A randomized comparative study of sulbactam plus ampicillin vs. metronidazole plus cefotaxime in the management of acute appendicitis in children.

PubMed

Foster, M C; Kapila, L; Morris, D L; Slack, R C

1986-01-01

Sulbactam is a beta-lactamase inhibitor that, when combined with ampicillin, gives the latter antibiotic a broad spectrum of activity, making it suitable for use as a prophylactic agent in acute appendicitis. In a single-blind, randomized trial, the efficacy of sulbactam plus ampicillin was compared with that of metronidazole plus cefotaxime. Thirty-five children undergoing appendectomy received intravenous sulbactam and ampicillin, while 38 children received metronidazole and cefotaxime. Single doses were given unless the appendix was considered gangrenous or perforated, in which case the drugs were administered for 72 hr. There were three wound infections in the group given sulbactam and ampicillin and five in the group given metronidazole and cefotaxime. The combination of sulbactam and ampicillin was well tolerated and appeared to be at least as effective as that of metronidazole and cefotaxime in the prevention of sepsis following appendectomy.

Addition of Ceftriaxone and Amikacin to a Ciprofloxacin plus Metronidazole Regimen for Preventing Infectious Complications of Transrectal Ultrasound-Guided Prostate Biopsy: A Randomized Controlled Trial

PubMed Central

Izadpanahi, Mohammad-Hossein; Majidi, Seyed Mahmood; Khorrami, Mohammad-Hatef; Mohammadi-Sichani, Mehrdad

2017-01-01

Background. The objective of this study was to evaluate the efficacy of adding single doses of ceftriaxone and amikacin to a ciprofloxacin plus metronidazole regimen on the reduction of infectious complications following transrectal ultrasound-guided prostate biopsy (TRUS Bx). Materials and Methods. Four hundred and fifty patients who were candidates for TRUS Bx were divided into two groups of 225 each. The control group received ciprofloxacin 500 mg orally every 12 hours together with metronidazole 500 mg orally every 8 hours from the day prior to the procedure until the fifth postoperative day. In the second group, single doses of ceftriaxone 1 g by intravenous infusion and amikacin 5 mg/kg intramuscularly were administered 30–60 minutes before TRUS Bx in addition to the oral antimicrobials described for group 1. The incidence of infection was compared between the groups. Results. The incidence of infectious complications in the intervention group was significantly lower than that in the control group (4.6% versus 0.9%, p = 0.017). Conclusion. The addition of single doses of intramuscular amikacin and intravenously infused ceftriaxone to our prophylactic regimen of ciprofloxacin plus metronidazole resulted in a statistically significant reduction of infectious complications following TRUS Bx. PMID:28167960

Addition of Ceftriaxone and Amikacin to a Ciprofloxacin plus Metronidazole Regimen for Preventing Infectious Complications of Transrectal Ultrasound-Guided Prostate Biopsy: A Randomized Controlled Trial.

PubMed

Izadpanahi, Mohammad-Hossein; Nouri-Mahdavi, Kia; Majidi, Seyed Mahmood; Khorrami, Mohammad-Hatef; Alizadeh, Farshid; Mohammadi-Sichani, Mehrdad

2017-01-01

Background. The objective of this study was to evaluate the efficacy of adding single doses of ceftriaxone and amikacin to a ciprofloxacin plus metronidazole regimen on the reduction of infectious complications following transrectal ultrasound-guided prostate biopsy (TRUS Bx). Materials and Methods. Four hundred and fifty patients who were candidates for TRUS Bx were divided into two groups of 225 each. The control group received ciprofloxacin 500 mg orally every 12 hours together with metronidazole 500 mg orally every 8 hours from the day prior to the procedure until the fifth postoperative day. In the second group, single doses of ceftriaxone 1 g by intravenous infusion and amikacin 5 mg/kg intramuscularly were administered 30-60 minutes before TRUS Bx in addition to the oral antimicrobials described for group 1. The incidence of infection was compared between the groups. Results. The incidence of infectious complications in the intervention group was significantly lower than that in the control group (4.6% versus 0.9%, p = 0.017). Conclusion. The addition of single doses of intramuscular amikacin and intravenously infused ceftriaxone to our prophylactic regimen of ciprofloxacin plus metronidazole resulted in a statistically significant reduction of infectious complications following TRUS Bx.

Influence of intravenous opioid dose on postoperative ileus.

PubMed

Barletta, Jeffrey F; Asgeirsson, Theodor; Senagore, Anthony J

2011-07-01

Intravenous opioids represent a major component in the pathophysiology of postoperative ileus (POI). However, the most appropriate measure and threshold to quantify the association between opioid dose (eg, average daily, cumulative, maximum daily) and POI remains unknown. To evaluate the relationship between opioid dose, POI, and length of stay (LOS) and identify the opioid measure that was most strongly associated with POI. Consecutive patients admitted to a community teaching hospital who underwent elective colorectal surgery by any technique with an enhanced-recovery protocol postoperatively were retrospectively identified. Patients were excluded if they received epidural analgesia, developed a major intraabdominal complication or medical complication, or had a prolonged workup prior to surgery. Intravenous opioid doses were quantified and converted to hydromorphone equivalents. Classification and regression tree (CART) analysis was used to determine the dosing threshold for the opioid measure most associated with POI and define high versus low use of opioids. Risk factors for POI and prolonged LOS were determined through multivariate analysis. The incidence of POI in 279 patients was 8.6%. CART analysis identified a maximum daily intravenous hydromorphone dose of 2 mg or more as the opioid measure most associated with POI. Multivariate analysis revealed maximum daily hydromorphone dose of 2 mg or more (p = 0.034), open surgical technique (p = 0.045), and days of intravenous narcotic therapy (p = 0.003) as significant risk factors for POI. Variables associated with increased LOS were POI (p < 0.001), maximum daily hydromorphone dose of 2 mg or more (p < 0.001), and age (p = 0.005); laparoscopy (p < 0.001) was associated with a decreased LOS. Intravenous opioid therapy is significantly associated with POI and prolonged LOS, particularly when the maximum hydromorphone dose per day exceeds 2 mg. Clinicians should consider alternative, nonopioid-based pain

Metronidazole-induced encephalopathy in a patient with liver cirrhosis.

PubMed

Cheong, Hyeong Cheol; Jeong, Taek Geun; Cho, Young Bum; Yang, Bong Joon; Kim, Tae Hyeon; Kim, Haak Cheoul; Cho, Eun-Young

2011-06-01

Encephalopathy is a disorder characterized by altered brain function, which can be attributed to various causes. Encephalopathy associated with metronidazole administration occurs rarely and depends on the cumulative metronidazole dose, and most patients with this condition recover rapidly after discontinuation of therapy. Because metronidazole is metabolized in the liver and can be transported by the cerebrospinal fluid and cross the blood-brain barrier, it may induce encephalopathy even at a low cumulative dose in patients with hepatic dysfunction. We experienced a patient who showed ataxic gait and dysarthric speech after receiving metronidazole for the treatment of hepatic encephalopathy that was not controlled by the administration of lactulose. The patient was diagnosed as metronidazole-induced encephalopathy, and stopping drug administration resulted in a complete recovery from encephalopathy. This case shows that caution should be exercised when administering metronidazole because even a low dose can induce encephalopathy in patients with liver cirrhosis.

Treatment of trichomoniasis with metronidazole rectal suppositories

PubMed Central

Panja, S K

1982-01-01

Since a single dose of metronidazole in suppository form is very effective in the prevention of postoperative Gram-negative anaerobic infections, 84 patients with vaginal trichomoniasis were treated with metronidazole suppositories (two 1-g suppositories in a single dose). The cure rate in this series was 94%. PMID:7104657

Systemic antibiotic prophylaxis prior to gastrointestinal surgery - is oral administration of doxycycline and metronidazole adequate?

PubMed

Giske, Anneli; Nymo, Linn Såve; Fuskevåg, Ole-Martin; Amundsen, Siri; Simonsen, Gunnar Skov; Lassen, Kristoffer

Antibiotic prophylaxis is recommended prior to a wide range of gastrointestinal operations to reduce the rate of surgical site infections (SSIs). Traditional intravenous (IV) drugs are costly and their preparation strains nursing resources at the wards. While oral administration may attenuate these limitations, its use remains limited. We aimed to assess whether a dual oral antibiotic prophylaxis regimen provides adequate serum concentrations throughout the surgical procedure. We measured serum concentrations of doxycycline and metronidazole following single oral doses of 400 mg doxycycline and 1200 mg metronidazole at first incision and repeated at wound closure in a cohort of patients undergoing elective gastrointestinal surgery. Both drugs were dispensed at least two hours before skin incision. Serum concentrations were compared to minimum inhibitory concentrations (MIC) and epidemiological cut-off values (ECOFFs) for relevant pathogens. Mean serum concentrations of doxycycline at first incision and at wound closure were 5.75 mg/L and 4.66 mg/L and of metronidazole 18.88 mg/L and 15.56 mg/L, respectively. Metronidazole concentrations were above ECOFF (2 mg/L) for relevant anaerobic species in 103/104 of patients in both samples. Doxycycline serum concentrations were above the ECOFF for common Enterobacteriaceae species (4 mg/L) in both samples in 58/104 patients (55.8%). A single dose of orally administered metronidazole provides adequate concentrations throughout surgery in a heterogeneous cohort of patients. Uncertainty persists regarding the adequacy of doxycycline concentrations, as the optimal serum level of doxycycline in a prophylactic setting has not been established.

Metronidazole stewardship initiative at Christchurch hospitals-achievable with immediate benefits.

PubMed

Gardiner, Sharon J; Metcalf, Sarah Cl; Chin, Paul Kl; Doogue, Matthew P; Dalton, Simon C; Chambers, Stephen T

2018-04-13

To evaluate an antimicrobial stewardship (AMS) initiative to change hospital prescribing practice for metronidazole. In October 2015, the Canterbury District Health Board (CDHB) AMS committee changed advice for metronidazole to promote two times daily dosing for most indications, prioritisation of the oral route and avoidance of double anaerobic cover. Adoption of the initiative was facilitated via change in prescribing guidelines, education and ongoing pharmacy support. Usage and expenditure on metronidazole for adult inpatients were compared for the five years pre- and two years post-change. Other district health boards (DHBs) were surveyed to determine their dosing recommendation for metronidazole IV. Mean annual metronidazole IV use, as defined daily doses per 1,000 occupied bed days, decreased by 43% post-initiative. Use of non-IV (oral or rectal) formulations increased by 104%. Total savings associated with the initiative were approximately $33,400 in drug costs plus $78,200 per annum in IV giving sets and post-dose flushes. Twelve of 20 (60%) DHBs (including CDHB) endorse twice daily IV dosing. In addition to financial savings, reduction in IV doses has potential benefits, including avoidance of IV catheter-associated complications such as bloodstream infections. Approaches to metronidazole dosing vary across DHBs and could benefit from national coordination.

[Clinical Characteristics of Metronidazole-induced Encephalopathy: A Report of Two Cases and a Review of 32 Japanese Cases in the Literature].

PubMed

Kato, Hideaki; Sosa, Hiroko; Mori, Masaaki; Kaneko, Takeshi

2015-09-01

Metronidazole is an antibiotic classically used against most anaerobic bacteria and protozoa. Because an intravenous form of metronidazole has recently entered the market, the use of this antibiotic is attracting renewed interest in many clinical settings in Japan. However, neurotoxicity is a major adverse event: in the central nervous system metronidazole-induced encephalopathy is a rare but serious condition. We performed a literature review of 34 cases including 2 of our cases, 25 from domestic conference abstracts, and 7 cases presented in full research papers. The mean patient age was 64.7 years. The conditions most commonly treated with metronidazole were brain abscess (35.3%), liver abscess (17.6%), and Clostridium difficile infection (14.7%). The most common predisposing conditions were liver dysfunction (26.5%), diabetes and other metabolic disorders (20.6%), and hematologic or solid organ malignancy (14.7%). The mean period of administration before the onset of encephalopathy symptoms was 61.3 days, and the mean total dose was 95.9g. The initial chief complaints were dysarthria (in 70.6% of the cases) and ataxia (61.8%); 82.4% of the cases were diagnosed on the basis of MRI (T2-weighted or FLAIR imaging). The key imaging finding was high intensity in the dentate nucleus bilaterally (82.4%). Stopping the metronidazole led to symptom remission within 8.5 days, but the MRI changes remained longer than the clinical symptoms. Two patients (6.0%) developed irreversible disturbance of consciousness. Although the mechanisms of this type of encephalopathy have not yet been elucidated, localized nerve-cell edema is likely caused by decreased metronidazole metabolism associated with liver and metabolic dysfunction. Careful observation for neurologic signs should be conducted during the treatment of brain abscesses associated with metronidazole administration, because patients with brain abscesses are naturally at high risk of metronidazole-induced encephalopathy.

Unit-Dose Bags For Formulating Intravenous Solutions

NASA Technical Reports Server (NTRS)

Finley, Mike; Kipp, Jim; Scharf, Mike; Packard, Jeff; Owens, Jim

1993-01-01

Smaller unit-dose flowthrough bags devised for use with large-volume parenteral (LVP) bags in preparing sterile intravenous solutions. Premeasured amount of solute stored in such unit-dose bag flushed by predetermined amount of water into LVP bag. Relatively small number of LVP bags used in conjunction with smaller unit-dose bags to formulate large number of LVP intravenous solutions in nonsterile environment.

Review of high-dose intravenous vitamin C as an anticancer agent.

PubMed

Wilson, Michelle K; Baguley, Bruce C; Wall, Clare; Jameson, Michael B; Findlay, Michael P

2014-03-01

In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid). These studies were criticized for their retrospective nature and lack of standardization of key prognostic factors including performance status. Subsequently, several well-designed randomized controlled trials failed to demonstrate a significant survival benefit, although these trials used high-dose oral vitamin C. Marked differences are now recognized in the pharmacokinetics of vitamin C with oral and IV administration, opening the issue of therapeutic efficacy to question. In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant but may have pro-oxidant activity at high concentrations. The mechanism of its pro-oxidant action is not fully understood, and both intra- and extracellular mechanisms that generate hydrogen peroxide have been proposed. It remains to be proven whether vitamin C-induced reactive oxygen species occur in vivo and, if so, whether this will translate to a clinical benefit. Current clinical evidence for a therapeutic effect of high-dose IV vitamin C is ambiguous, being based on case series. The interpretation and validation of these studies is hindered by limited correlation of plasma vitamin C concentrations with response. The methodology exists to determine if there is a role for high-dose IV vitamin C in the treatment of cancer, but the limited understanding of its pharmacodynamic properties makes this challenging. Currently, the use of high-dose IV vitamin C cannot be recommended outside of a clinical trial. © 2014 Wiley Publishing Asia Pty Ltd.

Metronidazole combined with nystatin (vagitories) in the prevention of bacterial vaginosis after initial treatment with oral metronidazole.

PubMed

Pulkkinen, P; Saranen, M; Kaaja, R

1993-01-01

In a double-blind trial comprising 66 patients we assessed the effect of metronidazole-nystatin vagitories on the prevention of bacterial vaginosis (BV) in women using IUD as a contraceptive method after an initial oral single dose of 2.0 g metronidazole and 7 days of intravaginal metronidazole-nystatin or placebo treatment. The prophylactic treatment consisted of metronidazole-nystatin or placebo vagitories applied at bedtime for 3 days after menstruation over 6 consecutive menstrual periods. The patients were randomized in two study groups: a treatment group of 32 patients (group A) and a placebo group of 34 patients (group B). The overall objective cure rate after the initial treatment was 97% in group A and 91% in group B. After 6 months of follow-up, the overall cumulative objective cure rate in group A was 100%, and 76% in group B. The single-dose oral treatment was well tolerated and no notable side effects were recorded.

High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy.

PubMed

Depositario-Cabacar, Dewi T; Peters, Jurriaan M; Pong, Amanda W; Roth, Julie; Rotenberg, Alexander; Riviello, James J; Takeoka, Masanori

2010-07-01

We review our experience with high-dose intravenous levetiracetam (IV-LEV) for acute seizure exacerbations in nine children with medically intractable epilepsy. All children had acute repetitive seizures-while on chronic antiepileptic drugs-that either led to hospitalization (eight) or occurred during hospitalization (one), and received doses of IV-LEV of 150 mg/kg/day or greater, with a mean dose of 228 +/- 48 mg/kg/day. Eight of nine children had resolution of the acute repetitive seizures. Seizure frequency was reduced to less than baseline in seven children (seizure-free in two, >/=80% reduction in four, and 50% reduction in one). Except for one child with increased seizures, IV-LEV was well tolerated in all children without complications.

[Metronidazole-induced reversible cerebellar lesions and peripheral neuropathy].

PubMed

Toumi, S; Hammouda, M; Essid, A; Medimagh, L; Slamia, L Ben; Laouani-Kechrid, C

2009-12-01

Metronidazole is a widely prescribed treatment for amoebic and anaerobic germ infections. Its neurologic toxicity is rare but can be serious. We report the case of a 27-year-old male patient, treated with metronidazole for a cerebral abscess. He presented with a cerebellar syndrome and peripheral neuropathy at a cumulative metronidazole dose of 60g. The MRI aspect of the cerebellar lesions in addition to their reversibility after treatment cessation led to the diagnosis of metronidazole induced neurologic toxicity. The occurrence of neurologic disorders in patients treated with metronidazole must suggest drug toxicity and lead to cessation of treatment.

Effect of high-dose intravenous vitamin C on inflammation in cancer patients.

PubMed

Mikirova, Nina; Casciari, Joseph; Rogers, Andrea; Taylor, Paul

2012-09-11

An inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP) are associated with poor prognosis and decreased survival in many types of cancer.Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels.Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients. 45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g) after standard treatments by conventional methods.CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests. According to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment.There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3) and changes in the levels of C-reactive protein.Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments. The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.In summary, our data support the hypothesis that

Effect of high-dose intravenous vitamin C on inflammation in cancer patients

PubMed Central

2012-01-01

Background An inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP) are associated with poor prognosis and decreased survival in many types of cancer. Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels. Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients. Methods 45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g) after standard treatments by conventional methods. CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests. Results According to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment. There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3) and changes in the levels of C-reactive protein. Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments. Conclusions The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels. In

Intravaginal metronidazole gel versus metronidazole plus nystatin ovules for bacterial vaginosis: a randomized controlled trial.

PubMed

Sanchez, Sixto; Garcia, Patricia J; Thomas, Katherine K; Catlin, Mary; Holmes, King K

2004-12-01

We compared metronidazole 0.75% gel (containing 37.5 mg metronidazole per dose) with ovules containing metronidazole 500 mg and nystatin 100,000 U, for intravaginal treatment of bacterial vaginosis (BV). In a single-blinded trial, symptomatic women with BV by both Amsel and Nugent criteria were randomly assigned to gel or ovules, once nightly for 5 nights, and asked to return 3 times after treatment. Analyses were intent-to-treat. Of 151 women with BV by both criteria at enrollment, 138 (91%) returned at least once. Product limit estimates for persistence or recurrence of BV at 14, 42, and 104 days were 20% (95% CI 10%-29%), 38% (95% CI 25%-48%), and 52% (95% CI 37%-63%) after gel treatment, and 4% (95% CI 0%-9%), 17% (95% CI 7%-26%), and 33% (95% CI 21%-46%) after ovule treatment ( P = .01). Among women without BV at first follow-up, subsequent intercourse without condoms independently predicted subsequent recurrence ( P Metronidazole/nystatin ovules were significantly more effective than metronidazole gel. Unprotected sex predicted recurrence after initial improvement.

The role of single-shot metronidazole in the prevention of Clostridium difficile infection following ileostomy reversal surgery.

PubMed

Fernandes, Roland; Robinson, Paul; Rangarajan, Karan; Scott, Sophie; Angco, Laura

2017-05-01

Symptomatic infection with Clostridium difficile is strongly linked to antibiotic use and rates are higher for colorectal surgery. In February 2015, trust policy for antibiotic prophylaxis of ileostomy reversal surgery was changed from three doses of metronidazole plus cefuroxime to single-dose metronidazole, in a bid to reduce rates of Clostridium difficile infection. A retrospective cohort study was conducted at a single, large hospital trust between February 2014 and February 2016, before and after change in antimicrobial policy. Theatre data, clinical notes and pathology results were all reviewed. Outcome data, patient age, gender, length of operation and hospital stay were extracted. One hundred three patients underwent ileostomy reversal surgery between February 2014 and February 2015. All received cefuroxime together with metronidazole at induction of anaesthesia followed by two further post-operative doses as operative prophylaxis. Ninety-six patients underwent ileostomy reversal surgery between February 2015 and February 2016. All received single-dose metronidazole at induction as prophylaxis. Post-operative diarrhoea was significantly reduced in patients given single-dose metronidazole compared with patients managed with multiple dose, dual antibiotic therapy (32 vs 12.5%, P 0.001). Rates of CDI were also significantly reduced in patients given single-dose metronidazole (6.8 vs 1%, P 0.038). Single-dose, pre-operative metronidazole is effective at reducing post-operative diarrhoea and CDI in ileostomy reversal surgery compared with multiple-dose cefuroxime plus metronidazole. Metronidazole may be effective as a prophylactic antibiotic against CDI in colonic surgery.

Metronidazole-induced encephalopathy: not always a reversible situation.

PubMed

Hobbs, Kyle; Stern-Nezer, Sara; Buckwalter, Marion S; Fischbein, Nancy; Finley Caulfield, Anna

2015-06-01

Metronidazole is a nitroimidazole antimicrobial drug prescribed to treat infections caused by anaerobic bacteria and protozoa. Uncommonly, it causes central nervous system (CNS) toxicity manifesting as metronidazole-induced encephalopathy (MIE). Case report. A 65-year-old woman with hepatitis B cirrhosis (Child-Pugh class C, MELD 21) developed progressive encephalopathy to GCS 4 during a 3-week course of metronidazole for cholecystitis. Initial MRI was consistent with CNS metronidazole toxicity, with symmetrical T2 hyperintensity and generally restricted diffusion in bilateral dentate nuclei, corpus callosum, midbrain, superior cerebellar peduncles, internal capsules, and cerebral white matter. Laboratory values did not demonstrate significant electrolyte shifts, and continuous EEG was without seizure. High-dose thiamine was empirically administered. Lumbar puncture was not performed due to coagulopathy and thrombocytopenia. Despite discontinuation of metronidazole and keeping ammonia levels near normal, the patient did not improve. MRI was repeated 1 week after discontinuation of metronidazole. Although there was decreased DWI hyperintensity in the dentate nuclei, diffuse T2 hyperintensity persisted and even progressed in the brainstem, basal ganglia, and subcortical white matter. Petechial hemorrhages developed in bilateral corticospinal tracts and subcortical white matter. T1 hypointensity appeared in the corpus callosum. She was transitioned to comfort measures only and died 12 days later. MIE is an uncommon adverse effect of treatment with metronidazole that characteristically affects the dentate nuclei but may also involve the brainstem, corpus callosum, subcortical white matter, and basal ganglia. While the clinical symptoms and neuroimaging changes are usually reversible, persistent encephalopathy with poor outcome may occur.

Survey of pain specialists regarding conversion of high-dose intravenous to neuraxial opioids

PubMed Central

Gorlin, Andrew W; Rosenfeld, David M; Maloney, Jillian; Wie, Christopher S; McGarvey, Johnathan; Trentman, Terrence L

2016-01-01

The conversion of high-dose intravenous (IV) opioids to an equianalgesic epidural (EP) or intrathecal (IT) dose is a common clinical dilemma for which there is little evidence to guide practice. Expert opinion varies, though a 100 IV:10:EP:1 IT conversion ratio is commonly cited in the literature, especially for morphine. In this study, the authors surveyed 724 pain specialists to elucidate the ratios that respondents apply to convert high-dose IV morphine, hydromorphone, and fentanyl to both EP and IT routes. Eighty-three respondents completed the survey. Conversion ratios were calculated and entered into graphical scatter plots. The data suggest that there is wide variation in how pain specialists convert high-dose IV opioids to EP and IT routes. The 100 IV:10 EP:1 IT ratio was the most common answer of survey respondent, especially for morphine, though also for hydromorphone and fentanyl. Furthermore, more respondents applied a more aggressive conversion strategy for hydromorphone and fentanyl, likely reflecting less spinal selectivity of those opioids compared with morphine. The authors conclude that there is little consensus on this issue and suggest that in the absence of better data, a conservative approach to opioid conversion between IV and neuraxial routes is warranted. PMID:27703394

Effect of metronidazole use on tacrolimus concentrations in transplant patients treated for Clostridium difficile.

PubMed

Early, C R; Park, J M; Dorsch, M P; Pogue, K T; Hanigan, S M

2016-10-01

Two case reports suggest that metronidazole treatment for Clostridium difficile infections (CDI) increases tacrolimus (TAC) trough levels. The primary objective of this study was to determine the clinical significance of this potential interaction in transplant patients receiving CDI treatment. Currently, no robust literature exists to estimate a magnitude of pharmacokinetic interaction between metronidazole and TAC. In this retrospective study, the effects of CDI and metronidazole treatment on TAC levels in 52 adult solid organ transplant patients were investigated. The primary outcome was to determine the difference in dose-normalized TAC levels between baseline and symptom resolution in patients treated with metronidazole or vancomycin. The secondary outcome was to determine the difference in dose-normalized TAC levels at baseline and CDI diagnosis. The average change in log-transformed dose-normalized TAC levels from baseline to symptom resolution was 0.99 for metronidazole (n = 35) and 1.04 for vancomycin (n = 17) treatment. The mean difference between the groups was 0.96 (95% confidence interval: 0.74-1.24). No significant difference was found between dose-normalized TAC levels at CDI diagnosis and baseline (P = 0.37). CDI treatment with metronidazole was not associated with a >30% increase in TAC levels compared with vancomycin. Both treatment groups required TAC dose adjustments to maintain goal TAC levels and those treated with metronidazole did not require a significantly greater dose adjustment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tinidazole versus Metronidazole for the Treatment of Bacterial Vaginosis

PubMed Central

SCHWEBKE, Jane R.; DESMOND, Renee A.

2010-01-01

Objective To compare the efficacy of two different doses of tinidazole with metronidazole for treatment of bacterial vaginosis and compare side effects of the drugs. Study design Women were randomized to metronidazole 500 mg BID, tinidazole 500 mg BID, or tinidazole 1 gm BID all for 7 days. Follow-up visits were conducted at day 14 and day 28. Results 593 women were enrolled. There were no significant differences between the treatment arms. Overall cure rates were 76.8% at 14 days and 64.5% at one month. Women who admitted to engaging in sexual intercourse during the study were significantly more likely to have BV at follow-up. There were no significant differences in adverse events across treatment arms. Conclusions There were no differences in cure rates between metronidazole and either of the tinidazole dosing regimens studied. In addition, there were no important differences in the side effect profiles of metronidazole and tinidazole. PMID:21167471

Putative metronidazole neurotoxicosis in a cat.

PubMed

Olson, E J; Morales, S C; McVey, A S; Hayden, D W

2005-09-01

A presumptive case of metronidazole toxicity in a 3.4-kg adult cat is described. The cat had been treated for suspected inflammatory bowel disease with an anti-inflammatory dose of prednisone and metronidazole (73.5-147 mg/kg PO q24h) for approximately 40 days prior to presentation. Clinical signs were primarily related to the central nervous system, including acute tetraparesis, unresponsiveness, tremors, and vocalization. The patient was euthanatized after 12 days of supportive care. Necropsy revealed no significant macroscopic lesions. Histologic evaluation revealed multifocal, fairly well-demarcated foci of necrosis in the brainstem, extending from the diencephalon to the medulla oblongata. To our knowledge, this is the first report to document histologic lesions associated with metronidazole administration in a cat.

Metronidazole excretion in human milk and its effect on the suckling neonate.

PubMed Central

Passmore, C M; McElnay, J C; Rainey, E A; D'Arcy, P F

1988-01-01

1. Milk and plasma metronidazole and hydroxymetronidazole concentrations were measured in 12 breast-feeding patients following multiple doses of metronidazole (400 mg three times daily). All patients received metronidazole in combination with other broad spectrum antibiotics. 2. Plasma concentrations of both parent drug and metabolite were measured in seven suckling infants. Thirty-five infants were monitored for adverse reactions to maternal metronidazole therapy and two further groups of suckling infants, those whose mothers received either ampicillin alone or no drug therapy, were recruited as controls. 3. The mean milk to plasma ratio (M/P) was 0.9 for metronidazole and 0.76 for hydroxymetronidazole while the mean milk metronidazole concentrations (around Cmax) were 15.5 micrograms ml-1. The mean milk hydroxymetronidazole concentration was 5.7 micrograms ml-1. 4. Infant plasma metronidazole concentrations ranged from 1.27 micrograms ml-1 to 2.41 micrograms ml-1, and the corresponding hydroxymetronidazole concentrations from 1.1 to 2.4 micrograms ml-1. 5. There were no significant increases in adverse effects in infants which could be attributable to maternal metronidazole therapy. 6. Metronidazole was excreted in milk at concentrations which caused no serious reactions in the infants studied. The drug may therefore be administered at doses of 400 mg three times daily to mothers wishing to breast-feed their infants. PMID:3203060

Safety and Pharmacokinetics of Multiple 750-Milligram Doses of Intravenous Levofloxacin in Healthy Volunteers

PubMed Central

Chow, Andrew T.; Fowler, Cynthia; Williams, R. Rex; Morgan, Nancy; Kaminski, Susan; Natarajan, Jaya

2001-01-01

The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation. PMID:11408234

Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers.

PubMed

Chow, A T; Fowler, C; Williams, R R; Morgan, N; Kaminski, S; Natarajan, J

2001-07-01

The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation.

Cost effectiveness of high-dose intravenous esomeprazole for peptic ulcer bleeding.

PubMed

Barkun, Alan N; Adam, Viviane; Sung, Joseph J Y; Kuipers, Ernst J; Mössner, Joachim; Jensen, Dennis; Stuart, Robert; Lau, James Y; Nauclér, Emma; Kilhamn, Jan; Granstedt, Helena; Liljas, Bengt; Lind, Tore

2010-01-01

Peptic ulcer bleeding (PUB) is a serious and sometimes fatal condition. The outcome of PUB strongly depends on the risk of rebleeding. A recent multinational placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT00251979) showed that high-dose intravenous (IV) esomeprazole, when administered after successful endoscopic haemostasis in patients with PUB, is effective in preventing rebleeding. From a policy perspective it is important to assess the cost efficacy of this benefit so as to enable clinicians and payers to make an informed decision regarding the management of PUB. Using a decision-tree model, we compared the cost efficacy of high-dose IV esomeprazole versus an approach of no-IV proton pump inhibitor for prevention of rebleeding in patients with PUB. The model adopted a 30-day time horizon and the perspective of third-party payers in the USA and Europe. The main efficacy variable was the number of averted rebleedings. Healthcare resource utilization costs (physician fees, hospitalizations, surgeries, pharmacotherapies) relevant for the management of PUB were also determined. Data for unit costs (prices) were primarily taken from official governmental sources, and data for other model assumptions were retrieved from the original clinical trial and the literature. After successful endoscopic haemostasis, patients received either high-dose IV esomeprazole (80 mg infusion over 30 min, then 8 mg/hour for 71.5 hours) or no-IV esomeprazole treatment, with both groups receiving oral esomeprazole 40 mg once daily from days 4 to 30. Rebleed rates at 30 days were 7.7% and 13.6%, respectively, for the high-dose IV esomeprazole and no-IV esomeprazole treatment groups (equating to a number needed to treat of 17 in order to prevent one additional patient from rebleeding). In the US setting, the average cost per patient for the high-dose IV esomeprazole strategy was $US14 290 compared with $US14 239 for the no-IV esomeprazole strategy (year 2007 values). For

Treatment of Infections Caused by Metronidazole-Resistant Trichomonas vaginalis

PubMed Central

Cudmore, Sarah L.; Delgaty, Kiera L.; Hayward-McClelland, Shannon F.; Petrin, Dino P.; Garber, Gary E.

2004-01-01

Infections with the sexually transmitted protozoan Trichomonas vaginalis are usually treated with metronidazole, a 5-nitroimidazole drug derived from the antibiotic azomycin. Metronidazole treatment is generally efficient in eliminating T. vaginalis infection and has a low risk of serious side effects. However, studies have shown that at least 5% of clinical cases of trichomoniasis are caused by parasites resistant to the drug. The lack of approved alternative therapies for T. vaginalis treatment means that higher and sometimes toxic doses of metronidazole are the only option for patients with resistant disease. Clearly, studies of the treatment and prevention of refractory trichomoniasis are essential. This review describes the mechanisms of metronidazole resistance in T. vaginalis and provides a summary of trichomonicidal and vaccine candidate drugs. PMID:15489348

Drug library screening against metronidazole-sensitive and metronidazole-resistant Trichomonas vaginalis isolates.

PubMed

Goodhew, E Brook; Secor, W Evan

2013-09-01

Metronidazole and tinidazole are effective treatments for most patients with trichomoniasis but not for individuals who are infected with very resistant strains of Trichomonas vaginalis or persons with hypersensitivity to the 5-nitroimidazole drugs. Thus, there is a need for additional oral therapies to treat trichomoniasis. We screened the US Drug Collection Library against metronidazole-susceptible and resistant strains of T vaginalis. Activity was measured by incubating parasites and drugs for 48 h in the presence of tritiated thymidine. Growth inhibition was determined by the reduction of incorporated radioactivity by compounds at 20 μM in comparison to media control. Drugs that showed good initial activity were further tested to calculate IC50 values. Drugs with the most promise were tested together with metronidazole to see if there was any combinatorial effect. Of the 1040 drugs in the library, 83 (8%) reduced growth of a metronidazole-susceptible T vaginalis strain by at least 20%. Of these, IC50 values were calculated for 27 compounds and 8 drugs were evaluated in combination with metronidazole. Disulfiram and nithiamide were non-5-nitroimidazole drugs that showed the best activity against parasites when used alone. Albendazole and coenzyme B12 were the most promising compounds to boost the efficacy of metronidazole. No one drug was as effective as any of the 5-nitroimidazole compounds. However, disulfiram and nithiamide may be useful to treat individuals with hypersensitivity to 5-nitroimidazole drugs and albendazole and coenzyme B12 may be helpful in combination with metronidazole or tinidazole for treatment of persons with highly resistant T vaginalis infections.

Metronidazole-induced central nervous system toxicity: a systematic review.

PubMed

Kuriyama, Akira; Jackson, Jeffrey L; Doi, Asako; Kamiya, Toru

2011-01-01

To assess patient and medication factors that contribute to metronidazole toxicity. We searched PUBMED from 1965 through April 7, 2011, and performed a hand search of bibliographies. Case reports or case series reporting metronidazole-induced central nervous toxicity. Two authors independently abstracted demographics, metronidazole indication, dose and duration, neurological manifestations, and outcomes as well as brain imaging findings. Among 64 patients, 48 (77%) had cerebellar dysfunction, 21 (33%) had altered mental status, and 8 (15%) had seizures. Patients' ages averaged 53.3 years (range, 12-87 years), and 64% were male. The median duration of metronidazole was 54 days, although 26% had taken it less than a week and 11% had taken it less than 72 hours. Among cases with outcome data, most patients either improved (n = 18 [29%]) or had complete resolution of their symptoms with discontinuation of metronidazole (n = 41 [65%]). There was no difference in resolution of symptom by age (P = 0.71) or sex (P = 0.34). The patients with cerebellar dysfunction were less likely to experience complete resolution than those with mental status changes or seizures (relative risk, 0.67; 95% confidence interval (CI), 0.49-0.92). Nearly all patients (n = 55 [86%]) underwent imaging of the brain: 44 (69%) underwent magnetic resonance imaging (MRI) and 12 (19%) underwent computed tomographic studies. All patients with cerebellar dysfunction had abnormalities on imaging: 93% (n = 39) had a cerebellar lesion, although numerous areas in the brain were affected. On follow-up MRIs, 25 patients (83%) had complete resolution of abnormalities. Metronidazole can rarely cause central nervous system toxicity; it does not seem to be a dose- or duration-related phenomenon. Most patients will have MRI abnormalities. Prognosis is excellent with metronidazole cessation.

Influence of metronidazole particle properties on granules prepared in a high-shear mixer-granulator.

PubMed

Di Martino, Piera; Censi, Roberta; Malaj, Ledjan; Martelli, Sante; Joiris, Etienne; Barthélémy, Christine

2007-02-01

Metronidazole is a good example of high-dose drug substance with poor granulating and tableting properties. Tablets are generally produced by liquid granulation; however, the technological process failure is quite frequent. In order to verify how the metronidazole particle characteristics can influence granule properties, three metronidazole batches differing for crystal habit, mean particle size, BET surface area and wettability were selected, primarily designed according to their different elongation ratio: needle-shaped, stick-shaped, and isodimensional. In the presence of lactose monohydrate and pregelatinized maize starch, respectively as diluent and binder, they were included in a formula for wet granulation in a high-shear mixer-granulator. In order to render the process comparable as far as possible, all parameters and experimental conditions were maintained constant. Four granule batches were obtained: granules from placebo (G-placebo), granules from needle-shaped crystals (G-needle-shaped), granules from stick-shaped crystals (G-stick-shaped), and granules from isodimensional crystals (G-isodimensional). Different granule properties were considered, in particular concerning porosity, friability, loss on drying (LOD), and flowability. In order to study their tabletability and compressibility, the different granules obtained were then compressed in a rotary press. The best tabletability was obtained with the isodimensional batch, while the poorest was exhibited by the stick-shaped one. Differences in tabletability are in good accordance with compressibility results: to a better tabletability corresponds an important granule ability to undergo a volume reduction as a result of an applied pressure. In particular, it was proposed that the greatest compressibility of the G-isodimensional must be related to the greatest granule porosity percentage.

Metronidazole-Induced Encephalopathy in Alcoholic Liver Disease: A Diagnostic and Therapeutic Challenge.

PubMed

Sonthalia, Nikhil; Pawar, Sunil V; Mohite, Ashok R; Jain, Samit S; Surude, Ravindra G; Rathi, Pravin M; Contractor, Qais

2016-10-01

Acute encephalopathy in a patient with alcoholic liver disease (ALD) is a commonly encountered emergency situation occurring most frequently due to liver failure precipitated by varying etiologies. Acute reversible cerebellar ataxia with confusion secondary to prolonged metronidazole use has been reported rarely as a cause of encephalopathy in patients with ALD. We describe a decompensated ALD patient with recurrent pyogenic cholangitis associated with hepatolithiasis who presented to the emergency department with sudden-onset cerebellar ataxia with dysarthria and mental confusion after prolonged use of metronidazole. Magnetic resonance imaging (MRI) of the brain was suggestive of bilateral dentate nuclei hyper intensities on T2 and fluid-attenuated inversion recovery sections seen classically in metronidazole-induced encephalopathy (MIE). Decompensated liver cirrhosis resulted in decreased hepatic clearance and increased cerebrospinal fluid concentration of metronidazole leading to toxicity at a relatively low total cumulative dose of 22 g. Both the clinical symptoms and MRI brain changes were reversed at 7 days and 6 weeks, respectively, after discontinuation of metronidazole. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A patient with ALD presenting with encephalopathy creates a diagnostic dilemma for the emergency physician regarding whether to continue metronidazole and treat for hepatic encephalopathy or to suspect for MIE and withhold the drug. Failure to timely discontinue metronidazole may worsen the associated hepatic encephalopathy in these patients. Liver cirrhosis patients have higher mean concentration of metronidazole and its metabolite in the blood, making it necessary to keep the cumulative dose of metronidazole to < 20 g in them. Copyright © 2016 Elsevier Inc. All rights reserved.

Ceruletide intravenous dose-response study by a simplified scintigraphic technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krishnamurthy, G.T.; Turner, F.E.; Mangham, D.

1985-04-01

The intravenous dose response of a ceruletide diethylamine (ceruletide) was established by a simplified scintigraphic technique where multiple graded doses were given sequentially on a single occasion. The gallbladder volume was presented nongeometrically by /sup 99m/Tc-IDA counts. The mean latent period, ejection period, and ejection rate were similar for all four groups of subjects given 1-20 ng/kg of ceruletide. The ejection fractions were similar to the values when the identical dose of ceruletide was administered sequentially either before or after another dose. A dose of 5 ng/kg produced the most physiologic type of emptying. Intravenous doses of 10 ng/kg andmore » larger caused adverse reactions in 42% of the total doses in the form of abdominal pain, nausea, systolic and diastolic hypotension, or bradycardia. It is concluded that the dose response of a cholecystokininlike agent (ceruletide) can be established reliably by a scintigraphic technique where multiple graded doses are given on a single occasion.« less

Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software.

PubMed

Batchelor, Hannah; Appleton, Richard; Hawcutt, Daniel B

2015-12-01

To use a physiologically based pharmacokinetic (PBPK) modelling system to predict the serum levels achieved by two different intravenous loading doses of phenytoin. A phenytoin pharmacokinetic model was used in the Simcyp population-based ADME simulator, simulating 100 children age 2-10 years receiving intravenous phenytoin (18 and 20mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model. Loading with doses of 18 mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2h post infusion (C2h) <10 μg/mL), therapeutic in 62/100 (C2h 10-20 μg/mL), and supra-therapeutic in 16/100 (C2h>20 μg/mL). Loading with 20mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20 mg/kg increased the mean C2h from 16.0 to 17.9 μg/mL, and the mean AUC from 145 to 162 μg/mL/h. A C2h>30 μg/mL was predicted in 4% and 8% of children in the 18 and 20 mg/kg doses, with 3% predicted to have a C2h>40 μg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5mg/kg (intravenous) given at 12h (after either 18 or 20 mg/kg loading) gives the highest percentages of 10-20 μg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20 mg/kg), a 1st maintenance dose (intravenous) of 10mg/kg will achieve therapeutic concentrations in 93%. Use of PBPK modelling suggests that children receiving the 20 mg/kg intravenous loading dose are at slightly increased risk of supra-therapeutic blood levels. Ideally, therapeutic drug monitoring is required to monitor serum concentrations, although the dose regime suggested by the BNFc appear appropriate. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Intravenous Single Dose Toxicity of Sweet Bee Venom in Sprague-Dawley Rats

PubMed Central

Lee, Kwang-Ho; Yu, JunSang; Sun, Seungho; Kwon, KiRok

2015-01-01

Objectives: Anaphylactic shock can be fatal to people who become hypersensitive when bee venom pharmacopuncture (BVP) is used. Thus, sweet bee venom (SBV) was developed to reduce these allergic responses. SBV is almost pure melittin, and SBV has been reported to have fewer allergic responses than BVP. BVP has been administered only into acupoints or intramuscularly, but we thought that intravenous injection might be possible if SBV were shown to be a safe medium. The aim of this study is to evaluate the intravenous injection toxicity of SBV through a single-dose test in Sprague-Dawley (SD) rats. Methods: Male and female 6-week-old SD rats were injected intravenously with SBV (high dosage: 1.0 mL/animal; medium dosage: 0.5 mL/animal; low dosage: 0.1 mL/animal). Normal saline was injected into the control group in a similar method. We conducted clinical observations, body weight measurements, and hematology, biochemistry, and histological observations. Results: No death was observed in any of the experimental groups. Hyperemia was observed in the high and the medium dosage groups on the injection day, but from next day, no general symptoms were observed in any of the experimental groups. No significant changes due to intravenous SBV injection were observed in the weights, in the hematology, biochemistry, and histological observations, and in the local tolerance tests. Conclusion: The results of this study confirm that the lethal dose of SBV is over 1.0 mL/animal in SD rats and that the intravenous injection of SBV is safe in SD rats. PMID:26389001

Low-dose intravenous lidocaine as treatment for proctalgia fugax.

PubMed

Peleg, Roni; Shvartzman, Pesach

2002-01-01

Proctalgia fugax is characterized by a sudden internal anal sphincter and anorectic ring attack of pain of a short duration. Description of the influence of intravenous lidocaine treatment for proctalgia fugax. A 28-year-old patient suffering of proctalgia fugax for 8 months. Conventional treatment efforts did not improve his condition. A single dose of an intravenous lidocaine infusion completely stopped his pain attacks. Based on the experience reported in this case and the potential benefit of this treatment for proctalgia fugax, controlled studies comparing intravenous lidocaine with placebo should be conducted to confirm the observation and to provide a more concrete basis for the use of intravenous lidocaine for this indication.

In Vitro Metronidazole and Tinidazole Activities against Metronidazole- Resistant Strains of Trichomonas vaginalis

PubMed Central

Crowell, Andrea L.; Sanders-Lewis, Kolby A.; Secor, W. Evan

2003-01-01

The in vitro activities of tinidazole and metronidazole against Trichomonas vaginalis isolates clinically resistant to metronidazole were compared. Minimal lethal concentrations (MLCs) of tinidazole were significantly lower than MLCs of metronidazole. Increased metronidazole resistance correlated with increased tinidazole resistance. These data support a role for tinidazole in the treatment of trichomoniasis. PMID:12654679

Evaluating the effect of metronidazole plus amoxicillin-clavulanate versus amoxicillin-clavulanate alone in canine haemorrhagic diarrhoea: a randomised controlled trial in primary care practice.

PubMed

Ortiz, V; Klein, L; Channell, S; Simpson, B; Wright, B; Edwards, C; Gilbert, R; Day, R; Caddy, S L

2018-06-07

To investigate the benefit of supplementing amoxicillin-clavulanic acid therapy with metronidazole in dogs presenting to a primary care veterinary practice with severe haemorrhagic diarrhoea. Prospective randomised blinded trial on dogs presenting with haemorrhagic diarrhoea of less than 3 days duration to a primary care veterinary hospital and also requiring intravenous fluid therapy. Cases were randomised to receive either metronidazole or saline, in addition to standard supportive therapy consisting of amoxicillin-clavulanic acid, intravenous fluid therapy, buprenorphine and omeprazole. Treatment efficacy was measured by duration of hospitalisation and daily scoring of disease severity. Thirty-four cases successfully completed the trial. There was no significant difference in hospitalisation time between treatment groups (mean for dogs receiving metronidazole was 29.6 hours and for controls was 26.3 hours) nor in daily clinical scores. This study strongly suggests that addition of metronidazole is not an essential addition to amoxicillin-clavulanic acid therapy for treatment of severe cases of haemorrhagic diarrhoea in dogs. © 2018 British Small Animal Veterinary Association.

Potential of bisbenzimidazole-analogs toward metronidazole-resistant Trichomonas vaginalis isolates.

PubMed

Korosh, Travis; Bujans, Emmanuel; Morada, Mary; Karaalioglu, Canan; Vanden Eynde, Jean Jacques; Mayence, Annie; Huang, Tien L; Yarlett, Nigel

2017-10-01

A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH 2 to C 10 H 20 ) containing a meta- (m) or para (p)-benzimidazole linkage to the phenylene ring was tested for ability to inhibit the growth of metronidazole-susceptible (C1) and metronidazole-refractory (085) Trichomonas vaginalis isolates under aerobic and anaerobic conditions. Compound 3m, 2,2'-[α,ω-propanediylbis(oxy-1,3-phenylene)]bis-1H-benzimidazole, displayed a 5.5-fold lower minimum inhibitory concentration (MIC) toward T. vaginalis isolate 085 than metronidazole under aerobic growth conditions, (26 μm compared to 145 μm). A dose of 25 mg/kg per day for four days of compound 3m cured a subcutaneous mouse model infection using T. vaginalis isolates 286 (metronidazole susceptible) and 085 (metronidazole refractory). Compound 3m was weakly reduced by pyruvate:ferredoxin oxidoreductase, but unlike metronidazole was not dependent upon added ferredoxin. It is concluded from structure-activity relationships that there was no obvious trend based on the length of the central aliphatic chain, or the steric position of the bisbenzimidazole enabling prediction of biological activity. The compounds generally fulfill Lipinski's rile of five, indicating their potential as drug leads. © 2017 John Wiley & Sons A/S.

Stability of Metronidazole Suspensions.

PubMed

Donnelly, Ronald F; Ying, James

2015-01-01

Metronidazole is an antiprotozoal agent used in the treatment of bacterial and protozoal anaerobic infections. The objectives of this study were to develop concentrated metronidazole suspensions that are inexpensive and easy to prepare and determine the stability of these suspensions after storage in amber polyvinyl chloride bottles at room temperature (23°C) and under refrigeration (5°C). Metronidazole suspensions (50 mg/mL) were prepared from powder using Ora-Blend or simple syrup as the vehicles. Samples were collected in triplicate from each container on days 0, 7, 14, 28, 56, and 93. Samples were assayed using a high-performance liquid chromatography method that had been validated as stability indicating. Color, change in physical appearance, and pH were also monitored at each time interval. There was no apparent change in color or physical appearance. The pH values changed by less than 0.20 units over the 93 days. The stability of metronidazole suspensions compounded from United States Pharmacopeia powder using Ora-Blend or simple syrup and packaged in amber polyvinyl chloride bottles was determined to be 93 days when stored at either room temperature or under refrigeration.

Conversion from intravenous to oral medications: assessment of a computerized intervention for hospitalized patients.

PubMed

Fischer, Michael A; Solomon, Daniel H; Teich, Jonathan M; Avorn, Jerry

2003-11-24

Many hospitalized patients continue to receive intravenous medications longer than necessary. Earlier conversion from the intravenous to the oral route could increase patient safety and comfort, reduce costs, and facilitate earlier discharge from the hospital without compromising clinical care. We examined the effect of a computer-based intervention to prompt physicians to switch appropriate patients from intravenous to oral medications. This study was performed at Brigham and Women's Hospital, an academic tertiary care hospital at which all medications are ordered online. We targeted 5 medications with equal oral and intravenous bioavailability: fluconazole, levofloxacin, metronidazole, ranitidine, and amiodarone. We used the hospital's computerized order entry system to prompt physicians to convert appropriate intravenous medications to the oral route. We measured the total use of the targeted medications via each route in the 4 months before and after the implementation of the intervention. We also measured the rate at which physicians responded to the intervention when prompted. The average intravenous defined daily dose declined by 11.1% (P =.002) from the preintervention to the postintervention period, while the average oral defined daily dose increased by 3.7% (P =.002). Length of stay, case-mix index, and total drug use at the hospital increased during the study period. The average total monthly use of the intravenous preparation of all of the targeted medications declined in the 4 months after the intervention began, compared with the 4 months before. In 35.6% of 1045 orders for which a prompt was generated, the physician either made a conversion from the intravenous to the oral version or canceled the order altogether. Computer-generated reminders can produce a substantial reduction in excessive use of targeted intravenous medications. As online prescribing becomes more common, this approach can be used to reduce excess use of intravenous medications

Metronidazole: newly recognized cause of autonomic neuropathy.

PubMed

Hobson-Webb, Lisa D; Roach, E Steve; Donofrio, Peter D

2006-05-01

Metronidazole is a commonly used antibiotic prescribed for the treatment of anaerobic and protozoal infections of the gastrointestinal and genitourinary tracts. It is associated with numerous neurologic complications, including peripheral neuropathy. Neuropathy is typically detected in patients on chronic therapy, although it has been documented in those taking large doses for acute infections. Numerous case reports have been published describing motor and sensory neuropathy, yet autonomic neuropathy has not been described with metronidazole use. A previously healthy 15-year-old girl presented with complaints of burning pain in her feet following a short course of metronidazole for vaginitis. She could obtain pain relief only by submerging her feet in ice water. Examination revealed cold and swollen lower extremities that became erythematous and very warm when removed from the ice water. Temperature perception was reduced to the upper third of the shin bilaterally. Deep tendon reflexes and strength were preserved. Nerve conduction studies demonstrated a peripheral neuropathy manifested by reduced sensory nerve and compound muscle action potentials. Reproducible sympathetic skin potential responses could not be obtained in the hand and foot, providing evidence of a concurrent autonomic neuropathy. A thorough evaluation revealed no other cause for her condition. Repeated nerve conduction studies and sympathetic skin potentials returned to normal over the course of 6 months, paralleling the patient's clinical improvement. Metronidazole is a potential cause of reversible autonomic neuropathy.

[Late sequelae of central nervous system prophylaxis in children with acute lymphoblastic leukemia: high doses of intravenous methotrexate versus radiotherapy of the central nervous system--review of literature].

PubMed

Zając-Spychała, Olga; Wachowiak, Jacek

2012-01-01

Acute lymphoblastic leukemia is the most common malignancy in children. All current therapy regimens used in the treatment of childhood acute lymphoblastic leukemia include prophylaxis of the central nervous system. Initially it was thought that the best way of central nervous system prophylaxis is radiotherapy. But despite its effectiveness this method, may cause late sequelae and complications. In the programme currently used in Poland to treat acute lymphoblastic leukemia, prophylactic radiotherapy has been reduced by 50% (12 Gy) and is used only in patients stratified into the high risk group and in patients diagnosed as T-cell ALL (T-ALL). Complementary to radiotherapy, intrathecal methotrexate is given alone or in combination with cytarabine and hydrocortisone is given, as well as systemic chemotherapy with intravenous methotrexate is administered in high or medium doses (depending on risk groups and leukemia immunophenotype). Recent studies have shown that high dose irradiation of the central nervous system impairs cognitive development causing memory loss, visuomotor coordination impairment, attention disorders and reduction in the intelligence quotient. It has been proved that the degree of cognitive impairment depends on the radiation dose directed to the medial temporal lobe structures, particularly in the hippocampus and the surrounding cortex. Also, methotrexate used intravenously in high doses, interferes with the metabolism of folic acid which is necessary for normal development and the optimal functioning of neurons in the central nervous system. It has been proved that patients who have been treated with high doses of methotrexate are characterized by reduced memory skills and a lower intelligence quotient. The literature data concerning long term neuroanatomical abnormalities and neuropsychological deficits are ambiguous, and there is still no data concerning current methods of central nervous system prophylaxis with low doses of irradiation in

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke.

PubMed

Anderson, Craig S; Robinson, Thompson; Lindley, Richard I; Arima, Hisatomi; Lavados, Pablo M; Lee, Tsong-Hai; Broderick, Joseph P; Chen, Xiaoying; Chen, Guofang; Sharma, Vijay K; Kim, Jong S; Thang, Nguyen H; Cao, Yongjun; Parsons, Mark W; Levi, Christopher; Huang, Yining; Olavarría, Verónica V; Demchuk, Andrew M; Bath, Philip M; Donnan, Geoffrey A; Martins, Sheila; Pontes-Neto, Octavio M; Silva, Federico; Ricci, Stefano; Roffe, Christine; Pandian, Jeyaraj; Billot, Laurent; Woodward, Mark; Li, Qiang; Wang, Xia; Wang, Jiguang; Chalmers, John

2016-06-16

Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively

Metronidazole Vaginal Gel 1.3% in the Treatment of Bacterial Vaginosis: A Dose-Ranging Study

PubMed Central

Chavoustie, Steven E.; Jacobs, Mark; Reisman, Howard A.; Waldbaum, Arthur S.; Levy, Sharon F.; Hillier, Sharon L.; Nyirjesy, Paul

2015-01-01

Objective Metronidazole vaginal gel (MVG) 0.75% is a US Food and Drug Administration–approved, 5-day treatment for bacterial vaginosis (BV). This study tested the hypothesis that a shorter treatment course at a higher dose (MVG 1.3%) would yield similar efficacy to 5 days of MVG 0.75%. Materials and Methods This phase 2, multicenter, randomized, controlled, investigator-blinded, dose-ranging study enrolled women with a clinical diagnosis of BV. Patients were assigned to MVG 1.3% once daily for 1, 3, or 5 days or MVG 0.75% once daily for 5 days. The therapeutic cure rate, requiring clinical and bacteriological cure, at the end-of-study visit was determined for the per-protocol population. A Kaplan-Meier analysis was used to estimate median time-to-symptom resolution. Results In total, 255 women (mean age = 35 y) were enrolled. The per-protocol population included 189 patients. The therapeutic cure rate was higher in the 1-day (13/43, 30.2%), 3-day (12/48, 25.0%), and 5-day (16/49, 32.7%) MVG 1.3% groups versus the MVG 0.75% group (10/49, 20.4%). Median time-to-resolution of fishy odor was shorter in the 3 MVG 1.3% groups versus the MVG 0.75% group. The 5-day MVG 1.3% group had the lowest rate of symptom return. No clinically important differences were observed in adverse events across treatment groups; most events were mild or moderate in intensity and considered unrelated to treatment. Similar results were found in the modified intent-to-treat population. Conclusions Metronidazole vaginal gel 1.3% applied once daily for 1, 3, or 5 days showed similar efficacy, safety, and tolerability as MVG 0.75% once daily for 5 days. PMID:24983350

Metronidazole vaginal gel 1.3% in the treatment of bacterial vaginosis: a dose-ranging study.

PubMed

Chavoustie, Steven E; Jacobs, Mark; Reisman, Howard A; Waldbaum, Arthur S; Levy, Sharon F; Hillier, Sharon L; Nyirjesy, Paul

2015-04-01

Metronidazole vaginal gel (MVG) 0.75% is a US Food and Drug Administration-approved, 5-day treatment for bacterial vaginosis (BV). This study tested the hypothesis that a shorter treatment course at a higher dose (MVG 1.3%) would yield similar efficacy to 5 days of MVG 0.75%. This phase 2, multicenter, randomized, controlled, investigator-blinded, dose-ranging study enrolled women with a clinical diagnosis of BV. Patients were assigned to MVG 1.3% once daily for 1, 3, or 5 days or MVG 0.75% once daily for 5 days. The therapeutic cure rate, requiring clinical and bacteriological cure, at the end-of-study visit was determined for the per-protocol population. A Kaplan-Meier analysis was used to estimate median time-to-symptom resolution. In total, 255 women (mean age = 35 y) were enrolled. The per-protocol population included 189 patients. The therapeutic cure rate was higher in the 1-day (13/43, 30.2%), 3-day (12/48, 25.0%), and 5-day (16/49, 32.7%) MVG 1.3% groups versus the MVG 0.75% group (10/49, 20.4%). Median time-to-resolution of fishy odor was shorter in the 3 MVG 1.3% groups versus the MVG 0.75% group. The 5-day MVG 1.3% group had the lowest rate of symptom return. No clinically important differences were observed in adverse events across treatment groups; most events were mild or moderate in intensity and considered unrelated to treatment. Similar results were found in the modified intent-to-treat population. Metronidazole vaginal gel 1.3% applied once daily for 1, 3, or 5 days showed similar efficacy, safety, and tolerability as MVG 0.75% once daily for 5 days.

Bacteremia Caused by a Metronidazole-Resistant Prevotella sp. Strain

PubMed Central

Mory, Francine; Carlier, Jean-Philippe; Alauzet, Corentine; Thouvenin, Maxime; Schuhmacher, Hélène; Lozniewski, Alain

2005-01-01

Metronidazole resistance among Prevotella spp. is rare. We report here the first case of bacteremia due to a high-level metronidazole-resistant Prevotella sp. responsible for treatment failure. PMID:16208024

Low dose intravenous immunoglobulin in systemic lupus erythematosus: analysis of 62 cases.

PubMed

Sherer, Yaniv; Kuechler, Sabine; Jose Scali, Juan; Rovensky, Josef; Levy, Yair; Zandman-Goddard, Gisele; Shoenfeld, Yehuda

2008-01-01

Systemic lupus erythematosus is an autoimmune disease with diverse clinical manifestations that cannot always be regulated by steroids and immunosuppressive therapy. Intravenous immunoglobulin is an optional immunomodulatory agent for the treatment of SLE, but the appropriate indications for its use, duration of therapy and recommended dosage are yet to be established. In SLE patients, most publications report the utilization of a high dose (2 g/kg body weight) protocol. To investigate whether lower doses of IVIg are beneficial for SLE patients. We retrospectively analyzed the medical records of 62 patients who received low dose IVIg (approximately 0.5 g/kg body weight). The treatment was associated with clinical improvement in many specific disease manifestations, along with a continuous decrease in SLEDAI scores (SLE Disease Activity Index). However, thrombocytopenia, alopecia and vasculitis did not improve following IVIg therapy. Low dose IVIg is a possible therapeutic option in SLE and is associated with lower cost than the high dose regimen and possibly fewer adverse effects.

Laboratory studies with the systemic trichononacide, metronidazole

PubMed Central

Jennison, R. F.; Stenton, P.; Watt, Leslie

1961-01-01

Laboratory studies with the trichomonacidal agent, metronidazole, show that 66 strains of T. vaginalis were killed in three days by concentrations of 0·0625 μg./ml. to 1 μg./ml. Estimations of serum and urine levels in nine volunteers, the serum levels in 31 women, and the urine levels in 33 women show that metronidazole is rapidly absorbed and excreted in high concentration in the urine. Development of resistance to metronidazole by T. vaginalis has not been demonstrated either in vivo or in vitro. No toxic effect was demonstrated in the blood, liver, or kidney. PMID:13789871

Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis.

PubMed

Moretti, Michele; Buiatti, Alessandra; Merlo, Marco; Massa, Laura; Fabris, Enrico; Pinamonti, Bruno; Sinagra, Gianfranco

2013-11-01

The management of refractory recurrent pericarditis is challenging. Previous clinical reports have noted a beneficial effect of high-dose intravenous human immunoglobulins (IvIgs) in isolated and systemic inflammatory disease-related forms. In this article, we analyzed retrospectively our clinical experience with IvIg therapy in a series of clinical cases of pericarditis refractory to conventional treatment. We retrospectively analyzed 9 patients (1994 to 2010) with refractory recurrent pericarditis, who received high-dose IvIg as a part of their medical treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine treatment was not discontinued during IvIg treatment. No patients had a history of autoimmune or connective tissue diseases. During an average period of 11 months from the first recurrence, patients had experienced a mean of 5 relapses before the first IvIg treatment. In 4 cases, patients showed complete clinical remission with no further relapse after the first IvIg cycle. Two patients experienced a single minor relapse, responsive to short-term nonsteroidal anti-inflammatory drugs. In 2 patients, we performed a second cycle of IvIg after a recurrence of pericarditis, with subsequent complete remission. One patient did not respond to 3 cycles of IvIg and subsequently underwent pericardial window and long-term immunosuppressive treatment. No major adverse effect was observed in consequence of IvIg administration in all the cases. In conclusion, although IvIg mode of action is still poorly understood in this setting, this treatment can be considered as an option in patients with recurrent pericarditis refractory to conventional medical treatment and, in our small series, has proved to be effective in 8 of 9 cases. Copyright © 2013 Elsevier Inc. All rights reserved.

Bismuth, Metronidazole, and Tetracycline

MedlinePlus

Helidac® (as a kit containing Bismuth Subsalicylate, Metronidazole, Tetracycline) ... Bismuth, metronidazole, and tetracycline is used along with other ulcer medications to treat duodenal ulcers. It is in a ...

Metronidazole-induced encephalopathy after prolonged metronidazole course for treatment of C. difficile colitis

PubMed Central

Godfrey, Mark S; Finn, Arkadiy; Zainah, Hadeel; Dapaah-Afriyie, Kwame

2015-01-01

A 65-year-old woman with a diagnosis of Clostridium difficile colitis undergoing prolonged treatment with metronidazole was admitted to hospital for altered mentation, slurred speech and weakness. She was diagnosed with metronidazole-induced encephalopathy, confirmed with brain MRI and improved when the offending agent was removed. This case report highlights encephalopathy as a complication of prolonged metronidazole treatment, which has become more common in clinical practice for the treatment of C. difficile infection. PMID:25596288

Efficacy of high-dose intravenous immunoglobulins in two patients with idiopathic recurrent pericarditis refractory to previous immunosuppressive treatment.

PubMed

Tona, Francesco; Bellotto, Fabio; Laveder, Francesco; Meneghin, Alessia; Sinagra, Gianfranco; Marcolongo, Renzo

2003-01-01

Although idiopathic acute pericarditis is usually a self-limiting disease, in many patients it may recur over a period of months or years. Even if some evidence seems to suggest the possible role of a deranged immune reactivity in the pathogenesis of idiopathic recurrent pericarditis, the etiology of the disease is still unknown. Furthermore, while some trial data confirm the usefulness of colchicine, its medical treatment is not yet clearly established. We here report the clinical history of 2 patients with idiopathic recurrent pericarditis resistant to prednisone, colchicine and other immunosuppressive drugs, who have been successfully treated with high-dose intravenous immunoglobulins.

In vitro activity of nitazoxanide against some metronidazole-resistant and susceptible Trichomonas vaginalis isolates.

PubMed

Abdel-Magied, Aida A; Hammouda, Marwa M; Mosbah, Alaa; El-Henawy, Abeer A

2017-04-01

Trichomonas vaginalis cases refractory to metronidazole (MTZ) treatment had been reported. This study aimed to the assessment of in vitro metronidazole resistance among Trichomonas positive cases with treatment failure by determination of metronidazole minimal lethal concentration (MLC), and to the evaluation of the in vitro efficacy of nitazoxanide (NTZ) as compared to metronidazole (MTZ) in both resistant and susceptible isolates. Drug testing was carried out by an aerobic tube assay where suspension of Trichomonas trophozoites was exposed for 24 and 48 h to serial dilution of metronidazole and nitazoxanide. In refractory isolates n = 30, median MLC conc. for MTZ was 100 μg/ml versus 50 μg/ml for NTZ (P < .0001). After 48 h median MLC conc. for MTZ was 25 μg/ml versus 12 μg/ml for NTZ (P < .0001). NTZ against resistant isolates was twice as active as MTZ at 24 h and increased to 2.5 times at 48 h while in susceptible isolates, NTZ was twice as active as MTZ at both 24 h and 48 h. MTZ was about 8 times more active in susceptible than in resistant isolates. So, high doses of metronidazole in resistant cases will likely increase side effects. The study proved the activity of NTZ against trichomoniasis especially in cases with MTZ resistance. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Metronidazole (Flagyl) and Pregnancy

MedlinePlus

Metronidazole (Flagyl®) In every pregnancy, a woman starts out with a 3-5% chance of having a ... risk. This sheet talks about whether exposure to metronidazole may increase the risk for birth defects over ...

High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome.

PubMed

Wakim, M; Alazard, M; Yajima, A; Speights, D; Saxon, A; Stiehm, E R

1998-08-01

High dose intravenous immunoglobulin (IVIG) has immunoregulatory and anti-inflammatory properties that might benefit illnesses with exaggerated IgE responses including atopic dermatitis and hyper-IgE immunodeficiency syndrome. To determine if high-dose IVIG would be of benefit to patients with severe atopic dermatitis and/or hyper-IgE syndrome using serial clinical, pulmonary, and laboratory studies for evaluation. This was an open label study in which we gave patients with hyper-IgE syndrome (n = 1) or severe atopic dermatitis (n = 9) IVIG as a 10% solution (Venoglobulin I-Alpha Therapeutic Corporation, Los Angeles, CA) at a dose of 2 g/kg every 30 days for seven infusions. Therapy was completed in nine of the ten patients. Skin disease improved slightly in six patients, remained unchanged in two patients, and worsened slightly in one patient. The average daily prednisone dosage was 6.8 mg/day prior to treatment and 5.1 mg/day during IVIG therapy (P = .1250). The three patients with abnormal pulmonary function showed very mild improvement of pulmonary function during treatment, but returned to baseline during follow-up. Flow cytometric studies showed no consistent pattern of change. IgA and IgM levels were unchanged. The mean serum IgE levels went from 3221+/-2454 IU/mL (SD) before IVIG to 2944+/-2491 IU/mL (P = .4609) during IVIG and then to 2321+/-2229 IU/mL (P = .1484) during the 6-month follow-up period. In vitro IgE production of peripheral blood mononuclear cells (PBMC) following IL-4 and anti-CD40 stimulation before IVIG was 6.6+/-3.1 ng/mL (SD) and 4.3+/-3.1 ng/mL (P = .1641) after six IVIG treatments. There were no significant trends in lymphocyte proliferative responses to PHA (phytohemaglutinin), Candida, tetanus, and anti-CD3 monoclonal antibody. Radioallergosorbent (RAST) testing showed no clear changes from positivity to negativity. We conclude that IVIG was of no clear clinical benefit in these nine patients and did not significantly decrease Ig

Population Pharmacokinetics of Metronidazole Evaluated Using Scavenged Samples from Preterm Infants

PubMed Central

Ouellet, Daniele; Smith, P. Brian; James, Laura P.; Ross, Ashley; Sullivan, Janice E.; Walsh, Michele C.; Zadell, Arlene; Newman, Nancy; White, Nicole R.; Kashuba, Angela D. M.; Benjamin, Daniel K.

2012-01-01

Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were ≤32 weeks of gestational age at birth and <120 postnatal days. A 5-center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 × (weight/1.5) × (PMA/32)2.49 using a volume of distribution (V) (liter) of 1.07 × (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this

Clinical and economic consequences of wound sepsis after appendicectomy and their modification by metronidazole or povidone iodine.

PubMed

Foster, G E; Bourke, J B; Bolwell, J; Doran, J; Balfour, T W; Holliday, A; Hardcastle, J D; Marshall, D J

1981-04-04

The effects of intrarectal metronidazole and intraincisional povidone iodine on sepsis after emergency appendicectomy were compared in a double-blind randomised controlled trial in 496 patients. Wound sepsis occurred in 12.3% of metronidazole-treated patients compared with 24% in the povidone-iodine group and 23.5% in an untreated control group. The metronidazole-treated patients left hospital approximately 2 days earlier than patients in the other two groups. They returned to work sooner and receiver fewer visits from the district nursing service. A short six-dose course of metronidazole significantly reduces the wound-infection rate in patients over the age of 12 undergoing emergency appendicectomy. If the clinical and economic benefits of metronidazole shown by this study are confirmed, the drug should be considered for routine use in emergency appendicectomy.

Cumulative irritation potential among metronidazole gel 1%, metronidazole gel 0.75%, and azelaic acid gel 15%.

PubMed

Colón, Luz E; Johnson, Lori A; Gottschalk, Ronald W

2007-04-01

Topical therapy for rosacea aims to reduce inflammatory lesions and decrease erythema but can carry side effects such as stinging, pruritus, and burning. Metronidazole and azelaic acid gel 15% are U.S. Food and Drug Administration-approved for the treatment of rosacea. The current study was conducted to assess the cumulative irritation potential of 2 formulations of metronidazole 0.75% gel and 1% gel--and azelaic acid gel 15% over 21 days (N=36). Results of this study demonstrated a significantly greater poten tial for irritation from azelaic acid compared with metronidazole gel 0.75% (P < .0001), which had significantly greater potential for irritation compared with metronidazole gel 1% (P = .0054). Metronidazole gel 1% had a similar profile to white petrolatum.

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Biodistribution after Intravenous Dosing in Rats

PubMed Central

Beekman, Christopher R.; Matta, Murali K.; Thomas, Christopher D.; Mohammad, Adil; Stewart, Sharron; Xu, Lin; Chockalingam, Ashok; Shea, Katherine; Sun, Dajun; Jiang, Wenlei; Patel, Vikram; Rouse, Rodney

2017-01-01

Relative biodistribution of FDA-approved innovator and generic sodium ferric gluconate (SFG) drug products was investigated to identify differences in tissue distribution of iron after intravenous dosing to rats. Three equal cohorts of 42 male Sprague-Dawley rats were created with each cohort receiving one of three treatments: (1) the innovator SFG product dosed intravenously at a concentration of 40 mg/kg; (2) the generic SFG product dosed intravenously at a concentration of 40 mg/kg; (3) saline dosed intravenously at equivalent volume to SFG products. Sampling time points were 15 min, 1 h, 8 h, 1 week, two weeks, four weeks, and six weeks post-treatment. Six rats from each group were sacrificed at each time point. Serum, femoral bone marrow, lungs, brain, heart, kidneys, liver, and spleen were harvested and evaluated for total iron concentration by ICP-MS. The ICP-MS analytical method was validated with linearity, range, accuracy, and precision. Results were determined for mean iron concentrations (µg/g) and mean total iron (whole tissue) content (µg/tissue) for each tissue of all groups at each time point. A percent of total distribution to each tissue was calculated for both products. At any given time point, the overall percent iron concentration distribution did not vary between the two SFG drugs by more than 7% in any tissue. Overall, this study demonstrated similar tissue biodistribution for the two SFG products in the examined tissues. PMID:29283393

Action of ethanol low doses on heart rate variability following intravenous administration in rabbits.

PubMed

Khvedelidze, M; Chitanava, E; Nadareishvili, D; Jiqia, G; Gvasalia, M

2007-05-01

Effects of low ethanol doses on the vagosympathetic mechanisms of heart rate regulation were studied in rabbits. Analysis of heart rate variability showed that single intravenous administration of 0.5 mg/kg ethanol caused a higher probability of heart electrophysiological instability in sympathicotonics in contrast to vagotonics. This was associated with activation of the whole complex of regulatory mechanisms. In vagotonics, perturbations in power spectrum indicated on rapidly shunting of regulatory activity from lower to high levels of regulatory mechanisms to realize a "first class" undifferentiated response on stress induction. Sympathicotonics were unready to ethanol intravenous administration that resulted in reduction of all spectral component. Intravenous administration of ethanol caused a higher probability of heart electrophysiological instability in sympathicotonics then in vagotonics. It is important to consider these differences for therapeutic application of ethanol to some acute poisoning (methyl alcohol, ethylene glycol).

Clinical relevance of metronidazole and peripheral neuropathy: a systematic review of the literature.

PubMed

Goolsby, Tiffany A; Jakeman, Bernadette; Gaynes, Robert P

2018-03-01

The objective of this paper was to review and evaluate the literature on metronidazole-associated peripheral neuropathy and determine the relevance in clinical practice. MEDLINE/PubMed, EBSCO, and Google Scholar were searched through February 2017 using the search terms metronidazole and peripheral neuropathy, or polyneuropathy, or paresthesia, or neurotoxicity. Relevant case reports, retrospective studies, surveys, and review articles were included. Bibliographies of all relevant articles were reviewed for additional sources. Overall, metronidazole is generally well tolerated, but serious neurotoxicity, including peripheral neuropathy, has been reported. The overall incidence of peripheral neuropathy associated with metronidazole is unknown. Our review found 36 case reports (40 unique patients) of metronidazole-associated peripheral neuropathy, with most cases (31/40) receiving a >42 g total (>4 weeks) of therapy. In addition, we reviewed 13 clinical studies and found varying rates of peripheral neuropathy from 0 to 50%. Within these clinical studies, we found a higher incidence of peripheral neuropathy in patients receiving >42 g total (>4 weeks) of metronidazole compared with those patients receiving ≤42 g total (17.9% vs. 1.7%). Nearly all patients had complete resolution of symptoms. In conclusion, peripheral neuropathy is rare in patients who receive ≤42 g total of metronidazole. Patients who receive higher total doses may be at higher risk of peripheral neuropathy, but symptoms resolve after discontinuation of therapy in most patients. Antimicrobial stewardship programs may consider use of antibiotic combinations that include metronidazole over broad-spectrum alternatives when treating with ≤42 g total of the drug (≤4 weeks). Published by Elsevier B.V.

Metronidazole

MedlinePlus

... by too much of certain types of harmful bacteria in the vagina) in women. Metronidazole is in ... antimicrobials. It works by stopping the growth of bacteria.Antibiotics will not work for colds, flu, or ...

A pilot clinical trial comparing an acid-buffering formulation (ACIDFORM gel) with metronidazole gel for the treatment of symptomatic bacterial vaginosis

PubMed Central

Simoes, Jose A; Bahamondes, Luis G; Camargo, Rodrigo P S; Alves, Valeria M N; Zaneveld, Lourens J D; Waller, Donald P; Schwartz, Jill; Callahan, Marianne M; Mauck, Christine K

2006-01-01

Aim To compare the effectiveness of an acid-buffering formulation gel (ACIDFORM) with metronidazole gel in the treatment of symptomatic bacterial vaginosis (BV). Methods After a confirmed diagnosis of BV according to the criteria established by Nugent and Amsel, 30 nonpregnant women were enrolled in a randomized, double-blind clinical study. The women were randomly assigned to receive either 5 g ACIDFORM gel (n = 13) or 10% metronidazole gel (n = 17) intravaginally once daily for five consecutive days. Participants were evaluated in two follow-up visits (7–12 days and 28–35 days after treatment). Therapeutic success was defined as the presence of less than three of Amsel's criteria. If three or more criteria were present at first or second follow-up visit, the woman was excluded from the study and treated orally with metronidazole. Nugent scores were recorded at each visit but these were not used to define cure. Results At the first follow-up visit, 15 (88%) of the women in the metronidazole group were cured compared with only three (23%) in the ACIDFORM group (P < 0.001). The remaining 12 women (10 of the ACIDFORM group and two of the metronidazole group) were considered as failure and were treated orally with metronidazole. At the second follow-up visit, two of the ACIDFORM-treated women and six of the metronidazole-treated women presented recurrent BV. Four women in the ACIDFORM group and one in the metronidazole group reported occasional burning and itching during product use. Conclusion ACIDFORM gel was significantly less effective than high-dose metronidazole gel for the treatment of symptomatic BV. PMID:16433875

Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

PubMed Central

Zhao, Wei; Qi, Tengfei; Shi, Mei; Guan, Zhifang; Lu, Haikong; Long, Fuquan; Gao, Zixiao; Zhang, Sufang; Zhou, Pingyu

2017-01-01

Background Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. Methodology/Principal findings Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38–4.13%) and 0.35% (95% CI: 0.06–1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. Conclusions/Significance Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use

Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

PubMed

Peng, Rui-Rui; Wu, Juan; Zhao, Wei; Qi, Tengfei; Shi, Mei; Guan, Zhifang; Lu, Haikong; Long, Fuquan; Gao, Zixiao; Zhang, Sufang; Zhou, Pingyu

2017-03-01

Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13%) and 0.35% (95% CI: 0.06-1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for patients in

Trichomonas vaginalis Flavin Reductase 1 and its Role in Metronidazole Resistance

PubMed Central

Leitsch, David; Janssen, Brian D.; Kolarich, Daniel; Johnson, Patricia J.; Duchêne, Michael

2015-01-01

Summary The enzyme flavin reductase 1 (FR1) from Trichomonas vaginalis, formerly known as NADPH oxidase, was isolated and identified. Flavin reductase is part of the antioxidative defense in T. vaginalis and indirectly reduces molecular oxygen to hydrogen peroxide via free flavins. Importantly, a reduced or absent flavin reductase activity has been reported in metronidazole-resistant T. vaginalis, resulting in elevated intracellular oxygen levels and futile cycling of metronidazole. Interestingly, FR1 has no close homologue in any other sequenced genome, but seven full-length and three truncated isoforms exist in the T. vaginalis genome. However, out of these, only FR1 has an affinity for flavins, i.e. FMN, FAD, and riboflavin, which is high enough to be of physiological relevance. Although there are no relevant changes in the gene sequence or any alterations of the predicted FR1-mRNA structure in any of the strains studied, FR1 is not expressed in highly metronidazole-resistant strains. Transfection of a metronidazole-resistant clinical isolate (B7268), which does not express any detectable amounts of FR, with a plasmid bearing a functional FR1 gene nearly completely restored metronidazole sensitivity. Our results indicate that FR1 has a significant role in the emergence of metronidazole resistance in T. vaginalis. PMID:24256032

Metronidazole and 5-aminosalicylic acid enhance the contractile activity of histaminergic agonists on the guinea-pig isolated ileum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Winbery, S.L.; Barker, L.A.

1986-03-01

The effects of metronidazole and 5-aminosalicylic acid (5-ASA) on histamine receptor-effector systems in the small intestine and right atrium of the guinea pig were studied. In an apparently all-or-none manner, both caused a sinistral shift in dose-response curves for the phasic component of the contractile response to histamine at H1 receptors on the ileum. In the presence of either, the EC50 value for histamine was reduced from 0.07 to about 0.03 microM. Similarly, in an apparently all-or-none fashion, both produced an elevation in the dose-response curve for the actions of dimaprit at H2-receptors in the ileum; the response to allmore » doses was increased about 30% with no significant change in the EC50 value. Metronidazole and 5-ASA did not alter dose-response curves for the tonic contractile response to histamine or curves generated by the cumulative addition of histamine. Also, neither altered the positive chronotropic response on isolated right atria or the phasic contractile response on isolated segments of jejunum and duodenum to histamine or dimaprit. Likewise, neither altered dose-response curves for the direct action of carbamylcholine at muscarinic receptors or for the indirect actions of dimethylphenylpiperazinium on the ileum. The effects of 5-ASA or metronidazole on the response to histamine could be prevented as well as reversed by scopolamine or tetrodotoxin. The results suggest that metronidazole and 5-ASA enhance the actions of histamine and dimaprit on the ileum by an action on myenteric plexus neurons.« less

Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice

PubMed Central

Tanaka, Emi; Ogawa, Yuko; Mukai, Takeo; Sato, Yoshiaki; Hamazaki, Takashi; Nagamura-Inoue, Tokiko; Harada-Shiba, Mariko; Shintaku, Haruo; Tsuji, Masahiro

2018-01-01

Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating

Comparison of Intravenous/Oral Ciprofloxacin Plus Metronidazole Versus Piperacillin/Tazobactam in the Treatment of Complicated Intraabdominal Infections

PubMed Central

Cohn, Stephen M.; Lipsett, Pamela A.; Buchman, Timothy G.; Cheadle, William G.; Milsom, Jeffery W.; O’Marro, Steven; Yellin, Albert E.; Jungerwirth, Steven; Rochefort, Estela V.; Haverstock, Daniel C.; Kowalsky, Steven F.

2000-01-01

Objective To compare the safety and efficacy of intravenous (IV) ciprofloxacin plus IV metronidazole (CIP+MET) with that of IV piperacillin/tazobactam (PIP/TAZO) in adults with complicated intraabdominal infections, and to compare the efficacy of sequential IV-to-oral CIP+MET therapy with that of the IV CIP-only regimen. Summary Background Data Treatment of intraabdominal infections remains a challenge, mainly because of their polymicrobial etiology and attendant death and complications. Antimicrobial regimens using sequential IV-to-oral therapy may reduce the length of hospital stay. Methods In this multicenter, randomized, double-blind trial involving 459 patients, clinically improved IV-treated patients were switched to oral therapy after 48 hours. Overall clinical response was the primary efficacy measurement. Results A total of 282 patients (151 CIP+MET, 131 PIP/TAZO) were valid for efficacy. Of these patients, 64% CIP+MET and 57% PIP/TAZO patients were considered candidates for oral therapy. Patients had a mean APACHE II score of 9.6. The most common diagnoses were appendicitis (33%), other intraabdominal infection (29%), and abscess (25%). Overall clinical resolution rates were statistically superior for CIP+MET (74%) compared with PIP/TAZO (63%). Corresponding rates in the subgroup suitable for oral therapy were 85% for CIP+MET and 70% for PIP/TAZO. Postsurgical wound infection rates were significantly lower in CIP+MET (11%) versus PIP/TAZO patients (19%). Mean length of stay was 14 days for CIP+MET and 17 days for PIP/TAZO patients. Conclusion CIP+MET, initially administered IV and followed by CIP+MET oral therapy, was clinically more effective than IV PIP/TAZO for the treatment of patients with complicated intraabdominal infections. PMID:10903605

Pharmacoeconomics of ciprofloxacin plus metronidazole vs. piperacillin-tazobactam for complicated intra-abdominal infections.

PubMed

Paladino, Joseph A; Gilliland-Johnson, Kristin K; Adelman, Martin H; Cohn, Stephen M

2008-06-01

A series of 459 hospitalized adults with complicated intra-abdominal infections participated in a randomized, double-blind, multicenter clinical trial. The present study was conducted to add a pharmacoeconomic analysis to the results. A cost-effectiveness analysis from the perspective of the hospital provider was carried out. Decision analysis was used to illustrate outcomes and to provide a basis on which to conduct a sensitivity analysis. Cost-effectiveness ratios, representing the cost per expected successfully treated patient, were calculated to determine the most cost-effective alternative. Among 244 economically evaluable patients, enrolled from 34 centers in the U.S. and Canada, 131 patients received ciprofloxacin-metronidazole (75% clinical success rate), and 113 received piperacillin-tazobactam (65% clinical success rate; p = 0.06). Switch to oral antibiotics was possible for 81 patients who received ciprofloxacin-metronidazole (85% clinical success rate) and 67 piperacillin-tazobactam patients (70% clinical success rate; p = 0.027). The mean hospital cost was US$10,662 +/- 7,793 for patients in the ciprofloxacin-metronidazole group and $10,009 +/- 7,023 for patients in the piperacillin-tazobactam group (p = 0.492). Significantly lower costs were documented for patients who could be switched to oral antibiotics than for those continued on intravenous antibiotic orders ($8,684 +/- 4,120 vs. $12,945 +/- 10,204, respectively; p < 0.001). Patients with appendicitis had lower mean hospital costs than those with other infections ($7,169 +/- 3,705 vs. $12,097 +/- 8,342, respectively; p < 0.001). The cost-effectiveness ratios were $14,216:1 for patients in the ciprofloxacin-metronidazole group and $15,398:1 for patients in the piperacillin-tazobactam group. The mean hospital costs associated with ciprofloxacin-metronidazole were similar to those of piperacillin-tazobactam for the treatment of adults with complicated intra-abdominal infections. Lower costs were

Metronidazole as a protector of cells from electromagnetic radiation of extremely high frequencies

NASA Astrophysics Data System (ADS)

Kuznetsov, Pavel E.; Malinina, Ulia A.; Popyhova, Era B.; Rogacheva, Svetlana M.; Somov, Alexander U.

2006-08-01

It is well known that weak electromagnetic fields of extremely high frequencies cause significant modification of the functional status of biological objects of different levels of organization. The aim of the work was to study the combinatory effect of metronidazole - the drug form of 1-(2'hydroxiethil)-2-methil-5-nitroimidazole - and electromagnetic radiation of extremely high frequencies (52...75 GHz) on the hemolytic stability of erythrocytes and hemotaxis activity of Infusoria Paramecium caudatum.

Interaction of metronidazole with resistant and susceptible Bacteroides fragilis.

PubMed Central

McLafferty, M A; Koch, R L; Goldman, P

1982-01-01

The kinetics of the lethal action of metronidazole and the formation of acetamide have been studied in a strain of Bacteroides fragilis which is relatively resistant to metronidazole. As with a susceptible strain of B. fragilis, the data are consistent with a model in which a labile intermediate in metronidazole metabolism interacts either with water to form acetamide or with a bacterium to cause its death. Although the relatively resistant strain grows more slowly than the susceptible one and is killed less rapidly by metronidazole, the resistant strain displays the same relationship between the lethal action of metronidazole and metronidazole metabolism to acetamide. The relatively resistant strain, like the susceptible one, has an enhanced lethal response to metronidazole in the presence of a strain of Escherichia coli. The results suggest that the proposed labile reactive intermediate of metronidazole forms more slowly in the resistant strains. PMID:7081970

Alternative Pathway of Metronidazole Activation in Trichomonas vaginalis Hydrogenosomes

PubMed Central

Hrdý, Ivan; Cammack, Richard; Stopka, Pavel; Kulda, Jaroslav; Tachezy, Jan

2005-01-01

Metronidazole and related 5-nitroimidazoles are the only available drugs in the treatment of human urogenital trichomoniasis caused by the protozoan parasite Trichomonas vaginalis. The drugs are activated to cytotoxic anion radicals by their reduction within the hydrogenosomes. It has been established that electrons required for metronidazole activation are released from pyruvate by the activity of pyruvate:ferredoxin oxidoreductase and transferred to the drug by a low-redox-potential carrier, ferredoxin. Here we describe a novel pathway involved in the drug activation within the hydrogenosome. The source of electrons is malate, another major hydrogenosomal substrate, which is oxidatively decarboxylated to pyruvate and CO2 by NAD-dependent malic enzyme. The electrons released during this reaction are transferred from NADH to ferredoxin by NADH dehydrogenase homologous to the catalytic module of mitochondrial complex I, which uses ferredoxin as electron acceptor. Trichomonads acquire high-level metronidazole resistance only after both pyruvate- and malate-dependent pathways of metronidazole activation are eliminated from the hydrogenosomes. PMID:16304169

Metronidazole-triazole conjugates: Activity against Clostridium difficile and parasites

PubMed Central

Jarrad, Angie M.; Karoli, Tomislav; Debnath, Anjan; Tay, Chin Yen; Huang, Johnny X.; Kaeslin, Geraldine; Elliott, Alysha G.; Miyamoto, Yukiko; Ramu, Soumya; Kavanagh, Angela M.; Zuegg, Johannes; Eckmann, Lars; Blaskovich, Mark A.T.; Cooper, Matthew A.

2015-01-01

Metronidazole has been used clinically for over 50 years as an antiparasitic and broad-spectrum antibacterial agent effective against anaerobic bacteria. However resistance to metronidazole in parasites and bacteria has been reported, and improved second-generation metronidazole analogues are needed. The copper catalysed Huigsen azide-alkyne 1,3-dipolar cycloaddition offers a way to efficiently assemble new libraries of metronidazole analogues. Several new metronidazole-triazole conjugates (Mtz-triazoles) have been identified with excellent broad spectrum antimicrobial and antiparasitic activity targeting Clostridium difficile, Entamoeba histolytica and Giardia lamblia. Cross resistance to metronidazole was observed against stable metronidazole resistant C. difficile and G. lamblia strains. However for the most potent Mtz-triazoles, the activity remained in a therapeutically relevant window. PMID:26117821

Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents

PubMed Central

Rocha, Luis B.; Schaberle, Fábio; Dąbrowski, Janusz M.; Simões, Sérgio; Arnaut, Luis G.

2015-01-01

We assessed the tolerability and safety in rodents of a single intravenous (i.v.) dose of redaporfin, a novel photosensitizer for Photodynamic Therapy (PDT) of cancer. Two approaches were used to evaluate acute toxicity: (i) a dose escalation study in BALB/c mice to evaluate the maximum tolerated dose of redaporfin; and (ii) a safety toxicology study in Wistar rats, of a single dose of redaporfin, with or without illumination, to evaluate possible signs of systemic toxicity. Redaporfin formulation was well tolerated by mice, with no signs of adverse reactions up to 75 mg/kg. In rats, there were no relevant changes, except for a significant, but transient, increase in the blood serum markers for hepatic function and muscle integrity, and also on neutrophil counts, observed after the application of light. The overall results showed that redaporfin-PDT is very well tolerated. No abnormalities were observed, including reactions at the injection site or skin phototoxicity, although the animals were maintained in normal indoor lighting. Redaporfin also showed a high efficacy in the treatment of male BALB/c mice with subcutaneously implanted colon (CT26) tumours. Vascular-PDT with 1.5 mg/kg redaporfin and a light dose of 74 J/cm2 led to the complete tumour regression in 83% of the mice. PMID:26670231

Metronidazole Injection

MedlinePlus

... surround the brain and spinal cord), and certain respiratory infections, including pneumonia. Metronidazole injection is also to ... later that resists antibiotic treatment.infections of the respiratory tract, including bronchitis, pneumonia

Topical and low-dose intravenous tranexamic acid in cyanotic cardiac surgery.

PubMed

Patel, Jigar; Prajapati, Mrugesh; Patel, Hardik; Gandhi, Hemang; Deodhar, Shilpa; Pandya, Himani

2017-02-01

Background Coagulopathy is a major problem in surgery for cyanotic congenital heart disease. Tranexamic acid has been used both topically and systemically and plays a vital role in pediatric cardiac surgery by reducing blood loss and blood product requirement. We aimed to determine the anti-fibrinolytic effectiveness of low-dose systemic or topical tranexamic acid or a combination of both. Methods Seventy-five patients were divided in 3 groups of 25. Group A patients were given tranexamic acid 20 mg kg -1 intravenously after sternotomy and 20 mg kg -1 after heparin reversal. Group B patients were given tranexamic acid 50 mg kg -1 in 20 mL of saline intrapericardially before sternal closure, with the drain clamped for 20 min. Group C patients were given tranexamic acid 20 mg kg -1 intravenously after sternotomy and 50 mg kg -1 intrapericardially before sternal closure. A number of clinical variables were recorded in the first 3 postoperative days. Ventilator time, intensive care unit stay, and outcome were also recorded. Results Chest tube drainage and blood product requirements were lowest in group C. Blood urea and serum creatinine levels were higher in groups A and C ( p < 0.05). Intensive care unit stay and ventilator time were similar in all 3 groups. No patient died and none had a seizure or other neurological event or thromboembolic complication postoperatively. Conclusion The combination of low-dose intravenous and topical tranexamic acid reduces postoperative blood loss and blood product requirement without incurring neurological, renal or thromboembolic complications. We recommend the routine use of topical and low-dose systemic tranexamic acid in cyanotic pediatric cardiac surgery.

High dose Intravenous Anti-D Immune Globulin is More Effective and Safe in Indian Paediatric Patients of Immune Thrombocytopenic Purpura

PubMed Central

Jena, Rabindra Kumar; Swain, Kali Prasanna

2016-01-01

Introduction Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. Aim To compare the safety and efficacy of higher dose (75μg/kg) intravenous Anti-D immune globulin against the standard dose of 50μg/kg for the management of ITP in Indian patients. Materials and Methods One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50μg/kg (standard dose) or 75μg /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. Results Seventy one out of 84 patients treated with Anti-D at 75μg/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50μg/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. Conclusion A 75μg/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50μg dose for treatment of newly diagnosed Indian patients of ITP. PMID:28208873

Influence of the intravenous contrast media on treatment planning dose calculations of lower esophageal and rectal cancers.

PubMed

Nasrollah, Jabbari; Mikaeil, Molazadeh; Omid, Esnaashari; Mojtaba, Seyed Siahi; Ahad, Zeinali

2014-01-01

The impact of intravenous (IV) contrast media (CM) on radiation dose calculations must be taken into account in treatment planning. The aim of this study is to evaluate the effect of an intravenous contrast media on dose calculations in three-dimensional conformal radiation therapy (3D-CRT) for lower esophageal and rectal cancers. Seventeen patients with lower esophageal tumors and 12 patients with rectal cancers were analyzed. At the outset, all patients were planned for 3D-CRT based on the computed tomography (CT) scans with IV contrast media. Subsequently, all the plans were copied and replaced on the scans without intravenous CM. The radiation doses calculated from the two sets of CTs were compared. The dose differences between the planning image set using intravenous contrast and the image set without contrast showed an average increase in Monitor Units (MUs) in the lower esophageal region that was 1.28 and 0.75% for 6 and 15 MV photon beams, respectively. There was no statistical significant difference in the rectal region between the two sets of scans in the 3D-CRT plans. The results showed that the dose differences between the plans for the CT scans with and without CM were small and clinically tolerable. However, the differences in the lower esophageal region were significant in the statistical analysis.

Efficacy and Safety of Metronidazole for Pulmonary Multidrug-Resistant Tuberculosis

PubMed Central

Carroll, Matthew W.; Jeon, Doosoo; Mountz, James M.; Lee, Jong Doo; Jeong, Yeon Joo; Zia, Nadeem; Lee, Myungsun; Lee, Jongseok; Via, Laura E.; Lee, Soyoung; Eum, Seok-Yong; Lee, Sung-Joong; Goldfeder, Lisa C.; Cai, Ying; Jin, Boyoung; Kim, Youngran; Oh, Taegwon; Chen, Ray Y.; Dodd, Lori E.; Gu, Wenjuan; Dartois, Veronique; Park, Seung-Kyu; Kim, Cheon Tae

2013-01-01

Pulmonary lesions from active tuberculosis patients are thought to contain persistent, nonreplicating bacilli that arise from hypoxic stress. Metronidazole, approved for anaerobic infections, has antituberculosis activity against anoxic bacilli in vitro and in some animal models and may target persistent, nonreplicating bacilli. In this double-blind, placebo-controlled trial, pulmonary multidrug-resistant tuberculosis subjects were randomly assigned to receive metronidazole (500 mg thrice daily) or placebo for 8 weeks in addition to an individualized background regimen. Outcomes were measured radiologically (change on high-resolution computed tomography [HRCT]), microbiologically (time to sputum smear and culture conversion), and clinically (status 6 months after stopping therapy). Enrollment was stopped early due to excessive peripheral neuropathies in the metronidazole arm. Among 35 randomized subjects, 31 (15 metronidazole, 16 placebo) were included in the modified intent-to-treat analysis. There were no significant differences by arm in improvement of HRCT lesions from baseline to 2 or 6 months. More subjects in the metronidazole arm converted their sputum smear (P = 0.04) and liquid culture (P = 0.04) to negative at 1 month, but these differences were lost by 2 months. Overall, 81% showed clinical success 6 months after stopping therapy, with no differences by arm. However, 8/16 (50%) of subjects in the metronidazole group and 2/17 (12%) of those in the placebo group developed peripheral neuropathy. Subjects who received metronidazole were 4.3-fold (95% confidence interval [CI], 1.1 to 17.1) more likely to develop peripheral neuropathies than subjects who received placebo. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer term. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens. PMID

Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis.

PubMed

Carroll, Matthew W; Jeon, Doosoo; Mountz, James M; Lee, Jong Doo; Jeong, Yeon Joo; Zia, Nadeem; Lee, Myungsun; Lee, Jongseok; Via, Laura E; Lee, Soyoung; Eum, Seok-Yong; Lee, Sung-Joong; Goldfeder, Lisa C; Cai, Ying; Jin, Boyoung; Kim, Youngran; Oh, Taegwon; Chen, Ray Y; Dodd, Lori E; Gu, Wenjuan; Dartois, Veronique; Park, Seung-Kyu; Kim, Cheon Tae; Barry, Clifton E; Cho, Sang-Nae

2013-08-01

Pulmonary lesions from active tuberculosis patients are thought to contain persistent, nonreplicating bacilli that arise from hypoxic stress. Metronidazole, approved for anaerobic infections, has antituberculosis activity against anoxic bacilli in vitro and in some animal models and may target persistent, nonreplicating bacilli. In this double-blind, placebo-controlled trial, pulmonary multidrug-resistant tuberculosis subjects were randomly assigned to receive metronidazole (500 mg thrice daily) or placebo for 8 weeks in addition to an individualized background regimen. Outcomes were measured radiologically (change on high-resolution computed tomography [HRCT]), microbiologically (time to sputum smear and culture conversion), and clinically (status 6 months after stopping therapy). Enrollment was stopped early due to excessive peripheral neuropathies in the metronidazole arm. Among 35 randomized subjects, 31 (15 metronidazole, 16 placebo) were included in the modified intent-to-treat analysis. There were no significant differences by arm in improvement of HRCT lesions from baseline to 2 or 6 months. More subjects in the metronidazole arm converted their sputum smear (P = 0.04) and liquid culture (P = 0.04) to negative at 1 month, but these differences were lost by 2 months. Overall, 81% showed clinical success 6 months after stopping therapy, with no differences by arm. However, 8/16 (50%) of subjects in the metronidazole group and 2/17 (12%) of those in the placebo group developed peripheral neuropathy. Subjects who received metronidazole were 4.3-fold (95% confidence interval [CI], 1.1 to 17.1) more likely to develop peripheral neuropathies than subjects who received placebo. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer term. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens.

[Is combining metronidazole and alcohol really hazardous?].

PubMed

Fjeld, Hilde; Raknes, Guttorm

2014-09-16

It is common practice to warn against intake of alcohol (ethanol) when taking metronidazole because of the risk of an effect similar to disulfiram (Antabuse). In this article we investigate whether such a warning has any real basis. KNOWLEDGE BASE: The article is based on a review of relevant literature retrieved through a search in PubMed. A search was also made in the WHO's database on adverse effects. No in-vitro studies, animal models, reports of adverse effects or clinical studies provide any convincing evidence of a disulfiram-like interaction between ethanol and metronidazole. The warning against simultaneous use of alcohol and metronidazole appear to be based on laboratory experiments and individual case histories in which the reported reactions are equally likely to have been caused by ethanol alone or by adverse effects of metronidazole. Recent research does not confirm a clinically relevant interaction between ethanol and metronidazole.

Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

PubMed

Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

2016-07-01

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

Reversible metronidazole-induced cerebellar toxicity in a multiple transplant recipient.

PubMed

Graves, Tracey D; Condon, Marie; Loucaidou, Marina; Perry, Richard J

2009-10-15

Metronidazole-induced central nervous system (CNS) toxicity causes a spectrum of neurological symptoms including ataxia, encephalopathy and peripheral neuropathy. It is associated with characteristic MRI changes of high signal intensity in the dentate nuclei. Given the increasing use of metronidazole, it is import to recognise this drug as a cause of ataxia, as it is entirely reversible on drug withdrawal.

Intravenous heparin dosing strategy in hospitalized patients with atrial dysrhythmias.

PubMed

Roswell, Robert O; Greet, Brian; Shah, Sunny; Bernard, Samuel; Milin, Alexandra; Lobach, Iryna; Guo, Yu; Radford, Martha J; Berger, Jeffrey S

2016-08-01

Patients with non-valvular atrial fibrillation (AF) have an elevated stroke risk that is 2-7 times greater than in those without AF. Intravenous unfractionated heparin (UFH) is commonly used for hospitalized patients with atrial fibrillation and atrial flutter (AFL) to prevent stroke. Dosing strategies exist for intravenous anticoagulation in patients with acute coronary syndromes and venous thromboembolic diseases, but there are no data to guide providers on a dosing strategy for intravenous anticoagulation in patients with AF/AFL. 996 hospitalized patients with AF/AFL on UFH were evaluated. Bolus dosing and initial infusion rates of UFH were recorded along with rates of stroke, thromboemobolic events, and bleeding events as defined by the International Society on Thrombosis and Haemostasis criteria. Among 226 patients included in the analysis, 76 bleeding events occurred. Using linear regression analysis, initial rates of heparin infusion ranging from 9.7 to 11.8 units/kilogram/hour (U/kg/h) resulted in activated partial thromboplastin times that were within therapeutic range. The median initial infusion rate in patients with bleeding was 13.3 U/kg/h, while in those without bleeding it was 11.4 U/kg/h; p = 0.012. An initial infusion rate >11.0 U/kg/h yielded an OR 1.95 (1.06-3.59); p = 0.03 for any bleeding event. Using IV heparin boluses neither increased the probability of attaining a therapeutic aPTT (56.1 vs 56.3 %; p = 0.99) nor did it significantly increase bleeding events in the study (35.7 vs 31.3 %; p = 0.48). The results suggest that higher initial rates of heparin are associated with increased bleeding risk. From this dataset, initial heparin infusion rates of 9.7-11.0 U/kg/h without a bolus can result in therapeutic levels of anticoagulation in hospitalized patients with AF/AFL without increasing the risk of bleeding.

Three-dimensional visualization of endolymphatic hydrops after intravenous administration of single-dose gadodiamide.

PubMed

Naganawa, Shinji; Yamazaki, Masahiro; Kawai, Hisashi; Bokura, Kiminori; Sone, Michihiko; Nakashima, Tsutomu

2013-01-01

Endolymphatic hydrops can be visualized with high contrast-to-noise ratio even after intravenous injection of single-dose gadolinium-based contrast material (IV-SD-GBCM) using HYDROPS-Mi2 images. We applied 3-dimensional rendering software to process HYDROPS-Mi2 images of 15 ears with and without suspected Ménière's disease and separately visualized the volumes of endo- and perilymph in patients with Ménière's disease even after IV-SD-GBCM. Such dimensional visualization will aid understanding of the pathophysiology of Ménière's disease.

Effect of Post-Cesarean Delivery Oral Cephalexin and Metronidazole on Surgical Site Infection Among Obese Women: A Randomized Clinical Trial.

PubMed

Valent, Amy M; DeArmond, Chris; Houston, Judy M; Reddy, Srinidhi; Masters, Heather R; Gold, Alison; Boldt, Michael; DeFranco, Emily; Evans, Arthur T; Warshak, Carri R

2017-09-19

The rate of obesity among US women has been increasing, and obesity is associated with increased risk of surgical site infection (SSI) following cesarean delivery. The optimal perioperative antibiotic prophylactic regimen in this high-risk population undergoing cesarean delivery is unknown. To determine rates of SSI among obese women who receive prophylactic oral cephalexin and metronidazole vs placebo for 48 hours following cesarean delivery. Randomized, double-blind clinical trial comparing oral cephalexin and metronidazole vs placebo for 48 hours following cesarean delivery for the prevention of SSI in obese women (prepregnancy BMI ≥30) who had received standard intravenous preoperative cephalosporin prophylaxis. Randomization was stratified by intact vs rupture of membranes prior to delivery. The study was conducted at the University of Cincinnati Medical Center, Cincinnati, Ohio, an academic and urban setting, between October 2010 and December 2015, with final follow-up through February 2016. Participants were randomly assigned to receive oral cephalexin, 500 mg, and metronidazole, 500 mg (n = 202 participants), vs identical-appearing placebo (n = 201 participants) every 8 hours for a total of 48 hours following cesarean delivery. The primary outcome was SSI, defined as any superficial incisional, deep incisional, or organ/space infections within 30 days after cesarean delivery. Among 403 randomized participants who were included (mean age, 28 [SD, 6] years; mean BMI, 39.7 [SD, 7.8]), 382 (94.6%) completed the trial. The overall rate of SSI was 10.9% (95% CI, 7.9%-14.0%). Surgical site infection was diagnosed in 13 women (6.4%) in the cephalexin-metronidazole group vs 31 women (15.4%) in the placebo group (difference, 9.0% [95% CI, 2.9%-15.0%]; relative risk, 0.41 [95% CI, 0.22-0.77]; P = .01). There were no serious adverse events, including allergic reaction, reported in either the antibiotic group or the placebo group. Among obese women

Trichomoniasis in a Closed Community: Efficacy of Metronidazole

PubMed Central

Keighley, Elizabeth E.

1971-01-01

A retrospective survey of women treated in prison for trichomonal vaginitis with metronidazole showed that 488 of 496 (98·3%) were cured after one course of drugs. Five of the eight treatment failures were successfully treated by further courses of metronidazole. A regimen of 400 mg metronidazole twice daily for seven days is simple and effective when taken in prescribed dosage. Metronidazole is still the drug of choice for trichomonal vaginitis. No toxic reactions were observed and there was no evidence that the drug has lost efficacy in the last ten years. PMID:5099972

[Giardia muris infection in laboratory rats (Rattus norvegicus) and treatment with metronidazole].

PubMed

Beyhan, Yunus Emre; Hökelek, Murat

2014-01-01

This study was conducted to determine the effectiveness of metronidazole for treatment of Giardia muris infection in laboratory rats. The feces of rats was yellow watery diarrhea and brought to the surgery research center of University of Ondokuz Mayis in order to be a study. Stool samples were examined by native examination, evaluation of infection rates was done with an X40 lens, and results were recorded as positive from 1 to 4. Metronidazole was administered to infected animals orally for 5 days with a 20 mg/kg dose. As a result of fecal examination of 64 rats held in groups of four in cages, 15 of the cages (60 rats) were found to be infected with G. muris. While agents were not observed in collected stool samples following 5, 7, and 14 days of drug administration of 14 groups, trophozoite density in one cage was decreased (75%), and adverse effects were not seen in rats. Metronidazole was found to be an effective drug for the treatment of giardiasis.

Dose-ranging pharmacokinetics of colistin methanesulphonate (CMS) and colistin in rats following single intravenous CMS doses.

PubMed

Marchand, Sandrine; Lamarche, Isabelle; Gobin, Patrice; Couet, William

2010-08-01

The aim of this study was to evaluate the effect of colistin methanesulphonate (CMS) dose on CMS and colistin pharmacokinetics in rats. Three rats per group received an intravenous bolus of CMS at a dose of 5, 15, 30, 60 or 120 mg/kg. Arterial blood samples were drawn at 0, 5, 15, 30, 60, 90, 120, 150 and 180 min. CMS and colistin plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of CMS and colistin were calculated by non-compartmental analysis. Linear relationships were observed between CMS and colistin AUCs to infinity and CMS doses, as well as between CMS and colistin C(max) and CMS doses. CMS and colistin pharmacokinetics were linear for a range of colistin concentrations covering the range of values encountered and recommended in patients even during treatment with higher doses.

Metronidazole Vaginal

MedlinePlus

... is used to treat vaginal infections such as bacterial vaginosis (an infection caused from too much of certain bacteria in the vagina). Metronidazole is in a class of medications called nitroimidazole antimicrobials. It works by stopping the growth of bacteria.

A 1-year trial of repeated high-dose intravenous iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease.

PubMed

Reinisch, Walter; Altorjay, Istvan; Zsigmond, Ferenc; Primas, Christian; Vogelsang, Harald; Novacek, Gottfried; Reinisch, Sieglinde; Thomsen, Lars L

2015-01-01

Iron isomaltoside 1000 (Monofer®) is a high-dose intravenous (IV) iron, which in a recent 8 weeks trial in inflammatory bowel disease (IBD) subjects with iron deficiency anemia (IDA) demonstrated good tolerability and efficacy. The present trial is an extension to this trial, which evaluates the need for additional high IV iron doses to maintain a stable hemoglobin (Hb) ≥12.0 g/dl. This was a prospective, open-label, 12 months trial of European IBD subjects willing to participate after completing the lead-in trial. Subjects were allowed re-dosing with 500-2000 mg single doses of iron isomaltoside 1000 infused over ∼15 min at 3 months intervals depending on a predefined algorithm. Outcome measures included Hb, safety parameters and need for additional iron dosing. A total of 39 subjects were enrolled of which 34 subjects required re-dosing with a median cumulative 1-year dose of 1.8 g (mean cumulative dose 2.2 g). The mean (SD) Hb was 12.3 (1.5) g/dl at baseline, 12.8 (1.6) g/dl at 3 months, 12.8 (1.6) g/dl at 6 months, 12.9 (1.4) g/dl at 9 months and 12.9 (1.6) g/dl at 12 months. Seventy-four percent of subjects who had an Hb ≥12.0 g/dl at baseline were able to maintain Hb ≥12.0 g/dl till the end of the trial at 12 months. Nonserious probably related hypersensitivity reactions without significant hypotension were reported at the beginning of the infusion in two subjects, who recovered without sequelae. Repeated treatment of iron deficiency with iron isomaltoside 1000 could avoid episodes of IDA without major safety issues.

A 1-year trial of repeated high-dose intravenous iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease

PubMed Central

Reinisch, Walter; Altorjay, Istvan; Zsigmond, Ferenc; Primas, Christian; Vogelsang, Harald; Novacek, Gottfried; Reinisch, Sieglinde; Thomsen, Lars L.

2015-01-01

Abstract Objective. Iron isomaltoside 1000 (Monofer®) is a high-dose intravenous (IV) iron, which in a recent 8 weeks trial in inflammatory bowel disease (IBD) subjects with iron deficiency anemia (IDA) demonstrated good tolerability and efficacy. The present trial is an extension to this trial, which evaluates the need for additional high IV iron doses to maintain a stable hemoglobin (Hb) ≥12.0 g/dl. Material and methods. This was a prospective, open-label, 12 months trial of European IBD subjects willing to participate after completing the lead-in trial. Subjects were allowed re-dosing with 500–2000 mg single doses of iron isomaltoside 1000 infused over ∼15 min at 3 months intervals depending on a predefined algorithm. Outcome measures included Hb, safety parameters and need for additional iron dosing. Results. A total of 39 subjects were enrolled of which 34 subjects required re-dosing with a median cumulative 1-year dose of 1.8 g (mean cumulative dose 2.2 g). The mean (SD) Hb was 12.3 (1.5) g/dl at baseline, 12.8 (1.6) g/dl at 3 months, 12.8 (1.6) g/dl at 6 months, 12.9 (1.4) g/dl at 9 months and 12.9 (1.6) g/dl at 12 months. Seventy-four percent of subjects who had an Hb ≥12.0 g/dl at baseline were able to maintain Hb ≥12.0 g/dl till the end of the trial at 12 months. Nonserious probably related hypersensitivity reactions without significant hypotension were reported at the beginning of the infusion in two subjects, who recovered without sequelae. Conclusion. Repeated treatment of iron deficiency with iron isomaltoside 1000 could avoid episodes of IDA without major safety issues. PMID:25900645

Interaction of metronidazole with DNA repair mutants of Escherichia coli.

PubMed

Yeung, T C; Beaulieu, B B; McLafferty, M A; Goldman, P

1984-01-01

It has been proposed that one of metronidazole's partially reduced intermediates interacts either with DNA to exert a bactericidal effect or with water to form acetamide. To test this hypothesis we have examined the effect of metronidazole on several mutants of Escherichia coli that are defective in DNA repair. UV-susceptible RecA- and UvrB- point mutants have an increased susceptibility to metronidazole as manifested by both a decreased minimal inhibitory concentration and a greater bactericidal response to metronidazole in resting cultures. By these criteria, however, we find that UvrB- deletion mutants, which lack the ability to reduce nitrate and chlorate, are no more susceptible to metronidazole than is the wild type. We find, however, that these deletion mutants also lack the ability to reduce metronidazole and thus possibly to form its reactive species. When metronidazole's bactericidal effect is expressed in terms of the concurrent accumulation of acetamide derived from metronidazole, then all RecA- and UvrB- mutants are killed more efficiently than their wild types. The data are consistent, therefore, with metronidazole's lethal effect being mediated by a partially reduced intermediate on the metabolic pathway between metronidazole and acetamide. Defects in other aspects of the DNA repair system do not confer this increased susceptibility to the proposed intermediate. A Tag- mutant, for example, which is defective in 3-methyl-adenine-DNA glycosylase, does not have this increased susceptibility to the presumed precursor of acetamide. Thus, these results provide further support for the hypothesis that the bactericidal effect of metronidazole is mediated by a partially reduced intermediate in the metabolic conversion of metronidazole to acetamide and suggest that this intermediate interacts with DNA to produce a lesion similar to that caused by UV light.

Interaction of metronidazole with DNA repair mutants of Escherichia coli.

PubMed Central

Yeung, T C; Beaulieu, B B; McLafferty, M A; Goldman, P

1984-01-01

It has been proposed that one of metronidazole's partially reduced intermediates interacts either with DNA to exert a bactericidal effect or with water to form acetamide. To test this hypothesis we have examined the effect of metronidazole on several mutants of Escherichia coli that are defective in DNA repair. UV-susceptible RecA- and UvrB- point mutants have an increased susceptibility to metronidazole as manifested by both a decreased minimal inhibitory concentration and a greater bactericidal response to metronidazole in resting cultures. By these criteria, however, we find that UvrB- deletion mutants, which lack the ability to reduce nitrate and chlorate, are no more susceptible to metronidazole than is the wild type. We find, however, that these deletion mutants also lack the ability to reduce metronidazole and thus possibly to form its reactive species. When metronidazole's bactericidal effect is expressed in terms of the concurrent accumulation of acetamide derived from metronidazole, then all RecA- and UvrB- mutants are killed more efficiently than their wild types. The data are consistent, therefore, with metronidazole's lethal effect being mediated by a partially reduced intermediate on the metabolic pathway between metronidazole and acetamide. Defects in other aspects of the DNA repair system do not confer this increased susceptibility to the proposed intermediate. A Tag- mutant, for example, which is defective in 3-methyl-adenine-DNA glycosylase, does not have this increased susceptibility to the presumed precursor of acetamide. Thus, these results provide further support for the hypothesis that the bactericidal effect of metronidazole is mediated by a partially reduced intermediate in the metabolic conversion of metronidazole to acetamide and suggest that this intermediate interacts with DNA to produce a lesion similar to that caused by UV light. PMID:6367636

[Metronidazole-Induced Encephalopathy during Brain Abscess Treatment:Two Case Reports].

PubMed

Yokoyama, Yuka; Asaoka, Katsuyuki; Sugiyama, Taku; Uchida, Kazuki; Shimbo, Daisuke; Kobayashi, Satoshi; Itamoto, Koji

2015-10-01

Metronidazole is a widely used antibiotic against anaerobic bacteria and protozoa. We report two cases of metronidazole-induced encephalopathy(MIE)during treatment of a brain abscess with metronidazole. The patients developed mental disturbance, and brain MRI showed reversible signals on DWI, FLAIR, and T2. Case 1: A 48-year-old woman was admitted to our hospital with a cerebellar abscess. We initiated treatment with oral metronidazole. After taking the medication, she developed mental disturbance, and her brain MRI showed a hyperintensity within the corpus callosum. We suspected metronidazole toxicity and discontinued metronidazole treatment. The symptoms resolved rapidly within a week, and the hyperintensity on the MRI disappeared. Case 2: A 22-year-old man was admitted to our hospital with a brain abscess. We initiated treatment with oral metronidazole. On day 38, he developed mental disturbance, and his MRI showed hyperintensities within the bilateral dentate nuclei and corpus callosum. These symptoms were consistent with MIE. After cessation of metronidazole, his symptoms and abnormal MRI signals completely disappeared.

High-pressure liquid chromatography and microbiological assay of serum ofloxacin levels in adults receiving intravenous and oral therapy for skin infections.

PubMed Central

Auten, G M; Preheim, L C; Sookpranee, M; Bittner, M J; Sookpranee, T; Vibhagool, A

1991-01-01

Thirty-two adults hospitalized with skin and skin structure infections received intravenous ofloxacin followed by oral ofloxacin. The standard treatment was 400 mg every 12 h. One patient with renal failure received 400 mg every 24 h. Serum ofloxacin levels were measured (1.5 h postdose and 1 h predose) during intravenous (32 patients) and oral (30 patients) therapy. Levels were assayed by high-pressure liquid chromatography (HPLC) and microbiological assay (MBA). Mean levels +/- standard deviation (in micrograms per milliliter) when measured by MBA after intravenous dosing were (postdose versus predose) 6.23 +/- 2.49 versus 2.42 +/- 1.56, and those after oral dosing were 6.17 +/- 3.25 versus 3.49 +/- 2.77. When measured by HPLC, mean levels +/- standard deviation after intravenous dosing were 5.81 +/- 2.08 versus 2.14 +/- 1.26 and those after oral dosing were 5.63 +/- 2.92 versus 3.41 +/- 2.98. There were no significant differences between levels achieved with oral or intravenous dosing when measured by either MBA or HPLC. Levels in serum did not correlate with side effects. The MICs for 50 and 90% of the 40 aerobic pathogens isolated from 21 patients were 0.5 and 2.0 micrograms/ml, respectively. Cure or improvement was achieved in 30 patients. Intravenous and oral administration of ofloxacin yielded similar levels in serum which were safe and effective in the therapy of skin infections in adult patients. PMID:1810189

Intravenous paracetamol with a lower dose is also effective for the treatment of patent ductus arteriosus in pre-term infants.

PubMed

Tekgündüz, Kadir Şerafettin; Ceviz, Naci; Caner, İbrahim; Olgun, Haşim; Demirelli, Yaşar; Yolcu, Canan; Şahin, İrfan Oğuz; Kara, Mustafa

2015-08-01

Haemodynamically significant patent ductus arteriosus is a significant cause of morbidity and mortality in pre-term infants. This retrospective study was conducted to investigate the usefulness of lower-dose paracetamol for the treatment of patent ductus arteriosus in pre-term infants. A total of 13 pre-term infants who received intravenous paracetamol because of contrindications or side effects to oral ibuprofen were retrospectively enrolled. In the first patient, the dose regimen was 15 mg/kg/dose, every 6 hours. As the patient developed significant elevation in transaminase levels, the dose was decreased to 10 mg/kg/dose, every 8 hours in the following 12 patients. Echocardiographic examination was conducted daily. In case of closure, it was repeated after 2 days and when needed thereafter in terms of reopening. A total of 13 patients received intravenous paracetamol. Median gestational age was 29 weeks ranging from 24 to 31 weeks and birth weight was 950 g ranging from 470 to 1390 g. The median postnatal age at the first intravenous paracetamol dose was 3 days ranging from 2 to 9 days. In 10 of the 13 patients (76.9%), patent ductus arteriosus was closed at the median 2nd day of intravenous paracetamol ranging from 1 to 4 days. When the patient who developed hepatotoxicity was eliminated, the closure rate was found to be 83.3% (10/12). Intravenous paracetamol may be a useful treatment option for the treatment of patent ductus arteriosus in pre-term infants with contrindication to ibuprofen. In our experience, lower-dose paracetamol is effective in closing the patent ductus arteriosus in 83.3% of the cases.

Metronidazole with Lactacyd vaginal gel in bacterial vaginosis.

PubMed

Decena, Ditas Cristina D; Co, Jennifer T; Manalastas, Ricardo M; Palaypayon, Evelyn P; Padolina, Christia S; Sison, Judith M; Dancel, Louella A; Lelis, Marievi A

2006-04-01

To assess the efficacy and tolerability of lactic acid (Lactacyd vaginal gel; LVG) when given as an adjunct to metronidazole in the treatment of bacterial vaginosis (BV) among Filipino patients. A multicenter, open-labeled, controlled, randomized, three-arm comparative study on 90 women aged 18 years or over with clinically and microbiologically proven BV. The lactobacilli colony count significantly increased over time in all three arms. At day 14, growth of lactobacilli was significantly higher among patients in the lactic acid gel and combination treatment arms. Significant reduction of malodorous vaginal discharge (whiff test) and lowest recurrence of BV were noted in the metronidazole plus lactic acid gel arm. Regarding disappearance of signs of BV, there was significant decrease in the pH level and frequency of clue cell positive patients across time but was not significantly different across treatment groups. Only one patient (3%, 1/60) among those who received lactic acid gel complained of increased curd-like discharge. Six patients (10%, 6/60) who received metronidazole complained of epigastric pain/discomfort, dizziness and dyspnea. Lactic acid gel (LVG) is safe and as efficacious as metronidazole in the treatment of BV. There is evidence that LVG when combined with metronidazole is superior to metronidazole alone in promoting lactobacilli colonization. LVG as an adjunct to metronidazole, having the least number of recurrent BV, appears to result in better long-term treatment effect on bacterial vaginosis.

Proteomic Analysis of a NAP1 Clostridium difficile Clinical Isolate Resistant to Metronidazole

PubMed Central

Chong, Patrick M.; Lynch, Tarah; McCorrister, Stuart; Kibsey, Pamela; Miller, Mark; Gravel, Denise; Westmacott, Garrett R.; Mulvey, Michael R.

2014-01-01

Background Clostridium difficile is an anaerobic, Gram-positive bacterium that has been implicated as the leading cause of antibiotic-associated diarrhea. Metronidazole is currently the first-line treatment for mild to moderate C. difficile infections. Our laboratory isolated a strain of C. difficile with a stable resistance phenotype to metronidazole. A shotgun proteomics approach was used to compare differences in the proteomes of metronidazole-resistant and -susceptible isolates. Methodology/Principal Findings NAP1 C. difficile strains CD26A54_R (Met-resistant), CD26A54_S (reduced- susceptibility), and VLOO13 (Met-susceptible) were grown to mid-log phase, and spiked with metronidazole at concentrations 2 doubling dilutions below the MIC. Peptides from each sample were labeled with iTRAQ and subjected to 2D-LC-MS/MS analysis. In the absence of metronidazole, higher expression was observed of some proteins in C. difficile strains CD26A54_S and CD26A54_R that may be involved with reduced susceptibility or resistance to metronidazole, including DNA repair proteins, putative nitroreductases, and the ferric uptake regulator (Fur). After treatment with metronidazole, moderate increases were seen in the expression of stress-related proteins in all strains. A moderate increase was also observed in the expression of the DNA repair protein RecA in CD26A54_R. Conclusions/Significance This study provided an in-depth proteomic analysis of a stable, metronidazole-resistant C. difficile isolate. The results suggested that a multi-factorial response may be associated with high level metronidazole-resistance in C. difficile, including the possible roles of altered iron metabolism and/or DNA repair. PMID:24400070

Proteomic analysis of a NAP1 Clostridium difficile clinical isolate resistant to metronidazole.

PubMed

Chong, Patrick M; Lynch, Tarah; McCorrister, Stuart; Kibsey, Pamela; Miller, Mark; Gravel, Denise; Westmacott, Garrett R; Mulvey, Michael R

2014-01-01

Clostridium difficile is an anaerobic, Gram-positive bacterium that has been implicated as the leading cause of antibiotic-associated diarrhea. Metronidazole is currently the first-line treatment for mild to moderate C. difficile infections. Our laboratory isolated a strain of C. difficile with a stable resistance phenotype to metronidazole. A shotgun proteomics approach was used to compare differences in the proteomes of metronidazole-resistant and -susceptible isolates. NAP1 C. difficile strains CD26A54_R (Met-resistant), CD26A54_S (reduced- susceptibility), and VLOO13 (Met-susceptible) were grown to mid-log phase, and spiked with metronidazole at concentrations 2 doubling dilutions below the MIC. Peptides from each sample were labeled with iTRAQ and subjected to 2D-LC-MS/MS analysis. In the absence of metronidazole, higher expression was observed of some proteins in C. difficile strains CD26A54_S and CD26A54_R that may be involved with reduced susceptibility or resistance to metronidazole, including DNA repair proteins, putative nitroreductases, and the ferric uptake regulator (Fur). After treatment with metronidazole, moderate increases were seen in the expression of stress-related proteins in all strains. A moderate increase was also observed in the expression of the DNA repair protein RecA in CD26A54_R. This study provided an in-depth proteomic analysis of a stable, metronidazole-resistant C. difficile isolate. The results suggested that a multi-factorial response may be associated with high level metronidazole-resistance in C. difficile, including the possible roles of altered iron metabolism and/or DNA repair.

Isolate resistance of Blastocystis hominis to metronidazole.

PubMed

Haresh, K; Suresh, K; Khairul Anus, A; Saminathan, S

1999-04-01

Isolates of Blastocystis hominis from infected immigrant workers from Indonesia, Bangladesh and infected individuals from Singapore and Malaysia were assessed for growth pattern and degree of resistance to different concentrations of metronidazole. Viability of the cells was assessed using eosin-brillian cresyl blue which stained viable cells green and nonviable cells red. The Bangladeshi and Singaporean isolates were nonviable even at the lowest concentration of 0.01 mg/ml, whereas 40% of the initial inoculum of parasites from the Indonesian isolate at day one were still viable in cultures with 1.0 mg/ml metronidazole. The study shows that isolates of B. hominis of different geographical origin have different levels of resistance to metronidazole. The search for more effective drugs to eliminate th parasite appears inevitable, especially since surviving parasites from metronidazole cultures show greater ability to multiply in subcultures than controls.

Dose-response of intrathecal morphine when administered with intravenous ketorolac for post-cesarean analgesia: a two-center, prospective, randomized, blinded trial.

PubMed

Berger, J S; Gonzalez, A; Hopkins, A; Alshaeri, T; Jeon, D; Wang, S; Amdur, R L; Smiley, R

2016-12-01

The appropriate dose of intrathecal morphine for post-cesarean analgesia is unclear. With the inclusion of routine non-steroidal anti-inflammatory drugs, the required dose of morphine may be significantly less than the 200-300μg common a decade ago. We performed a two-center, prospective, randomized, blinded trial comparing three doses of intrathecal morphine, combined with routine intravenous ketorolac, in 144 healthy women undergoing elective cesarean delivery. Patients received an intrathecal injection of hyperbaric bupivacaine 12mg, fentanyl 15μg and a randomized dose of 50, 100, or 150μg morphine in a volume of 2.2mL. Patients received intravenous ketorolac 30mg before leaving the operating room and 15mg intravenously every 6h for the duration of the study (24h). All received postoperative patient-controlled intravenous morphine. The primary endpoint was total intravenous morphine administered postoperatively over 24h, analyzed using mixed model regression. There were no differences between dose groups (or institutions) in intravenous morphine use over 24h. Visual analog scale scores for pain and nausea did not differ. Pruritus was greater in the 100 and 150μg groups than the 50μg group at 6h and 12h, but there was no difference between groups in nausea or pruritus treatments. Respiratory depression or significant sedation did not occur. The dose-response relationship of intrathecal morphine for multimodal post-cesarean analgesia suggests that 50μg produces analgesia similar to that produced by either 100μg or 150μg. Copyright © 2016 Elsevier Ltd. All rights reserved.

Single-dose pharmacokinetics of intravenous clavulanic acid with amoxicillin in pediatric patients.

PubMed Central

Schaad, U B; Casey, P A; Cooper, D L

1983-01-01

Pharmacokinetics of a parenteral formulation comprised of 5 parts of amoxicillin and 1 part of clavulanic acid were determined in 12 pediatric patients, 2 to 14 years of age. A single dose amounting to 25 mg of amoxicillin and 5 mg of clavulanic acid per kg of body weight was infused intravenously over 2 min. Mean plasma concentrations 5 min after dosing were 89.4 micrograms of amoxicillin per ml and 19.5 micrograms of clavulanic acid per ml. Terminal phase plasma half-lives were 1.2 and 0.8 h, respectively. The data acquired in this study indicate that amoxicillin and clavulanic acid are pharmacokinetically compatible. Moreover, taken with assessment of microbiological activities by others, the present data suggest that intravenous administration of 25 mg of amoxicillin plus 5 mg of clavulanic acid per kg every 6 h is a reasonable starting regimen for assessing the activity of the combined drug formulation in noninvasive childhood diseases caused by Haemophilus influenzae, Staphylococcus aureus, Streptococci spp., Neisseria spp., Branhamella catarrhalis, and other susceptible organisms. Images PMID:6838187

Single-dose pharmacokinetics of intravenous clavulanic acid with amoxicillin in pediatric patients.

PubMed

Schaad, U B; Casey, P A; Cooper, D L

1983-02-01

Pharmacokinetics of a parenteral formulation comprised of 5 parts of amoxicillin and 1 part of clavulanic acid were determined in 12 pediatric patients, 2 to 14 years of age. A single dose amounting to 25 mg of amoxicillin and 5 mg of clavulanic acid per kg of body weight was infused intravenously over 2 min. Mean plasma concentrations 5 min after dosing were 89.4 micrograms of amoxicillin per ml and 19.5 micrograms of clavulanic acid per ml. Terminal phase plasma half-lives were 1.2 and 0.8 h, respectively. The data acquired in this study indicate that amoxicillin and clavulanic acid are pharmacokinetically compatible. Moreover, taken with assessment of microbiological activities by others, the present data suggest that intravenous administration of 25 mg of amoxicillin plus 5 mg of clavulanic acid per kg every 6 h is a reasonable starting regimen for assessing the activity of the combined drug formulation in noninvasive childhood diseases caused by Haemophilus influenzae, Staphylococcus aureus, Streptococci spp., Neisseria spp., Branhamella catarrhalis, and other susceptible organisms.

The Rise and Fall of Metronidazole for Clostridium difficile Infection.

PubMed

Chahine, Elias B

2018-06-01

Clostridium difficile is posing urgent health threats. Older studies have shown that metronidazole and vancomycin are equally effective in the treatment of Clostridium difficile infection (CDI). Given its inexpensive cost and low propensity to select antimicrobial resistant organisms, metronidazole became rapidly the drug of choice despite its pharmacokinetic limitations in the treatment of CDI. However, newer studies demonstrated that metronidazole is inferior to vancomycin, prompting clinicians to change their long-standing position on using metronidazole for mild to moderate infections and on reserving vancomycin for severe infections. Moving forward, metronidazole will fall out of favor in the treatment of CDI.

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical

Efficacy of Single-dose and 2-dose Intravenous Administration of Ramosetron in Preventing Postoperative Nausea and Vomiting After Laparoscopic Gynecologic Operation: A Randomized, Double-blind, Placebo-controlled, Phase 2 Trial.

PubMed

Lee, Banghyun; Kim, Kidong; Suh, Dong Hoon; Shin, Hyun-Jung; No, Jae Hong; Lee, Jung Ryeol; Jee, Byung Chul; Hwang, Jung Won; Do, Sang Hwan; Kim, Yong Beom

2017-06-01

This randomized trial investigated whether a 2-dose administration of intravenous ramosetron (5-hydroxytryptamine type 3 receptor antagonist) is more effective than a single-dose administration in preventing postoperative nausea and vomiting (PONV) in 89 patients who were scheduled to undergo laparoscopic operation for benign gynecologic diseases and to receive intravenous patient-controlled analgesia for relief of postoperative pain. After assignment at a ratio of 1:1, intravenous ramosetron (0.3 mg) was initially administered at the end of skin closure in all patients. Thereafter, ramosetron (0.3 mg) and placebo were administered to the study and control groups, respectively, at 4 hours after the operation. The baseline and operative characteristics were similar between the groups. The incidence of PONV during the 24-hour period after operation which was assessed as the primary endpoint did not differ between the groups. No serious adverse events occurred in either group. A 2-dose administration of intravenous ramosetron may not be superior to a single-dose administration in preventing PONV in patients undergoing laparoscopic operation for benign gynecologic diseases.

[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (1)--Single oral and intravenous dose toxicity studies in rats].

PubMed

Yahara, I; Furukawa, H; Sato, K; Nishimura, K; Harihara, A; Yabuuchi, K; Miyauchi, H; Kii, Y; Muraoka, Y; Kitamura, T; Kato, I

2001-05-01

A single oral dose toxicity study of Cefmatilen hydrochloride hydrate (S-1090) and a single intravenous dose toxicity study of its sodium salt (S-1090-Na) were conducted in rats. One dose level of 2000 mg potency/kg was set in both studies. Single oral dose toxicity study of S-1090 No deaths occurred. Diarrhea occurred on the dosing day and slightly soft feces lasted until 6 days after administration. These changes were considered to result from changes of intestinal flora induced by the antibiotic activity of S-1090. Reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet) were also observed until the next day after administration. Body weights increased favorably, and no S-1090-related pathological changes were observed. The oral lethal dose of S-1090 was estimated to be more than 2000 mg potency/kg. Single intravenous dose toxicity study of S-1090-Na No deaths occurred. The rats showed characteristic clinical signs such as hypoactivity, abnormal gait and hypopnea immediately after dosing, and some rats showed prone position or paleness of eyeballs and ear auricles in due course. These signs disappeared by 4 hr after administration. Slightly soft feces and reddish-brown feces were observed much the same as in the orally-treated rats. Body weights increased favorably. In the pathological examinations, slight cecal enlargement and increased basophilia, dilatation and calcification of the renal tubules in the kidney were observed. The intravenous lethal dose of S-1090-Na was estimated to be more than 2000 mg potency/kg.

A high dose of intravenous immunoglobulin increases CD94 expression on natural killer cells in women with recurrent spontaneous abortion.

PubMed

Shimada, Shigeki; Takeda, Masamitsu; Nishihira, Jun; Kaneuchi, Masanori; Sakuragi, Noriaki; Minakami, Hisanori; Yamada, Hideto

2009-11-01

A high dose of intravenous immunoglobulin (HIVIg) therapy is effective in various diseases such as autoimmune diseases, and also is expected to have efficacy in recurrent spontaneous abortion (RSA). The aim of this study was to understand immunological mechanisms of this therapy. By flowcytometric analyses, we examined phenotypic changes of a variety of immunological cells including natural killer (NK) cells, cytotoxic T cells, regulatory T cells and macrophages in peripheral blood of RSA women with HIVIg therapy (n = 8). Expression percentages of inhibitory CD94 on NK cells significantly (P = 0.01) increased after the therapy (58.8 +/- 21.4% versus 71.0 +/- 17.6%). Mechanisms of possible efficacy of HIVIg therapy for RSA may include enhancement of CD94 expression and subsequent suppression of NK cell cytotoxicity.

The efficacy of combined therapy with metronidazole and broad-spectrum antibiotics on postoperative outcomes for pediatric patients with perforated appendicitis.

PubMed

Shang, Qingjuan; Geng, Qiankun; Zhang, Xuebing; Guo, Chunbao

2017-11-01

The aim of this study was to evaluate the efficacy of combined therapy with metronidazole and broad-spectrum antibiotics for patients with perforated appendicitis who underwent surgical intervention.Broad-spectrum antibiotic therapy is warranted in the treatment of perforated appendicitis. Metronidazole has been used as anaerobic antimicrobial therapy. However, few studies about the use of metronidazole in perforated appendicitis have been reported.The medical records of 249 patients treated with metronidazole combined with broad-spectrum antibiotics following perforated appendicitis surgery were reviewed retrospectively and compared with the medical records of 149 patients treated only with broad-spectrum antibiotics. Propensity score matching was performed to adjust for selected baseline variables. Clinical outcomes, including postoperative complications and length of hospital stay, were compared between the 2 groups.No differences were found between the use of combined therapy with metronidazole and the use of solely broad-spectrum antibiotic agents with regard to postoperative duration of intravenous antibiotic treatment (6.8 ± 1.3 vs 7.9 ± 2.1 days, respectively, P = .18), inflammation variables at POD 5 (white blood cell [WBC] [risk ratio [RR], 1.06; 95% confidence interval [CI], 0.67-1.93, P = .15] and C-reactive protein [CRP] [RR, 1.18; 95% CI, 0.73-2.25, P = .36]) (Table 2), and the mean postoperative length of hospital stay (LOS) (RR, 0.68, 95% CI, 0.41-0.94, P = .41). There were also no differences in the incidence of postoperative complications, including the intra-abdominal or pelvic abscess rate (7[7.1%] vs 9[9.2%], respectively, P = .40), the incidence of wound infection (14[14.3%] vs 15[15.3%], respectively, P = .50), and the 30-day readmission rate (9[9.2%] vs 12[12.2%], respectively, P = .32).Regarding overall postoperative outcomes and complications, our study demonstrated no beneficial clinical effects of

The efficacy of combined therapy with metronidazole and broad-spectrum antibiotics on postoperative outcomes for pediatric patients with perforated appendicitis

PubMed Central

Shang, Qingjuan; Geng, Qiankun; Zhang, Xuebing; Guo, Chunbao

2017-01-01

Abstract The aim of this study was to evaluate the efficacy of combined therapy with metronidazole and broad-spectrum antibiotics for patients with perforated appendicitis who underwent surgical intervention. Broad-spectrum antibiotic therapy is warranted in the treatment of perforated appendicitis. Metronidazole has been used as anaerobic antimicrobial therapy. However, few studies about the use of metronidazole in perforated appendicitis have been reported. The medical records of 249 patients treated with metronidazole combined with broad-spectrum antibiotics following perforated appendicitis surgery were reviewed retrospectively and compared with the medical records of 149 patients treated only with broad-spectrum antibiotics. Propensity score matching was performed to adjust for selected baseline variables. Clinical outcomes, including postoperative complications and length of hospital stay, were compared between the 2 groups. No differences were found between the use of combined therapy with metronidazole and the use of solely broad-spectrum antibiotic agents with regard to postoperative duration of intravenous antibiotic treatment (6.8 ± 1.3 vs 7.9 ± 2.1 days, respectively, P = .18), inflammation variables at POD 5 (white blood cell [WBC] [risk ratio [RR], 1.06; 95% confidence interval [CI], 0.67–1.93, P = .15] and C-reactive protein [CRP] [RR, 1.18; 95% CI, 0.73–2.25, P = .36]) (Table 2), and the mean postoperative length of hospital stay (LOS) (RR, 0.68, 95% CI, 0.41–0.94, P = .41). There were also no differences in the incidence of postoperative complications, including the intra-abdominal or pelvic abscess rate (7[7.1%] vs 9[9.2%], respectively, P = .40), the incidence of wound infection (14[14.3%] vs 15[15.3%], respectively, P = .50), and the 30-day readmission rate (9[9.2%] vs 12[12.2%], respectively, P = .32). Regarding overall postoperative outcomes and complications, our study demonstrated no beneficial

Bioadhesive Controlled Metronidazole Release Matrix Based on Chitosan and Xanthan Gum

PubMed Central

Eftaiha, Ala’a F.; Qinna, Nidal; Rashid, Iyad S.; Al Remawi, Mayyas M.; Al Shami, Munther R.; Arafat, Tawfiq A.; Badwan, Adnan A.

2010-01-01

Metronidazole, a common antibacterial drug, was incorporated into a hydrophilic polymer matrix composed of chitosan xanthan gum mixture. Hydrogel formation of this binary chitosan-xanthan gum combination was tested for its ability to control the release of metronidazole as a drug model. This preparation (MZ-CR) was characterized by in vitro, ex vivo bioadhesion and in vivo bioavailability study. For comparison purposes a commercial extended release formulation of metronidazole (CMZ) was used as a reference. The in vitro drug-release profiles of metronidazole preparation and CMZ were similar in 0.1 M HCl and phosphate buffer pH 6.8. Moreover, metronidazole preparation and CMZ showed a similar detachment force to sheep stomach mucosa, while the bioadhesion of the metronidazole preparation was higher three times than CMZ to sheep duodenum. The results of in vivo study indicated that the absorption of metronidazole from the preparation was faster than that of CMZ. Also, MZ-CR leads to higher metronidazole Cmax and AUC relative to that of the CMZ. This increase in bioavailability might be explained by the bioadhesion of the preparation at the upper part of the small intestine that could result in an increase in the overall intestinal transit time. As a conclusion, formulating chitosan-xanthan gum mixture as a hydrophilic polymer matrix resulted in a superior pharmacokinetic parameters translated by better rate and extent of absorption of metronidazole. PMID:20559494

Split high-dose oral levothyroxine treatment as a successful therapy option in myxedema coma.

PubMed

Charoensri, Suranut; Sriphrapradang, Chutintorn; Nimitphong, Hataikarn

2017-10-01

High-dose intravenous thyroxine (T4) is the preferable treatment for myxedema coma. We describe the clinical course of a 69-year-old man who presented with myxedema coma and received oral levothyroxine (LT4) therapy (1 mg) in a split dose. This suggests split high-dose oral LT4 as a therapeutic option in myxedema coma.

[Reversible neurotoxicity secondary to metronidazole: report of one case].

PubMed

Retamal-Riquelme, Eva; Soto-San Martín, Hernán; Vallejos-Castro, José; Galdames-Poblete, Daniel

2014-03-01

Metronidazole can cause adverse effects both in the central and peripheral nervous system. We report a 34-year-old female who presented a reversible cerebellar syndrome and peripheral neuropathy as an adverse effect associated with the use of metronidazole. Brain magnetic resonance imaging (MRI) showed hyperintense T2 and FLAIR bilateral symmetrical cerebellar lesions, without contrast enhancement or mass effect, isointense in diffusion-weighted imaging and hypointense in apparent diffusion coefficient sequences. Also, electrophysiological evaluation was consistent with axonal polyneuropathy. She had received metronidazole for a liver abscess during 49 days. After discontinuation of metronidazole, she had rapid regression of cerebellar symptoms and normalization of MRI, with subsequent disappearance of peripheral symptoms. The brain MRI, electromyography and nerve conduction studies performed at 35 months later showed complete resolution of the lesions. Although metronidazole neurotoxicity is a rare event, it must be borne in mind because the prognosis is usually favorable after stopping the drug.

Reversible metronidazole-induced neurotoxicity after 10 weeks of therapy.

PubMed

AlDhaleei, Wafa; AlMarzooqi, Ayesha; Gaber, Nouran

2018-04-20

Metronidazole is a commonly used antimicrobial worldwide. The most common side effects that have been reported are nausea, vomiting and hypersensitivity reactions. However, neurotoxicity has been reported with the use of metronidazole but rather rare. The most common neurological manifestation is peripheral neuropathy involvement in the form of sensory loss. It is worth mentioning that central neurotoxicity is a rare side effect of metronidazole use but reversible. The manifestations vary from a headache, altered mental status to focal neurological deficits. The diagnosis is mainly by neuroimaging in the setting of acute neurological change in the patient status. Here, we report a case of metronidazole-induced neurotoxicity in a 38-year-old male patient who was admitted with a brain abscess and was started on metronidazole for more than 10 weeks. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Nitrimidazine Compared with Metronidazole in the Treatment of Vaginal Trichomoniasis

PubMed Central

Evans, B. A.; Catterall, R. D.

1971-01-01

A new substituted nitroimidazole, nitrimidazine (Naxogin), is compared with the established drug, metronidazole (Flagyl), for the treatment of vaginal trichomoniasis in a randomized double-blind trial. Nitrimidazine cured 39 (68%) out of 57 patients and showed no undesirable effects other than nausea in one patient. Metronidazole cured 51 (89%) out of 57 patients and also caused nausea in one patient; this cure rate corresponds with that previously reported in other trials. In the recommended dosage nitrimidazine is inferior to metronidazole, but is sufficiently effective to be useful in cases of intolerance to metronidazole. PMID:4939601

Randomized clinical trial of oral and intravenous versus intravenous antibiotic prophylaxis for laparoscopic colorectal resection.

PubMed

Ikeda, A; Konishi, T; Ueno, M; Fukunaga, Y; Nagayama, S; Fujimoto, Y; Akiyoshi, T; Yamaguchi, T

2016-11-01

The use of oral prophylactic antibiotics for the prevention of surgical-site infection (SSI) in patients undergoing laparoscopic surgery for colorectal cancer is controversial. The aim of this RCT was to evaluate whether intravenous perioperative antibiotics are inferior to combined preoperative oral and perioperative intravenous antibiotics in this setting. Patients undergoing elective laparoscopic colorectal resection in a single cancer centre were assigned randomly to combined preoperative oral antibiotics (metronidazole and kanamycin) and perioperative intravenous antibiotics (cefmetazole) (oral/IV group) or to perioperative intravenous antibiotics (cefmetazole) alone (IV-only group). Patients were stratified for the analyses based on type of operation (colonic surgery, anterior resection or abdominoperineal resection), preoperative use of mechanical bowel preparation, preoperative chemoradiotherapy and the presence of diabetes mellitus. The primary endpoint was the overall rate of SSI. Secondary endpoints were the rates of incisional site infection, organ/space infection, anastomotic leakage, intra-abdominal abscess, adverse events and postoperative complications. Of 540 patients offered participation in the trial in 2013-2014, 515 agreed to take part and were randomized. Some 256 patients in the IV-only group and 255 in the oral/IV group completed the treatment per protocol. The overall rate of SSI was 7·8 per cent (20 of 256) in the IV-only group and 7·8 per cent (20 of 255) in the oral/IV group, confirming that perioperative administration of intravenous antibiotics alone was not inferior to the combined regimen (P = 0·017). There were no differences in rates of incisional site infection (5·5 versus 5·9 per cent respectively), organ/space infection (2·3 versus 2·0 per cent) or other secondary endpoints between the two groups. Intravenous perioperative antimicrobial prophylaxis alone is not inferior to combined preoperative oral and intravenous

Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.

PubMed

Cohen-Wolkowiez, Michael; Sampson, Mario; Bloom, Barry T; Arrieta, Antonio; Wynn, James L; Martz, Karen; Harper, Barrie; Kearns, Gregory L; Capparelli, Edmund V; Siegel, David; Benjamin, Daniel K; Smith, P Brian

2013-09-01

Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections. We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N = 3) study using population PK modeling (NONMEM). Monte Carlo simulations (N = 1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated. Twenty-four premature infants (111 plasma and 51 dried blood spot samples) were enrolled: median (range) gestational age at birth 25 (23-31) weeks, postnatal age 27 (1-82) days, postmenstrual age 31 (24-39) weeks and weight 740 (431-1466) g. Population clearance (L/h/kg) was 0.038 × (postmenstrual age/30) and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and dried blood spot samples. Metabolic ratios correlated with clearance. Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using postmenstrual age-based dosing.

Determining Population and Developmental Pharmacokinetics of Metronidazole Using Plasma and Dried Blood Spot Samples from Premature Infants

PubMed Central

Cohen-Wolkowiez, Michael; Sampson, Mario; Bloom, Barry T.; Arrieta, Antonio; Wynn, James L.; Martz, Karen; Harper, Barrie; Kearns, Gregory L.; Capparelli, Edmund V.; Siegel, David; Benjamin, Daniel K.; Smith, P. Brian

2013-01-01

Background Limited pharmacokinetic (PK) data of metronidazole in premature infants has led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections. Methods We evaluated the PK of metronidazole using plasma and dried blood spot (DBS) samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N=3) study using population PK modeling (NONMEM). Monte Carlo simulations (N=1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated. Results Twenty-four premature infants (111 plasma and 51 DBS samples) were enrolled: median (range) gestational age at birth 25 (23–31) weeks, postnatal age 27 (1–82) days, postmenstrual age (PMA) 31 (24–39) weeks, and weight 740 (431–1466) g. Population clearance (CL, L/h/kg) was 0.038 × (PMA/30)2.45 and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and DBS samples. Metabolic ratios correlated with CL. Conclusion Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using PMA-based dosing. PMID:23587979

A RANDOMIZED TREATMENT TRIAL: SINGLE VERSUS 7 DAY DOSE OF METRONIDAZOLE FOR THE TREATMENT OF TRICHOMONAS VAGINALIS AMONG HIV-INFECTED WOMEN

PubMed Central

Kissinger, Patricia; Mena, Leandro; Levison, Judy; Clark, Rebecca A.; Gatski, Megan; Henderson, Harold; Schmidt, Norine; Rosenthal, Susan; Myers, Leann; Martin, David H.

2010-01-01

Objective To determine if the metronidazole (MTZ) 2 gm single dose (recommended) is as effective as the 7 day 500 mg BID dose (alternative) for treatment of Trichomonas vaginalis (TV) among HIV+ women. Methods Phase IV randomized clinical trial; HIV+ women with culture confirmed TV were randomized to treatment arm: MTZ 2 gm single dose or MTZ 500 mg BID 7 day dose. All women were given 2 gm MTZ doses to deliver to their sex partners. Women were re-cultured for TV at a test-of-cure (TOC) visit occurring 6-12 days after treatment completion. TV-negative women at TOC were again re-cultured at a 3 month visit. Repeat TV infection rates were compared between arms. Results 270 HIV+/TV+ women were enrolled (mean age = 40 years, ± 9.4; 92.2% African-American). Treatment arms were similar with respect to age, race, CD4 count, viral load, ART status, site, and loss-to-follow up. Women in the 7 day arm had: lower repeat TV infection rates at TOC [8.5% (11/130) versus 16.8% (21/125) (R.R. 0.50, 95% CI=0.25, 1.00; P<0.05)], and at 3 months [11.0% (8/73) versus 24.1% (19/79) (R.R. 0.46, 95% CI=0.21, 0.98; P=0.03)] compared to the single dose arm. Conclusions The 7 day MTZ dose was more effective than the single dose for the treatment of TV among HIV+ women. PMID:21423852

Effect of Admission Oral Diuretic Dose on Response to Continuous versus Bolus Intravenous Diuretics in Acute Heart Failure: An Analysis from DOSE-AHF

PubMed Central

Shah, Ravi V.; McNulty, Steven; O'Connor, Christopher M.; Felker, G. Michael; Braunwald, Eugene; Givertz, Michael M.

2014-01-01

Background Results from the Diuretic Optimization Strategies in Acute Heart Failure (DOSE-AHF) study suggest that an initial continuous infusion of loop diuretics is not superior to bolus dosing with regard to clinical endpoints in AHF. We hypothesized that outpatient furosemide dose was associated with congestion and poorer renal function, and explored the hypothesis that a continuous infusion may be more effective in patients on higher outpatient diuretic doses. Methods DOSE-AHF randomized 308 patients within 24 hours of admission to high vs. low initial intravenous diuretic dose given as either a continuous infusion or bolus. We compared baseline characteristics and assessed associations between mode of administration (bolus vs. continuous) and outcomes in patients receiving high-dose (≥120 mg furosemide equivalent, n=177) versus low-dose (<120 mg furosemide equivalent, n=131) outpatient diuretics. Results Patients on higher doses of furosemide were less frequently on renin-angiotensin system inhibitors (P=.01), and had worse renal function and more advanced symptoms. There was a significant interaction between outpatient dose and mode of therapy (P=0.01) with respect to net fluid loss at 72 hours after adjusting for creatinine and intensification strategy. Admission diuretic dose was associated with an increased risk of death or rehospitalization at 60 days (adjusted HR=1.08 per 20-mg increment in dose, 95% CI 1.01–1.16, P=.03). Conclusions In acute HF, patients on higher diuretic doses have greater disease severity, and may benefit from an initial bolus strategy. PMID:23194486

Preparation and Cyclodextrin Solubilization of the Antibacterial Agent Benzoyl Metronidazole

PubMed Central

Yang, Shuo

2013-01-01

A one-pot method for the preparation of benzoyl metronidazole was achieved by using N,N′-carbonyldiimidazole as a coupling reagent. Moreover, it was found that the byproduct imidazole as the catalyst promoted the reaction. In addition, the β-cyclodextrin solubilization of benzoyl metronidazole was investigated by phase-solubility method. The phase-solubility studies indicated that the solubility of benzoyl metronidazole (S = 0.1435 g/L) was substantially increased 9.7-fold (S′ = 1.3881 g/L) by formation of 1 : 1 benzoyl metronidazole/β-cyclodextrin complexes in water, and the association constant K a value was determined to be 251 (±23) dm3/mol. Therefore, β-cyclodextrin can work as a pharmaceutical solubilizer for benzoyl metronidazole and may improve its oral bioavailability. PMID:23970831

Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial.

PubMed

St Peter, Shawn D; Tsao, Kuojen; Spilde, Troy L; Holcomb, George W; Sharp, Susan W; Murphy, J Patrick; Snyder, Charles L; Sharp, Ronald J; Andrews, Walter S; Ostlie, Daniel J

2008-06-01

Appendicitis is the most common emergency condition in children. Historically, a 3-drug regimen consisting of ampicillin, gentamicin, and clindamycin (AGC) has been used postoperatively for perforated appendicitis. A retrospective review at our institution has found single day dosing of ceftriaxone and metronidazole (CM) to be a more simple and cost-effective antibiotic strategy. Therefore, we performed a prospective, randomized trial to compare efficacy and cost-effectiveness of these 2 regimens. After internal review board approval (IRB no. 04 12-149), children found to have perforated appendicitis at appendectomy were randomized to either once daily dosing of CM (2 total doses per day) or standard dosing of AGC (11 total doses per day). Perforation was defined as an identifiable hole in the appendix. The operative approach (laparoscopic), length of antibiotic use, and criteria for discharge were standardized for the groups. Based on our retrospective analysis using length of postoperative hospitalization as a primary end point, a sample size of 100 patients was calculated for an alpha of .5 and a power of 0.82. One hundred patients underwent laparoscopic appendectomy for perforated appendicitis. On presentation, there were no differences in sex distribution, days of symptoms, temperature, or leukocyte count. There was no difference in abscess rate or wound infections between groups. The CM group resulted in significantly less antibiotic charges then the AGC group. Once daily dosing with the 2-drug regimen (CM) offers a more efficient, cost-effective antibiotic management in children with perforated appendicitis without compromising infection control when compared to a traditional 3-drug regimen.

The incidence of phlebitis with intravenous amiodarone at guideline dose recommendations.

PubMed

Slim, Ahmad M; Roth, Jason E; Duffy, Benjamin; Boyd, Sheri Y N; Rubal, Bernard J

2007-12-01

Postoperative atrial fibrillation following cardiothoracic surgery is common and frequently managed with intravenous (IV) amiodarone. Phlebitis is the most common complication with peripheral infusion of this agent. Current practice guidelines for peripheral IV administration of <2 mg/mL amiodarone were established to reduce the risk of phlebitis. The present study examines the incidence of phlebitis in a postoperative patient population given current dose recommendations. A total of 273 patient charts were reviewed. The incidence of phlebitis in patients given IV amiodarone (n = 36) was 13.9% (95% confidence interval, 2.6-25.2%; p = 0.001). Logistic regression analysis with backward elimination of other therapeutic risk factors suggests that the odds ratio for phlebitis using current dose regimens without IV filters is 19-fold greater than baseline risk in this population. Phlebitis remains a significant complication associated with peripheral infusion of amiodarone within recommended dosing limits.

Randomized Trial of Periodic Presumptive Treatment With High-Dose Intravaginal Metronidazole and Miconazole to Prevent Vaginal Infections in HIV-negative Women

PubMed Central

McClelland, R. Scott; Balkus, Jennifer E.; Lee, Jeannette; Anzala, Omu; Kimani, Joshua; Schwebke, Jane; Bragg, Vivian; Lensing, Shelly; Kavak, Lale

2015-01-01

Background. Vaginal infections are common, frequently recur, and may increase women's risk for sexually transmitted infections (STIs). We tested the efficacy of a novel regimen to prevent recurrent vaginal infections. Methods. Human immunodeficiency virus (HIV)–negative women 18–45 years old with 1 or more vaginal infections, including bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), or Trichomonas vaginalis (TV), were randomly assigned to receive vaginal suppositories containing metronidazole 750 mg plus miconazole 200 mg or matching placebo for 5 consecutive nights each month for 12 months. Primary endpoints, evaluated every 2 months, were BV (Gram stain) and VVC (positive wet mount and culture). Results. Participants (N = 234) were randomly assigned to the intervention (N = 118) or placebo (N = 116) arm. Two hundred seventeen (93%) women completed an end-of-study evaluation. The intervention reduced the proportion of visits with BV compared to placebo (21.2% vs 32.5%; relative risk [RR] 0.65, 95% confidence interval [CI] .48–.87). In contrast, the proportion of visits with VVC was similar in the intervention (10.4%) versus placebo (11.3%) arms (RR 0.92, 95% CI .62–1.37). Conclusions. Monthly treatment with intravaginal metronidazole plus miconazole reduced the proportion of visits with BV during 12 months of follow-up. Further study will be important to determine whether this intervention can reduce women's risk of STIs. PMID:25526757

Single intravenous and oral dose pharmacokinetics of florfenicol in the channel catfish Ictalurus punctatus

USDA-ARS?s Scientific Manuscript database

Plasma distribution and elimination of florfenicol in channel catfish were investigated after a single dose (10mg/kg) of intravenous i.v.) or oral administration in freshwater at a mean water temperature of 25.4°C. Florfenicol concentrations in plasma were analyzed by means of liquid chromatography...

Does Intravenous Midazolam Dose Influence the Duration of Recovery Room Stay Following Outpatient Third Molar Surgery?

PubMed

Ettinger, Kyle S; Jacob, Adam K; Viozzi, Christopher F; Van Ess, James M; Fillmore, W Jonathan; Arce, Kevin

2015-12-01

To evaluate the impact of intravenous midazolam dose on the duration of recovery room stay for patients undergoing outpatient third molar surgery. Using a retrospective cohort study design, a sample of patients undergoing outpatient third molar surgery under intravenous sedation at Mayo Clinic from 2010 to 2014 was identified. All patients underwent extraction of all 4 third molars during a single operative procedure and the age range was limited to 14 to 29 years. The primary predictor variable was the total dose of intravenous midazolam administered during sedation. The primary outcome variable was recovery room length of stay (LOS) after completion of surgery. Multiple covariates also abstracted included patient age, gender, American Society of Anesthesiologists (ASA) score, duration of surgical procedure, complexity of surgical procedure, types and dosages of all intravenous medications administered during sedation, and volume of crystalloid fluid administered perioperatively. Univariable and multivariable models were developed to evaluate associations between the primary predictor variable and covariates relative to the primary outcome variable. The study sample was composed of 2,610 patients. Mean age was 18.3 years (SD, 3.0 yr; range, 14 to 29 yr) and gender distribution was 52% female. Mean dosage of midazolam administered was 4.1 mg (SD, 1.1 mg; range, 0.5 to 10.0 mg). Variables predicting shorter LOS at multivariable analysis included older age (P < .001), male gender (P = .004), and administration of larger crystalloid fluid volumes (P < .001). Variables predicting longer LOS included higher ASA score (P < .001), administration of ketamine (P < .001), and administration of ketorolac (P < .001). The dose of midazolam administered during sedation was not found to be significantly associated with prolonged recovery room LOS in univariable or multivariable settings. Dosage of intravenous midazolam does not appear to significantly impact the

Safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole sodium injections after single and multiple intravenous doses in healthy Chinese subjects.

PubMed

Jiao, Hui-Wen; Sun, Lu-Ning; Li, Yue-Qi; Yu, Lei; Zhang, Hong-Wen; Wang, Mei-Feng; Yu, Li-Yuan; Yuan, Zi-Qing-Yun; Xie, Li-Jun; Chen, Juan; Meng, Ling; Zhang, Xue-Hui; Wang, Yong-Qing

2018-03-01

The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole (PPZ) sodium injections following single and multiple intravenous doses in healthy Chinese subjects. The dosage groups were set as followed: 20 mg of single and multiple intravenous administration of S-(-)-PPZ, 40 mg of single and multiple intravenous administration of S-(-)-PPZ or pantoprazole, and 80 mg of single dosage group of S-(-)-PPZ. Subjects were sampled for pharmacokinetic analysis and were monitored for 24-h intragastric pH prior to and 48-h intragastric pH after administration for the pharmacodynamic study. The pharmacokinetic and pharmacodynamic parameters were compared between S-(-)-PPZ and PPZ. Safety was evaluated on the basis of adverse events, vital signs, laboratory tests, and physical examination. All adverse events were mild and of limited duration. Maximum plasma concentration and area under the concentration-time curve for S-(-)-PPZ were dose proportional over the range of 20-80 mg following a single intravenous administration. Elimination rate constant and half-life observed statistical difference from a single dose to multiple doses in 40 mg of S-(-)-PPZ groups. After administration of a single dose, the mean 24-h intragastric pH value was observed higher in 80-mg group than in 40- and 20-mg groups. Slightly increase of intragastric pH was found after a single dose of 40 mg S-(-)-PPZ than 40 mg PPZ; however, the differences were not statistically significant. Twice daily of 40 mg S-(-)-PPZ sodium injections is effective in achieving satisfying acid inhibition. Compared with plasma R-(+)-PPZ levels, most subjects presented more potent and prolonged suppression of gastric acid of S-(-)-PPZ, while a few subjects showed faster metabolic rate of S-(-)-PPZ in vivo.

Cost effectiveness of ciprofloxacin plus metronidazole versus imipenem-cilastatin in the treatment of intra-abdominal infections.

PubMed

Walters, D J; Solomkin, J S; Paladino, J A

1999-11-01

To compare the cost effectiveness of sequential intravenous (i.v.) to oral ciprofloxacin plus metronidazole (CIP/MTZ i.v./PO) with that of i.v. ciprofloxacin plus i.v. metronidazole (CIP/MTZ i.v.) and i.v. imipenem-cilastatin (IMI i.v.) in patients with intra-abdominal infections. Patients enrolled in a double-blind randomised clinical trial were eligible for inclusion into this cost-effectiveness analysis. Decision analysis was used to characterise the economic outcomes between groups and provide a structure upon which to base the sensitivity analyses. 1996 cost values were used throughout. The economic perspective of the analysis was that of a hospital provider. Among 446 economically evaluable patients, 176 could be switched from i.v. to oral administration. The 51 patients randomised to CIP/MTZ i.v./PO who received active oral therapy had a success rate of 98%, mean duration of therapy of 9.1 days and mean cost of $US7678. There were 125 patients randomized to either CIP/MTZ i.v. or IMI i.v. who received oral placebo while continuing on active i.v. antibacterials; their success rate was 94%, mean duration of therapy was 10.1 days and mean cost was $US8774 (p = 0.029 vs CIP/MTZ i.v./PO). Of the 270 patients who were unable to receive oral administration, 97 received IMI i.v. and had a success rate of 75%, mean duration of therapy of 13.8 days and a mean cost of $US12,418, and 173 received CIP/MTZ i.v. and had a success rate of 77%, mean duration of therapy of 13.4 days and mean cost of $US12,219 (p = 0.26 vs IMI i.v.). In patients able to receive oral therapy, sequential i.v. to oral treatment with ciprofloxacin plus metronidazole was cost effective compared with full i.v. courses of ciprofloxacin plus metronidazole or imipenem-cilastatin. In patients unable to receive oral therapy, no difference in mean cost was found between i.v. imipenem-cilastatin or i.v. ciprofloxacin plus i.v. metronidazole.

A Meta-analysis of the Effectiveness of Albendazole Compared with Metronidazole as Treatments for Infections with Giardia duodenalis

PubMed Central

Solaymani-Mohammadi, Shahram; Genkinger, Jeanine M.; Loffredo, Christopher A.; Singer, Steven M.

2010-01-01

Background Metronidazole is the most commonly used drug for the treatment of giardiasis in humans. In spite of its therapeutic efficacy for giardiasis, low patient compliance, especially in children, side effects, and the emergence of metronidazole-resistant strains may restrict its use. Albendazole has been used to treat Giardia duodenalis infections in recent years. However, efficacy studies in vivo and in vitro have produced diverse results as to its effectiveness. A moderately benign side effect profile, combined with established efficacy against many helminths, renders it promising for treatment of giardiasis in humans. Methodology and Principal Findings We performed a search in the PubMed, Scopus, EMBASE, the ISI Web of Science, LILIACS, and Cochrane Controlled Trials Register for trials published before February 2010 as well as in references of relevant research and review articles. Eight randomized clinical trials (including 900 patients) comparing the effectiveness of albendazole with that of metronidazole were included in meta-analysis. After extracting and validating the data, the pooled risk ratio (RR) was calculated using an inverse-variance random-effects model. Albendazole was found to be equally as effective as metronidazole in the treatment of giardiasis in humans (RR 0.97; 95% CI, 0.93, 1.01). In addition, safety analysis suggested that patients treated with albendazole had a lower risk of adverse effects compared with those who received metronidazole (RR 0.36; 95% CI, 0.10, 1.34), but limitations of the sample size precluded a definite conclusion. Conclusions/Significance The effectiveness of albendazole, when given as a single dose of 400 mg/day for 5 days, was comparable to that of metronidazole. Patients treated with albendazole tended to have fewer side effects compared with those who took metronidazole. Given the safety, effectiveness, and low costs of albendazole, this drug could be potentially used as an alternative and/or a replacement

Indirect electroreduction as pretreatment to enhance biodegradability of metronidazole.

PubMed

Saidi, I; Soutrel, I; Floner, D; Fourcade, F; Bellakhal, N; Amrane, A; Geneste, F

2014-08-15

The removal of metronidazole, a biorecalcitrant antibiotic, by coupling an electrochemical reduction with a biological treatment was examined. Electroreduction was performed in a home-made flow cell at -1.2V/SCE on graphite felt. After only one pass through the cell, analysis of the electrolyzed solution showed a total degradation of metronidazole. The biodegradability estimated from the BOD5/COD ratio increased from 0.07 to 0.2, namely below the value usually considered as the limit of biodegradability (0.4). In order to improve these results, indirect electrolysis of metronidazole was performed with a titanium complex known to reduce selectively nitro compounds into amine. The catalytic activity of the titanium complex towards electroreduction of metronidazole was shown by cyclic voltammetry analyses. Indirect electrolysis led to an improvement of the biodegradability from 0.07 to 0.42. To confirm the interest of indirect electroreduction to improve the electrochemical pretreatment, biological treatment was then carried out on activated sludge after direct and indirect electrolyses; different parameters were followed during the culture such as pH, TOC and metronidazole concentration. Both electrochemical processes led to a more efficient biodegradation of metronidazole compared with the single biological treatment, leading to an overall mineralization yield for the coupling process of 85%. Copyright © 2014 Elsevier B.V. All rights reserved.

Intravenous Iron Supplementation Practices and Short-Term Risk of Cardiovascular Events in Hemodialysis Patients

PubMed Central

Kshirsagar, Abhijit V.; Freburger, Janet K.; Ellis, Alan R.; Wang, Lily; Winkelmayer, Wolfgang C.; Brookhart, M. Alan

2013-01-01

Background & Objectives Intravenous iron supplementation is widespread in the hemodialysis population, but there is uncertainty about the safest dosing strategy. We compared the safety of different intravenous iron dosing practices on the risk of adverse cardiovascular outcomes in a large population of hemodialysis patients. Design settings, participants, & measurements A retrospective cohort was created from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the United States Renal Data System. Dosing comparisons were (1) bolus (consecutive doses ≥ 100 mg exceeding 600 mg during one month) versus maintenance (all other iron doses during the month); and (2) high (> 200 mg over 1 month) versus low dose (≤ 200 mg over 1 month). We established a 6-month baseline period (to identify potential confounders and effect modifiers), a one-month iron exposure period, and a three-month follow-up period. Outcomes were myocardial infarction, stroke, and death from cardiovascular disease. Results 117,050 patients contributed 776,203 unique iron exposure/follow-up periods. After adjustment, we found no significant associations of bolus dose versus maintenance, hazards ratio for composite outcome, 1.03 (95% C.I. 0.99, 1.07), or high dose versus low dose intravenous iron, hazards ratio for composite outcome, 0.99 (95% C.I. 0.96, 1.03). There were no consistent associations of either high or bolus dose versus low or maintenance respectively among pre-specified subgroups. Conclusions Strategies favoring large doses of intravenous iron were not associated with increased short-term cardiovascular morbidity and mortality. Investigation of the long-term safety of the various intravenous iron supplementation strategies may still be warranted. PMID:24223866

Metronidazole activation and isolation of Clostridium acetobutylicum electron transport genes.

PubMed Central

Santangelo, J D; Jones, D T; Woods, D R

1991-01-01

An Escherichia coli F19 recA, nitrate reductase-deficient mutant was constructed by transposon mutagenesis and shown to be resistant to metronidazole. This mutant was a most suitable host for the isolation of Clostridium acetobutylicum genes on recombinant plasmids, which activated metronidazole and rendered the E. coli F19 strain sensitive to metronidazole. Twenty-five E. coli F19 clones containing different recombinant plasmids were isolated and classified into five groups on the basis of their sensitivity to metronidazole. The clones were tested for nitrate reductase, pyruvate-ferredoxin oxidoreductase, and hydrogenase activities. DNA hybridization and restriction endonuclease mapping revealed that four of the C. acetobutylicum insert DNA fragments on recombinant plasmids were linked in an 11.1-kb chromosomal fragment. DNA sequencing and amino acid homology studies indicated that this DNA fragment contained a flavodoxin gene which encoded a protein of 160 amino acids that activated metronidazole and made the E. coli F19 mutant very sensitive to metronidazole. The flavodoxin and hydrogenase genes which are involved in electron transfer systems were linked on the 11.1-kb DNA fragment from C. acetobutylicum. Images PMID:1991710

Pharmacokinetics of escin Ia in rats after intravenous administration.

PubMed

Wu, Xiu-Jun; Cui, Xiang-Yong; Tian, Lian-tian; Gao, Feng; Guan, Xin; Gu, Jing-Kai

2014-10-28

Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is the chief active ingredient in escin and plays key role in mediating its pharmacological effects. Adequate pharmacokinetic data are essential for proper application of escin agent in clinical practice. However, pharmacokinetic properties of escin Ia are still poorly understood and this conflicts with the growing use of escin agent over the years. The goal of this study is to investigate the pharmacokinetic behavior of escin Ia in rats after low, medium and high-dose intravenous administration. Wistar rats were divided into 3 groups (n=6 per group) and escin Ia was administered via the caudal vein at doses of 0.5, 1.0 and 2.0 mg/kg, respectively. Subsequently, the concentrations of escin Ia and its metabolite isoescin Ia, a positional isomer of escin Ia, in rats׳ plasma were measured by an established liquid chromatography tandem mass spectrometry (LC-MS/MS) method at various time points following the administration of the drug. Main pharmacokinetic parameters were calculated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany). After intravenous administration, the Cmax and AUC of escin Ia increased in a dose-proportional manner at the dose of 0.5 mg/kg and 1.0 mg/kg, while increased in a more than dose-proportional manner at the doses of 1.0 mg/kg and 2.0 mg/kg. The t₁/₂ was significantly longer with increased intravenous doses, while other parameters such as CL and Vd also exhibit disagreement among three doses. Taken together, our data showed dose-dependent pharmacokinetic profile of escin Ia in rats after intravenous administration at the doses of 0.5-2.0 mg/kg. After intravenous administration, escin Ia was rapidly and extensively converted to isoescin Ia. The results suggested dose-dependent pharmacokinetics of escin Ia at the doses of 0.5-2.0 mg

Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation

PubMed Central

Lee, Seung-Shin; Jung, Sung-Hoon; Ahn, Seo-Yeon; Kim, Jae-Yong; Jang, Hee-Chang; Kang, Seung-Ji; Jang, Mi-Ok; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Lee, Je-Jung; Kim, Hyeoung-Joon

2015-01-01

Background/Aims BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC) in recipients of hematopoietic stem cell transplantation (HSCT). Cidofovir has been used at higher doses (3 to 5 mg/kg/wk) with probenecid prophylaxis; however, cidofovir may result in nephrotoxicity or cytopenia at high doses. Methods Allogeneic HSCT recipients with BKV-associated HC are treated with 1 mg/kg intravenous cidofovir weekly at our institution. A microbiological response was defined as at least a one log reduction in urinary BKV viral load, and a clinical response was defined as improvement in symptoms and stability or reduction in cystitis grade. Results Eight patients received a median of 4 weekly (range, 2 to 11) doses of cidofovir. HC occurred a median 69 days (range, 16 to 311) after allogeneic HSCT. A clinical response was detected in 7/8 patients (86%), and 4/5 (80%) had a measurable microbiological response. One patient died of uncontrolled graft-versus-host disease; therefore, we could not measure the clinical response to HC treatment. One microbiological non-responder had a stable BKV viral load with clinical improvement. Only three patients showed transient grade 2 serum creatinine toxicities, which resolved after completion of concomitant calcineurin inhibitor treatment. Conclusions Weekly intravenous low-dose cidofovir without probenecid appears to be a safe and effective treatment option for patients with BKV-associated HC. PMID:25750563

Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation.

PubMed

Lee, Seung-Shin; Ahn, Jae-Sook; Jung, Sung-Hoon; Ahn, Seo-Yeon; Kim, Jae-Yong; Jang, Hee-Chang; Kang, Seung-Ji; Jang, Mi-Ok; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Lee, Je-Jung; Kim, Hyeoung-Joon

2015-03-01

BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC) in recipients of hematopoietic stem cell transplantation (HSCT). Cidofovir has been used at higher doses (3 to 5 mg/kg/wk) with probenecid prophylaxis; however, cidofovir may result in nephrotoxicity or cytopenia at high doses. Allogeneic HSCT recipients with BKV-associated HC are treated with 1 mg/kg intravenous cidofovir weekly at our institution. A microbiological response was defined as at least a one log reduction in urinary BKV viral load, and a clinical response was defined as improvement in symptoms and stability or reduction in cystitis grade. Eight patients received a median of 4 weekly (range, 2 to 11) doses of cidofovir. HC occurred a median 69 days (range, 16 to 311) after allogeneic HSCT. A clinical response was detected in 7/8 patients (86%), and 4/5 (80%) had a measurable microbiological response. One patient died of uncontrolled graft-versus-host disease; therefore, we could not measure the clinical response to HC treatment. One microbiological non-responder had a stable BKV viral load with clinical improvement. Only three patients showed transient grade 2 serum creatinine toxicities, which resolved after completion of concomitant calcineurin inhibitor treatment. Weekly intravenous low-dose cidofovir without probenecid appears to be a safe and effective treatment option for patients with BKV-associated HC.

Down-regulation of flavin reductase and alcohol dehydrogenase-1 (ADH1) in metronidazole-resistant isolates of Trichomonas vaginalis

PubMed Central

Leitsch, David; Drinić, Mirjana; Kolarich, Daniel; Duchêne, Michael

2012-01-01

The microaerophilic parasite Trichomonas vaginalis is a causative agent of painful vaginitis or urethritis, termed trichomoniasis, and can also cause preterm delivery or stillbirth. Treatment of trichomoniasis is almost exclusively based on the nitroimidazole drugs metronidazole and tinidazole. Metronidazole resistance in T. vaginalis does occur and is often associated with treatment failure. In most cases, metronidazole-resistant isolates remain susceptible to tinidazole, but cross resistance between the two closely related drugs can be a problem. In this study we measured activities of thioredoxin reductase and flavin reductase in four metronidazole-susceptible and five metronidazole-resistant isolates. These enzyme activities had been previously found to be downregulated in T. vaginalis with high-level metronidazole resistance induced in the laboratory. Further, we aimed at identifying factors causing metronidazole resistance and compared the protein expression profiles of all nine isolates by application of two-dimensional gel electrophoresis (2DE). Thioredoxin reductase activity was nearly equal in all strains assayed but flavin reductase activity was clearly down-regulated, or even absent, in metronidazole-resistant strains. Since flavin reductase has been shown to reduce oxygen to hydrogen peroxide, its down-regulation could significantly contribute to the impairment of oxygen scavenging as reported by others for metronidazole-resistant strains. Analysis by 2DE revealed down-regulation of alcohol dehydrogenase 1 (ADH1) in strains with reduced sensitivity to metronidazole, an enzyme that could be involved in detoxification of intracellular acetaldehyde. PMID:22449940

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 2. Cerebrospinal Fluid Concentration Measurements in Patients with External Ventricular Drain

PubMed Central

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William

2014-01-01

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC0–τ ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC0–τ ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF. PMID:24277050

Metronidazole and hydroxymetronidazole central nervous system distribution: 2. cerebrospinal fluid concentration measurements in patients with external ventricular drain.

PubMed

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William; Marchand, Sandrine

2014-01-01

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC0-τ ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC0-τ ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.

Characterization of a Stable, Metronidazole-Resistant Clostridium difficile Clinical Isolate

PubMed Central

Lynch, Tarah; Chong, Patrick; Zhang, Jason; Hizon, Romeo; Du, Tim; Graham, Morag R.; Beniac, Daniel R.; Booth, Timothy F.; Kibsey, Pamela; Miller, Mark; Gravel, Denise; Mulvey, Michael R.

2013-01-01

Background Clostridium difficile are Gram-positive, spore forming anaerobic bacteria that are the leading cause of healthcare-associated diarrhea, usually associated with antibiotic usage. Metronidazole is currently the first-line treatment for mild to moderate C. difficile diarrhea however recurrence occurs at rates of 15–35%. There are few reports of C. difficile metronidazole resistance in the literature, and when observed, the phenotype has been transient and lost after storage or exposure of the bacteria to freeze/thaw cycles. Owing to the unstable nature of the resistance phenotype in the laboratory, clinical significance and understanding of the resistance mechanisms is lacking. Methodology/Principal Findings Genotypic and phenotypic characterization was performed on a metronidazole resistant clinical isolate of C. difficile. Whole-genome sequencing was used to identify potential genetic contributions to the phenotypic variation observed with molecular and bacteriological techniques. Phenotypic observations of the metronidazole resistant strain revealed aberrant growth in broth and elongated cell morphology relative to a metronidazole-susceptible, wild type NAP1 strain. Comparative genomic analysis revealed single nucleotide polymorphism (SNP) level variation within genes affecting core metabolic pathways such as electron transport, iron utilization and energy production. Conclusions/Significance This is the first characterization of stable, metronidazole resistance in a C. difficile isolate. The study provides an in-depth genomic and phenotypic analysis of this strain and provides a foundation for future studies to elucidate mechanisms conferring metronidazole resistance in C. difficile that have not been previously described. PMID:23349739

Standard and double-dose intravenous proton pump inhibitor injections for prevention of bleeding after endoscopic resection.

PubMed

Jung, Sung Woo; Kim, Seung Young; Choe, Jung Wan; Hyun, Jong Jin; Jung, Young Kul; Koo, Ja Seol; Yim, Hyung Joon; Lee, Sang Woo

2017-04-01

Endoscopic resection is commonly used to remove gastric neoplasms. However, effective dosing or scheduling of proton pump inhibitors for the prevention of delayed bleeding after endoscopic resection remains unclear. One hundred sixty-six patients with gastric adenoma or early gastric cancer were enrolled. After an endoscopic procedure, each subject was randomly assigned to 40 mg every 24 h (standard dose group) or 40 mg every 12 h (double-dose group) of intravenous pantoprazole for 48 h. Second-look endoscopy was performed on day 2 after endoscopic resection to compare signs of rebleeding and ulcer status between the two groups. Eighty-one patients of the standard dose group and 81 of the double-dose group were analyzed. There were no significant differences in the incidence of delayed bleeding events (1.3% vs 6.2%, P = 0.21) and bleeding ulcer at the second-look endoscopy (6.2% vs 3.9%, P = 0.69) between standard and double-dose groups. There were no other significant variables associated with delayed bleeding or bleeding ulcer on second-look endoscopy. Intravenous pantoprazole 40 mg every 24 h or 12 h for 2 days after endoscopic resection was equally effective for the prevention of delayed bleeding. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Intravenous immunoglobulin therapy for severe Clostridium difficile colitis

PubMed Central

Salcedo, J; Keates, S; Pothoulakis, C; Warny, M; Castagliuolo, I; LaMont, J; Kelly, C

1997-01-01

Background—Many individuals have serum antibodies against Clostridium difficile toxins. Those with an impaired antitoxin response may be susceptible to recurrent, prolonged, or severe C difficile diarrhoea and colitis. 
Aims—To examine whether treatment with intravenous immunoglobulin might be effective in patients with severe pseudomembranous colitis unresponsive to standard antimicrobial therapy. 
Patients—Two patients with pseudomembranous colitis not responding to metronidazole and vancomycin were given normal pooled human immunoglobulin intravenously (200-300 mg/kg). 
Methods—Antibodies against C difficile toxins were measured in nine immunoglobulin preparations by ELISA and by cytotoxin neutralisation assay. 
Results—Both patients responded quickly as shown by resolution of diarrhoea, abdominal tenderness, and distension. All immunoglobulin preparations tested contained IgG against C difficile toxins A and B by ELISA and neutralised the cytotoxic activity of C difficile toxins in vitro at IgG concentrations of 0.4-1.6 mg/ml. 
Conclusion—Passive immunotherapy with intravenous immunoglobulin may be a useful addition to antibiotic therapy for severe, refractory C difficile colitis. IgG antitoxin is present in standard immunoglobulin preparations and C difficile toxin neutralising activity is evident at IgG concentrations which are readily achieved in the serum by intravenous immunoglobulin administration. 

 Keywords: Clostridium difficile; toxin; diarrhoea; IgG; immunotherapy; antibiotic PMID:9378393

Management of trichomonas vaginalis in women with suspected metronidazole hypersensitivity.

PubMed

Helms, Donna J; Mosure, Debra J; Secor, W Evan; Workowski, Kimberly A

2008-04-01

Standard treatment for Trichomonas vaginalis is metronidazole or tinidazole. Hypersensitivity to these drugs has been documented but is poorly understood. Desensitization is an option described in limited reports of women with hypersensitivity to nitroimidazoles. The purpose of this analysis is to improve documentation of management for trichomonas infections among women with metronidazole hypersensitivity. Clinicians who consulted Centers for Disease Control and Prevention concerning patients with suspected hypersensitivity to metronidazole were provided with treatment options and asked to report outcomes. From September 2003-September 2006, complete information was obtained for 59 women. The most common reactions were urticaria (47%) and facial edema (11%). Fifteen of these women (25.4%) were treated with metronidazole desensitization and all had eradication of their infection. Seventeen women (28.8%) were treated with alternative intravaginal drugs, which were less successful; 5 of 17 infections (29.4%) were eradicated. Metronidazole desensitization was effective in the management of women with nitroimidazole hypersensitivity.

Evaluation of mechanical and rheological properties of metronidazole gel as local delivery system.

PubMed

Jelvehgari, Mitra; Montazam, Hassan

2011-06-01

Rosacea is a chronic multifactorial vascular skin disorder that affects about 10 percent of the general population. Metronidazole is an effective antibiotic in the treatment of moderate-to severe rosacea. Metronidazole is a suitable drug in cases of resistance to tetracycline or erythromycin, but it has also been shown that oral metronidazole may increase the side effects (e.g., peripheral neuropathy). Oral metronidazole should not be used for more than three months, and hence topical metronidazole gel is the best therapeutic choice in rosacea (especially during pregnancy). This study examined the mechanical (adhesiveness, cohesiveness, extrudability, spreadability, homogeneity) and rheological (viscosity), skin irritant and drug release properties of different metronidazole gel formulations that contain anionic emulsifying wax, glycerin and lactic acid in different proportions. The release studies were conducted using Franz diffusion cells and Silastic membrane as a barrier. The results indicated that gel compressibility, hardness, and adhesiveness, are the factors that influence the ease of gel removal from the container, ease of gel application onto the mucosal membrane, and gel bioadhesion. The findings showed that there exists a strong negative correlation between the spreadability of a formulation and its cohesiveness, the spreadability of a formulation is inversely proportional to its cohesiveness. However, sorbitol solution (70%) concentration was not significantly correlated with drug release. In addition, drug release was significantly reduced as the concentration of anionic emulsifying wax increased and the concentration of lactic acid decreased. The maximum metronidazole release was achieved at a pH of 4-6. Data obtained from in vitro release studies were fitted to various kinetic models and high correlation was obtained in the Higuchi and first order models. The results showed that all the gel formulations showed good extrudability, viscosity

Loss of Microbiota-Mediated Colonization Resistance to Clostridium difficile Infection With Oral Vancomycin Compared With Metronidazole

PubMed Central

Lewis, Brittany B.; Buffie, Charlie G.; Carter, Rebecca A.; Leiner, Ingrid; Toussaint, Nora C.; Miller, Liza C.; Gobourne, Asia; Ling, Lilan; Pamer, Eric G.

2015-01-01

Antibiotic administration disrupts the intestinal microbiota, increasing susceptibility to pathogens such as Clostridium difficile. Metronidazole or oral vancomycin can cure C. difficile infection, and administration of these agents to prevent C. difficile infection in high-risk patients, although not sanctioned by Infectious Disease Society of America guidelines, has been considered. The relative impacts of metronidazole and vancomycin on the intestinal microbiota and colonization resistance are unknown. We investigated the effect of brief treatment with metronidazole and/or oral vancomycin on susceptibility to C. difficile, vancomycin-resistant Enterococcus, carbapenem-resistant Klebsiella pneumoniae, and Escherichia coli infection in mice. Although metronidazole resulted in transient loss of colonization resistance, oral vancomycin markedly disrupted the microbiota, leading to prolonged loss of colonization resistance to C. difficile infection and dense colonization by vancomycin-resistant Enterococcus, K. pneumoniae, and E. coli. Our results demonstrate that vancomycin, and to a lesser extent metronidazole, are associated with marked intestinal microbiota destruction and greater risk of colonization by nosocomial pathogens. PMID:25920320

A rare adverse effect of metronidazole: nervous system symptoms.

PubMed

Kafadar, Ihsan; Moustafa, Fatma; Yalçın, Koray; Klç, Betül Aydn

2013-06-01

Metronidazole, as a 5-nitroimidazole compound, is effective on anaerobic bacteria and protozoon diseases. Mostly, metronidazole is a tolerable drug but rarely presents serious adverse effects on the nervous system. In case of these adverse effects, treatment must be stopped.In this report, a 3-year-old child hospitalized because of diarrhea is presented. During the metronidazole treatment, loss of sight, vertigo, ataxia, and headache occurred as the adverse effects. By this report, we want to express the rare adverse effects of drugs in the differential diagnoses of nervous system diseases.

Continuous Intravenous Sub-Dissociative Dose Ketamine Infusion for Managing Pain in the Emergency Department

PubMed Central

Drapkin, Jefferson; Likourezos, Antonios; Beals, Tyler; Monfort, Ralph; Fromm, Christian; Marshall, John

2018-01-01

Introduction Our objective was to describe dosing, duration, and pre- and post-infusion analgesic administration of continuous intravenous sub-dissociative dose ketamine (SDK) infusion for managing a variety of painful conditions in the emergency department (ED). Methods We conducted a retrospective chart review of patients aged 18 and older presenting to the ED with acute and chronic painful conditions who received continuous SDK infusion in the ED for a period over six years (2010–2016). Primary data analyses included dosing and duration of infusion, rates of pre- and post-infusion analgesic administration, and final diagnoses. Secondary data included pre- and post-infusion pain scores and rates of side effects. Results A total of 104 patients were enrolled in the study. Average dosing of SDK infusion was 11.26 mg/hr, and the mean duration of infusion was 135.87 minutes. There was a 38% increase in patients not requiring post-infusion analgesia. The average decrease in pain score was 5.04. There were 12 reported adverse effects, with nausea being the most prevalent. Conclusion Continuous intravenous SDK infusion has a role in controlling pain of various etiologies in the ED with a potential to reduce the need for co-analgesics or rescue analgesic administration. There is a need for more robust, prospective, randomized trials that will further evaluate the analgesic efficacy and safety of this modality across a wide range of pain syndromes and different age groups in the ED. PMID:29760856

Human kinetics of orally and intravenously administered low-dose 1,2-(13)C-dichloroacetate.

PubMed

Jia, Minghong; Coats, Bonnie; Chadha, Monisha; Frentzen, Barbara; Perez-Rodriguez, Javier; Chadik, Paul A; Yost, Richard A; Henderson, George N; Stacpoole, Peter W

2006-12-01

Dichloroacetate (DCA) is a putative environmental hazard, owing to its ubiquitous presence in the biosphere and its association with animal and human toxicity. We sought to determine the kinetics of environmentally relevant concentrations of 1,2-(13)C-DCA administered to healthy adults. Subjects received an oral or intravenous dose of 2.5 microg/kg of 1,2-(13)C-DCA. Plasma and urine concentrations of 1,2-(13)C-DCA were measured by a modified gas chromatography-tandem mass spectrometry method. 1,2-(13)C-DCA kinetics was determined by modeling using WinNonlin 4.1 software. Plasma concentrations of 1,2-(13)C-DCA peaked 10 minutes and 30 minutes after intravenous or oral administration, respectively. Plasma kinetic parameters varied as a function of dose and duration. Very little unchanged 1,2-(13)C-DCA was excreted in urine. Trace amounts of DCA alter its own kinetics after short-term exposure. These findings have important implications for interpreting the impact of this xenobiotic on human health.

Efficacy of New 5-Nitroimidazoles against Metronidazole-Susceptible and -Resistant Giardia, Trichomonas, and Entamoeba spp.

PubMed Central

Upcroft, Jacqueline A.; Campbell, Raymond W.; Benakli, Kamel; Upcroft, Peter; Vanelle, Patrice

1999-01-01

The efficacies of 12 5-nitroimidazole compounds and 1 previously described lactam-substituted nitroimidazole with antiparasitic activity, synthesized via SRN1 and subsequent reactions, were assayed against the protozoan parasites Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica. Two metronidazole-sensitive lines and two metronidazole-resistant lines of Giardia and one line each of metronidazole-sensitive and -resistant Trichomonas were tested. All except one of the compounds were as effective or more effective than metronidazole against Giardia and Trichomonas, but none was as effective overall as the previously described 2-lactam-substituted 5-nitroimidazole. None of the compounds was markedly more effective than metronidazole against Entamoeba. Significant cross-resistance between most of the drugs tested and metronidazole was evident among metronidazole-resistant lines of Giardia and Trichomonas. However, some drugs were lethal to metronidazole-resistant Giardia and had minimum lethal concentrations similar to that of metronidazole for drug-susceptible parasites. This study emphasizes the potential in developing new nitroimidazole drugs which are more effective than metronidazole and which may prove to be useful clinical alternatives to metronidazole. PMID:9869568

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 1. Microdialysis Assessment of Brain Extracellular Fluid Concentrations in Patients with Acute Brain Injury

PubMed Central

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William

2014-01-01

The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0–τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml−1. This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution. PMID:24277041

Metronidazole and hydroxymetronidazole central nervous system distribution: 1. microdialysis assessment of brain extracellular fluid concentrations in patients with acute brain injury.

PubMed

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William; Marchand, Sandrine

2014-01-01

The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0-τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml(-1). This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution.

Intravenous iron isomaltoside 1000 administered by high single-dose infusions or standard medical care for the treatment of fatigue in women after postpartum haemorrhage: study protocol for a randomised controlled trial.

PubMed

Holm, Charlotte; Thomsen, Lars Lykke; Norgaard, Astrid; Langhoff-Roos, Jens

2015-01-14

Postpartum haemorrhage can lead to iron deficiency with and without anaemia, the clinical consequences of which include physical fatigue. Although oral iron is the standard treatment, it is often associated with gastrointestinal side effects and poor compliance. To date, no published randomised controlled studies have compared the clinical efficacy and safety of standard medical care with intravenous administration of iron supplementation after postpartum haemorrhage.The primary objective of this study is to compare the efficacy of an intravenous high single-dose of iron isomaltoside 1000 with standard medical care on physical fatigue in women with postpartum haemorrhage. In a single centre, open-labelled, randomised trial, women with postpartum haemorrhage exceeding 700 mL will be allocated to either a single dose of 1,200 mg of iron isomaltoside 1000 or standard medical care. Healthy parturients with a singleton pregnancy will be included within 48 hours after delivery.Participants will complete structured questionnaires that focus on several dimensions of fatigue and mental health (Multidimensional Fatigue Inventory, Edinburgh Postnatal Depression Scale and the Postpartum Questionnaire), at inclusion and at follow-up visits after three days, one week, three weeks, eight weeks, and 12 weeks postpartum. The primary endpoint is the aggregated change in physical fatigue score within 12 weeks postpartum, as measured by a subscale of the Multidimensional Fatigue Inventory. The primary objective will be considered to have been met if an intravenous high single dose of iron isomaltoside 1000 is shown to be superior to standard medical care in women after postpartum haemorrhage regarding physical fatigue.For claiming superiority, we set the minimal clinically relevant difference between the mean scores at 1.8, and the assumed standard deviation at 4.2. Hence, 87 participants per treatment group are needed in order to demonstrate superiority; to provide an extra margin

Effects of intravenous Escherichia coli dose on the pathophysiological response of colostrum-fed Jersey calves

USDA-ARS?s Scientific Manuscript database

Objectives of the present study were to characterize the dose dependency of an intravenous Escherichia coli (E. coli) challenge in colostrum-fed Jersey calves and to identify biochemical markers indicative of septicemia. Eighteen 3-wk old colostrum-fed Jersey calves were completely randomized to 1 o...

Disposition of styrene-acrylonitrile (SAN) trimer in female rats: single dose intravenous and gavage studies.

PubMed

Gargas, Michael L; Collins, Brad; Fennell, Timothy R; Gaudette, Norman F; Sweeney, Lisa M

2008-04-21

Styrene-acrylonitrile trimer (SAN Trimer), a mixture of six isomers (four isomers of 4-cyano-1,2,3,4-tetrahydro-alpha-methyl-1-naphthaleneacetonitrile [THAN] and two isomers of 4-cyano-1,2,3,4-tetrahydro-1-naphthaleneproprionitrile [THNP]), is a by-product of a specific production process of styrene-acrylonitrile polymer. Disposition studies in female rats were conducted to evaluate the pharmacokinetic behavior of [3H]SAN Trimer following a single intravenous administration (26 mg/kg) to nonpregnant rats; a single gavage administration (nominal doses of 25 mg/kg, 75 mg/kg, or 200 mg/kg in corn oil) to nonpregnant rats; and a single gavage administration (nominal dose of 200 mg/kg in corn oil) to pregnant and lactating rats. SAN Trimer was rapidly eliminated from blood (T1/2 approximately 1h) following a single intravenous dose and following single oral doses (T1/2 approximately 3-4h). SAN Trimer was also rapidly excreted in the urine and feces following single oral doses, while total radioactivity was cleared more slowly. In pregnant rats, the concentrations of both radioactivity and SAN Trimer 2h after dosing were highest in the blood, followed by the placenta, with the lowest levels in the fetus. In lactating rats, the concentrations of both radioactivity and SAN Trimer were higher in milk than in maternal blood. Total radioactivity and SAN Trimer blood concentrations in nonpregnant, pregnant, and lactating rats were both higher in lactating rats compared to nonpregnant and pregnant rats.

Single dose intravenous methyl prednisolone versus oral prednisolone in Bell's palsy: A randomized controlled trial

PubMed Central

Giri, Prithvi; Garg, Ravindra Kumar; Singh, Maneesh Kumar; Verma, Rajesh; Malhotra, Hardeep Singh; Sharma, Praveen Kumar

2015-01-01

Objectives: Corticosteroids have been used in the treatment of Bell's palsy and several other postinfectious neurological conditions. We hypothesized that administration of a single dose of intravenous (IV) methylprednisolone might be an effective alternative to oral prednisolone. Materials and Methods: In this open label, randomized trial, patients with acute Bell's palsy were randomized into two groups. One group received single dose (500 mg) of IV methylprednisolone while the other group received 10 days of oral prednisone. Outcome was assessed at 1 and 3 months with House–Brackmann scale. Results: At 3 months, 93 (79.48%) patients had completely recovered. IV methylprednisolone and oral prednisolone groups had similar recovery rates (80% vs. 78.33%, P > 0.05). Patients with Grade 2 and 3 recovered completely. In patients with Grade 6, the recovery rate was 20%. A better outcome was observed if corticosteroids were administered within 3 days of onset of palsy. Conclusion: Intravenous methylprednisolone and oral prednisolone showed equivalent benefit in patients with acute Bell's palsy. PMID:25878371

Exacerbated symptoms in Blastocystis sp.-infected patients treated with metronidazole: two case studies.

PubMed

Rajamanikam, Arutchelvan; Kumar, Suresh; Samudi, Chandramathi; Kudva, Madhav

2018-06-05

Blastocystis sp. is a gastrointestinal (GI) protozoan parasite reported to cause non-specific GI symptoms including diarrhea, flatulence, abdominal pain, and nausea. Complete eradication of Blastocystis sp. is rather challenging even with the drug of choice, i.e., metronidazole. Here, we report on two Blastocystis sp.-infected individuals, who presented increased parasite load and exacerbated symptoms upon treatment with the usual recommended dosage and regime of metronidazole. The two studies uniquely demonstrate for the first time a cyst count as high as fivefold more than the original cyst count before treatment and show an exacerbation of GI symptoms despite treatment. The study provides additional support in recognizing metronidazole resistance in Blastocystis sp. and its consequences towards the pathogenicity of the parasite.

Low dose intravenous immunoglobulins and steroids in toxic epidermal necrolysis: a prospective comparative open-labelled study of 36 cases.

PubMed

Jagadeesan, Soumya; Sobhanakumari, K; Sadanandan, Sadeep Melethil; Ravindran, Sheeba; Divakaran, Manjula Velikkakathu; Skaria, Lissy; Kurien, George

2013-01-01

Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction associated with high mortality. Though different modalities of treatment are advocated, there is no consensus regarding specific therapy. Corticosteroids have shown conflicting results and for high dose intravenous immunoglobulins (IVIG), cost is a limiting factor. To find out the effectiveness of combination therapy with low-dose IVIG and steroids versus steroids alone in our TEN patients. After obtaining Ethical Committee approval, 36 consecutive TEN patients (2008-2012) were alternately allocated to 2 groups - Group A was given combination of low-dose IVIG (0.2-0.5 g/kg) and rapidly tapering course of steroids (intravenous dexamethasone 0.1- 0.3 mg/kg/day tapered in 1-2 weeks) while Group B was given same dose of steroids alone. Outcome parameters assessed were time taken for arrest of disease progression, time taken for re-epithelization, duration of hospital stay and mortality rates. Both groups had 18 patients. Baseline characteristics like age, sex ratio, SCORTEN, body surface area involvement and treatment interval were comparable. Time for arrest of disease progression and for re-epithelization was significantly lowered in Group A (P = 0.0001, P = 0.0009 respectively). Though duration of hospital stay and deaths were less in Group A, difference was not statistically significant. SCORTEN based standardized mortality ratio (SMR) analysis revealed that combination therapy reduced the probability of dying by 82% (SMR = 0.18 ± 0.36) and steroids by 37% (SMR = 0.63 ± 0.71). Difference in SMR was statistically significant (P = 0.00001). No significant side effects due to either modality were found in any of the patients. Combination therapy with low-dose IVIG and steroids is more effective in terms of reduced mortality and faster disease resolution when compared to steroids alone in TEN.

Acute Hepatotoxicity of Intravenous Amiodarone: Case Report and Review of the Literature.

PubMed

Chen, Chia-Chi; Wu, Chien-Chih

2016-01-01

Amiodarone is a class III antiarrhythmic drug widely used for the treatment of both supraventricular and ventricular arrhythmias in intensive care unit. Hepatotoxicity of amiodarone is usually mild and delayed onset. Acute hepatotoxicity is a rare side effect and usually correlated to intravenous form use. In this case, acute hepatocellular injury occurred within 24 hours after the administration of intravenous amiodarone. Liver enzyme significantly improved after holding intravenous amiodarone use. Because ventricular arrhythmia persisted and side effects occurred to alternative therapy, low dose of oral amiodarone was resumed and hepatotoxicity did not occur afterward. Acute hepatotoxicity of intravenous amiodarone is possibly related to polysorbate 80, the solubilizer of amiodarone infusion or higher dose. As a result, when intravenous amiodarone is prescribed, closely monitoring liver enzyme is highly suggested. If acute hepatitis takes place secondary to intravenous amiodarone, oral therapy should not be resumed afterward. If there is no alternative treatment, lower dose of oral amiodarone (≤200 mg/d) could be tried and should monitor liver function regularly.

Electroporation-delivered transdermal neostigmine in rats: equivalent action to intravenous administration

PubMed Central

Berkó, Szilvia; Szűcs, Kálmán F; Balázs, Boglárka; Csányi, Erzsébet; Varju, Gábor; Sztojkov-Ivanov, Anita; Budai-Szűcs, Mária; Bóta, Judit; Gáspár, Róbert

2016-01-01

Purpose Transdermal electroporation has become one of the most promising noninvasive methods for drug administration, with greatly increased transport of macromolecules through the skin. The cecal-contracting effects of repeated transdermal electroporation delivery and intravenous administration of neostigmine were compared in anesthetized rats. Methods The cecal contractions were detected with implantable strain gauge sensors, and the plasma levels of neostigmine were followed by high-performance liquid chromatography. Results Both intravenously and EP-administered neostigmine (0.2–66.7 μg/kg) increased the cecal contractions in a dose-dependent manner. For both the low doses and the highest dose, the neostigmine plasma concentrations were the same after the two modes of administration, while an insignificantly higher level was observed at a dose of 20 μg/kg after intravenous administration as compared with the electroporation route. The contractile responses did not differ significantly after the two administration routes. Conclusion The results suggest that electroporation-delivered neostigmine elicits action equivalent to that observed after intravenous administration as concerning both time and intensity. Electroporation permits the delivery of even lower doses of water-soluble compounds through the skin, which is very promising for clinical practice. PMID:27274203

Single-dose intravenous iron infusion or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled trial.

PubMed

Holm, C; Thomsen, L L; Norgaard, A; Langhoff-Roos, J

2017-04-01

To evaluate the clinical efficacy of a single-dose intravenous infusion of iron isomaltoside compared with current treatment practice with oral iron measured by physical fatigue in women after postpartum haemorrhage. Single-centre, open-label, randomized controlled trial. Participants received intravenous iron (n = 97) or oral iron (n = 99), and completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale, and haematological and iron parameters were measured. Primary outcome was the aggregated change in physical fatigue score from baseline to 12 weeks postpartum. The difference in physical fatigue score was -0·97 (95% CI: -1·65; -0·28, P = 0·006) in favour of intravenous iron, but did not meet the predefined difference of 1·8. Across visits, we found statistically significant differences in fatigue and depression scores, as well as in haematological and iron parameters, all in favour of intravenous iron. There were no serious adverse reactions. A single dose of intravenous iron was associated with a statistically significant reduction in aggregated physical fatigue within 12 weeks after postpartum haemorrhage compared to standard medical care with oral iron below the prespecified criteria of clinical superiority. As patient-reported outcomes improved significantly and intravenous iron resulted in a fast hematopoietic response without serious adverse reactions, intravenous iron may be a useful alternative after postpartum haemorrhage if oral iron is not absorbed or tolerated. © 2017 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration.

PubMed

Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas

2015-01-01

The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions.

Quantification of metronidazole in human plasma using a highly sensitive and rugged LC-MS/MS method for a bioequivalence study.

PubMed

Vanol, Pravin G; Sanyal, Mallika; Shah, Priyanka A; Shrivastav, Pranav S

2018-03-23

A highly sensitive, selective and rugged method has been described for the quantification of metronidazole (MTZ) in human plasma by liquid chromatography-tandem mass spectrometry using metronidazole-d4 as the internal standard (IS). The analyte and the IS were extracted from 100 μL plasma by liquid-liquid extraction. The clear samples obtained were chromatographed on an ACE C 18 (100 × 4.6 mm, 5 μm) column using acetonitrile and 10.0 mm ammonium formate in water, pH 4.00 (80:20, v/v) as the mobile phase. A triple quadrupole mass spectrometer system equipped with turbo ion spray source and operated in multiple reaction monitoring mode was used for the detection and quantification of MTZ. The calibration range was established from 0.01 to 10.0 μg/mL. The results of validation testing for precision and accuracy, selectivity, matrix effects, recovery and stability complied with current bioanalytical guidelines. A run time of 3.0 min permitted analysis of more than 300 samples in a day. The method was applied to a bioequivalence study with 250 mg MTZ tablet formulation in 24 healthy Indian males. Copyright © 2018 John Wiley & Sons, Ltd.

The aerobic activity of metronidazole against anaerobic bacteria.

PubMed

Dione, Niokhor; Khelaifia, Saber; Lagier, Jean-Christophe; Raoult, Didier

2015-05-01

Recently, the aerobic growth of strictly anaerobic bacteria was demonstrated using antioxidants. Metronidazole is frequently used to treat infections caused by anaerobic bacteria; however, to date its antibacterial activity was only tested in anaerobic conditions. Here we aerobically tested using antioxidants the in vitro activities of metronidazole, gentamicin, doxycycline and imipenem against 10 common anaerobic and aerobic bacteria. In vitro susceptibility testing was performed by the disk diffusion method, and minimum inhibitory concentrations (MICs) were determined by Etest. Aerobic culture of the bacteria was performed at 37°C using Schaedler agar medium supplemented with 1mg/mL ascorbic acid and 0.1mg/mL glutathione; the pH was adjusted to 7.2 by 10M KOH. Growth of anaerobic bacteria cultured aerobically using antioxidants was inhibited by metronidazole after 72h of incubation at 37°C, with a mean inhibition diameter of 37.76mm and an MIC of 1μg/mL; however, strains remained non-sensitive to gentamicin. No growth inhibition of aerobic bacteria was observed after 24h of incubation at 37°C with metronidazole; however, inhibition was observed with doxycycline and imipenem used as controls. These results indicate that bacterial sensitivity to metronidazole is not related to the oxygen tension but is a result of the sensitivity of the micro-organism. In future, both culture and antibiotic susceptibility testing of strictly anaerobic bacteria will be performed in an aerobic atmosphere using antioxidants in clinical microbiology laboratories. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Intravenous Iron Therapy in Patients with Iron Deficiency Anemia: Dosing Considerations

PubMed Central

Myers, Jennifer; Goodnough, Lawrence Tim

2015-01-01

Objective. To provide clinicians with evidence-based guidance for iron therapy dosing in patients with iron deficiency anemia (IDA), we conducted a study examining the benefits of a higher cumulative dose of intravenous (IV) iron than what is typically administered. Methods. We first individually analyzed 5 clinical studies, averaging the total iron deficit across all patients utilizing a modified Ganzoni formula; we then similarly analyzed 2 larger clinical studies. For the second of the larger studies (Study 7), we also compared the efficacy and retreatment requirements of a cumulative dose of 1500 mg ferric carboxymaltose (FCM) to 1000 mg iron sucrose (IS). Results. The average iron deficit was calculated to be 1531 mg for patients in Studies 1–5 and 1392 mg for patients in Studies 6-7. The percentage of patients who were retreated with IV iron between Days 56 and 90 was significantly (p < 0.001) lower (5.6%) in the 1500 mg group, compared to the 1000 mg group (11.1%). Conclusions. Our data suggests that a total cumulative dose of 1000 mg of IV iron may be insufficient for iron repletion in a majority of patients with IDA and a dose of 1500 mg is closer to the actual iron deficit in these patients. PMID:26257955

Stevens-Johnson syndrome following use of metronidazole in a dental patient.

PubMed

Mazumdar, Goutameswar; Shome, Koushik

2014-01-01

Metronidazole alone rarely causes Stevens-Johnson syndrome (SJS). We present a case of an elderly male patient who, following metronidazole use, developed neurological symptoms followed by pain and blisters on both soles, erythema of face and neck, scrotal itching and erosion, and hemorrhagic encrustation around the lips and oral mucous membrane. Initial neurological symptoms followed by mucocutaneous manifestation of SJS following metronidazole use is probably a new presentation of this case.

Pharmacokinetics of Oral and Intravenous Paracetamol (Acetaminophen) When Co-Administered with Intravenous Morphine in Healthy Adult Subjects.

PubMed

Raffa, Robert B; Pawasauskas, Jayne; Pergolizzi, Joseph V; Lu, Luke; Chen, Yin; Wu, Sutan; Jarrett, Brant; Fain, Randi; Hill, Lawrence; Devarakonda, Krishna

2018-03-01

Several features favor paracetamol (acetaminophen) administration by the intravenous rather than the oral route in the postoperative setting. This study compared the pharmacokinetics and bioavailability of oral and intravenous paracetamol when given with or without an opioid, morphine. In this randomized, single-blind, parallel, repeat-dose study in healthy adults, subjects received four repeat doses of oral or intravenous 1000 mg paracetamol at 6-h intervals, and morphine infusions (0.125 mg/kg) at the 2nd and 3rd intervals. Comparisons of plasma pharmacokinetic profiles were conducted before, during, and after opioid co-administrations. Twenty-two subjects were included in the pharmacokinetic analysis. Observed paracetamol peak concentration (C max ) and area under the plasma concentration-time curve over the dosing interval (AUC 0-6 ) were reduced when oral paracetamol was co-administered with morphine (reduced from 11.6 to 7.25 µg/mL and from 31.00 to 25.51 µg·h/mL, respectively), followed by an abruptly increased C max and AUC 0-6 upon discontinuation of morphine (to 13.5 µg/mL and 52.38 µg·h/mL, respectively). There was also a significantly prolonged mean time to peak plasma concentration (T max ) after the 4th dose of oral paracetamol (2.84 h) compared to the 1st dose (1.48 h). However, pharmacokinetic parameters of paracetamol were not impacted when intravenous paracetamol was co-administered with morphine. Morphine co-administration significantly impacted the pharmacokinetics of oral but not intravenous paracetamol. The abrupt release of accumulated paracetamol at the end of morphine-mediated gastrointestinal inhibition following oral but not intravenous administration of paracetamol suggests that intravenous paracetamol provides a better option for the management of postoperative pain. CLINICALTRIALS. NCT02848729.

Outcome of metronidazole therapy for Clostridium difficile disease and correlation with a scoring system.

PubMed

Belmares, Jaime; Gerding, Dale N; Parada, Jorge P; Miskevics, Scott; Weaver, Frances; Johnson, Stuart

2007-12-01

To determine the response rate of Clostridium difficile disease (CDD) to treatment with metronidazole and assess a scoring system to predict response to treatment with metronidazole when applied at the time of CDD diagnosis. Retrospective review of patients with CDD who received primary treatment with metronidazole. We defined success as diarrhea resolution within 6 days of therapy. A CDD score was defined prospectively using variables suggested to correlate with disease severity. Among 102 evaluable patients, 72 had a successful response (70.6%). Twenty-one of the remaining 30 patients eventually responded to metronidazole, but required longer treatment, leaving 9 'true failures'. The mean CDD score was higher among true failures (2.89+/-1.4) than among all metronidazole responders (0.77+/-1.0) (p<.0001). The score was greater than 2 in 67% of true failures and 2 or less in 94% of metronidazole responders. Leukocytosis and abnormal CT scan findings were individual factors associated with a higher risk of metronidazole failure. Only 71% of CDD patients responded to metronidazole within 6 days, but the overall response rate was 91%. A CDD score greater than 2 was associated with metronidazole failure in 6 of 9 true failures. The CDD score will require prospective validation.

Differential Expression and Immunolocalization of Antioxidant Enzymes in Entamoeba histolytica Isolates during Metronidazole Stress

PubMed Central

Iyer, Lakshmi Rani; Singh, Nishant; Verma, Anil Kumar; Paul, Jaishree

2014-01-01

Entamoeba histolytica infections are endemic in the Indian subcontinent. Five to eight percent of urban population residing under poor sanitary conditions suffers from Entamoeba infections. Metronidazole is the most widely prescribed drug used for amoebiasis. In order to understand the impact of metronidazole stress on the parasite, we evaluated the expression of two antioxidant enzymes, peroxiredoxin and FeSOD, in Entamoeba histolytica isolates during metronidazole stress. The results reveal that, under metronidazole stress, the mRNA expression levels of these enzymes did not undergo any significant change. Interestingly, immunolocalization studies with antibodies targeting peroxiredoxin indicate differential localization of the protein in the cell during metronidazole stress. In normal conditions, all the Entamoeba isolates exhibit presence of peroxiredoxin in the nucleus as well as in the membrane; however with metronidazole stress the protein localized mostly to the membrane. The change in the localization pattern was more pronounced when the cells were subjected to short term metronidazole stress compared to cells adapted to metronidazole. The protein localization to the cell membrane could be the stress response mechanism in these isolates. Colocalization pattern of peroxiredoxin with CaBp1, a cytosolic protein, revealed that the membrane and nuclear localization was specific to peroxiredoxin during metronidazole stress. PMID:25013795

The pharmacokinetics of methocarbamol and guaifenesin after single intravenous and multiple-dose oral administration of methocarbamol in the horse.

PubMed

Rumpler, M J; Colahan, P; Sams, R A

2014-02-01

A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration. © 2013 John Wiley & Sons Ltd.

High-dose methylprednisolone pulse therapy for treatment of refractory intestinal involvement caused by Henoch-Schönlein purpura: a case report.

PubMed

Kang, Hyun Sik; Chung, Hee Sup; Kang, Ki-Soo; Han, Kyoung Hee

2015-03-24

Henoch-Schönlein purpura is an immunoglobulin A-mediated, small vascular inflammatory disease that can be associated with palpable purpura, arthralgia, abdominal pain, or nephritis. The presence of purpura facilitates the diagnosis of Henoch-Schönlein purpura at the onset of associated symptoms, whereas the absence of purpura makes the diagnosis challenging. It is important to diagnose Henoch-Schönlein purpura with delayed-onset skin purpura to avoid unnecessary surgery for acute abdomen. Most cases of Henoch-Schönlein purpura with severe abdominal pain are treated with low-dose steroids and intravenous immunoglobulin. A 15-year-old Korean girl complained of severe abdominal pain and delayed-onset purpura on admission. Henoch-Schönlein purpura was diagnosed based on endoscopic findings of hemorrhagic duodenitis and duodenal vasculitis and abdominal computed tomography findings of edematous bowels. Two common initial treatments, a low-dose steroid and intravenous immunoglobulin, were administered, but there was no improvement for 1 month. Subsequently, we used high-dose intravenous methylprednisolone pulse therapy (30 mg/kg/day, with a maximum of 1g/day), which dramatically alleviated her abdominal symptoms. High-dose intravenous methylprednisolone pulse therapy can be used as the ultimate treatment for delayed-onset Henoch-Schönlein purpura with severe abdominal pain when symptoms do not improve after low-dose steroid and intravenous immunoglobulin treatments.

Metronidazole prodrugs: synthesis, physicochemical properties, stability, and ex vivo release studies.

PubMed

Mura, Carla; Valenti, Donatella; Floris, Costantino; Sanna, Roberta; De Luca, Maria Antonietta; Fadda, Anna Maria; Loy, Giuseppe

2011-09-01

The aim of the present study was to develop a colon targeted delivery system for metronidazole using polymeric prodrug formulation. Two chitosan amide conjugates of metronidazole were prepared by using two different spacers to covalently link the drug to the amino group of the chitosan glucosamine units. Glutaric and succinic hemiesters of metronidazole were thus prepared and then coupled to chitosan to obtain metronidazole-glutaryl- and metronidazole-succinyl-chitosan conjugates. Polymeric prodrugs were characterized by solid state NMR method, namely carbon 13 cross polarization magic angle spinning ((13)C NMR CPMAS). Prodrug stability study was carried out in acid (pH = 1.2) and in alkaline (pH = 7.4) buffers in a thermostatic bath at 37 °C. Drug release from the two prodrugs was studied by incubating each of them with 10% w/v cecal and colonic content of rats. Obtained results showed that both prodrugs were adequately stable in acid environment, while the succinyl conjugate was more stable than the glutaryl one in alkaline buffer. Both the prodrugs released the drug in cecal and colonic content, showing that the two systems could serve as colon specific delivery systems of metronidazole. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Oral metronidazole vs. Metrogel Vaginal for treating bacterial vaginosis. Cost-effectiveness evaluation.

PubMed

Ransom, S B; McComish, J F; Greenberg, R; Tolford, D A

1999-04-01

To compare the cost-effectiveness of metronidazole versus Metrogel Vaginal in the treatment of bacterial vaginosis. Sixty consecutive patients with a clinical diagnosis of bacterial vaginosis were randomly assigned prospectively into either the metronidazole, 500 mg (twice daily for seven days by mouth) or Metrogel Vaginal (one applicator twice daily for five days) treatment group. The study patients were aged 18-30 years, without other medical problems. The patients proceeded with outpatient therapy and returned 7-10 days after the completion of treatment for reevaluation. During the study, patients refrained from sexual relations, avoided alcohol and drugs, and avoided all medication. The physician evaluated the patients for bacterial vaginosis through standard wet preparation, whiff test and pH testing prior to and after treatment. The patients were randomized by a nurse and were blinded for study purposes to the evaluating physician. Successful treatment outcomes for bacterial vaginosis occurred in 27 and 28 patients for Metrogel Vaginal and metronidazole, respectively, out of the original 30 patients in each study group. All patients introduced into the study completed the study without difficulty. No significant complications were found in either treatment group. Three patients treated with metronidazole experienced nausea during the treatment interval. The entire cost of treatment was $19.71 and $1.51 for Metrogel Vaginal and metronidazole, respectively. The most cost-effective treatment for bacterial vaginosis was generic metronidazole. While the use of the more expensive Metrogel Vaginal may be reasonable for patients experiencing side effects of oral metronidazole, most patients should be treated with the less expensive generic metronidazole.

Studies on strain sensitivity of Trichomonas vaginalis to metronidazole.

PubMed Central

Meingassner, J G; Havelec, L; Mieth, H

1978-01-01

Ninety-four strains of Trichomonas vaginalis isolated from unselected patients in Vienna during the period from November 1975 to November 1975 were subjected to sensitivity tests against metronidazole in vitro and in vivo. Nearly 90% of the isolates examined showed in vitro growth inhibition at concentrations of 0.4 to 1.6 microgram metronidazole/ml and only about 10% at concentrations of less than 0.4 microgram/ml. All isolates showed some inhibition of growth after incubation for 48 hours with 3.2 microgram metroidazole/ml. Tests on treatment carried out on experimentally infected mice revealed that all strains of T. vaginalis examined were sensitive to metronidazole (MDE: less than 3 x 35 mg/kg peroral). PMID:305807

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

PubMed Central

Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas

2015-01-01

The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions. PMID:26073995

Pharmacodynamic studies of vancomycin, metronidazole and fusidic acid against Clostridium difficile.

PubMed

Odenholt, Inga; Walder, Mats; Wullt, Marlene

2007-01-01

Pharmacodynamic studies of antibiotics have attracted great interest in recent years. However, studies on the pharmacodynamics of different antibiotics against Clostridium difficile are scarce. The postantibiotic effects (PAE) and the postantibiotic sub-minimum inhibitory concentration (MIC) effects (PA SME) of vancomycin, metronidazole and fusidic acid were investigated by viable counts against three different strains of C. difficile. The killing rate and extent of the three antibiotics against the same strains were also studied by adding 2, 4, 8, 16 and 32x MIC of the three antibiotics, respectively. Metronidazole exerted a very rapid bactericidal effect at concentrations of 8x MIC and above against all three strains investigated. Vancomycin gave overall less kill in comparison to metronidazole and was bacteriostatic against two of the three strains. Fusidic acid exerted a concentration-dependent killing against two of the strains. Vancomycin exerted short PAEs and PA SMEs against all three strains. Significantly longer PAEs and PA SMEs were noted for fusidic acid. Metronidazole gave similar short PAEs like vancomycin but longer PA SMEs were noted against two of the investigated strains. Metronidazole exerted the most prominent bactericidal effect greater than fusidic acid and greater than vancomycin. Fusidic acid gave overall the longest PAEs and PA SMEs greater than metronidazole and greater than vancomycin. Copyright 2007 S. Karger AG, Basel.

Electrochemical Determination of Metronidazole in Tablet Samples Using Carbon Paste Electrode

PubMed Central

Nikodimos, Yosef

2016-01-01

Cyclic voltammetric investigation of metronidazole at carbon paste electrode revealed an irreversible reduction peak centered at about −0.4 V. Observed peak potential shift with pH in the range 2.0 to 8.5 indicated the involvement of protons during the reduction of metronidazole, whereas the peak potential shift with scan rate in the range 10–250 mV/s confirmed the irreversibility of the reduction reaction. A better correlation coefficient for the dependence of peak current on the scan rate than on the square root of scan rate indicated an adsorption controlled kinetics. Under the optimized method and solution parameters, an excellent linearity between the reductive peak current and the concentration of metronidazole was observed in the concentration range 1.0 × 10−6 to 5.0 × 10−4 M with a correlation coefficient, method detection limit (based on s = 3σ), and limit of quantification of 0.999, 2.97 × 10−7 M and 9.91 × 10−7 M, respectively. Good recovery results for spiked metronidazole in tablet samples and selective determination of metronidazole in tablet formulations in the presence of selected potential interferents such as rabeprazole, omeprazole, and tinidazole confirmed the potential applicability of the developed method for the determination of metronidazole in real samples like pharmaceutical tablets. PMID:27119041

Antibiotic prophylaxis for hysterectomy, a prospective cohort study: cefuroxime, metronidazole, or both?

PubMed

Brummer, T H I; Heikkinen, A-M; Jalkanen, J; Fraser, J; Mäkinen, J; Tomás, E; Seppälä, T; Sjöberg, J; Härkki, P

2013-09-01

To evaluate cefuroxime and metronidazole antibiotic prophylaxis. Observational nonrandomised 1-year prospective cohort study. Fifty-three hospitals in Finland. A total of 5279 women undergoing hysterectomy for benign indications, with cefuroxime given to 4301 and metronidazole given to 2855. Excluding other antibiotics, cefuroxime alone was given to 2019, metronidazole alone was given to 518, and they were administered in combination to 2252 women. Data on 1115 abdominal hysterectomies (AHs), 1541 laparoscopic hysterectomies (LHs), and 2133 vaginal hysterectomies (VHs) were analysed using logistic regression adjusted for confounding factors. Postoperative infections. Cefuroxime had a risk-reductive effect for total infections (adjusted odds ratio, OR, 0.29; 95% confidence interval, 95% CI, 0.22-0.39), but the independent effect of metronidazole and the interaction effect of cefuroxime and metronidazole were nonsignificant. In subgroup analyses of AHs, LHs, and VHs involving those receiving the two main antibiotics only, the effect of cefuroxime alone nonsignificantly differed from that of cefuroxime and metronidazole in combination for all types of infection. The absence of cefuroxime, assessed by comparing metronidazole alone with cefuroxime and metronidazole in combination, led to an increased risk for total infections in AHs (adjusted OR 3.63; 95% CI 1.99-6.65), in LHs (OR 3.53; 95% CI 1.74-7.18), and in VHs (OR 4.05; 95% CI 2.30-7.13), and also increased risks for febrile events in all categories (AHs, OR 2.86; 95% CI 1.09-7.46; LHs, OR 13.19; 95% CI 3.66-47.49; VHs, OR 12.74; 95% CI 3.01-53.95), wound infections in AHs (OR 6.88; 95% CI 1.09-7.49), and pelvic infections in VHs (OR 4.26; 95% CI 1.76-10.31). In this study, cefuroxime appeared to be effective in prophylaxis against infections. Metronidazole appeared to be ineffective, with no additional risk-reductive effect when combined with cefuroxime. © 2013 RCOG.

Association of Metronidazole with Cancer: A Potential Risk Factor or Inconsistent Deductions?

PubMed

Adil, Muhammad; Iqbal, Waheed; Adnan, Fazal; Wazir, Shabnam; Khan, Imran; Khayam, Mohammad Umar; Kamal, Mohammad Amjad; Ahmad, Shafiq; Ahmad, Jawad; Khan, Ishaq N

2018-03-29

Metronidazole is a synthetic derivative of nitroimidazole that has been widely used for the treatment of several bacterial and protozoal parasitic infections including trichomoniasis, amoebiasis, giardiasis, liver abscess, acute ulcerative gingivitis, syphilis and tropical phagedena. In addition to its toxicity in the gastrointestinal tract and central/peripheral nervous system, metronidazole has been reported to cause mucosal imbalance by affecting the expression of mucin (Muc2 gene), which is responsible to form an insoluble mucous barrier that protects the gut lumen from microbial colonization. Since metronidazole is a nitro-group containing compound and used significantly for therapeutic purposes, scientists evaluated its carcinogenicity in different preclinical in-vitro and in-vivo studies. In addition to the preclinical in-vitro validation of DNA damage, metronidazole has been reported to induce cancer in the variety of animal models including lung cancer, malignant lymphomas, breast cancer, hepatocellular carcinoma, pituitary tumors, testicular neoplasms and uterine cancer. Several retrospective cohort studies have reported metronidazole as a potential risk factor for lung cancer (n = 771), cervical cancer (n = 2500), breast cancer (n = 2), cholangiocarcinoma (n = 1), and neuroblastoma (n = 28). So far, all the reported data have confirmed metronidazole carcinogenicity in animals; however, it is still controversial in humans. Based on previous observations, the oxidative metabolites from metronidazole metabolism are shown to have more carcinogenic effects than the parent drug itself. Since ~40% of drug metabolism is reliant on cytochromes, the inter-patient' differences in metronidazole metabolism potentially indicate the individual susceptibility to developing cancer. Due to these potent carcinogenic behaviors, use of metronidazole for animals treatment and its uses in animal food products are barred in the USA and European countries; however, its clinical

Rifaximin therapy for metronidazole-unresponsive Clostridium difficile infection: a prospective pilot trial

PubMed Central

Patrick Basu, P.; Dinani, Amreen; Rayapudi, Krishna; Pacana, Tommy; Shah, Niraj James; Hampole, Hemant; Krishnaswamy, N. V.; Mohan, Vinod

2010-01-01

Background: Clostridium difficile infection (CDI) is a recent epidemic in the United States, particularly in the hospital setting. Oral metronidazole is standard therapy for C. difficile infection, but resistance to metronidazole is becoming a clinical challenge. Methods: We evaluated the efficacy of the nonsystemic oral antibiotic rifaximin for the treatment of metronidazole-resistant C. difficile infection. Twenty-five patients with C. difficile infection were enrolled in the study. All had mild-to-moderate C. difficile infection (5–10 bowel movements a day without sepsis) unresponsive to metronidazole (i.e. stools positive for toxins A and B after oral metronidazole 500 mg three times daily [t.i.d.] for 5 days). After discontinuation of metronidazole, rifaximin 400 mg t.i.d. for 14 days was prescribed. Patients were followed for 56 days and stool was tested for C. difficile using polymerase chain reaction (PCR) to assess the effect of treatment. A negative PCR test result was interpreted as a favorable response to rifaximin. Results: Sixteen of 22 patients (73%) were eligible for study inclusion and completed rifaximin therapy experienced eradication of infection (stool negative for C. difficile) immediately after rifaximin therapy and 56 days post-treatment. Three patients (12%) discontinued therapy because of abdominal distention. Rifaximin was generally well tolerated. Conclusions: In conclusion, rifaximin may be considered for treatment of mild-to-moderate C. difficile infection that is resistant to metronidazole. Larger randomized trials are needed to confirm these positive findings. PMID:21180604

Rifaximin therapy for metronidazole-unresponsive Clostridium difficile infection: a prospective pilot trial.

PubMed

Patrick Basu, P; Dinani, Amreen; Rayapudi, Krishna; Pacana, Tommy; Shah, Niraj James; Hampole, Hemant; Krishnaswamy, N V; Mohan, Vinod

2010-07-01

Clostridium difficile infection (CDI) is a recent epidemic in the United States, particularly in the hospital setting. Oral metronidazole is standard therapy for C. difficile infection, but resistance to metronidazole is becoming a clinical challenge. We evaluated the efficacy of the nonsystemic oral antibiotic rifaximin for the treatment of metronidazole-resistant C. difficile infection. Twenty-five patients with C. difficile infection were enrolled in the study. All had mild-to-moderate C. difficile infection (5-10 bowel movements a day without sepsis) unresponsive to metronidazole (i.e. stools positive for toxins A and B after oral metronidazole 500 mg three times daily [t.i.d.] for 5 days). After discontinuation of metronidazole, rifaximin 400 mg t.i.d. for 14 days was prescribed. Patients were followed for 56 days and stool was tested for C. difficile using polymerase chain reaction (PCR) to assess the effect of treatment. A negative PCR test result was interpreted as a favorable response to rifaximin. Sixteen of 22 patients (73%) were eligible for study inclusion and completed rifaximin therapy experienced eradication of infection (stool negative for C. difficile) immediately after rifaximin therapy and 56 days post-treatment. Three patients (12%) discontinued therapy because of abdominal distention. Rifaximin was generally well tolerated. In conclusion, rifaximin may be considered for treatment of mild-to-moderate C. difficile infection that is resistant to metronidazole. Larger randomized trials are needed to confirm these positive findings.

High-dose intravenously administered iron versus orally administered iron in blood donors with iron deficiency: study protocol for a randomised, controlled trial.

PubMed

Macher, Susanne; Drexler, Camilla; Lindenau, Ines; Sareban, Nazanin; Schlenke, Peter; Amrein, Karin

2016-10-28

About 2-3 % of the population participates in blood donation programmes. Each whole blood donation or ten apheresis donations cause a loss of 200-250 mg of iron. As a result, one of the most common risks of regular blood donors is iron deficiency. Although this has been known for decades, in most countries, iron status is currently not assessed or treated in this population. Premenopausal women are particularly affected, as they have lower iron reserves and higher daily requirements. Besides anaemia, iron deficiency may lead to fatigue and impaired cognitive and physical performance. Current iron preparations for intravenous administration are well tolerated and allow for application of large doses up to 1 g in one visit. Our hypothesis is that in blood donors with iron deficiency, intravenously administered iron is more efficient and as safe as oral iron supplementation. Since anaemia is one of the most frequent reasons for permanent or intermittent donor deferral, maintaining an iron-replete donor pool may help to prevent shortages in blood supply and to avoid iron deficiency-related comorbidities. In this randomised clinical trial we include male and female blood donors aged ≥18 and ≤65 years with a ferritin value of ≤30 ng/ml. Stratified by gender, participants are randomized with a web-based randomisation tool in a 1:1 ratio to either 1 g of intravenously administered ferric carboxymaltose or 10 g of iron fumarate supplements at one to two daily doses of 100 mg each. Eight to 12 weeks after the first visit, iron status, blood count and symptoms are assessed in both groups. The primary endpoint is the difference in transferrin saturation (%) following the intervention between both groups. Secondary endpoints include other parameters of iron metabolism and red blood cell count, the number of patients with drug-related adverse events, and subjective symptoms including those of the restless legs syndrome, quality of life, and fatigue. Iron

Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID: a new mechanism.

PubMed

Leite, A Z; Sipahi, A M; Damião, A O; Coelho, A M; Garcez, A T; Machado, M C; Buchpiguel, C A; Lopasso, F P; Lordello, M L; Agostinho, C L; Laudanna, A A

2001-02-01

The pathogenesis of non-steroidal anti-inflammatory drug (NSAID) enteropathy is complex. It involves uncoupling of mitochondrial oxidative phosphorylation which alters the intercellular junction and increases intestinal permeability with consequent intestinal damage. Metronidazole diminishes the inflammation induced by indomethacin but the mechanisms remain speculative. A direct effect on luminal bacteria has traditionally been thought to account for the protective effect of metronidazole. However, a protective effect of metronidazole on mitochondrial oxidative phosphorylation has never been tested. To assess the protective effect of metronidazole on mitochondrial uncoupling induced by indomethacin and also on the increased intestinal permeability and macroscopic damage. The protective effect of metronidazole was evaluated in rats given indomethacin; a macroscopic score was devised to quantify intestinal lesions, and intestinal permeability was measured by means of (51)Cr-ethylenediaminetetraacetic acid. The protective effect of metronidazole against mitochondrial uncoupling induced by indomethacin was assessed using isolated coupled rat liver mitochondria obtained from rats pretreated with metronidazole or saline. Metronidazole significantly reduced the macroscopic intestinal damage and increase in intestinal permeability induced by indomethacin; furthermore, at the mitochondrial level, it significantly reduced the increase in oxygen consumption in state 4 induced by indomethacin and caused less reduction of the respiratory control rate. Our study confirmed the beneficial effects of metronidazole on intestinal damage and intestinal permeability, and demonstrated, for the first time, a direct protective effect of metronidazole on uncoupling of mitochondrial oxidative phosphorylation caused by NSAIDs.

Pharmaceutical Wastewater Effluent—Source of Contaminants of Emerging Concern: Phytotoxicity of Metronidazole to Soybean (Glycine max)

PubMed Central

Yakubu, Okhumode H.

2017-01-01

Industrial discharge of active pharmaceutical ingredients (APIs) into the environment in some middle- and low-income countries is not sufficiently regulated. The phytotoxicity of metronidazole (FLAGYL)—one of the most commonly used over the counter (OTC) antibiotics, to soybean (Glycine max) is investigated. Relative growth rate (RGR) expressed in gram per gram per day (gg−1d−1) was applied to plants destructively harvested at maturity (42 d), to determine the toxicological impact. Differences between mean RGR of the three groups were performed at 0.05 significance level. Multiple comparisons suggest that there was a statistical significant difference among mean RGR for all treatment groups. Metronidazole is toxic to soybean plants (Glycine max) based on dose-response criterion. There is a need to enforce treatment of pharmaceutical wastewater effluent by Pharmaceutical Manufacturing Companies (PMCs) before discharge into the environment. PMID:29051442

High-Dose Vitamin C Injection to Cancer Patients May Promote Thrombosis Through Procoagulant Activation of Erythrocytes.

PubMed

Kim, Keunyoung; Bae, Ok-Nam; Koh, Sung-Hee; Kang, Seojin; Lim, Kyung-Min; Noh, Ji-Yoon; Shin, Sue; Kim, Inho; Chung, Jin-Ho

2015-10-01

Potential risk of high-dose vitamin C consumption is often ignored. Recently, gram-dose vitamin C is being intravenously injected for the treatment of cancer, which can expose circulating blood cells to extremely high concentrations of vitamin C. As well as platelets, red blood cells (RBCs) can actively participate in thrombosis through procoagulant activation. Here, we examined the procoagulant and prothrombotic risks associated with the intravenous injection of gram-dose vitamin C. Vitamin C (0.5-5 mM) increased procoagulant activity of freshly isolated human RBCs via the externalization of phosphatidylserine (PS) to outer cellular membrane and the formation of PS-bearing microvesicles. PS exposure was induced by the dysregulation of key enzymes for the maintenance of membrane phospholipid asymmetry, which was from vitamin C-induced oxidative stress, and resultant disruption of calcium and thiol homeostasis. Indeed, the intravenous injection of vitamin C (0.5-1.0 g/kg) in rats in vivo significantly increased thrombosis. Notably, the prothrombotic effects of vitamin C were more prominent in RBCs isolated from cancer patients, who are at increased risks of thrombotic events. Vitamin C-induced procoagulant and prothrombotic activation of RBCs, and increased thrombosis in vivo. RBCs from cancer patients exhibited increased sensitivity to the prothrombotic effects of vitamin C, reflecting that intravenous gram-dose vitamin C therapy needs to be carefully revisited. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

78 FR 19271 - Draft Guidance for Industry on Bioequivalence Recommendations for Metronidazole Vaginal Gel...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-29

... Metronidazole Vaginal Gel; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The... entitled ``Bioequivalence Recommendations for Metronidazole Vaginal Gel.'' The guidance provides specific...) for metronidazole vaginal gel. DATES: Although you can comment on any guidance at any time (see 21 CFR...

Immediate hypersensitivity to iodinated contrast media: diagnostic accuracy of skin tests and intravenous provocation test with low dose.

PubMed

Sesé, L; Gaouar, H; Autegarden, J-E; Alari, A; Amsler, E; Vial-Dupuy, A; Pecquet, C; Francès, C; Soria, A

2016-03-01

The diagnosis of HSR to iodinated contrast media (ICM) is challenging based on clinical history and skin tests. This study evaluates the negative predictive value (NPV) of skin tests and intravenous provocation test (IPT) with low-dose ICM in patients with suspected immediate hypersensitivity reaction (HSR) to ICM. Thirty-seven patients with suspected immediate hypersensitivity reaction to ICM were included retrospectively. Skin tests and a single-blind placebo-controlled intravenous provocation test (IPT) with low-dose iodinated contrast media (ICM) were performed. Skin tests with ICM were positive in five cases (one skin prick test and five intradermal test). Thirty-six patients were challenged successfully by IPT, and only one patient had a positive challenge result, with a grade I reaction by the Ring and Messmer classification. Ten of 23 patients followed up by telephone were re-exposed to a negative tested ICM during radiologic examination; two experienced a grade I immediate reaction. For immediate hypersensitivity reaction to ICM, the NPV for skin tests and IPT with low dose was 80% (95% CI 44-97%). © 2016 John Wiley & Sons Ltd.

Pharmacokinetics, Safety, and Tolerability of a Single 500-mg or 1000-mg Intravenous Dose of Dalbavancin in Healthy Japanese Subjects.

PubMed

Scoble, Patrick J; Owens, Robert C; Puttagunta, Sailaja; Yen, Mark; Dunne, Michael W

2015-12-01

Dalbavancin is a novel, once-weekly glycopeptide antibiotic approved for treatment of acute bacterial skin infections. Given the importance of understanding any pharmacokinetic variability across different patient populations, a double-blind, placebo-controlled study was conducted to evaluate the pharmacokinetics, safety, and tolerability of a single 500-mg and a single 1000-mg intravenous dose of dalbavancin in healthy Japanese subjects. Ten subjects received intravenous dalbavancin 1000 mg, five subjects received intravenous dalbavancin 500 mg, and three subjects received intravenous placebo. After a single infusion of dalbavancin, the maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC) increased in a proportional manner from 500 mg to 1000 mg (C max: 157 μg/ml and 299 μg/ml; AUClast: 10,850 μg·h/ml and 22,679 μg·h/ml, on the 500-mg and 1000-mg regimens, respectively) with low inter-subject variability. The mean terminal phase half-life (t 1/2) was 204 and 193 h after the 500-mg and 1000-mg dose, respectively. Clearance and volume of distribution were similar for the two dose concentrations. Treatment-emergent adverse events reported were considered to be of mild intensity. There were no relevant changes in laboratory values or vital signs over time in subjects in either treatment group. Overall, dalbavancin 500 mg and dalbavancin 1000 mg, administered as a single 30-min infusion, was well tolerated in this population and resulted in plasma exposures similar to those in non-Asians.

[Investigation of in vitro metronidazole resistance in the clinical isolates of Trichomonas vaginalis].

PubMed

Ertabaklar, Hatice; Yaman Karadam, Senem; Malatyalı, Erdoğan; Ertuğ, Sema

2016-10-01

Trichomonas vaginalis, a flagellated, urogenital anaerobic protozoon is reported as an important cause of vaginitis with a global distribution. Although metronidazole is the primary choice of drug for the treatment of trichomoniasis, the presence of resistant isolates from many different countries highlights the need of novel drugs for the treatment. Many studies from Turkey mostly dealing with the in vitro effects of compounds and natural products against T.vaginalis have been reported, however, only one study has been encountered searching the metronidazole resistance in a single T.vaginalis isolate. The aim of this study was to determine the in vitro metronidazole resistance and minimum lethal concentrations (MLCs) of the isolates from symptomatic cases. T.vaginalis strains isolated from vaginal discharge samples of symptomatic women that were sent to Adnan Menderes University Faculty of Medicine, Research and Training Hospital Parasitology Laboratory, between 2009-2014 period, were included in the study. The strains were isolated by the inoculation of samples into trypticase-yeast-maltose medium supplemented with 10% fetal calf serum. A total of 40 T.vaginalis isolates stored by cryopreservation were revived before the experiments. T.vaginalis trophozoites were incubated with different concentrations of metronidazole (200, 100, 50, 25, 12.5, 6.25, 3.12, 1.56 μg/ml) and the viability of cells were examined in both aerobic and anaerobic conditions under phase contrast microscope. Additionally, non-motile isolates were further inoculated into fresh media and viability was checked. The wells containing motile trophozoites after 48 hours of incubation with 15 µg/ml and/or higher metronidazole concentration in anaerobic condition and 75 µg/ml and/or higher metronidazole concentration in aerobic conditions were determined as resistant isolates. Of the 40 T.vaginalis isolates three (7.5%) were resistant to metronidazole. MLC mean values of metronidazole

Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial.

PubMed

Motov, Sergey; Yasavolian, Matthew; Likourezos, Antonios; Pushkar, Illya; Hossain, Rukhsana; Drapkin, Jefferson; Cohen, Victor; Filk, Nicholas; Smith, Andrew; Huang, Felix; Rockoff, Bradley; Homel, Peter; Fromm, Christian

2017-08-01

Nonsteroidal anti-inflammatory drugs are used extensively for the management of acute and chronic pain, with ketorolac tromethamine being one of the most frequently used parenteral analgesics in the emergency department (ED). The drugs may commonly be used at doses above their analgesic ceiling, offering no incremental analgesic advantage while potentially adding risk of harm. We evaluate the analgesic efficacy of 3 doses of intravenous ketorolac in ED patients with acute pain. We conducted a randomized, double-blind trial to assess the analgesic efficacy of 3 doses of intravenous ketorolac (10, 15, and 30 mg) in patients aged 18 to 65 years and presenting to the ED with moderate to severe acute pain, defined by a numeric rating scale score greater than or equal to 5. We excluded patients with peptic ulcer disease, gastrointestinal hemorrhage, renal or hepatic insufficiency, allergies to nonsteroidal anti-inflammatory drugs, pregnancy or breastfeeding, systolic blood pressure less than 90 or greater than 180 mm Hg, and pulse rate less than 50 or greater than 150 beats/min. Primary outcome was pain reduction at 30 minutes. We recorded pain scores at baseline and up to 120 minutes. Intravenous morphine 0.1 mg/kg was administered as a rescue analgesic if subjects still desired additional pain medication at 30 minutes after the study drug was administered. Data analyses included mixed-model regression and ANOVA. We enrolled 240 subjects (80 in each dose group). At 30 minutes, substantial pain reduction was demonstrated without any differences between the groups (95% confidence intervals 4.5 to 5.7 for the 10-mg group, 4.5 to 5.6 for the 15-mg group, and 4.2 to 5.4 for the 30-mg group). The mean numeric rating scale pain scores at baseline were 7.7, 7.5, and 7.8 and improved to 5.1, 5.0, and 4.8, respectively, at 30 minutes. Rates of rescue analgesia were similar, and there were no serious adverse events. Secondary outcomes showed similar rates of adverse effects per

Fracture during intravenous bisphosphonate treatment in a child with osteogenesis imperfecta: an argument for a more frequent, low-dose treatment regimen.

PubMed

Biggin, Andrew; Briody, Julie N; Ormshaw, Elizabeth; Wong, Karen K Y; Bennetts, Bruce H; Munns, Craig F

2014-01-01

Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices.

Significant Reduction of Brain Cysts Caused by Toxoplasma gondii after Treatment with Spiramycin Coadministered with Metronidazole in a Mouse Model of Chronic Toxoplasmosis

PubMed Central

Chew, Wai Kit; Ambu, Stephen; Mak, Joon Wah

2012-01-01

Toxoplasma gondii is a parasite that generates latent cysts in the brain; reactivation of these cysts may lead to fatal toxoplasmic encephalitis, for which treatment remains unsuccessful. We assessed spiramycin pharmacokinetics coadministered with metronidazole, the eradication of brain cysts and the in vitro reactivation. Male BALB/c mice were fed 1,000 tachyzoites orally to develop chronic toxoplasmosis. Four weeks later, infected mice underwent different treatments: (i) infected untreated mice (n = 9), which received vehicle only; (ii) a spiramycin-only group (n = 9), 400 mg/kg daily for 7 days; (iii) a metronidazole-only group (n = 9), 500 mg/kg daily for 7 days; and (iv) a combination group (n = 9), which received both spiramycin (400 mg/kg) and metronidazole (500 mg/kg) daily for 7 days. An uninfected control group (n = 10) was administered vehicle only. After treatment, the brain cysts were counted, brain homogenates were cultured in confluent Vero cells, and cysts and tachyzoites were counted after 1 week. Separately, pharmacokinetic profiles (plasma and brain) were assessed after a single dose of spiramycin (400 mg/kg), metronidazole (500 mg/kg), or both. Metronidazole treatment increased the brain spiramycin area under the concentration-time curve from 0 h to ∞ (AUC0–∞) by 67% without affecting its plasma disposition. Metronidazole plasma and brain AUC0–∞ values were reduced 9 and 62%, respectively, after spiramycin coadministration. Enhanced spiramycin brain exposure after coadministration reduced brain cysts 15-fold (79 ± 23 for the combination treatment versus 1,198 ± 153 for the untreated control group [P < 0.05]) and 10-fold versus the spiramycin-only group (768 ± 125). Metronidazole alone showed no effect (1,028 ± 149). Tachyzoites were absent in the brain. Spiramycin reduced in vitro reactivation. Metronidazole increased spiramycin brain penetration, causing a significant reduction of T. gondii brain cysts, with potential clinical

Metronidazole immediate release formulations: a fasting randomized open-label crossover bioequivalence study in healthy volunteers.

PubMed

de Freitas Silva, M; Schramm, S G; Kano, E K; Koono, E E M; Manfio, J L; Porta, V; dos Reis Serra, C H

2012-10-01

Metronidazole is a BCS (Biopharmaceutics Classification System) class 1 drug, traditionally considered the choice drug in the infections treatment caused by protozoa and anaerobic microorganisms. This study aimed to evaluate bioequivalence between 2 different marketed 250 mg metronidazole immediate release tablets. A randomized, open-label, 2×2 crossover study was performed in healthy Brazilian volunteers under fasting conditions with a 7-day washout period. The formulations were administered as single oral dose and blood was sampled over 48 h. Metronidazole plasma concentrations were determined by a liquid chromatography mass spectrometry (LC-MS/MS) method. The plasma concentration vs. time profile was generated for each volunteer and the pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC0-∞, ke, and t1/2 were calculated using a noncompartmental model. Bioequivalence between pharmaceutical formulations was determined by calculating 90% CIs (Confidence Intervall) for the ratios of Cmax, AUC0-t, and AUC0-∞ values for test and reference using log-transformed data. 22 healthy volunteers (11 men, 11 women; mean (SD) age, 28 (6.5) years [range, 21-45 years]; mean (SD) weight, 66 (9.3) kg [range, 51-81 kg]; mean (SD) height, 169 (6.5) cm [range, 156-186 cm]) were enrolled in and completed the study. The 90% CIs for Cmax (0.92-1.06), AUC0-t (0.97-1.02), and AUC0-∞ (0.97-1.03) values for the test and reference products fitted in the interval of 0.80-1.25 proposed by most regulatory agencies, including the Brazilian agency ANVISA. No clinically significant adverse effects were reported. After pharmacokinetics analysis, it concluded that test 250 mg metronidazole formulation is bioequivalent to the reference product according to the Brazilian agency requirements. © Georg Thieme Verlag KG Stuttgart · New York.

Comparative trial of two intravenous doses of granisetron (1 versus 3 mg) in the prevention of chemotherapy-induced acute emesis: a double-blind, randomized, non-inferiority trial.

PubMed

Tsuji, Daiki; Kim, Yong-Il; Taku, Keisei; Nakagaki, Shigeru; Ikematsu, Yoshito; Tsubota, Hiromi; Maeda, Masato; Hashimoto, Naoya; Kimura, Masayuki; Daimon, Takashi

2012-05-01

A single 3 mg or 40 μg/kg intravenous dose of granisetron combined with dexamethasone is routinely used in several countries, although the antiemetic guidelines have recommended granisetron at the dose of 1 mg or 10 μg/kg. A randomized, multicenter trial was conducted to determine the optimal intravenous granisetron dose, 1 or 3 mg, in cancer patients receiving emetogenic chemotherapy. We enrolled 365 patients and randomly assigned them to receive intravenous granisetron 3 mg (3-mg group) or 1 mg (1-mg group), combined with dexamethasone at an adequate dose fixed as per the emetic risk category. The primary end point was the proportion of patients with a complete response during the first 24 h after chemotherapy. The study demonstrated that 1 mg of granisetron was not inferior in effect to 3 mg. For the primary end point, 359 patients were evaluable according to the modified intention-to-treat (ITT) analysis. Complete protection was achieved in the modified ITT population, 90.6% and 88.8% for the 3- and 1-mg groups, respectively (p < 0.01 for non-inferiority). This study showed that 1 mg granisetron is not inferior to 3 mg when both doses are combined with dexamethasone. Therefore, 1-mg dose of intravenous granisetron should be the recommended prophylactic regimen for the prevention of acute emesis.

[Controlling wound odor with metronidazole: a systematic review].

PubMed

Castro, Diana Lima Villela de; Santos, Vera Lúcia Conceição de Gouveia

2015-10-01

Verifying the evidence of therapeutic efficacy in the topical application of metronidazole for controlling wound odor. A systematic literature review, according to the Cochrane Collaboration recommendations. 329 articles were identified in the Cochrane, LILACS, SciELO, CINAHL and PubMed databases, with 14 of them being included in the final sample. Two of the studies were double-blind randomized clinical trial studies. The actual effectiveness of metronidazole in controlling wound odor cannot yet be evidenced due to the absence of strong evidence from studies on the subject, despite clinical practice recommending its benefits.

Differential Effects of Bifidobacterium pseudolongum Strain Patronus and Metronidazole in the Rat Gut▿

PubMed Central

Vasquez, Nadia; Suau, Antonia; Magne, Fabien; Pochart, Philippe; Pélissier, Marie-Agnès

2009-01-01

In the luminal contents of metronidazole-treated rats, there was a dominant Bifidobacterium species. A strain has been isolated, its 16S rRNA gene has been sequenced, and the strain has been named Bifidobacterium pseudolongum strain Patronus. In this study, using an experimental model of healthy rats, the effects of metronidazole treatment and B. pseudolongum strain Patronus administration on the luminal and mucosa-associated microbiota and on gut oxidation processes were investigated. Metronidazole treatment and the daily gavage of rats with B. pseudolongum strain Patronus increased the numbers of bifidobacteria in cecal contents and in cecal mucosa-associated microbiota compared with those in control rats. Metronidazole reduced the colonic oxidative damage to proteins. This is the first evidence that B. pseudolongum strain Patronus exerts an effect on a biomarker of oxidative damage by reducing the susceptibility to oxidation of proteins in the colon and the small bowel. Antioxidant effects of metronidazole could be linked to the bifidobacterial increase but also to other bacterial modifications. PMID:19028910

A novel metronidazole fluorescent nanosensor based on graphene quantum dots embedded silica molecularly imprinted polymer.

PubMed

Mehrzad-Samarin, Mina; Faridbod, Farnoush; Dezfuli, Amin Shiralizadeh; Ganjali, Mohammad Reza

2017-06-15

A novel optical nanosensor for detection of Metronidazole in biological samples was reported. Graphene quantum dots embedded silica molecular imprinted polymer (GQDs-embedded SMIP) was synthesized and used as a selective fluorescent probe for Metronidazole detection. The new synthesized GQDs-embedded SMIP showed strong fluorescent emission at 450nm excited at 365nm which quenched in presence of Metronidazole as a template molecule.. The quenching was proportional to the concentration of Metronidazole in a linear range of at least 0.2μM to 15μM. The limit of detection for metronidazole determination was obtained 0.15μM. The nanosensor successfully worked in plasma matrixes. Copyright © 2016 Elsevier B.V. All rights reserved.

The effect of iron on metronidazole activity against Trichomonas vaginalis in vitro.

PubMed

Elwakil, Hala Salah; Tawfik, Rania Ayman; Alam-Eldin, Yosra Hussein; Nassar, Doaa Ashraf

2017-11-01

Metronidazole is administered in an inactive form then activated to its cytotoxic form within the hydrogenosome of trichomonads. Two hydrogenosomal proteins, pyruvate ferredoxin oxidoreductase (PFOR) and ferredoxin, play a critical role in the reductive activation of metronidazole. The expression of these proteins and other hydrogenosomal proteins are likewise positively regulated by iron. In the present study, the effect of iron on minimal lethal concentration (MLC) of metronidazole on in vitro cultured Trichomonas vaginalis(T. vaginalis) isolates was investigated. Interestingly, Addition of Ferrous ammonium sulphate (FAS) to T. vaginalis culture led to decrease in the MLC of metronidazole. On using aerobic assay, MLC of metronidazole on untreated T. vaginalis of both isolates was 12.5 μg/ml that decreased to 0.38 μg/ml on FAS treated trichomonads. Also anaerobic assay revealed that MLC on untreated parasites was 3.12 μg/ml that decreased to 0.097 μg/ml and 0.19 μg/ml for isolate 1 and isolate 2 respectively after iron addition. It was concluded that, addition of iron to in vitro cultured T. vaginalis decreases metronidazole MLC that was detected by both aerobic and anaerobic assays. Copyright © 2017 Elsevier Inc. All rights reserved.

Investigation of Metronidazole Use during Pregnancy and Adverse Birth Outcomes

PubMed Central

Koss, Catherine A.; Baras, Dana C.; Lane, Sandra D.; Aubry, Richard; Marcus, Michele; Markowitz, Lauri E.

2012-01-01

To assess whether treatment with metronidazole during pregnancy is associated with preterm birth, low birth weight, or major congenital anomalies, we conducted chart reviews and an analysis of electronic data from a cohort of women delivering at an urban New York State hospital. Of 2,829 singleton/mother pairs, 922 (32.6%) mothers were treated with metronidazole for clinical indications, 348 (12.3%) during the first trimester of pregnancy and 553 (19.5%) in the second or third trimester. There were 333 (11.8%) preterm births, 262 (9.3%) infants of low birth weight, and 52 infants (1.8%) with congenital anomalies. In multivariable analysis, no association was found between metronidazole treatment and preterm birth (odds ratio [OR], 1.02 [95% confidence interval [CI], 0.80 to 1.32]), low birth weight (OR, 1.05 [95% CI, 0.77 to 1.43]), or treatment in the first trimester and congenital anomalies (OR, 0.86 [0.30 to 2.45]). We found no association between metronidazole treatment during the first or later trimesters of pregnancy and preterm birth, low birth weight, or congenital anomalies. PMID:22751543

Pharmacokinetics of colistin methanesulfonate (CMS) in healthy Chinese subjects after single and multiple intravenous doses.

PubMed

Zhao, Miao; Wu, Xiao-Jie; Fan, Ya-Xin; Zhang, Ying-Yuan; Guo, Bei-Ning; Yu, Ji-Cheng; Cao, Guo-Ying; Chen, Yuan-Cheng; Wu, Ju-Fang; Shi, Yao-Guo; Li, Jian; Zhang, Jing

2018-05-01

The high prevalence of extensively drug-resistant Gram-negative pathogens has forced clinicians to use colistin as a last-line therapy. Knowledge on the pharmacokinetics of colistin methanesulfonate (CMS), an inactive prodrug, and colistin has increased substantially; however, the pharmacokinetics in the Chinese population is still unknown due to lack of a CMS product in China. This study aimed to evaluate the pharmacokinetics of a new CMS product developed in China in order to optimise dosing regimens. A total of 24 healthy subjects (12 female, 12 male) were enrolled in single- and multiple-dose pharmacokinetic (PK) studies. Concentrations of CMS and formed colistin in plasma and urine were measured, and PK analysis was conducted using a non-compartmental approach. Following a single CMS dose [2.36 mg colistin base activity (CBA) per kg, 1 h infusion], peak concentrations (C max ) of CMS and formed colistin were 18.0 mg/L and 0.661 mg/L, respectively. The estimated half-life (t 1/2 ) of CMS and colistin were 1.38 h and 4.49 h, respectively. Approximately 62.5% of the CMS dose was excreted via urine within 24 h after dosing, whilst only 1.28% was present in the form of colistin. Following multiple CMS doses, colistin reached steady-state within 24 h; there was no accumulation of CMS, but colistin accumulated slightly (R AUC  = 1.33). This study provides the first PK data in the Chinese population and is essential for designing CMS dosing regimens for use in Chinese hospitals. The urinary PK data strongly support the use of intravenous CMS for serious urinary tract infections. Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

[Efficacy of intravenous phenobarbital treatment for status epilepticus].

PubMed

Muramoto, Emiko; Mizobuchi, Masahiro; Sumi, Yoshihiro; Sako, Kazuya; Nihira, Atsuko; Takeuchi, Akiko; Nakamura, Hirohiko

2013-08-01

Intravenous phenobarbital (IV-PB) therapy was launched in Japan in October 2008. We retrospectively investigated its efficacy and tolerability in patients with status epilepticus. Forty-three consecutive patients received IV-PB for status epilepticus between June 2009 and April 2011. Among them, 39 patients had underlying diseases, which included acute diseases in 19 patients and chronic conditions in 20 patients. Although 18 patients had been taking antiepileptic drugs (AEDs) before the occurrence of status epilepticus, the blood AED concentrations in 8 patients was below the therapeutic levels. Before the administration of IV-PB, 39 patients were treated with intravenous benzodiazepine, 17 patients were treated with intravenous phenytoin, and 15 patients with intravenous infusion of lidocaine. The initial doses of IV-PB ranged from 125 to 1,250 mg (1.9-20.0 mg/kg). Additional doses of IV-PB were required in 12 patients. Seizures were controlled in 35 patients (81%) after IV-PB administration. Cessation of status epilepticus was attained in 24 patients after the initial dose and in 11 patients after additional doses. There were no serious adverse effects, although respiratory suppression was observed in 3 patients and drug eruption was observed in 1 patient. IV-PB is relatively safe and effective for controlling status epilepticus. If the first dose is not effective, additional doses are required up to the recommended maximum dose.

Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.

PubMed

Rosario, Maria; Wyant, Timothy; Leach, Timothy; Sankoh, Serap; Scholz, Catherine; Parikh, Asit; Fox, Irving; Feagan, Brian G

2016-11-01

Vedolizumab, a humanized monoclonal antibody against the α 4 β 7 integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers. Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α 4 β 7 saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored. Vedolizumab maximum observed serum concentration (C max ) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC 0-inf ) and shorter terminal elimination half-life (t 1/2 ) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α 4 β 7 was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent. Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α 4 β 7 saturation was observed at all doses. A single intravenous infusion of vedolizumab

Topical metronidazole can reduce pain after surgery and pain on defecation in postoperative hemorrhoidectomy.

PubMed

Ala, Shahram; Saeedi, Majid; Eshghi, Fariborz; Mirzabeygi, Parastou

2008-02-01

Topical metronidazole (10 percent) has been previously demonstrated to decrease postoperative pain after hemorrhoidectomy. The aim of this study was to evaluate the effect of topical metronidazole (10 percent) in reducing postoperative and after-defecation pain of hemorrhoidectomy. A double-blind, randomized trial was conducted to compare posthemorrhoidectomy pain with use of topical metronidazole (10 percent) vs. placebo carrier, applied to surgical site. Forty-seven patients were randomly allocated to receive metronidazole (n=25) or placebo (n=22). Pain was assessed using a visual analog scale preoperatively and on postoperative hours 6 and 12 and at days 1, 2, 7, and 14. The use of narcotic, additional analgesics, and complications were recorded. (Pain scores were calculated and compared with baseline values and control group (t test, SPSS ver.10). Patients in the topical metronidazole group had significantly less postoperative pain than those in the placebo group up to day 14 (P metronidazole group, after-defecation pain was ranked significantly lower at day 2 (P=0.016) and patients required fewer additional analgesics postoperatively on days 2 and 7 (P metronidazole significantly reduce posthemorrhoidectomy discomfort, and postoperative defecation pain is reduced compared with that of the placebo control group.

Failure of mebendazole to cure trichomonal vaginitis resistant to metronidazole: case reports.

PubMed Central

Pattman, R S; Sprott, M S; Kearns, A M; Earnshaw, M

1989-01-01

After a recent report showing the in vitro susceptibility to mebendazole of a strain of Trichomonas vaginalis that was resistant to metronidazole, we present two cases of metronidazole resistant infection, both of which failed to respond to oral mebendazole. PMID:2807288

Bioavailability of metronidazole in rabbits after administration of a rectal suppository.

PubMed

Ofoefule, Sabinus I; Ibezim, Emmanuel C; Esimone, Okechukwu C; Pepple, Miriam N; Njoku, Chinedu N; Orisakwe, Ebere O

2004-01-01

The bioavailability of metronidazole in rabbits was studied using plasma concentration measurements after the administration of the drug in a hydrophilic (glycerogelatin) suppository form. The peak in the plasma concentration time curve occurred about 1 hour after administration, indicating that the rate of absorption is fast and equivalent to that observed in humans after oral administration. There was rapid elimination of the drug, as indicated by a relatively high elimination rate constant and low plasma half-life. The in vitro dissolution profile of the suppositories further confirms rapid absorption of the drug from the suppositories in the rectum. The presence of Tween 80 enhanced the in vitro release of metronidazole, but the presence of a hydrogenated vegetable oil lubricant (Lubritab) caused retardation in the drug release from the suppositories.

Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection

PubMed Central

Cherian, Philip T.; Wu, Xiaoqian; Yang, Lei; Scarborough, Jerrod S.; Singh, Aman P.; Alam, Zahidul A.; Lee, Richard E.; Hurdle, Julian G.

2015-01-01

Objectives Metronidazole, a mainstay treatment for Clostridium difficile infection (CDI), is often ineffective for severe CDI. Whilst this is thought to arise from suboptimal levels of metronidazole in the colon due to rapid absorption, empirical validation is lacking. In contrast, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal tract. In this study, we modified metronidazole with reutericyclin's tetramic acid motif to obtain non-absorbed compounds, enabling assessment of the impact of pharmacokinetics on treatment outcomes. Methods A series of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in terms of anti-C. difficile activities, gastric permeability, in vivo pharmacokinetics, efficacy in the hamster model of CDI and mode of action. Results Most compounds were absorbed less than metronidazole in cell-based Caco-2 permeability assays. In hamsters, lead compounds compartmentalized in the colon rather than the bloodstream with negligible levels detected in the blood, in direct contrast with metronidazole, which was rapidly absorbed into the blood and was undetectable in caecum. Accordingly, four leads were more efficacious (P < 0.05) than metronidazole in C. difficile-infected animals. Improved efficacy was not due to an alternative mode of action, as the leads retained the mode of action of metronidazole. Conclusions This study provides the clearest empirical evidence that the high absorption of metronidazole lowers treatment outcomes for CDI and suggests a role for the tetramic acid motif for colon-specific drug delivery. This approach also has the potential to lower systemic toxicity and drug interactions of nitroheterocyclic drugs for treating gastrointestine-specific diseases. PMID:26286574

Scavenging properties of metronidazole on free oxygen radicals in a skin lipid model system.

PubMed

Narayanan, Sabrina; Hünerbein, Andreas; Getie, Melkamu; Jäckel, Andreas; Neubert, Reinhard H H

2007-08-01

Reactive oxygen species (ROS) play a vital role in the pathophysiology of the skin disease rosacea, a chronic, genetically-determined and UV-triggered disease, leading to facial redness and blemishes and exhibiting a deep impact on a patient's self-esteem and quality of life. ROS can cause oxidative damage to nucleic acids, sugars, proteins and lipids, thereby contributing to adverse effects on the skin. Metronidazole has been the first-line topical agent therapy for many years; nevertheless the mechanism of action is still not well understood. The therapeutic efficacy of metronidazole has been attributed to its antioxidant effects, which can involve two pathways: decreased generation of ROS within tissues or scavenging and inactivation of existing ROS. Previous investigations have shown that metronidazole reduces ROS by decreasing ROS production in cellular in-vitro systems. The aim of the following study was to demonstrate that metronidazole additionally exhibits antioxidative properties in a cell-free system, by acting as an antioxidant scavenger. A simple skin lipid model (oxidative) system and a complex skin adapted lipid system in conjunction with thiobarbituric acid (TBA) test, a quantitative assay for the detection of malondialdehyde (MDA) and therefore lipid peroxidation, were used to determine the antioxidative properties of metronidazole after UV irradiation. Results clearly show that metronidazole has antioxidative properties in a cell-free environment, acting as a free radical scavenger. Simple skin lipid model: in the presence of 10, 100 and 500 microg mL(-1)metronidazole the MDA concentration was reduced by 25, 36 and 49%, respectively. Complex skin lipid system: in the presence of 100 and 500 microg mL(-1)metronidazole the MDA concentration was reduced by 19 and 34%, respectively. The results obtained in this study and from previous publications strongly suggest that metronidazole exhibits antioxidative effects via two mechanisms: decrease in ROS

A prospective study of risk factors and historical trends in metronidazole failure for Clostridium difficile infection

PubMed Central

Hu, Mary Y.; Maroo, Seema; Kyne, Lorraine; Cloud, Jeffrey; Tummala, Sanjeev; Katchar, Kianoosh; Dreisbach, Valley; Noddin, Laura; Kelly, Ciarán P.

2009-01-01

Background & Aims Recent studies of C. difficile infection (CDI) indicate a dramatic increase in metronidazole failure. The aims of this study were to compare current and historical rates of metronidazole failure and identify risk factors for metronidazole failure. Methods 89 patients with CDI in 2004–2006 were followed for 60 days. Data were compared to a historical cohort of 63 CDI patients studied prospectively in 1998. Metronidazole failure was defined as persistent diarrhea after 10 days of therapy or a change of therapy to vancomycin. Stool samples were analyzed for the presence of NAP-1 strain. Results Metronidazole failure rates were 35% in both the 1998 and 2004–2006 cohorts. There was no difference in the median time to resolution of diarrhea (8 vs. 5 days, p = 0.52) or the proportion with more than 10 days of diarrhea (35% vs. 29%, p = 0.51). Risk factors for metronidazole failure included recent cephalosporin use (OR 32, 95% CI 5–219), CDI on admission (OR 23, 95% CI 3–156), and transfer from another hospital (OR 11, 95% CI 2–72). The frequency of NAP-1 infection in patients with and without metronidazole failure was similar (26% vs. 21%, p = 0.67). Conclusions We found no difference in metronidazole failure rates in 1998 and 2004–2006. Patients with recent cephalosporin use, CDI on admission, and transfer from another hospital were more likely to fail metronidazole and may benefit from early aggressive therapy. Infection with the epidemic NAP-1 strain was not associated with metronidazole failure in endemic CDI. PMID:19081526

Deficiency of the ferrous iron transporter FeoAB is linked with metronidazole resistance in Bacteroides fragilis

PubMed Central

Veeranagouda, Yaligara; Husain, Fasahath; Boente, Renata; Moore, Jane; Smith, C. Jeffrey; Rocha, Edson R.; Patrick, Sheila; Wexler, Hannah M.

2014-01-01

Background Metronidazole is the most commonly used antimicrobial for Bacteroides fragilis infections and is recommended for prophylaxis of colorectal surgery. Metronidazole resistance is increasing and the mechanisms of resistance are not clear. Methods A transposon mutant library was generated in B. fragilis 638R (BF638R) to identify the genetic loci associated with resistance to metronidazole. Results Thirty-two independently isolated metronidazole-resistant mutants had a transposon insertion in BF638R_1421 that encodes the ferrous transport fusion protein (feoAB). Deletion of feoAB resulted in a 10-fold increased MIC of metronidazole for the strain. The metronidazole MIC for the feoAB mutant was similar to that for the parent strain when grown on media supplemented with excess iron, suggesting that the increase seen in the MIC of metronidazole was due to reduced cellular iron transport in the feoAB mutant. The furA gene repressed feoAB transcription in an iron-dependent manner and disruption of furA resulted in constitutive transcription of feoAB, regardless of whether or not iron was present. However, disruption of feoAB also diminished the capacity of BF638R to grow in a mouse intraperitoneal abscess model, suggesting that inorganic ferrous iron assimilation is essential for B. fragilis survival in vivo. Conclusions Selection for feoAB mutations as a result of metronidazole treatment will disable the pathogenic potential of B. fragilis and could contribute to the clinical efficacy of metronidazole. While mutations in feoAB are probably not a direct cause of clinical resistance, this study provides a key insight into intracellular metronidazole activity and the link with intracellular iron homeostasis. PMID:25028451

Metronidazole within phosphatidylcholine lipid membranes: new insights to improve the design of imidazole derivatives.

PubMed

Lopes-de-Campos, Daniela; Nunes, Cláudia; Sarmento, Bruno; Jakobtorweihen, Sven; Reis, Salette

2018-05-30

Metronidazole is a benzimidazole derivative with antibacterial and antiprotozoal activity. Despite its therapeutic efficacy, several studies have been developing new imidazole derivatives with lower toxicity. Considering that drug-membrane interactions are key factors for drugs pharmacokinetic and pharmacodynamic properties, the aim of this work is to provide new insights into the structure-toxicity relationships of metronidazole within phosphatidylcholine membranes. For that purpose, lipid membrane models (liposomes and monolayers) composed of dipalmitoylphosphatidylcholine were used. Experimental techniques (determination of partition coefficients and Langmuir isotherm measurements) were combined with molecular dynamics simulations. Different pHs and lipid phases were evaluated to enable a better extrapolation for in vivo conditions. The partition of metronidazole depends on the pH and on the biphasic system (octanol/water or DPPC/water system). At pH 1.2, metronidazole is hydrophilic. At pH 7.4, metronidazole disturbs the order and the packing of phospholipids. For this toxic effect, the hydroxyl group of the side chain of metronidazole is a key by interacting with the water embedded in the membrane and with the phosphate group and the apolar chains of phospholipids. Copyright © 2018. Published by Elsevier B.V.

High-dose oxytocin is not associated with maternal temperature elevation: a retrospective cohort study of mid-trimester pregnancy with intrauterine fetal demise.

PubMed

Frölich, M A; Esame, A; Warren Iii, W M; Owen, J

2011-01-01

Maternal intrapartum fever has been associated with an increased incidence of neonatal morbidity. In this retrospective cohort study, we evaluated whether intravenous oxytocin has a fever-inducing effect. Oxytocin augments secretion of prostaglandins E(2) and F(2α) which are inflammatory mediators known to elevate body temperature. Between January 2005 and June 2008, 279 patients were admitted with mid-trimester fetal demise. Patients meeting inclusion criteria included 34 women who received a high-dose intravenous oxytocin regimen and 29 patients who delivered after spontaneous labor without the need for augmentation. Oral temperatures were measured on admission and at delivery. The median length of oxytocin infusion was 5.3h. The calculated temperature change was -0.14°C in the oxytocin group and +0.12°C in the control group. These findings were confirmed in a model adjusted for patients' white blood cell count and duration of labor. We did not observe an effect of analgesia type, epidural versus intravenous analgesia, on duration of labor. Based on this comparative analysis of pregnant women who received high-doses of oxytocin, we found insufficient evidence to support that high-dose intravenous oxytocin elevates intrapartum maternal temperature. Copyright © 2010 Elsevier Ltd. All rights reserved.

Effects of mesocaval shunt on the pharmacokinetics of metronidazole in young rats.

PubMed

Guillé, Beatriz E Perez; Alvarez, Fernando Villegas; Toledo López, Alejandra R; Bravo-Luna, Miguel A Jiménez; Soriano-Rosales, Rosa E; Lares-Asseff, Ismael; Arrellin, Gerardo; Guillé, Maria G Pérez

2005-01-01

Prophylactic and therapeutic management of portosystemic encephalopathies is based on protein restriction in the diet, and the use of lactulose and antibiotics such as metronidazole. These actions intend to reduce the main source of intestinal ammonia production and release into the systemic circulation. The aim of this study was to evaluate the medium-term effects of mesocaval shunt on the pharmacokinetics of metronidazole in rats with healthy livers. Male Lewis rats were divided into two groups. The first group was subjected to mesocaval shunt (MCS) and the other employed as a control. The following tests were carried out in both groups: metronidazole pharmacokinetics, determination of ALT, AST, albumin, urea and ammonium, liver weight and histomorphology. A loss in body and liver weight was registered in rats subjected to MCS. AST levels also increased compared to controls. Significant differences in almost all pharmacokinetic parameters were detected between MCS and control rats, especially in Kel, AUC and Cmax. Modifications in metronidazole pharmacokinetics and liver weight changes without microstructural modification secondary to MCS were found. We suggest that individual drug-monitoring and pharmacokinetic analysis must be carried out in metronidazole medicated patients with modifications in portal circulation with or with out macro or micro liver structural alterations.

Search for Novel Candidate Mutations for Metronidazole Resistance in Helicobacter pylori Using Next-Generation Sequencing

PubMed Central

Binh, Tran Thanh; Suzuki, Rumiko; Trang, Tran Thi Huyen; Kwon, Dong Hyeon

2015-01-01

Metronidazole resistance is a key factor associated with Helicobacter pylori treatment failure. Although this resistance is mainly associated with mutations in the rdxA and frxA genes, the question of whether metronidazole resistance is caused by the inactivation of frxA alone is still debated. Furthermore, it is unclear whether there are other mutations involved in addition to the two genes that are associated with resistance. A metronidazole-resistant strain was cultured from the metronidazole-susceptible H. pylori strain 26695-1 by exposure to low concentrations of metronidazole. The genome sequences of both susceptible and resistant H. pylori strains were determined by Illumina next-generation sequencing, from which putative candidate resistance mutations were identified. Natural transformation was used to introduce PCR products containing candidate mutations into the susceptible parent strain 26695-1, and the metronidazole MIC was determined for each strain. Mutations in frxA (hp0642), rdxA (hp0954), and rpsU (hp0562) were confirmed by the Sanger method. The mutated sequence in rdxA was successfully transformed into strain 26695-1, and the transformants showed resistance to metronidazole. The transformants containing a single mutation in rdxA showed a low MIC (16 mg/liter), while those containing mutations in both rdxA and frxA showed a higher MIC (48 mg/liter). No transformants containing a single mutation in frxA or rpsU were obtained. Next-generation sequencing was used to identify mutations related to drug resistance. We confirmed that the mutations in rdxA are mainly associated with metronidazole resistance, and mutations in frxA are able to enhance H. pylori resistance only in the presence of rdxA mutations. Moreover, mutations in rpsU may play a role in metronidazole resistance. PMID:25645832

Evaluation of Nitrofurantoin Combination Therapy of Metronidazole-Sensitive and -Resistant Helicobacter pylori Infections in Mice

PubMed Central

Jenks, Peter J.; Ferrero, Richard L.; Tankovic, Jacques; Thiberge, Jean-Michel; Labigne, Agnès

2000-01-01

The main objectives of this study were to determine whether the nitroreductase enzyme encoded by the rdxA gene of Helicobacter pylori was responsible for reductive activation of nitrofurantoin and whether a triple-therapy regimen with nitrofurantoin was able to eradicate metronidazole-sensitive and -resistant H. pylori infections from mice. The susceptibilities to nitrofurantoin of parent and isogenic rdxA mutant strains (three pairs), as well as a series of matched metronidazole-sensitive and -resistant strains isolated from mice (30) and patients (20), were assessed by agar dilution determination of the MIC. Groups of mice colonized with the metronidazole-sensitive H. pylori SS1 strain or a metronidazole-resistant rdxA SS1 mutant were treated with either metronidazole or nitrofurantoin as part of a triple-therapy regimen. One month after the completion of treatment the mice were sacrificed and their stomachs were cultured for H. pylori. The nitrofurantoin MICs for all strains tested were between 0.5 and 4.0 μg/ml. There was no significant difference between the susceptibility to nitrofurantoin of the parental strains and those of respective rdxA mutants or between those of matched metronidazole-sensitive and -resistant H. pylori isolates. The regimen with metronidazole eradicated infection from all eight SS1-infected mice and from one of eight mice inoculated with the rdxA mutant (P ≤ 0.001). The regimen with nitrofurantoin failed to eradicate infection from any of the six SS1-infected mice (P ≤ 0.001) and cleared infection from one of seven mice inoculated with the rdxA mutant. These results demonstrate that, despite the good in vitro activity of nitrofurantoin against H. pylori and the lack of cross-resistance between metronidazole and nitrofurantoin, eradication regimens involving nitrofurantoin are unable to eradicate either metronidazole-sensitive or -resistant H. pylori infections from mice. PMID:10991835

Pyruvate Decarboxylase, the Target for Omeprazole in Metronidazole-Resistant and Iron-Restricted Tritrichomonas foetus

PubMed Central

Sutak, Róbert; Tachezy, Jan; Kulda, Jaroslav; Hrdý, Ivan

2004-01-01

The substituted benzimidazole omeprazole, used for the treatment of human peptic ulcer disease, inhibits the growth of the metronidazole-resistant bovine pathogen Tritrichomonas foetus in vitro (MIC at which the growth of parasite cultures is inhibited by 50%, 22 μg/ml [63 μM]). The antitrichomonad activity appears to be due to the inhibition of pyruvate decarboxylase (PDC), which is the key enzyme responsible for ethanol production and which is strongly upregulated in metronidazole-resistant trichomonads. PDC was purified to homogeneity from the cytosol of metronidazole-resistant strain. The tetrameric enzyme of 60-kDa subunits is inhibited by omeprazole (50% inhibitory concentration, 16 μg/ml). Metronidazole-susceptible T. foetus, which expresses very little PDC, is only slightly affected. Omeprazole has the same inhibitory effect on T. foetus cells grown under iron-limited conditions. Similarly to metronidazole-resistant cells, T. foetus cells grown under iron-limited conditions have nonfunctional hydrogenosomal metabolism and rely on cytosolic PDC-mediated ethanol fermentation. PMID:15155220

Exploratory Investigation of Bacteroides fragilis Transcriptional Response during In vitro Exposure to Subinhibitory Concentration of Metronidazole

PubMed Central

de Freitas, Michele C. R.; Resende, Juliana A.; Ferreira-Machado, Alessandra B.; Saji, Guadalupe D. R. Q.; de Vasconcelos, Ana T. R.; da Silva, Vânia L.; Nicolás, Marisa F.; Diniz, Cláudio G.

2016-01-01

Bacteroides fragilis, member from commensal gut microbiota, is an important pathogen associated to endogenous infections and metronidazole remains a valuable antibiotic for the treatment of these infections, although bacterial resistance is widely reported. Considering the need of a better understanding on the global mechanisms by which B. fragilis survive upon metronidazole exposure, we performed a RNA-seq transcriptomic approach with validation of gene expression results by qPCR. Bacteria strains were selected after in vitro subcultures with subinhibitory concentration (SIC) of the drug. From a wild type B. fragilis ATCC 43859 four derivative strains were selected: first and fourth subcultures under metronidazole exposure and first and fourth subcultures after drug removal. According to global gene expression analysis, 2,146 protein coding genes were identified, of which a total of 1,618 (77%) were assigned to a Gene Ontology term (GO), indicating that most known cellular functions were taken. Among these 2,146 protein coding genes, 377 were shared among all strains, suggesting that they are critical for B. fragilis survival. In order to identify distinct expression patterns, we also performed a K-means clustering analysis set to 15 groups. This analysis allowed us to detect the major activated or repressed genes encoding for enzymes which act in several metabolic pathways involved in metronidazole response such as drug activation, defense mechanisms against superoxide ions, high expression level of multidrug efflux pumps, and DNA repair. The strains collected after metronidazole removal were functionally more similar to those cultured under drug pressure, reinforcing that drug-exposure lead to drastic persistent changes in the B. fragilis gene expression patterns. These results may help to elucidate B. fragilis response during metronidazole exposure, mainly at SIC, contributing with information about bacterial survival strategies under stress conditions in their

Exploratory Investigation of Bacteroides fragilis Transcriptional Response during In vitro Exposure to Subinhibitory Concentration of Metronidazole.

PubMed

de Freitas, Michele C R; Resende, Juliana A; Ferreira-Machado, Alessandra B; Saji, Guadalupe D R Q; de Vasconcelos, Ana T R; da Silva, Vânia L; Nicolás, Marisa F; Diniz, Cláudio G

2016-01-01

Bacteroides fragilis , member from commensal gut microbiota, is an important pathogen associated to endogenous infections and metronidazole remains a valuable antibiotic for the treatment of these infections, although bacterial resistance is widely reported. Considering the need of a better understanding on the global mechanisms by which B. fragilis survive upon metronidazole exposure, we performed a RNA-seq transcriptomic approach with validation of gene expression results by qPCR. Bacteria strains were selected after in vitro subcultures with subinhibitory concentration (SIC) of the drug. From a wild type B. fragilis ATCC 43859 four derivative strains were selected: first and fourth subcultures under metronidazole exposure and first and fourth subcultures after drug removal. According to global gene expression analysis, 2,146 protein coding genes were identified, of which a total of 1,618 (77%) were assigned to a Gene Ontology term (GO), indicating that most known cellular functions were taken. Among these 2,146 protein coding genes, 377 were shared among all strains, suggesting that they are critical for B. fragilis survival. In order to identify distinct expression patterns, we also performed a K-means clustering analysis set to 15 groups. This analysis allowed us to detect the major activated or repressed genes encoding for enzymes which act in several metabolic pathways involved in metronidazole response such as drug activation, defense mechanisms against superoxide ions, high expression level of multidrug efflux pumps, and DNA repair. The strains collected after metronidazole removal were functionally more similar to those cultured under drug pressure, reinforcing that drug-exposure lead to drastic persistent changes in the B. fragilis gene expression patterns. These results may help to elucidate B. fragilis response during metronidazole exposure, mainly at SIC, contributing with information about bacterial survival strategies under stress conditions in

Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study.

PubMed

Chiappella, Annalisa; Martelli, Maurizio; Angelucci, Emanuele; Brusamolino, Ercole; Evangelista, Andrea; Carella, Angelo Michele; Stelitano, Caterina; Rossi, Giuseppe; Balzarotti, Monica; Merli, Francesco; Gaidano, Gianluca; Pavone, Vincenzo; Rigacci, Luigi; Zaja, Francesco; D'Arco, Alfonso; Cascavilla, Nicola; Russo, Eleonora; Castellino, Alessia; Gotti, Manuel; Congiu, Angela Giovanna; Cabras, Maria Giuseppina; Tucci, Alessandra; Agostinelli, Claudio; Ciccone, Giovannino; Pileri, Stefano A; Vitolo, Umberto

2017-08-01

The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients. We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m 2 , cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , and vincristine 1·4 mg/m 2 on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m 2 and doxorubicin 70 mg/m 2 ) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m 2 on day 1 or 4 plus intravenous cytarabine 2000 mg/m 2 and dexamethasone 4 mg/m 2 every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m 2 on days 1-3) plus BEAM (intravenous carmustine 300 mg/m 2 on day -7, intravenous cytarabine 200 mg/m 2 twice a day on days -6 to -3, intravenous etoposide 100 mg/m 2 twice a day on days -6

A Redox Basis for Metronidazole Resistance in Helicobacter pylori▿

PubMed Central

Kaakoush, N. O.; Asencio, C.; Mégraud, F.; Mendz, G. L.

2009-01-01

Metronidazole resistance in Helicobacter pylori has been attributed to mutations in rdxA or frxA. Insufficient data correlating RdxA and/or FrxA with the resistant phenotype, and the emergence of resistant strains with no mutations in either rdxA or frxA, indicated that the molecular basis of H. pylori resistance to metronidazole required further characterization. The rdxA and frxA genes of four matched pairs of metronidazole-susceptible and -resistant strains were sequenced. The resistant strains had mutations in either rdxA, frxA, neither gene, or both genes. The reduction rates of five substrates suggested that metabolic differences between susceptible and resistant strains cannot be explained only by mutations in rdxA and/or frxA. A more global approach to understanding the resistance phenotype was taken by employing two-dimensional gel electrophoresis combined with tandem mass spectrometry analyses to identify proteins differentially expressed by the matched pair of strains with no mutations in rdxA or frxA. Proteins involved in the oxireduction of ferredoxin were downregulated in the resistant strain. Other redox enzymes, such as thioredoxin reductase, alkyl hydroperoxide reductase, and superoxide dismutase, showed a pI change in the resistant strain. The data suggested that metronidazole resistance involved more complex metabolic changes than specific gene mutations, and they provided evidence of a role for the intracellular redox potential in the development of resistance. PMID:19223619

The use of high-dose insulin therapy and intravenous lipid emulsion to treat severe, refractory diltiazem toxicosis in a dog.

PubMed

Maton, Barbara L; Simmonds, Erin E; Lee, Justine A; Alwood, Amy J

2013-01-01

To describe the novel use of high-dose insulin (HDI) therapy and intravenous lipid emulsion (ILE) to treat refractory, severe diltiazem toxicosis in a dog. A 4-year-old Pomeranian was presented for treatment 2.5 hours following ingestion of a diltiazem extended-release capsule. Toxic ingestion was calculated at a maximum exposure of 79 mg/kg, with a reported canine LD50 of 50 mg/kg. Clinical signs of progressive hypotension and severe bradycardia with atrial standstill were observed, which persisted despite treatment with atropine, calcium, glucagon, and dopamine. The novel use of HDI and ILE as part of therapy for diltiazem toxicosis resulted in clinical resolution of life-threatening signs. Within 1 hour of initiating HDI therapy, the clinical signs improved, and with continued treatment, the patient remained normotensive and survived to discharge. To the authors' knowledge, this is the first reported clinical case describing the use of both HDI and ILE therapy in the treatment of severe refractory diltiazem toxicosis in veterinary medicine. No significant adverse effects were observed from the treatment. In veterinary patients with severe refractory calcium channel blocker toxicosis, the use of HDI and ILE should be considered for life-threatening clinical signs. © Veterinary Emergency and Critical Care Society 2013.

Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats.

PubMed

Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

2015-12-01

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.

Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

PubMed Central

Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

2015-01-01

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats. PMID:26877840

Prevalence of metronidazole resistant Helicobacter pylori strains among Chinese peptic ulcer disease patients and normal controls in Hong Kong.

PubMed

Ching, C K; Leung, K P; Yung, R W; Lam, S K; Wong, B C; Lai, K C; Lai, C L

1996-05-01

A study was conducted to evaluate the prevalence of metronidazole resistant Helicobacter pylori strains among the Chinese in Hong Kong. The efficacy of the triple therapy that contains metronidazole as one of the anti-microbial agents in eradication of the metronidazole susceptible and the metronidazole resistant strains was also assessed. Culture for H pylori was attempted from antral biopsy specimens of 70 peptic ulcer and 51 control subjects. Successfully cultured H pylori strains were tested for metronidazole susceptibility. Twenty six peptic ulcer disease subjects who had received a course of triple therapy were also reassessed four to six weeks later for successful eradication of H pylori infection. H pylori was successfully cultured from antral biopsy specimens in 69 of 80 (86%) of the infected subjects. The overall metronidazole resistance rate was 53.5% (37 of 69). There was a significantly higher metronidazole resistance rate among H pylori isolates from the asymptomatic controls (20 of 25) than the peptic ulcer disease subjects (17 of 44) (p = 0.0007). Twenty three of 32 (73%) women and 14 of 37 (38%) men harboured the metronidazole resistant strains. There was no sex or age difference as far as the prevalence of metronidazole resistant strains were concerned within each study group. Pre-treatment metronidazole susceptible H pylori were significantly more likely to respond to the triple therapy used than those with the metronidazole resistant ones (14 of 15 v five of 10) (p = 0.021).

Potential intravenous drug incompatibilities in a pediatric unit.

PubMed

Leal, Karla Dalliane Batista; Leopoldino, Ramon Weyler Duarte; Martins, Rand Randall; Veríssimo, Lourena Mafra

2016-01-01

To investigate potential intravenous drug incompatibilities and related risk factors in a pediatric unit. A cross-sectional analytical study conducted in the pediatric unit of a university hospital in Brazil. Data on prescriptions given to children aged 0-15 years from June to October 2014 were collected. Prescriptions that did not include intravenous drugs and prescriptions with incomplete dosage regimen or written in poor handwriting were excluded. Associations between variables and the risk of potential incompatibility were investigated using the Student's t test and ANOVA; the level of significance was set at 5% (p<0.05). Relative risks were calculated for each drug involved in potential incompatibility with 95% confidence interval. A total of 222 children participated in the study; 132 (59.5%) children were male and 118 (53.2%) were aged between 0 and 2 years. The mean length of stay was 7.7±2.3 days. Dipyrone, penicillin G and ceftriaxona were the most commonly prescribed drugs. At least one potential incompatibility was detected in about 85% of children (1.2 incompatibility/patient ratio). Most incompatibilities detected fell into the non-tested (93.4%), precipitation (5.5%), turbidity (0.7%) or chemical decomposition (0.4%) categories. The number of drugs and prescription of diazepam, phenytoin, phenobarbital or metronidazole were risk factors for potential incompatibility. Most pediatric prescriptions involved potential incompatibilities, with higher prevalence of non-tested incompatibilities. The number of drugs and prescription of diazepam, phenobarbital, phenytoin or metronidazole were risk factors for potential incompatibilities. Avaliar o potencial de incompatibilidade dos medicamentos intravenosos, identificando possíveis fatores de risco em uma unidade pediátrica. Trata-se de um estudo observacional analítico do tipo transversal realizado na unidade de pediatria de um hospital de ensino no Brasil. Os dados foram coletados de junho a outubro de

Lon protease affects the RdxA nitroreductase activity and metronidazole susceptibility in Helicobacter pylori.

PubMed

Tu, I-Fan; Liao, Jiahn-Haur; Yang, Feng-Ling; Lin, Nien-Tsung; Chan, Hong-Lin; Wu, Shih-Hsiung

2014-10-01

The lon gene of Helicobacter pylori strains is constitutively expressed during growth. However, virtually nothing is understood concerning the role of Lon in H. pylori. This study examined the function and physiological role of Lon in H. pylori (HpLon) using a trapping approach to identify putative Lon binding partners in the bacterium. Protease-deficient Lon was expressed and served as the bait in trapping approach to capture the interacting partners in H. pylori. The antibiotic susceptibility of wild-type and lon derivative mutants was determined by the E test trips and the disc diffusion assay. The effect of HpLon on RdxA activity was detected the change in NADPH oxidation and metronidazole reduction by spectrophotometer. Lon in Helicobacter pylori (HpLon) interacting partners are mostly associated with metronidazole activation. lon mutant presents more susceptible to metronidazole than that of the wild type, and this phenotype is recovered by complementation of the wild-type Lon. We found that the ATPases associated with a variety of cellular activities (AAA(+) ) module of HpLon causes a decrease in both NADPH oxidase and Mtz reductase activity in RdxA, a major Mtz-activating enzyme in H. pylori. Metronidazole resistance of H. pylori causes the serious medical problem worldwide. In this study, HpLon is involved in metronidazole susceptibility among H. pylori strains. We provide the evidence that HpLon alters RdxA activity in vitro. The decrease in metronidazole activation caused by HpLon is possibly prior to accumulate mutation in rdxA gene before the metronidazole-resistant strains to be occurred. © 2014 John Wiley & Sons Ltd.

Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial.

PubMed

Zhu, Hong-Hu; Wu, De-Pei; Du, Xin; Zhang, Xi; Liu, Lin; Ma, Jun; Shao, Zong-Hong; Ren, Han-Yun; Hu, Jian-Da; Xu, Kai-Lin; Wang, Jing-Wen; Song, Yong-Ping; Fang, Mei-Yun; Li, Juan; Yan, Xiao-Yan; Huang, Xiao-Jun

2018-06-05

Intravenous arsenic trioxide plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non-high-risk acute promyelocytic leukaemia (white blood cell count ≤10 × 10 9 per L), resulting in cure in more than 95% of cases. However, a pilot study of treatment with oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy, which has a more convenient route of administration than the standard intravenous regimen, showed high efficacy. In this study, we compare an oral RIF plus ATRA treatment regimen with the standard intravenous arsenic trioxide plus ATRA treatment regimen in patients with non-high-risk acute promyelocytic leukaemia. We did a multicentre, non-inferiority, open-label, randomised, controlled phase 3 trial at 14 centres in China. Patients aged 18-70 years with newly diagnosed (within 7 days) non-high-risk acute promyelocytic leukaemia, and a WHO performance status of 2 or less were eligible. Patients were randomly assigned (2:1) to receive treatment with RIF-ATRA or arsenic trioxide-ATRA as the induction and consolidation therapy. Randomisation was done centrally with permuted blocks and stratification according to trial centre and was implemented through an interactive web response system. RIF (60 mg/kg bodyweight daily in an oral divided dose) or arsenic trioxide (0·15 mg/kg daily in an intravenous dose) and ATRA (25 mg/m 2 daily in an oral divided dose) were used until complete remission was achieved. The home-based consolidation therapy was RIF (60 mg/kg daily in an oral divided dose) or intravenous arsenic trioxide (0·15 mg/kg daily in an intravenous dose) in a 4-week on 4-week off regimen for four cycles and ATRA (25 mg/m 2 daily in an oral divided dose) in a 2-week on 2-week off regimen for seven cycles. Patients and treating physicians were not masked to treatment allocation. The primary outcome was event-free survival at 2 years. A non-inferiority margin of -10% was used to assess non

Exposure to Metronidazole In Vivo Readily Induces Resistance in Helicobacter pylori and Reduces the Efficacy of Eradication Therapy in Mice

PubMed Central

Jenks, Peter J.; Labigne, Agnes; Ferrero, Richard L.

1999-01-01

The Helicobacter pylori SS1 mouse model was used to characterize the development of resistance in H. pylori after treatment with metronidazole monotherapy and to examine the effect of prior exposure to metronidazole on the efficacy of a metronidazole-containing eradication regimen. Mice colonized with the metronidazole-sensitive H. pylori SS1 strain were treated for 7 days with either peptone trypsin broth or the mouse equivalent of 400 mg of metronidazole once a day or three times per day (TID). In a separate experiment, H. pylori-infected mice were administered either peptone trypsin broth or the mouse equivalent of 400 mg of metronidazole TID for 7 days, followed 1 month later by either peptone trypsin broth or the mouse equivalent of 20 mg of omeprazole, 250 mg of clarithromycin, and 400 mg of metronidazole twice a day for 7 days. At least 1 month after the completion of treatment, the mice were sacrificed and their stomachs were cultured for H. pylori. The susceptibilities of isolates to metronidazole were assessed by agar dilution determination of the MICs. Mixed populations of metronidazole-resistant and -sensitive strains were isolated from 70% of mice treated with 400 mg of metronidazole TID. The ratio of resistant to sensitive strains was 1:100, and the MICs for the resistant strains varied from 8 to 64 μg/ml. In the second experiment, H. pylori was eradicated from 70% of mice treated with eradication therapy alone, compared to 25% of mice pretreated with metronidazole (P < 0.01). Mice still infected after treatment with metronidazole and eradication therapy contained mixed populations of metronidazole-resistant and -sensitive isolates in a ratio of 1:25. These results demonstrate that H. pylori readily acquires resistance to metronidazole in vivo and that prior exposure of the organism to metronidazole is associated with failure of eradication therapy. H. pylori-infected mice provide a suitable model for the study of resistance mechanisms in H. pylori

[Tetracyclines, sulfonamides and metronidazole].

PubMed

Pérez-Trallero, Emilio; Iglesias, Luis

2003-11-01

Tetracyclines form a group of natural and semisynthetic products that acts inhibiting the bacterial protein synthesis. They are bacteriostatic agents, exhibiting activity against a wide range of organisms, but they are at the present of limited use because of their acquired resistance. Doxycycline is currently the most frequently used tetracycline in human medicine and it is included in the List of Essential Medicines of the World Health Organization. Sulfonamides are synthetic, broad-spectrum bacteriostatic antibiotics. They were the first effective systemic antimicrobial agents. Their mode of action is based on the inhibition of DNA synthesis. Due to their toxicity and high adquired resistance their use is currently very low. Metronidazole is the main compound of 5-nitroimidazole family. It is a very active bactericidal antibiotic against anaerobic and some microaerophilic bacteria and it is still very useful in the treatment of bacterian and parasitic infections.

Effects of metronidazole combined probiotics over metronidazole alone for the treatment of bacterial vaginosis: a meta-analysis of randomized clinical trials.

PubMed

Tan, Hongying; Fu, Yunque; Yang, Chunlin; Ma, Jianting

2017-06-01

To evaluate the curative effect of metronidazole combined probiotics over metronidazole alone in the treatment of BV. We are searching randomized controlled trials on major online databases including PubMed, Science Direct, and Cochrane Database between 1990 and 2015. The primary outcome measure was the cure rate of BV. Cochran's Chi-square test (Q test) was used to test for heterogeneity among trials, and the I 2 index. We used mixed-effects modeling for parameters of the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs). Analysis suggests the cure rate of BV [RR = 1.12, 95% CI (0.94-1.32), p = 0.20], and the I 2 index was 83%. The value of I 2 index decreased to 16% after removing the study of Anukam et al., and Amsel 1.04 (95% CI 0.96-1.13) (p = 0.35), Nugent 1.02 (95% CI 0.94-1.11), short-term 1.01 (95% CI 0.93-1.10) (p = 0.79), long-term 1.06 (95% CI 0.98-1.14) (p = 0.13), Europe 1.06 (95% CI 0.95-1.19) (p = 0.32), Non-Europe 0.99 (95% CI 0.94-1.05) (p = 0.83). When the two same groups data were combined, respectively, the RRs for all studies were the same as 1.03 (95% CI 0.96-1.09) (p = 0.42) showing that there is not statistically significant in relevant stratums. The result has showed an overall little significance for the efficacy of metronidazole combined probiotics over metronidazole alone for the treatment of BV. We need more further studies to provide enough evidence to confirm the benefits of probiotics in the treatment of BV.

Cellular internalization and morphological analysis after intravenous injection of a highly hydrophilic octahedral rhenium cluster complex - a new promising X-ray contrast agent.

PubMed

Krasilnikova, Anna A; Solovieva, Anastasiya O; Trifonova, Kristina E; Brylev, Konstantin A; Ivanov, Anton A; Kim, Sung-Jin; Shestopalov, Michael A; Fufaeva, Maria S; Shestopalov, Alexander M; Mironov, Yuri V; Poveshchenko, Alexander F; Shestopalova, Lidia V

2016-11-01

The octahedral cluster compound Na 2 H 8 [{Re 6 Se 8 }(P(C 2 H 4 CONH 2 )(C 2 H 4 COO) 2 ) 6 ] has been shown to be highly radio dense, thus becoming a promising X-ray contrast agent. It was also shown that this compound had low cytotoxic effect in vitro, low acute toxicity in vivo and was eliminated rapidly from the body through the urinary tract. The present contribution describes a more detailed cellular internalization assay and morphological analysis after intravenous injection of this hexarhenium cluster compound at different doses. The median lethal dose (LD 50 ) of intravenously administrated compound was calculated (4.67 ± 0.69 g/kg). Results of the study clearly indicated that the cluster complex H n [{Re 6 Se 8 }(P(C 2 H 4 CONH 2 )(C 2 H 4 COO) 2 ) 6 ] n-10 was not internalized into cells in vitro and induced only moderate morphological alterations of kidneys at high doses without any changes in morphology of liver, spleen, duodenum, or heart of mice. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Prehospital high-dose sublingual nitroglycerin rarely causes hypotension.

PubMed

Clemency, Brian M; Thompson, Jeffrey J; Tundo, Gina N; Lindstrom, Heather A

2013-10-01

High-dose intravenous nitroglycerin is a common in-hospital treatment for respiratory distress due to congestive heart failure (CHF) with hypertension. Intravenous (IV) nitroglycerin administration is impractical in the prehospital setting. In 2011, a new regional Emergency Medical Services (EMS) protocol was introduced allowing advanced providers to treat CHF with high-dose oral nitroglycerin. The protocol calls for patients to be treated with two sublingual tabs (0.8 mg) when systolic blood pressure (SBP) was >160 mm Hg, or three sublingual tabs (1.2 mg) when SBP was >200 mm Hg, every five minutes as needed. Hypothesis/Problem To assess the protocol's safety, the incidence of hypotension following prehospital administration of multiple simultaneous nitroglycerin (MSN) tabs by EMS providers was studied. This study was a retrospective cohort study of patients from a single commercial EMS agency over a 6-month period. Records from patients with at least one administration of MSN were reviewed. For each administration, the first documented vital signs pre- and post-administration were compared. Administrations were excluded if pre- or post-administration vital signs were missing. One hundred case-patients had at least one MSN administration by an advanced provider during the study period. Twenty-five case-patients were excluded due to incomplete vital signs. Seventy-five case-patients with 95 individual MSN administrations were included for analysis. There were 65 administrations of two tabs, 29 administrations of three tabs, and one administration of four tabs. The mean change in SBP following MSN was -14.7 mm Hg (SD = 30.7; range, +59 to -132). Three administrations had documented systolic hypotension in the post-administration vital signs (97/71, 78/50 and 66/47). All three patients were over 65 years old, were administered two tabs, had documented improved respiratory status, and had repeat SBP of at least 100. The incidence of hypotension following MSN

Efficacy and safety of once-daily metronidazole 1% gel compared with twice-daily azelaic acid 15% gel in the treatment of rosacea.

PubMed

Wolf, John E; Kerrouche, Nabil; Arsonnaud, Stephanie

2006-04-01

Rosacea is an inflammatory dermatologic disorder characterized by the presence of facial erythema, visible blood vessels, papules, and pustules. The National Rosacea Society has established a classification system that identifies 4 distinct rosacea subtypes based on clinical presentation: erythematotelangiectatic, papulopustular, phymatous, and ocular. The goal of topical therapy for rosacea is to reduce inflammatory lesion counts; decrease intensity of erythema; and reduce symptoms such as stinging, burning, and pruritus. Metronidazole and azelaic acid are thought to reduce the inflammation associated with rosacea by inhibiting the production of reactive oxygen species produced by neutrophils. Both metronidazole 1% gel and azelaic acid 15% gel recently have been approved for the treatment of rosacea. The current study was conducted to compare the once-daily application of metronidazole 1% gel with twice-daily applications of azelaic acid 15% gel for the treatment of patients with moderate rosacea (N=160). Both treatments showed similar reductions in inflammatory lesion counts (77% for metronidazole 1% gel and 80% for azelaic acid 15% gel) and high success rates in both global severity (53.7% vs 56.4% for metronidazole 1% gel and azelaic acid 15% gel, respectively) and erythema (42.7% vs 42.3% for metronidazole 1% gel and azelaic acid 15% gel, respectively). On average, the efficacy (including reduction in erythema) of the once-daily application of metronidazole 1% gel and twice-daily applications of azelaic acid 15% gel were similar.

Dosing of Intravenous Tocilizumab in a Real-World Setting of Rheumatoid Arthritis: Analyses from the Corrona Registry.

PubMed

Pappas, Dimitrios A; John, Ani; Curtis, Jeffrey R; Reed, George W; Karki, Chitra; Magner, Robert; Kremer, Joel M; Shewade, Ashwini; Greenberg, Jeffrey D

2016-06-01

In the United States, the recommended starting dose of intravenous tocilizumab (TCZ) is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response for patients with moderate to severe rheumatoid arthritis; however, data on how TCZ dose is escalated in real life are missing. The objective of this analysis was to describe patterns of early intravenous TCZ dose escalation in a real-world setting using data from the Corrona registry. All patients enrolled in the comparative effectiveness substudy (CERTAIN) nested within Corrona who initiated TCZ and completed 3- and 6-month study visits were eligible for inclusion. Patients who initiated TCZ 4 mg/kg were categorized into 1 of 2 groups: those who remained on TCZ 4 mg/kg at 3 months (Group 1) and those who escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Changes in clinical disease activity measures were provided. Of the 213 patients who were eligible for analysis, 86 (40.4%) remained on their initial dose of TCZ 4 mg/kg (Group 1) and 110 (51.6%) were escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Baseline demographic and clinical characteristics were similar between the 2 groups; except in Group 2, patients were older (58.3 vs. 54.0 years) and a lower proportion was female (75.5% vs. 89.4%) than in Group 1. Significant improvements in disease activity measures were observed at 3 and 6 months in both groups, with the majority of patients in both groups achieving moderate or good European League Against Rheumatism response. Real-world data demonstrated that physicians escalate TCZ dose at varying frequencies. The ability to administer TCZ in varying doses allows physicians to tailor TCZ therapy to disease activity. ClinicalTrials.gov identifier, NCT01625650.

[The first metronidazole-resistant Bacteroides species isolated at Marmara University Hospital: Bacteroides thetaiotaomicron].

PubMed

Toprak Ülger, Nurver; Sayın, Elvan; Soyad, Ad; Dane, Faysal; Söyletir, Güner

2013-10-01

Bacteroides species, the predominant constituents of the human intestinal microbiota can cause serious intraabdominal and postoperative wound infections and bacteremia. Moreover, these bacteria are more resistant to antimicrobial agents than the other anaerobes. The limited number of the antimicrobials, such as carbapenems, beta-lactam/beta-lactamase inhibitors and nitroimidazoles are highly effective in eliminating Bacteroides. However, a few metronidazole-resistant isolates have been reported from several countries recently. The nim genes (nim A-G) are suggested to be responsible for the majority of the metronidazole resistance. Here, we describe a metronidazole-resistant Bacteroides thetaiotaomicron isolated from a blood culture. A gram-negative obligate anaerobic rod was isolated from the postoperative 5th day blood culture of a 62-year-old male patient with adenocarcinoma of the pancreas head. The strain was identified as B.thetaiotaomicron by using a combination of conventional tests and commercially available biochemical kits. Antimicrobial susceptibility testing was performed by agar dilution method. The resistance genes were investigated by means of PCR using specific primer pairs for nim gene. The purified PCR product was sequenced and analyzed by comparison of the consensus sequences with GenBank sequences. The MIC for metronidazole was 16 mg/L. Although the strain was intermediate according the CLSI criteria, it was resistant (> 4 mg/L) according to EUCAST criteria. The isolate was nim gene positive, and nucleotide sequencing of the PCR product shared 100% similarity with nimE gene (emb |AM042593.1 |). On the other hand the isolate was susceptible to carbapenems and sulbactam-ampicillin. Following administration of ampicillin-sulbactam, the patient's fever disappeared after 24 hours. The clinical condition improved considerably and he was discharged at day 8. The patient was followed up at the medical oncology clinic; however he died due to disease

The effect of methylcellulose on metronidazole release from polyacrylic acid hydrogels.

PubMed

Musial, Witold

2007-08-01

Topical treatment of acne rosacea, a chronic condition characterized by recurrent course for many years, is primarily based on metronidazole preparations. The aim of this study was to evaluate the effect of various acrylic acid polymers, in composition with methylcellulose on metronidazole release rate from hydrogels proposed for the treatment of acne rosacea. Viscosity and release studies using "Paddle over Disk" system with semipermeable membrane of MWCO 3500 were performed. Compositions of Carbopol 971P and methylcellulose revealed an increase in viscosity with increasing concentration of methylcellulose in the range of 17200-26166 mPa.s. In all the examined formulations, the release process was characterized by a two-stage course. Among bipolymeric formulations, the highest first-stage release rate of 9.18 x 10(-3) min(-1) was determined for the gel consisting of 2.00% Carbopol 980NF with 1.00% methylcellulose. The second-stage release rates ranged between 2.88 x 10(-3) and 8.00 x 10(-3) min(-1). Two-stage release course can thus be attributed to metronidazole distribution into two compartments of hydrogel matrix. Proposed gels, with similar rheological properties, may be used for ex vivo and in vivo studies to obtain a suitable drug activity of metronidazole in the treatment of acne rosacea.

Effect of intravenous amino acids on interdigestive antroduodenal motility and small bowel transit time.

PubMed

Gielkens, H A; van den Biggelaar, A; Vecht, J; Onkenhout, W; Lamers, C B; Masclee, A A

1999-02-01

Patients on total parenteral nutrition have an increased risk of developing gallstones because of gall bladder hypomotility. High dose amino acids may prevent biliary stasis by stimulating gall bladder emptying. To investigate whether intravenous amino acids also influence antroduodenal motility. Eight healthy volunteers received, on three separate occasions, intravenous saline (control), low dose amino acids (LDA), or high dose amino acids (HDA). Antroduodenal motility was recorded by perfusion manometry and duodenocaecal transit time (DCTT) using the lactulose breath hydrogen test. DCTT was significantly prolonged during LDA and HDA treatment compared with control. The interdigestive motor pattern was maintained and migrating motor complex (MMC) cycle length was significantly reduced during HDA compared with control and LDA due to a significant reduction in phase II duration. Significantly fewer phase IIIs originated in the gastric antrum during LDA and HDA compared with control. Duodenal phase II motility index was significantly reduced during HDA, but not during LDA, compared with control. Separate intravenous infusion of high doses of amino acids in healthy volunteers: (1) modulates interdigestive antroduodenal motility; (2) shortens MMC cycle length due to a reduced duration of phase II with a lower contractile incidence both in the antrum and duodenum (phase I remains unchanged whereas the effect on phase III is diverse: in the antrum phase III is suppressed and in the duodenum the frequency is increased); and (3) prolongs interdigestive DCTT.

Depletion of metronidazole in brook trout (Salvelinus fontinalis).

PubMed

Watson, Lynn; MacNeil, James D; Potter, Ross; Hellou, Jocelyne

2015-01-01

Metronidazole (MNZ), which is effective in the treatment of intestinal infections in fish, is also a suspected carcinogen and has been banned in numerous jurisdictions for use in any food-producing animal, including fish. Few reports have been published on the depletion of MNZ in fish. A depletion study was therefore undertaken using MNZ in feed provided to trout under controlled conditions. The water was maintained at 17.5 ± 0.9°C throughout the medication and depletion periods in the study. Following a 20-day acclimatisation period in the holding tanks, the trout (approximately 150-200 g bodyweight at the start of the study) were subjected to two separate medication and withdrawal periods: (A) 5 day medication/5 day withdrawal and (B) 5 day medication/16 day withdrawal. This simulated a potential multiple dosing in an aquaculture setting. In both medication periods, the trout were dosed with medicated feed containing 3 g MNZ kg(-1) fish. Fish were sacrificed in accordance with accepted animal care protocols and tissue samples were analysed by UPLC-MS/MS. Analyte concentrations in trout muscle ranged from a high of 27,000 ± 10,000 ng g(-1) for MNZ and 830 ± 570 ng g(-1) for MNZ-OH on day 1 of withdrawal period A to a low of 1.8 ± 2.3 ng g(-1) for MNZ and < 0.4 ng g(-1) for MNZ-OH on day 16 of withdrawal period B. The results demonstrate that when using the UPLC-MS/MS method, residues of MNZ may be detected in fish treated with MNZ after 16 days of withdrawal.

Intravenous ketamine in a dissociating dose as a temporizing measure to avoid mechanical ventilation in adult patient with severe asthma exacerbation.

PubMed

Shlamovitz, Gil Z; Hawthorne, Tracy

2011-11-01

Patients experiencing severe asthma exacerbations occasionally deteriorate to respiratory failure requiring endotracheal intubation and mechanical ventilation. Mechanical ventilation in this setting exposes the patients to substantial iatrogenic risk and should be avoided if at all possible. To describe the use of intravenous ketamine in acute asthma exacerbation. We present a case of severe asthma exacerbation in an adult female patient who failed to improve with standard therapies, but promptly improved with the administration of intravenous ketamine (0.75 mg/kg i.v. bolus followed by continuous drip of 0.15 mg/kg/h). This case suggests that intravenous ketamine given in a dissociative dose may be an effective temporizing measure to avoid mechanical ventilation in adult patients with severe asthma exacerbations. Copyright © 2011 Elsevier Inc. All rights reserved.

Design, Optimization, and Evaluation of a Novel Metronidazole-Loaded Gastro-Retentive pH-Sensitive Hydrogel.

PubMed

El-Mahrouk, Galal M; Aboul-Einien, Mona H; Makhlouf, Amal I

2016-12-01

Floating pH-sensitive chitosan hydrogels containing metronidazole were developed for the eradication of Helicobacter pylori from the stomach. Hydrogels were prepared by crosslinking medium or high molecular weight chitosan in lyophilized solutions containing metronidazole using either citrate or tripolyphosphate (TPP) salts at 1% or 2% concentration. A 2 3 factorial design was developed to study the influence of formulation parameters on the physical characteristics of the prepared hydrogels. The interaction between hydrogel components was investigated. The morphology of the prepared hydrogels was inspected and their percentage swelling, release pattern, and moisture content were evaluated. The results revealed the absence of interaction between hydrogel components and their highly porous structure. Percentage swelling of the hydrogels was much higher, and drug release was faster in gastric pH compared with intestinal pH. The formula prepared using 2% high molecular weight chitosan and 2% TPP significantly swelled (700%) within the first 4 h and released the loaded drug over a period of 24 h. Its moisture content was not affected by storage at high relative humidity. Therefore, this formula was selected to be tested in dogs for its gastric retention (using X-ray radiography) and efficacy in the eradication of H. pylori (using histopathological and microbiological examination). The results revealed that the prepared hydrogel formula was retained in dog stomach for at least 48 h, and it was more effective against H. pylori than the commercially available oral metronidazole tablets (Flagyl®).

Controlling systematic perioperative anaerobic contamination during sinus-lift procedures by using metronidazole: an innovative approach.

PubMed

Choukroun, Joseph; Simonpieri, Alain; Del Corso, Marco; Mazor, Ziv; Sammartino, Gilberto; Dohan Ehrenfest, David M

2008-09-01

Analysis of tomodensitometric controls following sinus grafts clearly demonstrates a quite systematic lack of homogeneity. Sinus contamination by anaerobic bacteria seems almost unavoidable during bone graft surgery, and this problem may jeopardize the healing process. The aim of this study was to characterize in a systematic way the nonhomogeneities observed at 1, 2, or 3 months postsurgery within allogenous sinus grafts, and to assess the possible influence of a 0.5% sterile solution of metronidazole incorporated in the sinus bone graft. This clinical study was conducted on 72 patients treated with single or bilateral sinus-lifts: 94 sinus elevations performed with freeze-dried bone allograft (Phoenix, TBF, Mions, France), with (test group) or without (control group) metronidazole. In the test group, each bone graft was hydrated with 2 mL of a 0.5% metronidazole solution, i.e., only 10 mg of metronidazole. All the patients went through a first presurgical computerized tomography (CT)-scan followed by a second scan performed at 1, 2, or 3 months postsurgery (which was used as the preimplant reference scan). For 11 patients, 2 postsurgical CT-scans were performed respectively at 10 days and 2 months. Using an arbitrary gray scale (Arbitrary Densitometric Unit) which functions according to the Hounsfield unit principle, the degree of radiographic homogeneity of the grafts was established. Density scattering provides some information on the homogeneity or nonhomogeneity of the bone graft. The 12 grafts performed without metronidazole show significant nonhomogeneities at 1, 2, or 3 months. Moreover, when a CT-scan is performed during the first postoperative days (at 10 days), the presence of air bubbles in the graft is confirmed. The tomodensitometric aspects of all grafts treated with metronidazole in this series are absolutely identical: they show a high degree of homogeneity. Sixty-three cases (76.8%) are homogeneous, and 19 cases (23.2%) are significantly

Preparation and evaluation of topical microemulsion system containing metronidazole for remission in rosacea.

PubMed

Tirnaksiz, Figen; Kayiş, Ayşegül; Çelebi, Nevin; Adişen, Esra; Erel, Arzu

2012-01-01

The aim of this study was to prepare a topical water-in-oil type microemulsion containing metronidazole and to compare its effectiveness with a commercial gel product in the treatment of rosacea. A pseudo-ternary phase diagram (K(m)=2:1) was constructed using lecithin/butanol/isopropyl myristate/water. The microemulsion was chosen from the microemulsion region in the phase diagram. The formulation was a water-in-oil type microemulsion (droplet size: 11.6 nm, viscosity: 457.3 mPa·s, conductivity: 1.5 µs/cm, turbidity: 6.89 NTU) and the addition of the metronidazole did not alter the properties of the system. The release experiment showed that the release rate of metronidazole from the commercial gel product was higher than that of the microemulsion. Stability experiments showed that the metronidazole microemulsion remained stable for at least 6 months; none of the characteristic properties of the microemulsion had changed, the system retained its clarity and there was no sign that crystallization of metronidazole has occurred. Microemulsion was compared to a gel product in a randomized, double-blind, baseline-controlled, split-face clinical trial for the treatment of patients. After the 6-week treatment period there was a statistically significant difference in reduction of the main symptoms of rosacea. Of the patients treated with the microemulsion, 17% experienced complete relief from inflammatory lesions, and 50% from erythema. The microemulsion resulted in complete relief in 38% of the patients with telangiectasia while the commercial product did not provide any relief of telangiectasia symptoms. In conclusion, the microemulsion containing metronidazole was found to be more effective in reducing the symptoms of rosacea compared to the commercial gel product.

Anti-anaerobic activity of levofloxacin alone and combined with clindamycin and metronidazole.

PubMed

Credito, K L; Jacobs, M R; Appelbaum, P C

2000-11-01

Microdilution MICs of levofloxacin against twelve anaerobes ranged between 0.5-8.0 microg/ml and those of clindamycin and metronidazole between 0.008-2.0 and 0.25->16.0 microg/ml, respectively. Combination of levofloxacin with clindamycin and/or metronidazole in time-kill tests led to synergy at levofloxacin concentrations at or below the MIC in 7/12 strains.

Clinical and Neuroradiological Spectrum of Metronidazole Induced Encephalopathy: Our Experience and the Review of Literature

PubMed Central

Panwar, Ajay; Pandit, Alak; Das, Susanta Kumar; Joshi, Bhushan

2016-01-01

Metronidazole is an antimicrobial agent mainly used in the treatment of several protozoal and anaerobic infections, additionally, is often used in hepatic encephalopathy and Crohn disease. Apart from peripheral neuropathy, metronidazole can also cause symptoms of central nervous system dysfunction like ataxic gait, dysarthria, seizures, and encephalopathy which may result from both short term and chronic use of this drug and is collectively termed as “metronidazole induced encephalopathy”(MIE). Neuroimaging forms the backbone in clinching the diagnosis of this uncommon entity, especially in cases where there is high index of suspicion of intoxication. Although typical sites of involvement include cerebellum, brain stem and corpus callosum, however, lesions of other sites have also been reported. Once diagnosed, resolution of findings on Magnetic Resonance Imaging (MRI) of the Brain along with clinical improvement remains the mainstay of monitoring. Here we review the key clinical features and MRI findings of MIE as reported in medical literature. We also analyze implication of use of this drug in special situations like hepatic encephalopathy and brain abscess and discuss our experience regarding this entity. PMID:27504340

Metronidazole-but not IL-10 or prednisolone-rescues Trichuris muris infected C57BL/6 IL-10 deficient mice from severe disease.

PubMed

Kopper, Jamie J; Patterson, Jon S; Mansfield, Linda S

2015-09-15

Trichuris muris infected C57BL/6 mice are a frequently studied model of immune mediated resistance to helminths. Our objective was to characterize dose-dependent gastrointestinal (GI) disease and pathology due to Trichuris in C57BL/6 mice with varying degrees of IL-10 sufficiency. These mice can serve as a model for other animals (dogs, cattle) and humans where IL-10 polymorphisms have been associated with disease susceptibility and may affect susceptibility to whipworm. C57BL/6 IL-10(+/+), IL-10(+/-) and IL-10(-/-) mice were infected with T. muris (J strain) in a dose response study. T. muris produced dose-dependent disease in IL-10(-/-) mice. Ninety percent of mice receiving the high dose (75 ova) had severe disease necessitating early euthanasia, while the medium dose (50 ova) resulted in 100% early euthanasia of males/75% of females, and the low dose (25 ova) in 100% early euthanasia of males/25% of females. Having some IL-10 as in heterozygotes did not rescue all infected mice from effects of the high dose. 2/21 IL-10(-/-), 1/17 IL-10(+/-), and 0/17 IL-10(+/+) mice in the high dose group had severe peritonitis and extra-intestinal bacteria confirmed by fluorescent 16S rDNA analysis of peritoneal organ surfaces. Three of twenty one IL-10(-/-) had demonstrable extra-intestinal T. muris adults. Although free from viral pathogens, 12/21 IL-10(-/-), 6/17 IL-10(+/-), and 4/17 IL-10(+/+) infected mice had hepatitis, while control mice of all genotypes did not. Mice had evidence of inflammation of serosal surfaces of liver, spleen and GI tract even when extraintestinal Trichuris were not found. Blinded histopathology scoring revealed that even when infected IL-10(-/-) mice displayed few, if any, clinical signs, levels of gut inflammation did not vary significantly from those mice euthanized early due to severe disease. To examine whether antibiotics or corticosteroids could reverse severe disease and lesions, IL-10(-/-) mice infected with T. muris were treated with

Trichomonas vaginalis: metronidazole and other nitroimidazole drugs are reduced by the flavin enzyme thioredoxin reductase and disrupt the cellular redox system. Implications for nitroimidazole toxicity and resistance.

PubMed

Leitsch, David; Kolarich, Daniel; Binder, Marina; Stadlmann, Johannes; Altmann, Friedrich; Duchêne, Michael

2009-04-01

Infections with the microaerophilic parasite Trichomonas vaginalis are treated with the 5-nitroimidazole drug metronidazole, which is also in use against Entamoeba histolytica, Giardia intestinalis and microaerophilic/anaerobic bacteria. Here we report that in T. vaginalis the flavin enzyme thioredoxin reductase displays nitroreductase activity with nitroimidazoles, including metronidazole, and with the nitrofuran drug furazolidone. Reactive metabolites of metronidazole and other nitroimidazoles form covalent adducts with several proteins that are known or assumed to be associated with thioredoxin-mediated redox regulation, including thioredoxin reductase itself, ribonucleotide reductase, thioredoxin peroxidase and cytosolic malate dehydrogenase. Disulphide reducing activity of thioredoxin reductase was greatly diminished in extracts of metronidazole-treated cells and intracellular non-protein thiol levels were sharply decreased. We generated a highly metronidazole-resistant cell line that displayed only minimal thioredoxin reductase activity, not due to diminished expression of the enzyme but due to the lack of its FAD cofactor. Reduction of free flavins, readily observed in metronidazole-susceptible cells, was also absent in the resistant cells. On the other hand, iron-depleted T. vaginalis cells, expressing only minimal amounts of PFOR and hydrogenosomal malate dehydrogenase, remained fully susceptible to metronidazole. Thus, taken together, our data suggest a flavin-based mechanism of metronidazole activation and thereby challenge the current model of hydrogenosomal activation of nitroimidazole drugs.

In vitro susceptibility of Giardia lamblia trophozoites to metronidazole and tinidazole.

PubMed

Jokipii, L; Jokipii, A M

1980-03-01

The number of motile Giardia lamblia trophozoites approximately doubled in axenic culture in 24 hr when 50% fresh medium was provided every 24 hr. In a microculture modification involving no change of medium, similar multiplication took place during the first 24 hr, and trophozoites remained motile for four days or longer. Metronidazole and tinidazole were active against G. lamblia in vitro, an observation suggesting that their effect in therapy of giardiasis is a direct one. The effect was rapid--high drug concentrations immobilized most trophozoites within 3.5 hr. There was an inverse relationship between duration of exposure and concentration of drug needed for significant immobilization: the effect of 0.1 microgram/ml was detectable after two to four days. Tinidazole was 4.4-fold as active as metronidazole; the minimal concentrations that immobilized 100% of trophozoites by 24 hr ranged from 0.2 to 12.5 microgram/ml and from 1.6 to 50 microgram/ml, respectively.

Sustained Simultaneous Delivery of Metronidazole and Doxycycline From Polycaprolactone Matrices Designed for Intravaginal Treatment of Pelvic Inflammatory Disease.

PubMed

Pathak, Meenakshi; Coombes, Allan G A; Ryu, BoMi; Cabot, Peter J; Turner, Mark S; Palmer, Cheryn; Wang, Dongjie; Steadman, Kathryn J

2018-03-01

Poly(ɛ-caprolactone) (PCL) intravaginal matrices were produced for local delivery of a combination of antibacterials, by rapidly cooling a mixture of drug powders dispersed in PCL solution. Matrices loaded with different combinations of metronidazole (10%, 15%, and 20% w/w) and doxycycline (10% w/w) were evaluated in vitro for release behavior and antibacterial activity. Rapid "burst release" of 8%-15% of the doxycycline content and 31%-37% of the metronidazole content occurred within 24 h when matrices were immersed in simulated vaginal fluid at 37°C. The remaining drug was extracted gradually over 14 days to a maximum of 65%-73% for doxycycline and 62%-71% for metronidazole. High levels of antibacterial activity up to 89%-91% against Gardnerella vaginalis and 84%-92% against Neisseria gonorrhoeae were recorded in vitro for release media collected on day 14, compared to "nonformulated" metronidazole and doxycycline solutions. Based on the in vitro data, the minimum levels of doxycycline and metronidazole released from PCL matrices in the form of intravaginal rings into vaginal fluid in vivo were predicted to exceed the minimum inhibitory concentrations for N. gonorrhea (reported range 0.5-4.0 μg/mL) and G. vaginalis (reported range 2-12.8 μg/mL) respectively, which are 2 of the major causative agents for pelvic inflammatory disease. Copyright © 2018. Published by Elsevier Inc.

Single Intravenous Dose of Novel Flurbiprofen-Loaded Proniosome Formulations Provides Prolonged Systemic Exposure and Anti-inflammatory Effect.

PubMed

Verma, Preeti; Prajapati, Sunil K; Yadav, Rajbharan; Senyschyn, Danielle; Shea, Peter R; Trevaskis, Natalie L

2016-11-07

Vesicular and colloidal delivery systems can be designed to control drug release spatially and temporally to improve drug efficacy and side effect profiles. Niosomes (vesicles prepared from nonionic surfactants in aqueous media) are gaining interest as an alternative vesicular delivery system as they offer advantages such as biocompatibility, chemical stability, low cost, high purity, and versatility. However, the physical stability of niosomes, like other vesicular systems, is limited by vesicle fusion, aggregation, and leakage. Proniosomes (dehydrated powder or gel formulations that spontaneously form niosomes on hydration with aqueous media) can overcome these physical stability problems and are more convenient for sterilization, storage, transport, distribution, and dosing. Proniosomes have mostly been explored for their potential to enhance transdermal and oral absorption. In this study we assess, for the first time, the potential for hydrated proniosomes to sustain systemic exposure and therapeutic effect after intravenous delivery. Proniosomes carrying the anti-inflammatory drug, flurbiprofen, were prepared by spraying different nonionic surfactants (span 20, span 40, and span 60 in varying ratios with span 80) and cholesterol onto a sorbitol carrier. The proniosome powders were characterized for surface morphology and flow properties. Niosome formation was assessed at three different hydration temperatures (25, 37, and 45 °C), and the niosomes were assessed for vesicle size, entrapment efficiency, and sterility. OLP proniosomes prepared with a high ratio of span 80 to span 20 were found to spontaneously form vesicles of small size and high drug loading on hydration with aqueous media. The OLP derived niosomes successfully sustained in vitro drug release, in vivo pharmacokinetics, and the anti-inflammatory effect of flurbiprofen in an acute (rat paw edema) model of inflammation when compared to a control solution formulation. The study demonstrates that

Ethnicity association of Helicobacter pylori virulence genotype and metronidazole susceptibility

PubMed Central

Alfizah, Hanafiah; Rukman, Awang Hamat; Norazah, Ahmad; Hamizah, Razlan; Ramelah, Mohamed

2013-01-01

AIM: To characterise the cag pathogenicity island in Helicobacter pylori (H. pylori) isolates by analysing the strains’ vacA alleles and metronidazole susceptibilities in light of patient ethnicity and clinical outcome. METHODS: Ninety-five H. pylori clinical isolates obtained from patients with dyspepsia living in Malaysia were analysed in this study. Six genes in the cagPAI region (cagE, cagM, cagT, cag13, cag10 and cag67) and vacA alleles of the H. pylori isolates were identified by polymerase chain reaction. The isolates’ metronidazole susceptibility was also determined using the E-test method, and the resistant gene was characterised by sequencing. RESULTS: More than 90% of the tested isolates had at least one gene in the cagPAI region, and cag67 was predominantly detected in the strains isolated from the Chinese patients, compared with the Malay and Indian patients (P < 0.0001). The majority of the isolates (88%) exhibited partial deletion (rearrangement) in the cagPAI region, with nineteen different patterns observed. Strains with intact or deleted cagPAI regions were detected in 3.2% and 8.4% of isolates, respectively. The prevalence of vacA s1m1 was significantly higher in the Malay and Indian isolates, whereas the isolates from the Chinese patients were predominantly genotyped as vacA s1m2 (P = 0.018). Additionally, the isolates from the Chinese patients were more sensitive to metronidazole than the isolates from the Malay and Indian patients (P = 0.047). Although we attempted to relate the cagPAI genotypes, vacA alleles and metronidazole susceptibilities to disease outcome, no association was observed. The vacA alleles were distributed evenly among the strains with intact, partially deleted or deleted cagPAI regions. Interestingly, the strains exhibiting an intact cagPAI region were sensitive to metronidazole, whereas the strains with a deleted cagPAI were more resistant. CONCLUSION: Successful colonisation by different H. pylori genotypes is

Ethnicity association of Helicobacter pylori virulence genotype and metronidazole susceptibility.

PubMed

Alfizah, Hanafiah; Rukman, Awang Hamat; Norazah, Ahmad; Hamizah, Razlan; Ramelah, Mohamed

2013-02-28

To characterise the cag pathogenicity island in Helicobacter pylori (H. pylori) isolates by analysing the strains' vacA alleles and metronidazole susceptibilities in light of patient ethnicity and clinical outcome. Ninety-five H. pylori clinical isolates obtained from patients with dyspepsia living in Malaysia were analysed in this study. Six genes in the cagPAI region (cagE, cagM, cagT, cag13, cag10 and cag67) and vacA alleles of the H. pylori isolates were identified by polymerase chain reaction. The isolates' metronidazole susceptibility was also determined using the E-test method, and the resistant gene was characterised by sequencing. More than 90% of the tested isolates had at least one gene in the cagPAI region, and cag67 was predominantly detected in the strains isolated from the Chinese patients, compared with the Malay and Indian patients (P < 0.0001). The majority of the isolates (88%) exhibited partial deletion (rearrangement) in the cagPAI region, with nineteen different patterns observed. Strains with intact or deleted cagPAI regions were detected in 3.2% and 8.4% of isolates, respectively. The prevalence of vacA s1m1 was significantly higher in the Malay and Indian isolates, whereas the isolates from the Chinese patients were predominantly genotyped as vacA s1m2 (P = 0.018). Additionally, the isolates from the Chinese patients were more sensitive to metronidazole than the isolates from the Malay and Indian patients (P = 0.047). Although we attempted to relate the cagPAI genotypes, vacA alleles and metronidazole susceptibilities to disease outcome, no association was observed. The vacA alleles were distributed evenly among the strains with intact, partially deleted or deleted cagPAI regions. Interestingly, the strains exhibiting an intact cagPAI region were sensitive to metronidazole, whereas the strains with a deleted cagPAI were more resistant. Successful colonisation by different H. pylori genotypes is dependent on the host's genetic makeup and may

Cumulative irritation potential of metronidazole gel compared to azelaic acid gel after repeated applications to healthy skin.

PubMed

Ziel, Kristin; Yelverton, Christopher B; Balkrishnan, Rajesh; Feldman, Steven R

2005-01-01

Metronidazole 0.75% gel and azelaic acid 15% gel are commonly used to treat rosacea. Irritation is a common side effect. To assess the cumulative irritation potential of metronidazole 0.75% gel and azelaic acid 15% gel. Metronidazole 0.75% gel, azelaic acid 15% gel, and a white petrolatum negative control were applied under occlusive conditions to the upper back of a total of 33 healthy subjects. There were twelve 24-hour applications (4 times a week) and three 72-hour applications on weekends during a 3-week period. Skin reactions (erythema score +/- other local reaction) were assessed within 15 to 30 minutes of removal of the products. The mean cumulative irritancy index of metronidazole 0.75% gel was significantly lower than that of azelaic acid 15% gel and not significantly higher than the negative control product. There was increasing cumulative irritancy with azelaic acid; no cumulative irritancy was seen for either metronidazole or white petrolatum. Metronidazole 0.75% gel is less irritating in sustained use than azelaic acid 15% gel.

Pharmacokinetics and tolerability of intravenous ibuprofen injection in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose study
.

PubMed

Zhou, Huili; Xu, Wei; Wu, Guolan; Wu, Lihua; Shentu, Jianzhong; Pan, Zhengfei; Hu, Shuai; Liu, Yang

2016-11-01

Recently a formulation of intravenous (IV) ibuprofen was developed in China for management of mild to moderate pain in patients who could not take oral medications or where intravenous administration was preferable. The aim of this study was to evaluate the pharmacokinetic properties and tolerability of single and multiple doses of ibuprofen injection in healthy Chinese volunteers. This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. In the single-dose phase, subjects were randomized to receive a single dose of ibuprofen injection 0.2, 0.4, or 0.8 g administered as a 30-minute IV infusion with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 12.5 hours after drug administration and were analyzed using a validated LC-MS/MS method. In the multiple-dose phase, subjects received 0.4 g ibuprofen every 6 hours for 9 doses. Blood samples were obtained before the 7^th, 8^th, and 9^th administration to determine the C_min at steady state; on the 9^th intravenous administration, blood samples were also collected for 12.5 hours after drug administration. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). A total of 12 healthy male (n = 6) and female (n = 6) Chinese volunteers were enrolled and completed the trial. After IV administration of single dose, the mean (SD) C_max value increased from 35.77 (6.98) to 117.12 (19.78) µg/mL, and the mean (SD) AUC_0-t value increased from 67.63 (10.30) to 230.50 (33.55) µg×h/mL in the range of 0.2-g to 0.8-g dose. The terminal half-life in plasma was ~ 2.0 hours. After IV administration of 9 doses of ibuprofen 400 mg every 6 hours, the mean (SD) C_max was 66.49 (8.49) µg/mL, the AUC_0-t was 135.65 (26.91) µg×h/mL, the t₁

The genetic diversity of metronidazole susceptibility in Trichomonas vaginalis clinical isolates in an Egyptian population.

PubMed

Abdel-Magied, Aida A; El-Kholya, El-Said I; Abou El-Khair, Salwa M; Abdelmegeed, Eman S; Hamoudaa, Marwa M; Mohamed, Sara A; El-Tantawy, Nora Labeeb

2017-11-01

Trichomoniasis is the most common curable sexually transmitted disease worldwide. Resistance to metronidazole in treating trichomoniasis is a problematic health issue. We aimed to determine the minimum lethal concentration (MLC) of metronidazole for Trichomonas vaginalis isolates detected in Mansoura, Egypt and studied the genotypic profile of these isolates. Vaginal swab specimens were obtained from 320 symptomatic and 100 asymptomatic females, for whom clinical examination, vaginal discharge wet mount, Giemsa stain, and culture in modified Diamond's media were performed. Metronidazole susceptibility testing by an aerobic tube assay was performed. Both sensitive and resistant isolates were examined by PCR amplification followed by restriction fragment length polymorphism (RFLP). Trichomonas vaginalis was identified in 49/420 (11.7%) using either culture or PCR, while wet mount and Giemsa stain detected the parasite in 8.1 and 7.6% of participants, respectively. After 48 h incubation, most isolates were sensitive to metronidazole with a minimal lethal concentration (MLC) of 1 μg/ml. Mild resistance was observed in two isolates with MLCs of 64 μg\\ml and mild to moderate resistance was observed in an additional two isolates with MLCs of 128 μg/ml. The four isolates that demonstrated low to moderate metronidazole resistance displayed a unique genotype band pattern by RFLP compared to the other 45 samples that were metronidazole sensitive. Our results highlight the presence of in vitro metronidazole tolerance in a few T. vaginalis isolates in Mansoura, Egypt that may lead to the development of drug resistance as well as the possibility of an identifying RFLP pattern in the isolates.

Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial.

PubMed

Veal, G J; Nguyen, L; Paci, A; Riggi, M; Amiel, M; Valteau-Couanet, D; Brock, P; Ladenstein, R; Vassal, G

2012-11-01

Busulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study. Busulfan was administered four times daily for 4 days to children aged 0.7-13.1 years, either orally (1.45-1.55 mg/kg) or by the IV route (0.8-1.2mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography-mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach. Busulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146 ± 187 μM.min (range 838-1622), as compared to 953 ± 290 μM.min (range 434-1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900-1500 μM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177 ± 189 μM.min versus 913 ± 256 μM.min; p=0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration. The reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial. Copyright © 2012 Elsevier Ltd. All

The role of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea.

PubMed

Tart, Serina B

2013-10-01

For the treatment of Clostridium difficile-associated diarrhea (CDAD), metronidazole and vancomycin remain the most commonly used agents. The major advantage of metronidazole is its low cost, while the advantage of oral vancomycin is a more favorable pharmacokinetic profile. The epidemiology and clinical severity of CDAD have changed due to the emergence of a hypervirulent strain (BI/NAP1/027). In 2010, the Infectious Diseases Society of America/Society for Health Care Epidemiology of America expert panel defined severe CDAD and recommended oral vancomycin to treat these patients. Metronidazole remains the preferred agent for treatment of mild to moderate CDAD.

Intravenous ferric carboxymaltose for the treatment of iron deficiency anemia

PubMed Central

Friedrisch, João Ricardo; Cançado, Rodolfo Delfini

2015-01-01

Nutritional iron deficiency anemia is the most common deficiency disorder, affecting more than two billion people worldwide. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia, but in many conditions, oral iron is less than ideal mainly because of gastrointestinal adverse events and the long course needed to treat the disease and replenish body iron stores. Intravenous iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell made of polymers such as dextran, sucrose or gluconate. The first iron product for intravenous use was the high molecular weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to use intravenous iron for the treatment of iron deficiency anemia over many years. Intravenous ferric carboxymaltose is a stable complex with the advantage of being non-dextran-containing and a very low immunogenic potential and therefore not predisposed to anaphylactic reactions. Its properties permit the administration of large doses (15 mg/kg; maximum of 1000 mg/infusion) in a single and rapid session (15-minute infusion) without the requirement of a test dose. The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, and safety profile of ferric carboxymaltose in the treatment of patients with iron deficiency anemia. PMID:26670403

[Single intravenous tranexamic acid dose to reduce blood loss in primary total knee replacement].

PubMed

Sanz-Reig, J; Parra Ruiz, B; Ferrández Martínez, J; Martínez López, J F

2016-01-01

To evaluate the effectiveness and safety of a single intravenous dose of tranexamic acid in order to reduce blood loss in total knee replacement. Prospective observational study of the administration of tranexamic acid in patients undergoing primary total knee arthroplasty from November 2013 to February 2015, in which an autologous blood recovery system was used. The study included 98 patients, distributed into two groups of 49 patients according to whether or not they received intravenous tranexamic acid. The primary endpoint was the number of patients requiring autologous transfusion from the recovery system autologous blood recovery system. No drop-outs were recorded during follow-up. There were no significant differences between groups as regards the preoperative and hospital variables. The mean preoperative haemoglobin and haematocrit at 24 and 48 hours postoperatively were similar in both groups. The average volume of bleeding in the autologous blood recovery system and estimated average blood loss was lower in patients who had been administered tranexamic acid, with significant differences. No patients in the group that was administered tranexamic acid required blood autotransfusion. The transfusion rate was zero in the two groups. No adverse events related to the administration of tranexamic acid were recorded. Intravenous administration of tranexamic acid, according to the described protocol, has presented a non-autotransfusion or allo-transfusion rate of 100%, with no increased incidence of thrombotic events. Thus, its use in this group of patients is recommended. The indication should be individualized, its use justified in the patient medical records, and informed consent is mandatory. Copyright © 2015 SECOT. Published by Elsevier Espana. All rights reserved.

Resistance of Bacteroides isolates recovered among clinical samples from a major Costa Rican hospital between 2000 and 2008 to ß-lactams, clindamycin, metronidazole, and chloramphenicol.

PubMed

Cordero-Laurent, E; Rodríguez, C; Rodríguez-Cavallini, E; Gamboa-Coronado, M M; Quesada-Gómez, C

2012-12-01

To assess the susceptibility of 100 isolates of Bacteroides spp. recovered in a major Costa Rican hospital between 2000 and 2008 to several ß-lactams, chloramphenicol, clindamycin and metronidazole. Susceptibility to amoxicillin, amoxicillin with clavulanic acid, piperacillin, piperacillin with tazobactam, ticarcillin, ticarcillin with clavulanic acid, cefoxitin, cefotetan, imipenem, chloramphenicol, clindamycin, and metronidazole was determined with the ATB ANA® system. In addition, minimum inhibitory concentrations (MIC) of clindamycin and metronidazole were determined with the broth microdilution method because these drugs are the treatment of choice for anaerobic infections in Costa Rica. Reference strains ATCC® 25285 and ATCC® 29741 were employed as indicated. According to the ATB ANA® system, 93 isolates were resistant to at least one antibiotic. Resistance to ß-lactams was common. By contrast, resistance to ß-lactams supplemented with ß-lactamase inhibitors was rare. All of the strains were inhibited by imipenem and chloramphenicol. By a broth microdilución test, resistance to clindamycin was 20%, with MIC ranging from 64 mg/L to 256 mg/L; all of the strains were susceptible to metronidazole. The high MIC for clindamycin obtained for the majority of the resistant strains is highly suggestive of the presence of mechanisms of acquired resistance among the isolates, therefore surveillance studies are required to determine its efficacy. The low resistance to metronidazole observed underlines its value as a first-line drug. On the other hand, imipenem could be used to treat infections that do not respond well to metronidazole or clindamycin.

Metronidazole-Loaded Polyethyleneimine and Chitosan-Based Liquid Crystalline System for Treatment of Staphylococcal Skin Infections.

PubMed

Victorelli, Francesca Damiani; Calixto, Giovana Maria Fioramonti; Ramos, Matheus Aparecido Dos Santos; Bauab, Taís Maria; Chorilli, Marlus

2018-01-01

Staphylococcus aureus is a common gram-positive bacterium of the human skin microbiota. It is also a dangerous pathogen that can cause serious and even lethal skin infections. The topical administration of metronidazole via nanotechnology-based drug delivery systems, such as liquid crystalline systems, can modulate both the drug permeation and activity, decreasing its side effects and increasing the drug potent activity against the gram-positive bacteria. This study aimed at: (1) structurally developing and characterizing a liquid crystalline systems composed of chitosan and polyethyleneimine dispersion as the aqueous phase, oleic acid as the oily phase, and ethoxylated and propoxylated cetyl alcohol as the surfactant (FPC) for metronidazole incorporation (0.5% w/w); (2) evaluating the in vitro release and skin permeation and retention properties of the metronidazole-loaded liquid crystalline systems (FPC-M); (3) investigating the in vitro antibacterial activity of FPC-M against Staphylococcus aureus. Polarised light microscopy indicated that both FPC and FPC-M are hexagonal systems. Rheological, texture, and bioadhesion assays showed that both are elastic and bioadhesive systems. According to the results of the in vitro release, permeation, and retention assays, FPC can modulate metronidazole release and allow metronidazole to stay for a longer time on the skin. The determination of FPC-M activity against Staphylococcus aureus showed that it could target the bacterial cell. In conclusion, the liquid crystalline systems developed in this study can improve the clinical performance of metronidazole in the treatment of staphylococcal skin infections.

Waste Material of Propolis as a Film Forming Agent Intended to Modify the Metronidazole Release: Preparation and Characterization.

PubMed

de Toledo, Lucas de Alcântara Sica; Rosseto, Hélen Cássia; Ravani, Laura; Cortesi, Rita; Bruschi, Marcos Luciano

2016-01-01

Metronidazole is an antimicrobial agent utilized for the treatment of protozoa and anaerobic bacteria infections. Many times, it is necessary to modify the metronidazole release, and the development of modified release systems may be suggested. In this study, we are able to investigate the use of the residue normally thrown out from the preparation of propolis extracts (BP) as strategy to modify the metronidazole release. We prepared films containing polymeric adjuvant (gelatin or ethylcellulose) and metronidazole, by solvent casting method. Density, mechanical properties, water vapor permeability (WVP), moisture uptake capacity (MUC), thermogravimetry, differential scanning calorimetry, Fourier transform infrared spectroscopy (FT-IR), and in vitro metronidazole release were investigated. Thickness and density of the preparations indicated that the compounds were homogeneously dispersed throughout. Mechanical properties were influenced by film composition. Films containing gelatin showed higher resistance to stress while those containing ethylcellulose presented greater flexibility. The greater the adjuvant concentrations lower the resistance to rupture and the elasticity, but higher MUC and WVP of formulations. FT-IR tests suggested interactions between BP and the adjuvants. Films were capable to protect the metronidazole and changed its release profile. BP films are of great practical importance constituting a novel strategy to modify the metronidazole release.

Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg.

PubMed

Wark, J D; Bensen, W; Recknor, C; Ryabitseva, O; Chiodo, J; Mesenbrink, P; de Villiers, T J

2012-02-01

Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms. Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen. In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion. The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p < 0.0001) compared with background rates of 11.1% and 16.7%, respectively, in the absence of any active treatment. Overall incidence of adverse events was comparable for patients receiving acetaminophen/paracetamol or ibuprofen. Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg.

Metronidazole Resistance in Prevotella spp. and Description of a New nim Gene in Prevotella baroniae▿

PubMed Central

Alauzet, C.; Mory, F.; Teyssier, C.; Hallage, H.; Carlier, J. P.; Grollier, G.; Lozniewski, A.

2010-01-01

Nonduplicate clinical isolates of Prevotella spp. recovered from patients hospitalized between 2003 and 2006 in two French tertiary-care teaching hospitals were investigated for their susceptibility to metronidazole and the presence of nim genes. Of the 188 strains tested, 3 isolates displayed reduced susceptibility to metronidazole after 48 h of incubation, while 27 additional isolates exhibited heterogeneous resistance after prolonged incubation; all 30 of the isolates were nim negative. Among the remaining 158 isolates, 7 nim-positive isolates were detected. All of these strains were identified as Prevotella baroniae by 16S rRNA gene sequence analysis and contained a new nim gene, named nimI, as determined by DNA sequence analysis. Chromosomal localization of this single-copy gene was demonstrated in all clinical isolates as well as in type strain P. baroniae DSM 16972 by using Southern hybridization. No known associated insertion sequence elements were detected upstream of the nimI gene in any of the nim-positive strains by PCR mapping. After prolonged exposure to metronidazole, stable resistant subpopulations could be selected in nimI-positive Prevotella isolates (n = 6) as well as in nim-negative Prevotella isolates (n = 6), irrespective of their initial susceptibility to this antibiotic. This study is the first description of a new nitroimidazole resistance gene in P. baroniae which seems to be silent and which might be intrinsic in this species. Moreover, our findings highlight the fact that high-level resistance to metronidazole may be easily induced in both nim-positive and nim-negative Prevotella sp. strains. PMID:19805556

Comparison of two doses of intravenous temsirolimus in patients with relapsed/refractory mantle cell lymphoma.

PubMed

Jurczak, Wojciech; Ramanathan, Sundra; Giri, Pratyush; Romano, Alessandra; Mocikova, Heidi; Clancy, Jill; Lechuga, Mariajose; Casey, Michelle; Boni, Joseph; Giza, Agnieszka; Hess, Georg

2018-03-01

Temsirolimus 175 mg once-weekly for 3 weeks, followed by 75 mg once-weekly intravenously dosed (175/75 mg) is approved in the European Union for treatment of relapsed/refractory mantle cell lymphoma (MCL). A phase IV study explored whether similar efficacy, but improved safety could be achieved with 75 mg without 175 mg loading doses (ClinicaTrials.gov: NCT01180049). Patients with relapsed/refractory MCL were randomized to once-weekly temsirolimus 175/75 mg (n = 47) or 75 mg (n = 42). Treatment continued until objective disease progression. Primary endpoint: progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). Median PFS was 4.3 versus 4.5 months (hazard ratio [HR] 0.731; 80% confidence interval [CI], 0.520-1.027), and median OS 18.7 versus 11.0 months (HR 0.681; 80% CI, 0.472-0.982) with 175/75 mg versus 75 mg. There were fewer patients with serious AEs, dose reduction, or death with 175/75 mg (57.4%, 48.9%, and 48.9%) versus 75 mg (73.8%, 64.3%, and 65.1%). Temsirolimus 175/75 mg remains the preferred dosing regimen for relapsed/refractory MCL.

A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers.

PubMed

Agarwal, Suresh K; Kriel, Robert L; Cloyd, James C; Coles, Lisa D; Scherkenbach, Lisa A; Tobin, Michael H; Krach, Linda E

2015-01-01

Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose-adjusted areas under the curve between the oral and intravenous arms were statistically different (P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5-mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures. © The Author(s) 2014.

Evaluation of polycaprolactone matrices for the intravaginal delivery of metronidazole in the treatment of bacterial vaginosis.

PubMed

Pathak, Meenakshi; Turner, Mark; Palmer, Cheryn; Coombes, Allan G A

2014-09-01

Microporous, poly (ɛ-caprolactone) (PCL) matrices loaded with the antibacterial, metronidazole were produced by rapidly cooling suspensions of drug powder in PCL solutions in acetone. Drug incorporation in the matrices increased from 2.0% to 10.6% w/w on raising the drug loading of the PCL solution from 5% to 20% w/w measured with respect to the PCL content. Drug loading efficiencies of 40-53% were obtained. Rapid 'burst release' of 35-55% of the metronidazole content was recorded over 24 h when matrices were immersed in simulated vaginal fluid (SVF), due to the presence of large amounts of drug on matrix surface as revealed by Raman microscopy. Gradual release of around 80% of the drug content occurred over the following 12 days. Metronidazole released from PCL matrices in SVF retained antimicrobial activity against Gardnerella vaginalis in vitro at levels up to 97% compared to the free drug. Basic modelling predicted that the concentrations of metronidazole released into vaginal fluid in vivo from a PCL matrix in the form of an intravaginal ring would exceed the minimum inhibitory concentration of metronidazole against G. vaginalis. These findings recommend further investigation of PCL matrices as intravaginal devices for controlled delivery of metronidazole in the treatment and prevention of bacterial vaginosis. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Metronidazole and the immune system.

PubMed

Shakir, L; Javeed, A; Ashraf, M; Riaz, A

2011-06-01

Metronidazole (MTZ) is a nitroimidazole antibiotic used mainly for the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa. Distinct from its antibiotic, amoebicidal, and antiprotozoal effects, MTZ displays immunopharmacological behaviour. This review outlines multiple effects of MTZ on different aspects of immunity, including innate and acquired immunity, and also highlights the immunopharmacological behaviour of MTZ in terms of its relevance to inflammation, delayed type hypersensitivity (DTH) and graft versus host disease (GVHD).

Molecular and Proteomic Analysis of Levofloxacin and Metronidazole Resistant Helicobacter pylori.

PubMed

Hanafi, Aimi; Lee, Woon Ching; Loke, Mun Fai; Teh, Xinsheng; Shaari, Ain; Dinarvand, Mojdeh; Lehours, Philippe; Mégraud, Francis; Leow, Alex Hwong Ruey; Vadivelu, Jamuna; Goh, Khean Lee

2016-01-01

Antibiotic resistance in bacteria incurs fitness cost, but compensatory mechanisms may ameliorate the cost and sustain the resistance even under antibiotics-free conditions. The aim of this study was to determine compensatory mechanisms of antibiotic resistance in H. pylori . Five strains of levofloxacin-sensitive H. pylori were induced in vitro to develop resistance. In addition, four pairs of metronidazole-sensitive and -resistant H. pylori strains were isolated from patients carrying dual H. pylori populations that consist of both sensitive and resistant phenotypes. Growth rate, virulence and biofilm-forming ability of the sensitive and resistant strains were compared to determine effects of compensatory response. Proteome profiles of paired sensitive and resistant strains were analyzed by liquid chromatography/mass spectrophotometry (LC/MS). Although there were no significant differences in growth rate between sensitive and resistant pairs, bacterial virulence (in terms of abilities to induce apoptosis and form biofilm) differs from pair to pair. These findings demonstrate the complex and strain-specific phenotypic changes in compensation for antibiotics resistance. Compensation for in vitro induced levofloxacin resistance involving mutations of gyrA and gyrB was functionally random. Furthermore, higher protein translation and non-functional protein degradation capabilities in naturally-occuring dual population metronidazole sensitive-resistant strains may be a possible alternative mechanism underlying resistance to metronidazole without mutations in rdxA and frxA . This may explain the lack of mutations in target genes in ~10% of metronidazole resistant strains.

Molecular and Proteomic Analysis of Levofloxacin and Metronidazole Resistant Helicobacter pylori

PubMed Central

Hanafi, Aimi; Lee, Woon Ching; Loke, Mun Fai; Teh, Xinsheng; Shaari, Ain; Dinarvand, Mojdeh; Lehours, Philippe; Mégraud, Francis; Leow, Alex Hwong Ruey; Vadivelu, Jamuna; Goh, Khean Lee

2016-01-01

Antibiotic resistance in bacteria incurs fitness cost, but compensatory mechanisms may ameliorate the cost and sustain the resistance even under antibiotics-free conditions. The aim of this study was to determine compensatory mechanisms of antibiotic resistance in H. pylori. Five strains of levofloxacin-sensitive H. pylori were induced in vitro to develop resistance. In addition, four pairs of metronidazole-sensitive and -resistant H. pylori strains were isolated from patients carrying dual H. pylori populations that consist of both sensitive and resistant phenotypes. Growth rate, virulence and biofilm-forming ability of the sensitive and resistant strains were compared to determine effects of compensatory response. Proteome profiles of paired sensitive and resistant strains were analyzed by liquid chromatography/mass spectrophotometry (LC/MS). Although there were no significant differences in growth rate between sensitive and resistant pairs, bacterial virulence (in terms of abilities to induce apoptosis and form biofilm) differs from pair to pair. These findings demonstrate the complex and strain-specific phenotypic changes in compensation for antibiotics resistance. Compensation for in vitro induced levofloxacin resistance involving mutations of gyrA and gyrB was functionally random. Furthermore, higher protein translation and non-functional protein degradation capabilities in naturally-occuring dual population metronidazole sensitive-resistant strains may be a possible alternative mechanism underlying resistance to metronidazole without mutations in rdxA and frxA. This may explain the lack of mutations in target genes in ~10% of metronidazole resistant strains. PMID:28018334

A Reprofiled Drug, Auranofin, Is Effective against Metronidazole-Resistant Giardia lamblia

PubMed Central

Tejman-Yarden, Noa; Miyamoto, Yukiko; Leitsch, David; Santini, Jennifer; Debnath, Anjan; Gut, Jiri; McKerrow, James H.; Reed, Sharon L.

2013-01-01

Giardiasis is one of the most common causes of diarrheal disease worldwide. Treatment is primarily with 5-nitro antimicrobials, particularly metronidazole. Resistance to metronidazole has been described, and treatment failures can occur in up to 20% of cases, making development of alternative antigiardials an important goal. To this end, we have screened a chemical library of 746 approved human drugs and 164 additional bioactive compounds for activity against Giardia lamblia. We identified 56 compounds that caused significant inhibition of G. lamblia growth and attachment. Of these, 15 were previously reported to have antigiardial activity, 20 were bioactive but not approved for human use, and 21 were drugs approved for human use for other indications. One notable compound of the last group was the antirheumatic drug auranofin. Further testing revealed that auranofin was active in the low (4 to 6)-micromolar range against a range of divergent G. lamblia isolates representing both human-pathogenic assemblages A and B. Most importantly, auranofin was active against multiple metronidazole-resistant strains. Mechanistically, auranofin blocked the activity of giardial thioredoxin oxidoreductase, a critical enzyme involved in maintaining normal protein function and combating oxidative damage, suggesting that this inhibition contributes to the antigiardial activity. Furthermore, auranofin was efficacious in vivo, as it eradicated infection with different G. lamblia isolates in different rodent models. These results indicate that the approved human drug auranofin could be developed as a novel agent in the armamentarium of antigiardial drugs, particularly against metronidazole-resistant strains. PMID:23403423

Pharmacokinetics of marbofloxacin in pigs after intravenous and intramuscular administration of a single dose of 8 mg/kg: dose proportionality, influence of the age of the animals and urinary elimination

PubMed Central

Schneider, M; Paulin, A; Dron, F; Woehrlé, F

2014-01-01

The pharmacokinetics of marbofloxacin in pigs were evaluated as a function of dose and animal age following intravenous and intramuscular administration of a 16% solution (Forcyl®). The absolute bioavailability of marbofloxacin as well as the dose proportionality was evaluated in 27-week-old fattening pigs. Blood PK and urinary excretion of marbofloxacin were evaluated after a single intramuscular dose of 8 mg/kg in 16-week-old male pigs. An additional group of 12-week-old weaned piglets was used for the evaluation of age-related kinetics. The plasma and urine concentration of marbofloxacin was determined using a HPLC method. Pharmacokinetic parameters were calculated using noncompartmental methods. After intravenous administration in 27-week-old fattening pigs, the total body clearance was 0.065 L/h·kg. After intramuscular administration to the same animals, the mean observed Cmax was 6.30 μg/mL, and the AUCINF was 115 μg·h/mL. The absolute bioavailability was 91.5%, and dose proportionality was shown within the dose range of 4–16 mg/kg. The renal clearance was about half of the value of the total clearance. The total systemic clearance values significantly decreased as a function of age, being 0.092 L/h·kg and 0.079 L/h·kg in pigs aged 12 and 16 weeks, respectively. PMID:24666477

Biowaiver monographs for immediate release solid oral dosage forms: metronidazole.

PubMed

Rediguieri, Camila F; Porta, Valentina; G Nunes, Diana S; Nunes, Taina M; Junginger, Hans E; Kopp, Sabine; Midha, Kamal K; Shah, Vinod P; Stavchansky, Salomon; Dressman, Jennifer B; Barends, Dirk M

2011-05-01

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing metronidazole are reviewed. Metronidazole can be assigned to Biopharmaceutics Classification System Class I. Most BE studies that were identified reported the investigated formulations to be bioequivalent, indicating the risk of bioinequivalence to be low. Formulations showing differences in bioavailability showed dissimilarities in in vitro dissolution profiles. Furthermore, metronidazole has a wide therapeutic index. It is concluded that a biowaiver for solid IR formulations is justified, provided: (a) the test product and its comparator are both rapidly dissolving; (b) meet similarity of the dissolution profiles at pH 1.2, 4.5, and 6.8; (c) the test product contains only excipients present in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form; and (d) if the test product contains sorbitol, sodium laurilsulfate, or propylene glycol, the test product needs to be qualitatively and quantitatively identical to its comparator with respect to these excipients [corrected].. Copyright © 2011 Wiley-Liss, Inc.

Synthesis of metronidazole-imprinted molecularly imprinted polymers by distillation precipitation polymerization and their use as a solid-phase adsorbent and chromatographic filler.

PubMed

Liu, Jiang; Zhang, Lu; Li Han Song, Le; Liu, Yuan; Tang, Hui; Li, Yingchun

2015-04-01

Metronidazole-imprinted polymers with superior recognition properties were prepared by a novel strategy called distillation-precipitation polymerization. The as-obtained polymers were characterized by Fourier-transform infrared spectroscopy, laser particle size determination and scanning electron microscopy, and their binding performances were evaluated in detail by static, kinetic and dynamic rebinding tests, and Scatchard analysis. The results showed that when the fraction of the monomers was 5 vol% in the whole reaction system, the prepared polymers afforded good morphology, monodispersity, and high adsorption capacity and excellent selectivity to the target molecule, metronidazole. The optimal binding performance is 12.41 mg/g for metronidazole just before leakage occurred and 38.51 mg/g at saturation in dynamic rebinding tests. Metronidazole-imprinted polymers were further applied as packing agents in solid-phase extraction and as chromatographic filler, both of which served for the detection of metronidazole in fish tissue. The results illustrated the recoveries of spiked samples ranged from 82.97 to 87.83% by using molecularly imprinted solid-phase extraction combined with a C18 commercial column and 93.7 to 101.2% by directly using the polymer-packed chromatographic column. The relative standard deviation of both methods was less than 6%. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The appearance of facial foundation cosmetics applied after metronidazole gel 1%.

PubMed

Draelos, Zoe D; Colón, Luz E; Preston, Norman; Johnson, Lori A; Gottschalk, Ronald W

2011-05-01

The purpose of this study was to assess the cosmetic appearance of commonly marketed facial cosmetics when used after the application of metronidazole gel 1%. An observational. open-label, single-site study was conducted with women (N=30) aged 20 to 75 years and diagnosed with moderate papulopustular rosacea (investigator global severity score of 3). After cleansing the face with a gentle skin cleanser, participants applied metronidazole gel 1% once daily before applying their usual facial foundation. Two surveys were conducted: (1) investigator assessment of cosmetic appearance; and (2) participant assessment of cosmetic appearance. The investigator also evaluated erythema, disease severity, and tolerability at baseline and week 2. Adverse events were collected. The 28 per-protocol (PP) participants had a mean age (standard deviation [SD]) of 54.0 (10.3) years and a mean duration (SD) of rosacea of 15.4 (13.2) years. The median response score for both the investigator and participant assessments of cosmetic appearance was 10 (best) for each survey question. Signs and symptoms of rosacea did not increase with use of metronidazole gel 1% and the participants' selected cosmetic regimen. At baseline all 28 participants were classified as having moderate erythema. At week 2, 18 (64%) participants were classified as having moderate erythema and 10 (36%) mild. At baseline all 28 (100%) participants were classified as having moderate rosacea according to the investigator global severity score. At week 2, 10 (36%) participants were classified as mild and 18 (64%) moderate. In addition, few participants reported cutaneous irritation during the study. At week 2, 10 participants had dryness, 2 had itching, 8 had scaling, and 2 had stinging/burning. According to surveys completed by the investigator and the participants themselves, most participants had a good cosmetic appearance with their facial foundation cosmetics that were applied after metronidazole gel 1%. The use of

Ameliorative effects of curcumin on the spermatozoon tail length, count, motility and testosterone serum level in metronidazole-treated mice.

PubMed

Karbalay-Doust, S; Noorafshan, A

2011-01-01

Metronidazole (MTZ) is used as an antiparasitic drug. Curcumin is considered as anti-oxidant and anti-inflammatory agent. The ameliorative effects of curcumin on MTZ induced toxicity on mice spermatozoon tail length, count, motility and testosterone level were investigated. MTZ was administered in 500 and 165 (high and therapeutic doses) mg/kg/day, with and without curcumin (100 mg/kg/day). After 16 days the above parameters were assessed. Spermatozoon count and motility and serum testosterone level MTZ-treated (500 and 165) mice were reduced. In the mice treated with MTZ+curcumin these parameters decreased but in a lesser extent than the MTZ-treated animals. Mid-piece and total lengths of the spermatozoon tail in control animals were 31.6 ± 9.0 μm and 100.3 ± 15.0 μm and in the mice treated with high doses (500) of MTZ were reduced. The mid-piece and total spermatozoon tail length has been decreased in a lesser extent in the mice treated with high dose MTZ+curcumin than the mice treated with high dose MTZ (p<0.01). But the length was not changed in animals treated with therapeutic dose of MTZ. It means curcumin treated animals had ~52% and ~39% average increase in mid-piece and total lengths in comparison with the MTZ-treated (500) animals. Stereological estimation of the sperm tail length, including sampling of spermatozoa and also counting of the intersections of their tails with the stereological grids was a rapid technique and took only 5-10 minutes. It can be concluded that curcumin has an ameliorative effect on the spermatozoon, testosterone level and tail length in MTZ-treated mice.

Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study

PubMed Central

Steele, Megan L.; Axtner, Jan; Happe, Antje; Kröz, Matthias; Matthes, Harald; Schad, Friedemann

2014-01-01

Background. Traditional mistletoe therapy in cancer patients involves subcutaneous applications of Viscum album L. preparations, with doses slowly increasing based on patient responses. Intravenous infusion of high doses may improve therapeutic outcomes and is becoming more common. Little is known about the safety of this “off-label” application of mistletoe. Methods. An observational study was performed within the Network Oncology. Treatment with intravenous mistletoe applications is described. The frequency of adverse drug reactions (ADRs) to intravenous mistletoe applications was calculated and compared to ADR data from a study on subcutaneous applications. Results. Of 475 cancer patients who received intravenous infusions of Helixor, Abnoba viscum, or Iscador mistletoe preparations, 22 patients (4.6%) reported 32 ADRs of mild (59.4%) or moderate severity (40.6%). No serious ADRs occurred. ADRs were more frequently reported to i.v. mistletoe administered alone (4.3%), versus prior to chemotherapy (1.6%). ADR frequency differed with respect to preparation type, with Iscador preparations showing a higher relative frequency, compared to Abnoba viscum and Helixor. Overall, patients were almost two times less likely to experience an ADR to intravenous compared to subcutaneous application of mistletoe. Conclusion. Intravenous mistletoe therapy was found to be safe and prospective studies for efficacy are recommended. PMID:24955100

Intravenous immunoglobulin therapy for refractory recurrent pericarditis.

PubMed

del Fresno, M Rosa; Peralta, Julio E; Granados, Miguel Ángel; Enríquez, Eugenia; Domínguez-Pinilla, Nerea; de Inocencio, Jaime

2014-11-01

Recurrent pericarditis is a troublesome complication of idiopathic acute pericarditis and occurs more frequently in pediatric patients after cardiac surgery (postpericardiotomy syndrome). Conventional treatment with nonsteroidal antiinflammatory drugs, corticosteroids, and colchicine is not always effective or may cause serious adverse effects. There is no consensus, however, on how to proceed in those patients whose disease is refractory to conventional therapy. In such cases, human intravenous immunoglobulin, immunosuppressive drugs, and biological agents have been used. In this report we describe 2 patients with refractory recurrent pericarditis after cardiac surgery who were successfully treated with 3 and 5 monthly high-dose (2 g/kg) intravenous immunoglobulin until resolution of the effusion. Our experience supports the effectiveness and safety of this therapy. Copyright © 2014 by the American Academy of Pediatrics.

Two Multidrug-Resistant Clinical Isolates of Bacteroides fragilis Carry a Novel Metronidazole Resistance nim Gene (nimJ)

PubMed Central

Veeranagouda, Yaligara; Hsi, Justin; Meggersee, Rosemary; Abratt, Valerie; Wexler, Hannah M.

2013-01-01

Two multidrug-resistant Bacteroides fragilis clinical isolates contain and express a novel nim gene, nimJ, that is not recognized by the “universal” nim primers and can confer increased resistance to metronidazole when introduced into a susceptible strain on a multicopy plasmid. HMW615, an appendiceal isolate, contains at least two copies of nimJ on its genome, while HMW616, an isolate from a patient with sepsis, contains one genomic copy of nimJ. B. fragilis NimJ is phylogenetically closer to Prevotella baroniae NimI and Clostridium botulinum NimA than to the other known Bacteroides Nim proteins. The predicted protein structure of NimJ, based on fold recognition analysis, is consistent with the crystal structures derived for known Nim proteins, and specific amino acid residues important for substrate binding in the active site are conserved. This study demonstrates that the “universal” nim primers will not detect all nim genes with the ability to confer metronidazole resistance, but nimJ alone cannot account for the very high metronidazole MICs of these resistant clinical isolates. PMID:23716049

Backscattering measuring system for optimization of intravenous laser irradiation dose

NASA Astrophysics Data System (ADS)

Rusina, Tatyana V.; Popov, V. D.; Melnik, Ivan S.; Dets, Sergiy M.

1996-11-01

Intravenous laser blood irradiation as an effective method of biostimulation and physiotherapy becomes a more popular procedure. Optimal irradiation conditions for each patient are needed to be established individually. A fiber optics feedback system combined with conventional intravenous laser irradiation system was developed to control of irradiation process. The system consists of He-Ne laser, fiber optics probe and signal analyzer. Intravenous blood irradiation was performed in 7 healthy volunteers and 19 patients with different diseases. Measurements in vivo were related to in vitro blood irradiation which was performed in the same conditions with force-circulated venous blood. Comparison of temporal variations of backscattered light during all irradiation procedures has shown a strong discrepancy on optical properties of blood in patients with various health disorders since second procedure. The best cure effect was achieved when intensity of backscattered light was constant during at least five minutes. As a result, the optical irradiation does was considered to be equal 20 minutes' exposure of 3 mW He-Ne laser light at the end of fourth procedure.

Intravenous immunoglobulin in treatment of cardiac tamponade in a patient with systemic lupus erythematosus.

PubMed

Grenader, Tal; Shavit, Linda

2004-12-01

We describe a 23-year-old female patient with a history of systemic lupus erythematosus and pulmonary hypertension who developed a large pericardial effusion with cardiac tamponade. Invasive interventions such as pericardial window or pericardiectomy were ruled out because of the posterior localization of the effusion and high risk of general anesthesia in a patient with severe pulmonary hypertension. The patient received high-dose steroids intravenously with no response. A 5-day course of intravenous immunoglobulin resulted in gradual decrease of the pericardial effusion and resolution of cardiac tamponade within 2 weeks.

Entirely S-protected chitosan: A promising mucoadhesive excipient for metronidazole vaginal tablets.

PubMed

Lupo, Noemi; Fodor, Benjamin; Muhammad, Ijaz; Yaqoob, Muhammad; Matuszczak, Barbara; Bernkop-Schnürch, Andreas

2017-12-01

Synthesis and evaluation of an entirely S-protected chitosan as mucoadhesive excipient for vaginal drug delivery. N-acetyl-cysteine was linked to 6-mercaptonicotinamide via disulphide exchange reaction. The obtained ligand, NAC-6-MNA, was subsequently attached to chitosan by carbodiimide mediated amide bond formation in two concentrations. The synthesized S-protected chitosan was chemically characterized and mucoadhesive properties and stability against oxidation were investigated. Moreover, metronidazole tablets comprising the S-protected chitosan were evaluated regarding water uptake capacity, disintegration behaviour, residence time on vaginal mucosa, release of the encapsulated drug and antimicrobial activity. S-protected chitosan displayed 160±19 (CS-MNA-160) and 320±38 (CS-MNA-320)µmol of ligand per gram of polymer. At pH 4.2, CS-MNA-160 and CS-MNA-320 showed 5.2-fold and 6.2-fold increase in mucus viscosity in comparison to unmodified chitosan (One-way ANOVA, p<.001), whereas, 9.9-fold (CS-MNA-160) and 15.6-fold (CS-MNA-320) (One-way ANOVA, p<.001) increase in viscosity was measured at pH 6. The S-protected chitosan remained stable against oxidation in presence of 0.5%v/v hydrogen peroxide. Metronidazole tablets consisting in S-protected chitosan showed prolonged residence time on vaginal mucosa and improved water uptake capacity and disintegration time in comparison to tablets consisting of unmodified chitosan. Moreover, CS-MNA-320 metronidazole tablets displayed prolonged drug release and antimicrobial activity. On the basis of the achieved results, entirely S-protected chitosan represents a promising excipient for the development of metronidazole vaginal tablets. S-protected thiomers are polymers modified with thiol groups protected by aromatic ligands and characterized by strong mucoadhesive properties and high stability against oxidation. Up to date, the entirely S-protection of thiol groups was achieved via the synthesis of the ligand 2-((2-amino-2

Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI)

PubMed Central

Solomkin, Joseph; Hershberger, Ellie; Miller, Benjamin; Popejoy, Myra; Friedland, Ian; Steenbergen, Judith; Yoon, Minjung; Collins, Sylva; Yuan, Guojun; Barie, Philip S.; Eckmann, Christian

2015-01-01

Background. Increasing antimicrobial resistance among pathogens causing complicated intra-abdominal infections (cIAIs) supports the development of new antimicrobials. Ceftolozane/tazobactam, a novel antimicrobial therapy, is active against multidrug-resistant Pseudomonas aeruginosa and most extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae. Methods. ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours or meropenem (1 g) every 8 hours intravenously for 4–14 days. The prospectively defined objectives were to demonstrate statistical noninferiority in clinical cure rates at the test-of-cure visit (24–32 days from start of therapy) in the microbiological intent-to-treat (primary) and microbiologically evaluable (secondary) populations using a noninferiority margin of 10%. Microbiological outcomes and safety were also evaluated. Results. Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, −4.2%; 95% confidence interval [CI], −8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, −1.0%; 95% CI, −4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea. Conclusions. Treatment with ceftolozane/tazobactam plus metronidazole was noninferior to

Microbiologic Response to Treatment of Bacterial Vaginosis with Topical Clindamycin or Metronidazole

PubMed Central

Austin, M. N.; Beigi, R. H.; Meyn, L. A.; Hillier, S. L.

2005-01-01

To compare the frequencies, concentrations, and antimicrobial susceptibilities of vaginal microbes isolated from women with bacterial vaginosis (BV) before and after therapy, 119 nonpregnant women aged 18 to 45 with clinical and Gram stain evidence of BV were randomized to receive intravaginal clindamycin or metronidazole. Vaginal swabs were collected at baseline and 7 to 12 days, 35 to 45 days, and 70 to 90 days following therapy for quantitative vaginal culture. For the 99 women completing all four visits, statistical analyses were performed comparing differences in vaginal microflora between the two treatment arms and between visits in the same treatment group. Antimicrobial susceptibility testing using the agar dilution method was performed for anaerobic gram-negative rods. Although both therapies resulted in decreased colonization by Gardnerella vaginalis and Mycoplasma hominis, only metronidazole treatment resulted in a significant decrease in the frequency and concentration of Prevotella bivia and black-pigmented Prevotella species. Of the 865 anaerobic gram-negative rods evaluated for susceptibility, only 3 (0.3%) were resistant to metronidazole, whereas clindamycin resistance increased significantly for P. bivia and black-pigmented anaerobic gram-negative rods persisting following clindamycin therapy. Clindamycin-resistant subpopulations of P. bivia and black-pigmented Prevotella species emerged 7 to 12 days after therapy even among women colonized initially by clindamycin-susceptible strains. These resistant subpopulations persisted at high frequencies (42 to 50%) 70 to 90 days following therapy. The two topical agents for treatment of BV have differing microbiologic effects on the vaginal microflora. The emergence of clindamycin-resistant anaerobic gram-negative rods following therapy is of concern. PMID:16145097

Development of serratiopeptidase and metronidazole based alginate microspheres for wound healing.

PubMed

Rath, G; Johal, E S; Goyal, Amit K

2011-02-01

The objective of this study was to establish an effective therapy system for wound management. The present work describes preparation of metronidazole/serratiopeptidase loaded alginate microspheres by emulsification method. In vitro characterizations like particle size analysis, % yield, % encapsulation, and in vitro release were carried out. Wound healing assessment was determined by physical, histological, and biochemical methods. Wound healing performance of experimental formulations was compared with marketed product in rabbits. Result obtained for alginate microspheres showed good loading efficiency with spherical in shape. Experimentation suggests wound healing is improved by using serratiopeptidase and metronidazole in full thickness wounds in rabbits.

Optimization of initial propofol bolus dose for EEG Narcotrend Index-guided transition from sevoflurane induction to intravenous anesthesia in children.

PubMed

Dennhardt, Nils; Boethig, Dietmar; Beck, Christiane; Heiderich, Sebastian; Boehne, Martin; Leffler, Andreas; Schultz, Barbara; Sümpelmann, Robert

2017-04-01

Sevoflurane induction followed by intravenous anesthesia is a widely used technique to combine the benefits of an easier and less traumatic venipuncture after sevoflurane inhalation with a recovery with less agitation, nausea, and vomiting after total intravenous anesthesia (TIVA). Combination of two different anesthetics may lead to unwanted burst suppression in the electroencephalogram (EEG) during the transition phase. The objective of this prospective clinical observational study was to identify the optimal initial propofol bolus dose for a smooth transition from sevoflurane induction to TIVA using the EEG Narcotrend Index (NI). Fifty children aged 1-8 years scheduled for elective pediatric surgery were studied. After sevoflurane induction and establishing of an intravenous access, a propofol bolus dose range 0-5 mg·kg -1 was administered at the attending anesthetist's discretion to maintain a NI between 20 and 64, and sevoflurane was stopped. Anesthesia was continued as TIVA with a propofol infusion dose of 15 mg·kg -1 ·h -1 for the first 15 min, followed by stepwise reduction according to McFarlan's pediatric infusion regime, and remifentanil 0.25 μg·kg -1 ·min -1 . Endtidal concentration of sevoflurane, NI, and hemodynamic data were recorded during the whole study period using a standardized case report form. Propofol plasma concentrations were calculated using the paedfusor dataset and a TIVA simulation program. Median endtidal concentration of sevoflurane at the time of administration of the propofol bolus was 5.1 [IQR 4.7-5.9] Vol%. The median propofol bolus dose was 1.2 [IQR 0.9-2.5] mg·kg -1 and median NI thereafter was 33 [IQR 23-40]. Nine children presented with a NI 13-20 and three children with burst suppression in the EEG (NI 0-12); all of them received an initial propofol bolus dose >2 mg·kg -1 . Regression equation demonstrated that NI 20-64 was achieved with a 95% probability when using a propofol bolus dose of 1 mg·kg -1 after

High-dose levofloxacin in community-acquired pneumonia: a randomized, open-label study.

PubMed

Lee, Jin Hwa; Kim, Seo Woo; Kim, Ji Hye; Ryu, Yon Ju; Chang, Jung Hyun

2012-09-01

The conventional treatment for community-acquired pneumonia (CAP) involves combination therapy consisting of a β-lactam penicillin or a cephalosporin with a macrolide. Alternatively, high-dose levofloxacin treatment has been used as single-agent therapy for treating CAP, covering atypical pathogens. This study compared the clinical efficacy and safety of high-dose levofloxacin with combined ceftriaxone and azithromycin for the treatment of CAP. This phase IV, prospective, randomized, open-label trial enrolled patients admitted to a tertiary referral hospital for CAP treatment from 2010 to 2011. Hospital admission was decided based on clinical judgement and the pneumonia severity index. Forty subjects were enrolled and assigned to two treatment arms using a random numbers table. The 20 subjects in the experimental group were given levofloxacin 750 mg intravenously once daily, followed by the same dose of oral levofloxacin at discharge when clinically improved and the 20 subjects in the control group were given ceftriaxone 2.0 g intravenously once daily plus oral azithromycin 500 mg for 3 consecutive days, followed by oral cefpodoxime 200 mg per day at discharge after clinical improvement. The primary outcome was the clinical success rate. Secondary outcomes were the microbiological success rate and adverse events during the study. Of the 40 subjects enrolled, 36 completed the study: 17 in the experimental group and 19 in the control group. The groups did not differ in terms of demographic factors or clinical findings at baseline. The clinical success rate (cured + improved) was 94% in the experimental (levofloxacin) group and 84% in the control group (p > 0.05). The microbiological success rate and overall adverse events were also similar in both groups. Single-agent, high-dose levofloxacin treatment exhibited excellent clinical and microbiological efficacy with a safety profile comparable to that of ceftriaxone plus azithromycin therapy. Large-scale clinical

A simple reagent-free spectrophotometric assay for monitoring metronidazole therapy in aquarium water.

PubMed

Webb, D Harry; Marrero, Cynthia; Ellis, Helen; Merriwether, Lea; Dove, Alistair D M

2013-09-01

A reagent-free spectrophotometric assay was developed to measure the concentration of metronidazole (a 5-nitroimidazole) in both freshwater and seawater matrices. This assay is simple, repeatable, sensitive, and precise and is ideal for use when a rapid, selective test to determine metronidazole concentration in aqueous matrices is necessary. The assay was practically tested on a South American fishes display during treatment with metronidazole for an outbreak of the flagellated parasite Spironucleus in a mixed cichlid (family Cichlidae) and tetra (family Characidae) community. The assay clearly illustrated the course of treatment for the system during a real clinical application. The assay is not without limitations, as interferences can occur from other drugs in the matrix with similar absorbance spectra. Nonetheless, this type of assay illustrates the potential for use of native absorbance assays in aqueous matrices for this and other therapeutic compounds.

Effect of MMX® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials.

PubMed

Pierce, David; Corcoran, Mary; Martin, Patrick; Barrett, Karen; Inglis, Susi; Preston, Peter; Thompson, Thomas N; Willsie, Sandra K

2014-01-01

MMX(®) mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections. To evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies. In all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1-4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1-3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1-3 and once on day 4 (N=44). MMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) fell within the predefined equivalence range (0.80-1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in Cmax at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild. MMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of these antibiotics. NCT01442688, NCT01402947, NCT

New Advances in the Treatment of Neurological Diseases Using High Dose Intravenous Immunoglobulins

PubMed Central

2008-01-01

Since the incidental discovery in 1981 that intravenous immunoglobulins (IVIg) are immunomodulatory, they have been investigated in a large number of putative autoimmune diseases. This has led to licensing for idiopathic thrombocytopenic purpura, Kawasaki disease, and in neurological disorders for Guillain-Barré syndrome (GBS). Although not licensed, randomized controlled trials have also shown IVIg efficacy in other neuroimmunological diseases such as multifocal motor neuropathy (MMN), chronic inflammatory demyelinating neuropathy (CIDP), myasthenia gravis, dermatomyositis, and stiff-person syndrome. However, other indications are currently being explored including Alzheimer's disease, postpolio syndrome, and narcolepsy. There are even reports from experimental studies in stroke. The results of recently published clinical trials in both the classical neuroimmunological disorders as well as for new indications are reported and their role in clinical practice is discussed. PMID:21180569

Unexplained abdominal pain as a driver for inappropriate therapeutics: an audit on the use of intravenous proton pump inhibitors

PubMed Central

Wong, Yin Yen; Low, Yong Chia; Lau, Hui Ling; Chin, Kin-Fah; Mahadeva, Sanjiv

2014-01-01

Background. Proton pump inhibitors (PPIs) are currently the most effective agents for acid-related disorders. However, studies show that 25–75% of patients receiving intravenous PPIs had no appropriate justification, indicating high rates of inappropriate prescribing. Objective. To examine the appropriate use of intravenous PPIs in accordance with guidelines and the efficacy of a prescribing awareness intervention at an Asian teaching institution. Setting. Prospective audit in a tertiary hospital in Malaysia. Method. Every 4th intravenous PPI prescription received in the pharmacy was screened against hospital guidelines. Interventions for incorrect indication/dose/duration were performed. Patients’ demographic data, medical history and the use of intravenous PPI were collected. Included were all adult inpatients prescribed intravenous PPI. Main Outcome Measure. Proportion of appropriate IV PPI prescriptions. Results. Data for 106 patients were collected. Most patients were male [65(61.3%)], Chinese [50(47.2%)], with mean age ± SD = 60.3 ± 18.0 years. Most intravenous PPI prescriptions were initiated by junior doctors from the surgical [47(44.3%)] and medical [42(39.6%)] departments. Only 50/106(47.2%) patients had upper gastrointestinal endoscopy/surgery performed to verify the source of bleeding. Unexplained abdominal pain [81(76.4%)] was the main driver for prescribing intravenous PPIs empirically, out of which 73(68.9%) were for suspected upper gastrointestinal bleed. Overall, intravenous PPI was found to be inappropriately prescribed in 56(52.8%) patients for indication, dose or duration. Interventions on the use of intravenous PPI were most effective when performed by senior doctors (100%), followed by clinical pharmacists (50%), and inpatient pharmacists (37.5%, p = 0.027). Conclusion. Inappropriate intravenous PPI usage is still prevalent despite the enforcement of hospital guidelines. The promotion of prescribing awareness and evidence

Unexplained abdominal pain as a driver for inappropriate therapeutics: an audit on the use of intravenous proton pump inhibitors.

PubMed

Lai, Pauline Siew Mei; Wong, Yin Yen; Low, Yong Chia; Lau, Hui Ling; Chin, Kin-Fah; Mahadeva, Sanjiv

2014-01-01

Background. Proton pump inhibitors (PPIs) are currently the most effective agents for acid-related disorders. However, studies show that 25-75% of patients receiving intravenous PPIs had no appropriate justification, indicating high rates of inappropriate prescribing. Objective. To examine the appropriate use of intravenous PPIs in accordance with guidelines and the efficacy of a prescribing awareness intervention at an Asian teaching institution. Setting. Prospective audit in a tertiary hospital in Malaysia. Method. Every 4th intravenous PPI prescription received in the pharmacy was screened against hospital guidelines. Interventions for incorrect indication/dose/duration were performed. Patients' demographic data, medical history and the use of intravenous PPI were collected. Included were all adult inpatients prescribed intravenous PPI. Main Outcome Measure. Proportion of appropriate IV PPI prescriptions. Results. Data for 106 patients were collected. Most patients were male [65(61.3%)], Chinese [50(47.2%)], with mean age ± SD = 60.3 ± 18.0 years. Most intravenous PPI prescriptions were initiated by junior doctors from the surgical [47(44.3%)] and medical [42(39.6%)] departments. Only 50/106(47.2%) patients had upper gastrointestinal endoscopy/surgery performed to verify the source of bleeding. Unexplained abdominal pain [81(76.4%)] was the main driver for prescribing intravenous PPIs empirically, out of which 73(68.9%) were for suspected upper gastrointestinal bleed. Overall, intravenous PPI was found to be inappropriately prescribed in 56(52.8%) patients for indication, dose or duration. Interventions on the use of intravenous PPI were most effective when performed by senior doctors (100%), followed by clinical pharmacists (50%), and inpatient pharmacists (37.5%, p = 0.027). Conclusion. Inappropriate intravenous PPI usage is still prevalent despite the enforcement of hospital guidelines. The promotion of prescribing awareness and evidence-based prescribing

Pharmacokinetics of marbofloxacin in pigs after intravenous and intramuscular administration of a single dose of 8 mg/kg: dose proportionality, influence of the age of the animals and urinary elimination.

PubMed

Schneider, M; Paulin, A; Dron, F; Woehrlé, F

2014-12-01

The pharmacokinetics of marbofloxacin in pigs were evaluated as a function of dose and animal age following intravenous and intramuscular administration of a 16% solution (Forcyl(®) ). The absolute bioavailability of marbofloxacin as well as the dose proportionality was evaluated in 27-week-old fattening pigs. Blood PK and urinary excretion of marbofloxacin were evaluated after a single intramuscular dose of 8 mg/kg in 16-week-old male pigs. An additional group of 12-week-old weaned piglets was used for the evaluation of age-related kinetics. The plasma and urine concentration of marbofloxacin was determined using a HPLC method. Pharmacokinetic parameters were calculated using noncompartmental methods. After intravenous administration in 27-week-old fattening pigs, the total body clearance was 0.065 L/h·kg. After intramuscular administration to the same animals, the mean observed Cmax was 6.30 μg/mL, and the AUCINF was 115 μg·h/mL. The absolute bioavailability was 91.5%, and dose proportionality was shown within the dose range of 4-16 mg/kg. The renal clearance was about half of the value of the total clearance. The total systemic clearance values significantly decreased as a function of age, being 0.092 L/h·kg and 0.079 L/h·kg in pigs aged 12 and 16 weeks, respectively. © 2014 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

Evaluation of antitumor activity and development of solid lipid nanoparticles of metronidazole analogue.

PubMed

Lages, Eduardo Burgarelli; de Freitas, Maria Betânia; Gonçalves, Isadora Marques Brum; Alves, Ricardo José; Vianna-Soares, Cristina Duarte; Ferreira, Lucas Antônio Miranda; de Oliveira, Mônica Cristina; de Oliveira, Renata Barbosa

2013-11-01

Nitroheterocyclic compounds have received considerable interest as hypoxia-selective cytotoxins (HSC) for cancer treatment. In the present study, we investigated antitumor activity of an iodide analogue of metronidazole, 1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I), using Swiss mice bearing solid Ehrlich tumor. MTZ-I showed potent anti-cancer activity at a dose of 40 mg/kg. MTZ-I loaded solid lipid nanoparticles (SLN) were developed as an alternative colloidal carrier system to enhance tumor drug uptake. SLN were characterized for particle size, polydispersity index, zeta potential and entrapment efficiency. In addition, the influence of presence of the cationic lipid stearylamine (STE) on stability of formulation was assessed. The results of DSC study showed that MTZ-I exhibited interaction with STE.

IN VIVO EVALUATION OF SAFETY OF NANOPOROUS SILICON CARRIERS FOLLOWING SINGLE AND MULTIPLE DOSE INTRAVENOUS ADMINISTRATIONS IN MICE

PubMed Central

Tanaka, T.; Godin, B.; Bhavane, R.; Nieves-Alicea, R.; Gu, J.; Liu, X.; Chiappini, C.; Fakhoury, J. R.; Amra, S.; Ewing, A.; Li, Q.; Fidler, I.J.; Ferrari, M.

2010-01-01

Porous silicon (pSi) is being extensively studied as an emerging material for use in biomedical applications, including drug delivery, based on the biodegradability and versatile chemical and biophysical properties. We have recently introduced multistage nanoporous silicon microparticles (S1MP) designed as a cargo for nanocarrier drug delivery to enable the loaded therapeutics and diagnostics to sequential overcoming of the biological barriers to reach their target. In this first report on biocompatibility of intravenously administered pSi structures, we examined biocompatibility of negatively (−32.5±3.1mV) and positively (8.7±2.5mV) charged S1MP in acute single dose (107, 108, 5×108 S1MP/animal) and subchronic multiple dose (108 S1MP/animal/week for 4 weeks) administration schedules. Our data demonstrate that S1MP did not change plasma levels of renal (BUN and creatinine) and hepatic (LDH) biomarkers as well as23 plasma cytokines. LDH plasma levels of 145.2±23.6, 115.4±29.1 vs. 127.0±10.4; and 155.8±38.4, 135.5±52.3 vs. 178.4±74.6 were detected in mice treated with 108 negatively charged S1MP, 108 positively charged S1MP vs. saline control in single and multiple dose schedules, respectively. The S1MPs did not alter LDH levels in liver and spleen, nor lead to infiltration of leukocytes into the liver, spleen, kidney, lung, brain, heart, and thyroid. Collectively, these data provide evidence of a safe intravenous administration of S1MPs as a drug delivery carrier. PMID:20883755

Preincisional administration of intravenous or subcutaneous infiltration of low-dose ketamine suppresses postoperative pain after appendectomy

PubMed Central

Honarmand, Azim; Safavi, Mohammadreza; Karaky, Hasan

2012-01-01

Background Ketamine, an N-methyl-D-aspartate receptor antagonist, can suppress hyperalgesia and allodynia. The purpose of the present study was to evaluate the clinical efficacy of preincisional intravenous or subcutaneous infiltration of ketamine for postoperative pain relief after appendectomy. Methods Ninety patients, aged 18–60 years, scheduled for appendectomy was enrolled in this study. Patients were divided into three groups of 30 each and received subcutaneous infiltration of ketamine 0.5 mg/kg (KS), intravenous ketamine 0.5 mg/kg (KI), or subcutaneous infiltration of normal saline 3 mL (C) before surgery. Visual analog scale (VAS) values and analgesic consumption were evaluated for 24 hours after surgery. Results VAS scores were significantly lower at the time of arrival in the recovery room, and at 10, 20, and 30 minutes thereafter in group KI and group KS compared with group C (P < 0.05). VAS scores were not significantly different between group KI and group KS at these intervals. Postoperative VAS scores were significantly lower at 6, 12, 18, and 24 hours in group KI compared with group C (P < 0.05). In group KS, the postoperative VAS score was significantly lower at 6 hours (P < 0.05). VAS scores were significantly lower at 12, 18, and 24 hours after surgery in group KI compared with group KS (P < 0.05). Conclusion A 0.5 mg/kg dose of ketamine given at approximately 15 minutes before surgery by the intravenous route provided analgesia for 24 hours after surgery in patients undergoing appendectomy. PMID:22328829

[In vitro anti-Trichomonas vaginalis effects of a mixture of dihydroartemisinin and metronidazole].

PubMed

Tang, Zi-Hao; Liu, Ke-Yue; Mei, Jun; Gao, Xing-Zheng

2010-12-30

To observe the effect of a mixture of dihydroartemisinin and metronidazole on ultrastructure of Trichomonas vaginalis trophozoites in vitro for exploring trichomonacidal mechanism of the drug mixture. The trophozoites were cultivated with liver extract solution medium that contained 2.5 x 10(6) parasites/ml. There were dihydroartemisinin 0.5 mg/ml and metronidazole 0.002 mg/ml in the experimental tubes of the drug mixture group. Groups of control (without drug), dihydroartemisinin (1 mg/ml) and metronidazole (5 mg/ml) were established and performed in the same experimental conditions. The parasites were observed by scanning and transmission electron microscopes after having treated with the drugs at 37 degrees for 3.5-5 h. Under scanning electron microscope, the cell membrane of T. vaginalis treated only with dihydroartemisinin for 35 h was damaged, part of pellicle peeled off. Although the surface of the trophozoites treated only with metronidazole for 5 h showed many small bubbles and hollows, the cell membrane looked integral. However, surface of the parasite exposed to the drug mixture for 3.5-4.2 h showed deep folds and cracks, the cell membrane was damaged and even peeled off. When the cell ruptured, the nucleus, axostyle, pelta and hydrogenosomes were exposed, and the cytoplasm spilled out. Transmission electron microscopy showed that the membrane system of the trophozoites treated only with dihydroartemisinin for 3.5 h was damaged considerably. The cytoplasm of damaged parasite spilled out. The cytoplasm of the parasite treated only with metronidazole for 3.5-5 h was damaged seriously. Vacuoles and crevices were visible in the cytoplasm. The cell membrane and the content of the parasites treated with the drug mixture for 3.5-4.5 h were damaged seriously. There were some vacuoles and crevices, dilated endoplasmic reticulum, injured and deformed hydrogenosomes in the cytoplasm. The cell organelles mostly disappeared. Crevices also existed in the nucleus. The

Nifurpirinol: A more potent and reliable substrate compared to metronidazole for nitroreductase-mediated cell ablations.

PubMed

Bergemann, David; Massoz, Laura; Bourdouxhe, Jordane; Carril Pardo, Claudio A; Voz, Marianne L; Peers, Bernard; Manfroid, Isabelle

2018-04-17

The zebrafish is a popular animal model with well-known regenerative capabilities. To study regeneration in this fish, the nitroreductase/metronidazole-mediated system is widely used for targeted ablation of various cell types. Nevertheless, we highlight here some variability in ablation efficiencies with the metronidazole prodrug that led us to search for a more efficient and reliable compound. Herein, we present nifurpirinol, another nitroaromatic antibiotic, as a more potent prodrug compared to metronidazole to trigger cell-ablation in nitroreductase expressing transgenic models. We show that nifurpirinol induces robust and reliable ablations at concentrations 2,000 fold lower than metronidazole and three times below its own toxic concentration. We confirmed the efficiency of nifurpirinol in triggering massive ablation of three different cell types: the pancreatic beta cells, osteoblasts, and dopaminergic neurons. Our results identify nifurpirinol as a very potent prodrug for the nitroreductase-mediated ablation system and suggest that its use could be extended to many other cell types, especially if difficult to ablate, or when combined pharmacological treatments are desired. © 2018 by the Wound Healing Society.

Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression.

PubMed

Loo, C K; Gálvez, V; O'Keefe, E; Mitchell, P B; Hadzi-Pavlovic, D; Leyden, J; Harper, S; Somogyi, A A; Lai, R; Weickert, C S; Glue, P

2016-07-01

This pilot study assessed the feasibility, efficacy and safety of an individual dose-titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. Fifteen treatment-refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double-blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose-related. Antidepressant response occurred at a range of doses and at <0.5 mg/kg. The dose-titration approach is a practical method for optimizing the efficacy - side-effects trade-off on an individual patient basis. This pilot study provides preliminary evidence for SC injection as a practical, feasible and efficacious treatment approach. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Efficacy of topical azelaic acid (AzA) gel 15% plus oral doxycycline 40 mg versus metronidazole gel 1% plus oral doxycycline 40 mg in mild-to-moderate papulopustular rosacea.

PubMed

Del Rosso, James Q; Bruce, Suzanne; Jarratt, Michael; Menter, Alan; Staedtler, Gerald

2010-06-01

Rosacea is a leading reason why people seek the care of a dermatologist, accounting for nearly 7 million office visits annually. Pharmacologic treatments include both topical and oral medications, which are increasingly being used in combination, especially at the outset of therapy. This exploratory study assesses the safety, effectiveness and speed of onset of two common topical agents for the treatment of rosacea--azelaic acid gel (AzA) 15% and metronidazole gel 1%--used in conjunction with anti-inflammatory dose doxycycline (40 mg once daily). Men and women (n = 207) with mild-to-moderate papulopustular rosacea were enrolled and randomized to receive either AzA gel 15% twice daily plus doxycycline 40 mg once daily (AzA group) or metronidazole gel 1% once daily plus doxycycline 40 mg once daily (Metro group) for 12 weeks. Both regimens were safe, efficacious and well tolerated. Efficacy parameters revealed a possible trend toward greater and earlier benefit with the AzA-based regimen than with the metronidazole-based regimen. These findings warrant further investigation in a sufficiently powered study.

Effect of Oral Administration of Metronidazole or Prednisolone on Fecal Microbiota in Dogs

PubMed Central

Ohno, Koichi; Horigome, Ayako; Odamaki, Toshitaka; Tsujimoto, Hajime

2014-01-01

Gastrointestinal microbiota have been implicated in the pathogenesis of various gastrointestinal disorders in dogs, including acute diarrhea and chronic enteropathy. Metronidazole and prednisolone are commonly prescribed for the treatment of these diseases; however, their effects on gastrointestinal microbiota have not been investigated. The objective of this study was to evaluate the effects of these drugs on the gastrointestinal microbiota of dogs. Metronidazole was administered twice daily at 12.5 mg/kg to a group of five healthy dogs, and prednisolone at 1.0 mg/kg daily to a second group of five healthy dogs for 14 days. Fecal samples were collected before and after administration (day 0 and 14), and 14 and 28 days after cessation (day 28 and 42). DNA was extracted, and the bacterial diversity and composition of each sample were determined based on 16S ribosomal RNA (rRNA) gene sequences using next-generation sequencing (Illumina MiSeq). In the group administered metronidazole, bacterial diversity indices significantly decreased at day 14, and recovered after the cessation. Principal coordinates analysis and hierarchical dendrogram construction based on unweighted and weighted UniFrac distance matrices revealed that bacterial composition was also significantly altered by metronidazole at day 14 compared with the other time points. The proportions of Bacteroidaceae, Clostridiaceae, Fusobacteriaceae, Lachnospiraceae, Ruminococcaceae, Turicibacteraceae, and Veillonellaceae decreased, while Bifidobacteriaceae, Enterobacteriaceae, Enterococcaceae, and Streptococcaceae increased at day 14 and returned to their initial proportions by day 42. Conversely, no effect of prednisolone was observed on either the bacterial diversity or composition. Reducing pathogenic bacteria such as Fusobacteria and increasing beneficial bacteria such as Bifidobacterium through the administration of metronidazole may be beneficial for promoting gastrointestinal health; however, further

Comparison of intravenous pantoprazole with intravenous ranitidine in peptic ulcer bleeding.

PubMed

Demetrashvili, Z M; Lashkhi, I M; Ekaladze, E N; Kamkamidze, G K

2013-10-01

Following successful endoscopic therapy in patients with peptic ulcer bleeding, rebleeding occurs in 4% to 30% of cases. Rebleeding remains the most important determinant of poor prognosis. The aim of our study is to compare the efficacy of intravenous pantoprazole and ranitidine for prevention of rebleeding of peptic ulcers following initial endoscopic hemostasis. In our study patients who had gastric or duodenal ulcers with bleeding received combined endoscopy therapy with injection of epinephrine and thermocoagulation. Patients with initial hemostasis were randomly assigned to two groups. One group (45 patients) was treated with intravenous pantoprazole, with an initial dose of 40 mg and subsequently with 40 mg every twelve hours during the first three days, followed by 40 mg a day orally. The other group (44 patients) was treated with intravenous ranitidine, with an initial dose of 50 mg and subsequently every eight hours during the first three days, followed by 150 mg ranitidine every 12 h. In all case of rebleeding repeated endoscopy was performed. One patient (2,2%) had rebleeding in pantoprazole group. Bleeding could not be blocked by repeated endoscopic intervention, thus the patient underwent emergency surgery. 6 patients (13,6%) from ranitidine group had recurrence of bleeding. Repeated endoscopy was performed in all these patients: bleeding was stopped in 3 cases endoscopically, other 3 patients were surgically treated urgently as endoscopic hemostasis was not successful. None of the patients died of uncontrolled rebleeding. The frequency of rebleeding was significantly low in the group of pantoprazole compared to ranitidine group (2,2% vs 13,6% P=0,046). There were no statistically significant differences between the groups with regard to need for emergency surgery (2,2% vs 6,8%), the length of hospital stay (6,7±3,3 vs 7,4±4,3 d) and mortality (0%vs 0%). After endoscopic treatment of bleeding peptic ulcers, intravenous pantoprazole is more effective

A case of metronidazole-resistant Trichomonas vaginalis in pregnancy.

PubMed

Forbes, Georgina L; Drayton, Rachel; Forbes, Gavin D

2016-09-01

Trichomonas vaginalis is a sexually transmitted protozoan infection resulting in vulvo-vaginitis and altered vaginal discharge in symptomatic women. Trichomoniasis has been implicated in causing adverse pregnancy outcomes such as low birth weight and pre-term labour. Metronidazole is the recommended first-line treatment for trichomonal infection. Other nitroimidazoles, such as tinidazole, are used as alternative regimens with similar activity but at a greater expense. Treatment failure usually represents patient non-compliance or re-infection, although metronidazole resistance has previously been documented. Antimicrobial susceptibility testing for T. vaginalis is currently not available in the UK. Patients with disease unresponsive to first-line treatments pose a major challenge, as therapeutic options are limited. We present the case of a patient with presumed resistant infection during pregnancy, and the additional treatment issues that this presented. © The Author(s) 2015.

Herb-drug interaction: a case study of effect of ginger on the pharmacokinetic of metronidazole in rabbit.

PubMed

Okonta, J M; Uboh, M; Obonga, W O

2008-01-01

The effect of ginger on the pharmacokinectic of metronidazole was studied using rabbits in a crossover study method. The relevance of this study borders on the wide use of ginger for culinary and phytotherapeutic purposes, and metronidazole that is commonly used for every gastrointestinal complain in our communities without prescription. Ginger significantly increased the absorption and plasma half-life, and significantly decreased the elimination rate constant and clearance of metronidazole (P<0.05). Thus, in clinical practice, the patients should be advised on the serious implication of using both items together.

Results of intravenous steroid injection on reduction of postoperative edema in rhinoplasty.

PubMed

Alajmi, Monther Ali; Al-Abdulhadi, Khalid A; Al-Noumas, Hamoud Saud; Kavitha, Gopalan

2009-12-01

To determine the efficacy of intravenous dexamethasone in reducing postrhinoplasty edema. A prospective, randomized clinical trial with placebo control. Department of Otorhinolaryngology, Al-Sabah and Zain Hospital, Kuwait. Eighty-four patients (male = 28; female = 56) aged between 20 and 40 years, undergoing open rhinoplasty with hump removal and bilateral lateral osteotomies were enrolled in this study. Patients were randomized to receive two doses of 10 mg of dexamethasone intravenously or placebo, first dose during surgery and second dose 12 hours after surgery. Patients were evaluated postoperatively at 24 hours, days 2, 5, 7 and 10 for periorbital edema. 10 mg of dexamethasone given intravenously during rhinoplasty and a second dose 12 hours after surgery, reduced postoperative periorbital edema significantly. This study showed a statistically significant benefit of dexamethasone over placebo in reducing periorbital edema after rhinoplasty. No complications were attributed to the administration of dexamethasone.

Successful outcome after intravenous gasoline injection.

PubMed

Domej, Wolfgang; Mitterhammer, Heike; Stauber, Rudolf; Kaufmann, Peter; Smolle, Karl Heinz

2007-12-01

Gasoline, ingested intentionally or accidentally, is toxic. The majority of reported cases of gasoline intoxication involve oral ingestion or inhalation. Data are scarce on complications and outcomes following hydrocarbon poisoning by intravenous injection. Following a suicide attempt by intravenous self-injection of 10 ml of gasoline, a 26-year-old medical student was admitted to the intensive care unit (ICU) with hemoptysis, symptoms of acute respiratory failure, chest pain, and severe abdominal cramps. Gas exchange was severely impaired and a chest x-ray indicated chemical pneumonitis. Initial treatment consisted of mechanical ventilation, supportive hyperventilation, administration of nitrogen oxide (NO), and prednisone. Unfortunately, the patient developed multi-organ dysfunction syndrome (MODS) complicated by life-threatening severe vasoplegia within 24 hours after gasoline injection. High doses of vasopressors along with massive amounts of parenteral fluids were necessary. Despite fluid replacement, renal function worsened and required hemofiltration on 5 sequential days. After 12 days of intensive care management, the patient recovered completely and was discharged to a psychiatric care facility. Intravenous gasoline injection causes major injury to the lungs, the organ bearing the first capillary bed encountered. Treatment of gasoline poisoning is symptomatic because no specific antidote is available. Early and aggressive supportive care may be conducive to a favorable outcome with minimal residual pulmonary sequelae.

Aminothiol Receptors for Decorporation of Intravenously Administered 60Co in the Rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levitskaia, Tatiana G.; Morris, James E.; Creim, Jeffrey A.

2010-01-01

The reported investigation provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic cobalt-60 (60Co) to that observed following intravenous administration of GSH and Cys in F344 rats. L-histidine (His) was tested intravenously to compare in vivo efficacy of the aminothiol GSH and Cys chelators with that of aminoimidazole (His) chelator. 60Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24 hour intervals for a total of 5 doses. The results suggest that GSH and Cys are potentmore » decorporation agents for 60Co in the rat model, although the efficacy of treatment depends largely on systemic availability of a chelator. The intravenous GSH or Cys were most effective in reducing tissue 60Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. Oral administration of ReadiSorb reduced 60Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted.« less

Tribulus terrestris ameliorates metronidazole-induced spermatogenic inhibition and testicular oxidative stress in the laboratory mouse.

PubMed

Kumari, Mrinalini; Singh, Poonam

2015-01-01

The present study was undertaken to evaluate the protective effects of the fruit extract of Tribulus terrestris (TT) on the metronidazole (MTZ)-induced alterations in spermatogenesis, sperm count, testicular functions, and oxidative stress. Thirty adult Swiss strain mice were divided into six groups. Animals of Groups I and II served as untreated and vehicle-treated controls, while that of Groups III and IV were administered with MTZ (500 mg/kg BW/day) and TT (200 mg/kg BW/day) alone for 28 days, respectively. Low (100 mg/kg BW/day) and high (200 mg/kg BW/day) doses of TT along with MTZ (500 mg/kg BW/day) were administered for 28 days in the mice of Groups V and VI, respectively. Twenty four hours after the last treatment, all the animals were euthanized to study the histological changes in the testis and sperm count in the epididymis. Testicular functional markers, lipid peroxidation (LPO) and the activities of antioxidant enzymes, e.g., superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, were also assessed in the mice of all the groups. Metronidazole caused marked alterations in the testicular weight, spermatogenesis, activities of antioxidant enzymes, lactate dehydrogenase, alkaline phosphatase, and the level of LPO. The epididymal sperm count also declined significantly in MTZ-treated group. These changes were partially restored following co-administration of 500 mg/kg BW/day of MTZ and 100 mg/kg BW/day of TT. However, in the mice co-administered with 500 mg/kg BW/day of MTZ and 200 mg/kg BW/day of TT, the changes reverted back completely, similar to that of the controls. The fruit extract of TT ameliorates the MTZ-induced alterations in the testis.

Tribulus terrestris ameliorates metronidazole-induced spermatogenic inhibition and testicular oxidative stress in the laboratory mouse

PubMed Central

Kumari, Mrinalini; Singh, Poonam

2015-01-01

Objective: The present study was undertaken to evaluate the protective effects of the fruit extract of Tribulus terrestris (TT) on the metronidazole (MTZ)-induced alterations in spermatogenesis, sperm count, testicular functions, and oxidative stress. Materials and Methods: Thirty adult Swiss strain mice were divided into six groups. Animals of Groups I and II served as untreated and vehicle-treated controls, while that of Groups III and IV were administered with MTZ (500 mg/kg BW/day) and TT (200 mg/kg BW/day) alone for 28 days, respectively. Low (100 mg/kg BW/day) and high (200 mg/kg BW/day) doses of TT along with MTZ (500 mg/kg BW/day) were administered for 28 days in the mice of Groups V and VI, respectively. Twenty four hours after the last treatment, all the animals were euthanized to study the histological changes in the testis and sperm count in the epididymis. Testicular functional markers, lipid peroxidation (LPO) and the activities of antioxidant enzymes, e.g., superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, were also assessed in the mice of all the groups. Results: Metronidazole caused marked alterations in the testicular weight, spermatogenesis, activities of antioxidant enzymes, lactate dehydrogenase, alkaline phosphatase, and the level of LPO. The epididymal sperm count also declined significantly in MTZ-treated group. These changes were partially restored following co-administration of 500 mg/kg BW/day of MTZ and 100 mg/kg BW/day of TT. However, in the mice co-administered with 500 mg/kg BW/day of MTZ and 200 mg/kg BW/day of TT, the changes reverted back completely, similar to that of the controls. Conclusion: The fruit extract of TT ameliorates the MTZ-induced alterations in the testis. PMID:26069369

Nonsurgical therapy of chronic periodontitis with adjunctive systemic azithromycin or amoxicillin/metronidazole.

PubMed

Jentsch, Holger F R; Buchmann, Andreas; Friedrich, Abel; Eick, Sigrun

2016-09-01

The objective of the present study is to compare the effect of systemic adjunctive use of azithromycin with amoxicillin/metronidazole to scaling and root planing (SRP) in a clinical study. Data from 60 individuals with chronic periodontitis were evaluated after full-mouth SRP. Antibiotics were given from the first day of SRP, in the test group (n = 29), azithromycin for 3 days and, in the control group (n = 31), amoxicillin/metronidazole for7 days. Probing depth (PD), attachment level (AL), and bleeding on probing (BOP) were recorded at baseline and after 3 and 12 months. Gingival crevicular fluid was analyzed for matrix metalloprotease (MMP)-8 and interleukin (IL)-1beta levels. Subgingival plaque was taken for assessment of the major bacteria associated with periodontitis. In both groups, PD, AL, and BOP were significantly reduced (p < 0.001). A few significant differences between the groups were found; AL and BOP were significantly better in the test than in the control group at the end of the study (p = 0.020 and 0.009). Periodontopathogens were reduced most in the test group. A noninferiority of the treatment with azithromycin in comparison with amoxicillin/metronidazole can be stated. The administration of azithromycin could be an alternative to the use of amoxicillin/metronidazole adjunctive to SRP in patients with moderate or severe chronic periodontitis; however, a randomized placebo-controlled multicenter study is needed. Application of azithromycin as a single antibiotic for 3 days might be considered as an additional adjunctive antibiotic to SRP in selected patients.

Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques

PubMed Central

Lin, Philana Ling; Dartois, Veronique; Johnston, Paul J.; Janssen, Christopher; Via, Laura; Goodwin, Michael B.; Klein, Edwin; Barry, Clifton E.; Flynn, JoAnne L.

2012-01-01

Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential to shorten therapy for active tuberculosis (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. tuberculosis infection, equal proportions of cynomolgus macaques develop active disease or latent infection and that latently infected animals reactivated upon neutralization of TNF. Using this model we now show that chemoprophylaxis of latently infected cynomolgus macaques with 6 mo of isoniazid (INH) effectively prevented anti-TNF antibody-induced reactivation. Similarly, 2-mo treatment of latent animals with a combination of INH and rifampicin (RIF) was highly effective at preventing reactivation disease in this model. Metronidazole (MTZ), which has activity only against anaerobic, nonreplicating bacteria, was as effective as either of these treatments in preventing reactivation of latent infection. Because hypoxic lesions also occur during active TB, we further showed that addition of MTZ to INH/RIF effectively treated animals with active TB within 2 mo. Healing lesions were associated with distinct changes in cellular pathology, with a shift toward increasingly fibrotic and calcified lesions. Our data in the nonhuman primate model of active and latent TB supports targeting bacteria in hypoxic environments for preventing reactivation of latent infection and possibly shortening the duration of therapy in active TB. PMID:22826237

Comparison of the pharmacokinetics of imipenem after intravenous and intrathecal administration in rabbits.

PubMed

Wang, Y; Qiu, L; Dong, J; Wang, B; Shi, Z; Liu, B; Wang, W; Zhang, J; Cai, S; Ye, G; Cai, X

2013-03-01

Intrathecal administration of antibiotics has potentially high effectiveness for the treatment for severe intracranial infections, particularly nosocomial meningitis. The use of intrathecal injection of antibiotics has been reported mostly in case reports. However, there is sparse data regarding the pharmacokinetics of antibiotics after intrathecal administration. This study investigated whether intrathecal injection is an effective method for the administration of imipenem. The pharmacokinetics of imipenem after intrathecal and intravenous administration of 1:1 imipenem: cilastatin (IMI/CIL) to rabbits were compared. The AUC0-t in the cerebrospinal fluid for intrathecal administration was approximately twice that of an equal dose of intravenous administration at doses of 0.35, 0.7, and 1.4 mg/kg. Brain concentrations of imipenem after intrathecal injection were three times greater than observed after intravenous injection and remained high for at least 8 hours post-injection. Elimination of imipenem after administration by either route was primarily via urine, but a transient surge of imipenem in bile and intestinal tissue was observed. Results indicate that there is a clinical potential for intrathecally administered IMI/CIL. Further studies are warranted to investigate the potential for seizure and to assess the translatability of the rabbit model to human treatment.

The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose.

PubMed

Funk, Felix; Ryle, Peter; Canclini, Camillo; Neiser, Susann; Geisser, Peter

2010-01-01

An ideal preparation for intravenous iron replacement therapy should balance effectiveness and safety. Compounds that release iron rapidly tend to cause toxicity, while large molecules can induce antibody formation and cause anaphylactic reactions. There is therefore a need for an intravenous iron preparation that delivers appropriate amounts of iron in a readily available form but with minimal side effects and thus with an excellent safety profile. In this paper, a review is given on the chemistry, pharmacology, and toxicology of ferric carboxymaltose (FCM, Ferinject), a stable and robust complex formulated as a colloidal solution with a physiological pH. The complex is gradually taken up mainly from the hepatic reticulo-endothelial system (RES), followed by effective delivery of iron to the endogeneous transport system for the haem synthesis in new erythrocytes, as shown in studies on the pharmacodynamics and pharmacokinetics with radio-labelled FCM. Studies with radio-labelled FCM also demonstrated a barrier function of the placenta and a low transfer of iron into the milk of lactating rats. Safety pharmacology studies indicated a favourable profile with regard to cardiovascular, central nervous, respiratory, and renal toxicity. A high maximum non-lethal dose was demonstrated in the single-dose toxicity studies. Furthermore, based on the No-Observed-Adverse-Effect-Levels (NOAELs) found in repeated-dose toxicity studies and on the cumulative doses administered, FCM has good safety margins. Reproductive and developmental toxicity studies did not reveal any direct or indirect harmful effects. No genotoxic potential was found in in vitro or in vivo studies. Moreover, antigenicity studies showed no cross-reactivity of FMC with anti-dextran antibodies and also suggested that FCM does not possess sensitizing potential. Lastly, no evidence of irritation was found in local tolerance studies with FCM. This excellent toxicity profile and the high effectiveness of FCM allow

Release and diffusional modeling of metronidazole lipid matrices.

PubMed

Ozyazici, Mine; Gökçe, Evren H; Ertan, Gökhan

2006-07-01

In this study, the first aim was to investigate the swelling and relaxation properties of lipid matrix on diffusional exponent (n). The second aim was to determine the desired release profile of metronidazole lipid matrix tablets. We prepared metronidazole lipid matrix granules using Carnauba wax, Beeswax, Stearic acid, Cutina HR, Precirol ATO 5, and Compritol ATO 888 by hot fusion method and pressed the tablets of these granules. In vitro release test was performed using a standard USP dissolution apparatus I (basket method) with a stirring rate of 100 rpm at 37 degrees C in 900 ml of 0.1 N hydrochloric acid, adjusted to pH 1.2, as medium for the formulations' screening. Hardness, diameter-height ratio, friability, and swelling ratio were determined. Target release profile of metronidazole was also drawn. Stearic acid showed the highest and Carnauba wax showed the lowest release rates in all formulations used. Swelling ratios were calculated after the dissolution of tablets as 9.24%, 6.03%, 1.74%, and 1.07% for Cutina HR, Beeswax, Precirol ATO 5, and Compritol ATO 888, respectively. There was erosion in Stearic acid, but neither erosion nor swelling in Carnauba wax, was detected. According to the power law analysis, the diffusion mechanism was expressed as pure Fickian for Stearic acid and Carnauba wax and the coupling of Fickian and relaxation contributions for other Cutina HR, Beeswax, Compritol ATO 888, and Precirol ATO 5 tablets. It was found that Beeswax (kd=2.13) has a very close drug release rate with the target profile (kt=1.95). Our results suggested that swelling and relaxation properties of lipid matrices should be examined together for a correct evaluation on drug diffusion mechanism of insoluble matrices.

Synergic activity, for anaerobes, of trovafloxacin with clindamycin or metronidazole: chequerboard and time-kill methods.

PubMed

Ednie, L M; Credito, K L; Khantipong, M; Jacobs, M R; Appelbaum, P C

2000-05-01

Chequerboard titrations were used to test the activity of trovafloxacin, alone and in combination with clindamycin or metronidazole, against 156 Gram-positive or Gram-negative anaerobes, including 47 Bacteroides fragilis group, 36 Prevotella spp., 26 fusobacteria, 21 peptostreptococci and 26 clostridia. MIC50/MIC90 values (mg/L) of each drug alone against all 156 strains were: trovafloxacin, 0.5/1; clindamycin, 0.25/2; metronidazole, 1/2. Synergy (FIC indices metronidazole. All other combinations were additive (FIC indices >0. 5-2.0); no antagonism (FIC indices >4.0) was seen. In addition, synergy was tested by time-kill methodology for each of the above combinations against 12 Gram-positive or Gram-negative strains. Results indicated that synergy (defined as a >/= 2 log(10) decrease in cfu/mL at 48 h compared with the more active drug alone) was found between trovafloxacin at or below the MIC and both clindamycin and metronidazole at or below the MIC in one strain each of Bacteroides fragilis, Bacteroides thetaiotaomicron, Prevotella intermedia, Fusobacterium varium, Peptostreptococcus asaccharolyticus and Clostridium bifermentans. Synergy between trovafloxacin (metronidazole alone was seen in one strain each of Bacteroides distasonis, Prevotella bivia, Fusobacterium mortiferum, P. asaccharolyticus and C. bifermentans. In many cases of synergy, including those at the trovafloxacin MIC, regrowth after 48 h, which was commonly seen with trovafloxacin alone, was inhibited, and 99.9% killing was observed with the combination after 48 h, but not with trovafloxacin alone.

Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension: Safe and Tolerable.

PubMed

El-Kersh, Karim; Ruf, Kathryn M; Smith, J Shaun

There is no standard protocol for intravenous treprostinil dose escalation. In most cases, slow up-titration is performed in the outpatient setting. However, rapid up-titration in an inpatient setting is an alternative that provides opportunity for aggressive treatment of common side effects experienced during dose escalation. In this study, we describe our experience with inpatient rapid up-titration of intravenous treprostinil. This was a single-center, retrospective study in which we reviewed the data of subjects with pulmonary arterial hypertension treated at our center who underwent inpatient rapid up-titration of intravenous treprostinil. Our treprostinil dose escalation protocol included initiation at 2 ng·kg·min with subsequent up-titration by 1 ng·kg·min every 6 to 8 hours as tolerated by side effects. A total of 16 subjects were identified. Thirteen subjects were treprostinil naive (naive group), and 3 subjects were receiving subcutaneous treprostinil but were hospitalized for further intravenous up-titration of treprostinil dose (nonnaive group). In the naive group, the median maximum dose achieved was 20 ng·kg·min with an interquartile range (IQR) of 20-23 ng·kg·min. The median up-titration interval was 6 days (IQR: 4-9). In the nonnaive group, the median maximum dose achieved was 20 ng·kg·min (range: 17-30). The median up-titration interval was 8.5 days (range: 1.5-11). Overall, the median maximum dose achieved was 20 ng·kg·min (IQR: 20-23.5), and the median up-titration interval was 6 days (IQR: 4.6-9.25), with no reported significant adverse hemodynamic events. In patients with pulmonary arterial hypertension, rapid inpatient titration of intravenous treprostinil is safe and tolerable.

Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Shin-Ae; Tsolmon, Bilegtsaikhan; Mann, Aman P.

2015-08-15

The medical applications of aptamers have recently emerged. We developed an antagonistic thioaptamer (ESTA) against E-selectin. Previously, we showed that a single injection of ESTA at a dose of 100 μg inhibits breast cancer metastasis in mice through the functional blockade of E-selectin. In the present study, we evaluated the safety of different doses of intravenously administered ESTA in single-dose acute and repeat-dose subacute studies in ICR mice. Our data indicated that intravenous administration of up to 500 μg ESTA did not result in hematologic abnormality in either study. Additionally, intravenous injection of ESTA did not affect the levels ofmore » plasma cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, GM-CSF, IFN-γ, and TNF-α) or complement split products (C3a and C5a) in either study. However, repeated injections of ESTA slightly increased plasma ALT and AST activities, in accordance with the appearance of small necrotic areas in the liver. In conclusion, our data demonstrated that intravenous administration of ESTA does not cause overt hematologic, organs, and immunologic responses under the experimental conditions. - Highlights: • Intravenous administration of ESTA was well tolerated. • ESTA up to 500 μg does not cause hematologic, organs, and immunologic responses. • ESTA-mediated hepatic abnormality was considered minor.« less

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate.

PubMed

Yap, B S; McCredie, K B; Benjamin, R S; Bodey, G P; Freireich, E J

1978-09-16

Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m(2) methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m(2). Seven days later intravenous methotrexate, 120 mg/m(2) was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m(2) with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m(2) (median 200 mg/m(2)). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m(2) caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.

Comparison of oral and vaginal metronidazole for treatment of bacterial vaginosis in pregnancy: impact on fastidious bacteria.

PubMed

Mitchell, Caroline M; Hitti, Jane E; Agnew, Kathy J; Fredricks, David N

2009-06-10

Bacterial vaginosis (BV) is a common condition that is associated with preterm birth and acquisition of complex communities of vaginal bacteria that include several fastidious species. Treatment of BV in pregnancy has mixed effects on the risk of preterm delivery, which some hypothesize is due to variable antibiotic efficacy for the fastidious bacteria. Both oral and intravaginal metronidazole can be used to treat bacterial vaginosis in pregnancy, but little is known about the impact of different routes of antibiotic administration on concentrations of fastidious vaginal bacteria. This was a sub-study of a larger randomized trial of oral versus vaginal metronidazole for treatment of BV in pregnancy. Fifty-three women were evaluated, including 30 women who received oral metronidazole and 23 who received intravaginal metronidazole. Bacterial taxon-specific quantitative PCR assays were used to measure concentrations of bacterial vaginosis associated bacterium (BVAB) 1, 2, and 3, Gardnerella vaginalis, Atopobium species, Leptotrichia/Sneathia species, Megasphaera species, and Lactobacillus crispatus before and after antibiotic treatment. Concentrations of Leptotrichia and Sneathia spp. and the fastidious Clostridia-like bacterium designated BVAB1 decreased significantly with oral (p = .002, p = .02) but not vaginal therapy (p = .141, p = .126). The fastidious bacterium BVAB3 did not significantly decrease with either treatment. Concentrations of Atopobium spp., reportedly resistant to metronidazole in vitro, dropped significantly with oral (p = .002) and vaginal (p = .001) treatment. There was no significant difference in the magnitude of change in bacterial concentrations between oral and vaginal treatment arms for any of the bacterial species. Lactobacillus crispatus concentrations did not change. Both oral and vaginal metronidazole therapy in pregnant women result in a significant decrease in concentrations of most BV-associated anaerobic bacteria, with the

Comparison of oral and vaginal metronidazole for treatment of bacterial vaginosis in pregnancy: impact on fastidious bacteria

PubMed Central

2009-01-01

Background Bacterial vaginosis (BV) is a common condition that is associated with preterm birth and acquisition of complex communities of vaginal bacteria that include several fastidious species. Treatment of BV in pregnancy has mixed effects on the risk of preterm delivery, which some hypothesize is due to variable antibiotic efficacy for the fastidious bacteria. Both oral and intravaginal metronidazole can be used to treat bacterial vaginosis in pregnancy, but little is known about the impact of different routes of antibiotic administration on concentrations of fastidious vaginal bacteria. Methods This was a sub-study of a larger randomized trial of oral versus vaginal metronidazole for treatment of BV in pregnancy. Fifty-three women were evaluated, including 30 women who received oral metronidazole and 23 who received intravaginal metronidazole. Bacterial taxon-specific quantitative PCR assays were used to measure concentrations of bacterial vaginosis associated bacterium (BVAB) 1, 2, and 3, Gardnerella vaginalis, Atopobium species, Leptotrichia/Sneathia species, Megasphaera species, and Lactobacillus crispatus before and after antibiotic treatment. Results Concentrations of Leptotrichia and Sneathia spp. and the fastidious Clostridia-like bacterium designated BVAB1 decreased significantly with oral (p = .002, p = .02) but not vaginal therapy (p = .141, p = .126). The fastidious bacterium BVAB3 did not significantly decrease with either treatment. Concentrations of Atopobium spp., reportedly resistant to metronidazole in vitro, dropped significantly with oral (p = .002) and vaginal (p = .001) treatment. There was no significant difference in the magnitude of change in bacterial concentrations between oral and vaginal treatment arms for any of the bacterial species. Lactobacillus crispatus concentrations did not change. Conclusion Both oral and vaginal metronidazole therapy in pregnant women result in a significant decrease in concentrations of most BV

Safety of intravenous lacosamide in critically ill children.

PubMed

Welsh, Sarah S; Lin, Nan; Topjian, Alexis A; Abend, Nicholas S

2017-11-01

Acute seizures are common in critically ill children. These patients would benefit from intravenous anti-seizure medications with few adverse effects. We reviewed the usage and effects of intravenous lacosamide in critically ill children with seizures or status epilepticus. This retrospective series included consecutive patients who received at least one dose of intravenous lacosamide from April 2011 to February 2016 in the pediatric intensive care unit of a quaternary care children's hospital, including patients with new lacosamide initiation and continuation of outpatient oral lacosamide. Dosing and prescribing practices were reviewed. Adverse effects were defined by predefined criteria, and most were evaluated during the full admission. We identified 51 intensive care unit admissions (47 unique patients) with intravenous lacosamide administration. Lacosamide was utilized as a third or fourth-line anti-seizure medication for acute seizures or status epilepticus in the lacosamide-naïve cohort. One patient experienced bradycardia and one patient experienced a rash that were considered potentially related to lacosamide. No other adverse effects were identified, including no evidence of PR interval prolongation. Lacosamide was well tolerated in critically ill children. Further study is warranted to evaluate the effectiveness of earlier lacosamide use for pediatric status epilepticus and acute seizures. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Experimental acute alcohol pancreatitis-related liver damage and endotoxemia: synbiotics but not metronidazole have a protective effect.

PubMed

Marotta, F; Barreto, R; Wu, C C; Naito, Y; Gelosa, F; Lorenzetti, A; Yoshioka, M; Fesce, E

2005-01-01

The aim of this study was to test the effect of gut manipulation by either novel synbiotics or by metronidazole on either endotoxemia or the severity of liver damage in the course of acute pancreatitis from alcohol ingestion. Sprague-Dawley rats were fed for 1 week through an intragastric tube a liquid diet with either: (i) 1 mL t.i.d. of a mixture of synbiotics (Lactobacillus acidophilus, Lactobacillus helveticus and Bifidobacterium in an enriched medium); (ii) 20 mg/kg t.i.d. metronidazole; or (iii) standard diet. Then, acute pancreatitis was induced by caerulein and when the disease was full-blown, rats were fed an alcohol-rich diet. Synbiotic and metronidazole treatment was given for a further 2 weeks. Transaminase and endotoxemia levels were measured before treatment, after 6 h, after 24 h and 2 weeks later, at the time the rats were killed. Liver samples were obtained for histological analysis. Synbiotics but not metronidazole improved the acute pancreatitis-induced increase in endotoxemia and transaminase levels. The addition of alcohol worsened these variables to a limited extent in the synbiotic-treated group, while metronidazole had a negative effect on liver damage. Gut flora pretreatment with synbiotics was able to effectively protect against endotoxin/bacterial translocation, as well as liver damage in the course of acute pancreatitis and concomitant heavy alcohol consumption. The beneficial effect of synbiotics on liver histology seems to be correlated with endotoxemia. Metronidazole did not produce such a beneficial effect; in fact, it further worsened liver damage when alcohol was added to the background of ongoing acute pancreatic inflammation.

A randomized, double-blinded, controlled trial of the effects of fluid rate and/or presence of dextrose in intravenous fluids on the labor course of nulliparas.

PubMed

Fong, Alex; Serra, Allison E; Caballero, Deysi; Garite, Thomas J; Shrivastava, Vineet K

2017-08-01

Prolonged labor has been demonstrated to increase adverse maternal and neonatal outcome. A practice that may decrease the risk of prolonged labor is the modification of fluid intake during labor. Several studies demonstrated that increased hydration in labor as well as addition of dextrose-containing fluids may be associated with a decrease in length of labor. The purpose of our study was to characterize whether high-dose intravenous fluids, standard-dose fluids with dextrose, or high-dose fluids with dextrose show a difference in the duration of labor in nulliparas. Nulliparous subjects with singletons who presented in active labor were randomized to 1 of 3 groups of intravenous fluids: 250 mL/h of normal saline, 125 mL/h of 5% dextrose in normal saline, or 250 mL/h of 2.5% dextrose in normal saline. The primary outcome was total length of labor from initiation of intravenous fluid in vaginally delivered subjects. Secondary outcomes included cesarean delivery rate and length of second stage of labor, among other maternal and neonatal outcomes. In all, 274 subjects who met inclusion criteria were enrolled. There were no differences in baseline characteristics among the 3 groups. There was no difference in the primary outcome of total length of labor in vaginally delivered subjects among the 3 groups. First stage of labor duration, second stage of labor duration, and cesarean delivery rates were also equivalent. There were no differences identified in other secondary outcomes including clinical chorioamnionitis, postpartum hemorrhage, blood loss, Apgar scores, or neonatal intensive care admission. There is no difference in length of labor or delivery outcomes when comparing high-dose intravenous fluids, addition of dextrose, or use of high-dose intravenous fluids with dextrose in nulliparous women who present in active labor. Copyright © 2017 Elsevier Inc. All rights reserved.

Genotoxicity Revaluation of Three Commercial Nitroheterocyclic Drugs: Nifurtimox, Benznidazole, and Metronidazole

PubMed Central

Buschini, Annamaria; Ferrarini, Lisa; Franzoni, Susanna; Galati, Serena; Lazzaretti, Mirca; Mussi, Francesca; Northfleet de Albuquerque, Cristina; Maria Araújo Domingues Zucchi, Tânia; Poli, Paola

2009-01-01

Nitroheterocyclic compounds are widely used as therapeutic agents against a variety of protozoan and bacterial infections. However, the literature on these compounds, suspected of being carcinogens, is widely controversial. In this study, cytotoxic and genotoxic potential of three drugs, Nifurtimox (NFX), Benznidazole (BNZ), and Metronidazole (MTZ) was re-evaluated by different assays. Only NFX reduces survival rate in actively proliferating cells. The compounds are more active for base-pair substitution than frameshift induction in Salmonella; NFX and BNZ are more mutagenic than MTZ; they are widely dependent from nitroreduction whereas microsomal fraction S9 weakly affects the mutagenic potential. Comet assay detects BNZ- and NFX-induced DNA damage at doses in the range of therapeutically treated patient plasma concentration; BNZ seems to mainly act through ROS generation whereas a dose-dependent mechanism of DNA damaging is suggested for NFX. The lack of effects on mammalian cells for MTZ is confirmed also in MN assay whereas MN induction is observed for NFX and BNZ. The effects of MTZ, that shows comparatively low reduction potential, seem to be strictly dependent on anaerobic/hypoxic conditions. Both NFX and BNZ may not only lead to cellular damage of the infective agent but also interact with the DNA of mammalian cells. PMID:20981287

Genotoxicity revaluation of three commercial nitroheterocyclic drugs: nifurtimox, benznidazole, and metronidazole.

PubMed

Buschini, Annamaria; Ferrarini, Lisa; Franzoni, Susanna; Galati, Serena; Lazzaretti, Mirca; Mussi, Francesca; Northfleet de Albuquerque, Cristina; Maria Araújo Domingues Zucchi, Tânia; Poli, Paola

2009-01-01

Nitroheterocyclic compounds are widely used as therapeutic agents against a variety of protozoan and bacterial infections. However, the literature on these compounds, suspected of being carcinogens, is widely controversial. In this study, cytotoxic and genotoxic potential of three drugs, Nifurtimox (NFX), Benznidazole (BNZ), and Metronidazole (MTZ) was re-evaluated by different assays. Only NFX reduces survival rate in actively proliferating cells. The compounds are more active for base-pair substitution than frameshift induction in Salmonella; NFX and BNZ are more mutagenic than MTZ; they are widely dependent from nitroreduction whereas microsomal fraction S9 weakly affects the mutagenic potential. Comet assay detects BNZ- and NFX-induced DNA damage at doses in the range of therapeutically treated patient plasma concentration; BNZ seems to mainly act through ROS generation whereas a dose-dependent mechanism of DNA damaging is suggested for NFX. The lack of effects on mammalian cells for MTZ is confirmed also in MN assay whereas MN induction is observed for NFX and BNZ. The effects of MTZ, that shows comparatively low reduction potential, seem to be strictly dependent on anaerobic/hypoxic conditions. Both NFX and BNZ may not only lead to cellular damage of the infective agent but also interact with the DNA of mammalian cells.

Differentiation of Metronidazole-Sensitive and -Resistant Clinical Isolates of Helicobacter pylori by Immunoblotting with Antisera to the RdxA Protein

PubMed Central

Latham, Stephanie R.; Owen, Robert J.; Elviss, Nicola C.; Labigne, Agnès; Jenks, Peter J.

2001-01-01

Antimicrobial resistance in Helicobacter pylori is a serious and increasing problem, and the development of rapid, reliable methods for detecting resistance would greatly improve the selection of antibiotics used to treat gastric infection with this organism. We assessed whether detection of the RdxA protein could provide the basis for determining the susceptibility of H. pylori to metronidazole. In order to raise polyclonal antisera to RdxA, we cloned the rdxA gene from H. pylori strain 26695 into the commercial expression vector pMAL-c2, purified the resultant fusion protein by affinity chromatography, and used this recombinant RdxA preparation to immunize rabbits. We then used this specific anti-RdxA antibody to perform immunoblotting on whole bacterial cell lysates of 17 metronidazole-sensitive and 27 metronidazole-resistant clinical isolates of H. pylori. While a 24-kDa immunoreactive band corresponding to the RdxA protein was observed in all metronidazole-sensitive strains, this band was absent in 25 of 27 resistant isolates. Our results indicate that testing for the absence of the RdxA protein would identify the majority of clinical isolates that will respond poorly to metronidazole-containing eradication regimens and have implications for the development of assays capable of detecting metronidazole resistance in H. pylori. PMID:11526127

[Intravenous clomipramine for depressive disorders].

PubMed

Landowski, Jerzy; Lamparska, Ewa; Wichowicz, Hubert; Gizińska, Dorota; Godlewska, Beata; Wiglusz, Mariusz

2002-01-01

51 patients with depressive episode (40--recurrent depressive disorder, 11--bipolar affective disorder) were treated by the clomipramine intravenous infusions. The number of infusions varied from 5 to 21 (mostly 10-16). The median of maximal dose was 150 mg. There were significant clinical improvement measured by CGI. The therapy was well tolerated.

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) induced by oral metronidazole.

PubMed

Şikar Aktürk, Aysun; Bayramgürler, Dilek; Salman, Selma; Yıldız, Kürşat Demir; Odyakmaz Demirsoy, Evren

2014-12-01

Baboon syndrome is a special form of systemic contact dermatitis to systemic or local administration of contact allergens. Baboon syndrome without known previous cutaneous sensitisation was also described as drug-related baboon syndrome or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). The major drugs causing SDRIFE was beta-lactam antibiotic such as amoxicillin and ampicillin. We report a case of 16-year-old woman who developed pruritic eruptions after oral metronidazole treatment for diarrhea. She was diagnosed SDRIFE according to her clinical and histopathological findings. To our knowledge, our patient is the first case who developed SDRIFE due to metronidazole in the literature.

Desensitization and renal transplant: plasmapheresis/IVIG standard dose in patients with high immunological risk.

PubMed

Flores-Gama, Francisco; Mondragón-Ramírez, Guillermo Antonio; Bochicchio-Riccardelli, Tommaso

2009-01-01

Patients with high immunological risk have been relegated to the growing waiting list for an immunologically compatible donor. Our objective was to report the experience of a transplant center in desensitization of patients with high immunological risk. We carried out a descriptive and retrospective study. Included were all the renal transplant patients from November 1999 to January 2008 in which we used plasmapheresis and standard dose of intravenous immunoglobulin (IVIG) as desensitization. Eight patients had history of alloimmunity (positive crossmatch or high panel-reactive antibodies (PRA >30%). Desensitization was accomplished with plasmapheresis and exchange of 1.5 plasma volume. Subsequent to each session we administered a standard dose of IVIG (5 g/dose). Immunosuppression began equal to the first plasmapheresis with calcineurin inhibitor (tacrolimus) plus six patients with mycophenolate mofetil and two patients with sirolimus. In seven cases, negative crossmatches were obtained before the transplantation, except in the eighth case in whom it was not done. Two patients received human antibodies against CD25 (basiliximab, 20 mg/dose). During their evolution, all patients maintained stable graft function. According to our experience, renal graft outcome in patients with high immunological risk after an adequate desensitization protocol is similar to that observed in nonsensitized patients, at least during the first year of transplantation.

[Influence of iron nanoparticles on cardiac performance and hemodynamics in rabbits after intravenous administration in acute experiment].

PubMed

Doroshenko, A M

2014-01-01

Iron nanoparticles are possessed by high potential in the creation of effective and safe antianemic drugs due to the enhanced biological activity of metal nanoparticles. As a step of intravenous dosage form development the study of short-term effects of iron nanoparticles on the cardiovascular system is important. Dose-dependent changes of systemic hemodynamics' parameters were established in acute experiment on rabbits after several intravenous injections of zero-valent iron nanoparticles solution.

High-dose ifosfamide by infusion with Mesna in advanced refractory sarcomas.

PubMed

Güllü, I; Yalçin, S; Tekuzman, G; Barişta, I; Alkiş, N; Celik, I; Zengin, N; Güler, N; Kars, A; Baltali, E

1996-01-01

Twenty patients with advanced sarcomas entered a pilot study with ifosfamide (IF) and mercaptoethane sulfonate sodium (Mesna) as a second-line treatment for six planned cycles. All patients had received prior doxorubicin- and cyclophosphamide-based chemotherapies. IF was administered at a dose of 3 g/m2 given as continuous intravenous infusion for 24 hr on day 1-5 with Mesna. In the absence of disease progression, chemotherapy was planned to be repeated every 4 weeks for six consecutive cycles. Following chemotherapy, only 2 patients (11%) achieved partial response with response durations of 6 and 9 months. There was no complete response. When considered for only high-grade tumors, the response rate reached up to 22%. Toxicity was reported for 48 cycles and the dose-limiting toxicities were myelosuppression (22%) and encephalopathy (17%). Chemotherapy protocol was changed after two or three courses in 16 patients with stable or progressive disease. IF/Mesna chemotherapy at this dose and schedule was not found to be very promising in refractory sarcomas as a second-line chemotherapy.

Effect of MMX® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials

PubMed Central

Pierce, David; Corcoran, Mary; Martin, Patrick; Barrett, Karen; Inglis, Susi; Preston, Peter; Thompson, Thomas N; Willsie, Sandra K

2014-01-01

Background MMX® mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections. Aim To evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies. Methods In all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1–4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1–3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1–3 and once on day 4 (N=44). Results MMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) fell within the predefined equivalence range (0.80–1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in Cmax at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild. Conclusion MMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of

Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers

PubMed Central

Chiesa, Joseph; Lückermann, Mark; Fischer, Carsten; Dalhoff, Axel; Fuhr, Uwe

2017-01-01

ABSTRACT Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination

Long-term, low-dose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients.

PubMed

Canavese, Caterina; Petrarulo, Michele; Massarenti, Paola; Berutti, Silvia; Fenoglio, Roberta; Pauletto, Daniela; Lanfranco, Giacomo; Bergamo, Daniela; Sandri, Luisa; Marangella, Martino

2005-03-01

Ascorbate supplementation for patients on regular dialysis treatment (RDT) is advised to obviate deficiency and improve epoetin response in those with functional iron deficiency. However, clear-cut safety concerns regarding hyperoxalemia are still poorly understood. This study tries to establish safety/efficacy profiles of ascorbate and oxalate during long-term intravenous ascorbate supplementation. A prospective study was performed in 30 patients on RDT showing ascorbate deficiency (plasma ascorbate < 2.6 mg/L [<15 micromol/L]): 18 patients were administered intravenous ascorbate during 18 months (250 mg/wk, subsequently increased to 500 mg), and 12 patients were taken as reference untreated cases. Plasma ascorbate and oxalate assays and dialytic balance determinations were performed (ion chromatography and reverse-phase high-performance liquid chromatography, respectively) at baseline, during treatment, and 12 months after withdrawal. Plasma ascorbate levels increased dose dependently with supplementation (1.6 +/- 0.8 mg/L [9.1 +/- 4.6 mumol/L] at baseline, 2.8 +/- 1.8 mg/L [15.9 +/- 10.1 micromol/L]) with 250 mg of ascorbate, and 6.6 +/- 2.8 mg/L [37.5 +/- 16.0 micromol/L] with 500 mg/wk of ascorbate), but only normalized with greater dosages for several months in 94% of patients. Baseline plasma oxalate levels increased from 3.2 +/- 0.8 mg/L (35.8 +/- 8.8 micromol/L) to 3.6 +/- 0.8 mg/L (39.5 +/- 9.1 micromol/L) and 4.5 +/- 0.9 mg/L (50.3 +/- 10.4 micromol/L) with 250 and 500 mg, respectively ( P < 0.001). The calcium oxalate saturation threshold was exceeded by 7 of 18 patients (40%) during 6 months therapy with 500 mg/wk. Ascorbate dialysis removal increased from 37.8 +/- 23.2 mg (215 +/- 132 micromol) to 99.6 +/- 51.7 mg (566 +/- 294 micromol) during supplementation (P < 0.001), with corresponding increases in oxalate removal from 82.5 +/- 33.2 mg (917 +/- 369 micromol) to 111.2 +/- 32.6 mg/L (1,236 +/- 362 micromol; P < 0.01). Withdrawal reverted plasma

High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial.

PubMed

Hoffer, L John; Robitaille, Line; Zakarian, Robert; Melnychuk, David; Kavan, Petr; Agulnik, Jason; Cohen, Victor; Small, David; Miller, Wilson H

2015-01-01

Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail. We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement. Despite IVC's biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC's value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify specific clusters of cancer type, chemotherapy

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma

PubMed Central

Hordeaux, Juliette; Bouchaert, Emmanuel; Gomes, Bruno

2017-01-01

Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans’ solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas. PMID:28505195

[Comparative study on the tolerance and efficacy of high doses of metoclopramide and clebopride in vomiting induced by cisplatin].

PubMed

Martín, M; Díaz-Rubio, E

1989-06-10

Forty-one patients treated with cisplatin (100-120 mg/m2), alone or associated with vindesine (3 mg/m2), were included in a randomized crossover pilot study which compared 3 different doses of intravenous clebopride with intravenous metoclopramide. The patients were randomly assigned to receive clebopride in the first chemotherapy course in one of the three dose levels used (0.5 mg/kg, 21 patients; 0.75 mg/kg, 11 patients; 1 mg/kg, 10 patients) or metoclopramide (10 mg/kg). In the second course of the same chemotherapy the patients received the alternative antiemetic, and thus each patient was his own control. The total dose of both antiemetic drugs was infused in 5 intravenous fractions given every 2 hours. The antiemetic activity of clebopride was moderately lower to that of metoclopramide with the first two tested doses (overall doses of 0.5 and 0.75 mg/kg) and similar with the last dose (1 mg/kg). Clebopride was reasonably well tolerated at the used dosages, inducing sedation in 20% of cases (versus 24% with metoclopramide) and diarrhea in 37% (versus 20% with metoclopramide). Extrapyramidal reactions developed in 17% of the courses which included metoclopramide and in none including clebopride. This difference was statistically significant.

Single‐dose intravenous iron in Southeast Asian heart failure patients: A pilot randomized placebo‐controlled study (PRACTICE‐ASIA‐HF)

PubMed Central

Yeo, Poh Shuan Daniel; Hadi, Farid Abdul; Cushway, Timothy; Lee, Kim Yee; Yin, Fang Fang; Ching, Anne; Li, Ruili; Loh, Seet Yoong; Lim, Shir Lynn; Wong, Raymond Ching‐Chiew; Tai, Bee Choo; Richards, Arthur Mark; Lam, Carolyn S.P.

2018-01-01

Abstract Aims Iron deficiency is highly prevalent in Southeast Asians with heart failure (HF) and associated with worse outcomes. This trial aimed to assess the effect of intravenous iron in Southeast Asians hospitalized with decompensated HF. Methods and results Fifty patients hospitalized for acute decompensated HF, regardless of ejection fraction, with iron deficiency (defined as serum ferritin <300 ng/mL if transferrin saturation is <20%) were randomized to receive either one dose of intravenous ferric carboxymaltose (FCM) 1000 mg or placebo (0.9% saline) following HF stabilization and before discharge in two Singapore tertiary centres. The primary endpoint was difference in 6‐min walk test (6MWT) distance over 12 weeks, while secondary endpoints were quality of life assessed using validated Kansas City Cardiomyopathy Questionnaire (KCCQ) and Visual Analogue Scale (VAS). Improvement in 6MWT distance at Week 12 was observed in both FCM and placebo groups (from 252 ± 123 to 334 ± 128 m and from 243 ± 67 to 301 ± 83 m, respectively). Unadjusted analysis showed 6MWT distance for FCM exceeded that for placebo, but adjustment for baseline covariates and time attenuated this effect {adjusted mean difference between groups: 0.88 m [95% confidence interval (CI) −30.2 to 32.0, P = 0.956]}. KCCQ overall summary and VAS were similar in both groups [adjusted mean difference: KCCQ −1.48 (95% CI −8.27 to 5.31, P = 0.670) and VAS 0.26 (95% CI −0.33 to 0.86, P = 0.386)]. FCM was well tolerated with no serious treatment‐related adverse events. Conclusions Intravenous FCM administered pre‐discharge in Southeast Asians hospitalized with decompensated HF is clinically feasible. Changes in 6MWT distance should be measured beyond Week 12 to account for background therapy effects. PMID:29345426

A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial.

PubMed

Elewski, Boni E; Fleischer, Alan B; Pariser, David M

2003-11-01

To compare the efficacy and safety of a novel formulation of 15% azelaic acid gel (Finacea; Berlex Laboratories, Inc, Montville, NJ) with 0.75% metronidazole gel (MetroGel; Galderma Laboratories LP, Fort Worth, Tex) as topical therapy for moderate, papulopustular facial rosacea. Multicenter, double-blind, randomized, parallel-group study. Thirteen US centers. A total of 251 patients with papulopustular rosacea with persistent erythema and telangiectasia. Patients were randomized to receive azelaic acid gel or metronidazole gel twice daily for 15 weeks. Nominal and percent change in inflammatory lesion count, change in erythema and telangiectasia severity ratings, investigator's global assessment of rosacea, and investigator's and patient's overall improvement ratings. Azelaic acid gel was superior to metronidazole gel in reduction of mean nominal lesion count (-12.9 vs -10.7, respectively) (P =.003) and mean percent decrease in inflammatory lesions (-72.7% vs -55.8%, respectively) (P<.001). With respect to erythema severity, 56% of azelaic acid gel-treated patients were rated improved vs 42% of metronidazole gel-treated patients (P =.02). The effectiveness of metronidazole gel on these variables seemed to plateau after week 8, whereas azelaic acid gel demonstrated progressive improvement through week 15. Neither treatment had a clinically appreciable effect on telangiectasia. Both the investigator's global assessment (P =.02) and overall assessment of improvement (P =.005) showed a significant therapeutic advantage for azelaic acid gel. Azelaic acid gel also scored higher on the patient's overall assessment of efficacy. Both treatments were rated as having high cosmetic acceptability. No serious or systemic treatment-related adverse events were reported in either group. Use of 15% azelaic acid gel twice daily for 15 weeks demonstrated significant superiority over using 0.75% metronidazole gel in improving principal signs of rosacea (inflammatory lesions and

Safety of intravenous metoprolol use in unmonitored wards: a single-centre observational study.

PubMed

Kelly, D; Hawdon, G; Reeves, J; Morris, A; Cunningham, M; Barrett, J

2015-09-01

This study aims to examine and quantify the risks associated with the use of intravenous metoprolol on unmonitored wards. This study was a retrospective single-centre observational study from 1 January 2009 to 31 December 2013. The study hospital was a 415-bed, private hospital in Melbourne, Victoria. The study population was all patients who received intravenous metoprolol on an unmonitored ward. The primary outcome measure was the rate of serious adverse events (SAE), defined as a complication of intravenous metoprolol resulting in transfer to a critical-care environment, a medical emergency team call or death. Six hundred and nine patients received a total of 8260 doses of intravenous metoprolol. Seven cases were identified with a SAE deemed possibly related to beta-blocker use and there was one death. All SAE were hypotension, giving an overall rate of hypotension of 7/609 or 1.1% (95% confidence interval (CI), 0.5 to 2.4%) with a rate per dose delivered of 0.8/1000 doses (95% CI 0.3 to 1.7). The death occurred in a 94-year-old woman with abdominal sepsis. After case file review, consensus opinion deemed this to be unrelated to intravenous metoprolol. The use of intravenous metoprolol on unmonitored wards appears to be safe. The complication rate was low, suggesting that this may be a sensible approach to the management of in-hospital populations at risk of beta-blocker withdrawal. © 2015 Royal Australasian College of Physicians.

A pilot study of high-dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation.

PubMed

Melamed, Isaac R; Heffron, Melinda; Testori, Alessandro; Lipe, Kellie

2018-03-01

Research has shown that a subset of the autism spectrum disorder (ASD) population presents with immune dysregulation. To explore this topic further, we investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD. In this study, participants were recruited based on a diagnosis of autistic disorder, Asperger's disorder, or pervasive developmental disorder not otherwise specified. Participants also showed evidence of immune dysfunction based on abnormal levels of specific biomarkers, including CD40 ligand (CD154), lymphocyte stimulation, and T or B cell dysfunction. Of 17 screened patients, 14 completed the trial and received IVIG treatment (1 g/kg dose) for ten 21-day treatment cycles. The primary endpoint was disease improvement assessed using standardized cognitive and behavioral tests (Children's Communication Checklist [CCC-2], Social Responsiveness Scale [SRS], Aberrant Behavior Checklist [ABC], Clinical Global Impressions-Severity [CGI-S] and -Improvement [CGI-I], Autism Diagnostic Observation Schedule [ADOS], and Peabody Picture Vocabulary Test [PPVT]). Secondary endpoints included experimental biomarkers such as CD154, toll-like receptor-4, memory B cells, FOXP3, and lymphocyte stimulation. Significant improvements from baseline to study endpoint were observed in several subscales of the CCC-2, SRS, CGI-I, CGI-S, and ADOS, including Associated Maladaptive Behaviors (P ≤ .043), Reciprocal Social Interaction (P = .015), Communication (P < .001), and Stereotyped Behaviors and Repetitive Interests (P ≤ .013). Statistically significant reductions were also seen in numerous secondary outcomes of immunological biomarkers indicative of neuroinflammation. IVIG was well tolerated; no subjects withdrew due to an adverse event, and clinical data showed no evidence of thromboembolic events. Autism Res 2018, 11: 421-433. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. Since

Update of a comparative analysis of cost minimization following the introduction of newly available intravenous iron therapies in hospital practice

PubMed Central

Bhandari, Sunil

2011-01-01

Background The clinical need to be able to administer high doses of intravenous iron conveniently as a rapid infusion has been addressed by the recent introduction of ferric carboxymaltose and subsequently iron isomaltoside 1000. Neither requires a test dose. The maximum dose of ferric carboxymaltose is 1000 mg. The maximum dose of iron isomaltoside 1000 is based on 20 mg/kg body weight without a specified ceiling dose, thereby increasing the scope of being able to achieve total iron repletion with a single infusion. This ability to give high doses of iron is important in the context of managing iron deficiency anemia, which is associated with a number of clinical conditions where demands for iron are high. It is also an important component of the strategy as an alternative to blood transfusion. Affordability is a key issue for health services. Recent price changes affecting iron sucrose and ferric carboxymaltose, plus modifications to the manufacturers’ prescribing information, have provoked this update. Methods This study is a comparative analysis of the costs of acquiring and administering the newly available intravenous iron formulations against standard treatments in the hospital setting. The costs include the medication, nursing costs, equipment, and patient transportation. Three dosage levels (600 mg, 1000 mg, and 1600 mg) are considered. Results and conclusion The traditional standard treatments, blood and iron sucrose, cost more than the alternative intravenous iron preparations across the dose spectrum and sensitivities. Low molecular weight iron dextran is the least expensive option at the 1600 mg dose level but has the caveat of a prolonged administration time and requirement for a test dose. At 600 mg and 1000 mg dose levels, both iron isomaltoside 1000 and ferric carboxymaltose are more economical than low molecular weight iron dextran. Iron isomaltoside 1000 is less expensive than ferric carboxymaltose at all dose levels. Newly available iron

Age-Stratified Treatment Response Rates in Hospitalized Patients with Clostridium difficile Infection Treated with Metronidazole

PubMed Central

Pham, Vy P.; Luce, Andrea M.; Ruppelt, Sara C.; Wei, Wenjing; Aitken, Samuel L.; Musick, William L.; Roux, Ryan K.

2015-01-01

Consensus on the optimal treatment of Clostridium difficile infection (CDI) is rapidly changing. Treatment with metronidazole has been associated with increased clinical failure rates; however, the reasons for this are unclear. The purpose of this study was to assess age-related treatment response rates in hospitalized patients with CDI treated with metronidazole. This was a retrospective, multicenter cohort study of hospitalized patients with CDI. Patients were assessed for refractory CDI, defined as persistent diarrhea after 7 days of metronidazole therapy, and stratified by age and clinical characteristics. A total of 242 individuals, aged 60 ± 18 years (Charlson comorbidity index, 3.8 ± 2.4; Horn's index, 1.7 ± 1.0) were included. One hundred twenty-eight patients (53%) had severe CDI. Seventy patients (29%) had refractory CDI, a percentage that increased from 22% to 28% and to 37% for patients aged less than 50 years, for patients from 50 to 70 years, and for patients aged >70 years, respectively (P = 0.05). In multivariate analysis, Horn's index (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.50 to 2.77; P < 0.001), severe CDI (OR, 2.25; 95% CI, 1.15 to 4.41; P = 0.018), and continued use of antibiotics (OR, 2.65; 95% CI, 1.30 to 5.39; P = 0.0072) were identified as significant predictors of refractory CDI. Age was not identified as an independent risk factor for refractory CDI. Therefore, hospitalized elderly patients with CDI treated with metronidazole had increased refractory CDI rates likely due to increased underlying severity of illness, severity of CDI, and concomitant antibiotic use. These results may help identify patients that may benefit from alternative C. difficile treatments other than metronidazole. PMID:26195522

Age-Stratified Treatment Response Rates in Hospitalized Patients with Clostridium difficile Infection Treated with Metronidazole.

PubMed

Pham, Vy P; Luce, Andrea M; Ruppelt, Sara C; Wei, Wenjing; Aitken, Samuel L; Musick, William L; Roux, Ryan K; Garey, Kevin W

2015-10-01

Consensus on the optimal treatment of Clostridium difficile infection (CDI) is rapidly changing. Treatment with metronidazole has been associated with increased clinical failure rates; however, the reasons for this are unclear. The purpose of this study was to assess age-related treatment response rates in hospitalized patients with CDI treated with metronidazole. This was a retrospective, multicenter cohort study of hospitalized patients with CDI. Patients were assessed for refractory CDI, defined as persistent diarrhea after 7 days of metronidazole therapy, and stratified by age and clinical characteristics. A total of 242 individuals, aged 60 ± 18 years (Charlson comorbidity index, 3.8 ± 2.4; Horn's index, 1.7 ± 1.0) were included. One hundred twenty-eight patients (53%) had severe CDI. Seventy patients (29%) had refractory CDI, a percentage that increased from 22% to 28% and to 37% for patients aged less than 50 years, for patients from 50 to 70 years, and for patients aged >70 years, respectively (P = 0.05). In multivariate analysis, Horn's index (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.50 to 2.77; P < 0.001), severe CDI (OR, 2.25; 95% CI, 1.15 to 4.41; P = 0.018), and continued use of antibiotics (OR, 2.65; 95% CI, 1.30 to 5.39; P = 0.0072) were identified as significant predictors of refractory CDI. Age was not identified as an independent risk factor for refractory CDI. Therefore, hospitalized elderly patients with CDI treated with metronidazole had increased refractory CDI rates likely due to increased underlying severity of illness, severity of CDI, and concomitant antibiotic use. These results may help identify patients that may benefit from alternative C. difficile treatments other than metronidazole. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol.

PubMed

Simons, P J; Cockshott, I D; Douglas, E J; Gordon, E A; Hopkins, K; Rowland, M

1988-04-01

1. An intravenous dose of 14C-propofol (0.47 mg/kg) administered to six male volunteers was rapidly eliminated with 88% recovered in the urine in 5 days and less than 2% in faeces. 2. The dose was cleared by metabolism with less than 0.3% excreted unchanged. The major metabolites were the glucuronic acid conjugate of propofol and the glucuronic acid and sulphate conjugates of its hydroxylated derivative, 2,6-diisopropyl-1,4-quinol. Propofol glucuronide accounted for about 53% of the urinary radioactivity and was the major metabolite in plasma from 30 min post dose. 3. The blood concentration of propofol declined in a biphasic manner from a maximum mean value of 0.44 microgram/ml, 2 min after injection. The half-lives of the first and second exponential phases, mean values 5 min and 97 min respectively, varied widely among subjects. A proportion of the dose was cleared slowly, probably due to slow release from less well perfused tissues. Propofol accounted for 94% of the total blood radioactivity at 2 min but only about 6% from 3 to 8 h post dose. 4. Propofol has a volume of distribution equivalent to about 3 to 4 times body weight, and a mean total body clearance of 2.2 1/min.

Brain temperature effects of intravenous heroin: State dependency, environmental modulation, and the effects of dose.

PubMed

Bola, R Aaron; Kiyatkin, Eugene A

2017-11-01

Here we examined how intravenous heroin at a dose that maintains self-administration (0.1 mg/kg) affects brain temperature homeostasis in freely moving rats under conditions that seek to mimic some aspects of human drug use. When administered under standard laboratory conditions (quiet rest at 22 °C ambient temperature), heroin induced moderate temperature increases (1.0-1.5 °C) in the nucleus accumbens (NAc), a critical structure of the brain motivation-reinforcement circuit. By simultaneously recording temperatures in the temporal muscle and skin, we demonstrate that the hyperthermic effects of heroin results primarily from inhibition of heat loss due to strong and prolonged skin vasoconstriction. Heroin-induced brain temperature increases were enhanced during behavioral activation (i.e., social interaction) and in a moderately warm environment (29 °C). By calculating the "net" effects of the drug in these two conditions, we found that this enhancement results from the summation of the hyperthermic effects of heroin with similar effects induced by either social interaction or a warmer environment. When the dose of heroin was increased (to 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 mg/kg), brain temperature showed a biphasic down-up response. The initial temperature decrease was dose-dependent and resulted from a transient inhibition of intra-brain heat production coupled with increased heat loss via skin surfaces-the effects typically induced by general anesthetics. These initial inhibitory effects induced by large-dose heroin injections could be related to profound CNS depression-the most serious health complications typical of heroin overdose in humans. Published by Elsevier Ltd.

Pharmacokinetics of intraperitoneal and intravenous fosfomycin in automated peritoneal dialysis patients without peritonitis.

PubMed

Tobudic, Selma; Matzneller, Peter; Stoiser, Brigitte; Wenisch, Judith Maria; Zeitlinger, Markus; Vychytil, Andreas; Jaeger, Walter; Boehmdorfer, Michaela; Reznicek, Gottfried; Burgmann, Heinz

2012-07-01

Blood and dialysate concentrations of fosfomycin were determined after intravenous and intraperitoneal application of 4 mg/liter in patients undergoing automated peritoneal dialysis. Maximum serum concentrations after intravenous (287.75 ± 86.34 mg/liter) and intraperitoneal (205.78 ± 66.78 mg/liter) administration were comparable. Ratios of intraperitoneal to systemic exposure were 1.12 (intraperitoneal administration) and 0.22 (intravenous administration), indicating good systemic exposure after intraperitoneal application but limited penetration of fosfomycin into the peritoneal fluid after the intravenous dose.

Radiosynthesis and Biodistribution of 99mTc-Metronidazole as an Escherichia coli Infection Imaging Radiopharmaceutical.

PubMed

Iqbal, Anam; Naqvi, Syed Ali Raza; Rasheed, Rashid; Mansha, Asim; Ahmad, Matloob; Zahoor, Ameer Fawad

2018-05-01

Bacterial infection poses life-threatening challenge to humanity and stimulates to the researchers for developing better diagnostic and therapeutic agents complying with existing theranostic techniques. Nuclear medicine technique helps to visualize hard-to-diagnose deep-seated bacterial infections using radionuclide-labeled tracer agents. Metronidazole is an antiprotozoal antibiotic that serves as a preeminent anaerobic chemotherapeutic agent. The aim of this study was to develop technetium-99m-labeled metronidazole radiotracer for the detection of deep-seated bacterial infections. Radiosynthesis of 99m Tc-metronidazole was carried by reacting reduced technetium-99m and metronidazole at neutral pH for 30 min. The stannous chloride dihydrate was used as the reducing agent. At optimum radiolabeling conditions, ~ 94% radiochemical was obtained. Quality control analysis was carried out with a chromatographic paper and instant thin-layer chromatographic analysis. The biodistribution study of radiochemical was performed using Escherichia coli bacterial infection-induced rat model. The scintigraphic study was performed using E. coli bacterial infection-induced rabbit model. The results showed promising accumulation at the site of infection and its rapid clearance from the body. The tracer showed target-to-non-target ratio 5.57 ± 0.04 at 1 h post-injection. The results showed that 99m Tc-MNZ has promising potential to accumulate at E. coli bacterial infection that can be used for E. coli infection imaging.

Levofloxacin plus Metronidazole Administered Once Daily versus Moxifloxacin Monotherapy against a Mixed Infection of Escherichia coli and Bacteroides fragilis in an In Vitro Pharmacodynamic Model

PubMed Central

Hermsen, Elizabeth D.; Hovde, Laurie B.; Sprandel, Kelly A.; Rodvold, Keith A.; Rotschafer, John C.

2005-01-01

Moxifloxacin has been suggested as an option for monotherapy of intra-abdominal infections. Recent data support the use of a once-daily metronidazole regimen. The purpose of this study was to investigate the activity of levofloxacin (750 mg every 24 h [q24h]) plus metronidazole (1,500 mg q24h) compared with that of moxifloxacin (400 mg q24h) monotherapy in a mixed-infection model. By using an in vitro pharmacodynamic model in duplicate, Escherichia coli and Bacteroides fragilis were exposed to peak concentrations of 8.5 mg of levofloxacin/liter q24h, 32 mg of metronidazole/liter q24h, and 2 mg for moxifloxacin/liter q24h for 24 h. The activities of levofloxacin, metronidazole, moxifloxacin, and levofloxacin plus metronidazole were evaluated against E. coli, B. fragilis, and E. coli plus B. fragilis. The targeted half-lives of levofloxacin, metronidazole, and moxifloxacin were 8, 8, and 12 h, respectively. Time-kill curves were analyzed for time to 3-log killing, slope, and regrowth. Pre- and postexposure MICs were determined. The preexposure levofloxacin, metronidazole, and moxifloxacin MICs for E. coli and B. fragilis were 0.5 and 1, >64 and 0.5, and 1 and 0.25 mg/liter, respectively. Levofloxacin and moxifloxacin achieved a 3-log killing against E. coli and B. fragilis in all experiments, as did metronidazole against B. fragilis. Metronidazole did not decrease the starting inoculum of E. coli. The area under the concentration-time curve/MIC ratios for E. coli and B. fragilis were 171.7 and 85.9, respectively, for levofloxacin and 26 and 103.9, respectively, for moxifloxacin. Levofloxacin plus metronidazole exhibited the fastest rates of killing. The levofloxacin and moxifloxacin MICs for B. fragilis increased 8- to 16-fold after the organism was exposed to moxifloxacin. No other changes in the postexposure MICs were found. Levofloxacin plus metronidazole administered once daily exhibited activity similar to that of moxifloxacin against the mixed E. coli and B

Levofloxacin plus metronidazole administered once daily versus moxifloxacin monotherapy against a mixed infection of Escherichia coli and Bacteroides fragilis in an in vitro pharmacodynamic model.

PubMed

Hermsen, Elizabeth D; Hovde, Laurie B; Sprandel, Kelly A; Rodvold, Keith A; Rotschafer, John C

2005-02-01

Moxifloxacin has been suggested as an option for monotherapy of intra-abdominal infections. Recent data support the use of a once-daily metronidazole regimen. The purpose of this study was to investigate the activity of levofloxacin (750 mg every 24 h [q24h]) plus metronidazole (1,500 mg q24h) compared with that of moxifloxacin (400 mg q24h) monotherapy in a mixed-infection model. By using an in vitro pharmacodynamic model in duplicate, Escherichia coli and Bacteroides fragilis were exposed to peak concentrations of 8.5 mg of levofloxacin/liter q24h, 32 mg of metronidazole/liter q24h, and 2 mg for moxifloxacin/liter q24h for 24 h. The activities of levofloxacin, metronidazole, moxifloxacin, and levofloxacin plus metronidazole were evaluated against E. coli, B. fragilis, and E. coli plus B. fragilis. The targeted half-lives of levofloxacin, metronidazole, and moxifloxacin were 8, 8, and 12 h, respectively. Time-kill curves were analyzed for time to 3-log killing, slope, and regrowth. Pre- and postexposure MICs were determined. The preexposure levofloxacin, metronidazole, and moxifloxacin MICs for E. coli and B. fragilis were 0.5 and 1, >64 and 0.5, and 1 and 0.25 mg/liter, respectively. Levofloxacin and moxifloxacin achieved a 3-log killing against E. coli and B. fragilis in all experiments, as did metronidazole against B. fragilis. Metronidazole did not decrease the starting inoculum of E. coli. The area under the concentration-time curve/MIC ratios for E. coli and B. fragilis were 171.7 and 85.9, respectively, for levofloxacin and 26 and 103.9, respectively, for moxifloxacin. Levofloxacin plus metronidazole exhibited the fastest rates of killing. The levofloxacin and moxifloxacin MICs for B. fragilis increased 8- to 16-fold after the organism was exposed to moxifloxacin. No other changes in the postexposure MICs were found. Levofloxacin plus metronidazole administered once daily exhibited activity similar to that of moxifloxacin against the mixed E. coli and B

A Case of Type 2 Amiodarone-Induced Thyrotoxicosis That Underwent Total Thyroidectomy under High-Dose Steroid Administration

PubMed Central

Hashimoto, Koshi; Ota, Masaki; Irie, Tadanobu; Takata, Daisuke; Nakajima, Tadashi; Kaneko, Yoshiaki; Tanaka, Yuko; Matsumoto, Shunichi; Nakajima, Yasuyo; Kurabayashi, Masahiko; Oyama, Tetsunari; Takeyoshi, Izumi; Mori, Masatomo; Yamada, Masanobu

2015-01-01

Amiodarone is used commonly and effectively in the treatment of arrhythmia; however, it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism (type 1 amiodarone-induced thyrotoxicosis (AIT)) and destructive thyroiditis (type 2 AIT). We experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in a complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone), the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid administration have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under high-dose steroid administration. PMID:25664188

[Sensory aphasia during therapy with metronidazole--an important differential diagnosis of acute cerebral ischemia].

PubMed

Kowar, M; Frackowiak, M; Friedrich, C; Wilhelm, K; Walger, P; Jacobs, A H

2014-11-01

A 74-year old man was admitted after neurosurgical treatment of a lumbar vertebral fracture. He had a slight paresis of the right leg in combination with bladder dysfunction. There were signs of a postoperative anemia (hemoglobin 10.4 mg/dl) and mildly elevated infection parameters (CRP 2 mg/dl). Routine ECG and chest X-ray were normal. Physical training was initiated, but diarrhea occurred 2 days after admission. As the patient had received antibiotics after the operation, a treatment with metronidazole was initiated under the suspicion of diarrhoea induced by clostridium difficile. At day 6 of treatment a hypertensive crisis (blood pressure 230/120 mmHg) developed, followed by sensory aphasia. Despite treatment at the stroke unit and blood pressure regulation, the clinical signs of aphasia persisted. MRI could not detect an acute cerebral infarction. After discontinuation of metronidazole complete reconstitution occurred within 72 h. Metronidazole should be taken into account as cause of severe neurological side effects including ischemia-like syndromes like aphasia. © Georg Thieme Verlag KG Stuttgart · New York.

Pharmacokinetics of a single dose of intravenous and oral meloxicam in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus).

PubMed

Lacasse, Claude; Gamble, Kathryn C; Boothe, Dawn M

2013-09-01

Pharmacokinetic data were determined after a single dose of meloxicam in red-tailed hawks (RTH; Buteo jamaicensis) and great horned owls (GHO; Bubo virginianus). In a nonrandomized crossover design, individual birds of each species received 1 dose of intravenous meloxicam (0.5 mg/kg i.v.; n = 7 for each species) followed by a 2-week washout period, and then each received 1 dose of oral meloxicam (0.5 mg/kg PO; n = 5 for each species). Blood samples were collected intermittently after administration, and meloxicam was detected in plasma by high-performance liquid chromatography. Time versus plasma concentration data were subjected to noncompartmental analysis. Red-tailed hawks were determined to have the shortest elimination half-life for meloxicam (0.49 +/- 0.5 hours) of any species documented. Great horned owls also eliminated meloxicam very rapidly (0.78 +/- 0.52 hours). Great horned owls achieved higher plasma concentrations (368 +/- 87 ng/mL) of meloxicam than RTH (182 +/- 167 ng/mL) after oral administration, although RTH had a markedly higher volume of distribution (832 +/- 711 mL/kg) than GHO (137.6 +/- 62.7 mL/kg). The differences in meloxicam pharmacokinetics between these 2 raptor species supports the need for species-dependent studies and underlines the challenges of extrapolating drug dosages between species. Results of this study suggest that the current recommended once-daily dosing interval of oral meloxicam is unlikely to maintain plasma concentrations anticipated to be therapeutic in either RTH or GHO, and practical dosing options are questionable for this nonsteriodal anti-inflammatory drug in these raptor species.

High-dose, single-bolus eptifibatide: a safe and cost-effective alternative to conventional glycoprotein IIb/IIIa inhibitor use for elective coronary interventions.

PubMed

Fischell, Tim A; Attia, Tamer; Rane, Santosh; Salman, Waddah

2006-10-01

Adjunctive pharmacotherapy with eptifibatide, a glycoprotein (GP) IIb/IIIa inhibitor, as an intravenous bolus followed by infusion has been shown to improve outcomes in elective coronary interventions (PCI). However, bleeding complications and costs have limited the routine adoption of this regimen. The goal of this study was to examine the safety, efficacy and cost-effectiveness of high-dose, single-bolus eptifibatide, without post-intervention infusion, in "real-world" patients undergoing elective PCI. We studied 401 patients with stable and unstable angina who were treated with a high-dose (20 mg), single bolus of eptifibatide plus heparin prior to the start of elective PCI. Exclusion criteria included recent MI, stenting of bypass graft(s), rotational atherectomy and/or brachytherapy. The primary study endpoints were major adverse clinical events (MACE), defined as the in-hospital and 30-day incidence of death from any cause, Q-wave or non-Q-wave MI, repeat target vessel revascularization and/or major bleeding complications. Relevant demographic and procedural characteristics included mean age: 66.4 +/- 11.2; male gender: 242/401 (61%); number of vessels treated per patient: 1.46 +/- 0.42; and number of stents deployed per patient: 1.82 +/- 0.65. In-hospital non-Q-wave MI (CPK and/or CPK-MB > 3 times the upper limit of normal) occurred in 7/401 patients (1.75%) and MACE was 2.25%. Major bleeding complications were seen in 2/401 patients (0.49%). There were 4 additional MACE events at 30-day follow up (total MACE and bleeding = 3.25%). The average anticoagulation cost was 66 dollars/patient. Intravenous eptifibatide, administered as a high-dose (20 mg) single-vial bolus, is a safe, effective and highly cost-effective alternative to the conventional regimens of bolus plus prolonged intravenous GP IIb/IIIa inhibitor infusion for patients undergoing elective PCI.

Pharmacokinetics of Intraperitoneal and Intravenous Fosfomycin in Automated Peritoneal Dialysis Patients without Peritonitis

PubMed Central

Tobudic, Selma; Matzneller, Peter; Stoiser, Brigitte; Wenisch, Judith Maria; Vychytil, Andreas; Jaeger, Walter; Boehmdorfer, Michaela; Reznicek, Gottfried; Burgmann, Heinz

2012-01-01

Blood and dialysate concentrations of fosfomycin were determined after intravenous and intraperitoneal application of 4 mg/liter in patients undergoing automated peritoneal dialysis. Maximum serum concentrations after intravenous (287.75 ± 86.34 mg/liter) and intraperitoneal (205.78 ± 66.78 mg/liter) administration were comparable. Ratios of intraperitoneal to systemic exposure were 1.12 (intraperitoneal administration) and 0.22 (intravenous administration), indicating good systemic exposure after intraperitoneal application but limited penetration of fosfomycin into the peritoneal fluid after the intravenous dose. PMID:22564843

Neurotoxicity of misonidazole in rats following intravenous administration.

PubMed

Graziano, M J; Henck, J W; Meierhenry, E F; Gough, A W

1996-06-01

Misonidazole is a hypoxic cell radiosensitizer that induces a peripheral neuropathy in humans after exceeding a schedule-dependent cumulative threshold dose. Clinical studies of misonidazole have been conducted using oral administration, whereas most other radiosensitizers have been administered intravenously. Since route of exposure can potentially influence the toxicity of xenobiotics, the objective of this study was to assess the neurotoxicity of misonidazole in rats following intravenous dosing using a battery of routine clinical, neurofunctional, biochemical, and histopathologic screening methods. Male Sprague-Dawley rats were administered intravenous doses of misonidazole at 0 (vehicle control), 100, 200, 300, or 400 mg kg-1 once per day, 5 days per week, for 2 weeks. Animals were evaluated for neurofunctional and pathological changes following termination of treatment (Days 15-17) and at the end of a 4 week observation period (Days 43-45). During the dosing phase, hypoactivity, salivation, rhinorrhea, chromodacryorrhea, rough pelage and ataxia were observed at 400 mg kg-1, and body weight gain of the 300 and 400 mg kg-1 groups was significantly decreased relative to the vehicle controls by 24% and 49%, respectively. Corresponding reductions in food consumption were 8% and 23%, respectively. Although most 400 mg kg-1 animals appeared normal on Day 15 prior to the neurofunctional evaluations, rotorod testing precipitated a number of clinical signs including: ataxia, impaired righting reflex, excessive rearing, tremors, vocalization, circling, head jerking, excessive sniffing and hyperactivity. All of these animals recovered and appeared normal from Day 17 through study termination. There were no treatment-related effects on motor activity, acoustic startle response, rotorod performance, forelimb group strength, toe and tail pinch reflexes, tibial nerve beta-glucuronidase activity or tail nerve conduction velocity. Although hindlimb grip strength of the 400 mg

Pharmacokinetics and clinical application of intravenous valproate in Thai epileptic children.

PubMed

Visudtibhan, Anannit; Bhudhisawadi, Kasama; Vaewpanich, Jarin; Chulavatnatol, Suvatna; Kaojareon, Sming

2011-03-01

Roles of intravenous administration of valproate in status epilepticus and serial seizures are documented in adults and children. Pharmacokinetic parameters are necessary to predict the optimum therapeutic level after administration. A cross-sectional study to determine the pharmacokinetic parameters and safety of intravenous valproate for future application was conducted in Thai children from January to December 2008. There were eleven children, age-range 1-15 years (mean age 9.5 years) enrolled. Valproate of 15-20 mg/kg was administrated intravenously at the rate of 3 mg/kg/min, followed by 6 mg/kg every 6 h. Valproate level was determined prior to the initial dose and at ½, 1, 2, 4, 5, and 6 h postdose. Complete blood count, serum ammonia, and liver function tests were collected prior to the initial dose and at 6 h. Median loading dose was 19 mg/kg (range 15-20.5 mg/kg). Median maximum concentration at 30 min after infusion was 98.8 mcg/mL (range 67-161 mcg/mL). Median volume of distribution was 0.20 L/kg (range 0.15-0.53 L/kg). Median half-life was 9.5 h (range 4.4-24.2 h). Median clearance was 0.02 L/h/kg (range 0.01-0.05 L/h/kg). Six hours after initial dose, eight children did not have recurrent seizure. One child had brief seizure at 20 min after initial dose. Seizure recurred in two children at 4th and 5th hour. Asymptomatic transient elevation of serum ammonia was observed in two children. Volume of distribution of 0.20 L/kg could be applied for initial intravenous administration with a favorable efficacy. Copyright © 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

A meta-analysis of metronidazole and vancomycin for the treatment of Clostridium difficile infection, stratified by disease severity.

PubMed

Di, Xiuzhen; Bai, Nan; Zhang, Xin; Liu, Bin; Ni, Wentao; Wang, Jin; Wang, Kai; Liang, Beibei; Liu, Youning; Wang, Rui

2015-01-01

The aim of this meta-analysis was to compare the efficacy of metronidazole and vancomycin for the treatment of Clostridium difficile infection, especially to investigate which agent was superior for treating either mild or severe C. difficile infection. A meta-analysis of randomized controlled trials and cohort studies identified in Pubmed, Embase, and the Cochrane Library was conducted. Four randomized controlled trials and two cohort studies involving 1218 patients were included in this meta-analysis. Metronidazole was inferior to vancomycin for treating C. difficile infection in terms of both initial clinical cure rates (risk ratio, RR=0.91, 95% confidence interval, CI=0.84-0.98, p=0.02) and sustained cure rates (RR=0.88, 95% CI=0.82-0.96, p=0.003). For mild C. difficile infection, the efficacy of metronidazole and vancomycin resulted in similar clinical cure rates (RR=0.94, 95% CI=0.84-1.04, p=0.21) and sustained cure rates (RR=0.93, 95% CI=0.83-1.05, p=0.26). For severe C. difficile infection the efficacy of vancomycin was superior to metronidazole in terms of clinical cure rates (RR=0.81, 95% CI=0.69-0.95, p=0.009), whereas sustained cure rates were similar (RR=0.86, 95% CI=0.72-1.02, p=0.08). Regarding microbiological cure metronidazole therapy was as effective as vancomycin therapy (RR=0.88, 95% CI=0.64-1.21, p=0.43). Recurrence rates with metronidazole and vancomycin for both mild C. difficile infection (RR=0.95, 95% CI=0.56-1.60, p=0.85) and severe C. difficile infection (RR=1.27, 95% CI=0.85-1.91, p=0.25) were not different. Likewise, no difference in all-cause mortality was found as well (RR=0.87, 95% CI=0.56-1.35, p=0.53). In conclusion, vancomycin provides improved initial clinical and sustained cure rates in patients with C. difficile infection compared with metronidazole, especially in patients with severe C. difficile infection. In view of these data, vancomycin may be considered first line therapy for severe C. difficile infection. Copyright �

Effect of metronidazole versus standard care on length of stay of patients admitted with severe infectious mononucleosis: a randomized controlled trial.

PubMed

Lennon, P; O'Neill, J P; Fenton, J E

2014-07-01

Metronidazole may be of use in the treatment of infectious mononucleosis (IM). Our aim is to show that metronidazole shortens hospital stay for patients with severe IM. A single-centre randomized controlled trial was undertaken in patients admitted with severe IM, who were with a similar group treated by the standard care. Patients were blinded to which treatment arm they were in. Forty-two of these patients were enrolled in the trial. The primary endpoint was the difference in length of stay. This was significantly less in the metronidazole group (3.67 days v 4.67) (p 0.032). This study demonstrates that metronidazole has a role to play in severe infectious mononucleosis. © 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

Effectiveness of intravenous levetiracetam as an adjunctive treatment in pediatric refractory status epilepticus.

PubMed

Kim, Jon Soo; Lee, Jeong Ho; Ryu, Hye Won; Lim, Byung Chan; Hwang, Hee; Chae, Jong-Hee; Choi, Jieun; Kim, Ki Joong; Hwang, Yong Seung; Kim, Hunmin

2014-08-01

Intravenous levetiracetam (LEV) has been shown to be effective and safe in treating adults with refractory status epilepticus (SE). We sought to investigate the efficacy and safety of intravenous LEV for pediatric patients with refractory SE. We performed a retrospective medical-record review of pediatric patients who were treated with intravenous LEV for refractory SE. Clinical information regarding age, sex, seizure type, and underlying neurological status was collected. We evaluated other anticonvulsants that were used prior to administration of intravenous LEV and assessed loading dose, response to treatment, and any adverse events from intravenous LEV administration. Fourteen patients (8 boys and 6 girls) received intravenous LEV for the treatment of refractory SE. The mean age of the patients was 4.4 ± 5.5 years (range, 4 days to 14.6 years). Ten of the patients were neurologically healthy prior to the refractory SE, and the other 4 had been previously diagnosed with epilepsy. The mean loading dose of intravenous LEV was 26 ± 4.6 mg/kg (range, 20-30 mg/kg). Seizure termination occurred in 6 (43%) of the 14 patients. In particular, 4 (57%) of the 7 patients younger than 2 years showed seizure termination. No immediate adverse events occurred during or after infusions. The current study demonstrated that the adjunctive use of intravenous LEV was effective and well tolerated in pediatric patients with refractory SE, even in patients younger than 2 years. Intravenous LEV should be considered as an effective and safe treatment option for refractory SE in pediatric patients.

Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia.

PubMed

van der Westhuizen, J; Kuo, P Y; Reed, P W; Holder, K

2011-03-01

Gastric absorption of oral paracetamol (acetaminophen) may be unreliable perioperatively in the starved and stressed patient. We compared plasma concentrations of parenteral paracetamol given preoperatively and oral paracetamol when given as premedication. Patients scheduled for elective ear; nose and throat surgery or orthopaedic surgery were randomised to receive either oral or intravenous paracetamol as preoperative medication. The oral dose was given 30 minutes before induction of anaesthesia and the intravenous dose given pre-induction. All patients were given a standardised anaesthetic by the same specialist anaesthetist who took blood for paracetamol concentrations 30 minutes after the first dose and then at 30 minute intervals for 240 minutes. Therapeutic concentrations of paracetamol were reached in 96% of patients who had received the drug parenterally, and 67% of patients who had received it orally. Maximum median plasma concentrations were 19 mg.l(-1) (interquartile range 15 to 23 mg.l(-1)) and 13 mg.l(-1) (interquartile range 0 to 18 mg.l(-1)) for the intravenous and oral group respectively. The difference between intravenous and oral groups was less marked after 150 minutes but the intravenous preparation gave higher plasma concentrations throughout the study period. It can be concluded that paracetamol gives more reliable therapeutic plasma concentrations when given intravenously.

High-dose diazepam facilitates core cooling during cold saline infusion in healthy volunteers.

PubMed

Hostler, David; Northington, William E; Callaway, Clifton W

2009-08-01

Studies have suggested that inducing mild hypothermia improves neurologic outcomes after traumatic brain injury, major stroke, cardiac arrest, or exertional heat illness. While infusion of cold normal saline is a simple and inexpensive method for reducing core temperature, human cold-defense mechanisms potentially make this route stressful or ineffective. We hypothesized that intravenous administration of diazepam during a rapid infusion of 30 mL.kg-1 of cold (4 degrees C) 0.9% saline to healthy subjects would be more comfortable and reduce core body temperature more than the administration of cold saline alone. Fifteen subjects received rapidly infused cold (4 degrees C) 0.9% saline. Subjects were randomly assigned to receive, intravenously, 20 mg diazepam (HIGH), 10 mg diazepam (LOW), or placebo (CON). Main outcomes were core temperature, skin temperature, and oxygen consumption. Data for the main outcomes were analyzed with generalized estimating equations to identify differences in group, time, or a group x time interaction. Core temperature decreased in all groups (CON, 1.0 +/- 0.2 degrees C; LOW, 1.4 +/- 0.2 degrees C; HIGH, 1.5 +/- 0.2 degrees C), while skin temperature was unchanged. Mean (95% CI) oxygen consumption was 315.3 (253.8, 376.9) mL.kg-1.min-1 in the CON group, 317.9 (275.5, 360.3) in the LOW group, and 226.1 (216.4, 235.9) in the HIGH group. Significant time and group x time interaction was observed for core temperature and oxygen consumption (p < 0.001). Administration of high-dose diazepam resulted in decreased oxygen consumption during cold saline infusion, suggesting that 20 mg of intravenous diazepam may reduce the shivering threshold without compromising respiratory or cardiovascular function.

[Adult-onset Still's disease with pulmonary and cardiac involvement and response to intravenous immunoglobulin].

PubMed

Neto, Nilton Salles Rosa; Waldrich, Leandro; de Carvalho, Jozélio Freire; Pereira, Rosa Maria Rodrigues

2009-01-01

Cardiopulmonary manifestations of adult-onset Still's disease (AOSD) include pericarditis, pleural effusion, transient pulmonary infiltrates, pulmonary interstitial disease and myocarditis. Serositis are common but pneumonitis and myocarditis are not and bring elevated risk of mortality. They may manifest on disease onset or flares. Previously reported cases were treated with high-dose glucocorticoids and immunosupressants and, when refractory, intravenous immunoglobulin (IVIG). We report an AOSD patient whose flare presented with severe pleupneumonitis and myopericarditis and, following nonresponse to a methylprednisolone pulse, high dose of prednisone and cyclosporine A, recovered after a 2-day 1g/kg/day IVIG infusion.

High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: neural consequences and comparison with methamphetamine.

PubMed

Motbey, Craig P; Clemens, Kelly J; Apetz, Nadine; Winstock, Adam R; Ramsey, John; Li, Kong M; Wyatt, Naomi; Callaghan, Paul D; Bowen, Michael T; Cornish, Jennifer L; McGregor, Iain S

2013-09-01

Mephedrone (MMC) is a relatively new recreational drug that has rapidly increased in popularity in recent years. This study explored the characteristics of intravenous MMC self-administration in the rat, with methamphetamine (METH) used as a comparator drug. Male Sprague-Dawley rats were trained to nose poke for intravenous MMC or METH in daily 2 h sessions over a 10 d acquisition period. Dose-response functions were then established under fixed- and progressive-ratio (FR and PR) schedules over three subsequent weeks of testing. Brains were analyzed ex vivo for striatal serotonin (5-HT) and dopamine (DA) levels and metabolites, while autoradiography assessed changes in the regional density of 5-HT and serotonin transporter (SERT) and DA transporter (DAT) and induction of the inflammation marker translocator protein (TSPO). Results showed that MMC was readily and vigorously self-administered via the intravenous route. Under a FR1 schedule, peak responding for MMC was obtained at 0.1 mg/kg/infusion, versus 0.01 mg/kg/infusion for METH. Break points under a PR schedule peaked at 1 mg/kg/infusion MMC versus 0.3 mg/kg/infusion for METH. Final intakes of MMC were 31.3 mg/kg/d compared to 4 mg/kg/d for METH. Rats self-administering MMC, but not METH, gained weight at a slower rate than control rats. METH, but not MMC, self-administration elevated TSPO receptor density in the nucleus accumbens and hippocampus, while MMC, but not METH, self-administration decreased striatal 5-hydroxyindolacetic acid (5-HIAA) concentrations. In summary, MMC supported high levels of self-administration, matching or exceeding those previously reported with other drugs of abuse.

Pharmacokinetics, Biotransformation, and Excretion of [14C]Etelcalcetide (AMG 416) Following a Single Microtracer Intravenous Dose in Patients with Chronic Kidney Disease on Hemodialysis.

PubMed

Subramanian, Raju; Zhu, Xiaochun; Hock, M Benjamin; Sloey, Bethlyn J; Wu, Benjamin; Wilson, Sarah F; Egbuna, Ogo; Slatter, J Greg; Xiao, Jim; Skiles, Gary L

2017-02-01

Etelcalcetide (AMG 416) is a novel synthetic peptide calcium-sensing receptor activator in clinical development as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. Etelcalcetide is composed of seven D-aminoacids with an L-cysteine linked to a D-cysteine by a disulfide bond. A single intravenous dose of [ 14 C]etelcalcetide (10 mg; 26.3 kBq; 710 nCi) was administered to patients with CKD on hemodialysis to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in this setting. Blood, dialysate, urine, and feces were collected to characterize the pharmacokinetics, biotransformation product profiles, mass balance, and formation of anti-etelcalcetide antibodies. Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [ 14 C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces. Biotransformation resulted from disulfide exchange with endogenous thiols, and preserved the etelcalcetide D-amino acid backbone. Drug-related radioactivity circulated primarily as serum albumin peptide conjugate (SAPC). Following removal of plasma etelcalcetide by hemodialysis, re-equilibration occurred between SAPC and L-cysteine present in blood to partially restore the etelcalcetide plasma concentrations between dialysis sessions. No unanticipated safety signals or anti-etelcalcetide or anti-SAPC antibodies were detected.

BmeRABC5 is a multidrug efflux system that can confer metronidazole resistance in Bacteroides fragilis.

PubMed

Pumbwe, Lilian; Chang, Abraham; Smith, Rachel L; Wexler, Hannah M

2007-01-01

The RND-family efflux pump gene bmeB5 was previously shown to be overexpressed in metronidazole-resistant laboratory mutants of Bacteroides fragilis. In the present study, we characterized the bmeABC5 genes and an upstream putative TetR-family regulator gene (bmeR5). bmeR5 (645 bp) was located 51 bp upstream of bmeA5 and encoded a 24.9-kDa protein. Deletant strains lacking bmeB5 or bmeR5 were constructed from a wild-type B. fragilis strain ADB77. Strain antimicrobial susceptibility was determined and gene expression was quantified. bmeR5 was overexpressed in Escherichia coli using a 6x-His tag system; BmeR5-His6 was isolated from inclusion bodies and its binding to bmeABC5 promoter regions was determined. BmeR5-His6 bound specifically to the bmeR5-bmeC5 intergenic region (IT1). Deletion of bmeR5 (ADB77DeltabmeR5) resulted in a significant (p < 0.05) increase in expression of bmeA5, bmeB5, and bmeC5, and > two-fold increase in minimum inhibitory concentrations (MICs) of ampicillin, cefoxitin, cefoperazone, ciprofloxacin, imipenem, metronidazole, ethidium bromide, and sodium dodecyl sulfate (SDS). MICs were reduced by the efflux pump inhibitor carbonyl cyanide m-chlorophenyl hydrazone (CCCP). The MICs of ampicillin, cefoperazone, metronidazole, and SDS were reduced by approximately two-fold in ADB77DeltabmeB5. A multidrug (metronidazole)-resistant, nim-negative B. fragilis clinical isolate overexpressed bmeABC5 genes, had a G-->T point mutation in IT1, and significantly reduced binding to BmeR5-His6. These data demonstrate that BmeR5 is a local repressor of bmeABC5 expression and that mutations in IT1 can lead to a derepression and resistance to multiple antimicrobial agents, including metronidazole.

Clinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis.

PubMed

Anukam, Kingsley C; Osazuwa, Emmanuel; Osemene, Gibson I; Ehigiagbe, Felix; Bruce, Andrew W; Reid, Gregor

2006-10-01

Bacterial vaginosis (BV) is particularly common in black women, and in Nigeria it is often caused by Mycoplasma, as well as Atopobium, Prevotella and Gardnerella sp. Antimicrobial metronidazole oral therapy is poorly effective in eradicating the condition and restoring the Lactobacillus microbiota in the vagina. In this study, 40 women diagnosed with BV by discharge, fishy odor, sialidase positive test and Nugent Gram stain scoring, were randomized to receive either two dried capsules containing Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 each night for 5 days, or 0.75% metronidazole gel, applied vaginally twice a day (in the morning and evening). Follow-up at day 6, 15 and 30 showed cure of BV in significantly more probiotic treated subjects (16, 17 and 18/20, respectively) compared to metronidazole treatment (9, 9 and 11/20: P=0.016 at day 6, P=0.002 at day 15 and P=0.056 at day 30). This is the first report of an effective (90%) cure of BV using probiotic lactobacilli. Given the correlation between BV and HIV, and the high risk of the latter in Nigeria, intravaginal use of lactobacilli could provide women with a self-use therapy, similar to over-the-counter anti-yeast medication, for treatment of urogenital infections.

Understanding the Recent Increase in Ferritin Levels in United States Dialysis Patients: Potential Impact of Changes in Intravenous Iron and Erythropoiesis-Stimulating Agent Dosing.

PubMed

Karaboyas, Angelo; Zee, Jarcy; Morgenstern, Hal; Nolen, Jacqueline G; Hakim, Raymond; Kalantar-Zadeh, Kamyar; Zager, Philip; Pisoni, Ronald L; Port, Friedrich K; Robinson, Bruce M

2015-10-07

Anemia management changed substantially among dialysis patients in the United States around the time of implementation of the new Centers for Medicare & Medicaid Services bundled payment system and erythropoiesis-stimulating agent (ESA) label change in 2011. Among these, average ferritin levels increased dramatically and have remained high since; this study sought to gain understanding of this sustained rise in ferritin levels. Trends in mean ferritin, hemoglobin, IV iron dose, and ESA dose from 2009 to 2013 were examined in 9735 patients from 91 United States Dialysis Outcomes and Practice Patterns Study facilities. Linear mixed models were used to assess the extent to which intravenous (IV) iron and ESA dose accounted for patients' changes in ferritin over time. Mean ESA dose and hemoglobin levels declined throughout the study. Mean IV iron dose increased from 210 mg/mo in 2009-2010 to a peak of 280 mg/mo in 2011, then declined back to 200 mg/mo and remained stable from 2012 to 2013. Mean ferritin increased from 601 ng/ml in the third quarter of 2009 to 887 ng/ml in the first quarter of 2012; models suggest that higher IV iron dosing was a primary determinant during 2011, but lower ESA doses contributed to the sustained high ferritin levels thereafter. In a subset of 17 facilities that decreased IV iron dose in 2011, mean ferritin rose by 120 ng/ml to 764 ng/ml, which appeared to be primarily due to ESA reduction. Together, changes in IV iron and ESA doses accounted for 46% of the increase in ferritin over the study period. In contrast to expectations, the rise in average IV iron dose did not persist beyond 2011. The sustained rise in ferritin levels in United States dialysis patients after policy changes in 2011, to average levels well in excess of 800 ng/ml, appeared to be partly due to reductions in ESA dosing and not solely IV iron dosing practices. The effect of these changes in ferritin on health outcomes requires further investigation. Copyright © 2015 by

Understanding the Recent Increase in Ferritin Levels in United States Dialysis Patients: Potential Impact of Changes in Intravenous Iron and Erythropoiesis-Stimulating Agent Dosing

PubMed Central

Zee, Jarcy; Morgenstern, Hal; Nolen, Jacqueline G.; Hakim, Raymond; Kalantar-Zadeh, Kamyar; Zager, Philip; Pisoni, Ronald L.; Port, Friedrich K.; Robinson, Bruce M.

2015-01-01

Background and objectives Anemia management changed substantially among dialysis patients in the United States around the time of implementation of the new Centers for Medicare & Medicaid Services bundled payment system and erythropoiesis-stimulating agent (ESA) label change in 2011. Among these, average ferritin levels increased dramatically and have remained high since; this study sought to gain understanding of this sustained rise in ferritin levels. Design, setting, participants, & measurements Trends in mean ferritin, hemoglobin, IV iron dose, and ESA dose from 2009 to 2013 were examined in 9735 patients from 91 United States Dialysis Outcomes and Practice Patterns Study facilities. Linear mixed models were used to assess the extent to which intravenous (IV) iron and ESA dose accounted for patients’ changes in ferritin over time. Results Mean ESA dose and hemoglobin levels declined throughout the study. Mean IV iron dose increased from 210 mg/mo in 2009–2010 to a peak of 280 mg/mo in 2011, then declined back to 200 mg/mo and remained stable from 2012 to 2013. Mean ferritin increased from 601 ng/ml in the third quarter of 2009 to 887 ng/ml in the first quarter of 2012; models suggest that higher IV iron dosing was a primary determinant during 2011, but lower ESA doses contributed to the sustained high ferritin levels thereafter. In a subset of 17 facilities that decreased IV iron dose in 2011, mean ferritin rose by 120 ng/ml to 764 ng/ml, which appeared to be primarily due to ESA reduction. Together, changes in IV iron and ESA doses accounted for 46% of the increase in ferritin over the study period. Conclusions In contrast to expectations, the rise in average IV iron dose did not persist beyond 2011. The sustained rise in ferritin levels in United States dialysis patients after policy changes in 2011, to average levels well in excess of 800 ng/ml, appeared to be partly due to reductions in ESA dosing and not solely IV iron dosing practices. The effect of

Effects of Intrarenal and Intravenous Infusion of the Phosphodiesterase 3 Inhibitor Milrinone on Renin Secretion

NASA Technical Reports Server (NTRS)

Kumagai, Kazuhiro; Reid, Ian A.

1994-01-01

We have reported that administration of the phosphodiesterase III inhibitor milrinone increases renin secretion in conscious rabbits. The aim of the present study was to determine if the increase in renin secretion results from a direct renal action of milrinone, or from an indirect extrarenal effect of the drug. This was accomplished by comparing the effects of intrarenal and intravenous infusion of graded doses of milrinone on plasma renin activity in unilaterally nephrectomized conscious rabbits. Milrinone was infused into the renal artery in doses of 0.01, 0.1 and 1.0 micro-g/kg/min, and intravenously in the same rabbits in doses of 0.01, 0.1, 1.0 and 10 micro-g/kg/min. Each dose was infused for 15 min. No intrarenal dose of milrinone altered plasma renin activity or arterial pressure, although at the highest dose, there was a small increase in heart rate. Intravenous infusion of milrinone at 1.0 micro-g/kg/min increased plasma renin activity to 176 +/- 55% of the control value (P less than 0.05). Heart rate increased but arterial pressure did not change. Intravenous infusion of milrinone at 1O micro-g/kg/min increased plasma renin activity to 386 +/- 193% of control in association with a decrease in arterial pressure and an increase in heart rate. These results confirm that milrinone increases renin secretion, and indicate that the stimulation is due to an extrarenal effect of the drug.

[High dose L-dopa infusion during general anesthesia for gastrectomy in a patient with parkinsonism].

PubMed

Horai, Tetsuya; Nishiyama, Tomoki; Yamamoto, Hirotoshi; Hanaoka, Kazuo

2002-01-01

A 68-year-old man with parkinsonism was scheduled for gastrectomy. Levodopa 1400 mg, droxidopa 300 mg and bromocriptine-mesylate 7.5 mg had been administered orally per day to control the symptom before surgery. On the day before surgery, oral medication was stopped and intravenous infusion of levodopa 100 mg.h-1 was started. Without any premedication but with levodopa infusion, anesthesia was induced with thiopental 175 mg and fentanyl 0.05 mg. Tracheal intubation was facilitated with vecuronium 6 mg and an epidural catheter was inserted. Anesthesia was maintained with O2, N2O and sevoflurane, combined with epidural block using mepivacaine. When blood pressure decreased, phenylephrine but not ephedrine was effective to increase blood pressure. Intravenous infusion of levodopa was continued for 19 days with decreasing doses from 8th postoperative day when injection of levodopa into the intestinal tube was started. On the 53rd day, he left the hospital without any complications. Serum concentrations of levodopa during and after surgery were 50 to 100 times higher than the therapeutic levels. However, he developed no complications, which suggests a wide safety range of levodopa. In conclusion, high dose levodopa infusion was effective in controlling the symptoms of Parkinsonism during general anesthesia.

INTRAVENOUS VALPROATE: A NEW PERSPECTIVE IN THE TREATMENT OF MANIC SYMPTOMS

PubMed Central

Duggal, Harpreet S.; Jagadheesan, K.; Gupta, Subhash; Basu, Soumya; Akhtar, Sayeed; Nizamie, Haque S.

2002-01-01

Over the last few years, the use of valproate in psychiatry has increased considerably. With the advent of oral loading dose strategy, its role in rapid treatment of acute mania has been demonstrated. The intravenous formulation of valproate, while retaining the rapidity of action of oral loading, also avoids some of the adverse effects of the oral preparation. Moreover, reports are pouring in that intravenous valproate loading may be more efficacious than oral valproate loading in the treatment of acute mania. We report two patients whose manic symptoms showed a dramatic response to intravenous valproate without adverse effects. The pharmacology of intravenous valproate and its clinical relevance to psychiatry are discussed. PMID:21206565

Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans

PubMed Central

D'Souza, Deepak Cyril; Fridberg, Daniel J; Skosnik, Patrick D; Williams, Ashley; Roach, Brian; Singh, Nagendra; Carbuto, Michelle; Elander, Jacqueline; Schnakenberg, Ashley; Pittman, Brian; Sewell, R Andrew; Ranganathan, Mohini; Mathalon, Daniel

2012-01-01

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory ‘oddball' P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective ‘high' in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact

Intravenous augmentative citalopram versus clomipramine in partial/nonresponder depressed patients: a short-term, low dose, randomized, placebo-controlled study.

PubMed

Altamura, Alfredo Carlo; Dell'Osso, Bernardo; Buoli, Massimiliano; Zanoni, Silvia; Mundo, Emanuela

2008-08-01

The aim of the present study was to evaluate the efficacy of short-term low-dose intravenous augmentative citalopram (10 mg/d) versus clomipramine (25 mg/d) versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors (SSRIs). Fifty-four patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, MDE and partial or no response to SSRIs per os (21-item Hamilton Depression Rating Scale [HAM-D21] score reduction, <50% or < or =25%, respectively, compared with pretreatment scores) were selected and randomized to citalopram (n = 18), clomipramine (n = 18), or placebo (n = 18) intravenous augmentation. The augmentation regimen lasted 5 days during which patients were maintained on their previous treatment with oral SSRIs. Analyses of variance with repeated measures on HAM-D(21), collected daily in blind-raters design, were performed to detect any change of depressive symptoms between the 3 groups. In addition, the number of responders and remitters was computed in the 3 groups of treatment. At end point, a significant treatment effect (F= 4.57; P = 0.015) and time-by-treatment effect (F = 11.22; P < 0.0001) were found on HAM-D21 total scores in favor of citalopram and clomipramine versus placebo, with a superiority of citalopram over clomipramine on overall symptoms (P = 0.05) as well as on anxiety-somatization symptoms (P = 0.027). The number of responders was significantly superior in the active treatment groups versus the placebo group ([chi](2)(2) = 16.36; P < 0.0001). The same result was found, considering the number of remitters ([chi](2)(2) = 13.50; P < 0.0001). Present findings suggest that both clomipramine and citalopram intravenous augmentation at low doses and for a short period are well tolerated and superior to placebo in major depressives with partial or no response to oral SSRIs with a possible superiority of citalopram over clomipramine with regard to

Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study

PubMed Central

2013-01-01

Introduction Use of colistin methanesulfonate (CMS) was abandoned in the 1970s because of excessive nephrotoxicity, but it has been reintroduced as a last-resort treatment for extensively drug-resistant infections caused by gram-negative bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumonia). We conducted a retrospective cohort study to evaluate risk factors for new-onset acute kidney injury (AKI) in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics. Methods The cohort consisted of 279 adults admitted to two general ICUs in teaching hospitals between 1 April 2009 and 30 June 2011 with 1) no evidence on admission of acute or chronic kidney disease; and 2) treatment for more than seven days with CMS and/or other nephrotoxic antimicrobials (NAs, that is, aminoglycosides, glycopeptides). Logistic regression analysis was used to identify risk factors associated with this outcome. Results The 279 cases that met the inclusion criteria included 147 patients treated with CMS, alone (n = 90) or with NAs (n = 57), and 132 treated with NAs alone. The 111 (40%) who developed AKI were significantly older and had significantly higher Simplified Acute Physiology Score II (SAPS II) scores than those who did not develop AKI, but rates of hypertension, diabetes mellitus and congestive heart failure were similar in the two groups. The final logistic regression model showed that in the 147 patients who received CMS alone or with NAs, onset of AKI during the ICU stay was associated with septic shock and with SAPS II scores ≥43. Similar results were obtained in the 222 patients treated with CMS alone or NAs alone. Conclusions In severely ill ICU patients without pre-existing renal disease who receive CMS high-dose for more than seven days, CMS therapy does not appear to be a risk factor for this outcome. Instead, the development of AKI was strongly correlated with the presence of septic

Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans

PubMed Central

Manini, Alex F.; Yiannoulos, Georgia; Bergamaschi, Mateus M.; Hernandez, Stephanie; Olmedo, Ruben; Barnes, Allan J.; Winkel, Gary; Sinha, Rajita; Jutras-Aswad, Didier; Huestis, Marilyn A.; Hurd, Yasmin L.

2015-01-01

Objectives Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. Methods This double-blind, placebo-controlled cross-over study of CBD co-administered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21–65 years with prior opioid exposure, regardless of route. Blood samples were obtained before and after 400 or 800 mg CBD pretreatment, followed by a single 0.5 (Session 1) or 1.0mcg/Kg (Session 2) intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. Results SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. Following low dose CBD, tmax occurred at 3 and 1.5h (Sessions 1 and 2, respectively). Following high dose CBD, tmax occurred at 3 and 4h in Sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC p=NS) between sessions. Conclusions CBD does not exacerbate adverse effects associated with intravenous fentanyl administration. Co-administration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse. PMID:25748562

Pharmacokinetics, metabolism and urinary detection time of flunixin after intravenous administration in camels.

PubMed

Wasfi, I A; Boni, N S; Abdel Hadi, A; Elghazali, M; Zorob, O; Alkatheeri, N A; Barezaiq, I M

1998-06-01

The pharmacokinetics of flunixin were determined after an intravenous dose of 1.1 mg/kg body weight in six camels and 2.2 mg/kg body weight in four camels. The data obtained (mean +/- SEM) for the low and high dose, respectively, were as follows: The elimination half-lives (t1/2 beta) were 3.76 +/- 0.24 and 4.08 +/- 0.49 h, the steady state volumes of distribution (Vdss) were 320.61 +/- 38.53 and 348.84 +/- 35.36 mL/kg body weight, total body clearances (ClT) were 88.96 +/- 6.63 and 84.86 +/- 4.95 mL/h/kg body weight and renal clearances (Clr) were 0.52 +/- 0.09 and 0.62 +/- 0.18 mL/h/kg body weight. A hydroxylated metabolite of flunixin was identified by gas chromatography/mass spectrometry (GC/MS) under electron and chemical ionization and its major fragmentation pattern was verified by tandem mass spectrometry (GC/MS/MS) using neutral loss, daughter and parent scan modes. The detection times for flunixin and its hydroxylated metabolite in urine after an intravenous (i.v.) dose of 2.2 mg/kg body weight were 96 and 48 h, respectively.

SOLITAIRE-IV: A Randomized, Double-Blind, Multicenter Study Comparing the Efficacy and Safety of Intravenous-to-Oral Solithromycin to Intravenous-to-Oral Moxifloxacin for Treatment of Community-Acquired Bacterial Pneumonia.

PubMed

File, Thomas M; Rewerska, Barbara; Vucinic-Mihailovic, Violeta; Gonong, Joven Roque V; Das, Anita F; Keedy, Kara; Taylor, David; Sheets, Amanda; Fernandes, Prabhavathi; Oldach, David; Jamieson, Brian D

2016-10-15

Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team [PORT] class II-IV) were randomized 1:1 to receive either intravenous-to-oral solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. In the ITT population, 79.3% of solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, -0.46; 95% confidence interval [CI], -6.1 to 5.2). In the micro-ITT population, 80.3% of solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, -8.1 to 10.6). In the ITT population, 84.6% of solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the solithromycin group. Other adverse events were comparable between treatment groups. Intravenous-to-oral solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. NCT01968733. © The Author 2016. Published by Oxford University Press for the Infectious

Aspirin increases susceptibility of Helicobacter pylori to metronidazole by augmenting endocellular concentrations of antimicrobials.

PubMed

Zhang, Xiao-Ping; Wang, Wei-Hong; Tian, Yu; Gao, Wen; Li, Jiang

2009-02-28

To investigate the mechanisms of aspirin increasing the susceptibility of Helicobacter pylori (H pylori) to metronidazole. H pylori reference strain 26695 and two metronidazole-resistant isolates of H pylori were included in this study. Strains were incubated in Brucella broth with or without aspirin (1 mmol/L). The rdxA gene of H pylori was amplified by PCR and sequenced. The permeability of H pylori to antimicrobials was determined by analyzing the endocellular radioactivity of the cells after incubated with [7-(3)H]-tetracycline. The outer membrane proteins (OMPs) of H pylori 26695 were depurated and analyzed by SDS-PAGE. The expression of 5 porins (hopA, hopB, hopC, hopD and hopE) and the putative RND efflux system (hefABC) of H pylori were analyzed using real-time quantitative PCR. The mutations in rdxA gene did not change in metronidazole resistant isolates treated with aspirin. The radioactivity of H pylori increased when treated with aspirin, indicating that aspirin improved the permeability of the outer membrane of H pylori. However, the expression of two OMP bands between 55 kDa and 72 kDa altered in the presence of aspirin. The expression of the mRNA of hopA, hopB, hopC, hopD, hopE and hefA, hefB, hefC of H pylori did not change when treated with aspirin. Although aspirin increases the susceptibility of H pylori to metronidazole, it has no effect on the mutations of rdxA gene of H pylori. Aspirin increases endocellular concentrations of antimicrobials probably by altering the OMP expression.

Aspirin increases susceptibility of Helicobacter pylori to metronidazole by augmenting endocellular concentrations of antimicrobials

PubMed Central

Zhang, Xiao-Ping; Wang, Wei-Hong; Tian, Yu; Gao, Wen; Li, Jiang

2009-01-01

AIM: To investigate the mechanisms of aspirin increasing the susceptibility of Helicobacter pylori (H pylori) to metronidazole. METHODS: H pylori reference strain 26 695 and two metronidazole-resistant isolates of H pylori were included in this study. Strains were incubated in Brucella broth with or without aspirin (1 mmol/L). The rdxA gene of H pylori was amplified by PCR and sequenced. The permeability of H pylori to antimicrobials was determined by analyzing the endocellular radioactivity of the cells after incubated with [7-3H]-tetracycline. The outer membrane proteins (OMPs) of H pylori 26 695 were depurated and analyzed by SDS-PAGE. The expression of 5 porins (hopA, hopB, hopC, hopD and hopE) and the putative RND efflux system (hefABC) of H pylori were analyzed using real-time quantitative PCR. RESULTS: The mutations in rdxA gene did not change in metronidazole resistant isolates treated with aspirin. The radioactivity of H pylori increased when treated with aspirin, indicating that aspirin improved the permeability of the outer membrane of H pylori. However, the expression of two OMP bands between 55 kDa and 72 kDa altered in the presence of aspirin. The expression of the mRNA of hopA, hopB, hopC, hopD, hopE and hefA, hefB, hefC of H pylori did not change when treated with aspirin. CONCLUSION: Although aspirin increases the susceptibility of H pylori to metronidazole, it has no effect on the mutations of rdxA gene of H pylori. Aspirin increases endocellular concentrations of antimicrobials probably by altering the OMP expression. PMID:19248190

Efficacy and safety of intravenous secukinumab in noninfectious uveitis requiring steroid-sparing immunosuppressive therapy.

PubMed

Letko, Erik; Yeh, Steven; Foster, C Stephen; Pleyer, Uwe; Brigell, Mitchell; Grosskreutz, Cynthia L

2015-05-01

safe and was well tolerated. Intravenous secukinumab was effective and well tolerated in noninfectious uveitis requiring systemic corticosteroid-sparing immunosuppressive therapy. Greater activity with IV dosing suggests that patients may not receive sufficient drug with SC administration. High-dose IV secukinumab may be necessary to deliver secukinumab in therapeutic concentrations. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Effects of caffeine on fractional flow reserve values measured using intravenous adenosine triphosphate.

PubMed

Nakayama, Masafumi; Chikamori, Taishiro; Uchiyama, Takashi; Kimura, Yo; Hijikata, Nobuhiro; Ito, Ryosuke; Yuhara, Mikio; Sato, Hideaki; Kobori, Yuichi; Yamashina, Akira

2018-04-01

We investigated the effects of caffeine intake on fractional flow reserve (FFR) values measured using intravenous adenosine triphosphate (ATP) before cardiac catheterization. Caffeine is a competitive antagonist for adenosine receptors; however, it is unclear whether this antagonism affects FFR values. Patients were evenly randomized into 2 groups preceding the FFR study. In the caffeine group (n = 15), participants were given coffee containing 222 mg of caffeine 2 h before the catheterization. In the non-caffeine group (n = 15), participants were instructed not to take any caffeine-containing drinks or foods for at least 12 h before the catheterization. FFR was performed in patients with more than intermediate coronary stenosis using the intravenous infusion of ATP at 140 μg/kg/min (normal dose) and 170 μg/kg/min (high dose), and the intracoronary infusion of papaverine. FFR was followed for 30 s after maximal hyperemia. In the non-caffeine group, the FFR values measured with ATP infusion were not significantly different from those measured with papaverine infusion. However, in the caffeine group, the FFR values were significantly higher after ATP infusion than after papaverine infusion (P = 0.002 and P = 0.007, at normal and high dose ATP vs. papaverine, respectively). FFR values with ATP infusion were significantly increased 30 s after maximal hyperemia (P = 0.001 and P < 0.001 for normal and high dose ATP, respectively). The stability of the FFR values using papaverine showed no significant difference between the 2 groups. Caffeine intake before the FFR study affected FFR values and their stability. These effects could not be reversed by an increased ATP dose.

Evaluation of an every-other-day palonosetron schedule to control emesis in multiple-day high-dose chemotherapy.

PubMed

Mirabile, Aurora; Celio, Luigi; Magni, Michele; Bonizzoni, Erminio; Gianni, Alessandro Massimo; Di Nicola, Massimo

2014-12-01

Efficacy of intermittent palonosetron dosing in patients undergoing multiple-day, high-dose chemotherapy (HDC) was investigated. Fifty-eight patients received palonosetron (0.25 mg intravenous [iv.]) every other day plus daily dexamethasone (8 mg iv. twice daily) dosing. The primary end point was complete control (CC; no emesis, no rescue anti-emetics, and no more than mild nausea) in the overall acute-period (until 24 h after chemotherapy completion). Acute-period CC occurred in 81% and 50% of patients receiving palonosetron and ondansetron (historical control cohort), respectively. Palonosetron (odds ratio [OR]: 4.37; p = 0.001) and a longer duration of HDC regimen (OR: 3.47; p = 0.011) independently predicted a better anti-emetic outcome. Palonosetron every other day plus daily dexamethasone is an effective anti-emetic coverage in patients undergoing HDC.

FOLLICULITIS ET PERIFOLLICULITIS CAPITIS ABSCEDENS ET SUFFODIENS CONTROLLED WITH A COMBINATION THERAPY: SYSTEMIC ANTIBIOSIS (METRONIDAZOLE PLUS CLINDAMYCIN), DERMATOSURGICAL APPROACH, AND HIGH-DOSE ISOTRETINOIN

PubMed Central

Tchernev, Georgi

2011-01-01

Folliculitis et perifolliculitis capitis abscedens et suffodiens is a rare disease of unknown etiology. It is a suppurative process that involves the scalp, eventually resulting in extensive scarring and irreversible alopecia. The condition is also known as ‘acne necrotica miliaris’ or ‘Proprionibacterium’ folliculitis. Most often the disease affects men of African-American or African-Caribbean descent between 20 and 40 years of age. The clinical picture is determined by fluctuating painful fistule-forming conglomerates of abscesses in the region of the occipital scalp. The cause of scalp folliculitis is not well understood. It is generally considered to be an inflammatory reaction to components of the hair follicle, particularly the micro-organisms. These include: bacteria (especially Propionibacterium acnes, but in severe cases, also Staphylococcus aureus), Yeasts (Malassezia species) and mites (Demodex folliculorum). The initial histopathologic finding is an exclusively neutrophilic infiltration followed by a granulomatous infiltrate. The treatment of the disease is usually difficult and often disappointing. Successful treatment with isotretinoin 1 mg/kg body mass could be achieved only after regular systematic administration in the course of 3–4 months. Here we describe a patient with eruptive purulent form of the disease, which has been controlled with combination therapy: systemic antibiosis with metronidazole and clindamycin, dermatosurgical removal of single nodular formations, and isotretinoin 1 mg/kg body mass for 3–5 months. PMID:21772598

Oral triazolam pretreatment for intravenous sedation.

PubMed Central

Stopperich, P. S.; Moore, P. A.; Finder, R. L.; McGirl, B. E.; Weyant, R. J.

1993-01-01

This double-blind, controlled clinical trial assessed the anxiety relief provided by oral triazolam given before intravenous sedation. Twenty-two healthy adults undergoing third-molar surgery with intravenous sedation were enrolled in this study. Subjects were randomly assigned to receive either 0.25 mg of triazolam p.o. or an identically appearing placebo 45 to 60 min before venipuncture. Immediately before test drug administration, subjects completed the Corah Anxiety Scale, a Visual Analog Scale (VAS) assessing state anxiety, and the Interval Scale of Anxiety Response (ISAR). The VAS and ISAR were repeated immediately before venipuncture. Intravenous sedation medications consisted of fentanyl, midazolam, and methohexital. At 24 hr, assessments of the venipuncture and global experience were obtained. Results indicated that the characteristics of the triazolam and placebo patients were similar at baseline. With triazolam pretreatment, both the VAS and ISAR scores decreased significantly. Dose requirements for conscious sedation medications were decreased in the triazolam group. Patients rated the venipuncture experience significantly less unpleasant when pretreated with triazolam, and global ratings of the overall surgical experience favored triazolam. An oral-intravenous combination sedation technique using 0.25 mg of triazolam may have a significant therapeutic advantage for outpatient oral surgery. PMID:7943920

Study of the newborn feeding behaviors and fentanyl concentration in colostrum after an analgesic dose of epidural and intravenous fentanyl in cesarean section.

PubMed

Goma, Hala M; Said, Reem N; El-Ela, Amr M

2008-05-01

To compare the effects of epidural and intravenous fentanyl on breast feeding behaviors and fentanyl concentration in the colostrum after an analgesic dose. This study was conducted at the Obstetrics Department of Kasr El-Aini Hospital-Cairo University, Cairo, Egypt. The studied mothers were 100 multipara, who have been subjected to cesarean section, and have a previous history of successful breast feeding. The study was conducted from May 2005 to May 2007. They were divided into 2 groups: group I included 50 patients who received epidural anesthesia with fentanyl, and group II included 50 patients who received spinal anesthesia with intravenous fentanyl, and both groups were observed for initial breast feeding behaviors of newborns, and fentanyl concentration in the colostrum at 45 minutes, and 24 hours after birth. The study included 100 multipara, 2 samples of colostrum were taken from each patients at 45 minutes, and at 24 hours. The levels of fentanyl concentration were greatest at 45 minutes of the initial sampling time, reaching 0.40+/-0.059 ng/ml in the epidural group, and 0.19+/-0.019 ng/ml in intravenous fentanyl group. There was no statistical difference in breast feeding behaviors at birth, or at 24 hours of age in both groups. Although the levels of fentanyl concentration were greatest at 45 minutes of the initial sampling time, it can be used safely as intravenous or epidural without affecting the initial breast feeding behaviors of the newborn.

Low-Dose Intravenous Paracetamol for Patent Ductus Arteriosus in Indomethacin-Resistant or Contraindicated Preterm Infants: Three Cases Reports.

PubMed

Matsumura, Shun; Oshima, Ayumi; Fujinuma, Sumie; Tanaka, Kosuke; Nagano, Nobuhiko; Miyake, Fuyu; Masutani, Satoshi; Tamura, Masanori; Ueda, Keiko; Namba, Fumihiko

2017-10-01

Background  Although indomethacin (IND) is the standard treatment for hemodynamically significant patent ductus arteriosus (hsPDA) in Japan, it may be associated with renal impairment and gastrointestinal complications. The use of paracetamol for hsPDA closure has recently increased. Unlike IND, paracetamol does not have a peripheral vasoconstrictive effect and can be given to infants with contraindications to IND. Based on limited data available from randomized trials, paracetamol and IND seem to have similar effects. However, there have been no reports of the use of paracetamol for hsPDA in Japan. Cases  Our drug administration protocol was approved by the institutional ethics committee after purchasing a clinical trial insurance. In three premature infants in whom IND was contraindicated or ineffective, a 7.5 mg/kg of paracetamol was intravenously administered every 6 hour for 3 days after obtaining parental consents. A temporary hsPDA closure was observed in two of the three infants. However, all three infants eventually needed surgical closure. No side effects, such as hepatic and renal dysfunctions, and adverse events were reported. Conclusion  The intravenous administration of paracetamol was safe and feasible in premature infants with hsPDA. Future clinical trials with optimized dose and timing of administration are needed.

High-Dose Intravenous Vitamin C Combined with Cytotoxic Chemotherapy in Patients with Advanced Cancer: A Phase I-II Clinical Trial

PubMed Central

Hoffer, L. John; Robitaille, Line; Zakarian, Robert; Melnychuk, David; Kavan, Petr; Agulnik, Jason; Cohen, Victor; Small, David; Miller, Wilson H.

2015-01-01

Background Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail. Methods and Findings We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement. Conclusions Despite IVC’s biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC’s value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify

The effect of Calendula officinalis versus metronidazole on bacterial vaginosis in women: A double-blind randomized controlled trial

PubMed Central

Pazhohideh, Zahra; Mohammadi, Solmaz; Bahrami, Nosrat; Mojab, Faraz; Abedi, Parvin; Maraghi, Elham

2018-01-01

Bacterial vaginosis (BV) is a common disorder among women of reproductive age. This study aimed to compare the effect of a Calendula officinalis extract-based cream and metronidazole on BV among women of reproductive age. In this study, 80 women of reproductive age with BV were randomly assigned to the C. officinalis (n = 40) or metronidazole (n = 40). Diagnosis of BV was confirmed when at least 3 of the 4 Amsel criteria were met (pH >4.5, whitish grey or thin homogeneous discharge, release of a fishy odor on adding 10% KOH, and detection of clue cells on microscopic examination). For each group, either a methanol extract of C. officinalis or metronidazole vaginal cream (5 g) was used for 1 week intravaginally, and all signs and symptoms were assessed 1 week after treatment completion. Before the intervention, the two groups did not differ significantly with regard to vaginal burning, odor, dysuria, and dyspareunia, but itching was significantly more common in the C. officinalis group than in the metronidazole group (22.5% vs. 2.5%, P = 0.01). One week after the intervention, all women in both groups were free of symptoms, including vaginal itching and burning sensation, odor, dysuria, and dyspareunia. None of the women in either group suffered any side effects from C. officinalis or metronidazole. C. officinalis was effective for the treatment of BV in women of reproductive age, without any side effects. This herb could be recommended for women of reproductive age who uncomfortable with the potential side effects of synthetic drugs. PMID:29441319

Inversion-based propofol dosing for intravenous induction of hypnosis

NASA Astrophysics Data System (ADS)

Padula, F.; Ionescu, C.; Latronico, N.; Paltenghi, M.; Visioli, A.; Vivacqua, G.

2016-10-01

In this paper we propose an inversion-based methodology for the computation of a feedforward action for the propofol intravenous administration during the induction of hypnosis in general anesthesia. In particular, the typical initial bolus is substituted with a command signal that is obtained by predefining a desired output and by applying an input-output inversion procedure. The robustness of the method has been tested by considering a set of patients with different model parameters, which is representative of a large population.

BASIC study: is intravaginal boric acid non-inferior to metronidazole in symptomatic bacterial vaginosis? Study protocol for a randomized controlled trial.

PubMed

Zeron Mullins, Melinda; Trouton, Konia M

2015-07-26

Bacterial vaginosis is associated with increased transmission of sexually transmitted infections, preterm labor, post-surgical infections, and endometritis. Current treatment for symptomatic bacterial vaginosis includes antibiotics, such as metronidazole, which are 70-80 % effective at one month after treatment and result in high recurrence rates and secondary candida infections. Intravaginal boric acid has been used for over a hundred years to treat vaginal infections, such as bacterial vaginosis. Boric acid is inexpensive, accessible, and has shown to be an effective treatment for other infections, such as vaginal candidiasis. To date, there has been no clinical trial evaluation of boric acid effectiveness to treat bacterial vaginosis. The BASIC (Boric Acid, Alternate Solution for Intravaginal Colonization) trial is a randomized, double-blinded, multicenter study. The study will enroll a minimum of 240 women of 16-50 years of age who are symptomatic with bacterial vaginosis. Eligible participants will have Amsel and Nugent scores confirming bacterial vaginosis. Women who are pregnant or menopausal or have other active co-infections will be excluded. Consenting participants who meet exclusion and inclusion criteria will be randomly assigned to one of three treatment groups: boric acid, metronidazole, or an inert placebo. Self-administration of treatment intravaginally for 10 days will be followed by clinical assessment at 7 and 30 days (days 17 and 40, respectively) after the end of the treatment phase. Primary outcome is a non-inferiority, per-protocol comparison of the effectiveness of boric acid with that of metronidazole at day 17, as measured by the Nugent score in 16-50 year olds. Secondary outcomes include: non-inferiority, intention-to-treat comparison of effectiveness of boric acid with that of metronidazole at day 17, analysis for both per-protocol and intention-to-treat at day 40, and safety considerations, including adverse effects requiring patient

Short-term intravenous antimicrobial prophylaxis for elective rectal cancer surgery: results of a prospective randomized non-inferiority trial.

PubMed

Ishibashi, Keiichiro; Ishida, Hideyuki; Kuwabara, Kouki; Ohsawa, Tomonori; Okada, Norimichi; Yokoyama, Masaru; Kumamoto, Kensuke

2014-04-01

To investigate the non-inferiority of postoperative single-dose intravenous antimicrobial prophylaxis to multiple-dose intravenous antimicrobial prophylaxis in terms of the incidence of surgical site infections (SSIs) in patients undergoing elective rectal cancer surgery by a prospective randomized study. Patients undergoing elective surgery for rectal cancer were randomized to receive a single intravenous injection of flomoxef (group 1) or five additional doses (group 2) of flomoxef after the surgery. All the patients had received preoperative oral antibiotic prophylaxis (kanamycin and erythromycin) after mechanical cleansing within 24 h prior to surgery, and had received intravenous flomoxef during surgery. A total of 279 patients (including 139 patients in group 1 and 140 in group 2) were enrolled in the study. The incidence of SSIs was 13.7% in group 1 and 13.6% in group 2 (difference [95% confidence interval]: -0.2% [-0.9 to 0.7%]). The incidence of SSIs was not significantly different in patients undergoing elective rectal surgery who were treated using a single dose of postoperative antibiotics compared to those treated using multiple-dose antibiotics when preoperative mechanical and chemical bowel preparations were employed.

A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro

PubMed Central

Dunn, Linda A.; Burgess, Anita G.; Krauer, Kenia G.; Eckmann, Lars; Vanelle, Patrice; Crozet, Maxime D.; Gillin, Frances D.; Upcroft, Peter; Upcroft, Jacqueline A.

2010-01-01

The 5-nitroimidazole (NI) compound C17, with a side chain carrying a remote phenyl group in the 2-position of the imidazole ring, is at least 14-fold more active against the gut protozoan parasite Giardia lamblia than the 5-NI drug metronidazole (MTR), with a side chain in the 1-position of the imidazole ring, which is the primary drug for the treatment of giardiasis. Over 10 months, lines resistant to C17 were induced in vitro and were at least 12-fold more resistant to C17 than the parent strains. However, these lines had ID90 values (concentration of drug at which 10% of control parasite ATP levels are detected) for MTR of >200 μM, whilst lines induced to be highly resistant to MTR in vitro have maximum ID90 values around 100 μM (MTR-susceptible isolates typically have an ID90 of 5–12.8 μM). The mechanism of MTR activation in Giardia apparently involves reduction to toxic radicals by the activity of pyruvate:ferredoxin oxidoreductase (PFOR) and the electron acceptor ferredoxin. MTR-resistant Giardia have decreased PFOR activity, which is consistent with decreased activation of MTR in these lines, but C17-resistant lines have normal levels of PFOR. Therefore, an alternative mechanism of resistance in Giardia must account for these super-MTR-resistant cells. PMID:20456926

Buprenorphine Maintenance Subjects Are Hyperalgesic and Have No Antinociceptive Response to a Very High Morphine Dose.

PubMed

Athanasos, Peter; Ling, Walter; Bochner, Felix; White, Jason M; Somogyi, Andrew A

2018-03-05

Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Ambulatory. Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2-22 mg); no dose change for 1.5-12 months. Ten healthy controls. Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Cold pressor responses (seconds): baseline: control 34 ± 6 vs buprenorphine 17 ± 2 (P = 0.009); morphine infusion-end: control 52 ± 11(P = 0.04), buprenorphine 17 ± 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 ± 6 vs buprenorphine 53 ± 5 (P = 0.13); infusion-end: control 74 ± 5 (P = 0.007), buprenorphine 53 ± 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 ± 1

Intravenous Esomeprazole for Prevention of Peptic Ulcer Rebleeding: A Randomized Trial in Chinese Patients.

PubMed

Bai, Yu; Chen, Dong-Feng; Wang, Rong-Quan; Chen, You-Xiang; Shi, Rui-Hua; Tian, De-An; Chen, Huifang; Eklund, Stefan; Li, Zhao-Shen

2015-11-01

High-dose intravenous esomeprazole is the only approved pharmacological treatment for the prevention of peptic ulcer rebleeding (currently approved in over 100 countries worldwide), but has not yet been approved in China. This study aimed to evaluate a high-dose esomeprazole intravenous regimen vs. an active control (cimetidine) for the prevention of rebleeding in Chinese patients with a high risk of peptic ulcer rebleeding who had undergone primary endoscopic hemostatic treatment. This was a parallel-group study conducted at 20 centers in China. The study comprised a randomized, double-blind, intravenous treatment phase of 72 h in which 215 patients received either high-dose esomeprazole (80 mg + 8 mg/h) or cimetidine (200 mg + 60 mg/h), followed by an open-label oral treatment phase in which all patients received esomeprazole 40 mg tablets once daily for 27 days. The primary outcome was the rate of clinically significant rebleeding within the first 72 h after initial endoscopic hemostatic therapy. Secondary outcomes included the rates of clinically significant rebleeding within 7 and 30 days; proportions of patients who had endoscopic retreatment and other surgery due to rebleeding; and number of blood units transfused. The rate of clinically significant rebleeding within 72 h was low overall (3.3%) and numerically lower in patients treated with esomeprazole compared with cimetidine (0.9% vs. 5.6%). Overall, the results of the secondary outcomes also showed a numerical trend towards superiority of esomeprazole over cimetidine. All treatments were well tolerated. In this phase 3, multicenter, randomized trial conducted in China, esomeprazole showed a numerical trend towards superior clinical benefit over cimetidine in the prevention of rebleeding in patients who had successfully undergone initial hemostatic therapy of a bleeding peptic ulcer, with a similar safety and tolerability profile. These findings suggest that esomeprazole may be an

Scurvy in an alcoholic patient treated with intravenous vitamins

PubMed Central

Ong, John; Randhawa, Rabinder

2014-01-01

Vitamin C deficiency is rare in developed countries but there is an increased prevalence in chronic alcohol abusers. In the UK, it is common practice to treat patients with chronic alcoholism who are admitted to hospital with intravenous vitamins B1, B2, B3, B6 and C for 2–3 days, followed by oral thiamine and vitamin B-compound tablets. This is a case of a 57-year-old man with a history of chronic alcoholism and chronic obstructive lung disease who was admitted to the intensive care unit for pneumonia requiring ventilatory support. He was given high doses of intravenous vitamins B1, B2, B3, B6 and C for 3 days then oral thiamine and vitamin B compound tablets but developed scurvy 4 days later. He was restarted on oral vitamin C supplementation and showed signs of improvement within 3 days of treatment. PMID:24728889

Safety, Tolerability, and Pharmacokinetic Properties of Intravenous Delafloxacin After Single and Multiple Doses in Healthy Volunteers.

PubMed

Hoover, Randall; Hunt, Thomas; Benedict, Michael; Paulson, Susan K; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

2016-01-01

The objective of this report was to determine the pharmacokinetic properties, safety, and tolerability of single and multiple doses of intravenous delafloxacin. In addition, the absolute bioavailability (BA) of the 450-mg tablet formulation of delafloxacin was determined. Three clinical trials are summarized. The first study was a randomized, double-blind, placebo-controlled, single- (300, 450, 600, 750, 900, and 1200 mg) ascending-dose study of IV delafloxacin in 62 (52 active, 10 placebo) healthy volunteers. The second study was a randomized, double-blind, placebo-controlled study of IV delafloxacin (300 mg) given as a single dose on day 1, followed by twice-daily dosing on days 2 through 14; 12 (8 active, 4 placebo) healthy volunteers were enrolled. The third study was an open-label, randomized, 2-period, 2-sequence crossover study in which 56 healthy volunteers were randomly assigned to 1 of 2 sequences of a single oral dose of delafloxacin (450-mg tablet) or IV delafloxacin (300 mg). Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were calculated. Delafloxacin Cmax values increased proportionally with increasing single IV dose for the dose range of 300 to 1200 mg, whereas the AUC values increased more than proportionally to dose for the same dose range. The mean terminal half-life of delafloxacin was approximately 12 hours (ranging from 8 to 17 hours). The volume of distribution (Vd) at steady state was approximately 35 L, which is similar to the volume of total body water. There was minimal accumulation of delafloxacin after twice-daily IV administration of 300 mg with an accumulation ratio of 1.09. The delafloxacin total exposure after a single 1-hour IV infusion of 300 mg and a single oral dose of a 450-mg tablet were equivalent with geometric least square mean ratio (90% CI) of 0.8768 (0.8356-0.9200) for AUC0-∞ and 0.8445 (0.8090-0.8815) for AUC0-t, respectively. The Cmax values of delafloxacin were not

Single jugular vein cannulated rats may not be suitable for intravenous pharmacokinetic screening of high logP compounds.

PubMed

Gaud, Nilesh; Kumar, Anoop; Matta, Muralikrishna; Kole, Prashant; Sridhar, Srikanth; Mandlekar, Sandhya; Holenarsipur, Vinay K

2017-03-01

Rat is commonly used for pharmacokinetic screening during pharmaceutical lead optimization. To handle the large number of compounds, rats with a single jugular vein cannulation are commonly utilized for intravenous pharmacokinetic studies, where the same cannula is used both for dose administration and blood sampling. We demonstrate that the single cannula method is not suitable for all compounds, especially for high logP compounds. We propose an alternative dual cannulation technique in which two cannulas are placed in the same jugular vein, thus avoiding an additional surgery. Compounds were administered orally or via intravenous infusion to compare PK parameters, including bioavailability, using both procedures. For itraconazole and amiodarone, known to bind to the cannula, the measured plasma exposures were substantially higher in the single cannulated rats than those from dual cannulated rats. Area under the plasma concentration time curve differed by 79% and 74% for itraconazole and amiodarone, respectively. When compared to the single cannulation approach, clearance, volume of distribution and bioavailability determined by dual cannulation were 39%, 60% and 38% higher for itraconazole, and 46%, 34% and 42% higher for amiodarone, respectively. In contrast, all pharmacokinetic parameters were similar between single and dual-cannulated rats for the hydrophilic compound atenolol. Based on these results, we recommend the use of dual cannulated rats for intravenous pharmacokinetic studies when testing a series of hydrophobic compounds that may be prone to non-specific binding to the cannula. If single cannulated model is selected for pharmacokinetic screening, we recommend a bridging study with dual cannulated rats with representative compounds of a given chemical series. Copyright © 2016 Elsevier B.V. All rights reserved.

In situ forming implants for the delivery of metronidazole to periodontal pockets: formulation and drug release studies.

PubMed

Kilicarslan, Muge; Koerber, Martin; Bodmeier, Roland

2014-05-01

This study was performed to obtain prolonged drug release with biodegradable in situ forming implants for the local delivery of metronidazole to periodontal pockets. The effect of polymer type (capped and uncapped PLGA), solvent type (water-miscible and water-immiscible) and the polymer/drug ratio on in vitro drug release studies were investigated. In situ implants with sustained metronidazole release and low initial burst consisted of capped PLGA and N-methyl-2-pyrolidone as solvent. Mucoadhesive polymers were incorporated into the in situ implants in order to modify the properties of the delivery systems towards longer residence times in vivo. Addition of the polymers changed the adhesiveness and increased the viscosity and drug release of the formulations. However, sustained drug release over 10 days was achievable. Biodegradable in situ forming implants are therefore an attractive delivery system to achieve prolonged release of metronidazole at periodontal therapy.

Oral pyridoxine can substitute for intravenous pyridoxine in managing patients with severe poisoning with isoniazid and rifampicin fixed dose combination tablets: a case report.

PubMed

Dilrukshi, M D S A; Ratnayake, C A P; Gnanathasan, C A

2017-08-08

Fixed drug combination of isoniazid and rifampicin is a rare cause of poisoning even in endemic countries for tuberculosis infection. Severe poisoning can cause severe morbidity and mortality if not treated promptly. Though intravenous pyridoxine is the preferred antidote for severe standard isoniazid poisoning it is not freely available even in best of care centers. We describe a case of severe poisoning with fixed drug combination of isoniazid and rifampicin successfully managed with oral pyridoxine at national hospital of Sri Lanka. A 22 year old, Sri Lankan female presented to a local hospital 1 h after self-ingestion of 28 tablets of fixed drug combination of isoniazid and rifampicin which contained 4.2 g of standard isoniazid and 7.2 g of rifampicin. One and half hours after ingestion she developed generalized tonic-clonic seizure with loss of consciousness. She was given intravenous diazepam 5 mg immediately and transferred to national hospital of Sri Lanka, for further care. Upon arrival to tertiary care hospital in 3.5 h of poisoning she had persistent vomiting, dizziness and headache. On examination, she was drowsy but arousable, orange-red discoloration of the body was noted even with the dark skin complexion. She also had orange-red colour urine and vomitus. Pulse rate was 104 beats/min, blood pressure 130/80 mmHg, respiratory rate was 20 breaths/min. The arterial blood gas analysis revealed compensated metabolic acidosis and mildly elevated lactic acid level. Considering the clinical presentation with neurological toxicity and the large amount of isoniazid dose ingested, crushed oral tablets of pyridoxine 4.2 g (equal to standard isoniazid dose ingested) administered immediately via a nasogastric tube since intravenous preparation was not available in the hospital. Simultaneously forced diuresis using intravenous 0.9% saline was commenced in order to enhance excretion of toxic metabolites via kidneys. She had no recurrence of seizures but had

Detection of metronidazole in honey and metronidazole tablets using carbon dots-based sensor via the inner filter effect.

PubMed

Zhao, Jianru; Pan, Xiaohua; Sun, Xiaobo; Pan, Wei; Yu, Guifeng; Wang, Jinping

2018-06-01

In this work, carbon dots (CDs) with a high quantum yield (22.3%) were easily prepared by hydrothermal pyrolysis of acid fuchsin 6B and hydrogen peroxide at 180°C for 10 h. The resultant CDs possess a narrow size distribution in the range of 2.6 to 3.2 nm and emit blue fluorescence. Interestingly, the absorption band of metronidazole (MTZ) centered at 318 nm can complementary overlap with the excitation band of the as-prepared CDs centered at 320 nm, resulting in an inner filter effect (IFE) in high efficiency. In fact, the fluorescence quenching of the CDs depends on the concentration of MTZ. Therefore, a simple method for the detection of MTZ can be established using the CDs-based sensor via the IFE. The linear range of the proposed method was 0-10 μg mL -1 with the limit of detection as low as 0.257 μg mL -1 . This CDs-based sensor had been applied for the detection of MTZ in honey and MTZ tablets with the recoveries in the range of 98.0% to 105.1% and 95.7% to 106.5%, respectively. Therefore, the as-prepared CDs have a potential to be developed as a MTZ sensor with high selectivity, sensitivity and accuracy. Copyright © 2018 John Wiley & Sons, Ltd.