[side effects of drugs annual] volume 22 || antiprotozoal drugs

Isabela Ribeiro, Charles Woodrow and Sanjeev Krishna

28 Antiprotozoal drugs ANTIMALARIAL DRUGS (SED-13, 799; SEDA-19, 262; SEDA-20, 257; SEDA-21, 293)

The current recommendations on the prevention and treatment of malaria have been reviewed (SEDA-20, 257; (1R), (2R)).

Drug combinations As with other antimicro- bial agents, the combination of two or more antimalarial drugs in treatment regimens for primary infections is being developed as a strategy to limit the emergence of drug resistance. Two related advantages accrue with combination regimens: the use of existing antimalarials to which resistance is developing may be prolonged, and resistance to new classes of antimalarials may be delayed. The potential disadvantage of combination regimens results from toxicity, which may arise through drug interactions as well as adverse effects of individual drug. The artemisinin derivatives seem to be relatively free from major toxicity, and for these and other reasons are now being studied in combination with a number of other, longer-acting antimalarials in many parts of the world. Chlorproguanil- dapsone and atovaquone-proguanil are also combinations under intensive investigation.

Artemisinin and derivatives (SED-13, 818; SEDA-19, 262; SEDA-20, 259; SEDA-21, 293)

For reviews of the safety of artemisinin derivatives, see SEDA-21 (p. 293) and (3R).

The artemisinin family of antimalarial drugs comprises a number of derivatives that are effective in the treatment of both uncomplicated and severe P. falciparum malaria.

�9 1999 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 22 J.K. Aronson, ed.

302

Five compounds are available in an array of formulations: artesunate (intravenous, rectal, and oral), artemisinin (intramuscular, rectal, and oral), dihydroartemisinin (oral), artemether (intramuscular, rectal, and oral), and arteether (intramuscular).

Until recently there was a paucity of pharmacokinetic studies on these derivatives, hampered by the non-availability of adequate analytical methods. However, in the last 2 years several studies have been published (4c)-(11c). Comparative studies on the antimalarial activity of these compounds have shown that short treatment courses are associated with significant incidence of recrudescence; regimens lasting 5-7 days minimize this risk. Shorter courses may achieve higher efficacy when combined with a longer-acting antimalarial, such as mefloquine (12c)-(24c). The combination of mefloquine (25 mg/kg) and 3 days artesunate (12 mg/kg) remains an effective treatment in areas of multi-drug resistance (18c), (24c), but concerns about the tolerability of mefioquine have led to a search for alternative partners for artemisinin derivatives, such as benflumetol (see below).

Recent reviews of clinical trials have con- firmed the benign safety profile of artemisinin derivatives (3R), (5R). Most adverse events were mild and transient, none resulted in dis- continuation of treatment, and no adverse drug interactions were observed. Indeed, the incidence of vomiting induced by mefloquine appears to be lower when it is given after artesunate (3R). Although most artemisinin derivatives produce a highly characteristic neurological lesion in several animal species, so far there is no convincing evidence of neurotoxicity in man.

The drug known as CGP 56697 includes a variety of oral formulations of artemether and benflumetol in a fixed ratio of 1:6. Benflume- tol (lumefantrine) is a Chinese fluorene deri- vative conforming to the arylamino alcohol group of antimalarials (which includes quin-

Antiprotozoal drugs Chapter 28 303

ine, mefloquine, and halofantrine) and has an elimination half-life of 4-5 days. CGP 56697 was efficacious and well tolerated in adults with uncomplicated malaria in China (25c). A phase II study in children and adults in Thailand (26 c) showed that CGP 56697 was less efficacious but better tolerated than the standard artesunate-mefloquine regimen. There were no serious adverse effects, although 4% of patients in the CGP 56697 arm experienced pruritus and/or a rash. In Gam- bian children CGP 56697 was efficacious and did not cause neurodevelopmental delay (27c), (28c). In Tanzania this drug combination was much more effective than chloroquine alone, although this study was carried out in an area of high chloroquine resistance (29c). Artemether-benflumetol is a promis- ing option for the treatment of uncomplicated malaria in areas of multi-drug resistance.

Atovaquone (SED-13, 828; SEDA-19, 266; SEDA-20, 259; SEDA-21, 294)

Atovaquone is considered under the section on the treatment and prophylaxis of Pneumo- cystis carinii pneumonia. The combination of atovaquone with proguanil is safe and effective in malaria and has recently been shown to be prophylactic in African children (30c).

CHLOROQUINE AND C O N G E N E R S (SED-13, 801; SEDA-19, 262; SEDA-20, 260; SEDA-21, 294)

Chloroquine and hydroxychloroquine

The efficacy of chloroquine in P. falciparum infection is now limited by parasite resistance in most parts of the world, and several African countries no longer use chloroquine as routine first-line treatment. However, it is still used to treat P. malariae, P. ovale, and P. vivax infections and as prophylaxis (in combination with proguanil) in pregnant women or when mefloquine is inappropriate.

Skin and appendages 'Pruritus' or scvcrc skin discomfort, predominantly in the palmar

and plantar areas occurs in 20% of Africans. Prednisolone (10mg, single dose) can miti- gate this adverse effect (31c). Other cutaneous reactions include eruptions, mucocut- aneous hyperpigmentation, and exacerbation of psoriasis. Acute generalized exanthematous pustulosis has been reported to be associatcd with chloroquine (100 mg/day) plus proguanil (32c).

Immunological and hypersensitivity reactions Immunosuppression has been documented in soldiers taking chloroquine as long-term prophylaxis (33c), although the likelihood of opportunistic infections is low. An area of imme- diate practical concern to physicians managing travellers is the potential for antimalarials to interfere with vaccination, as previously ex- emplified by depressed immune responses to live rabies vaccination. Chloroquine and chlorproguanil, respectively, interfere with immunization with the live cholera vaccine CVD103-HgR (34 c) and the live typhoid vaccine Ty21a. The mechanism of this interfer- ence may involve inhibition of antigen pre- sentation and does not represent direct antibacterial activity of antimalarials. Chloro- quine had no significant effect on tetanus- diphtheria vaccination (35(:).

Amodiaquine (SED-13, 807; SEDA-20, 260)

Amodiaquine, a 4-aminoquinoline, has been used to treat and prevent malaria in the past. In the mid-1980s reports of fatal adverse reactions appeared, including agranulocytosis, hepatotoxicity, and aplastic anemia, and its licence for prophylaxis and first-line treatment was withdrawn. However, a review of amodiaquine treatment for uncomplicated malaria (36 R) showed that tolerability was no worse than chloroquine or pyrimethamine-sulfadoxine and that life-threatening adverse reactions were reported only when the drug was uscd as prophylaxis. This conclusion was based on retrospective data only. Although there is partial cross-resistance between chloroquine and amodiaquine, amodiaquine remains a valuable drug that may have potential as first- line treatment of malaria.

304 Chapter 28 lsabela Ribeiro, Charles Woodrow and Sanjeev Krishna

Halofantrine (SED-13, 820; SEDA-19, 263; SEDA-20, 260; SEDA-21, 295)

Mefloquine (SED-13, 808; SEDA-19, 265; SEDA-20, 261; SEDA-21, 296)

Halofantrine is a phenanthrene methanol belonging to the arylaminoalcohol family. It is used as an alternative t reatment for uncomplicated P. falciparum malaria in areas with a high prevalence of multiple drug resistance. No cross-resistance with chloroquine and atovaquone has been documented (37c), but there may be cross-susceptibility with quinine, mefloquine, and ar temether (38c). Over the past year, there has been a sharp fall in susceptibility in isolates from Gabon (39 c) and Burkina Faso (40c). In view of its potential for cardiotoxicity, cautious use of halofantrine has been advocated, particularly as a stand-by treatment for febrile illness among travellers (41 r) or as a second-line t reatment of P. falciparum malaria (42c), (43~ A combinat ion regimen of halofantrine with pr imaquine was superior to chloroquine for the t rea tment of uncomplicated P. falciparum and P. vivax infections in Indonesia, with 100% cure rates at 28-day follow-up (44c). The regimen was well tolerated with no serious adverse effects.

Cardiovascular Halofantr ine prolongs cardiac repolarization and prolongs the QT interval. It causes dose-related life-threatening cardiac dysrhythmias, such as torsade de pointes (SEDA-20, 263; SEDA-21, 295; (41r)). A recent review of the literature and databases of the F D A has shown clear sex differences in the incidence of this phenome- non, women being at a higher risk for the development of halofantrine-related ventricular dysrhythmias (45r). The case of a young woman with no predisposing prolongation of the QTc interval has recently been reported (46c).

Hematological Hemolysis imitating blackwater fever can follow treatment with halofantrine, as illustrated in two patients with a history of previous uncomplicated quinine treatment (47c).

Hypersensitivity and immunological reactions Thc first case of anaphylactic shock with halofantrine has been reported (48c).

Mefloquine remains useful in the t reatment of uncomplicated malaria in areas of chloroquine resistance. The recommendat ions for mefloquine as prophylaxis in travellers are under constant review. An examinat ion of the value of mefloquine prophylaxis has prompted debate about the tolerability of the drug (49c).

Cardiovascular Mefloquine pre- t reatment exacerbated the QT,, prolongation caused by halofantrine (50c), but mefloquine itself does not prolong the QT~ interval (51c), (52c). Two recent reports have described abnormali- ties of atrial and nodal conduction associated with mefloquine (53c), (54c).

A 32-year-old man with no previous cardiac history took weekly mefloquine at the recommended dose during a trip to Thailand. Two days after each of the fourth, fifth, sixth, and seventh doses he had palpitation, dizziness, and vertigo. These symptoms disappeared within 2 days on all occasions. An electrocardiogram 3 days after the seventh dose showed aberrantly conducted beats, each followed by an aberrantly conducted echo-beat. There was no prolongation of the QTc interval. Cardiac enzymes, echocardiography, and stress ECG showed no evidence of coronary insufficiency. The coupled aberrantly conducted beats occurred less often after withdrawal of mefloquine., Cardiograms later showed a relatively short PR interval, possibly related to a hitherto symptom-free Lown-Ganong- Levine syndrome.

A 63-year-old man, with a short history of bouts of palpitation 35 years before, presented with palpitation and chest discomfort 2 days after taking a first dose (250 mg) of mefloquine for a planned jour- ney to Thailand. His electrocardiogram showed a regular narrow-complex tachycardia of 260/min. Administration of adenosine revealed atrial activity, confirming a diagnosis of atrial flutter with 1 :l A:V conduction. Administration of digoxin and sotalol changed A:V conduction to 2:1 before sinus rhythm was restored. Electrolytes, thyroid hormone concentrations, and echocardiogram were all normal.

Nervous system Disabling neuropsychiatric reactions after t reatment and as prophylaxis have been reported in a child for the first time (55c). A comparison of ar tesunate-mefloquine with ar temether-benf lumetol (26 c) has given an estimate of the true incidence of mefloquine-attr ibutable neurological adverse


effects (overall 10%), such as dizziness, sleep disorders, abnormal gait, paresthesia, tremor, nystagmus, and ataxia. The association of the postmalaria neurological syndrome with mefloquine treatment suggests that mefloquine should not be used in the treatment of severe malaria.

Skin and appendages Mefloquine has previously been associated with erythema multi- forme and Stevens-Johnson syndrome. The first case of toxic epidermal necrolysis associated with mefloquine prophylaxis has now been reported (56c).

A 6-year-old healthy Nigerian girl, resident in the UK, began to take 125 mg mefloquine weekly a week before travelling to Nigeria. Five weeks later she developed blistering of the oral mucosa with periorbital and facial swelling. The blistering wors- ened and progressed to exfoliation of 95% of the body surface over 48 h. There was ulceration of the mueosal surfaces and her hair and nails were shed. She developed several complications of severe skin loss and was managed in a pediatric intensive care unit. Measures included careful attention to fluid balance, broad-spectrum antibiotics, and total par- enteral nutrition. Although her pyrexia resolved and re-epithelialization began, cardiac asystole occurred and resuscitation attempts were unsuccess- ful. Necropsy was refused.

Use in pregnancy Mefloquine is teratogenic in animals given 5-20 times the recommended human dose. However, analysis of 1627 spon- taneous reports of mefloquine exposure (data collected by the manufacturer) immediately before or during pregnancy has failed to de- monstrate any particular type or increased prevalence of malformations (57(:). In the US mefloquine is considered by the FDA as class III, i.e. it may be appropriate prophylaxis in pregnant women who travel to malarial areas, since the benefit of prophylaxis outweighs the risk of teratogenicity.

Primaquine and congeners (8-aminoquinolines) (SED-13. 810: SEDA-19, 264; SEDA-21, 296)

Primaquine is an 8-aminoquinoline amima- larial used to eradicate the hepatic stages of P. vivax and P. ovale and as prophylaxis against P. falciparum. It is less immunosup- pressive than chloroquine (33c). Primaquine prophylaxis enhanced anti-tetanus antibody titres after diphtheria-tetanus immunization (35%.

Etaquine (WR 238605) (SED-13. 811)

Etaquine, an analog of primaquine with a half-life of 14 days, had greater efficacy and less toxicity than primaquine in preclinical studies. Initial studies in healthy volunteers showed only mild, transient gastrointestinal adverse effects at doses of 300-600 mg (59c). The relative hemolytic potential of WR 238605 compared with primaquine is un- known, since individuals with G6PD defi- ciency were excluded. In a subsequent efficacy study a single dose of 300 mg had good efficacy, protecting three of four subjects challenged with malaria (60c). In the subject who developed malaria, patcncy was delayed for 3 weeks compared with controls, and symptoms were less severe. These safety, efficacy, and pharmacokinetic properties make etaquine a strong candidate for further testing as a prophylactic, radical curative, and termi- nal eradication drug.

P r o g u a n i l a n d c o n g e n e r s (SED-13,

811)

Interactions The combination of mefloquine with quinine may be encountered in self-med- ication polypharmacy or when failed mefloquine treatment requires a course of quinine (or vice versa). Understandably, there has been concern that the two drugs may have a clinically significant pharmacodynamic interaction, but there was no evidence for this in one small study (58c).

Hematological The potential of proguanil to cause serious bone marrow toxicity when it accumulates in patients with chronic renal failure has again been demonstrated (61c).

Immunological and hypersensitivity reactions Chlorproguanil interferes with immunization with the live typhoid vaccine Ty21a, as noted above.

306 Chapter 28 Isabela Ribeiro, Charles Woodrow and Sanjeev Krishna

Chiorproguanil-dapsone

The antifolate combination chlorproguanil- dapsone is cleared more rapidly from the body than the pyrimethamine-sulfadoxine combination and may therefore exert less long-term selection pressure on parasites. Furthermore, the mutation that is thought to confer resistance to chlorcycloguanil (the active metabolite of chlorproguanil) is relatively rare in Africa, and chlorproguanil-dapsone is more potent in vitro than pyrimethamine- sulfadoxine. A pharmacokinetic study (62 c) and a trial (63 c) in Kenya have shown that a 3-day course of daily chlorproguanil-dapsone is safe and effective in children with uncomplicated malaria. A comparable regimen had a high failure rate in Thailand, where multi- drug resistance is more prevalent. Chlorprog- uanil-dapsone is a relatively cheap drug combination that may find use as an effective alternative to pyrimethamine-sulfadoxine in areas such as East Africa, where resistance to antifolates is present but not so entrenched as in South-East Asia.

Pyronaridine (SEDA-21, 297)

Pyronaridine is an acridine antimalarial with a relatively slow action that has been used to treat uncomplicated P. falciparum and P. vivax malaria in China for the past 20 years. Pyronaridine was efficacious and safe for the treatment of uncomplicated chloroquine-resistant falciparum malaria in children in Cameroon; adverse effects associated with it were minor, transient, and mainly limited to the gastrointestinal tract (64c). Pyronaridine was also effective against P. ovale and P. malariae infections in this population (65c). How- ever, on the China-Laos PDR border the average defervescence time of falciparum malaria treated by pyronaridine has increased from 33 to 56 h, with recrudescence rates rising from 15 to 38% in 1995 (66c).

Quinine and congeners (SED-13,

814; SEDA-19, 265; SEDA-20, 261;

SEDA-21, 297)

Overdosage Quinine is widely prescribed as symptomatic treatment for leg cramps, and cases of self-poisoning appear to be common (67c). Acute intoxication is associated with blindness, cardiotoxicity, and acute renal failure; death has been reported with a dose of as little as 8 g. Management consists of measures to reduce quinine absorption. Hyp- erbaric oxygen has been proposed as specific therapy for blindness.

M a l a r i a v a c c i n e s (SED-13, 822;

SEDA-21, 298)

For reviews of the current strategies for vaccine development, see (68R)--(70R).

Candidate malaria vaccines have failed to elicit consistently protective immune responses against challenge with P. falciparum (71c)-(76c). To circumvent difficulties due to parasite polymorphism and genetic restriction of T-cell responses, new strategies are being devised, such as the use o f DNA vaccines. Phase I studies o f a DNA vaccine containing sequence from 10 peptides demonstrated good cytotoxie T-lymphocyte 'responses (77c); the toxicity profile will be reported in the near future. Optimization of multigene P. falciparum DNA vaccines will require extensive clinical trials during coming years (78c).

Another vaccine candidate is the multiple antigen peptide (MAP) system consisting of multiple copies o f a B-cell epitope from the central repeat region of the P. falciparum circumsporozoite protein (PfCSP), in combination with a universal T-cell epitope, the P2P3O portion of tetanus toxin. Rodent studies showed high immunogenicity o f this vaccine formulated with a different adjuvant, speci- fically in liposomes, lipid A , and aluminium hydroxide (79c).

Recombinant constructs representing both major allelic forms of the P. falciparum merozoite surface antigen (MSA-2) have been formulated with a range of adjuvants, with good results (80c). The merozoite surface protein-1 (MSP- 1) has also emerged as a potential target.


Two new types o f vaccines are under preliminary clinical evaluation. One is directed against sexual-stage surface antigens o f P. falciparum (Pfs25 and Pfs28) and can block the transmission o f the disease (81c)-(83c). The other is an antisporozoite vaccine with a new immunogen (RTS, S) in which the circumsporozoite protein is fused to the hepatitis B surface antigen and can protect against infection (84c), (85c).

Another strategy in vaccine development is the use o f enhancers, such as recombinant vac- einia viruses (86 c) and GM-CSF (87c). NY- VAC-Pf7, a highly attenuated vaccinia virus with fragments o f seven P. falciparum genes inserted into its genome, was recently tested in a phase l/lla trial in healthy volunteers, who received three immunizations o f two different dosages o f N Y V A C - P f 7 (88c). The vaccine was safe and well tolerated but variably immunogenic. While antibody responses were generally poor, cellular immune responses were detected in over 90% of the volunteers.

DRUGS USED FOR P N E U M O C Y S T I S CARINI1 PNEUMONIA

The drugs used for the treatment and prophylaxis of Pneumocystis carinii pneumonia have been reviewed (SEDA-20, 266; (89R) - (92R)).

Atovaquone (SED-13, 828; SEDA-19,

266; SEDA-20, 264; SEDA-21, 298)

Atovaquone is a hydroxynaphthaquinone compound active in the prevention and treatment of Pneumocystis carinii pneumonia, P. falciparum malaria, and Toxoplasma gondii infections.

The oral suspension of micronized atovaquone is under investigation in infants and children. A recent Phase I study conducted by the Pediatric AIDS Clinical Trials Group has shown that this formulation is safe and well tolerated in children. A single daily dose of 30 mg/kg may be adequate for therapy of P. carinii pneumonia, but infants aged 3-24

months may require a dosage of 45 mg/kg per day (93c).

Co-trimoxazole (trimethoprim- sulfamethoxazole) (SED-13, 826;

SEDA-19, 268; SEDA-20, 264; SEDA-21, 299)

Co-trimoxazole remains the mainstay for the prophylaxis and treatment of a variety of opportunistic infections in HIV-infected patients (89R)--(91R). Nevertheless, it is under- used because of the high incidence of adversc events. A recent meta-analysis has been published on the relative efficacy and toxicity of P. carinii prophylactic regimens (94R). Re- gardless of dose, co-trimoxazole was almost universally effective for patients who tolerated it. Substituting one double-strength tablet (1600/320 mg) three times a week instead of the standard tablet daily led to a reduction of 43% (95% CI 30-54%) in the number of patients who had to discontinue the drug because of adverse effects.

Nervous system Co-trimoxazole-induced aseptic meningitis has been described before (SEDA-19, 269; SEDA-21, 299). A similar adverse effect reported in a patient treated solely with trimethoprim was also associated with uveitis (95c). Although the trimethoprim component has been implicated as a cause of aseptic meningitis in the past (96c), (97c), uveitis has so far been attributed to sulfonam- ides (98r

An 18-year-old woman presented with a recent history of recurrent urinary tract infections. During her second episode of urinary tract infection treated with trimethoprim, she developed headache, red and sore eyes, and neck ache within hours of the first dose. She was given amoxicillin-clavulanatc instead and completed a 7-day course. Her eye pain persisted for 2 weeks. Two months later, she developed headache, fever, painful red eyes, and photo- phobia after having been given trimethoprim for urinary tract symptoms. She had neck stiffness and a positive Kernig's sign. A slit lamp examination showed white cells in the anterior chamber and a proteinaceous 'flare', consistent with a diagnosis of bilateral anterior uveitis.

Other neurological adverse effects include headaches, ataxia, peripheral neuritis, sei-

308 Chapter 28 lsabela Ribeiro, Charles Woodrow and San jeer Krishna

zures, hallucinations, and tremor. T he first case of isolated t r e m o r ascr ibed to co-tr imoxazole has been r epo r t ed in a pa t i en t with A I D S (99c).

A 46-year-old man with a 6-year history of AIDS was evaluated for 'shakes'. He had taken co-trimoxazole for PCP for 13 days and had experienced increasing tremulousness over the preceding 10 days. His other medications included paroxetine, didanosine, prednisone, leucovorin, clotrimazole, and diazepam, none of which had been started recently. He had no known AIDS-related neurological complication, except for mild sensory neuro- pathy, thought to be associated with didanosine. Neurological examination showed a bilateral, high frequency, low amplitude postural tremor, greater in the arms than the legs. It was less prominent on finger-nose and heel-shin testing and absent at rest. He had a similar tremor of the head. His handwriting was markedly impaired. His gait was hesitant but not wide-based. He was slightly un- steady but did not tend to fall to one side or the other. The remainder of the physical examination was unremarkable. A cranial CT scan and lumbar puncture were within normal limits. A tentative diagnosis of co-trimoxazole-induced tremor was made, and the drug was withheld. His symptoms resolved within 3 days.

Endocr ine , metabol ic Because they are structurally s imilar to suifonylureas , sulfona- mides may cause hypoglycemia in suscept ible individuals by increas ing pancreat ic secre t ion of insulin. Hypoglycemia resul t ing f rom a combina t ion of sulfonylureas and sulfonam- ides is well recognised. Nine cases of hypoglycemia have b e e n r epo r t ed with the isolated use of co- t r imoxazole alone. Ove r the past year, two fur ther cases have b e e n descr ibed, one in a pa t ien t with acute renal fai lure and ano the r in a ma lnour i shed pat ient with severe infect ion (100~), (101c).

Urinary system The t r ime thopr im component of co- t r imoxazole can cause mild reversible increases in serum creatinine, repor ted ly by inhibi t ing its renal tubu la r secre t ion (102c).

Minera l and fluid ba lance T r i m e t h o p r i m has also been implicated in an amilor ide- l ike ac- t ion on the distal tubule , leading to hyperkale- mia with bo th h igh and low doses (103c), (104c), (105c). Severe symptomat ic hyper- kalemia has recent ly b e e n repor ted in a pa- t ient with hyporen inemic hypoa ldos te ron i sm taking a s tandard dose of co- t r imoxazole

(106c). This case h ighl ighted the impor tance of careful fol low-up of pa t i en t s with distur- bances of po tass ium homeos tas i s , and espe- cially of renal potass ium handl ing , who are t rea ted with co-tr imoxazole. A new mechanism of hyperka lemia has also b e e n descr ibed in a pa t ien t taking a s t andard dose of co- t r imoxazole for p ro longed t r e a t m e n t of a urinary tract infect ion: vo l t age -dependen t renal tubu la r acidosis with consequen t hyperkale- mia and hyperch loremic me tabo l i c acidosis (107c).

Liver and bi l iary The first case of vanishing bile duct syndrome has b e e n repor ted with co- t r imoxazole (108c). This rare syndrome is charac ter ized by progressive cholestasis, caused by the i r reversible loss of bile ducts, which can lead to progressive l iver failure.

A 57-year-old Samoan-American man with no significant past medical history developed jaundice within 5 days of taking a therapeutic course of co- trimoxazole (800/160mg) for prostatitis. Before therapy, liver enzymes and hematological tests had been within normal limits. Five days after the start of co-trimoxazole the AsT was 205 U/1 (reference range 10-45 U/l), the AIT was 465 U/1 (10-45 U/l), the alkaline phosphatase 295 U/1 (30-130 U/I), and the total bilirubin 34 i~mol/1 (under 20 Ixmol/1). Prothrombin, partial thromboplastin, serum iron concentration, and iron-binding capacity were normal. Drug-induced cholestasis was suspected and co-trimoxazole was withdrawn. A liver biopsy 12 weeks later showed severe intrahepatic cholestasis and bile ducts in fewer than 25% of the portal tracts. Antinuclear and antimitochondrial antibodies, hepatitis A, B, and C virus serology, HIV testing, abdominal CT scan, and endoscopic retro- grade cholangiopancreatography were normal. Anti-smooth muscle antibodies were positive (1:640). Prednisone 40 rag/day produced no significant response. After orthotopic liver transplanta- tion, histology showed extensive fibrosis and almost complete loss of bile ducts from the portal tracts.

Drug- induced duc topen ia can progress long af ter the of fending drug is wi thdrawn. Al- though the t i ters of an t i - smooth muscle antibodies were raised in this case, the diagnosis of a u t o i m m u n e hepat i t is was felt to be un- likely, given the histological fea tures and the absence of response to steroids.

Skin and appendages Two repor t s of fixed drug eruption have appeared , one descr ibed as l inear (ex tending from the la teral aspect of


the fourth and fifth finger, along the wrist and lateral aspect of the extensor surface of the arm) and the other post-coitally on the cor- onal sulcus of the penis (109c), (110c).

Immunological and hypersensitivity reactions Some cutaneous reactions to co-trimoxazole may be immunologically mediated and may be due to common antigenic determinants between drug and viruses or the build-up of toxic hydroxyalamine metabolites of sulfamethoxazole that can function as haptens. There is increasing confidence in the efficacy of desensitization protocols for non-life-threatening adverse reactions to co-trimoxazole, with success rates of 45-97% ( l l lR)- - ( l l3R) , (114C), (115C). Some questions, however, still remain. It is unclear whether reinstitution of full-dose therapy (rechailenge) or a dose es- calation regimen ('desensitization') is better. However, desensitization, although useful, is not entirely safe.

There have been reports of anaphylactoid reactions (l13R), consisting of erythematous rash, conjunctivitis, acute fever, intense pruritus, and hypotension on re-exposure, oc- casionally associated with pulmonary infil- trates, dyspnea, hypoxemia, and renal failure.

A co-trimoxazole desensitization syndrome with delayed hematological toxicity has also been described (l16R).

Interactions A case of hyperpigmentation of flexures and pancytopenia has been reported with the combined used of co-trimoxazole and pyrimethamine (117c). This reaction was thought to be a manifestation of folate defi- ciency caused by the use of the two folate antagonists.

It also has activity against other human patho- gens, e.g. Mycobacterium leprae, and has been used in the treatment of chronic autoim- mune thrombocytopenic purpura. Dapsone is well absorbed (70%-80%) from the gastrointestinal tract, reaches a peak serum concentration in 2-6 h, and is adequately distributed to the fluid of the alveolar spaces. The combination with trimethoprim is recommended for therapeutic use for P. carinii pneumonia in patients who cannot tolerate co-trimoxazole. Dapsone is also active against P. falciparum and is used in combination with proguanil (scc above) and pyrimethamine.

Evidence from more than 40 studies of dapsone as prophylaxis for P. carinii pneumonia in AIDS patients has shown that dapsone, either alone or in combination with pyrimethamine, is as effective as aerosolized pentamid- ine or atovaquone but slightly less effective than co-trimoxazole (l18R). A recent meta- analysis (94 R) has shown that among 100 patients given dapsone 100 mg/day instead of twice a week for 1 year for primary prophylaxis of P. carinii, seven fewer patients would develop it, but 17 more would have significant toxic reactions. Thus, low doses of dapsone reduce toxic effects, but at the expense of some loss of efficacy. Adverse effects include rash, anemia, methemoglobinemia, agranulocytosis, hepatic dysfunction, and dose-dependent hemolysis, particularly in patients with glucose-6-phosphate dehydrogenase defi- ciency. There has been a recent report of urinary tract carcinoma among 12 leprosy patients treated with dapsone for long periods (2-25 years); however, all these patients had also taken phenacetin-containing analgesics (119c).

Dapsone (SED-13, 826)

The use of dapsone for the treatment and prevention of P. carinii infection has recently been reviewed (l18R).

Dapsone, with or without trimethoprim or pyrimethamine, has strong activity against P. carinii, as demonstrated by in vitro methods, animal studies, and clinical trials. Dapsone blocks folic acid synthesis in P. carinii by inhibition of dihydroptcroatc synthctase activity.

DRUGS USED FOR TOXOPLASMOSIS

Sulfadiazine

Sulfadiazine-pyrimethamine is the drug combination of choice in thc treatment of toxoplasmosis.

Urinary system Sulfonamide-induced crys-


talluria with renal failure is well documented and there have been several case reports of this complication among patients with AIDS treated for cerebral toxoplasmosis. A third case of sulfadiazine-induced obstructive renal failure secondary to crystalluria, requiring surgical intervention has now been described (120c).

Salivary glands The first case of sialadenitis induced by sulfadiazine has been described (121c).

A 50-year-old man, a long-time smoker with a history of chronic bronchitis and allergy to/3-1actam antibiotics, was given Bronco-aseptilex | (sulfadiazine 350 mg/5 ml, cyclamate, and guaiacol) for an exacerbation of chronic bronchitis. Two hours after the first dose (5 ml of syrup), he noted a swelling in his throat and the floor of his mouth, and plug- ging of his ears. He was treated with antihistamines and prednisone and Bronco-aseptilex | was discon- tinued. He recovered completely after 3 days. Prick testing with an undiluted solution of Bronco-aseptilex | and diluted sulfadiazine was negative. There was bilateral swelling of the parotid and submandib- ular glands after single-blind oral challenges with Bronco-aseptilex | and sulfadiazine.

DRUGS FOR VISCERAL LEISHMANIASIS

Pentavalent antimonials have been the mainstay in the treatment of visceral leishmaniasis (kala-azar). These drugs commonly cause myalgia and arthralgia, and case reports have emphasized the potential of sodium antimony gluconate to cause cardiotoxicity (122c), (123c).

Cardiovascular Lot-to-lot variations occur in the manufacture of antimony formulations, and these may influence clinical efficacy and toxicity. All eight cases of visceral leishmaniasis treated with sodium antimony gluconate 20 mg/kg per day from one relatively high osmolarity lot developed cardiotoxicity 3-28 days after starting therapy. This consisted of congestive cardh~c failure, prolongation of the QTc interval, and ventricular extra beats followed by ventricular tachycardia, torsade de pointes, and ventricular fibrillation; three patients died. No patient had taken a total dose of more than 600 mg/kg. The authors pro-

posed that the osmolarity of formulations should be measured to help identify inappro- priately manufactured drug (124c).

Visceral leishmaniasis is becoming increas- ingly resistant to sodium antimony gluconate in Bihar State, India, so that new drugs (or preferably combinations of drugs to prevent the emergence of resistance) are urgently needed (125r). Amphotericin B is efficacious, but has a poor safety profile in this population (in addition to which the lipid complex form is prohibitively expensive) and furthermore increases the cardiotoxicity associated with sodium antimony gluconate. In a study of patients treated with amphotericin B after failure to respond to sodium antimony gluconate, amphotericin B precipitated ventricular dysrhythmias and cardiac arrest on the first day of infusion in three of seven patients who still had electrocardiographic evidence of antimonial-related cardiotoxicity (126c). Patients given a 10-day rest period after treatment with sodium antimony gluconate before starting amphotericin B, allowing the cardiogram to stabilize, did not develop any cardiac prob- lem. In patients with visceral leishmaniasis who fail to respond to sodium antimony gluconate but have electrocardiographic evidence of cardiotoxicity, amphotericin B should be delayed for at least 10 days to allow resolution of antimonial-related cardiotoxicity. It must be noted that this interaction could reasonably have been predicted in advance, given the potential of amphotericin B to cause hypokalemia, itself a cause of a long QT interval. Intravenous aminosidine (a 21-day course of 16 or 20 mg/kg) is highly efficacious in this area (127c), but its adverse effects profile is not fully documented, particularly in terms of neuro-ototoxicity. Furthermore, intravenous aminosidine is not currently being marketed.

OTHER COMPOUNDS

Furazolidone (SED-13, 837)

Psychiatric A prolonged course of furazolidone given to a patient with AIDS for the treatment of giardiasis resistant to metronida-


zole was associated with an episode of hypo- mania (128c). The mechan i sm may have involved cumulat ive m o n o a m i n e oxidase inhi- bit ion.

Metronidazole (SED-13, 831; SEDA-19, 270; SEDA-21, 301)

Neuropsychia t r ic Met ron idazo le can cause a n u m b e r of neuropsychia t r ic adverse effects, such as encephalopathy, cerebellar dysfunction, seizures, states of confusion, excitation, and depression. An episode of major psycho- sis has b e e n a t t r ibu ted to a 5-day course of in t ravenous met ron idazo le (129c).

Use in pregnancy Met ron idazo le readily

crosses the p lacenta , and its use in pregnancy is controvers ia l . It is classified according to the F D A risk categories for d rug use dur ing p regnancy as a B risk drug: i.e. e i ther animal reproduc t ion studies have not shown risk to the fetus but there are no cont ro l led studies in p regnan t women , or animal studies have shown an adverse effect on the fetus tha t was not conf i rmed in control led studies in women in the first t r imes ter of p regnancy . The manu- fac turer and the Centers for Disease Cont ro l have s ta ted that met ron idazo le should not bc used dur ing the first t r imester . However , since the re are no opt ions for the t r ea tmen t of trich- omonias is , me t ron idazo le is of ten used to t rea t this infect ion dur ing p regnancy (130"). A recen t recta-analysis did not show any re la t ion be t ween met ron idazo le exposure dur ing the first t r imes ter of p regnancy and bir th defects (131R).

R E F E R E N C E S

1. Bradley D J, Warhurst DC. Guidelines for the prevention of malaria in travellers from the United Kingdom. Commun Dis Rep CDR Rev 1997;7:R137-52

2. White NJ. The treatment of malaria. New Engl J Med 1997;335:800-6.

3. Ribeiro I, Olliaro P. Safety of artemisinin and its derivatives. A systematic review of published and unpublished clinical trials. Paper presented at 'The rational use of qinghaosu and its derivatives', a conference convened by the International Lav- eran Association, Annecy, France, 19-22 April 1998.

4. Hassan-Alin M, Ashton M, Kihamia CM, Mtey G J, Bjorkman A. Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg 1996;90:61-5.

5. Alin MH, Ashton M, Kihamia CM, Mtey GJB, Bjorkman A. Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria. Br J Clin Pharmacol 1996; 41:587-92. 6. Batty KT, Thu LTA, Davis TME, Ilett KF, Mai TX, Hung NC, Tien NP, Powell SM, Thien HV, Binh TQ, Kim NV. A pharmacokinetic and pharmacodynamic study of intravenous vs. oral artesunate in uncomplicated malaria. Br J Clin Pharmacol 1998;45:123-9.

7. Benakis A, Paris M, Loutan L, Plessas CT, Plessas ST. Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Mcd Hyg 1997;56:17-23.

8. Benakis A, Paris M, Loutan L, Plessas CT,

Plessas ST. Pharmacokinetic study of a new phar- maceutical form of artesunate (Plasmotrim 200 Rectocaps) administered in healthy volunteers by rectal route. Jpn J Trop Med Hyg 1996;24 (Suppl 1):39-45.

9. Bethell DB, Teja-Isavadharm P, Phuong CXT, Thuy PT1 ~, Mai TTF, Thuy TTN, Ha NJ'F, Phuong PT, Kyle D, Day NPJ, White NJ. Phar- macokinetics of oral artcsunate in children with moderately severe Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 1997;91:195- 8.

10. De Vries PJ, Tran Khac Dien, Nguyen Xuan Khanh, Le Nguyen Binh, Pham Thi Yen, Dao Din Duc, Van Boxtel CJ, Kager PA. The pharmacokinetics of a single dose of artemisinin in patients with uncomplicated falciparum malaria. Am J Trop Med Hyg 1997;56:503-7.

11. Benakis A, Paris M, Anh TK, Binh TQ, Plessas CT, Plessas ST. Pharmacokinetic study of dihidroartemisinin in malaria patients in Vietnam. Jpn J Trop Med Hyg 1996;24 (Suppl 1):71-6.

12. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Suntharasamai P, Charoenlarp P, Arnold K, Kyle D, Canfield C, Webster K. Ran- domised trial of artesunatc and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet 1992;339:821-4.

13. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Pitisuttithum P, Andrial M. Com- parative clinical trial of artesunate followed by mefloquine in the treatment of acute uncomplicated falciparum malaria: two- and three-day regimens. Am J Trop Med Hyg 1996;54:210-13.

14. Looareesuwan S, Vanijanonta S, Viravan C, Wilairatana P, Charoenlarp P, Andrial M. Ran-


domised trial of mefloquine alone and artesunate followed by mefloquine for the treatment of acute uncomplicated falciparum malaria. Ann Trop Med Parasitol 1994;88:131-6.

15. Luxemburger C, ter Kuile FO, Nosten F, Dolan G, Bradol JH, Phaipun L, Chongsuphajais- iddhi T, White NJ. Single day mefloquine-artesunate combination in the treatment of multidrug resistant falciparum malaria. Trans R Soc Trop Mcd Hyg 1994;88:213-17.

16. Nosten F Artemisinin: large community studies Trans R Soc Trop Med Hyg 1994;88 (Suppl 1):$45-6.

17. Looareesuwan S, Wilairatana P, Vanijanonta S, Viravan C, Andrial M. Efficacy and tolerability of a sequential, artesunate suppository followed by mefloquine, treatment of severe falciparum malaria. Ann Trop Med Parasitol 1995;89:469- 75.

18. Sabchareon A, Attanath P, Chanthavanich P, Phanuaksook, Prarinyanupharb V, Poonpanich Y, Mookamanee P, Teja-Isavadharm P, Heppner DG, Brewer TG, Chongsuphajaisiddhi T. Com- parative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria. Am J Trop Med Hyg 1998;58:11- 16.

19. Looareesuwan S, Wilairatana P, Molunto W, Chalermrut K, Olliaro P, Andrial M. A comparative clinical trial of sequential treatments of severe malaria with artesunate suppository followed by mefloquine in Thailand. Am J Trop Med Hyg 1997 ;57: 348-53.

20. Bhatt KM, Bhatt SM, Omonge E, Oteko L, Andrial M. Efficacy and tolerability of a sequential artesunate suppository-mefloquine treatment of severe falciparum malaria. Jpn J Trop Med Hyg 1996;24 (Suppl 1):59-63.

21. G6mez-Landires EA. Efficacy of artesunate suppository followed by oral mefloquine in the treatment of severe falciparum malaria in endemic areas where resistance to chloroquine exists in Ecuador. Jpn J Trop Med Hyg 1996;24 (Suppl 1):17-24.

22. Thwe Y, Than M, Phay S, Oo AZ, Soe AY. Artesunate suppository-mefloquine tablets (Plas- motrim, Rectocaps, Mefloquine, Lactab) in the treatment of severe falciparum malaria. Jpn J Trop Med Hyg 1996;24 (Suppl 1):25-32.

23. Kyaw W, Than M, Thwe Y, Gyi KK, Soe AY, Sabai, Ye H, Tint K, Aye KM. Efficacy of artemether and artesunate suppositories (Recto- caps) in the treatment of uncomplicated falciparum malaria. Jpn J Trop Med Hyg 1996;24 (Suppl 1):55-8.

24. Price RN, Nosten F, Luxemburger C, van Vugt M, Phaipun L, Chongsuphajaisiddhi T, White NJ. Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Trans R Soc Trop Med Hyg 1997;91:574-7.

25. Jiao X, Liu GY, Shan CO, Zhao X, Li XW, Gathmann 1, Royce C. Phase II trial in China of a new, rapidly-acting and effective oral antima-

larial, CGP 56697, for the treatment of Plasmo- dium falciparum malaria. Southeast Asian J Trop Med Public Health 1997;28:476-81.

26. Van Vugt M, Brockman A, Gemperli B, Lux- emburger C, Gathmann 1, Royce C, Slight T, Looareesuwan S, White N J, Nosten F. Random- ized comparison of artemetherbenflumetol and ar- tesunatemefloquine in treatment of multidrug- resistant falciparum malaria. Antimicrob Agents Chemother 1998;42:135-9.

27. Von Seidlein L, Jaffar S, Pinder M, Haywood M, Snounou G, Gemperli B, Gathmann I, Royce C, Greenwood B. Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697. J Infect Dis 1997;176:1113-16.

28. Von Seidlein L, Bojang K, Jones P, Jaffar S, Pinder M, Obaro S, Doherty T, Haywood M, Snounou G, Gemperli B, Gathmann I, Royce C, McAdam K, Greenwood B. A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children. Am J Trop Med Hyg 1998 ;58:638-44.

29. Hatz C, Abdulla S, Mull R, Schellenberg D, Gathmann I, Kibatala P, Beck H-P, Tanner M, Royce C. Efficacy and safety of CGP 56697 (artemether and benflumetol) compared with chloroquine to treat acute falciparum malaria in Tanzan- ian children aged 1-5 years. Trop Med Int Health 1998;3:498-504.

30. Lell B, Luckner D, Ndjave M, Scott T, Kremsner PG. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet 1998;351:709-13.

31. Adebayo RA, Sofowora GG, Onayemi O, Udoh S J, Ajayi AA. Chloroquine-induced pruritus in malaria fever: contribution of malaria para- sitaemia and the effects of prednisolone, niacin, and their combination, compared with antihista- mine. Br J Ctin Pharmacol 1997;44:157-61.

32. Janier M, Froidevaux D, Lons-Danic D, Dan- iel F. Acute generalized exanthematous pustulosis due to the combination of chloroquine and proguanil. Dermatology 1998;196:271.

33. Fryauff D J, Church LW, Richards AL, Wid- jaja H, Mouzin E, Ratiwayanto S, Hadiputranto H, Sutamihardja MA, Richie TL, Subianto B, Tjitra E, Hoffman SL. Lymphocyte response to tetanus toxoid among Indonesian men immunized with tetanus-diphtheria during extended chloroquine or primaquine prophylaxis. J Infect Dis 1997; 176:1644-8.

34. Kollaritsch H, Que JU, Kunz C, Wiedermann G, Herzog C, Cryz SJ Jr. Safety and immunogenicity of live oral cholera and typhoid vaccines administered alone or in combination with antimalarial drugs, oral polio vaccine, or yellow fever vaccine. J Infect Dis 1997;175:871-5.

35. Fryauff D J, Cryz SJ, Widjaja H, Mouzin E, Church LW, Sutamihardja MA, Richards AL, Su- bianto B, Hoffman SL. Humoral immune response to tetanus-diphtheria vaccine given during


extended use of chloroquine or primaquine malaria chemoprophylaxis. J Infect Dis 1998; 177:1762-5.

36. Olliaro P, Nevill C, LeBras J, Ringwald P, Mussano P, Garner P, Brasseur P. Systematic review of amodiaquine treatment in uncomplicated malaria. Lancet 1996;348:1196-201.

37. Gay F, Bustos D, Traore B, Jardinel C, Sou- thammavong M, Ciceron L, Danis MM. In vitro response of Plasmodium falciparum to atovaquone and correlation with other antimalarials: comparison between African and Asian strains. Am J Trop Med Hyg 1997;56:315-7.

38. Pradines B, Rogier C, Fusai T, Tall A, Trape JF, Doury JC. In vitro activity of artemether against African isolates (Senegal) of Plasmodium falciparum in comparison with standard antimalarial drugs. Am J Trop Med Hyg 1998;58:354-7.

39. Philipps J, Radloff PD, Wernsdorfer W, Kremsner PG. Follow-up of the susceptibility of Plasmodium falciparum to antimalarials in Gabon. Am J Trop Med Hyg 1998;58:612-18.

40. Ouedraogo JB, Dutheil Y, Tinto H, Traore B, Zampa H, Tall F, Coulibaly SO, Guiguemde T. In vitro sensitivity of Plasmodium falciparum to halofantrine compared with chloroquine, quinine and mefloquine in the region of Bobo-Dioul- asso, Burkina Faso (West Africa). Trop Med Int Health 1998;3:381-4.

41. Touze JE, Fourcade L, Peyron F, Heno P, Deharo JC. Is halofantrine still advisable in malaria attacks? Ann Trop Med Parasitol 1997; 91:867-73.

42. Touze JE, Perret JL, Nicolas X, Fourcade L, Bernard J, Keundjian A, Soares JM, Doury JC. Efficacy of low-dose halofantrine for second treatment of uncomplicated falciparum malaria. Lan- cet 1997;349:255-6.

43. Tish KN, Pillans PI. Recrudescence of Plas- modium falciparum malaria contracted in Lom- bok, Indonesia after quinine/doxycycline and mefloquine: case report. New Zealand Med J 1997;110:255-6.

44. Fryauff D J, Baird JK, Basri H, Wiady I, Pur- nomo, Bangs M J, Subianto B, Harjosuwarno S, Tjitra E, Richie TL, Hoffman SL. Halofantrine and primaquine for radical cure of malaria in Irian Jaya, Indonesia. Ann Trop Med Parasitol 1997; 91:7-16.

45. Ebert SN, Liu X-K, Woosley RL. Female gen- der as a risk factor for drug-induced cardiac ar- rhythmias: evaluation of clinical and experimental evidence. J Womens Health 1998;7:547-57.

46. Gundersen SG, Rostrup M, vonder Lippe E, Platou ES, Myrvang B, Edwards G. Halofantrine- associated ventricular fibrillation in a young woman with no predisposing QTc prolongation. Scand J Infect Dis 1997;29:207-8.

47. Van den Ende J, Coppens G, Verstraeten T, Van Haegenborgh T, Depraetere K, Van Gompel A, Van den Enden E, Clerinx J, Colebunders R, Pcetermans WE, Schroyens W. Recurrence of blackwater fever: triggering of relapses by different antimalarials. Trop Med Int Health 1998; 3:632-9.

48. Fourcade L, Gachot B, De Pina J J, Hcno P, Laurent G, Touze JE. Anaphylactic shock associated with halofantrine treatment for malaria. Presse Med 1997;26:559.

49. Croft A, Garner P. Mcfloquine to prevent malaria: a systematic review of trials. Br Mcd J 1997;315:1412-16.

50. Nosten F, Ter Kuile FO, Luxemburger C, Woodrow C, Kylc DE, Chongsuphajaisiddhi T, White NJ. Cardiac effects of antimalarial treatment with halofantrine. Lancet 1993;341:1054-6.

51. Davis TM, Dembo LG, Kayc-Eddie SA, Hewitt B J, Hislop RG, Batty KT. Neurological, cardiovascular and metabolic effects of mefloquine in healthy volunteers: a double-blind, placebo-controlled trial. Br J Clin Pfiarmacol 1996; 42:415-21.

52. Evans S J, Waller PC. Neurological, cardiovascular and metabolic effects of mefloquine in healthy volunteers: a double-blind, placebo-controlled trial. Br J Clin Pharmacol 1997;43:665,

53. Richter J, Burbach G, Hellgren U, Dengler A, Bienzle U. Aberrant atrioventricular conduction triggered by antimalarial prophylaxis with mefloquine. Lancet 1997;349:101-2.

54. Fonteyne W, Bauwens A, Jordaens L. Atrial flutter with l:1 conduction after administration of the antimalarial drug mefloquine. Clin Cardiol 1996; 19:967-8.

55. Clattenburg RN, Donnelly CL. Case study: ncuropsychiatric symptoms associated with the antimalarial agent mefloquinc. J Am Acad Child Adolesc Psychiatry 1997;36:1606-8.

56. McBride SR, Lawrence CM, Pape SA, Reid CA. Fatal toxic epidermal necrolysis associated with mefloquine antimalarial prophylactics. Lan- cet 1997;349:9045.

57. Vanhauwere B, Maradit H, Kerr L. Post-mar- keting surveillance of prophylactic mefloquine (Lariam) use in pregnancy. Am J Trop Med Hyg 1998;58:17-21.

58. Supanaranond W, Suputtamongkol Y, Davis TME, Pukrittayakamee S, Teja-Isavadharm P, Webster HK, White NJ. Lack of a significant adverse cardiovascular effect of combined quinine and mefloquine therapy for uncomplicated malaria. Trans R Soc Trop Med Hyg 1997;91:694- 6.

59. Brueckner RP, Lasseter KC, Lin ET, Schuster BG. First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial. Am J Trop Med Hyg 1998;58:645-9.

60. Brueckner RP, Coster T, Wesche DL, Shmu- klarsky M, Schuster BG. Prophylaxis of Plasmo- dium falciparum infection in a human challenge model with WR 238605, a new 8-aminoquinoline antimalarial. Antimicrob Agents Chemother 1998; 42:1293-4.

61. Sirsat RA, Dasgupta A. Haematological complications of proguanil in a patient with chronic renal failure. Nephron 1997;75:108.

62. Winstanley P, Watkins W, Muhia D, Szwandt S, Amukoye E, Marsh K. Chlorproguanil/dapsone for uncomplicated Plasmodium falciparum

314 Chapter 28 Isabela Ribeiro, Charles Woodrow and Sanjeev Krishna

malaria in young children: pharmacokinetics and therapeutic range. Trans R Soc Trop Med Hyg 1997;91:322-7.

63. Amukoye E, Winstanley PA, Watkins WM, Snow RW, Hatcher J, Mosobo M, Ngumbao E, Lowe B, Ton M, Minyiri G, Marsh K. Chlorpro- guanil-dapsone: effective treatment for uncomplicated falciparum malaria. Antimicrob Agents Chemother 1997;41:2261-4.

64. Ringwald P, Bickii J, Basco LK. Efficacy of oral pyronaridine for the treatment of acute uncomplicated falciparum malaria in African children. Clin Infect Dis 1998;26:946-53.

65. Ringwald P, Bickii J, Same Ekobo A, Basco LK. Pyronaridine for treatment of Plasmodium ovale and Plasmodium malariae infections. Anti- microb Agents Chemother 1997;41:2317-19.

66. Yang HL, Liu DQ, Yang YM, Huang KG, Dong Y, Yang PF, Liao MZ, Zhang CY. In vitro sensitivity of Plasmodium falciparum to eight antimalarials in China-Myanmar and China-Lao PDR border areas. Southeast Asian J Trop Med Public Health 1997;28:460-4.

67. Mackie MA, Davidson J, Clarke J. Quinine- acute self-poisoning and ocular toxicity. Scott Med J 1997;42:8-9.

68. Hoffman SL, Doolan DL, Sedegah M, Wang R, Scheller LF, Kumar A, Weiss WR, Le TP, Klinman DM, Hobart P, Norman JA, Hedstrom RC. Toward clinical trials of DNA vaccines against malaria. Immunol Cell Biol 1997;75:376- 81.

69. Doolan DL, Hedstrom RC, Wang R, Sedegah M, Scheller LF, Hobart P, Norman JA, Hoffman SL. DNA vaccines for malaria: the past, the present, and the future. Indian J Med Res 1997;106:109-19.

70. Kwiatkowski D, Marsh K. Development of a malaria vaccine. Lancet 1997;350:1696-707.

71. Bojang KA, Obaro SK, Leach A, D'Alessan- dro U, Bennett S, Metzger W, Ripley-Ballou W, Targett GAT, Greenwood BM. Follow-up of Gambian children recruited to a pilot safety and immunogenicity study of the malaria vaccine SPf66. Parasite Immunol 1997;19:579-81.

72. Migasena S, Heppner DG, Kyle DE, Chong- suphajaisiddhi T, Gordon DM, Suntharasamai P, Permpanich B, Brockman A, Pitiuttutham P, Wongsrichanalai C, Srisuriya P, Phonrat B, Pav- anand K Viravan C, Ballou WR. SPf66 malaria vaccine is safe and immunogenic in malaria naive adults in Thailand. Acta Trop 1997;67:215-27.

73. Nosten F, Luxemburger C, Kyle DE, Gordon DM, Ballou WR, Sadoff JC, Brockman A, Permpanich B, Chongsuphajaisiddhi T, Heppner DG. Phase I trial of the SPf66 malaria vaccine in a malaria-experienced population in Southeast Asia. Am J Trop Med Hyg 1997;56:526-32.

74. Urdaneta M, Prata A, Struchiner CJ, Tosta CE, Tauil P, Boulos M. Evaluation of SPf66 malaria vaccine efficacy in Brazil. Am J Trop Med Hyg 1998;58:378-85.

75. Bojang KA, Obaro SK, D'Alessandro U, Bennett S, Langerock P, Targett GA, Greenwood

BM. An efficacy trial of the malaria vaccine SPf66 in Gambian infants: second year of follow-up. Vaccine 1998;16:62-7.

76. Alonso PL, Lopez MC, Bordmann G, Smith TA, Aponte J J, Weiss NA, Urassa H, Armstrong Schellenberg JR, Kitua AY, Masanja H, Thomas MC, Oettli A, Hurt N, Hayes R, Kilama WL, Tanner M. Immune responses to Plasmodium falciparum antigens during a malaria vaccine trial in Tanzanian children. Parasite Immunol 1998; 20:63-71.

77. Wang R, Doolan DL, Le TP, Hedstrom RC, Coonan KM, Charoenvit Y, Jones TR, Hobart P, Margalith M, Ng J, Weiss WR, Sedegah M, de Taisne C, Norman JA, Hoffman SL. Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science 1998;282:476-80.

78. Hoffman SL, Doolan DL, Sedegah M, Aguiar JC, Wang R, Malik A, Gramzinski RA, Weiss WR, Hobart P, Norman JA, Margalith M, Hed- strom RC. Strategy for development of a pre- erythrocytic Plasmodium falciparum DNA vaccine for human use. Vaccine 1997;15:842-5.

79. Le TP, Church LW, Corradin G, Hunter RL, Charoenvit Y, Wang R, de la Vega P, Sacci J, Ballou WR, Kolodny N, Kitov S, Glenn GM, Richards RL, Alving CR, Hoffman SL. Immuno- genicity of Plasmodium falciparum circumsporozoite protein multiple antigen peptide vaccine formulated with different adjuvants. Vaccine 1998; 16:305-12.

80. Pye D, Vandenberg KL, Dyer SL, Irving DO, Goss NH, Woodrow GC, Saul A, Alving CR, Richards RL, Baltou WR, Wu M J, Skoff K, And- ers RF. Selection of an adjuvant for vaccination with the malaria antigen, MSA-2. Vaccine 1997;15:1017-23.

81. Duffy PE, Kaslow DI2. A novel malaria protein, Pfs28, and Pfs25 are genetically linked and synergistic as falciparum malaria transmission- blocking vaccines. Infect Immun 1997;65:1109- 13.

82. Gozar MMG, Price VL, Kaslow DC. Sacchar- omyces cerevisiae-secreted fusion proteins Pfs25 and Pfs28 elicit potent Plasmodium falciparum transmission-blocking antibodies in mice. Infect Immun 1998;66:59-64.

83. Ambroise Thomas P. Vaccination against malaria. Disappointments and hopes. Bull Acad Natl Med 1997;181:1637-48.

84. Stoute JA, Slaoui M, Heppner DG, Momin P, Kester KE, Desmons P, Wellde BT, Garcon N, Krzych U, Marchand M, Ballou WR, Cohen JD. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmo- dium falciparum malaria. New Engl J Med 1997 ;336:86-91.

85. Wang R, Doolan DL, Charoenvit Y, Hed- strom RC, Gardner M J, Hobart P, Tine J, Sede- gah M, Fallarme V, Sacci JB Jr, Kaur M, Klinman DM, Hoffman SL, Weiss WR. Simultaneous induction of multiple antigen-specific cytotoxic T lymphocytes in nonhuman primates by immuniza-


tion with a mixture of four Plasmodium falciparum DNA plasmids. Infect lmmun 1998;66:4193- 202.

86. Sedegah M, Jones TR, Kaur M, Hedstrom R, Hobart P, Tine JA, Hoffman SL. Boosting with recombinant vaccinia increases immunogenicity and protective efficacy of malaria DNA vaccine. Proc Natl Acad Sci USA 1998;95:7648-53.

87. Weiss WR, Ishii KJ, Hedstrom RC, Sedegah M, lchino M, Barnhart K, Klinman DM, Hoffman SL. A plasmid encoding murine granulocyte- macrophage colony-stimulating factor increases protection conferred by a malaria DNA vaccine. J Immunol 1998;161:2325-32.

88. Ockenhouse CF, Sun PF, Lanar DE, Wellde BT, Hall BT, Kester K, et al. (27 authors). Phase 1/lla safety, immunogenicity, and efficacy trial of NYVAC-Pf7, a poxvectored, multiantigen, mul- tistage vaccine candidate for Plasmodium falciparum malaria. J Infect Dis 1998;177:1664-73.

89. Miller RF, Le Noury J, Corbett EL, Felton JM, De Cock KM. Pneumocystis carinii infection: current treatment and prevention. J Antimicrob Chemother 1996;37 Suppl B:33-53.

90. Warren E, George S, You J, Kazanjian P. Advances in the treatment and prophylaxis of Pneumocystis carinii pneumonia. Pharmacother- apy 1997;17:900-16.

91. Santamauro JT, Stover DE. Pneumocystis carinii pneumonia. Med Clin North Am 1997; 81:299-318.

92. Fishman JA. Treatment of infection due to Pneumocystis carinii. Antimicrob Agents Chem- other 1998;42:1309-14.

93. Hughes W, Dorenbaum A, Yogev R, Beau- champ B, Xu J, McNamara J, Moye J, Purdue L, van Dyke R, Rogers M, Sadler B. Phase I safety and pharmacokinetics study of micronized atovaquone in human immunodeficiency virus-infected infants and children. Pediatric AIDS Clinical Tri- als Group. Antimicrob Agents Chemother 1998; 42:1315-18.

94. loannidis JP, Cappelleri JC, Skolnik PR, Lau J, Sacks HS. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Arch Intern Med 1996;156:177- 88.

95. Gilroy N, Gottlieb T, Spring P, Peiris O. Trimethoprim-induced aseptic meningitis and uvcitis. Lancet 1997;350:112.

96. Carlson J, Wilholm B-E. Trimethoprim associated aseptic meningitis. Scand J Infect Dis 1987;19:687-91.

97. Derbes SJ. Trimethoprim-induced aseptic meningitis. J Am Med Assoc 1984;252;2865-6.

98. Northrop CV, Moore Shepherd S, Abbuhl S. Sulphonamide-induced iritis. Am J Emerg Med 1996;14:577-9.

99. Van Gerpen JA. Tremor caused by trimethoprim-sulfamethoxazole in a patient with AIDS. Neurology 1997;48:537-8.

100. Lee A J, Maddix DS. Trimethoprim/sulfamethoxazole-induced hypoglycemia in a patient with acute renal failure. Ann Pharmacother 1997; 31:727-2.

101. Hekimsoy Z, Biberoglu S, Comlekci A, Tar- han O, Mermut C, Biberoglu K. Trimethoprim/ sulfamethoxazole-induced hypoglycemia in a malnourished patient with severe infection. Eur J Endocrinol 1997;136:304-6.

102. Naderer O, Nafziger AN, Bertino JS. Effects of moderate-dose versus high-dose trimcthoprim on serum creatinine and creatinine clearance and adverse reactions. Antimicrob Agents Chemother 1997;41:2466-70.

103. Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, Cheung T, Soeiro R, Hojczyk P, Black JR. Comparison of three regimens for treatment of mild to moderate Pneumo- cystis carinii in patients with AIDS. A double- blind, randomised trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clinda- mycin-primaquine. Ann Intern Med 1996; 124:792-802.

104. Alappan R, Pcrazclla MA, Buller GK. Hy- pcrkalemia in hospitalised patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996;124:316-20.

105. Safrin S, Finkelstein D. Comparison of oral agents for treatment of Pneumocystis carinii pneumonia. Ann Intern Med 1997;126:407-8.

106. Elisaf M, Terrovitou C, Tomos P, Siamo- poulos KC. Severe hyperkalaemia after co-trimoxazole administration in a patient with hypor- eninaemic hypoaldosteronism. Nephrol Dial Transplant 1997;12:1254-5.

107. Lin S-H, Kuo AA, Yu F-C, Lin Y-F. Rever- sible voltage-dependent distal renal tubular acidosis in a patient receving standard doses of trimethoprim-sulphamethoxazole. Nephrol Dial Transplant 1997;12:1031-3.

108. Yao F, Behling CA, Saab S, Li S, Hart M, Lyche KD. Trimethoprim-sulfamcthoxazolc-induced vanishing bile duct syndrome. Am J Gas- troenterol 1997;92:167-9.

109. Gruber F, Stasic A, Lenkovic M, Brajac I. Postcoital fixed drug eruption in a man sensitive to trimethoprim-sulfamethoxazole. Clin Exp Dermatol 1997;22:144-5.

110. Ozkaya-Bayazit E, Baykal C. Trimethoprim- induced linear fixed drug eruption. Br J Dermatol 1997;137;1028-9.

11l. Everson-Mays RE, Wcidle PJ. Restarting trimethoprim-sulfamethoxazole after a hypcrscnsi- tivity reaction in patients with the human defi- ciency virus. Am J Health-Syst Pharm 1997; 54:1545-50.

112. Stein GE. Trimcthoprim/sulfamethoxazolc- induced hypersensitivity syndrome. Ann Pharma- cother 1997;31:1259.

113. Carr A. Role of desensitisation for drug hypersensitivity in patients with H1V infection. Drug Saf 1997;17:119-26.

114. Rieder MJ, King SM, Read S. Adverse reactions to trimethoprim-sulfamcthoxazolc among children with human immunodeficiency virus infection. Pediatr Infcct Dis J 1997;16:1028-31.

115. Caumes E, Guermonprcz G, Lecomte C, Katlama C, Bricaire F. Efficacy and safety of de-


sensitization with sulfamethoxazole and trimethoprim in 48 previously hypersensitive patients infected with human immunodeficiency virus. Arch Dermatol 1997;133:465-9.

116. Stricker RB, Gullet JH, Williams LE, Gold- berg B. Co-trimoxazole desensitization syndrome: delayed hematologic toxicity complicating prophylactic therapy in AIDS patients. AIDS 1996;10:927-9.

117. Jucgla A, Sais G, Berlanga J, Servitje O. Hyperpigmentation of the flexures and pancytopenia during treatment with folate antagonists. Acta Dermatol Venereol 1997;77:165-6.

118. Hughes WT. Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review. Clin Infect Dis 1998;1:191- 204.

119. Hironaka K, Mizushima M, Tsuzi C, Makino H. Urinary tract carcinoma in leprosy patients treated with dapsone for a long period. Nephron 1997;76:358-9.

120. Mir N, O'Farrell N, Creagh TA, Knowles C. Obstructive renal failure requiring surgical intervention in an AIDS patient being treated with sulfadiazine. Int J STD AIDS 1997;8:61-2.

121. Anibarro B, Fontela JL. Sulfadiazine-induced sialadenitis. Ann Pharmacother 1996; 30:59-60.

122. Ortega-Carnicer J, Alcazar R, De la Torre M, Benezet J. Pentavalent antimonial-induced torsade de pointes. J Electrocardiol 1997;30:143- 5.

123. Nazmul-Ahasan HAM, Jalil-Chowdhury MA, Azhar MA, Rafiqueuddin AKM, Fakrul-

Islam M. Conduction defect following pentavalent antimony therapy in visceral leishmaniasis. Trop Doct 1997;27:59-61.

124. Sundar S, Sinha PR, Agrawal NK, Srivastava R, Rainey PM, Berman JD, Murray HW, Singh VP. A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate. Am J Trop Med Hyg 1998;59:139-43.

125. Lockwood DNJ. Some good news for treatment of visceral leishmaniasis in Bihar. Br Med J 1998;316:1205.

126. Thakur CP. Sodium antimony gluconate, amphotericin, and myocardial damage. Lancet 1998;351:1928-9.

127. Jha TK, Olliaro P, Thakur CP, Kanyok TP, Singhania BL, Singh I J, Akhoury S, Jha S. Ran- domised controlled trial of aminosidinc (paromo- mycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India. Br Med J 1998;316:1200-5.

128. Elliott AM, Klaus BD, North DS, Martin HP. Furazolidone-induced mood disorder during the treatment of refractory giardiasis in a patient with AIDS. Clin Infect Dis 1998;26:1015.

129. Schreiber W, Spernal J. Metronidazole-induced psychotic disorder. Am J Psychiatry 1997; 154:1170-1.

130. Sobel JD. Vaginitis. New Engl J Med 1997;337:1896-1903.

131. Caro-Paton T, Carvajal A, De Diego IM, Martin-Arias LH, Alvarez-Requejo A, Rodri- guez-Pinilla E. Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol 1997;44:179- 82.

[side effects of drugs annual] volume 22 || antiprotozoal drugs

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