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Psychiatric adverse effects of chloroquine

June 2017
Psychiatria i Psychologia Kliniczna 17(2):111-114

DOI:10.15557/PiPK.2017.0012

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Dialog Therapy & Counselling Centre

Chloroquine is a prototype antimalarial drug, widely used in several branches of medicine. Antimalarial drugs are used in the treatment of various dermatological, immunological, rheumatological and infectious diseases. Examples of off-labelled indications for chloroquine analogues use include dermatomyositis, sarcoidosis, polymorphous light eruption, disseminated granuloma annulare and porfiria cutanea tarda. There is a relatively small number of adverse effects related to chloroquine analogues used in standard doses, such as gastrointestinal disturbances, headaches, skin reactions, hypotension, convulsions, extrapyramidal symptoms and visual disturbances. Psychiatric side effects of chloroquine seem to be rare, but may manifest in a wide range of symptoms, such as confusion, disorientation, ideas of persecution, agitation, outbursts of violence, loss of interest, feeling sad, suicidal ideas and impaired insight. There is also a report of a manic episode with psychotic features in the course of bipolar disorder, and another case report of persecutory delusions, anxiety, derealisation and visual illusions triggered by chloroquine. The duration of psychiatric symptoms usually ranges from one to two weeks, and symptoms usually disappear within several days following cessation of chloroquine usage and starting psychiatric treatment where indicated. This article reviews the case studies of patients diagnosed with mental disorders resulting from the use of chloroquine, and discusses the management in such cases.

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111

Psychiatric adverse effects ofchloroquine

Psychiatryczne działania niepożądane chlorochiny

Department ofMedical Psychology, Medical University ofLodz, Łódź, Poland

Correspondence: Anna Bogaczewicz, MD, PhD, Department ofMedical Psychology, Medical University ofLodz, Sterlinga 5, 91-425 Łódź, Poland, tel.: +48 42 630 15 73, +48 42 632 25 94,

fax: +48 42 630 15 73, e-mail: anna.bogaczewicz@umed.lodz.pl

Chloroquine isa prototype antimalarial drug, widely used inseveral branches ofmedicine. Antimalarial drugs are used inthe

treatment ofvarious dermatological, immunological, rheumatological andinfectious diseases. Examples ofoff-labelled

indications for chloroquine analogues use include dermatomyositis, sarcoidosis, polymorphous light eruption, disseminated

granuloma annulare andporfiria cutanea tarda. There isa relatively small number ofadverse effects related tochloroquine

analogues used instandard doses, such as gastrointestinal disturbances, headaches, skin reactions, hypotension, convulsions,

extrapyramidal symptoms andvisual disturbances. Psychiatric side effects ofchloroquine seem tobe rare, but may manifest

ina wide range ofsymptoms, such as confusion, disorientation, ideas ofpersecution, agitation, outbursts ofviolence, loss

ofinterest, feeling sad, suicidal ideas andimpaired insight. There isalso a report ofa manic episode with psychotic features

inthe course ofbipolar disorder, andanother case report ofpersecutory delusions, anxiety, derealisation andvisual illusions

triggered by chloroquine. Theduration ofpsychiatric symptoms usually ranges from one totwo weeks, andsymptoms usually

disappear within several days following cessation ofchloroquine usage andstarting psychiatric treatment where indicated.

This article reviews the case studies ofpatients diagnosed with mental disorders resulting from the use ofchloroquine,

anddiscusses the management insuch cases.

Keywords: chloroquine, antimalarial drugs, mental disorders, adverse effects, side effects

Chlorochina jest prototypowym lekiem przeciwmalarycznym, szeroko stosowanym w kilku gałęziach medycyny. Leki

przeciwmalaryczne wykorzystuje się w leczeniu różnych chorób dermatologicznych, immunologicznych, reumatologicznych

i chorób zakaźnych. Przykłady pozarejestracyjnych wskazań użycia analogów chlorochiny obejmują zapalenie skórno-

-mięśniowe, sarkoidozę, wielopostaciowe osutki świetlne, rozsiany ziarniniak obrączkowaty i porfirię skórną późną.

W standardowych dawkach chlorochina powoduje stosunkowo niewielką liczbę działań niepożądanych, takich jak zaburzenia

żołądkowo-jelitowe, bóle głowy, reakcje skórne, obniżone ciśnienie, drgawki, objawy pozapiramidowe i zaburzenia widzenia.

Wydaje się, iż psychiatryczne objawy niepożądane chlorochiny występują rzadko, ale w szerokim zakresie możliwości – od

splątania, dezorientacji, urojeń prześladowczych, pobudzenia i zachowań agresywnych po utratę zainteresowań, uczucie

smutku, myśli samobójcze oraz zaburzenie wglądu. Istnieje również doniesienie, w którym opisuje się epizod manii z cechami

psychotycznymi w przebiegu choroby afektywnej dwubiegunowej, a także opis przypadku z urojeniami prześladowczymi,

niepokojem, derealizacją i iluzjami wzrokowymi wywołanymi zastosowaniem chlorochiny. Czas trwania objawów

psychiatrycznych zazwyczaj zawiera się w przedziale od jednego do dwóch tygodni, a objawy zazwyczaj ustępują w ciągu

kilku dni po zaprzestaniu przyjmowania chlorochiny oraz po włączeniu leczenia psychiatrycznego, jeżeli istnieją do tego

wskazania. W artykule przedstawiono opisy przypadków pacjentów z rozpoznaniem zaburzeń psychicznych wynikających

z zastosowania chlorochiny, a także przedstawiono zastosowane postępowanie w takich przypadkach.

Słowa kluczowe: chlorochina, leki przeciwmalaryczne, zaburzenia psychiczne, objawy niepożądane, działania uboczne

Abstract

Streszczenie

Anna Bogaczewicz, Tomasz Sobów

(CC BY-NC-ND). Reproduct ion ispermitte d for personal, edu cational, non- commercial us e, provided that t he origina l article isin w hole, unmodi fied, andprope rly cited.

Received: 16.02.2017

Accepted: 15.03.2017

Published: 30.06.2017

DOI: 10.15557/PiPK.2017.0012

Anna Bogaczewicz, Tomasz Sobów

112

INTRODUCTION

Chloroquine iswidely used inmedicine. Its registered

indications include chemoprophylaxis andtreat-

ment ofmalaria, rheumatoid arthritis andlupus

erythematosus (British Medical Association andthe Royal

Pharmaceutical Society ofGreat Britain, 2014). However,

its o-labelled use iswider. Chloroquine, a 4-aminoquino-

line, was synthesised inthe 1930s by German scientists, who

named it resochin (Nevin andCroft, 2016). Inthe 1940s

chloroquine was valuated as an antimalarial drug with ac-

tivity against Plasmodium vivax andfalciparum infections

inhumans (Loeb, 1946). erst discovered natural anti-

malarial drug was quinine, which was isolated from the

bark ofthe cinchona tree inthe 1920s andmade it possi-

ble tolive intropical countries despite lethal tropical malaria

(Chen etal., 2006). However, chemical synthesis ofantima-

larial drugs andchloroquine analogues started earlier, in1891,

when Paul Ehrlich’s group developed methylene blue (Al-Bari,

2015). Aer that pamaquine, quinacrine, sontoquine, prima-

quine andhydroxychloroquine were discovered (Al-Bari,

2015). During the World War II it was found that taking anti-

malarial prophylaxis improved soldiers’ rashes andinamma-

tory arthritis (Al-Bari, 2015). Nowadays, antimalarial drugs

are benecial for many dermatological, immunological, rheu-

matological andinfectious diseases (Al-Bari, 2015).

INDICATIONS FOR CHLOROQUINE USAGE

A typical indication for chloroquine (base) usage isprophy-

laxis ofmalaria, where chloroquine isadministered 1 week

before entering an endemic area andcontinued for 4 weeks

aer leaving it, at a dosage of310mg once weekly (British

Medical Association andthe Royal Pharmaceutical Society

ofGreat Britain, 2014). Itisalso used with proguanil where

chloroquine-resistant falciparum malaria ispresent (British

Medical Association andthe Royal Pharmaceutical Society

ofGreat Britain, 2014).

Another indication isthe treatment ofrheumatoid arthri-

tis andlupus erythematosus, where chloroquine (base)

isused at a dosage of150mg daily (max. 2.5mg/kg daily)

based on ideal body weight. In the treatment ofrheuma-

toid arthritis andlupus erythematosus chloroquine sulfate

isused at a daily dosage of200mg, andchloroquine phos-

phate at 250mg (British Medical Association andthe Royal

Pharmaceutical Society ofGreat Britain, 2014).

Despite a relatively small number ofregistered indications

ofchloroquine usage, there are numerous o-labelled in-

dications, such as dermatomyositis, sarcoidosis, polymor-

phous light eruption, disseminated granuloma annulare

andporria cutanea tarda (Al-Bari, 2015).

MECHANISM OF ACTION

It was shown that chloroquine absorption from the gastroin-

testinal tract iscomplete ornearly complete, andconsiderable

amounts ofchloroquine are deposited intissues andnucle-

ated cells, especially inthose ofthe liver, spleen, kidneys

andlungs, andthese organs contain the highest concentra-

tions, from 200 to500 times the amount found inthe plasma

(Loeb, 1946). Antimalarials accumulate indierent concen-

trations invarious body tissues andorgans. Fat, bone, ten-

don andbrain contain relatively small amounts, close tothe

plasma level ofthe drug, incontrast tohigher concentra-

tions inkidney, bone marrow, spleen, lungs, adrenal glands

andliver, where the concentration may be higher than the

plasma level (Wozniacka andMcCaulie, 2005). Withinthe

cell, chloroquine isaccumulated inlysosomes, therefore

chloroquine analogues are known as lysosomotropic agents

(Al-Bari, 2015). Chloroquine analogues interfere with lyso-

somal acidication, which inturn inhibits proteolysis, che-

motaxis, phagocytosis andthe process ofantigen presen-

tation by decreasing the number ofautoantigenic peptides

appearing on the cell surface. us, the synthesis ofcytokines

by both T cells andantigen-presenting cells also decreases

(Al-Bari, 2015).

SIDE EFFECTS

Taking into account how widely chloroquine analogues are

used, there isa relatively small number ofside eects at

the standard doses ofchloroquine analogues. Side eects

include gastrointestinal disturbances, headaches, skin re-

actions (rashes, pruritus), hypotension, convulsions, ex-

trapyramidal symptoms, visual disturbances, depigmen-

tation andloss of hair, andmore rarely bone marrow

suppression orhypersensitivity reactions such as urticar-

ia andangioedema (British Medical Association andthe

Royal Pharmaceutical Society ofGreat Britain, 2014).

Chloroquine has been found tocause deposits inthe corne-

al epithelium andto cause retinopathy (Hobbs etal., 1961),

andits retinal toxicity isa serious adverse eect (Geamănu

Pancă etal., 2014). Other serious adverse eects include

cardiomyopathy characterised by concentric hypertrophy

andconduction abnormalities (Yogasundaram etal., 2014),

QT prolongation andrefractory ventricular arrhythmia

(Chen etal., 2006).

PSYCHIATRIC SIDE EFFECTS

In contrast tothe numerous reports ofpsychiatric side ef-

fects ofother antimalarial drugs, the reports regarding chlo-

roquine seem tobe rare. Nevertheless, the list ofdescribed

psychiatric side eects induced by chloroquine represents

a wide range ofsymptoms. Rab (1963) described lighthead-

edness, confusion, disorientation, ideas ofpersecution, ag-

itation andoutbursts ofviolence. A confused state was re-

ported by Brookes (1966). Das andMohan (1981) described

loss ofinterest, feeling sad, suicidal ideas, a weeping spell,

andimpaired insight. Overactivity, irritability, talkativeness,

experiencing racing thoughts, expressing delusions ofref-

erence andgrandeur were reported by Lovestone (1991).

Psychiatric adverse effects of chloroquine / Psychiatryczne działania niepożądane chlorochiny

113

Collins andMcAllister (2008) presented a case offemale

patient with irritability, confusion, andparanoia associ-

ated with delusions andvisual hallucinations progress-

ing toa catatonic state caused by chloroquine. ere are

also reports ofa manic episode with psychotic features

inthe course ofbipolar disorder (Bogaczewicz etal., 2014)

andfeelings oflightheadedness andderealisation, perse-

cutory delusions, anxiety, andvisual illusions triggered by

chloroquine (Bogaczewicz etal., 2016).

In the aforementioned cases chloroquine was used due

tovarious indications, such as amoebic hepatitis, discoid

lupus erythematosus, malaria, antimalarial prophylax-

is andsystemic lupus erythematosus. Theonset ofchlo-

roquine-induced psychiatric side eects may vary largely

interms oftime. Biswas etal. (2014) reported the laten-

cy between chloroquine usage andthe onset ofpsychosis

tobe within a range of6 to432 hours, with mean andstan-

dard deviation equal to100.08±96.00 hours. Mohan etal.

(1981) indicated that the symptoms were not dose-related.

Similarly, Biswas etal. (2014) found no linear relationship

between the amount ofconsumed chloroquine andthe se-

verity ofpsychosis. eduration ofpsychiatric symptoms

usually ranges from one totwo weeks, with symptoms typ-

ically disappearing within two days toone week following

the cessation ofchloroquine usage andonset ofthe psychi-

atric treatment where indicated (Mohan etal., 1981; Rab,

1963). During the dierential diagnosis ofpsychiatric side

eects following chloroquine usage, many more common

comorbidities should be excluded, such as metabolic dis-

orders, primary mental disorders, neuropsychiatric lupus,

anda glucocorticoid-induced psychotic disorder. Asa meth-

od ofestimating the likelihood ofadverse drug reactions the

algorithm by Naranjo etal. (1981) can be used.

MOLECULAR MECHANISMS

INVOLVEDINCHLOROQUINE-INDUCED

PSYCHIATRIC SIDE EFFECTS

e molecular mechanisms responsible for the psychiat-

ric complications following chloroquine use are not fully

understood, andwhen initial reports appeared the mode

ofaction on the brain was a matter ofspeculation (Rab,

1963). Interference ofchloroquine with the muscarinic cho-

linergic systems was revealed 30 years ago, when Schmidt

andOettling (1987), using a chick embryo, found that chlo-

roquine displaced a specic muscarinic ligand from its re-

ceptor andacted as a muscarinic antagonist. In another

animal study, inwhich chloroquine increased the locomo-

tion ofrats andelicited their stereotyped behaviour, itwas

concluded that chloroquine produces excitatory eects via

dopaminergic mechanisms andthat it may be involved

inthe observed eects ofchloroquine (Amabeoku, 1994).

However, it would be an oversimplication tosearch for

mechanisms responsible for chloroquine-induced psychi-

atric side eects only inmuscarinic anddopaminergic path-

ways. In a recent study by ompson andLummis (2008)

chloroquine was found tobe an antagonist for both 5-HT3A

and5-HT3AB receptors, yet it isnot known whether 5-HT3

receptors are inhibited inpatients taking chloroquine,

even though blood andits tissue concentrations indicate

that it ispossible. ompson andLummis (2008) suggest-

ed that nausea, a reported side eects ofchloroquine, could

be caused by 5HT3-mediated eects. Interestingly, GABAA

receptors were also inhibited by chloroquine, but at high-

er concentrations, whereas no inhibition was observed at

GABAC receptors (ompson andLummis, 2008). In the

view ofneuropsychiatric side eects ofchloroquine usage,

its impact on the nervous system seems tobe underestimated.

Hirata et al. (2011) revealed that chloroquine protected

mouse hippocampal HT22 cells from glutamate-induced ox-

idative stress by attenuating production ofexcess reactive ox-

ygen species, andsuggested that chloroquine could be a neu-

roprotective agent against oxidative stress that seems tooccur

ina variety ofneurodegenerative diseases.

MANAGEMENT

When diagnosis ofa chloroquine-induced psychiatric side

eect ismade, the best solution isto discontinue chloro-

quine. enext steps depend on the clinical manifestation

ofthe psychiatric disorders. In one report, when a diagnosis

oftoxic psychosis was made, chloroquine was discontinued

andchlorpromazine administered, with the patient’s men-

tal status reverting tonormal within three days (Rab, 1963).

In the case ofa confused state, reported by Brookes (1966),

when chloroquine was discontinued, during the following

week the patient became quite well. In chloroquine-induced

subacute paranoid-like disorder, all the symptoms resolved

two days aer chloroquine discontinuation (Bogaczewicz

etal., 2016). In the case ofmoderate tosevere depression

with suicidal ideas andweeping spells with impaired in-

sight, amitriptyline 100mg per day improved the patient’s

condition aer 4 days (Das andMohan, 1981). In hypo-

mania, a single dose of5mg ofhaloperidol returned the

mental state tonormal within three days (Lovestone, 1991).

More problematic are situations where chloroquine exacer-

bates the primary psychiatric disorder.

In a case ofthe patient with exacerbations ofbipolar dis-

order triggered by chloroquine used totreat systemic lu-

pus erythematosus, where the patient suered from a se-

vere depressive episode with psychiatric features, perazine,

mirtazapine, sertraline andhydroxyzine were adminis-

tered, while during the manic episode with psychotic fea-

tures quetiapine andlamotrigine were used (Bogaczewicz

etal., 2014).

Conict ofinterest

e authors have no conicts ofinterest todeclare.

Funding/Support androle ofthe sponsor

e work was supported by grant No. 503/6-074-03/503-61-001 from

the Medical University ofLodz, Poland.

Anna Bogaczewicz, Tomasz Sobów

114

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Aug 2021

Amaç: Bu çalışmanın amacı Sjögren Sendromlu (SS) hastalarda aleksitimi ile depresyon, anksiyete, yaşam kalitesi, hastalık durasyonu ve inflamatuar belirteçler arasındaki ilişkinin incelenmesidir. Materyal-metot: Çalışmaya yaş ortalaması 51.14±9.42 yıl olan 168 primer SS’li (pSS) birey (145 kadın, 23 erkek) dahil edildi. Aleksitimiyi değerlendirmek için Toronto Aleksitimi Ölçeği, anksiyete ve depresyonu değerlendirmek için Beck Anksiyete ve Depresyon Ölçeği, yaşam kalitesini değerlendirmek için Dünya Sağlık Örgütü Yaşam Kalitesi Ölçeği Kısa Formu Türkçe Versiyonu kullanıldı. Bulgular: pSS’li bireylere ait aleksitimi ortalaması 53.83±12.61 puan bulundu. Aleksitimi ile anksiyete (r:0.514, p:0.00), depresyon (r:0.522, p:0.00), yaşam kalitesinin ruhsal (r:0.474, p:0.0) ve sosyal (r:0.486, p:0.04) alt parametreleri ve ESR değerleri (r:0.432, p:0.03) arasında düşük ve orta düzeyde anlamlı ilişki bulundu. Sonuç: Bu çalışmanın sonuçlarına göre pSS’li bireylerde aleksitimi arttıkça depresyon, anksiyete ve inflamatuar belirteç düzeyleri artmakta, ruhsal ve sosyal yönden yaşam kalitesi azalmaktadır. Sonuçlarımız iki yönlüdür. Aleksitiminin pSS'de depresif belirtilerin aracılık ettiği göz önünde bulundurularak, pSS’de aleksitimi, depresyon ve anksiyete gibi psikolojik hastalıkların varlığı ile birlikte tedavi için ayrıntılı değerlendirme ve çok boyutlu bir yaklaşıma olan ihtiyacı desteklemektedir.

Delirium in hospitalized COVID-19 patients: A case series

Article

Oct 2021
PSYCHIAT RES

The Nociceptive and Inflammatory Responses Induced by the Ehrlich Solid Tumor Are Changed in Mice Healed of Plasmodium berghei Strain ANKA Infection after Chloroquine Treatment

Article

Full-text available

May 2024

Comorbidities that involve infectious and noninfectious diseases, such as malaria and cancer, have been described. Cancer and malaria induce changes in the nociceptive and inflammatory responses through similar pathophysiological mechanisms. However, it is unclear whether malaria and antimalarial treatment can change the inflammatory and nociceptive responses induced by solid cancer. Therefore, the present study experimentally evaluated the effect of infection by Plasmodium berghei strain ANKA and chloroquine treatment on the nociceptive and inflammatory responses induced by the solid Ehrlich tumor in male BALB/c mice. On the 1st experimental day, mice were infected with Plasmodium berghei and injected with tumor cells in the left hind paw. From the 7th to the 9th experimental day, mice were treated daily with chloroquine. The parasitemia was evaluated on the 7th and 10th days after infection. On the 11th experimental day, mice were evaluated on the von Frey filament test, the hot plate test, and the paw volume test. At the end of the experimental tests on the 11th day, the peripheral blood of all mice was collected for dosing of IL-1β and TNF-α. The blood parasitemia significantly increased from the 7th to the 10th day. The chloroquine treatment significantly decreased the parasitemia on the 10th day. The presence of the tumor did not significantly change the parasitemia on the 7th and 10th days in mice treated and nontreated with chloroquine. On the 11th day, the mechanical and thermal nociceptive responses significantly increased in mice with tumors. The treatment with antimalarial significantly reduced the mechanical nociceptive response induced by tumors. The hyperalgesia induced by tumors did not change with malaria. The mechanical and thermal hyperalgesia induced by the tumor was significantly reduced in mice treated and healed from malaria. On the 11th day, the volume of the paw injected by the tumor was significantly increased. The mice treated with chloroquine, infected with malaria, or healed of malaria showed reduced paw edema induced by the tumor. Mice with tumors did not show a change in IL-β and TNF-α serum levels. Mice with tumors showed a significant increase in serum levels of IL-1β but not TNF-α when treated with chloroquine, infected with malaria, or healed of malaria. In conclusion, the results show that malaria infection and chloroquine treatment can influence, in synergic form, the nociceptive and inflammatory responses induced by the solid tumor. Moreover, the mechanical antinociception, the thermal hyperalgesia, and the antiedema effect observed in mice treated with chloroquine and healed from malaria can be related to the increase in the serum level of IL-1β.

The Ignored Psychiatric Aspect of Chloroquine in the Coronavirus Disease 2019 Outbreak Period: A Narrative Review Study

Article

Full-text available

Jul 2023

Context: Several studies have shown that chloroquine can effectively diminish the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As such, other studies have also supported this statement, but the psychiatric side effects of chloroquine have not been taken into account. So, the current study aimed to briefly review and discuss the safety of chloroquine. Methods: A narrative literature search on databases was carried out on studies without time limitations. A combination of the two main keywords of “Chloroquine” and “Psychiatric Side Effects” was used to search databases. A manual search was performed to find the relevant articles, and finally, 15 studies were reviewed. Data were shown in the table and then summarized by narrative synthesis. Results: The literature review revealed the pharmaceutical characteristics of chloroquine, the safety of chloroquine, and the management of chloroquine's side effects. Also, the studies showed that chloroquine had psychiatric symptoms varying from insomnia to catatonia, toxic psychosis, and suicidal attempts, as well as behavioral manifestations, including most frequently extreme irritability, restlessness, abusiveness, distractibility, pressured speech, flight of ideas, grandiosity delusion, and auditory and visual hallucinations. Conclusions: Given the probability of a wide range of possible psychiatric symptoms following chloroquine, physicians should cautiously prescribe antiviral agents, and healthcare workers should also notice any psychiatric symptoms after administrating the chloroquine.

Systematic Review of Psychiatric Adverse Effects Induced by Chloroquine and Hydroxychloroquine: Case Reports and Population Studies

Article

Aug 2022

Objective To perform a systematic review on the psychiatric adverse effects of chloroquine (CQ) and hydroxychloroquine (HCQ); to summarize what is known about psychiatric adverse effects of these drugs; to compare clinical trials, populational studies, and case report studies; and to increase awareness of the potential psychiatric adverse effects of these drugs. Data Sources A literature search of PubMed, Scopus, and Web of Science was performed to identify manuscripts published between December 1962 and June 2022. Search terms included CQ, HCQ, psychiatry, psychosis, depression, anxiety, bipolar disorder, delirium, and psychotic disorders. Study Selection and Data Extraction Relevant studies included reports of adverse effects after CQ or HCQ ingestion. Data Synthesis The current literature presents evidence for a risk of short-term psychiatric adverse effects induced by either CQ or HCQ. However, the populational-level studies presented some limitations regarding the voluntary response in survey data, self-report adverse effects, and placebo group reporting similar symptoms to the case group. Thus, populational-level studies addressing the discussed limitations and the nature and extent of possible psychiatric adverse effects are needed. Relevance to Patient Care and Clinical Practice Most of the patients who developed such adverse effects did not report a family history of psychiatric disease. The frequency of psychiatric adverse effects depends on the patient’s biological sex, age, and body mass index, but not on the drug dosage. Conclusions Based on clinical trials and case reports, the current literature presents evidence for a risk of short-term psychiatric adverse effects induced by either drug.

An efficient synthesis of rearranged new biologically active benzimidazoles derived from 2-formyl carvacrol

Article

Full-text available

Jan 2022
RES CHEM INTERMEDIAT

A new series of benzimidazole derivatives was synthesized by one-pot two-step reaction as a result of unexpected rearrangement during reaction of 2-formyl carvacrol and corresponding 2-phenylenediamines in DMF, by using Na2S2O5 as an oxidizing reagent. The newly synthesized compounds were characterized by ¹H NMR, ¹³C NMR, FT-IR, mass spectroscopy techniques, and single-crystal X-ray crystallography. The docking studies of all nine compounds were carried out against the active site of the Plasmodium falciparum dihydroorotate dehydrogenase enzyme. To inspect their antimalarial, antimicrobial, and antioxidant activity, all the synthesized compounds were screened in vitro for their antimalarial activity against the malaria parasite Plasmodium falciparum strain and four bacterial as well as three fungal strains. The biological screening revealed that some synthesized compounds have very good antimalarial activity. The physicochemical properties were calculated for all the synthesized benzimidazoles and were found to be good oral bioavailability drugs as resolute by Lipinski's rule. Graphic abstract

Neurological manifestations in COVID-19: An overview

Article

May 2021

The novel coronavirus disease 2019 (COVID-19) is a causative agent of severe lower respiratory tract infection in patients. Since its discovery in December 2019, COVID-19 has spread to five continents and to this date, affected approximately 6,260,000 people. COVID-19 patients typically present with symptoms related to the respiratory system while neurological manifestations have scarcely been reported. Neurological presentations of COVID-19 infection are classified into two groups: CNS symptoms and peripheral nervous system (PNS) symptoms. CNS symptoms include headache, dizziness, loss of consciousness, convulsion, ataxia and acute cerebrovascular disease. The PNS symptoms consist of hypoplasia, hyposmia, hypogeusia and neuralgia. The association between COVID-19 and neurological problems needs further clarification and warrants detailed microbiological and pathological studies to better understand the virus and its impact on the brain and nervous system.

Nanoformulations of old and new antimalarial drugs

Chapter

Jan 2021

Malaria remains a global health burden in the tropical regions and it has resulted in a high rate of mobility and mortality. Although several drug design strategies have been utilized to combat the disease, several limitations impede the efficacy of several antimalarials such as poor drug bioavailability, drug resistance, poor pharmacokinetics, drug toxicity, and poor drug solubility. The most virulent malaria pathogen responsible for drug resistance with life-threatening symptoms is Plasmodium falciparum followed by Plasmodium vivax. Nanoformulations of antimalarials which are prepared from systems such as nanomicelles, dendrimers, nanoparticles, polymer-drug conjugates, nanoliposomes, in situ gels, hydrogels, and nanocapsules are promising therapeutics that can be utilized to overcome the aforementioned antimalarial drugs limitations. This chapter will be focused on the therapeutic outcomes of nanoformulations of old and new antimalarials.

Psychiatric effects of malaria and anti-malarial drugs: Historical and modern perspectives

Article

Full-text available

Jun 2016
MALARIA J

The modern medical literature implicates malaria, and particularly the potentially fatal form of cerebral malaria, with a risk of neurocognitive impairment. Yet historically, even milder forms of malaria were associated in the literature with a broad range of psychiatric effects, including disorders of personality, mood, memory, attention, thought, and behaviour. In this article, the history of psychiatric effects attributed to malaria and post-malaria syndromes is reviewed, and insights from the historical practice of malariotherapy in contributing to understanding of these effects are considered. This review concludes with a discussion of the potentially confounding role of the adverse effects of anti-malarial drugs, particularly of the quinoline class, in the unique attribution of certain psychiatric effects to malaria, and of the need for a critical reevaluation of the literature in light of emerging evidence of the chronic nature of these adverse drug effects.

Chloroquine analogues in drug discovery: New directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases

Article

Full-text available

Feb 2015
J ANTIMICROB CHEMOTH

Alim Al-Bari

Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Retinal toxicity associated with chronic exposure to hydroxychloroquine and its ocular screening. Review

Article

Full-text available

Sep 2014

Hydroxychloroquine sulfate (HCQ, Plaquenil) is an analogue of chloroquine (CQ), an antimalarial agent, used for the treatment of systemic lupus erythematosus, rheumatoid arthritis and other autoimmune disorders. Its use has been associated with severe retinal toxicity, requiring a discontinuation of therapy. Because it presents potential secondary effects including irreversible maculopathy, knowledge of incidence, risk factors, drug toxicity and protocol screening of the patients it represents important data for the ophthalmologists. Thus, it is imperative that rheumatologists, medical internists and ophthalmologists are aware of the toxicity from hydroxychloroquine they should also be careful to minimize its occurrence and effects.

Hydroxychloroquine-Induced Cardiomyopathy: Case Report, Pathophysiology, Diagnosis and Treatment

Article

Full-text available

Aug 2014

Drug-induced heart and vascular disease remains an important health burden. Hydroxychloroquine and its predecessor chloroquine are medications commonly used in the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other connective tissue disorders. Hydroxychloroquine interferes with malarial metabolites, confers immunomodulatory effects, and also affects lysosomal function. Clinical monitoring and early recognition of toxicity is an important management strategy in patients undergoing long-term treatment with hydroxychloroquine. Retinal toxicity, neuromyopathy, and cardiac disease are recognized adverse effects of hydroxychloroquine. Immediate withdrawal of hydroxychloroquine is essential if toxicity is suspected due to the early reversibility of cardiomyopathy. In addition to recommended ophthalmological screening, regular screening with 12-lead electrocardiogram and transthoracic echocardiography to detect conduction system disease and/or biventricular morphological or functional changes should be considered in hydroxychloroquine-treated patients. Cardiac magnetic resonance imaging and endomyocardial biopsy are valuable tools to provide prognostic insights and confirm the diagnosis of hydroxychloroquine-induced cardiomyopathy. In conclusion, chronic use of hydroxychloroquine can result in an acquired lysosomal storage disorder, leading to a drug-induced cardiomyopathy characterized by concentric hypertrophy and conduction abnormalities associated with increased adverse clinical outcomes and mortality.

Exacerbations of bipolar disorder triggered by chloroquine in systemic lupus erythematosus—a case report

Article

Full-text available

Dec 2013
LUPUS

Despite precise definitions and exclusions for 19 syndromes of neuropsychiatric systemic lupus erythematosus (NPSLE), under some circumstances it appears to be difficult to differentiate whether neuropsychiatric symptoms are caused by SLE or by other reasons such as primary mental disorders or substance-induced mood disorders, especially induced by glucocorticoids or antimalarials. We report the case of a male patient with SLE who presented with an exacerbation of bipolar disorder triggered by chloroquine. Firstly, when the patient was diagnosed with SLE, he underwent six months of therapy with chloroquine without any psychiatric symptoms. Later, the SLE returned and the patient was prescribed chloroquine again, without any mental illness. When the third exacerbation of SLE occurred, it coincided with a severe depressive episode with psychotic features that became aggravated for the first time after the administration of chloroquine. The chloroquine was subsequently replaced with hydroxychloroquine for the next six months without any behavioral problems, following which, the SLE and mood disorder were in remission. Later, a bipolar disorder relapse occurred, manifested by a manic episode, and in the following three months, despite psychiatric treatment, a manic episode with psychotic features developed four days after chloroquine was prescribed for arthritis. It was the second time that the mood disorder was exacerbated by chloroquine. Since that time, chloroquine has been withdrawn. Currently the patient is undergoing treatment with hydroxychloroquine and psychiatric drugs with good response. Our case points out that although chloroquine-induced psychosis is rare, patients presenting with behavioral changes need physicians’ attention in order to diagnose early and efficiently treat encountered mood disorders.

Chloroquine-related depression

Article

Full-text available

Apr 1981

Drugs are known to induce depressive states. Chloroquine, an antimalarial, in therapeutic doses administered for malaria therapy, may produce symptoms rather indistinguishable from endogenous depression. The possible mechanisms of production of depression related to chloroquine use are hypothesised.

Chloroquine inhibits glutamate-induced death of a neuronal cell line by reducing reactive oxygen species through sigma-1 receptor

Article

Full-text available

Aug 2011
J NEUROCHEM

J. Neurochem. (2011) 119 , 839–847. Abstract Chloroquine, a widely used anti‐malarial and anti‐rheumatoid agent, has been reported to induce apoptotic and non‐apoptotic cell death. Accumulating evidence now suggests that chloroquine can sensitize cancer cells to cell death and augment chemotherapy‐induced apoptosis by inhibiting autophagy. However, chloroquine is reported to induce GM1 ganglioside accumulation in cultured cells at low μM concentrations and prevent damage to the blood brain barrier in mice. It remains unknown whether chloroquine has neuroprotective properties at concentrations below its reported ability to inhibit lysosomal enzymes and autophagy. In the present study, we demonstrated that chloroquine protected mouse hippocampal HT22 cells from glutamate‐induced oxidative stress by attenuating production of excess reactive oxygen species. The concentration of chloroquine required to rescue HT22 cells from oxidative stress was much lower than that sufficient enough to induce cell death and inhibit autophagy. Chloroquine increased GM1 level in HT22 cells at low μM concentrations but glutamate‐induced cell death occurred before GM1 accumulation, suggesting that GM1 induction is not related to the protective effect of chloroquine against glutamate‐induced cell death. Interestingly, BD1047 and NE‐100, sigma‐1 receptor antagonists, abrogated the protective effect of chloroquine against glutamate‐induced cell death and reactive oxygen species production. In addition, cutamesine (SA4503), a sigma‐1 receptor agonist, prevented both glutamate‐induced cell death and reactive oxygen species production. These findings indicate that chloroquine at concentrations below its ability to inhibit autophagy and induce cell death is able to rescue HT22 cells from glutamate‐induced cell death by reducing excessive production of reactive oxygen species through sigma‐1 receptors. These results suggest potential use of chloroquine, an established anti‐malarial agent, as a neuroprotectant against oxidative stress, which occurs in a variety of neurodegenerative diseases.

Chloroquine-induced subacute paranoid-like disorder as a complication of dermatological treatment

Article

Mar 2016

Activity of a new antimalarial agent, chloroquine (SN 7618)

Article

Psychosis following chloroquine ingestion: A 10-year comparative study from a malaria-hyperendemic district of India

Article

Nov 2013

Serious adverse effects such as acute psychoses have been reported following treatment with chloroquine. Chloroquine can cause cell death, including neurons. We aimed to identify the most frequent type of psychiatric manifestation and symptomatological characteristics of psychosis following chloroquine ingestion (PFC). Out of a total of 4471 randomly selected recent-onset psychosis patients, 3610 consecutive patients who had responded to standard treatment were screened for entry in the study. We compared background clinicodemographic profile information and psychopathology of 51 PFC patients, who were either drug free or drug naive, to 51 brief psychotic disorder (BPD) patients who were matched in terms of age, sex and education. Only those patients who remitted within 8weeks (PFC patients) or 4weeks (BPD patients) were included. Cranial computed tomography, electroencephalography and lumbar puncture of the entire experimental group were normal, and none had Mini Mental Status Examination score <22. Group difference and correlational statistics (parametric and nonparametric) have been used to test the hypotheses and explain the results. The most common (76.2%) type of psychiatric disturbance in PCF group was mood disorder (mixed episode) accompanied by predominant irritability with little blunting of affect. PFC patients characteristically had prominent positive symptoms with visual hallucination and derealization experiences. They were more restless, agitated and anxious and had more disturbed thought content and orientation, but better preserved insight. There was no linear relationship between the amount of chloroquine consumed and the severity of psychosis. Considering the large number of patients still receiving chloroquine especially in developing countries, this study has been presented to draw attention of the psychiatrists and other health professionals to the hazardous effect of chloroquine on mental health.

Psychiatric adverse effects of chloroquine

Abstract

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