Quinine Exposure Research Articles

P0578QUININE EXPOSURE AND THE RISK OF ACUTE KIDNEY INJURY: A POPULATION BASED OBSERVATIONAL STUDY OF OLDER PEOPLE

Abstract Background and Aims Quinine can precipitate Acute Kidney Injury (AKI) by immune-mediated reactions. Cramps, for which quinine is traditionally prescribed, may be a symptom of conditions that are risk factors for AKI. The relationship between quinine and AKI at a population level is unclear. The aim of this study was to establish and quantify any observable association between the exposure to community prescriptions for quinine and AKI events in a population of older adults. Method We performed two observational studies of older adults (60+ years) who received quinine prescriptions in Tayside, Scotland, between January 2004 and December 2015. The first study was a retrospective longitudinal cohort study with the primary outcome AKI. Creatinine measurements less than seven days apart were grouped as episodes of care. Multivariable logistic regression was used to calculate odds ratios (OR) for AKI comparing between episodes with and without recent quinine exposure after adjustment for demographics, comorbidities and concomitant medications. A self-controlled case series (SCCS) was then conducted with follow-up divided into periods “on” and “off” quinine for the same individual, calculating incidence rate ratios (IRR) for AKI adjusting for age. Results The first study included 12,744 individuals who experienced 13,616 AKI events during cohort follow-up (crude incidence 12.5 per 100 person-years). Exposure to quinine before an episode of care was significantly associated with an increased probability of AKI (adjusted OR=1.27, 95% CI 1.21-1.33). The SCCS cohort included 5,907 people with quinine exposure with ≥1 AKI event. Exposure to quinine was associated with an increased relative incidence of AKI compared to unexposed periods (IRR=1.20, 95% CI 1.15-1.26), with the greatest risk observed within 30 days of quinine initiation (IRR=1.48, 95% CI 1.35-1.61). Conclusion Exposure to quinine in patients aged 60 years and over was associated with an increased risk of AKI, the incidence of which is unlikely to simply be explained be immune-mediated reactions only. Further research is required to determine exact reasons for the increased risk of AKI.

Quinine exposure and the risk of acute kidney injury: a population-based observational study of older people.

Objectivesto establish and quantify any observable association between the exposure to community prescriptions for quinine and acute kidney injury (AKI) events in a population of older adults.Designtwo observational studies using the same dataset, a retrospective longitudinal cohort study and a self-controlled case series (SCCS).SettingNHS health board in Scotland.Participantsolder adults (60+ years) who received quinine prescriptions in Tayside, Scotland, between January 2004 and December 2015. The first study included 12,744 individuals. The SCCS cohort included 5,907 people with quinine exposure and more than or equal to one AKI event.Main outcome measuredin the first study, multivariable logistic regression was used to calculate odds ratios (ORs) for AKI comparing between episodes with and without recent quinine exposure after adjustment for demographics, comorbidities and concomitant medications. The SCCS study divided follow-up for each individual into periods ‘on’ and ‘off’ quinine, calculating incidence rate ratios (IRRs) for AKI adjusting for age.Resultsduring the study period, 273,596 prescriptions for quinine were dispensed in Tayside. A total of 13,616 AKI events occurred during follow-up (crude incidence 12.5 per 100 person-years). In the first study, exposure to quinine before an episode of care was significantly associated with an increased probability of AKI (adjusted OR = 1.27, 95% confidence interval (CI) 1.21–1.33). In the SCCS study, exposure to quinine was associated with an increased relative incidence of AKI compared to unexposed periods (IRR = 1.20, 95% CI 1.15–1.26), with the greatest risk observed within 30 days following quinine initiation (IRR = 1.48, 95% CI 1.35–1.61).Conclusioncommunity prescriptions for quinine in an older adult population are associated with an increased risk of AKI.

Quinine induced thrombotic microangiopathy and thrombocytopenia: A teaching hospital's perspective

Although quinine is an infrequently prescribed drug, with malaria treatment being its only FDA-approved indication, unwitting exposure via beverages (e.g., tonic water), over the counter herbal remedies and illegal recreation drugs still occur. We present a unique case of a female patient who denied any known prior history of quinine exposure, who after being prescribed quinine tablets for restless leg syndrome, developed an immune-related thrombotic microangiopathy with thrombocytopenia and subsequent multi-organ failure. It was later elucidated that her only known potential source of prior quinine exposure was a remote history of crack-cocaine use. The patient survived this rare and severe inflammatory response with recovery of renal function and was able to discontinue dialysis.

Brief Exposures to the Taste of Ethanol (EtOH) and Quinine Promote Subsequent Acceptance of EtOH in a Paradigm that Minimizes Postingestive Consequences.

Aversion to the orosensory properties of concentrated ethanol (EtOH) solutions is often cited as a primary barrier to initiation of drinking and may contribute to abstention. These aversive properties include gustatory processes which encompass both bitter-like taste qualities and trigeminal-mediated irritation. Chronic intermittent EtOH access (CIA) results in substantial and persistent increases in EtOH consumption, but the degree to which this facilitation involves sensory responding to EtOH and other bitter stimuli is currently undetermined. Long-Evans rats were given brief-access licking tests designed to examine the immediate, taste-guided assessment of the palatability of EtOH and quinine solutions. Rats were assessed once in a naïve state and again following previous brief-access exposure, or following 4weeks of CIA. The relationship between the sensitivity to the aversive orosensory properties of EtOH and quinine following EtOH access and the impact of antecedent quinine exposure on the acceptance of EtOH were determined in 2 parallel studies. Both brief access to EtOH and 4-week CIA resulted in substantial rightward shifts in the concentration-response function of brief-access EtOH licking, indicating that EtOH exposure increased acceptance of the taste of EtOH. The initial sensitivity to the aversive orosensory properties of EtOH and quinine was positively correlated in naïve rats, such that rats that were initially more accepting of quinine were also more accepting of EtOH. Rats that sampled quinine immediately prior to tasting EtOH exhibited successive positive contrast in that they were more accepting of highly concentrated EtOH, relative to a water-control group. Increased EtOH acceptance following exposure is, at least in part, facilitated by a decrease in its aversive sensory properties. Both long- and short-term access increase the palatability of the taste of EtOH in brief-access licking tests. Moreover, the sensitivity to the bitterness of quinine was predictive of acceptance of EtOH indicating some commonality in the sensory mechanisms that mediate the initial acceptance of the 2 stimuli. Accordingly, immediate prior exposure to quinine results in increased acceptance of EtOH, suggesting that successive positive contrast between oral stimuli may contribute to increased alcohol consumption.

Quinine-Induced Thrombotic Microangiopathy: A Report of 19 Patients

Quinine can cause diverse and severe immune-mediated adverse reactions, including thrombotic microangiopathy (TMA). Our objective was to describe the presenting features and long-term outcomes of patients with quinine-induced TMA. A case series of 19 patients with quinine-induced TMA treated with plasma exchange. Patients with quinine-induced TMA initially suspected of having thrombotic thrombocytopenic purpura (TTP) were identified among patients enrolled in the Oklahoma TTP-Hemolytic Uremic Syndrome Registry. The clinical course of the initial episode and morbidity and mortality following recovery. The diagnosis of quinine-induced TMA was confirmed by documentation of quinine-dependent antibodies reactive with platelets or neutrophils and/or by previous quinine-associated systemic symptoms. Clinical data from the initial episode and long-term follow-up were described, focusing on kidney function. 19 of the 509 patients enrolled in the registry in 1989 to 2015 had quinine-induced TMA. 18 patients had quinine-dependent antibodies reactive with platelets and/or neutrophils (1 patient died before testing); 8 patients had a history of quinine-associated systemic symptoms. All patients were white; 18 were women. Quinine exposure was in pill form for 18 patients and as tonic water for 1. All patients had microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. All were initially misdiagnosed as having TTP or hemolytic uremic syndrome, and adverse reactions to quinine were not initially suspected. 1 patient died before treatment began; 17 of the 18 surviving patients required dialysis. 14 patients developed chronic kidney disease, 3 of whom developed end-stage renal disease. 8 patients died. Patients for whom plasma exchange was not requested were not identified. Quinine-induced TMA causes severe acute kidney injury that commonly results in chronic kidney disease.

Long-Term Quinine Exposure and Mortality

The U.S. Food and Drug Administration issued a safety announcement in July 2010, which stated that quinine should not be used to treat leg cramps. To

Association Between Long-term Quinine Exposure and All-Cause Mortality

Quinine has been used since the 1930s to treat idiopathic muscular cramps. However, in 2006, because of efficacy and safety issues, the US Food and Drug Administration cautioned about this off-label use of quinine, citing “665 reports of adverse events with serious outcomes…including 93 deaths.”1 Despite warnings, quinine is still prescribed to individuals with idiopathic muscular cramps. Furthermore, many drinks such as bitter lemon or tonic waters contain quinine, and hence, many may be exposed to quinine daily. This study explored the association between long-term quinine exposure and all-cause mortality.

Long-term quinine exposure associated with increased mortality

Long-term quinine exposure associated with increased mortality

Cortical circuit dynamics during punishment‐resistant alcohol drinking

A great deal of research has highlighted the role of the medial prefrontal cortex (mPFC) in encoding motivational value and decision making. Further, alcohol‐induced plasticity in mPFC has been implicated in aberrant alcohol drinking behaviors; however, we have little understanding of how neurons in mPFC are encoding alcohol related stimuli in real time, and what downstream circuits are involved. Here, we sought to dissect the role of projection‐defined subpopulations within mPFC in punishment resistant alcohol drinking. To allow for in vivo recordings of neural activity from defined populations, we delivered a Cre‐dependent viral vector carrying the genetically encoded calcium indicator GCaMP6m in the mPFC of male C57BL/6J mice. A second retrograde virus carrying Cre recombinase was injected into either the nucleus accumbens (NAc) or periaqueductal gray area (PAG) resulting in selective expression of the indicator in either mPFC:NAc or mPFC:PAG cells. By implanting a lens into the mPFC and attaching a miniature head‐mounted microscope we were then able to record calcium dynamics with single‐cell resolution during a Pavlovian conditioning task for alcohol, or alcohol adulterated with the bitter tastant quinine. We found that the activity of mPFC:PAG tracked stimulus value of both the conditioned and unconditioned stimulus throughout the course of alcohol and alcohol+quinine exposure. Indeed, mPFC:PAG cells were predominately inhibited by the presentation of an alcohol predictive cue, and during the consumption of alcohol. In animals that decreased their intake when quinine was present, mPFC:PAG showed excitation to the cue and during consumption, while animals that continued to drink despite quinine punishment continued to show an inhibitory response in this pathway. Additionally, we found that photostimulation of PFC‐PAG neurons produced robust avoidance, demonstrating a causal role for this pathway in encoding avoidance of aversive stimuli. Together, these results support a model where inhibition of the mPFC:PAG circuit encodes rewarding stimuli and promotes seeking, while activation encodes aversive stimuli and produces avoidance. Further, dysregulation of this pathway resulting from chronic alcohol use may blunt responsiveness to aversive stimuli and result in inflexible, punishment resistant alcohol drinking.

Quinine-Induced Thrombotic Microangiopathy (Q-TMA): Frequency, Presenting Features, Outcomes

Q-TMA is an acute, severe, immune-mediated, drug-induced disorder. Q-TMA is suspected when symptoms suddenly begin within hours following quinine (Q) exposure. Diagnosis of Q-TMA is established by the history of recurrent acute symptoms following recurrent Q exposures and/or by documentation of Q-dependent antibodies reactive with platelets and/or neutrophils. The Oklahoma TTP-HUS Registry enrolls all patients for whom plasma exchange (PEX) is requested for suspected TTP or HUS. Since 1995, when routine measurement of ADAMTS13 activity began, the Registry has diagnosed 78 patients with acquired TTP (ADAMTS13 <10%). During this time we have also diagnosed 17 patients with Q-TMA; 2 additional patients were diagnosed before 1995. Seventeen of these 19 patients were tested for Q-dependent antibodies; all were positive. Nine patients had a history of recurrent acute symptoms with recurrent Q exposure, including the 2 patients not tested for Q-dependent antibodies. Q exposure was a pill in 18 patients, tonic water in one. Remarkably, 18 patients were women; all 19 patients were white. Common presenting symptoms were fever, chills, nausea and vomiting. No patients had focal neurologic abnormalities. All patients had microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. Eight patients had elevated serum alanine aminotransferase (231-1345 U/L). Three patients had neutropenia (absolute neutrophil counts, 184-486). Two patients had coagulation abnormalities suggesting disseminated coagulation (DIC).One patient died from complications of the central venous catheter insertion, performed for PEX and dialysis; all other patients recovered normal platelet counts. Three of the 18 surviving patients had end-stage renal disease (2 had kidney transplants). The median estimated glomerular filtration rate (GFR) for the other 15 patients, at 2.7-19.2 years (median, 10.2) after recovery, was 36 ml/min (range, 19-98). Only two patients had normal GFR (≥90 ml/min). Eleven patients had chronic kidney disease, defined by GFR <60 ml/min. Seven of 18 patients have died 4.1-12.7 years (median, 7.8) following recovery at ages 59-87 years. Conclusion. Quinine can cause severe immune-mediated toxicities involving multiple organ systems (Am J Hematol 2016; 91: 461). Q-TMA is an acute disorder causing severe kidney injury and, in some patients, also liver toxicity, neutropenia, and/or DIC. Q-TMA is not rare. During 20 years, we enrolled 17 Q-TMA patients compared to 78 patients with acquired TTP. Chronic kidney disease is a common long-term outcome. Explicit questions are required to discover the association of systemic symptoms with quinine ingestion. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diversity and severity of adverse reactions to quinine: A systematic review.

Quinine is a common cause of drug-induced thrombocytopenia and the most common cause of drug-induced thrombotic microangiopathy. Other quinine-induced systemic disorders have been described. To understand the complete clinical spectrum of adverse reactions to quinine we searched 11 databases for articles that provided sufficient data to allow evaluation of levels of evidence supporting a causal association with quinine. Three reviewers independently determined the levels of evidence, including both immune-mediated and toxic adverse reactions. The principal focus of this review was on acute, immune-mediated reactions. The source of quinine exposure, the involved organ systems, the severity of the adverse reactions, and patient outcomes were documented. One hundred-fourteen articles described 142 patients with definite or probable evidence for a causal association of quinine with acute, immune-mediated reactions. These reactions included chills, fever, hypotension, painful acral cyanosis, disseminated intravascular coagulation, hemolytic anemia, thrombocytopenia, neutropenia, acute kidney injury, rhabdomyolysis, liver toxicity, cardiac ischemia, respiratory failure, hypoglycemia, blindness, and toxic epidermal necrolysis. One hundred-two (72%) reactions were caused by quinine pills; 28 (20%) by quinine-containing beverages; 12 (8%) by five other types of exposures. Excluding 41 patients who had only dermatologic reactions, 92 (91%) of 101 patients had required hospitalization for severe illness; 30 required renal replacement therapy; three died. Quinine, even with only minute exposure from common beverages, can cause severe adverse reactions involving multiple organ systems. In patients with acute, multi-system disorders of unknown origin, an adverse reaction to quinine should be considered.

The neural encoding of cocaine-induced devaluation in the ventral pallidum

Cocaine experience affects motivation structures such as the nucleus accumbens (NAc) and its major output target, the ventral pallidum (VP). Previous studies demonstrated that both NAc activity and hedonic responses change reliably as a taste cue comes to predict cocaine availability. Here we extended this investigation to examine drug-experience induced changes in hedonic encoding in the VP. VP activity was first characterized in adult male Sprague–Dawley rats in response to intraoral infusions of palatable saccharin and unpalatable quinine solutions. Next, rats received 7 daily pairings of saccharin that predicted either a cocaine (20mg/kg, ip) or saline injection. Finally, the responses to saccharin and quinine were again assessed. Of 109 units recorded in 11 rats that received saccharin–cocaine pairings, 71% of responsive units significantly reduced firing rate during saccharin infusions and 64% increased firing rate during quinine exposure. However, as saccharin came to predict cocaine, and elicited aversive taste reactivity, VP responses changed to resemble quinine. After conditioning, 70% of saccharin-responsive units increased firing rate. Most units that encoded the palatable taste (predominantly reduced firing rate) were located in the anterior VP, while most units that were responsive to aversive tastes were located in the posterior VP. This study reveals an anatomical complexity to the nature of hedonic encoding in the VP.

Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya.

BackgroundThe artemisinin anti-malarials are widely deployed as artemisinin-based combination therapy (ACT). However, they are not recommended for uncomplicated malaria during the first trimester because safety data from humans are scarce.MethodsThis was a prospective cohort study of women of child-bearing age carried out in 2011–2013, evaluating the relationship between inadvertent ACT exposure during first trimester and miscarriage. Community-based surveillance was used to identify 1134 early pregnancies. Cox proportional hazard models with left truncation were used.ResultsThe risk of miscarriage among pregnancies exposed to ACT (confirmed + unconfirmed) in the first trimester, or during the embryo-sensitive period (≥6 to <13 weeks gestation) was higher than among pregnancies unexposed to anti-malarials in the first trimester: hazard ratio (HR) = 1.70, 95 % CI (1.08–2.68) and HR = 1.61 (0.96–2.70). For confirmed ACT-exposures (primary analysis) the corresponding values were: HR = 1.24 (0.56–2.74) and HR = 0.73 (0.19–2.82) relative to unexposed women, and HR = 0.99 (0.12–8.33) and HR = 0.32 (0.03–3.61) relative to quinine exposure, but the numbers of quinine exposures were very small.ConclusionACT exposure in early pregnancy was more common than quinine exposure. Confirmed inadvertent artemisinin exposure during the potential embryo-sensitive period was not associated with increased risk of miscarriage. Confirmatory studies are needed to rule out a smaller than three-fold increase in risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0950-6) contains supplementary material, which is available to authorized users.

Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort.

BackgroundThere is limited data available regarding safety profile of artemisinins in early pregnancy. They are, therefore, not recommended by WHO as a first-line treatment for malaria in first trimester due to associated embryo-foetal toxicity in animal studies. The study assessed birth outcome among pregnant women inadvertently exposed to artemether-lumefantrine (AL) during first trimester in comparison to those of women exposed to other anti-malarial drugs or no drug at all during the same period of pregnancy.MethodsPregnant women with gestational age <20 weeks were recruited from Maternal Health clinics or from monthly house visits (demographic surveillance), and followed prospectively until delivery.Results2167 pregnant women were recruited and 1783 (82.3%) completed the study until delivery. 319 (17.9%) used anti-malarials in first trimester, of whom 172 (53.9%) used (AL), 78 (24.4%) quinine, 66 (20.7%) sulphadoxine-pyrimethamine (SP) and 11 (3.4%) amodiaquine. Quinine exposure in first trimester was associated with an increased risk of miscarriage/stillbirth (OR 2.5; 1.3–5.1) and premature birth (OR 2.6; 1.3–5.3) as opposed to AL with (OR 1.4; 0.8–2.5) for miscarriage/stillbirth and (OR 0.9; 0.5–1.8) for preterm birth. Congenital anomalies were identified in 4 exposure groups namely AL only (1/164[0.6%]), quinine only (1/70[1.4%]), SP (2/66[3.0%]), and non-anti-malarial exposure group (19/1464[1.3%]).ConclusionExposure to AL in first trimester was more common than to any other anti-malarial drugs. Quinine exposure was associated with adverse pregnancy outcomes which was not the case following other anti-malarial intake. Since AL and quinine were used according to their availability rather than to disease severity, it is likely that the effect observed was related to the drug and not to the disease itself. Even with this caveat, a change of policy from quinine to AL for the treatment of uncomplicated malaria during the whole pregnancy period could be already envisaged.

Chronic myelomonocytic leukemia presenting as relapsing thrombotic thrombocytopenic purpura

A 67-year-old woman presented with fever, purpura, and confusion. A preliminary diagnosis of thrombotic thrombocytopenic purpura (TTP) was made on the basis of clinical presentation and lab findings, such as reduced platelet count, increased bilirubin, and so on. She was treated with therapeutic plasma exchange (TPE) and methylprednisolone. During the treatment, peripheral blood monocytosis (monocyte 4×10(9)/L) was noticed. The monocytes were CD56 positive. A putative diagnosis of chronic myelomonocytic leukemia (CMML) was proposed. Three months later, the diagnosis of CMML was established on the basis of persistent monocytosis. All other potential causes were considered (e.g., quinine exposure, diarrhea) and excluded. This case highlights the needs to consider hematological malignancy such as CMML in patients with TTP.

Population Pharmacokinetic and Pharmacodynamic Properties of Intramuscular Quinine in Tanzanian Children with Severe Falciparum Malaria

Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.).

Quinine localizes to a non-acidic compartment within the food vacuole of the malaria parasite Plasmodium falciparum

BackgroundThe naturally fluorescent compound quinine has long been used to treat malaria infections. Although some evidence suggests that quinine acts in the parasite food vacuole, the mechanism of action of quinine has not yet been resolved. The Plasmodium falciparum multidrug resistance (pfmdr1) gene encodes a food vacuolar membrane transporter and has been linked with parasite resistance to quinine. The effect of multiple pfmdr1 copies on the subcellular localization of quinine was explored.MethodsFluorescence microscopy was used to evaluate the subcellular localization of quinine in parasites containing different pfmdr1 copy numbers to determine if copy number of the gene affects drug localization. The acidotropic dye LysoTracker Red was used to label the parasite food vacuole. Time-lapse images were taken to determine quinine localization over time following quinine exposure.ResultsRegardless of pfmdr1 copy number, quinine overlapped with haemozoin but did not colocalize with LysoTracker Red, which labeled the acidic parasite food vacuole.ConclusionsQuinine localizes to a non-acidic compartment within the food vacuole possibly haemozoin. Pfmdr1 copy number does not affect quinine subcellular localization.

Quinine-Induced Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS): Characteristic Clinical Presentation and High Risk for Chronic Kidney Disease (CKD)

Abstract▪2216▪This icon denotes a clinically relevant abstract Introduction:Quinine is the most common cause of drug-induced TTP-HUS in the Oklahoma Registry, 1989–2010. In 52 of all 415 clinically diagnosed patients the cause of TTP-HUS was attributed to a drug; in 25 of these 52 patients, quinine was the suspected drug; in the other 27 patients, chemotherapy agents were the suspected cause in 17, cyclosporine in 3, and 6 different drugs in the other 7 patients. Our goal was to describe the presenting clinical features and long term outcomes of patients with quinine-induced TTP-HUS. Methods:We developed an algorithm to define the causal relation between a drug and the occurrence of TTP-HUS that included patient history (precise time interval between drug exposure and onset of symptoms, occurrence of systemic symptoms with previous exposure to the drug) and documentation of drug-dependent antibodies. Presenting clinical features of patients with quinine induced TTP-HUS were compared to patients with TTP and severe ADAMTS13 deficiency. ADAMTS13 activity has been measured in 299 of 321 (93%) patients, 1995–2010. 68 of 299 (23%) had severe ADAMTS13 deficiency. Glomerular filtration rate (GFR) was calculated by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation (Ann Int Med 2009;150:604). Results:Using this algorithm, 19 of 25 quinine patients had a definite causal relation of quinine to TTP-HUS; among the other 6 quinine patients the causal relation was probable in 1, possible in 2, and unlikely in 3. Among the 27 patients with other suspected drugs, only 1 (gemcitabine) had a definite and 1 (alendronate) had a probable causal relation. In the other 25 patients the causal relationship between the drug and TTP-HUS was only possible or unlikely. The characteristic presenting symptoms of the 19 patients with a definite quinine cause were the sudden onset of fever and chills, gastrointestinal (GI) symptoms, and oliguria. Nine of the 19 patients had had previous systemic symptoms with previous quinine exposure, including two patients with previous episodes of TTP-HUS for which the quinine cause had not been recognized. Sixteen of the 19 patients had ADAMTS13 activity measurements (median, 63%; range 25–100%); their presenting clinical features were significantly different from the 68 patients who had TTP associated with severe ADAMTS13 deficiency, except the frequency of female gender.Clinical featureQuinine (N = 16)ADAMT S13 <10% (N = 68)PAge (median, range)57 (35–77)40 (9–71)<0.001Race (% white)16 (100%)42 (62%)0.002Gender (% women)15 (94%)55 (81%)0.214Fever/chills9 (56%)7 (10%)<0.001GI symptoms16 (100%)47 (69%)0.009Severe neurologic abnormalities1 (6%)35 (52%)<0.001Oliguria/anuria16 (100%)2 (3%)<0.001Hematocrit (%, median, range)23 (19–36)21 (13–33)0.011Platelet count (/uL, median, range)28 (6–54)10 (2–101)<0.001LDH (U/ml, median, range)2762 (339–5878)1372 (256–3909)0.001Creatinine (mg/dL, median, range)8.8 (3.7–15.2)1.5 (0.7–6.6)<0.001Pentad of presenting features4 (25%)4 (6%)0.040Of the 19 patients with a definite quinine cause of TTP-HUS, 1 died and 3 recovered with end-stage renal disease, requiring permanent dialysis and kidney transplantation in two patients. The remaining 15 patients have been followed for a median of 4.8 years (range, 1.2 – 13.8 years). Four have CKD with severely decreased glomerular filtration rate [GFR] (15–29 ml/min/1.73 m2), 7 have CKD with moderately decreased GFR (30–59 ml/min/1.73 m2), and 4 have normal GFR (≥60 ml/min/1.73 m2). Conclusion:Quinine is a common cause of drug-induced TTP-HUS with characteristic clinical features. It is a severe systemic disorder that can cause death and commonly causes CKD. The quinine cause may not be recognized because quinine exposure, from occasional tablets for leg cramps or from tonic water, may be overlooked. Disclosures:No relevant conflicts of interest to declare.

Diminished Plasmodium falciparum sensitivity to quinine exposure in vitro and in a sequential multi-drug regimen : A preliminary investigation in Guyana, South America

This preliminary study sought to investigate the response of uncomplicated falciparum infections to semi-supervised drug administration with quinine and two adjunctive schizontocidal drugs in infected patients in Guyana. Quinine and chloroquine cross-sensitivity was also assessed in vitro. Patients were treated with quinine 10mg/kg for 7 days followed by sulfadoxine/pyrimethamine 25mg/kg single dose (in children) or doxycycline 100mg daily for 7 days (in adults). Independently, falciparum-infected blood-medium mixtures were cultured in standardized pre-dosed quinine and chloroquine test plates, according to the protocol of the World Health Organization Mark III in vitro test system, for analysis. The quinine/doxycycline regimen (N=12) produced 100% clinical cure (12/12) at day 14 and 100% parasitological cure (11/11) at day 28. However, with the quinine/sulfadoxine/pyrimethamine scheme, 1/12 therapeutic failure (on day 14) and 2/9 parasitological failures (on day 28) were observed. In vitro, parasite development beyond the cut-off concentrations and high IC(50) values (geometric mean IC(50) quinine 504.65nM and IC(50) chloroquine 506.69nM), confirmed diminished Plasmodium falciparum sensitivity to both drugs. These findings suggest P. falciparum resistance to both quinine and chloroquine, and support either the use of antibiotics as adjuncts to quinine therapy or drugs with alternate pharmacodynamics as first-line therapy.

Are one or two dangerous? Quinine and quinidine exposure in toddlers

Quinine and quinidine have been cited as drugs that may cause significant morbidity and mortality in toddlers who ingest one or two pills. The use of both of these drugs has declined in the United States since the 1980s. A review of the literature and Poison Control data reveals that large quinine and quinidine ingestions, although rare in this country, may lead to severe toxicity and death related to cardiovascular and neurological effects in both children and adults. Although the majority of cases of quinine and quinidine toxicity in toddlers occur after ingestions of more than two pills, a single report each of severe toxicity after the equivalent of an ingestion of two pills or less by a toddler exists for both quinine and quinidine. Although the risk to the toddler exposed to one or two tablets seems to be small, triage to an Emergency Department is warranted after quinidine ingestion of any amount and after quinine ingestion that exceeds the age-appropriate therapeutic dose.