Chlorpromazine and promethazine reduces Brain injury through RIP1-RIP3 regulated activation of NLRP3 inflammasome following ischemic stroke.

Objectives: Stroke is an important cause of death and disability. Recent evidence suggests that post-stroke inflammation is an important factor in stroke pathology and a root cause of its lasting consequences. Phenothiazine drugs, like chlorpromazine and promethazine (C + P), induce hypothermia and have been shown to play a major role in neuroprotection. In the present study, we investigated this neuroprotective mechanism by assessing the anti-inflammatory effect of these drugs.Methods: Adult Sprague-Dawley rats underwent 2 h of middle cerebral artery occlusion (MCAO) followed by 6 or 24 h of reperfusion, with or without C + P (8 mg/kg). Infarct volumes, neurological deficits, along with mRNA and protein quantities of receptor-interacting protein 1 (RIP1), receptor-interacting protein 3 (RIP3), NLRPyrin domain containing 3 (NLRP3), and interleukin-1ß (IL-1ß) were assessed, as well as the infiltration of neutrophils and macrophages.Results: C + P induced hypothermia that significantly reduced RIP1, RIP3, NLRP3 and IL-1ß expression, infarction, and immune cell infiltration, while C + P treatment with temperature control at 37°C induced lesser effect.Conclusion: These findings suggest that the anti-inflammatory effect of C + P may be dependent on drug-induced hypothermia and regulation of the NLRP3 inflammasome via the RIP1/RIP3 complex. Future investigations are needed regarding C + P as potential treatment of ischemic stroke.

Muscarinic receptor blockade causes postcontraction enhancement in corticospinal excitability following maximal contractions.

Although synaptic transmission in motor pathways can be regulated by neuromodulators, such as acetylcholine, few studies have examined how cholinergic activity affects cortical and spinal motor circuits following muscle contractions of varying intensities. This was a human, double-blinded, placebo-controlled, crossover study. Participants attended two sessions where they were administered either a placebo or 25 mg of promethazine. Electromyography of the abductor digiti minimi (ADM) was measured for all conditions. Motor evoked potentials (MEPs) were obtained via motor cortical transcranial magnetic stimulation (TMS), and F waves were obtained via ulnar nerve electrical stimulation. MEPs and F waves were examined: 1) when the muscle was at rest; 2) after the muscle had been active; and 3) after the muscle had been fatigued. MEPs were unaffected by muscarinic receptor blockade when measurements were recorded from resting muscle or following a 50% isometric maximal voluntary contraction (MVC). However, muscarinic receptor blockade increased MEP area following a 10-s MVC (P = 0.019) and following a fatiguing 60-s MVC (P = 0.040). F wave area and persistence were not affected by promethazine for any muscle contraction condition. Corticospinal excitability was influenced by cholinergic effects when voluntary drive to the muscle was high. Given that spinal motoneurone excitability remained unaffected, it is likely that cholinergic effects are influential within the motor cortex during strong muscle contractions. Future research should evaluate how cholinergic effects alter the relationship between subcortical structures and the motor cortex, as well as brainstem neuromodulatory pathways and spinal motoneurons.NEW & NOTEWORTHY The relationship between motor function and cholinergic circuitry in the central nervous system is complex. Although many studies have approached this issue at the cellular level, few studies have examined cholinergic mechanisms in humans performing muscle contractions. This study demonstrates that blockade of muscarinic acetylcholine receptors enhances motor evoked potentials (elicited with transcranial magnetic stimulation) following strong muscle contractions, but not weak muscle contractions.

Beyond the 'purple drank': Study of promethazine abuse according to the European Medicines Agency adverse drug reaction reports.

BACKGROUND: Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have however indicated that promethazine may have a misuse potential, especially in adolescents. OBJECTIVE: We here aimed at studying how this phenomenon has been reported to the European Monitoring Agency Adverse Drug Reactions database. METHODS: After a formal request to the European Monitoring Agency, the promethazine-specific dataset has been studied, performing a descriptive analysis of misuse/abuse/dependence-related adverse drug reaction reports. The study was approved by the University of Hertfordshire (LMS/PGR/UH/03234). RESULTS: The analysis of promethazine data showed increasing levels of misuse/abuse/ dependence issues over time (2003-2019). Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used. CONCLUSION: Anecdotal promethazine misuse/abuse reports have been confirmed by European Monitoring Agency data. Promethazine misuse/abuse appears to be an alarming issue, being associated with drug-related fatalities. Thus, healthcare professionals should be warned about a possible misuse of promethazine and be vigilant, as in some countries medicinal products containing promethazine can be purchased over the counter. Since promethazine is often available in association with opioids, its abuse may be considered a public health issue, with huge implications for clinical practice.

Promethazine and Oral Midazolam Preanesthetic Children Medication.

AIMS: Several kinds of drugs have been investigated in preschool children as a preanesthetic sedation after various routes of administration for surgeries. This study aims to compare the efficacy of promethazine and oral midazolam for premedication in children aged 3 to 9 years who were scheduled for surgeries. METHODS: This is a double-blind randomized controlled study conducted on 93 patients between the age of 3 and 9 years at Loresten University of Medical Sciences Teaching Hospital, Khoramabad, Iran. The subjects were grouped into P (promethazine), M (midazolam), and C (control). About 0.3 mg/kg of oral promethazine was administered to patients in group P, 0.5 mg/kg of oral midazolam was administered to patients in group M, and 3 mL of normal saline as placebo was administered to patients in group C. Patient satisfaction, sedation and emotional score, systolic blood pressure (SBP), diastolic blood pressure, respiratory rate (RR), and heart rate (HR) were recorded. RESULTS: There was no statistically significant difference among the 3 groups. However, the period after medication, it was observed that SBP, diastolic blood pressure, RR, and HR in group C were statistically significantly higher than those in groups M and P. These 2 groups are similar in terms of SBP, RR, and HR. The emotional scores were comparable for the 2 groups. It was between 3.97 ± 0.6 to 1.7 ± 0.5 in group M and from 3.45 ± 1.17 to 2.745 ± 0.997 in group P in a Kruskal-Wallis test. CONCLUSIONS: This study shows that both test groups reduce stress at the time of anesthetic induction and separation from their parents with similar effect. Both of the anesthetics are easily administered without the necessity of an additional equipment. A shorter period to maximal sedation for midazolam is an advantage, thus, making the drug helpful, mostly in the outpatient setting.

TCTP from Loxosceles Intermedia (Brown Spider) Venom Contributes to the Allergic and Inflammatory Response of Cutaneous Loxoscelism.

LiTCTP is a toxin from the Translationally Controlled Tumor Protein (TCTP) family identified in Loxosceles brown spider venoms. These proteins are known as histamine-releasing factors (HRF). TCTPs participate in allergic and anaphylactic reactions, which suggest their potential role as therapeutic targets. The histaminergic effect of TCTP is related to its pro-inflammatory functions. An initial characterization of LiTCTP in animal models showed that this toxin can increase the microvascular permeability of skin vessels and induce paw edema in a dose-dependent manner. We evaluated the role of LiTCTP in vitro and in vivo in the inflammatory and allergic aspects that undergo the biological responses observed in Loxoscelism, the clinical condition after an accident with Loxosceles spiders. Our results showed LiTCTP recombinant toxin (LiRecTCTP) as an essential synergistic factor for the dermonecrotic toxin actions (LiRecDT1, known as the main toxin in the pathophysiology of Loxoscelism), revealing its contribution to the exacerbated inflammatory response clinically observed in envenomated patients.

Promethazine inhibits neuronal apoptosis via PI3K/Akt signaling pathway in rats with cerebral infarction.

OBJECTIVE: To study the effect of promethazine on neuronal apoptosis in rats with cerebral infarction (CI) through the phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/Akt) signaling pathway. MATERIALS AND METHODS: A total of 36 Sprague-Dawley rats were randomly divided into the sham group (n=12), model group (n=12), and promethazine group (n=12). The external carotid artery was only exposed in the model group, and the ischemia-reperfusion model after CI was established using the suture method in the other two groups. After modeling, the normal saline was intraperitoneally injected in the sham group and model group, while promethazine was intraperitoneally injected in the promethazine group. The rats were sampled after 1 week of intervention. The neurological deficits of rats were evaluated using the Zea-Longa score, and the cognitive function, the spatial learning, and memory of rats were detected via the water maze test. Moreover, the expressions of B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in brain tissues were detected via immunohistochemistry, and the relative protein expressions of PI3K p85, PI3K p110, and p-Akt were detected via Western blotting. The mRNA expressions of Bax and Bcl-2 were detected via quantitative Polymerase Chain Reaction (qPCR), and the apoptosis was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. RESULTS: The Zea-Longa score was significantly increased in the model group and promethazine group compared with that in the sham group (p<0.05), while it significantly declined in the promethazine group compared with that in the model group (p<0.05). The escape latency was significantly prolonged and the times of crossing platform were significantly reduced in the model group and promethazine group compared with those in the sham group (p<0.05), while the escape latency was significantly shortened and the times of crossing platform were significantly increased in the promethazine group compared with those in the model group (p<0.05). Compared with those in the sham group, the positive expression of Bax was significantly increased, while the positive expression of Bcl-2 was remarkably decreased in the model group and promethazine group (p<0.05). Compared with those in the model group, the positive expression of Bax was significantly decreased, while the positive expression of Bcl-2 was remarkably increased in the promethazine group (p<0.05). Besides, the model group and promethazine group had evidently higher relative protein expressions of PI3K p85, PI3K p110, and p-Akt than the sham group (p<0.05), while the promethazine group also had evidently higher relative protein expressions of PI3K p85, PI3K p110, and p-Akt than the model group (p<0.05). Compared with the sham group, model group, and promethazine group had remarkably increased relative mRNA expression of Bax, and remarkably decreased relative mRNA expression of Bcl-2 (p<0.05). Compared with those in the model group, the relative mRNA expression of Bax was remarkably decreased, while the relative mRNA expression of Bcl-2 was remarkably increased in the promethazine group (p<0.05). Finally, the apoptosis rate was significantly higher in the model group and promethazine group than that in the sham group (p<0.05), while it was significantly lower in the promethazine group than that in the model group (p<0.05). CONCLUSIONS: Promethazine inhibits neuronal apoptosis in CI rats by upregulating the PI3K/Akt signaling pathway, thereby exerting a protective effect.

Low dose concomitant treatment with chlorpromazine and promethazine is safe in acute ischemic stroke.

BACKGROUND: Acute ischemic stroke (AIS) is associated with significant morbidity and mortality and has a very narrow window of treatment with fibrinolytics. We investigated the safety and efficacy of combined chlorpromazine and promethazine (C+P) treatment in AIS. METHODS: A total of 64 consecutive patients diagnosed with AIS were selected and were randomly (double-blind) assigned into either the control group (standard of care [SOC] treatment) or the treatment group (SOC+C+P [12.5+12.5 mg BID or 25+25 mg BID]) which were treated for 2 weeks. The National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) were computed prior to and after treatment to evaluate neurological deficits and daily functional status. RESULTS: In our study, 64 patients (males=81.3%) were divided into either the control (34 patients, 83.3% males, mean age=58.8±11.7 years) or the study group (30 patients, 79.4% males, mean age=62.3±9.1 years). While the NIHSS scores were not different between the control and treatment group at admission (P>0.05), a greater proportion of the cohort in both the groups (control group low NIHSS=79.4%, high NIHSS=20.6%, P<0.01) had a lower NIHSS at admission and (treatment group low NIHSS=83.3%, high NIHSS=16.7%, P<0.01). Interestingly, while both the control and treatment group had lower NIHSS and mRS scores at 90d post treatment compared to those at baseline, there were no significant differences in those scores between the two group (P>0.05) suggesting no improved benefit with C+P. Moreover, using C+P did not lead to any serious adverse effects when compared to the treatment group. CONCLUSIONS: While the addition of low dose chlorpromazine and promethazine to standard of care for acute ischemic stroke did not have any significant improvement in functional outcomes, there were no serious adverse effects. Thus, the use of chlorpromazine and promethazine in the acute ischemic stroke setting and future studies using higher doses of C+P are justified.

Luteinizing hormone signaling is involved in synchronization of Leydig cell's clock and is crucial for rhythm robustness of testosterone production†.

In mammals, circadian clock regulates concentration of many reproductive hormones including testosterone. Previously, we characterized pattern of circadian transcription of core clock genes in testosterone-producing Leydig cells. Here, the potential role of luteinizing hormone receptor (LHR)-cAMP signaling in synchronization of Leydig cell's circadian clock and rhythmic testosterone production were examined. Results showed that activation of LHR-cAMP signaling in primary rat Leydig cell culture increased Star/STAR and changed expression of many clock genes (upregulated Per1/PER1, Dec1/2, and Rorb, and downregulated Bmal1 and Rev-erba/b). Inhibition of protein kinase A prevented LHR-triggered increase in transcription of Per1 and Dec1. Effect of stimulated LHR-cAMP signaling on Leydig cell's clock transcription was also confirmed in vivo, using rats treated with single hCG injection. To analyze in vivo effect of low LH-cAMP activity on rhythmical Leydig cell function, rats with experimental hypogonadotropic hypogonadism were used. Characteristics of hypogonadal rats were decreased LH and testosterone secretion without circadian fluctuation; in Leydig cells decreased arrhythmic cAMP and transcription of steroidogenic genes (Cyp11a1 and Cyp17a1) were observed, while decreased Star/STAR expression retains circadian pattern. However, expression of clock genes, despite changes in transcription levels (increased Bmal1, Per2, Cry1, Cry2, Rora, Rorb, Rev-erba/b/REV-ERBB, Dec1, Csnk1e, and decreased Npas2 and PER1) kept circadian patterns observed in control groups. Altogether, the results strengthened the hypothesis about role of LH-cAMP signaling as synchronizer of Leydig cell's clock. However, clock in Leydig cells is not sufficient to sustain rhythmicity of testosterone production in absence of rhythmic activity of LH-cAMP signaling.

Does promethazine shorten the length of stay in the post anesthesia care unit?

The combination of promethazine and opioids is known to have an opioid-sparing effect, thereby facilitating a reduction in total patient opioid consumption. In recent years, this practice has fallen out of favor in many healthcare facilities, except primarily in the post anesthesia care unit (PACU). The goal of this study was to highlight the potential of promethazine as a direct or indirect adjuvant medication in acute pain management. The present investigation was undertaken with a case series of adult female patients who underwent open total abdominal hysterectomies. Data from the PACU was reviewed with patients being separated into two groups. Group 1 received only intravenous opioids for acute pain management. Group 2 received a combination of intravenous opioids for acute pain management and intravenous promethazine for nausea and/or vomiting. Patients were discharged from the PACU with a modified Aldrete score of 9 or 10. The study showed that patients who received promethazine in addition to opioids were discharged from the PACU an average of 19.2 minutes earlier than those patients who received only opioids (p=0.003). The time to achieve modified Aldrete score of 9 or higher was more quickly achieved when open abdominal hysterectomy patients received promethazine in addition to opioids in the PACU. The study concluded that promethazine, in combination with opioids, could potentially decrease PACU stay postoperatively. Based on the present investigation, the prospect of using promethazine in other facets of pain management are intriguing and warrant future studies. Specifically, it may be worth investigating whether promethazine is truly an adjunct in combination with opioids and to determine if there are any other antihistamines or neuroleptics which may have similar clinical effects to promethazine.

Digital gangrene induced by inadvertent intra-arterial cocktail injection of anesthetic agents such as pentazocine, promethazine, and atropine: A serious adverse drug experience.

Gangrenous changes in skin due to accidental intra-arterial injection of promethazine and pentazocine have been reported. Accidental intra-arterial injection is most commonly encountered in the antecubital fossa. However, recent reports in the radial and ulnar arteries have also been encountered. We hereby report a serious, preventable adverse drug experience in the form of digital gangrene induced by inadvertent intra-arterial cocktail injection of anesthetic agents such as pentazocine, promethazine, and atropine, which seems to be in the radial artery as the lateral three digits and dorsum of the hand are affected.

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children.

BACKGROUND: Paediatric neurodiagnostic investigations, including brain neuroimaging and electroencephalography (EEG), play an important role in the assessment of neurodevelopmental disorders. The use of an appropriate sedative agent is important to ensure the successful completion of the neurodiagnostic procedures, particularly in children, who are usually unable to remain still throughout the procedure. OBJECTIVES: To assess the effectiveness and adverse effects of chloral hydrate as a sedative agent for non-invasive neurodiagnostic procedures in children. SEARCH METHODS: We used the standard search strategy of the Cochrane Epilepsy Group. We searched MEDLINE (OVID SP) (1950 to July 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 7, 2017), Embase (1980 to July 2017), and the Cochrane Epilepsy Group Specialized Register (via CENTRAL) using a combination of keywords and MeSH headings. SELECTION CRITERIA: We included randomised controlled trials that assessed chloral hydrate agent against other sedative agent(s), non-drug agent(s), or placebo for children undergoing non-invasive neurodiagnostic procedures. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for their eligibility, extracted data, and assessed risk of bias. Results were expressed in terms of risk ratio (RR) for dichotomous data, mean difference (MD) for continuous data, with 95% confidence intervals (CIs). MAIN RESULTS: We included 13 studies with a total of 2390 children. The studies were all conducted in hospitals that provided neurodiagnostic services. Most studies assessed the proportion of sedation failure during the neurodiagnostic procedure, time for adequate sedation, and potential adverse effects associated with the sedative agent.The methodological quality of the included studies was mixed, as reflected by a wide variation in their 'Risk of bias' profiles. Blinding of the participants and personnel was not achieved in most of the included studies, and three of the 13 studies had high risk of bias for selective reporting. Evaluation of the efficacy of the sedative agents was also underpowered, with all the comparisons performed in single small studies.Children who received oral chloral hydrate had lower sedation failure when compared with oral promethazine (RR 0.11, 95% CI 0.01 to 0.82; 1 study, moderate-quality evidence). Children who received oral chloral hydrate had a higher risk of sedation failure after one dose compared to those who received intravenous pentobarbital (RR 4.33, 95% CI 1.35 to 13.89; 1 study, low-quality evidence), but after two doses there was no evidence of a significant difference between the two groups (RR 3.00, 95% CI 0.33 to 27.46; 1 study, very low-quality evidence). Children who received oral chloral hydrate appeared to have more sedation failure when compared with music therapy, but the quality of evidence was very low for this outcome (RR 17.00, 95% CI 2.37 to 122.14; 1 study). Sedation failure rates were similar between oral chloral hydrate, oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam.Children who received oral chloral hydrate had a shorter time to achieve adequate sedation when compared with those who received oral dexmedetomidine (MD -3.86, 95% CI -5.12 to -2.6; 1 study, moderate-quality evidence), oral hydroxyzine hydrochloride (MD -7.5, 95% CI -7.85 to -7.15; 1 study, moderate-quality evidence), oral promethazine (MD -12.11, 95% CI -18.48 to -5.74; 1 study, moderate-quality evidence), and rectal midazolam (MD -95.70, 95% CI -114.51 to -76.89; 1 study). However, children with oral chloral hydrate took longer to achieve adequate sedation when compared with intravenous pentobarbital (MD 19, 95% CI 16.61 to 21.39; 1 study, low-quality evidence) and intranasal midazolam (MD 12.83, 95% CI 7.22 to 18.44; 1 study, moderate-quality evidence).No data were available to assess the proportion of children with successful completion of neurodiagnostic procedure without interruption by the child awakening. Most trials did not assess adequate sedation as measured by specific validated scales, except in the comparison of chloral hydrate versus intranasal midazolam and oral promethazine.Compared to dexmedetomidine, chloral hydrate was associated with a higher risk of nausea and vomiting (RR 12.04 95% CI 1.58 to 91.96). No other adverse events were significantly associated with chloral hydrate (including behavioural change, oxygen desaturation) although there was an increased risk of adverse events overall (RR 7.66, 95% CI 1.78 to 32.91; 1 study, low-quality evidence). AUTHORS' CONCLUSIONS: The quality of evidence for the comparisons of oral chloral hydrate against several other methods of sedation was very variable. Oral chloral hydrate appears to have a lower sedation failure rate when compared with oral promethazine for children undergoing paediatric neurodiagnostic procedures. The sedation failure was similar for other comparisons such as oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam. When compared with intravenous pentobarbital and music therapy, oral chloral hydrate had a higher sedation failure rate. However, it must be noted that the evidence for the outcomes for the comparisons of oral chloral hydrate against intravenous pentobarbital and music therapy was of very low to low quality, therefore the corresponding findings should be interpreted with caution.Further research should determine the effects of oral chloral hydrate on major clinical outcomes such as successful completion of procedures, requirements for additional sedative agent, and degree of sedation measured using validated scales, which were rarely assessed in the studies included in this review. The safety profile of chloral hydrate should be studied further, especially the risk of major adverse effects such as bradycardia, hypotension, and oxygen desaturation.

Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke.

Physical hypothermia has long been considered a promising neuroprotective treatment of ischemic stroke, but the treatment's various complications along with the impractical duration and depth of therapy significantly narrow its clinical scope. In the present study, the model of reversible right middle cerebral artery occlusion (MCAO) for 2 h was used. We combined hypothermia (33-35 °C for 1 h) with phenothiazine neuroleptics (chlorpromazine & promethazine) as additive neuroprotectants, with the aim of augmenting its efficacy while only using mild temperatures. We also investigated its therapeutic effects on the Phosphatidylinositol 3 kinase/Protein kinase B (PI3K/Akt) apoptotic pathway. The combination treatment achieved reduction in ischemic rat temperatures in the rectum, cortex and striatum significantly (P < 0.01) faster than hypothermia alone, accompanied by more obvious (P < 0.01) reduction of brain infarct volume and neurological deficits. The combination treatment remarkably (P < 0.05) increased expression of p-Akt and anti-apoptotic proteins (Bcl-2 and Bcl-xL), while reduced expression of pro-apoptotic proteins (AIF and Bax). Finally, the treatment's neuroprotective effects were blocked by a p-Akt inhibitor. By combining hypothermia with phenothiazines, we significantly enhanced the neuroprotective effects of mild hypothermia. This study also sheds light on the possible molecular mechanism for these effects which involves the PI3K/Akt signaling and apoptotic pathway.

Neuroprotection by Chlorpromazine and Promethazine in Severe Transient and Permanent Ischemic Stroke.

Previous studies have demonstrated depressive or hibernation-like roles of phenothiazine neuroleptics [combined chlorpromazine and promethazine (C + P)] in brain activity. This ischemic stroke study aimed to establish neuroprotection by reducing oxidative stress and improving brain metabolism with post-ischemic C + P administration. Sprague-Dawley rats were subjected to transient (2 or 4 h) middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion, or permanent (28 h) MCAO without reperfusion. At 2 h after ischemia onset, rats received either an intraperitoneal (IP) injection of saline or two doses of C + P. Body temperatures, brain infarct volumes, and neurological deficits were examined. Oxidative metabolism and stress were determined by levels of ATP, NADH, and reactive oxygen species (ROS). Protein kinase C-δ (PKC-δ) and Akt expression were determined by Western blotting. C + P administration induced a neuroprotection in both transient and permanent ischemia models evidenced by significant reduction in infarct volumes and neurological deficits post-stroke. C + P induced a dose-dependent reduction in body temperature as early as 5 min post-ischemia and lasted up to 12 h. However, reduction in body temperature either only slightly or did not enhance C + P-induced neuroprotection. C + P therapy improved brain metabolism as determined by increased ATP levels and NADH activity, as well as decreased ROS production. These therapeutic effects were associated with alterations in PKC-δ and Akt protein expression. C + P treatments conferred neuroprotection in severe stroke models by suppressing the damaging cascade of metabolic events, most likely independent of drug-induced hypothermia. These findings further prove the clinical potential for C + P treatment and may direct us closer towards the development of an efficacious neuroprotective therapy.

Angio-oedema associated with colistin.

A 50-year-old woman known to have type 1 diabetes mellitus presented with a rare case of angio-oedema associated with colistin use. The angio-oedema was temporally associated with the use and discontinuation of colistin with the reasonable exclusion of important differential diagnoses. Pseudoallergy may be a probable underlying mechanism. However, we cannot exclude the possibility of hereditary angio-oedema type 2 or 3, or that her concomitant medications (particularly enalapril) and her renal impairment contributed to the risk and severity of her angio-oedema.

Histamine Receptor 1 and 2 Antagonists Alter Biodistribution of Radioiodine.

UNLABELLED: Nuclear medicine technology assumes responsibility for examination-specific patient preparation procedures. This requires a clear understanding of the possible effects of medications on the outcome of examinations. There is evidence that common over-the-counter drugs, histamine 1 (H1) and histamine 2 (H2) receptor blockers and proton pump inhibitors, may directly or indirectly affect thyroid function. The objective was to determine whether short-term use of these drugs alters biodistribution of radioiodine in a rat model. METHODS: Rats received no drug (controls) or daily subcutaneous injections of H1 blocker (promethazine), H2 blocker (famotidine), or proton pump inhibitor (esomeprazole) commencing 1 d before a single intraperitoneal injection of 0.037 MBq (1 µCi) of (131)I (NaI) and continuing daily until euthanasia at either 1 d or 8 d after (131)I. Organ uptake of (131)I by control and drug-treated rats was compared by γ-well counting. RESULTS: Promethazine significantly increased uptake of (131)I by the thyroid (drug-treated-to-control ratios) both at 1 d (1.32) and 8 d (1.52) after (131)I. Both famotidine and promethazine (respectively) significantly increased salivary gland uptake of (131)I (drug-treated-to-control ratios) at 1 d (1.37, 1.40) and 8 d (4.52, 5.57) after (131)I. Promethazine significantly increased gastric (131)I uptake (drug-treated-to-control ratios) at 1 d (1.47) and 8 d (1.46) after (131)I. Famotidine and promethazine (respectively) significantly decreased uptake of (131)I by the liver (drug-treated-to-control ratios) at 1 d (0.60, 0.71) after (131)I but resulted in a marked increase over control levels (11.21, 9.28) at 8 d. Blood levels of (131)I were not altered by drug treatment. Esomeprazole did not affect radioiodine distribution. CONCLUSION: H1 and H2 blockers alter the biodistribution of radioiodine in the rat. Although the findings remain to be confirmed in humans, these drugs could increase radiation exposure to nontarget tissues, particularly the stomach and salivary tissue, during (131)I therapy and consideration should be given toward avoiding the elective use of these drugs during radioiodine therapy.

Gluteal abscess and bacteremia following promethazine injection in a Marine.

Intramuscular injection is routinely used and rarely leads to adverse events such as abscess or tissue necrosis. Intramuscular promethazine has been documented to cause these problems. We discuss the case of a previously healthy 19-year-old U.S. Marine, who was diagnosed with methicillin sensitive Staphylococcus aureus bacteremia and abscess formation after receiving intramuscular promethazine for vomiting. After confirmation of abscess formation via magnetic resonance imaging, he underwent percutaneous drainage. He improved and was treated with 6 weeks of cefazolin. This case demonstrates an unusual and severe adverse reaction associated with intramuscular promethazine administration. Additionally, this case highlights the importance of proper antiseptic technique before promethazine administration and calls into question the utility and safety of intramuscular promethazine when oral dissolving antiemetic medications are available.

A comparison of two differing doses of promethazine for the treatment of postoperative nausea and vomiting.

PURPOSE: To compare the use of promethazine 6.25 mg intravenous (IV) (experimental group) with promethazine 12.5 mg IV (control group) among adult ambulatory surgery patients to control established postoperative nausea or vomiting (PONV). DESIGN/METHODS: In a double-blind, randomized controlled trial (n = 120), 59 subjects received promethazine 6.25 mg and 61 subjects received promethazine 12.5 mg to treat PONV. Study doses were administered postoperatively if the subject reported/exhibited nausea and/or vomiting. Outcomes for experimental and control groups were compared on the basis of relief of PONV and sedation levels. FINDINGS: Ninety-seven percent of subjects reported total relief of nausea with a single administration of promethazine at either dose. Sedation levels differed between groups at 30 minutes post-medication administration and at the time of discharge to home. CONCLUSIONS: Promethazine 6.25 mg is as effective in controlling PONV as promethazine 12.5 mg, while resulting in less sedation.

Drowsiness and motor responses to consecutive daily doses of promethazine and loratadine.

OBJECTIVES: Limited information is available regarding sedation and motor function following repeat dosing of antihistamines. This study examined how promethazine and loratadine affect day-time drowsiness, the commencement of voluntary movement, and involuntary movement when administered on consecutive days. METHODS: Ten healthy young subjects (24±5years) were recruited into a double-blind, placebo-controlled, three-way crossover study. Subjects ingested either promethazine, loratadine or a placebo, and ingested the same drug 24h later. Measures of drowsiness, simple reaction time (SRT), choice reaction time (CRT), and postural tremor were obtained pre-ingestion, 1h post-ingestion and 2h post-ingestion on each day. RESULTS: Consecutive daily doses of promethazine and loratadine affected SRT and CRT, respectively, whereby reaction time deficits were less pronounced following the repeat dose. A reduced tremor response was also observed following consecutive daily dosing of promethazine, in contrast to loratadine which caused an increase in tremor amplitude with the consecutive daily dose. CONCLUSIONS: Reaction time and tremor responses differed following the single dose compared to consecutive doses. SIGNIFICANCE: Sufferers of allergic rhinitis often require antihistamine dosing regimens that continue over multiple days. Future studies will benefit from examining drowsiness and movement responses following single doses as well as consecutive dosing.

Chloral hydrate, chloral hydrate--promethazine and chloral hydrate -hydroxyzine efficacy in electroencephalography sedation.

OBJECTIVE: To compare efficacy and safety of chloral hydrate (CH), chloral hydrate and promethazine (CH + P) and chloral hydrate and hydroxyzine (CH + H) in electroencephalography (EEG) sedation. METHODS: In a parallel single-blinded randomized clinical trial, ninety 1-7 y-old uncooperative kids who were referred to Pediatric Neurology Clinic of Shahid Sadoughi University, Yazd, Iran from April through August 2012, were randomly assigned to receive 40 mg/kg of chloral hydrate or 40 mg/kg of chloral hydrate and 1 mg/kg of promethazine or 40 mg/kg of chloral hydrate and 2 mg/kg of hydroxyzine. The primary endpoint was efficacy in sufficient sedation (obtaining four Ramsay sedation score) and successful completion of EEG. Secondary endpoint was clinical adverse events. RESULTS: Thirty nine girls (43.3 %) and 51 boys (56.7 %) with mean age of 3.34 ± 1.47 y were assessed. Sufficient sedation and completion of EEG were achieved in 70 % (N = 21) of chloral hydrate group, in 83.3 % (N = 25) of CH + H group and in 96.7 % (N = 29) of CH + P group (p = 0.02). Mild clinical adverse events including vomiting [16.7 % (N = 5) in CH, 6.7 % (N = 2) in CH + P, 6.7 % (N = 2) in CH + H], agitation in 3.3 % of CH + P (N = 1) group and mild transient hypotension in 3.3 % of CH + H (N = 1) group occurred. Safety of these three sedation regimens was not statistically significant different (p = 0.14). CONCLUSIONS: Combination of chloral hydrate-antihistamines can be used as the most effective and safe sedation regimen in drug induced sleep electroencephalography of kids.