication. In conclusion, these results do not support a role for T3 addition to selective serotonin reuptake inhibitors in the treatment of nonrefractory major depressive disorder. On the contrary, more adverse reactions occurred in T3-treated patients.

Adult↗
PubMed2002

Deviation from additivity in mixture toxicity: relevance of nonlinear dose-response relationships and cell line differences in genotoxicity assays with combinations of chemical mutagens and gamma-radiation.

Sublinear dose-response relationships are often seen in toxicity testing, particularly with bioassays for carcinogenicity. This is the result of a superimposition of various effects that modulate and contribute to the process of cancer formation. Examples are saturation of detoxification pathways or DNA repair with increasing dose, or regenerative hyperplasia and indirect DNA damage as a consequence of high-dose cytotoxicity and cell death. The response to a combination treatment can appear to be supra-additive, although it is in fact dose-additive along a sublinear dose-response curve for the single agents. Because environmental exposure of humans is usually in a low-dose range and deviation from linearity is less likely at the low-dose end, combination effects should be tested at the lowest observable effect levels (LOEL) of the components. This principle has been applied to combinations of genotoxic agents in various cellular models. For statistical analysis, all experiments were analyzed for deviation from additivity with an n-factor analysis of variance with an interaction term, n being the number of components tested in combination. Benzo[a]pyrene, benz[a]anthracene, and dibenz[a,c]anthracene were tested at the LOEL, separately and in combination, for the induction of revertants in the Ames test, using Salmonella typhimurium TA100 and rat liver S9 fraction. Combined treatment produced no deviation from additivity. The induction of micronuclei in vitro was investigated with ionizing radiation from a 137Cs source and ethyl methanesulfonate. Mouse lymphoma L5178Y cells revealed a significant 40% supra-additive combination effect in an experiment based on three independent replicates for controls and single and combination treatments. On the other hand, two human lymphoblastoid cell lines (TK6 and WTK1) as well as a pilot study with human primary fibroblasts from fetal lung did not show deviation from additivity. Data derived from one cell line should therefore not be generalized. Regarding the testing of mixtures for deviation from additive toxicity, the suggested experimental protocol is easily followed by toxicologists.

Animals↗