Reevaluating the nicotine delivery kinetics hypothesis

Rationale

The view of smoking as an addiction to nicotine implies that nicotine is an addictive drug and a primary reinforcer. However, nicotine other than in tobacco does not appear to be very rewarding for smokers. This potential anomaly to the nicotine addiction thesis is resolved by the proposition that the reward associated with smoking depends on “high-nicotine boli.” According to the nicotine delivery kinetics hypothesis, smoked nicotine reaches the brain in 5–10 s in high concentrations, which provide reinforcing “hits” of nicotine to the brain.

Objectives

Because of its essential role in the nicotine addiction thesis, this review set out to examine the current empirical basis of the nicotine delivery kinetics hypothesis.

Materials and methods

We reviewed studies that bear on two questions: First, does nicotine from cigarettes reach the brain significantly faster than from other nicotine delivery devices? Second, is there a relationship between delivery kinetics and any rewarding effects of nicotine?

Results

There is little empirical support for the nicotine delivery kinetics hypothesis. Several studies found that arterial nicotine levels associated with smoking are much lower than predicted by the nicotine delivery kinetics thesis and not higher than with other nicotine delivery devices. More importantly, comparisons of nicotine delivery devices with varying speeds of delivery do not suggest any correlation between nicotine delivery profile and subjective reward.

Conclusions

This review indicates that the wide endorsement of the nicotine delivery kinetics hypothesis is unjustified. Critical research is required to resolve the anomalies within the nicotine addiction theory of smoking.

     

Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study

Rationale

The behavioral effects of nicotine and the role of the beta2-containing nicotinic receptors in these behaviors are well documented. However, the behaviors altered by nicotine rely on the functioning on multiple brain circuits where the high-affinity beta2-containing nicotinic receptors (β2*nAChRs) are located.

Objectives

We intend to see which brain circuits are activated when nicotine is given in animals naïve for nicotine and whether the β2*nAChRs are needed for its activation of the blood oxygen level dependent (BOLD) signal in all brain areas.

Materials and methods

We used functional magnetic resonance imaging (fMRI) to measure the brain activation evoked by nicotine (1 mg/kg delivered at a slow rate for 45 min) in anesthetized C57BL/6J mice and beta2 knockout (KO) mice.

Results

Acute nicotine injection results in a significant increased activation in anterior frontal, motor, and somatosensory cortices and in the ventral tegmental area and the substantia nigra. Anesthetized mice receiving no nicotine injection exhibited a major decreased activation in all cortical and subcortical structures, likely due to prolonged anesthesia. At a global level, beta2 KO mice were not rescued from the globally declining BOLD signal. However, nicotine still activated regions of a meso-cortico-limbic circuit likely via alpha7 nicotinic receptors.

Conclusions

Acute nicotine exposure compensates for the drop in brain activation due to anesthesia through the meso-cortico-limbic network via the action of nicotine on β2*nAChRs. The developed fMRI method is suitable for comparing responses in wild-type and mutant mice.

     

Real-Time UV Imaging of Nicotine Release from Transdermal Patch

Purpose

This study was conducted to characterize UV imaging as a platform for performing in vitro release studies using Nicorette® nicotine patches as a model drug delivery system.

Methods

The rate of nicotine release from 2 mm diameter patch samples (Nicorette®) into 0.067 M phosphate buffer, pH 7.40, was studied by UV imaging (Actipix SDI300 dissolution imaging system) at 254 nm. The release rates were compared to those obtained using the paddle-over-disk method.

Results

Calibration curves were successfully established which allowed temporally and spatially resolved quantification of nicotine. Release profiles obtained from UV imaging were in qualitative agreement with results from the paddle-over-disk release method.

Conclusion

Visualization as well as quantification of nicotine concentration gradients was achieved by UV imaging in real time. UV imaging has the potential to become an important technology platform for conducting in vitro drug release studies.

     

Adjunctive Use of Ketamine for Benzodiazepine-Resistant Severe Alcohol Withdrawal: a Retrospective Evaluation

Introduction

Benzodiazepine (BZD)-resistant alcohol withdrawal remains a challenge for most institutions due to limited evidence with available agents. One published study currently exists utilizing the N-methyl-d-aspartate antagonist, ketamine, for alcohol withdrawal.

Objective

The purpose of our study was to evaluate the effect of adjunctive ketamine continuous infusion on symptom control and lorazepam infusion requirements for BZD-resistant alcohol withdrawal patients in the intensive care unit.

Methods

A retrospective review was conducted of patients receiving ketamine adjunctively with a lorazepam infusion for severe alcohol withdrawal between August 2012 and August 2014. Outcomes included time to symptom control, lorazepam infusion requirements, ketamine initial and maximum daily infusion rates, and adverse effects of ketamine.

Results

Thirty patients were included in the analysis. Mean time to initiation of ketamine after the initiation of a lorazepam infusion was 41.4 h. All patients achieved initial symptom control within 1 h of ketamine initiation. Median initial ketamine infusion rate was 0.75 mg/kg/h and the average maximum daily rate was 1.6 mg/kg/h. Significant decreases in lorazepam infusion rates from baseline were observed at 24 h (??4 mg/h; p?=?0.01) after ketamine initiation. No patients experienced documented CNS adverse effects. Two patients experienced hypertension and no patients experienced tachycardia related to ketamine.

Conclusion

Adjunctive ketamine could provide symptom control for BZD-refractory patients and may potentially reduce lorazepam infusion requirements. Future studies to determine optimal dosing, timing of initiation, and place in therapy for BZD-resistant alcohol withdrawal are needed. The mechanism of action via the NMDA receptor with ketamine may provide benefit for BZD-resistant alcohol withdrawal.

     

Prevalence of Use of Electronic Nicotine Delivery Systems (ENDS) to Vape Recreational Drugs by Club Patrons in South London

Introduction

Electronic nicotine delivery systems (ENDS, often called e-cigarettes) are nicotine delivery devices that heat nicotine into vapour that is inhaled, a process called ‘vaping’. Use eclipsed nicotine-replacement therapy (NRT) in 2014 but ENDS role in smoking cessation remains controversial. Safety has not been proven and there have been reports to US poison centres regarding potential ENDS-related nicotine toxicity. A further concern is use of ENDS to vape recreational drugs, but there is limited data to substantiate this. The aim of this study was to report on ENDS use to vape recreational drugs in patrons of a South London nightclub where high prevalence of recreational drug use has previously been shown.

Methods

A convenience sample of 101 participants was surveyed in March 2015 as part of a larger survey on drug use. Individuals were asked if they used ENDS to vape nicotine and/or other substances (and if so which substances).

Results

Ninety (89.1 %) of respondents were male with median age of 28 years (IQR 23–34). Eighty (79.2 %) currently smoked cigarettes; 20 (19.8 %) currently used ENDS for nicotine. Six (5.9 %) reported using ENDS to take other substances: 2 for ‘liquid cannabis’ and 4 did not elaborate on the substance(s) used. Of these 6, 3 were using ENDS to vape nicotine and 3 had never used them for nicotine.

Conclusion

5.9 % of individuals in this sample reported using ENDS to vape substances other than nicotine. Further work is required in larger populations to determine how common this is, evaluate which agents are being vaped and to inform appropriate public education.

     

Reversal of Opioid-Induced Ventilatory Depression Using Low-Dose Naloxone (0.04 mg): a Case Series

Introduction

Naloxone is commonly administered in emergency department (ED) to reverse opioid intoxication. Several naloxone dose recommendations exist for acute management of opioid intoxication based on limited published clinical data. A case series of ED patients with opioid-induced ventilatory depression that was reversed using a low-dose naloxone (0.04 mg with titration) is presented.

Methods

ED patients with opioid-induced ventilatory depression requiring naloxone administration were identified through medical toxicology consultation. Retrospective review of medical records was performed. Collected data included history, and pre- and post-naloxone data, including respiratory rate (RR), pulse oximetry (pulse ox), end-tidal CO₂ level (ET-CO₂), and Richmond Agitation Sedation Scale (RASS).

Results

Fifteen ED patients with moderate to severe opioid-induced ventilatory depression (median RR, 6 breaths/min) who were managed using low-dose naloxone strategy were identified. Twelve of 15 patients reported ingestion of methadone (range, 30 to 180 mg). The median naloxone dose of 0.08 mg (range, 0.04 to 0.12 mg) reversed opioid-induced ventilatory and CNS depression. Two patients experienced acute opioid withdrawal after receiving 0.08 mg.

Conclusion

ED patients with moderate to severe opioid-induced ventilatory depression can be reversed using 0.04 mg IV naloxone with appropriate dose titration.

     

Atorvastatin attenuates TNBS-induced rat colitis: the involvement of the TLR4/NF-kB signaling pathway

Aim

The aim of the present study is to explore whether atorvastatin improves intestinal inflammation through the inhibition of the TLR4/NFkB signaling pathway in TNBS-induced rat colitis.

Methods

Acute colitis was induced by intra-rectal administration of 100 mg/kg TNBS dissolved in 0.25 ml of 50 % ethanol. Twenty four hours after colitis induction, saline, atorvastatin (20 and 40 mg/kg) and sulfasalazine (100 mg/kg) were given to the animals by oral route. This was repeated daily for 1 week. Body weight changes, macroscopic and microscopic lesions were assessed. MPO and TNF-α activities were detected by immunohistochemistry (IHC) and the expression level of TLR4, MyD88 and NF-κB p65 proteins were measured by western blotting analysis.

Results

Atorvastatin and sulfasalazine reduced the body weight loss, macroscopic and microscopic lesions. Additionally, both drugs decreased the expression of MPO and TNF-α positive cells in the colon tissue. Furthermore, they inhibited the TNBS-induced expression of TLR4, MyD88 and NF-κB p65 proteins.

Conclusions

It is suggested that the anti-inflammatory effect of atorvastatin on TNBS-induced rat colitis may involve the inhibition of the TLR4/NFkB signaling pathway.

     

Safety,Stability and Pharmacokinetic Properties of <Superscript>super</Superscript>Factor Va,a Novel Engineered Coagulation Factor V for Treatment of Severe Bleeding

Purpose

Activated ^superFactor V (^superFVa) is a novel engineered FV with excellent prohemostatic efficacy. ^SuperFVa has three APC cleavage site mutations and an interdomain disulfide bond. Stability, pharmacokinetics, and immunogenic and thrombogenic potential are reported here.

Methods

Stability and circulating half-life were determined after incubation in buffer and human plasma, and after injection into FVIII-deficient mice. Immunogenicity potential was assessed by B- and T-cell specific epitope prediction and structural analysis using surface area and atomic depth computation. Thrombogenic potential was determined by quantification of lung fibrin deposition in wild-type mice after intravenous injection of ^superFVa (200 U/kg), recombinant human (rh) Tissue Factor (0.4–16 pmol/kg), rhFVIIa (3 mg/kg) or saline.

Results

FVa retained full activity over 30 h in buffer, the functional half-life in human plasma was 4.9 h, and circulating half-life in FVIII-deficient mice was ~30 min. Predicted immunogenicity was not increased compared to human FV. While rh Tissue Factor, the positive control, resulted in pronounced lung fibrin depositions (mean 121 μg/mL), ^superFVa did not (6.7 μg/mL), and results were comparable to fibrin depositions with rhFVIIa (7.6 μg/mL) or saline (5.6 μg/mL).

Conclusion

FVa has an appropriate safety and stability profile for further preclinical development as a prohemostatic against severe bleeding.

     

The effects of buprenorphine on fentanyl withdrawal in rats

Rationale

Fentanyl is a potent mu-opioid receptor agonist that is widely used for the treatment of severe chronic pain. Discontinuation of fentanyl administration has been shown to induce a negative emotional state.

Objectives

The aim of the present studies was to investigate the effects of the partial mu-opioid receptor agonist buprenorphine on the negative emotional state associated with precipitated and spontaneous fentanyl withdrawal in rats.

Materials and methods

Fentanyl and saline were chronically administered via osmotic minipumps. A discrete-trial intracranial self-stimulation procedure was used to provide a measure of brain reward function. Somatic signs were recorded from a checklist of opioid abstinence signs.

Results

Naloxone induced a deficit in brain reward function in rats chronically treated with fentanyl. Buprenorphine dose-dependently prevented the naloxone-induced deficit in brain reward function. Discontinuation of fentanyl administration was also associated with a deficit in brain reward function. After explantation of the minipumps, the administration of buprenorphine induced a potentiation of brain reward function in the fentanyl-withdrawing rats, but did not affect brain reward function of saline-treated control rats. Buprenorphine prevented the somatic withdrawal signs associated with spontaneous fentanyl withdrawal and attenuated the somatic signs associated with precipitated fentanyl withdrawal.

Conclusions

Buprenorphine prevents affective and somatic fentanyl withdrawal signs. Moreover, buprenorphine is rewarding in rats previously exposed to fentanyl, but not in opioid-naïve rats. This pattern of results suggests that buprenorphine may be an effective treatment for the anhedonic-state associated with fentanyl withdrawal, but further study of buprenorphine’s abuse potential is warranted.

     

Dinitrophenol (DNP) Fatality Associated with a Falsely Elevated Salicylate Level: a Case Report with Verification of Laboratory Cross Reactivity

Introduction

2,4-Dinitrophenol (DNP) is a known uncoupler of oxidative phosphorylation that clinically leads to hyperthermia, tachycardia, tachypnea, and metabolic acidosis. Intentional overdoses of DNP are often fatal. We present an analytically confirmed fatal case of DNP overdose with a falsely positive elevated salicylate concentration. We further explored this cross reactivity of DNP with two salicylate assays.

Methods

Clinically relevant serial dilutions of DNP were prepared in drug-free serum and analyzed using two different colorimetric NADH/NAD-based analytical methodologies.

Results

The enzymatic salicylate assay demonstrated a reproducible false elevation of salicylate starting at a DNP level of 100 mg/L while the EMIT-based methodology was without any such interference at the maximum concentration tested (150 mg/L).

Conclusions

DNP cross reacts with some salicylate assays. This knowledge is important for providers, as there are significant variations in the management of DNP versus salicylate toxicity.

     

Synthesis and In Vitro Evaluation of Polyethylene Glycol-Paclitaxel Conjugates for Lung Cancer Therapy

Purpose

Pulmonary drug delivery is considered an attractive route of drug administration for lung cancer chemotherapy. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lung. Therefore, achieving a sustained presence of chemotherapeutics in the lung is very challenging. In this study, we synthesized two different polyethylene glycol-paclitaxel ester conjugates with molecular weights of 6 and 20 kDa in order to achieve sustained release of paclitaxel in the lung.

Methods

One structure was synthesized with azide linker using “click” chemistry and the other structure was synthesized with a succinic spacer. The physicochemical and biological properties of the conjugates were characterized in vitro.

Results

Conjugation to polyethylene glycol improved the solubility of paclitaxel by up to four orders of magnitude. The conjugates showed good stability in phosphate buffer saline pH 6.9 (half-life ≥72 h) and in bronchoalveolar lavage (half-life of 3 to 9 h) at both molecular weights, but hydrolyzed quickly in mouse serum (half-life of 1 to 3 h). The conjugates showed cytotoxicity to B16-F10 melanoma cells and LL/2 Lewis lung cancer cells but less than free paclitaxel or Taxol, the commercial paclitaxel formulation.

Conclusions

These properties imply that the conjugates have the potential to retain paclitaxel in the lung for a prolonged duration and to sustain its release locally for a better efficacy.

     

Drug Interaction Between Clopidogrel and Ranitidine or Omeprazole in Stable Coronary Artery Disease: A Double-Blind,Double Dummy,Randomized Study

Background

Proton-pump inhibitors (PPIs) are often prescribed to patients receiving dual antiplatelet therapy (DAPT). However, this class of medication, especially omeprazole, has been associated with a reduction in clopidogrel efficacy, leading many clinicians to substitute omeprazole with ranitidine.

Objectives

Our objective was to compare the antiplatelet effect of clopidogrel before and after the addition of omeprazole or ranitidine.

Methods

We measured platelet aggregability at baseline and after 1 week of clopidogrel 75 mg daily. Subjects were then randomized in a double-blinded, double-dummy fashion to omeprazole 20 mg twice daily (bid) or ranitidine 150 mg bid. We repeated aggregability tests after 1 additional week, using VerifyNow P2Y12? (Accumetrics; San Diego, CA, USA), depicting aggregability as percent inhibition of platelet aggregation (IPA).

Results

We enrolled 41 patients in the omeprazole group and 44 in the ranitidine group. IPA was significantly decreased after the addition of omeprazole to clopidogrel (from 26.3 ± 32.9 to 17.4 ± 33.1 %; p = 0.025), with no statistical significant changes observed in the ranitidine group (from 32.6 ± 28.9 to 30.1 ± 31.3 %; p = 0.310). The comparison of IPA in both groups at the end of the follow-up showed a trend toward significance (p = 0.07, 95 % confidence interval [CI] ?1.19 to 26.59); after excluding homozygous patients for 2C19*2 genotype, the comparison of IPA between the groups reached statistical significance (32.7 ± 30.8 vs. 17.7 ± 33.4 %, respectively, for ranitidine and omeprazole groups; p = 0.04).

Conclusions

Unlike omeprazole, ranitidine did not influence platelet aggregability response to clopidogrel.

Clinical Trial Registration

NCT01896557.

     

Blood Urea Nitrogen/Creatinine Ratio and Response to Tolvaptan in Patients with Decompensated Heart Failure: A Retrospective Analysis

Introduction

Arginine vasopressin-stimulated reabsorption of urea occurs in the collecting duct via increased expression of the urea transporter.

Objective

The aim of this study was to evaluate whether the blood urea nitrogen/creatinine (BUN/Cr) ratio is useful for predicting tolvaptan response in patients with decompensated heart failure (HF).

Methods

Among 71 consecutive patients with HF who received oral tolvaptan between 2010 and 2014, we retrospectively studied 33 patients with decompensated HF without any mechanical circulatory assistance or inotropic support who had already been treated with loop diuretics. A responder to tolvaptan was defined as an individual who experienced a ≥30 % increase in their respective 24-h urine volume.

Results

Among the 33 patients, 21 met the criteria of a responder. The area under the receiver operating characteristic curves of BUN/Cr and BUN were 0.790 and 0.714, respectively, and the respective cut-off values for responders to tolvaptan were 23.8 and 49.0. BUN/Cr and BUN retained their significant relationships with the responder status (odds ratio for BUN/Cr >23.8: 20.9; 95 % confidence interval [CI] 2.7–531.1; p = 0.002; odds ratio for BUN ≥49: 7.7; 95 % CI 1.4–65.8; p = 0.02).

Conclusion

Our results suggest that high BUN/Cr may be a predictor of response to tolvaptan in decompensated HF patients. A prospective study with a large sample size is required to confirm this preliminary finding.

     

Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness

Rationale

Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.

Objectives

The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs.

Methods

Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA).

Results

Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine.

Conclusions

These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence.

Highlights

? Topiramate increases the rewarding properties of cocaine in CPP? Topiramate alters dopaminergic signaling in the mesolimbic circuit? Topiramate delays the extinction of cocaine-induced CPP? TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine? Results show that it should limit the use of topiramate in cocaine-dependent subjects

     

On the Road to Development of an <Emphasis Type="BoldItalic">in Vitro</Emphasis> Permeation Test (IVPT) Model to Compare Heat Effects on Transdermal Delivery Systems: Exploratory Studies with Nicotine and Fentanyl

Purpose

At elevated temperatures, the rate of drug release and skin permeation from transdermal delivery systems (TDS) may be higher than at a normal skin temperature. The aim of this study was to compare the effect of heat on the transdermal delivery of two model drugs, nicotine and fentanyl, from matrix-type TDSs with different formulations, using in vitro permeation tests (IVPT).

Methods

IVPT experiments using pig skin were performed on two nicotine and three fentanyl TDSs. Both continuous and transient heat exposures were investigated by applying heat either for the maximum recommended TDS wear duration or for short duration.

Results

Continuous heat exposure for the two nicotine TDSs resulted in different effects, showing a prolonged heat effect for one product but not the other. The J_max enhancement ratio due to the continuous heat effect was comparable between the two nicotine TDS, but significantly different (p < 0.05) among the three fentanyl TDSs. The J_max enhancement ratios due to transient heat exposure were significantly different for the two nicotine TDSs, but not for the three fentanyl TDSs. Furthermore, the transient heat exposure affected the clearance of drug from the skin depot after TDS removal differently for two drugs, with fentanyl exhibiting a longer heat effect.

Conclusions

This exploratory work suggests that an IVPT study may be able to discriminate differences in transdermal drug delivery when different TDS are exposed to elevated temperatures. However, the clinical significance of IVPT heat effects studies should be further explored by conducting in vivo clinical studies with similar study designs.

     

Effect of Permeation Enhancers on the Buccal Permeability of Nicotine: <Emphasis Type="BoldItalic">Ex vivo</Emphasis> Transport Studies Complemented by MALDI MS Imaging

Purpose

The purpose of this study was to assess the effect of several chemical permeation enhancers on the buccal permeability of nicotine and to image the spatial distribution of nicotine in buccal mucosa with and without buccal permeation enhancers.

Methods

The impact of sodium taurodeoxycholate (STDC), sodium dodecyl sulphate (SDS), dimethyl sulfoxide (DMSO) and Azone® on the permeability of [³H]-nicotine and [¹⁴C]-mannitol (a paracellular marker) across porcine buccal mucosa was studied ex vivo in modified Ussing chambers. The distribution of nicotine, mannitol and permeation enhancers was imaged using using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI).

Results

Despite STDC significantly increasing permeability of [¹⁴C]-mannitol, no enhancing effect was seen on [³H]-nicotine permeability with any of the permeation enhancers. Rather, SDS and DMSO retarded nicotine permeability, likely due to nicotine being retained in the donor compartment. The permeability results were complemented by the spatial distribution of nicotine and mannitol determined with MALDI MSI.

Conclusions

The buccal permeability of nicotine was affected in an enhancer specific manner, suggesting that nicotine primarily diffuses via the transcellular pathway. MALDI MSI was shown to complement ex vivo permeability studies and to be a useful qualitative tool for visualizing drug and penetration enhancer distribution in buccal mucosa.

     

Effect of Nanoparticle Surface on the HPLC Elution Profile of Liposomal Nanoparticles

Purpose

Nanoparticles have been used in diverse areas, and even broader applications are expected in the future. Since surface modification can influence the configuration and toxicity of nanoparticles, a rapid screening method is important to ensure nanoparticle quality.

Methods

We examined the effect of the nanoparticle surface morphology on the HPLC elution profile using two types of 100-nm liposomal nanoparticles (AmBisome^? and DOXIL^?).

Results

These 100-nm-sized nanoparticles eluted before the holdup time (about 4 min), even when a column packed with particles with a relatively large pore size (30 nm) was used. The elution time of the nanoparticles increased with pegylation of the nanoparticles and protein adsorption to the nanoparticles; however, the nanoparticles still eluted before the holdup time.

Conclusions

The results of this study indicate that HPLC is a suitable tool for rapid evaluation of the surface of liposomal nanoparticles.

     

A Retrospective Study of Clinical Effects of Powdered Caffeine Exposures Reported to Three US Poison Control Centers

Introduction

Anhydrous caffeine, often sold on the Internet as a powdered caffeine product, is sold as “pure caffeine” to be used as an additive to beverages and has also been used as an ingredient in energy supplement products.

Methods

This is a retrospective multiple-poison center chart review of calls regarding powdered caffeine to poison centers covering Oregon, Alaska, Guam, Washington, and Utah between January 1, 2013 and June 30, 2015.

Results

There were 40 calls to three poison centers over 30 months for powdered caffeine exposure. The majority of patients were over age 19 (52.5 %; 21/40) and male (70 %; 28/40). Sixty percent (24/40) of the patients were symptomatic but only 10 % (4/40) required admission; 52.5 % (21/40) of the patient calls were for inadvertent overdose of powdered caffeine; one patient overdosed in a self-harm attempt.

Discussion

Powdered caffeine calls to three poison centers during a 30-month study period were rare, and severe caffeine toxicity due to exposure was found in few patients. The majority of symptoms were reported after an inadvertent powdered caffeine overdose.

Conclusions

An analysis of calls to three poison centers for powdered caffeine found that exposures were uncommon, but did result in toxicity, and highlighted that the lack of clear dosing instructions on product packaging may place patients at risk of inadvertent overdose.

     

Modern Intermittent Haemodialysis (IHD) is an Effective Method of Removing Salicylate in Chronic Topical Salicylate Toxicity

Introduction

There are limited data on modern intermittent hemodialysis (IHD) efficacy on salicylate elimination from topical poisoning.

Case report

A 54-year-old male sought treatment for dyspnea but was then diagnosed with salicylate toxicity from topical application of Dencorub Extra Strength Heat Gel® for 1 week. Each tube contained 100 g with 26 % methylsalicylate (26 g). Laboratory workup was remarkable for an elevated anion gap of 30 and salicylate concentration of 78.7 mg/dL [5.7 mmol/L (N?<?0.4 mmol/L)]. Treatment with urinary alkalinization was followed by hemodialysis for 5 h. Extraction ratios were 0.44 with clearance rates of 78.5 mL/min. Salicylate concentrations fell rapidly following initiation of hemodialysis with no rebound observed.

Discussion

Modern high flux IHD is an effective method of removing salicylates in the treatment of chronic topical poisoning.