Phase I Trial of Intravenous Mistletoe Extract in Advanced Cancer.

Purpose: Mistletoe extract (ME) is widely used for patients with cancer to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration. Materials and Methods: This phase I trial of intravenous mistletoe (Helixor M) aimed to determine the recommended phase II dosing and to evaluate safety. Patients with solid tumor progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and QoL. Results: Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The MTD was 600 mg. Treatment-related adverse events (AE) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment-related AEs were noted in 3 patients (14.8%). Stable disease was observed in 5 patients who had one to six prior therapies. Reductions in baseline target lesions were observed in 3 patients who had two to six prior therapies. Objective responses were not observed. The disease control rate (percentage of complete/partial response and stable disease) was 23.8%. The median stable disease was 15 weeks. Serum cancer antigen-125 or carcinoembryonic antigen showed a slower rate of increase at higher dose levels. The median QoL by Functional Assessment of Cancer Therapy-General increased from 79.7 at week 1 to 93 at week 4. Conclusions: Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted. Significance: Although ME is widely used for cancers, its efficacy and safety are uncertain. This first phase I trial of intravenous mistletoe (Helixor M) aimed to determine phase II dosing and to evaluate safety. We recruited 21 patients with relapsed/refractory metastatic solid tumor. Intravenous mistletoe (600 mg, 3/week) demonstrated manageable toxicities (fatigue, nausea, and chills) with disease control and improved QoL. Future research can examine ME's effect on survival and chemotherapy tolerability.

Comparación de la eficacia de dexmedetomidina, meperidina y ketamina en la prevención de escalofrío postoperatorio / Comparison of the effectiveness of dexmedetomidine, meperidine and ketamine in the prevention of postoperative shivering

Objetivo. Comparar la eficacia de la dexmedetomidina, meperidina y ketamina profiláctica en el tratamiento del temblor postoperatorio. Materiales y métodos. Ensayo clínico, aleatorizado, controlado y de doble ciego. El estudio incluyó 160 pacientes (ASA I-II) bajo anestesia general mayor a 1h de duración. Se asignaron aleatoriamente a 4 grupos para recibir dosis única intravenosa: dexmedetomidina 1μg/kg (grupo A, n=33), meperidina 0,4mg/kg (grupo B, n=38), ketamina 0,5mg/kg (grupoC, n=40), o solución salina 0,9% (grupo D, n=45), administrados 20min antes de la sutura de piel. Para evitar sesgos, se estandarizó la técnica de inducción y mantenimiento anestésico así como el seguimiento postoperatorio. Resultados. Para cualquier grado de escalofrío, la mayor incidencia se presentó en el grupo placebo (47%) (p<0,01). La mayor incidencia para escalofrío (grados 3 y 4) se presentó en el grupo placebo (22 y 18% respectivamente). Para los grados 3 y 4 en todos los momentos de seguimiento no se presentó ningún caso de escalofrío en el grupo de meperidina (p<0,01). El grupo placebo (38%) fue el que mayor proporción de pacientes requirió tratamiento de rescate para escalofrío postoperatorio (p<0,01). Conclusión. La meperidina en dosis única de 0,4mg/kg intravenosa es una medida útil para la prevención del escalofrío postoperatorio (AU)

Objective. To compare the prophylactic effectiveness of dexmedetomidine, meperidine, and ketamine for postoperative shivering. Materials and methods. A randomized, controlled, double-blind, clinical trial, including 160 patients (ASA I - II) undergoing surgical procedures under general anaesthesia for longer than one hour. They were randomly assigned to four groups to receive a single intravenous dose: Dexmedetomidine 1ug/kg (group A, n=33), meperidine 0.4mg/kg (group B, n=38), ketamine 0.5mg/kg (groupC, n=40), or 0.9% saline solution (group D, n=45), administered 20min before the skin suture. To avoid bias, the anaesthetic induction and maintenance technique, as well as postoperative follow-up was standardised. Results. For any level of shivering, the greatest incidence was observed in the placebo group (47%) (P<.01). The greatest effect on shivering level 3 and 4 occurred in the placebo group (22% and 18%, respectively). For levels 3 and 4 during follow-up, there was not a single case of shivering at any time in the meperidine group (P<.01). The placebo group (38%) had the highest proportion of patients requiring treatment for post-operative shivering (P<.01). Conclusion. Meperidine given intravenously in a single dose of 0.4mg/kg is a useful means for preventing postoperative shivering (AU)

Non-steroidal anti-inflammatory drugs for the common cold.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for the treatment of pain and fever associated with the common cold. OBJECTIVES: To determine the effects of NSAIDs versus placebo (and other treatments) on signs and symptoms of the common cold, and to determine any adverse effects of NSAIDs in people with the common cold. SEARCH METHODS: We searched CENTRAL (2015, Issue 4, April), (January 1966 to April week 3, 2015), EMBASE (January 1980 to April 2015), CINAHL (January 1982 to April 2015) and ProQuest Digital Dissertations (January 1938 to April 2015). SELECTION CRITERIA: Randomised controlled trials (RCTs) of NSAIDS in adults or children with the common cold. DATA COLLECTION AND ANALYSIS: Four review authors extracted data. We subdivided trials into placebo-controlled RCTs and head-to-head comparisons of NSAIDs. We extracted and summarised data on global analgesic effects (such as reduction of headache and myalgia), non-analgesic effects (such as reduction of nasal symptoms, cough, sputum and sneezing) and side effects. We expressed dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI) and continuous data as mean differences (MD) or standardised mean differences (SMD). We pooled data using the fixed-effect and random-effects models. MAIN RESULTS: We included nine RCTs with 1069 participants, describing 37 comparisons: six were NSAIDs versus placebo and three were NSAIDs versus NSAIDs. The overall risk of bias in the included studies was mixed. In a pooled analysis, NSAIDs did not significantly reduce the total symptom score (SMD -0.40, 95% CI -1.03 to 0.24, three studies, random-effects model), or duration of colds (MD -0.23, 95% CI -1.75 to 1.29, two studies, random-effects model). For respiratory symptoms, cough did not improve (SMD -0.05, 95% CI -0.66 to 0.56, two studies, random-effects model) but the sneezing score significantly improved (SMD -0.44, 95% CI -0.75 to -0.12, two studies, random-effects model). For outcomes related to the analgesic effects of NSAIDs (headache, ear pain, and muscle and joint pain) the treatment produced significant benefits. The risk of adverse effects was not high with NSAIDs (RR 2.94, 95% CI 0.51 to 17.03, two studies, random-effects model) but it is difficult to conclude that such drugs are no different from placebo. The quality of the evidence may be estimated as 'moderate' because of imprecision. The major limitations of this review are that the results of the studies are quite diverse and the number of studies for one result is quite small. AUTHORS' CONCLUSIONS: NSAIDs are somewhat effective in relieving the discomfort caused by a cold but there is no clear evidence of their effect in easing respiratory symptoms. The balance of benefit and harms needs to be considered when using NSAIDs for colds.

Non-steroidal anti-inflammatory drugs for the common cold.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for the treatment of pain and fever associated with the common cold. However, there is no systematic review to assess the effects of NSAIDs in treating the common cold. OBJECTIVES: To determine the effects of NSAIDs versus placebo (and other treatments) on signs and symptoms of the common cold, and to determine any adverse effects of NSAIDs in people with the common cold. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2013, Issue 1), MEDLINE (January 1966 to April week 4, 2013), EMBASE (January 1980 to April 2013), CINAHL (January 1982 to April 2013) and ProQuest Digital Dissertations (January 1938 to April 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) of NSAIDS in adults or children with the common cold. DATA COLLECTION AND ANALYSIS: Four review authors extracted data. We subdivided trials into placebo-controlled RCTs and head-to-head comparisons of NSAIDs. We extracted and summarised data on global efficacies of analgesic effects (such as reduction of headache and myalgia), non-analgesic effects (such as reduction of nasal symptoms, cough, sputum and sneezing) and side effects. We expressed dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI) and continuous data as mean differences (MD) or standardised mean differences (SMD). We pooled data using the fixed- and random-effects models. MAIN RESULTS: We included nine RCTs with 1069 participants, describing 37 comparisons: six were NSAIDs versus placebo and three were NSAIDs versus NSAIDs. The overall risk of bias in the included studies was mixed. In a pooled analysis, NSAIDs did not significantly reduce the total symptom score (SMD -0.40, 95% CI -1.03 to 0.24, three studies, random-effects model), or duration of colds (MD -0.23, 95% CI -1.75 to 1.29, two studies, random-effects model). For respiratory symptoms, cough did not improve (SMD -0.05, 95% CI -0.66 to 0.56, two studies, random-effects model) but the sneezing score significantly improved (SMD -0.44, 95% CI -0.75 to -0.12, two studies, random-effects model). For outcomes related to the analgesic effects of NSAIDs (headache, ear pain, and muscle and joint pain) the treatment produced significant benefits. The risk of adverse effects was not high with NSAIDs (RR 2.94, 95% CI 0.51 to 17.03, two studies, random-effects model) and it is difficult to conclude that such drugs are not different from placebo. AUTHORS' CONCLUSIONS: NSAIDs are somewhat effective in relieving discomfort caused by a cold but there is no clear evidence of their effect in easing respiratory symptoms. The balance of benefit and harms needs to be considered when using NSAIDs for colds.

Dantrolene sodium for the treatment of aldesleukin-induced rigors in a melanoma patient.

OBJECTIVE: To report the case of a 58-year-old male with melanoma who developed aldesleukin-induced rigors and was successfully treated with intravenous dantrolene sodium 20 mg and provide a review of the literature discussing other agents that have been used to treat drug-induced rigors. CASE SUMMARY: A 58-year-old male was treated with 720,000 IU/kg of aldesleukin every 8 hours as part of his antimelanoma therapy. The patient developed rigors after aldesleukin administration and was successfully treated with 25 mg of meperidine. Later, he experienced renal dysfunction that was also linked to aldesleukin therapy and developed normeperidine-induced neurotoxicity requiring discontinuation of meperidine therapy. The rigors were treated with intravenous dantrolene sodium 20 mg every 4 hours, with complete resolution of symptoms. DISCUSSION: Several antineoplastic agents can cause rigors; many of these agents can also lead to renal failure. Several agents have been investigated for their use in the management of rigors but can cause adverse effects or are unsuitable in the setting of renal insufficiency or failure. Although meperidine remains the mainstay for the treatment and prevention of rigors, it can be associated with neurotoxicity in some patients, particularly those with impaired renal function. Given that dantrolene has been shown to be effective against rigors, it may be a useful alternative for patients who can not tolerate meperidine. Drugs with a more favorable adverse effect profile that are not eliminated through the kidneys are needed. CONCLUSIONS: In the oncology setting, severe rigors can result in the interruption of a patient's cancer therapy, which can increase the risk of treatment failure. Dantrolene may be a useful alternative for patients experiencing rigors who can not tolerate meperidine.

Misdiagnosis of Behçet's disease with unknown protracted fever and chill after surgical excision of cardiac tumor.

Behçet's disease involving the heart is extremely rare. Sometimes it is probable to misdiagnose as infective endocarditis when protracted fever and chill occurs. We report a case of protracted pyrexia of unknown origin after surgical excision of a cardiac tumour. Clinically and pathologically a diagnosis of infective endocarditis was probable but antibiotics had no effect. After case review the diagnosis of Behçet's disease was established and the patient was treated with glucocorticoids which resulted in resolution.

Improving outcome of treatment of kala-azar by supplementation of amphotericin B with physiologic saline and potassium chloride.

Complications of amphotericin B limit its wide application in the treatment of patients with kala-azar. This study was undertaken with an aim to minimize anti-renal complications and severe rigor in course of treatment with this drug. Parasitologically confirmed kala-azar cases (n = 230) were randomized equally into two groups: a control group received amphotericin B only at a dose of 1 mg/kg of body weight/day for 20 days and a patient (test) group received 500 mL of physiologic saline and 30 mL (60 meq/L) of KC1 with amphotericin B. We observed a significantly lower increase in serum creatinine levels (P = 0.0001) and a lower incidence of severe rigor and fever (P = 0.0165) in the test group than in the control group. However, the ultimate cure rate was not significantly different (P = 0.5637) between two groups after 12 months of follow-up. Relapses occurred after even after six months in both groups. Persons with relapses were treated with 25 infusions of amphotericin B and cured. Supplementation of amphotericin B with 500 mL of physiologic saline and 30 mL (60 meq/L) of KCl during treatment could help prevent an increase in serum creatinine levels and severe rigor and would make the treatment of kala-azar with amphotericin B easier.

Non-steroidal anti-inflammatory drugs for the common cold.

BACKGROUND: Although non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for the treatment of pain and fever associated with the common cold, there is no systematic review to assess the effects of NSAIDs in patients with the common cold. OBJECTIVES: To determine the effects of NSAIDs versus placebo and other treatments on the signs and symptoms of the common cold. To determine any adverse effects of NSAIDs in patients treated with NSAIDs for the common cold. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 1) which includes the Acute Respiratory Infections (ARI) Group's Specialized Register; MEDLINE (January 1966 to March 2009); EMBASE (January 1980 to March 2009); CINAHL (January 1982 to March 2009); ProQuest Digital Dissertations (January 1938 to March 2009); KoreaMed (January 1958 to March 2009) and KMbase (January 1949 to March 2009). SELECTION CRITERIA: Randomized controlled trials (RCTs) studying treatment of the common cold with NSAIDs in adults or children. DATA COLLECTION AND ANALYSIS: Four review authors extracted data (SYK, YSM, YJC, YWH). We subdivided trials into placebo-controlled RCTs and NSAIDs versus NSAIDs RCTs. We extracted and summarized data on global efficacies: analgesic effects such as reduction of headache and myalgia; non-analgesic effects such as reduction of nasal symptoms, cough, sputum and sneezing; and side effects. MAIN RESULTS: This review includes nine RCTs, describing 37 comparisons: six were NSAIDs versus placebo, and three were NSAIDs versus NSAIDs. A total of 1064 patients with the common cold were included. In a pooled analysis, NSAIDs did not significantly reduce the total symptom score, or duration of colds.However, for outcomes related to the analgesic effects of NSAIDs (headache, ear pain, and muscle and joint pain) NSAIDs produced significant benefits, and malaise showed a borderline benefit, although throat irritation was not improved. Chills showed mixed results. For respiratory symptoms, cough and nasal discharge scores were not improved, but the sneezing score significantly improved. We found no evidence of increased frequency of adverse effects in the NSAID treatment groups. AUTHORS' CONCLUSIONS: The authors recommend NSAIDs for relieving discomfort or pain caused by the common cold. Further research is needed to investigate the effect of NSAIDs in relieving respiratory symptoms such as cough and nasal discharge.

[Effects of Piper longum L. on chills in Japanese young women: time-dependent changes in skin surface temperature and its recovery rate following the exposure to mild cold stress].

Chills can lead to problems such as insomnia, mental fatigue, and unstable emotions. Increasing evidence shows that young women, as well as menopausal women, suffer from chills. The present study investigated the effect of Piper longum L. on chills in young women. Participants with (n = 16) and without (n = 16) chills were sampled randomly from female university students using reported discriminative criteria (Yamada et al, 2007). Each participant was randomly assigned to low- (15 mg) and high-dose (30 mg) P. longum groups. We determined the severity of complaints related to chills, physical parameters (body mass index, body fat ratio, and blood pressure), the peripheral circulation dynamics using a laser tissue blood flow-meter, and the skin surface temperature in the fingers using a thermograph. Mild cold stress was applied 10 min after taking a capsule containing P. longum or a dextrin placebo. Then, a thermograph was recorded every minute for 11 min. Piper longum significantly facilitated the recovery of skin surface temperature at either low or high dosages in participants with chills. In subjects without chills, neither high- nor low-dosage of P. longum had an effect. Our findings have important implications for the utility of P. longum in women with chills.

Chilliness: a vasomotor symptom in Japan.

OBJECTIVE: To examine the differences between biomedical and Japanese women's concepts of vasomotor symptoms and the relationships between the symptom of chilliness (hiesho) and menopause status, other vasomotor symptoms, and environmental factors such as soy isoflavone intake and exposure in Japan. DESIGN: Participants were healthy Japanese women, aged 45 to 55, living in Kyoto and Fukushima prefectures, divided into menopausal groups based on menstrual patterns. Women recalled 82 general health symptoms during the previous 2 weeks and collected finger-prick dried blood spots and matched 24-hour dietary records, which were analyzed, respectively, for isoflavone concentration by high-performance liquid chromatography coulometric electrode array detection and for soy isoflavone intake using a Japanese phytochemical database. RESULTS: An examination of konenki (Japanese for climacteric) symptoms suggests that chilliness (hiesho), which was reported by 29.3% of participants compared with a range of 3.0% to 22.1% for hot flushes, constitutes an important vasomotor symptom. Chilliness prevalence differed significantly between premenopausal and other menopausal status groups, with positive correlations with other estrogen-influenced sexual-vasomotor symptoms and negative correlations with isoflavone concentrations. Negative correlations with soy isoflavone intake were also found for sweating, although not for nobose and hoteri (two Japanese terms for hot flush). CONCLUSIONS: Chilliness seems to be a more important vasomotor symptom than hot flushes and sweats in Japanese women and may reflect differing thermoregulatory physiology, possibly influenced by dietary soy.

Comparison of effects of vitamin E and wen-jing-tang (unkei-to), an herbal medicine, on peripheral blood flow in post-menopausal women with chilly sensation in the lower extremities: a randomized prospective study.

We examined the association between blood flow and chilly sensation in the lower extremities, comparing the changes in blood flow induced by the vitamin E and herbal therapy (Wen-jing-tang) in perimenopausal women with chilly sensation. One hundred sixty-one perimenopausal women aged 42-61 years (mean: 50.4 +/- 3.8 years) with chilly sensation in the lower extremities participated in the study. The participants were randomized for treatment with Wen-jing-tang or a vitamin E preparation containing 600 mg tocopherol nictinate per day for 8 weeks. Blood flow measurement was performed by laser Doppler fluxmetry to determine tissue under the jaw, in the middle finger, and in the third toe. Wen-jing-tang significantly increased the peripheral blood flow in the skin surface in the tiptoe (12.8 +/- 8.8, p = 0.0068) from basal levels (6.0 +/- 5.1), although no significant change was observed in the blood flow in fingertip or under the jaw during treatment. The rate of increase of blood flow in the skin surface of in the lower extremities was significantly higher in the Wen-jing-tang treating group (116.4 +/- 46.5%) than in the vitamin E group (39.8 +/- 21.3%) (p < 0.0001). When the effects of herbal treatment and vitamin E treatment were compared in the subjects with baseline upper extremity blood flow above the mean + 1.5 SD, mean blood flow through the upper extremities was found to have been significantly decreased after Wen-jing-tang treatment (from 57.7 +/- 4.8 to 43.1 +/- 4.2, p = 0.0277), whereas it remained unchanged after treatment with vitamin E. Classical monographs described Wen-jing-tang as being particularly useful in curing chilly sensation in lower extremities. The present study using a laser Doppler fluxmeter demonstrated that treatment with this herbal medicine significantly increased blood flow through the periphery of lower extremities in patients with chilly sensation. It also showed that this herbal medicine suppresses excessive blood flow through the upper half of the body and thus stimulates restoration of physiological distribution of blood flow throughout the entire body.

Corticosteroids, ibuprofen, and acetaminophen for IFNbeta-1a flu symptoms in MS: a randomized trial.

OBJECTIVE: To compare the efficacy of acetaminophen, ibuprofen, and prednisone in the treatment of interferon beta-1a (IFNbeta-1a) flu-like syndrome (FLS). METHODS: Patients with relapsing-remitting multiple sclerosis initiating treatment with IM IFNbeta-1a were randomized in a multicenter, randomized, double-blind, controlled trial to receive acetaminophen 500 mg before and 6 and 12 hours after each injection, ibuprofen 400 mg before and 6 and 12 hours after each injection, or prednisone 60 mg daily for 1 week, plus tapering. Patients were instructed to keep a daily diary of fever severity, myalgia, chills, headache, and asthenia for 27 days. The sum of the scores of individual symptoms was used to obtain a daily FLS index. The primary outcome was the FLS index area under the curve (AUC) corrected by the number of measurement days. RESULTS: Eighty-four patients were randomized at 11 hospitals: acetaminophen (n = 28), ibuprofen (n = 28), and corticosteroids (n = 28). No differences were detected between treatments in the mean AUC of the FLS index. With limitation of the analysis to the days of IM IFNbeta-1a injection, differences favoring ibuprofen were observed in the mean FLS index (p = 0.0007). CONCLUSIONS: No prophylactic treatment for flu-like syndrome seems to be superior to another in terms of overall well-being during the first month of IM IFNbeta-1a therapy. However, ibuprofen confers better control of symptoms immediately following IM IFNbeta-1a injection.

Both paracetamol and ibuprofen are equally effective in managing flu-like symptoms in relapsing-remitting multiple sclerosis patients during interferon beta-1a (AVONEX) therapy.

Interferon beta-1a is an established therapy for patients with relapsing-remitting multiple sclerosis (MS). Adverse effects in the first weeks of treatment are common. This open-label, multicenter, randomized, prospective study compared treatment of flu-like symptoms (FLS) with paracetamol versus ibuprofen administered 48 h within interferon injection. The percentage of patients with FLS was comparable between both treatment groups and improved during the course of the study (baseline: paracetamol 92%, ibuprofen 90%; week 12: paracetamol 60%, ibuprofen 57%). More than 75% of patients receiving either paracetamol or ibuprofen reported no or only mild impairment of daily activities. There was no significant difference in general satisfaction or incidence of additional symptoms (weakness, nausea, headache; paracetamol 84.6% patients, ibuprofen 86.0% patients) between the two groups. A significant overall improvement from baseline to week 12 was observed for all parameters studied (paracetamol and ibuprofen groups were pooled). These results indicate that neither the paracetamol nor the ibuprofen treatment regimen is better.