Oral Paracetamol Research Articles

Laparoscopic extravesical detrusorraphy, a minimally invasive treatment option for vesicoureteral reflux: A single centre experience

Laparoscopy in pediatric patients offers more benefits than was earlier presumed and these widely reported benefits significantly outweigh any concerns regarding the technical difficulties. Laparoscopic correction of vesicoureteral reflux aims to duplicate the excellent results of open surgery while at the same time reducing perioperative morbidity and analgesic requirements, improving cosmesis and shortening hospital stay. To share our experience of laparoscopic extravesical detrusorraphy, highlight our technical modification of intraoperative minimal "atraumatic" ureteric handling of the ureter, which we hypothesize may decrease ureteral complications, and report our results. This was a retrospective chart review of 76 toilet-trained children (98 refluxing units), in the age group of 3-16 years, with Grade I-IV reflux, who underwent laparoscopic detrusorraphy from June 2006 to January 2014. A ureteric catheter is inserted into the refluxing ureter and is tied to the Foleys to drain into a common bag. A three port technique is used. During ureteral dissection, a vascular sling in the form of a Rumel loop is used for atraumatic handling of the ureter. A detrusor tunnel is created with hook electrocautery. A stay suture is later passed through the abdominal wall and slings around the dissected ureter, which helps in holding the ureter approximated against the mucosal trough during detrusorraphy. Detrusor fibers are approximated with 5-0 Vicryl. No drain is placed and the Foley and ureteric catheter(s) are removed after 24 h. Intravenous ketorolac is given every 6 h for the first 24 h. Oral paracetamol is used for analgesia after the first 24 h. Adequate bladder emptying is ensured by assessment of post void residual urine before discharge. Renal USG alone is performed 2 weeks post operatively and repeated after 3 months along with a VCUG (voiding cystourethrography). Success was defined as absence of reflux in the follow-up VCUG done at 3 months. Mean operative time was 102 ± 26.5 min for unilateral detrusorraphy and 165 ± 18 min for bilateral extravesical detrusorraphy. The mean duration of hospital stay was 1.5 ± 1.7 days. There was one case of urinary retention that was managed with temporary recatheterization. There were no cases of ureteral ischemia, obstruction, hematuria or bladder spasms. Surgery was successful in 97.9% of the refluxing units (96/98). In two patients with grade IV reflux, there was downgrading to grade II on VCUG done at 3 months' follow-up. The reflux resolved at 8 and 14 months' follow-up, respectively. Our technique of atraumatic handling of the ureter, initially with the help of a vascular sling and later with the help of a stay suture passed percutaneously through the abdominal wall, resulted in no ureteric injuries. The postoperative morbidity of this procedure is low because the bladder is not opened, the ureter is not transected, no new UVJ is created and there is no need for placement of a drain. The risk of postoperative bowel adhesions is low as the ureter is dissected out through a narrow peritoneal window, which is again extraperitonealized at the end of the procedure (see figure). The postoperative complications of gross hematuria and bladder spasms, which may be especially encountered in patients undergoing laparoscopic Cohen's, were not seen in our case series. Laparoscopic extravesical detrusorraphy provides a minimally invasive treatment option for treatment of unilateral/bilateral grade I-IV vesicoureteral reflux. The postoperative morbidity is low and the success rate is favorable. Our technical modification of a "vascular sling" around the ureter facilitates atraumatic ureteric handling, which may reduce distal ureteral complications like ureteral ischemia and obstruction.

Can intracutaneous sterile water injection be used as a possible treatment for acute renal colic pain in the emergency department? A short literature review.

Can intracutaneous sterile water injection be used as a possible treatment for acute renal colic pain in the emergency department? A short literature review.

Comparative study between paracetamol and two different doses of pregabalin on postoperative pain in laparoscopic cholecystectomy.

Background:Postoperative pain is the primary reason for prolonged hospital stay after laparoscopic cholecystectomy. This study compared the effect of a single oral preoperative administration of paracetamol (1 g) with 2 different doses of pregabalin (150 or 300 mg) for attenuating postoperative pain and analgesic consumption.Materials and Methods:Seventy-five patients, aged 18-60 years, American Society of Anesthesiologists’ physical status I and II undergoing elective laparoscopic cholecystectomy were included in this randomized controlled study. Patients were divided into three groups, 25 each to receive either oral paracetamol 1 g (group I, control group) or pregabalin 150 (group II) or 300 mg (group III), 2 h before surgery. Postoperative pain was evaluated based on visual analog scale over a period of 6 h and 1st time for rescue analgesia. Postoperative sedation, hemodynamic changes, serum cortisol level, and side effects were also evaluated.Results:There was a significant decrease in mean heart rate, mean systolic blood pressure, sedation score, pain score, and delayed the first request for analgesics postoperatively in group (II) and group (III) compared to group (I) 2 h postoperatively. There was no significant difference in group (III) compared to group (II) postoperatively. The incidence of postoperative side effects was more in group (III).Conclusion:The single oral preoperative dose administration of pregabalin had significant opioid-sparing effect in the first 6 h after surgery, whereas side effects were more common with administration of pregabalin 300 mg.

The Analgesic Efficacy of Preoperative Lornoxicam in Prevention of Postoperative Pain after Septoplasty

Background: Septoplasty operation is a commonly performed procedure, usually done on short stay basis. Postoperative pain and bleeding are two major concerns that influence delayed discharge or readmission. Lornoxicam, nonselective anti-inflammatory drugs belongs to oxicam group with balanced cycloxygenase inhibitor and is well tolerated by the patients. It is theoretically potential to reduce postoperative pain and perioperative bleeding. The role of preemptive analgesia in prevention of postoperative pain is controversial. Lornoxicam has proven role in the management of postoperative pain. However, comprehensive evidence is lacking regarding its preemptive use for postoperative pain relief. Materials and Methods: After getting ethical committee approval and written informed consents from 88 adult patients of either sex, ASA physical status I and II scheduled for septoplasty under local anaesthesia and monitored anaesthesia care, were allocated in this prospective randomised double blinded placebo controlled study to receive either intravenous single dose lornoxicam 16 mg diluted into 100 ml normal saline (Group A) or Normal Saline (Group B) over 10 minutes 30 min before surgical incision. Dexmedetomedine was infused 1 microgram/kg over 10 min as initial loading dose and 0.2-0.7 microgram/kg/hr as maintainance of anaesthesia. Severity of postoperative pain was assessed with Visual Analogue Scale (VAS) Score 0-100 mm at immediate postoperative period, 30 min and every 1 hr till 4 hrs postoperatively and then 4 hrly upto 12 hrs and 6 hrly till 24 hrs. Oral paracetamol 1 gm was used as rescue analgesic on demand. Patients’ refractory to paracetamol treated with 10 microgram iv fentanyl increments. Patients were followed up for satisfaction and complications till 24 hrs. Results: Patients of group A reported significantly lower pain score (p<0.05) and significantly less in patients of group A as compared to group B required rescue analgesia within first 6 hrs postoperatively. Time to first rescue analgesic request was also significantly prolonged in group A. Conclusion: Preemptive single dose lornoxicam appears to be effective in management of acute postoperative pain following septoplasty.

Safety of nalbuphine on neural tissues of rats and its efficacy in the treatment of acute herpetic pain in children with acute lymphoblastic leukemia

Background Acute lymphoblastic leukemia (ALL) has been previously shown to cause severe impairment in immunity, in turn making children more susceptible to viral infections, especially herpes zoster, which manifests with severe pain. Materials and methods The main purpose of this study was to experimentally evaluate the safety of nalbuphine on the neural tissues of rats treated with nalbuphine at doses of 0.5, 1, 2, 4, and 5 mg/kg injected intrathecally every alternate day for 14 days, and to determine the efficacy of caudal injection of nalbuphine with a minimal dose of oral paracetamol as an analgesic in pediatric patients with ALL suffering from acute herpetic pain. Results The results revealed that nalbuphine exerted no pathological changes in either the cerebellum or the spinal cord. However, the protective effect of nalbuphine with the minimal dose of paracetamol was associated with a significant analgesic effect in ALL children. Its analgesic effect was assessed by means of the Facial Pain Scale and the behavioral pain assessment scale, and motor block assessment was made on the basis of the Bromage score. Conclusion Caudal nalbuphine with a minimal dose of paracetamol has adequate analgesic effect on acute herpetic pain in pediatric patients with ALL, without any pathological changes in the cerebellum and spinal cord.

Oral versus intravenous paracetamol: which is better in closure of patent ductus arteriosus in very low birth weight infants?

Objectives: To compare the efficacy of oral and intravenous paracetamol for closure of hemodynamically significant patent ductus arteriosus (HSPDA) in very low birth weight (VLBW) preterm infants.Methods: Eighteen VLBW infants with HSPDA treated with either intravenous (n = 10) or oral (n = 8) paracetamol at 60 mg/kg/d for three consecutive days were analysed retrospectively. Ductal closure rate and evaluation of liver function tests were the major outcomes.Results: After two courses of treatment, HSPDA closure rate was higher in oral paracetamol group than that in the intravenous paracetamol group (88% versus 70%), but it was not statistically significant (p = 0.588). Liver function tests were normal after the treatment.Conclusion: Although it was not statistically significant, the cumulative closure rates were higher in oral paracetamol group than those in the intravenous group. Larger trials are needed to confirm these data.

Acetaminophen plus a nonsteroidal anti-inflammatory drug decreases acute postoperative pain more than either drug alone

A critical summary of Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg 2010;110(4):1170-1179.

Anaphylaxis to Paracetamol in a Twelve-Year-Old Girl

Paracetamol (acetaminophen) is widely used and considered safe, since adverse reactions to this drug in therapeutic doses are rare, especially in children.1,2 Only a few cases worldwide of anaphylaxis to paracetamol in children have previously been described.2-11 Anaphylaxis is defined as a life-threatening reaction resulting from mast cell derived mediator release.12 This report illustrates a case of anaphylaxis to oral paracetamol confirmed by an oral provocation test and an increase in serum tryptase level.

English

Spinal anesthesia is the most commonly performed anesthesia technique in patients undergoing cesarean sections. Postdural puncture headache (PDPH) is one of the common complications following spinal anesthesia more so in in obstetric patients. It is preventable complication, hence the study is undertaken to know the incidence of PDPH in patients undergoing cesarean sections.100 patients belonging to ASA grade I & II, age group ranging from 20-40 years who are subjected to LSCS considered for the study. Patients with acute or chronic headache, otolaryngeal, ophthalmic and neurological problems are excluded from this study. Study is conducted in District hospital attached to Belgaum Institute of Medical Sciences. 0.5% Bupivacaine hydrochloride is injected at L3-L4 level using 25G Quincke needle. In the postoperative period only 3% of cases developed PDPH.2 patients had mild headache and one patient developed moderate headache with vomiting, which was managed by analgesic oral paracetamol, antiemetic ondansetron and fluids.

Preemptive oral paracetamol in laparoscopic cholecystectomy surgery - a comparative study

Background Laparoscopic cholecystectomy causes a considerable pain in the post operative period. Preemptive use of oral paracetamol decreases the intensity of pain and subsequently reduces the dose of opioid as well as nausea and vomiting. Objective The study was designed to observe the effect of preemptive oral paracetamol reduces the dose of postoperative opioid and nausea and vomiting. Methods Fifty patients of ASA physical status I and II, age range 16-50 years and BMI 18.5-24.9 were randomly selected by cards sampling method. They were equally divided into two groups of 25 patients in each group. Group I received vitamin, Group-II received 1 g oral paracetamol 60 min before surgery. In the recovery room dose of opioid was measured in 1, 6, 12, 24 hours and frequency of nausea, vomiting were assessed. Results The total amount of pethidine needed significantly lower in the case group than that in the control group (p = 0.012). The pain scores were comparatively low in case group than that in the control group from beginning to endpoint of evaluation following operation (p = 0.027). The complaint of nausea at 6 and 12 hours was much less in the case group than that in the control group. Majority (80%) of patients in control group demanded analgesic (pethidine) 10 minutes earlier after operation as opposed to only 8% of the control group (p = 0.014). Conclusion Preemptive paracetamol reduces the intensity of postoperative pain and requirements of pethidine to a large extent with no significant side effects. DOI: http://dx.doi.org/10.3329/jbsa.v26i1.19814 Journal of Bangladesh Society of Anaesthesiologists 2013; 26(1): 33-38

A Survey of the Pain Management of Acute Painful Crisis among Patients with Sickle Cell Disease at Two Centres in Jamaica.

The aim of this survey was to establish the pain management approaches to acute painful crisis (APC) in sickle cell patients at two healthcare facilities and to compare with available guidelines. A multi-centre observational survey of the management of APC in sickle cell patients was conducted. Data were collected at the Sickle Cell Unit (SCU), Tropical Medicine Research Institute (TMRI) and Accident and Emergency Department (A&E), University Hospital of the West Indies. One hundred episodes of uncomplicated APC involving 81 patients managed at the SCU clinic and 64 episodes at the A&E in a total of 28 patients were included in the data set. Drugs used at the SCU included oral morphine, codeine and paracetamol and intramuscular diclofenac. At the A&E, parenteral morphine and pethidine were most commonly used. At the SCU, the mean time to initiation of analgesics was 38 minutes (IQR 25 to 50 minutes); at the A&E, this was 111 minutes (IQR 50 to 150 minutes). At the SCU, the mean duration of stay (DOS) was 2.9 hours (IQR 1.9 to 3.8 hours) with 94% of the patients being discharged home. At the A&E, the mean DOS was 13.0 hours (IQR 8.3 to 16.9 hours) with 93% of the patients being discharged home. The A&E patient group contained multiple high frequency presenters. Documentation of pain severity scores was inconsistent. The findings of the survey indicate that the management of APC at the two centres is substantially different. Further study is required to investigate patient satisfaction, centre preference and analgesic therapy efficacy.

Assesment of The Effect of Multimodal Preemptive Analgesia in Children

Background: Preemptive analgesia, an evolving clinical concept, involves the introduction of an analgesic regimen before the onset of noxious stimuli, with the goal of preventing sensitization of the nervous system to subsequent stimuli that could amplify pain. Pain is inevitable after any surgery. Surgery offers the most promising setting for preemptive analgesia because the timing of noxious stimuli is known.Materials &amp; Methods: This prospective double blind study included 60 children (30 in each group), undergoing major surgery under general anesthesia. Each patient in the study group (Group II) received pre-emptive analgesia (Local anesthesia, per-rectal diclofenac just prior to surgery, per-rectal paracetamol 2 hours prior to surgery) and regular pattern of postoperative pain intervention with per rectal diclofenac and per rectal or oral paracetamol in different phases of postoperative pain management up to 48 hours. On the other hand, each patient of control group (Group I) received pre-emptive analgesia (Local anesthesia &amp; per-rectal diclofenac) regular pattern of postoperative pain intervention with per-rectal diclofenac in different phases of postoperative pain up to 48 hours. The degree of postoperative pain was assessed by universal pain assessment tools (VAS) at defined intervals.Results: Most children in the study group (Group II) has significantly better postoperative pain control with only mild pain at 4th postoperative hours. It is obvious that less pain in Group-II due to synergistic effect of paracetamol and diclofenac. In the control group (Group I) there was persistence of mild pain throughout the observation period i.e. up to 48 postoperative hours. The breakthrough pain occurred more in latter group, two patients needed rescue analgesia. Whereas no patient experienced breakthrough pain requiring rescue analgesia in study group (Group II).Conclusion: Therefore this study concludes that administrations of multimodal pre-emptive analgesia control pain more effectively in children in view of both the degree of pain control and sustainability of pain free state.DOI: http://dx.doi.org/10.3329/jpsb.v2i2.19545

A dose–response study of caudal dexmedetomidine with ropivacaine in pediatric day care patients undergoing lower abdominal and perineal surgeries: a randomized controlled trial

This randomized double-blind study was conducted to evaluate the analgesic efficacy and safety of addition of three different doses of dexmedetomidine in caudal ropivacaine compared with plain ropivacaine for postoperative analgesia in pediatric day care patients. Eighty children of American Society of Anesthesiologists grade I-II, aged 1-8 years, undergoing lower abdominal and perineal surgery were included. Children were randomly allocated into four groups. Group 1 received 0.2% plain ropivacaine 0.75 ml·kg(-1), while group 2, 3, and 4 received dexmedetomidine 0.5, 1.0, and 1.5 μg·kg(-1), respectively, along with 0.2% ropivacaine 0.75 ml·kg(-1). Anesthesia was induced and maintained with sevoflurane and 50% N2O in oxygen. Children were observed for postoperative pain, nausea-vomiting, agitation, sedation, and adverse effects. Rescue analgesia was provided with oral paracetamol. Postoperative analgesia was significantly prolonged in all dexmedetomidine groups as compared to plain ropivacaine group (P < 0.001). All patients in the plain ropivacaine group required rescue analgesia within first 6 postoperative hours, while none in the other three groups. None of the patients showed delayed anesthetic emergence. Four patients in the plain ropivacaine group developed agitation, while none in the dexmedetomidine groups. Patients receiving dexmedetomidine 1.5 μg·kg(-1) were more sedated as compared to the other groups (P < 0.01), but it did not delay discharge of the patients. All three doses of caudal dexmedetomidine appear to be effective for preventing postoperative pain in pediatric day care patients. Caudal dexmedetomidine used in these doses seems to be safe for day care surgery.

Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies

We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA). Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy. Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05). The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.

Safety of Oral Paracetamol – Analysis of Data from a Spontaneous Reporting System in Poland

Purpose: To determine the safety of oral coated paracetamol tablets 500 mg and oral suspension 120 mg/5 mL produced by Hasco-Lek Poland.Methods: We analyzed sales volume and data obtained from the monitoring of spontaneous reports on the adverse effects of paracetamol collected in the period between November 2000 and June 2012.Results: A total of 45,694 units of coated paracetamol tablets (500 mg) and 6,048,289 units of paracetamol oral suspension (120 mg/5 mL) were marketed during that period. There were 4 spontaneous reports of adverse effects.Conclusion: Oral paracetamol is a safe medication rarely causing adverse effects but it is possible that the existing spontaneous monitoring system for adverse effects in Poland is not sensitive enough to detect all adverse effects, and needs improvement.Keywords: Adverse reaction, NSAIDs, Pharmacovigillance, Pharmoepidemiology

ABSTRACT 848

Background and aims: To study the effect of oral paracetamol in PDA closure in preterm neonate.Patent ductus arteriosus (PDA), in which there is a persistent communication between the descending thoracic aorta and the pulmonary artery that results from failure of normal physiologic closure of the fetal ductus. Aims: To study the effect of oral paracetamol in PDA closure in preterm neonates. Methods: An observational study to see the effect of oral paracetamol in PDA closure in preterm neonates. Results: We report 10 preterm neonates born at gestational age 27–33 weeks with birth weight range 800 grams to 1400 grams admitted to our NICU. All these preterm neonate were diagnosed to have haemodynamically significant (features of congestive cardiac failure) PDA at 4 – 7 days of life. Each of these neonate were given oral paracetamol in the dosage of 15mg/kg 8hrly for 48hrs. The ductal closure was achieved in all neonate by 48 hrs of administration. The ductal closure was confirmed with repeat echocardiography after 72hrs of administration of oral paracetamol. These neonates did not suffer any complication related to paracetamol. Conclusions: The exact mechanism use of oral paracetamol in ductal closure has not been studied on large scale, however with this study it is evident that oral paracetamol is equally effective in ductal closure with no side effects which was there with Brufen/Indomethacin. However a large randomized study is needed to validate this interesting observation.

LC-MS/MS and GC-MS/MS measurement of plasma and urine di-paracetamol and 3-nitro-paracetamol: proof-of-concept studies on a novel human model of oxidative stress based on oral paracetamol administration.

Paracetamol (acetaminophen) is a widely used safe analgesic drug when administered at therapeutic doses. Given the chemical reactivity of its phenolic group towards electrophilic species, we assumed that detection of paracetamol metabolites distinctly different from its known phase I metabolite N-acetyl-p-benzoquinone imine (NAPQI) and the phase II glucuronic, sulfuric and mercapturic acids in biological samples upon oral administration of paracetamol (e.g., a 500-mg tablet) may represent a novel model of oxidative stress in humans. Such potential paracetamol metabolites are di-paracetamol and 3-nitro-paracetamol, in analogy to the well-investigated endogenous biomarkers di-tyrosine and 3-nitro-tyrosine. Di-paracetamol and 3-nitro-paracetamol are known to be formed both by enzymatic and non-enzymatic routes. In the present work we report on mouse and human pilot studies on the formation and appearance of di-paracetamol and 3-nitro-paracetamol in blood of mice intraperitoneally administered paracetamol, as well as in plasma and urine samples of healthy subjects who received a 500-mg paracetamol tablet or placebo. For the analysis of di-paracetamol and 3-nitro-paracetamol in plasma and urine samples, analytes were extracted by solvent extraction with ethyl acetate and subsequently analyzed by LC-MS/MS without and with derivatization with pentafluorobenzyl bromide. GC-MS/MS was used to detect 3-nitro-paracetamol and quantify paracetamol as pentafluorobenzyl derivatives. Our studies indicate that di-paracetamol and 3-nitro-paracetamol appear in plasma and urine when paracetamol is given orally to healthy humans at the therapeutic dosage of 5-7 mg/kg. The molar ratio of di-paracetamol to paracetamol in urine was determined to be 1:535 in the paracetamol group and 1:6844 in the placebo group; the molar ratio of 3-nitro-paracetamol to paracetamol in urine was determined to be 1:199 in the paracetamol group and 1:8657 in the placebo group. Our studies suggest that a fraction of circulating and excretory di-paracetamol and 3-nitro-paracetamol may be formed artefactually during sample workup including derivatization. Further studies based on the quantitative determination of di-paracetamol and 3-nitro-paracetamol in biological samples by LC-MS/MS and/or GC-MS/MS using stable-isotope labeled analogues as internal standards are warranted to test the utility of paracetamol as a probe of oxidative stress in animals and in humans in health and disease.

Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study

3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.

Response to the letter by Sharma et al.: Intracutaneous sterile water injection versus oral paracetamol for renal colic during pregnancy: a randomized controlled trial. Int Urol Nephrol 2013; 45:321–325, DOI 10.1007/s11255-013-0405-3

1. We read this article with interest where the authors have compared oral paracetamol 1 g with intracutaneous sterile water injection at most painful site for renal colic in pregnancy. The authors showed that intracutaneous sterile water injection acts faster and significantly better in pain relief as compared to oral paracetamol. There are few points that need clarification. As mentioned in the manuscript, intracutaneous sterile water injection causes significant pain at the local site. The authors should have evaluated this pain at local site by visual analogue scale (VAS). Moreover, patient satisfaction with analgesic should have been reported. Answer: Thank you for your kind letter and giving us constructive advises. We have used visual analogue scale (VAS) to evaluate the severity of pain in our manuscript. Meantime, to record the patient satisfaction is a good advice and required further studies. We did not show the patient satisfaction in our manuscript because our data were incomplete. 2. Another issue is that the authors compared intracutaneous sterile water injection with oral paracetamol which is a poor analgesic. The time required by paracetamol to achieve maximum plasma concentration is more than 1 h. However, the authors have started rescue analgesia after 1 h. In our opinion, intramuscular paracetamol could have been used instead of oral paracetamol. Answer: As we mentioned in our manuscript, we evaluated the anodyne and immediate effects of oral paracetamol as a control in this study, but we did not compare the effects of sterile water injections to those of intravenous paracetamol because (1) the safety of intravenous paracetamol has not been previously evaluated in the management of pain associated with renal colic in pregnant women, and (2) oral paracetamol is classified as grade B according to the US Federal Drug Administration pregnancy categories, a system of classifying drugs based on their established risks for use during pregnancy. 3. Another point that needs clarification is that the patients with ureteral stone complain of recurrent colic and therefore require repeated doses of analgesia. The site of injection if the patient needs multiple injections for the same condition is a matter of debate. Answer: The initial management of symptomatic ureteric stones during pregnancy should be conservative, and most renal colic could be relieved with conservative therapy. However, when conservative approach fails, URSL may be a good alternative approach for definitive treatment [1].

Acute liver failure in a term neonate after repeated paracetamol administration

Objective: Severe hepatotoxicity caused by paracetamol is rare in neonates. We report a case of paracetamol-induced acute liver failure in a term neonate. Case description: A 26-day-old boy was admitted with intestinal bleeding, shock signs, slight liver enlargement, coagulopathy, metabolic acidosis (pH=7.21; bicarbonate: 7.1mEq/L), hypoglycemia (18mg/dL), increased serum aminotransferase activity (AST=4,039IU/L; ALT=1,087IU/L) and hyperbilirubinemia (total: 9.57mg/dL; direct: 6.18mg/dL) after receiving oral paracetamol (10mg/kg/dose every 4 hours) for three consecutive days (total dose around 180mg/kg; serum concentration 36-48 hours after the last dose of 77µg/ mL). Apart from supportive measures, the patient was successfully treated with intravenous N-acetylcysteine infusion during 11 consecutive days, and was discharged on day 34. The follow-up revealed full recovery of clinical and of laboratory findings of hepatic function. Comments: The paracetamol pharmacokinetics and pharmacodynamics in neonates and infants differ substantially from those in older children and adults. Despite the reduced rates of metabolism by the P-450 CYP2E1 enzyme system and the increased ability to synthesize glutathione - which provides greater resistance after overdoses -, it is possible to produce hepatotoxic metabolites (N-acetyl-p-benzoquinone) that cause hepatocellular damage, if glutathione sources are depleted. Paracetamol clearance is reduced and the half-life of elimination is prolonged. Therefore, a particular dosing regimen should be followed due to the toxicity risk of cumulative doses. This report highlights the risk for severe hepatotoxicity in neonates after paracetamol multiple doses for more than two to three days.