Indocyanine green fluorescence versus blue dye, technetium-99M, and the dual-marker combination of technetium-99M + blue dye for sentinel lymph node detection in early breast cancer-meta-analysis including consistency analysis.

BACKGROUND: Axillary sentinel lymph node biopsies are standard of care in patients with breast cancer and no clinically apparent metastases. Traditionally, technetium-99m, blue dye, or both have been used to identify sentinel lymph nodes. However, blue dyes miss up to 40% of sentinel lymph nodes, while technetium-99m use is complex, costly, and exposes patients to radiation. Over the past decade, studies have consistently found the biologically inert fluorescent indocyanine green to be 95% to 100% sensitive in detecting breast cancer sentinel lymph nodes, yet indocyanine green remains infrequently used. METHODS: We conducted an extensive meta-analysis comparing indocyanine green against blue dye, technetium-99m, and the dual-marker combination of technetium-99m + BD. Unlike prior meta-analyses that only assessed either per-case or per-node sentinel lymph node detection, we analyzed the following 5 metrics: per-case and per-node sentinel lymph node detection and metastasis-positive sentinel lymph node sensitivity, and mean number of sentinel lymph nodes/case. We further examined the consistency and magnitude of between-study superiority and statistically significant within-study superiority of each marker against others. RESULTS: For every metric and analysis approach, indocyanine green was clearly superior to blue dye and at least non-inferior, if not superior, to technetium-99m and technetium-99m + blue dye. Assessing the consistency of superiority by at least 2.0%, indocyanine green was superior to blue dye 73 times versus 1, to technetium-99m 42 times versus 9, and to technetium-99m + blue dye 6 times versus 0. Within-study statistically significant differences favored indocyanine green over blue dye 29 times versus 0 and over technetium-99m 11 times versus 2. DISCUSSION: For sentinel lymph node detection in patients with breast cancer with no clinically apparent metastases, indocyanine green is clearly and consistently superior to blue dye and either non-inferior or superior to technetium-99m and technetium-99m + blue dye.

[Health care of geriatric patients with urinary incontinence]. / Gesundheitsversorgung bei Harninkontinenz im Alter.

Urinary incontinence occurs frequently in geriatric patients. In the doctor's practice, the symptoms are often not mentioned by the patients; this may lead to loss of autonomy and social isolation. A screening for urinary incontinence should therefore be part of each geriatric assessment. In the presence of urinary incontinence, several treatment options are available, which need to be tailored according to the individual capabilities (mobility, motivation and cognitive performance) of the patient. Non-pharmacological treatment options, such as behavior modification, toilet training and pelvic floor training, should be exploited before any pharmacotherapy commences. If the pharmacological treatment involves the use of anticholinergic agents, the cognitive performance should be monitored. An interdisciplinary collaboration is a prerequisite for the optimized treatment and adequate health care of geriatric patients with urinary incontinence.

Pharmacokinetics and pharmacodynamics of calcium-vitamin D(3) chewable tablets: a single-blind, multiple-dose study in postmenopausal women.

OBJECTIVE: The objective of this study is to investigate the effect of a newly developed calcium carbonate-vitamin D3 chewable tablet formulation (600 mg of calcium + 400 IU of vitamin D3) on serum/urine calcium and serum parathyroid hormone (PTH) as measures of intestinal calcium absorption compared to a placebo. METHODS: This is a subject-blind, sequential study in 24 healthy postmenopausal women. Each subject received two placebo tablets once daily for 3 days (days -3 to -1) immediately followed by two calcium-vitamin D3 tablets (test) during the subsequent 3 days (days 1-3). Serial blood sampling and 24-h urine collection took place on days -1 and 3. The subjects fasted until 6 h post-dosing. Total urinary calcium excretion (Ae(0-24 h)) and AUC(0-6 h) for serum calcium were the primary outcome variables and were compared between treatments using a paired sample t-test. RESULTS: Ae(0-24 h) increased by 42% (uncorrected, p = 0.0001) and 30% (creatinine-corrected, p = 0.0001), after intake, compared with the placebo; serum calcium exposure (AUC(0-6 h)) was also, statistically, significantly greater. PTH, in serum, decreased by 28% (AUC(0-6 h), p = 0.0001) and 14% (AUC(0-24 h), p = 0.0009) when compared with the placebo. CONCLUSION: Daily intake of 1200 mg of calcium and 800 IU of vitamin D3, with a new chewable tablet, resulted in increased intestinal calcium absorption compared to the results from the placebo as confirmed by direct and indirect pharmacokinetic/pharmacodynamic measures.

Efficacy and tolerability of oral lactoferrin supplementation in mild to moderate acne vulgaris: an exploratory study.

OBJECTIVE: Lactoferrin, an innate defense iron-binding protein, possesses antimicrobial and anti-inflammatory activities. Beneficial systemic effects on inflammatory diseases have been proposed. The aim of the present study was to explore the efficacy and tolerability of oral bovine lactoferrin supplementation in subjects with mild to moderate facial acne vulgaris. METHODS: In this open-label, single-arm study, 43 adolescents and young adults were enrolled to take a chewable tablet formulation of bovine lactoferrin twice daily for 8 weeks. The primary efficacy endpoint was the improvement in acne lesion counts compared with baseline. Tolerability was evaluated on the basis of adverse event frequencies. RESULTS: Thirty-nine subjects, aged 17.5 ± 3.8 years, completed the study per protocol. At the end of the study (week 8), a mean reduction in inflammatory lesion count of 20.2% (-2.2 ± 7.0, p = 0.054), in non-inflammatory lesion count of 23.5% (-6.2 ± 9.8, p < 0.001), and in total lesion count of 22.5% (-8.4 ± 13.1, p < 0.001) was observed as compared with baseline. At study conclusion, 76.9% (30 of 39) of subjects showed a reduction in total lesion count. The results for inflammatory acne lesions were variable over the study course. None of the subjects experienced a lactoferrin-related adverse event during the trial. CONCLUSION: Despite the limitations of an uncontrolled, open-label study, the results from this study indicate that lactoferrin in mild to moderate acne vulgaris is well tolerated and may lead to an overall improvement in acne lesion counts in the majority of affected adolescents and young adults when administered as a dietary supplement on a twice daily regimen. Further randomized, placebo-controlled trials of longer duration appear warranted.

[Antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute lower urinary tract infections in adults]. / Antimikrobielle und klinische Wirksamkeit von Nitrofurantoin in der Behandlung akuter Infekte der unteren ableitenden Harnwege bei Erwachsenen.

BACKGROUND AND PURPOSE: In the light of increasing resistance to antibiotics used for the treatment of acute urinary tract infections, nitrofurantoin currently experiences a renaissance. Nitrofurantoin shows good efficacy against most bacteria expected in urinary tract infection, and the development of resistance is low. A study on the antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute lower urinary tract infections was conducted in Mexico City, an area where resistance rates of uropathogens to trimethoprim/sulfamethoxazole (cotrimoxazole) are high. PATIENTS AND METHODS: In this open-label, single-arm study 20 adult patients (18 females, 2 males) with positive urine culture were treated orally with nitrofurantoin sustained release 100 mg twice daily for 7 days. Urinary nitrofurantoin concentrations were determined at baseline and day 4 of the study. Primary endpoint was the antimicrobial efficacy of nitrofurantoin at 12 to 16 days after baseline, assessed by changes in urine culture results. RESULTS: In the patient population treated per protocol, primary endpoint analysis revealed a microbial eradication rate of 92.3%. At 35 to 42 days, the eradication rate was 83.3%. At these times, all patients in the per protocol population were free of symptoms. In patients with complicating factors, e.g. diabetic polyneuropathy, both antimicrobial and clinical efficacy appeared to be reduced. Urinary nitrofurantoin concentrations were mostly above minimum inhibitory concentrations of the isolated uropathogens. The study drug was generally well tolerated. Most frequent drug-related adverse event was mild headache, occurring in 10.8% of patients. Two patients discontinued the study due to rash. CONCLUSION: The results of the present study indicate good antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute uncomplicated urinary tract infections as well as acceptable tolerability in adults.

Tolerability and efficacy of a pediatric granule formulation of artesunate-mefloquine in young children from Cameroon with uncomplicated falciparum malaria.

A fixed-dose pediatric formulation of artesunate and mefloquine (Artequin Pediatric) has been developed. In this open, non-comparative study in Cameroonian children with uncomplicated falciparum malaria, the safety and efficacy of this formulation was tested, with a particular emphasis on the risk of neuropsychiatric adverse events (AEs). In total, 220 subjects, weighing between 10 and 20 kg, were enrolled; 213 qualified for analysis. Artesunate-mefloquine was given once daily for 3 days. Overall, 13.1% of patients reported mild to moderate neuropsychiatric AEs (elicited through a structured questionnaire or reported spontaneously) out of which 3.8% (mainly insomnia) were considered drug-related. Other drug-related AEs were infrequent (< 3%). Polymerase chain reaction-corrected cure rate (adequate clinical and parasitological response) determined by survival analysis at 28 and 63 days was 96.6%. New infections were observed in 11.2% of evaluable patients at 63 days. The new formulation was well tolerated and efficacious in the population investigated.

Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo-controlled trial.

OBJECTIVE: To investigate the extent and time course of pain intensity upon treatment with a topical diclofenac patch compared with placebo in acute traumatic sport injury based on a validated and established end point. METHODS: Post hoc analysis of a randomized, placebo-controlled, double-blind, multicentre, 1-week study in 120 patients with traumatic blunt soft tissue injury. Visual analogue scale (VAS) scores (in millimetres) for pain on movement were analysed. The mean absolute VAS changes in pain intensity from baseline over the study course were calculated for the diclofenac patch formulation (active) and placebo; mean differences between active and placebo were assessed twice daily during the first 3 days after enrolment and then once daily up to day 7. RESULTS: The diclofenac patch was consistently superior to placebo in relieving pain. The mean differences compared with placebo were greatest on day 2 (23.6 - 30.6 mm, p < 0.0001) and day 3 (24.5 - 24.6 mm, p < 0.0001). Diminishing differences were observed over the study course. CONCLUSION: The investigated diclofenac sodium patch provides clinically relevant pain relief in patients with acute traumatic injuries. Maximum effects versus placebo are detected at 2 - 3 days post-injury. This analysis may serve as useful information for the planning of clinical trials in acute traumatic injury.

[Risks associated with drug therapy. What do patients need to know? What can they do]. / Risiken in der Arzneimitteltherapie: Was müssen Patientinnen und Patienten wissen? Was können sie tun?

BACKGROUND: Errors can occur at any time during drug therapy. A not inconsiderable percentage of hospital admissions to internal medicine departments are caused by adverse drug events (ADEs), many of which could be avoided. Avoidable ADEs mainly result from suboptimal procedures in the medication process. In order to recognize and minimize these risks, cooperative interaction of all those involved in the medication process is required. This also includes involving patients. A plan of action to improve safety of drug therapy in Germany has recently been completed under the aegis of the Federal Ministry of Health. In a concerted effort, structures and procedures of pharmacotherapy are to be systematically analyzed and improved. The plan of action is focused on measures that can be achieved in the short term, with particular emphasis on the reduction of risks. PURPOSE: The purpose of this paper is to make a contribution to increasing the patients' awareness for the risks associated with drug therapy and to provide suggestions of what they can do to improve the safety of their own therapy. CONCLUSION: With relatively simple means, patients can make an important contribution to improving the safety of drug therapy. However, only a collective increased sensitization for potential medication errors can lead to a sustainable risk reduction.

[Cost-effectiveness evaluation of drugs: multidisciplinary collaboration and transparency are key]. / Kosten-Nutzen-Bewertung von Arzneimitteln: Fachübergreifende Zusammenarbeit und Transparenz sind entscheidend.

BACKGROUND: A new German law introduced the cost-effectiveness evaluation of drugs. In Germany, the Institute for Quality and Efficiency in Health Care (IQWiG) is responsible for such evaluations. Currently, however, there is a heavy and controversial debate about the correct method to be applied. A recent proposal of IQWiG on the method to be used for cost-effectiveness evaluations has been dismissed by an expert panel. Moreover, previous IQWiG assessments are criticized and the institute is accused of providing insufficient transparency of its evaluation procedures. The head organizations of the compulsory health insurances focus on their own method to analyze and judge new drugs (EVITA), which is claimed to provide the desired results faster than IQWiG. In Germany, the current situation appears obscure and there is the threat of confusing and contradictory methods for cost-effectiveness evaluations yielding inconsistent assessments. PURPOSE: This paper aims at outlining the current situation in Germany and providing potential solutions. CONCLUSION: It requires an early and multidisciplinary collaboration to achieve the goal of a valid and fully transparent cost-effectiveness evaluation.

Comparative efficacy and tolerability of two sustained-release formulations of diclofenac: results of a double-blind, randomised study in patients with osteoarthritis and a reappraisal of diclofenac's use in this patient population.

OBJECTIVE: To compare the analgesic efficacy and tolerability of a sustained-release pellet formulation of diclofenac (Olfen-100 SR Depocaps, SR-CAP, Mepha Ltd, Aesch, Switzerland) with the standard reference formulation (Voltaren retard 100, SR-TAB, Novartis Pharma AG, Basel, Switzerland), both containing 100 mg diclofenac sodium, in patients with osteoarthritis (OA) of the knee and/or hip. In addition, diclofenac's current place in the symptomatic therapy of OA is briefly reviewed. METHODS: In this 2-week double-blind, active-controlled, non-inferiority trial, 210 OA patients were randomised to receive either SR-CAP once daily or SR-TAB once daily (n = 105 for both groups). The primary efficacy endpoint was the change in visual analogue scale (VAS) pain score (0-100 mm) at rest at Day 14 compared with baseline. Secondary variables included the change in VAS pain score on movement and global assessments of efficacy and tolerability using verbal rating scales (VRS). RESULTS: Between baseline and Day 14, mean +/- SD VAS pain score at rest decreased by 44.4 +/- 18.5 mm in the SR-CAP group (n = 89) compared with 41.2 +/- 19.8 mm in the SR-TAB group (n = 82) based on the per protocol population. Comparable changes were observed in the intention-to-treat population. The lower bound of the 1-sided 97.5% confidence interval was -2.7 mm and greater than the prespecified non-inferiority limit of -10 mm. There was a trend towards a better tolerability with SR-CAP compared with SR-TAB based on mean +/- SD VRS scores (SR-CAP, 0.6 +/- 0.68; SR-TAB, 0.9 +/- 1.0 for assessment by patients; p = 0.063). CONCLUSION: SR-CAP is as effective as and possibly better tolerated than SR-TAB in patients suffering from painful OA.

Therapeutic drug monitoring of mycophenolic acid in solid organ transplant patients treated with mycophenolate mofetil: review of the literature.

Mycophenolate mofetil (MMF) has conventionally been administered at a fixed dose without routinely monitoring blood levels of mycophenolic acid (MPA), the active metabolite. The contribution of therapeutic drug monitoring (TDM) during MMF therapy remains controversial. A literature review was performed to explore the usefulness of TDM for MPA in solid organ transplantation. In addition, emphasis was placed on the potential clinical benefits and limitations of TDM for MPA. Available studies have limitations and report conflicting results. Although early after transplantation MPA area under the curve might have predictive value for the risk of acute rejection, predose levels appear less reliable. With regard to MPA toxicity, most studies showed no correlation between MPA pharmacokinetics and adverse effects. TDM is hampered by several factors such as the considerable intra-subject variability of MPA pharmacokinetics and the increasing number of different drug combinations. Proposed target ranges are restricted to the early posttransplant period when MMF is used in combination with cyclosporine. The current review of the literature indicates no clear support for a substantial clinical benefit of TDM and more data from prospective randomized trials are needed.

Efficacy and safety of the six-dose regimen of artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in adolescents and adults: a pooled analysis of individual patient data from randomized clinical trials.

To demonstrate the superiority of the six-dose over the four-dose regimen of artemether-lumefantrine (co-artemether, Coartem) in patients >12 years, data from 11 randomized clinical trials were pooled and analyzed. A total of 1368 patients with uncomplicated Plasmodium falciparum malaria (six-dose: 598; four-dose: 770) were included in the analysis, together with 717 patients treated with comparators. Analysis of the 28-day cure rate based on the ITT and evaluable populations yielded corrected cure rates for the six-dose regimen of 87% and 97% compared with 74% and 87%, respectively, with the four-dose regimen (P<0.0001, for both comparisons). For mefloquine/artesunate, the most frequently used comparator, cure rates were 87% and 99%, respectively. The six-dose regimen was well tolerated and not markedly different to the four-dose regimen. The main finding of our analysis is that the six-dose regimen of co-artemether is more effective than the four-dose regimen in adolescents and adults without compromising safety.

Efficacy and safety of the six-dose regimen of artemether-lumefantrine in pediatrics with uncomplicated Plasmodium falciparum malaria: a pooled analysis of individual patient data.

Patient data from eight clinical trials were pooled and analyzed to study the efficacy and safety of the six-dose versus four-dose regimen of artemether-lumefantrine (coartemether; Coartem) in children weighing 5-25 kg. A total of 544 patients with uncomplicated P. falciparum malaria (six-dose: 343; four-dose: 201), matched for demographic and baseline characteristics and individual coartemether doses were included in the analysis. Analysis of day 28 cure rate based on the intention-to-treat and evaluable populations yielded corrected cure rates for the six-dose regimen of 93% and 96% compared with 61% and 76%, respectively, for the four-dose regimen (P < 0.0001 for both comparisons). Similarly high cure rates were achieved with the six-dose regimen in non-immune infants weighing as little as 5 kg. The six- and four-dose regimens were equally well tolerated. The main finding of this analysis is that the six-dose regimen of coartemether is safe and more efficacious than the four-dose regimen in children.