Title: PHL%20417
1- PHL 417
- ALHARBI-LECTURES
- 1- PART-I
- IMMUNOMODULATORS
- 2- PART II
- ANTI-PARASITES
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3- IMMUNOSUPPRESSANTS
- GOALS OF IMMUNOTHERAPY IN ORGAN TRANSPLANTS
- 1- Prevention of the immune response example
acute rejection and vascular remodeling - 2- prevention of complications of
immunodeficiency - Such as infections and malignancy
- 3-minimize drug induced and other non-immune
toxicities
4CLONAL EXPANSION Produce CD4 Then CD8
RECOGNITION
Antigen presentation
Ag-presenting cell
Antigen processing
Antigen uptake
Foreign Cell or Protein
5Receptor-associated tyrosine kinases (ZAP-70, lck
fyn)
T-CELL RECEPTOR TCR
Phospholipase C?
DAG
phosphatidyl inositol
IP3
NF-?B Other TFs
?
PKC
Ca2
Calcineurin
IL-2
6Steps Towards T-cell Clonal Expansion
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8IMMUNOPHARMACOLOGY
0psonized bacteria
Macrophage
APC
B lymphocyte
T lymphocyte
IL-4,IL-5
IL-2
IL-2
TH1
TH2
IFN-? TNF-?
IFN-?
- Plasma Cells
- IgG - IgM
- IgA - IgD
IFN-?
Activated Macrophage
Activated Cytotoxic T cell
Activated NK cells
Memory B Cells
CELL-MEDIATED IMMUNITY
HUMORAL IMMUNITY
9- TYPE IMMUNE RESPONSES
- A- Primary immune system
- - it is efectively inhibited by
immunosuppressants - especially before antigen exposure
- i- celluar mediated immunity
- mediated by T-lymphocyted
- it causes lysis for foreign cell (cytotoxic
cells) - Responsible for Organ transplant Rejection
- Ii- Humoral immune response
- mediated by B-lymphocytes to produce
Antibodies - B- Secondary immune response (delayed)
- -it is in the memory of T-cells (CD8)
- - It is fast (1-3 days) in response
- It also has cellular humoral immunity
10- CLASSIFICATION OF
- IMMUNOSUPPRESSANTS
- 1- INHIBIT INTERLEUKIN-2 PRODUCTION
- (calcineurin inhibitors)
- Cyclosporine, tacrolimus
- 2-INHIBIT INTERLEUKIN-2 ACTION
- Sirolimus , Everolimus, MycophenolateCELLCEPT,
Azathioprine(imuran) - 3- INHIBIT CYTOKINE GENE EXPRESSION
- Glucocorticoid
11- 4- ALKYLATING CYTOTOXIC AGENTS
- - Cyclophosphamide, (methotrexate),
chlorambucil - 5- BLOCK T- CELL SURFACE MOLEUCULE INVOLVED IN
SIGNALING - Immunoglobulins
- Antibody against IL-2 RECEPTORS (Bsiliximab,
Simulect ) - OKT3 (Muromonab)
- Rh0d immunoglobulin (Gamulin Rh )
12Anti-CD3
Cyclosporin Tacrolimus Glucocorticoids
Sirolimus
IL-2
Mycophenolate
Mitogenesis
Glucocorticoids
13Preventing IL-2-driven clonal expansion
Prevent TCR signaling for IL-2 gene
transcriptionCYCLOSPORIN TACROLIMUS
GLUCOCORTICOIDS
Prevent mitogenic response to IL-2R
stimulationSirolimus Mycophenolate, IMURAN
IL-2
IL-2R
Prevent activation of T-cell Via TCR Anti-TCR
Antibody
? IL-2 mRNA Degradation GLUCOCORTICOIDS
Mitogenesis
IL-2
14CYCLOSPORIN
- MECHANISM OF ACTION
- Antigen binds to T cell receptor (TCR) --? ?Ca
intracellular - Ca calmodulin stimulates phospatase, calcineurin
?activation of transcription factors
--?transcription of IL-2 gene -
- CYCLOSPORIN binds to cytosolic protein,
cyclophilin (immunophilin) - Drug-immunophilin complex INHIBITS CALCINEURIN
and blocks transcription of IL-2 gene
15Receptor-associated tyrosine kinases (ZAP-70, lck
fyn)
TCR
Phospholipase C?
DAG
phosphatidyl inositol
IP3
NF-?B Other TFs
?
PKC
Ca2
Calcineurin
IL-2
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17ACTION OF CYCLOSPORIN OR TACROLIMUS
Cyclophilin
Cyclo
CALCINEURIN
NF-?B
IL-2
OAP
18ACTION OF CYCLOSPORIN OR TACROLIMUS
Cyclophilin
Cyclo
Calcineurin
NF-?B
IL-2
OAP
19CYCLOSPORIN ADVERSE EFFECTS
- Increase risk of infection
- Nephrotoxicity
- Liver dysfunction
- Regular blood level monitoring to avoid kidney
and liver toxicity -
- Hirsutism
- Gum hypertrophy
20TACROLIMUS (FK506)
- Mechanism of action similar to cyclosporin
- At cellular level, it binds to FK binding protein
(FKBP) - which inhibits cytoplasmic phosphatase,
calcineurin activation of transcription factor
--? ?IL-2 gene activation
21TACROLIMUS (FK506)
- Tacolimus can be given orally or intravenously
FOR LIVER TRANSPLANT - Half-life is 7 hrs
- It is 99 metabolised in the liver
- It is active in preventing organ transplant
rejection - Adverse effects are similar to Cyclosporin
22SIROLIMUS (RAPAMYCIN)
- It Binds to intracellular immunophilin FKBP does
not interfere with IL-2 gene transcription - But the complex binds to and modulates the
activity of Sirolimus effector protein - Inhibits mitogenic response to IL-2 leading to
- Interferes with IL-2 signal transduction pathway
blocking the cell cycle of activated T cell at G2
stage - Does not inhibit IL-2 or IL-2 Receptor
- Does not inhibit calcineurin
- Resulting in a decreased clonal proliferation of
T cells
23Preventing IL-2-driven clonal expansion
IL-2
IL-2R
Prevent mitogenic response to IL-2R
stimulationSirolimus (Rapamycin)
Mitogenesis
IL-2
24SIROLIMUS (RAPAMUNE)
- ADVERSE EFFECTS
- Hyperlipidemia (hypercholesterolemia 38)-57)may
requires statins gemfibrozil - Anemia 27-37 may require iron erythropoietin
- Thrombocytopenia
- Hypertension
- Peripheral edema 54-64
- Increased incidence of nephrotoxicity if given
with cyclosporin
25EVEROLIMUS (CERTICAN)
- MOA
- It acts at post IL-2 Receptor by blocking p70 s6
Kinase which involve cellular proliferation
signal - Leads to arrest cell cycle at the G1-S phase
(similar to sirolimus) - It is complementary to calcineurin inhibitor
- Which favor long-term graft survival
26GLUCOCORTICOIDS
- are potent immunosuppressive and
anti-inflammatory agents - Suppress inflammatory reaction
- Suppress immune response
- Decrease clonal expansion of T B cells and
cytokine secreting T cells - Decrease the production and action of cytokines
e.g. interleukins, TNF? , gM-CsF - Decrease the generation of IgG
27MECHANISM OF ACTION GLUCOCORTICOIDS
- Steroid interact with cytosolic receptors
- activated receptor ,form steroid-receptor
complexs - Move into nucleus, bind to steroid responsive
elements in the DNA - Either repress transcription of or induce
transcription of particular genes
28Glucocorticoids
- Suppression of transcription OF IL-2
- Reduced IL-2 mRNA stability
- (? IL-2 mRNA Degradation)
29GLUCOCORTICOID CLINICAL USES
- As anti-inflammatory immuno- suppressive
therapy - Asthma, allergic rhinitis, eczema, severe drug
allergic reaction, rheumatoid arthritis ,organ
transplant - In neoplastic disease
- Hodgkins disease, acute lymphocytic leukaemia
- Replacement therapy
- In adrenal insufficiency
30ADVERSE EFFECTS
- Suppress response to injury or infection
- Suppress patients capacity to synthesize
corticosteroids - Metabolic effect
- Water and electrolyte imbalance
- Osteoporosis
- GI bleeding
- hyperglycemia
31CYCLOPHOSPHAMIDE
- is a nitrogen mustard, an alkylating agent
- Is inactive until metabolised by the liver into
its active phosphoramide mustard - Have alkyl groups which can cross link to two
nucleophilic site of the DNA---?defective
replication -
- Resulting in subsequent cell death
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33CYCLOPHOSPHAMIDE
- Has pronounced effect on the lymphocytes
- Usually given orally for Autoimmune diseases
- ADVERSE EFFECTS
- Depress bone marrow function
- GI disturbance
- Toxic metabolite acrolein
- Haemorrhagic cystitis
34AZATHIOPURINE (IMURAN)
- It is metabolised to give mercapturine which is a
purine analog - interferes with purine synthesis and is
cytotoxic on the dividing cell -
- Inhibit clonal prolifeation in the induction
phase of the immune response - Inhibits both cell mediated and antibody mediated
immune reactions
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36AZATHIOPURINE
- USED
- - in organ transplant to prevent rejection
- - Autoimmune diseases with glucocorticoids
- MAJOR SIDE EFFECT
- - suppress bone marrow
- - Hepatotoxicity
- - Retinopathy
37MYCOPHENOLATE
- a- Mofetil salt CELLCEPT
- B- sodium salt (enteric coated) MYOFORTIC
- Administered orally and is well absorbed
- A semisynthetic derivative of fungal antibiotic
-
- Converted to mycophenolic acid
38esterase
Mycophenolate mofetil (prodrug)
Mycophenolate
39Mycophenolic Acid
- 1- MOA
- Inhibitor of de-novo guanosine monophosphate
synthesis - B and T cells depend on de-novo synthesis-lack
salvage pathway for guanine recovery - Other cells have salvage pathway
- Specific inhibition of DNA synthesis, RNA
synthesis other GTP or cGMP requiring pathways
40Ribose-5P ATP ?
5-phosphoribosyl-1-pyrophosphate (PRPP)
? Guanine ? Guanosine MP ? Inosine MP ??
Adenosine MP
Salvage Pathway (deficient in T B cells)
IMP dehydrogenase
Mycophenolate
41- 2- DRUG INTERACTION
- Magnesium and aluminium impairs absorption
- 3- USES
- - Trial used in kidney transplant with
cyclosporine and steroids - - Autoimmune diseases
42- 4- ADVERSE EFFECTS
- Peptic ulcer esophagitis
- Hypercholestrolemia
- Diarrhea
43IMMUNOSUPPRESSANT REGIMENS
- 1- Basiliximab, cyclosporin, prednisolone
- 2- Basiliximab, Azathioprine, cyclosporin,
prednisolone - 3- Basiliximab, MMF, cyclosporin, prednisolone
44- 4- Basiliximab, Everolimus, cyclosporin,
prednisolone - 5- Basiliximab, Sirolimus, cyclosporin,
prednisolone -
- Basiliximab 20 mg divided into two doses
- First dose should be given on day 0
- and second dose given on day 4 if needed
45IMMULOGLOBULINS
- Antibodies against human lymphocytes
- or their surface protein can have significant
immunosupressant action
46IMMULOGLOBULINS
- Antibodies against human lymphocytes
- or their surface protein can have significant
immunosupressant action
47POLYCLONAL ANTIBODIES
- Binds to protein on the surface of lymphocyte
triggering the complement response -? lysis of
the lymphocyte - Indiscriminate action on all T cells
- EXAMPLE
- ANTI-THYMPHOCYTE
- Lymphocyte immune globulin ( killer cell)
immunoglobulin (ATG, Atgam ) - Immunizing horse with human Thymphocyte
48ATG (Atgam )
- MOA
- - Eliminate antigen reactive
T-lymphocytes (killer cells - CLINICAL USES
- 1- Prevention treatment of acute renal
and other organ allograft rejection - 2- aplastic anemia who is not candidate for
bone marrow transplant
49ATG (Atgam )
- ADVERSE EFFECTS
- - FEVER
- - Allergic reaction
- Therefore, it is premedicated by paracetamol
diphenhydramine glucocorticoids
50MONOCLONAL ANTIBODIES
- Direct against surface components of T cells
- CD3 proteins with antigen receptors
- Example Muromonab-CD3 (Orthoclone )
51Muromonab-CD3 (Orthoclone )OKT3
- 1- MOA
- It binds with T-cell receptor-associated CD3
glycoprotein - 2- CLINICAL USES
- Acute allograft rejection resistant to
conventional therapy
52Muromonab-CD3 (Orthoclone )OKT3
- 3- ADVERSE EFFECTS
- First dose effects flu-like symptoms (cytokine
release syndrome) - Manifested by fever, respiratory dystress
- Hypervolemic pulmonary edema
53Rhd immunoglobulin (Gamulin)
- MOA
- - Immunoglobulin against Rh antigen D
- Which prevents the interactions between the Rh
antigen and maternal (mother) immune system - CLINICAL USES
- Prophylaxis in Erythroblastosis fetalis
- Idiopathic thrombocytopenia
54infliximab, Remicade
- MOA Antibody against tumor necrosis factor alpha
(TNF alpha) - USED
- - for crohns disease
- - Rheumatoid arthritis with methotrexate who
inadequate respond to methotrexate alone - CONTRAINDICATED
- - CHF
- - TUBERCULOSIS
55ETANERCEPT (Enbrel )
- MOA it binds with TNF and
- blocks its interaction with cell surface
receptor - CLINICAL USE
- - for rheumatoid arthritis crohn.s disease
56Daclizumab (Zenapax ) Basiliximab (Simulect )
- MOA IL-2 receptors antibody
- USE in combination with other standard
immunosuppressant such as - Cyclosporin, and glucorticoids
- It reduces the incidence of acute renal rejection
- ADVERSE EFFECTS NO CRS
57Interferon
- Type-I
- A- Interferon Alpha (prod. by leukocytes)
- (antiviral (hepatitis C, interferon alfa-2b ),
antiproliferative) - malignant melanoma, renal cell carcinoma, hairy
cell leukemia, Kaposis sarcoma - B- Interferon Beta (prod. by fibroblasts)
- (antiviral, antiproliferative)
- relapsing type Multiple Sclerosis
- Type-II
- Interferon Gamma (prod. by lymphocytes)
- (stimulates NK cells and macrophages)
- chronic granulomatous disease
58Interferon
- Many of these are in clinical use and are given
intramuscularly or subcutaneously - Recombinant forms of alpha interferon include
- Alpha-2a drug name Roferon
- Alpha-2b drug name Intron A
- Alpha-n1 drug name Wellferon
- Alpha-n3 drug name AlferonN
- Alpha-con1 drug name Infergen
- Pegasys is recombinant interferon alpha-2a that
is covalently conjugated with bis-monomethoxy
polyethylene glycol (PEG)
59Alpha-2a drug name Roferon
- Uses
- in the treatment of patients with chronic
hepatitis C - Hairy cell leukemia
- AIDS-related Kaposi's sarcoma.
- Side Effects
- Depressive illness and suicidal behavior,
including suicidal ideation, suicide attempt, and
suicides,
60Interferon
- Recombinant forms of beta interferon include
- Beta-1a drug name Avonex
- Beta-1b drug name Betaseron
- Recombinant forms of gamma interferon include
- Interferon Gamma (Actimmunex)
61Interferon BetaMechanism of Action
- Reduce the production of the TNFa , known to
induce damage to myelin - Reduce inflammation by
- Switching cytokine production from type 1
(pro-inflammatory) to type 2 (anti-inflammatory)
cells - Decrease antigen presentation, to reduce the
attack on myelin - Reduce the ability of immune cells to cross the
blood-brain barrier,
62Interferons ? Avonex (Interferon ?-1a)
manufacture by biogen, usa
- Indication relapsing forms of MS
- Dose 30 mcg IM once weekly
- Reduces rate of clinical relapse
- Reduces the development of new lesions
- May delay progression of disability
63Interferons ? Rebif (Interferon ?-1a)
- Interferon ?-1a
- Indication relapsing/remitting forms of MS
- Dose 22 or 44 mcg SC 3 times per week
- Decreases frequency of relapse
- Delays the increase in the volume of lesions
- May delay progression of disability
64Interferons ? Betaseron (interferon beta-1b
Bayer HealthCare Pharmaceuticals
- Indication Relapsing forms of MS
- Dose 8 million IU SC every other day
- Reduces rate of clinical relapse
- Reduces the development of new lesions
- Delays the increase in the volume of lesions
65Side Effects of Interferons
- Common
- Flu-like symptoms
- Chills
- Fever
- Muscle aches
- Asthenia (weakness)
- Betaseron and Rebif have injection site reactions
66Side Effects of Interferons
- Uncommon
- Severe depression
- Suicide
- Seizures
- Cardiac effects
- Anemia
- Elevated liver enzymes
- Severe hepatic injury, including cases of hepatic
failure, has been reported in patients taking
Avonex
67 68- ANTI-PARASITES
- 1- Drugs used in the treatment of Schisomiasis
- 2- Drugs used in the treatment of Malaria
- 3- Drugs used in the treatment of Amoebiasis
Filariasis - 4- Drugs used in the treatment of Ascariasis
Oxyyuriasis - 5- Drugs used in the treatment of Toxoplasmosis
- 6- Drugs used in the treatment of Tapeworms
infections Giardiasis
69- ANTI-PARASITES
- 1- Drugs used in the treatment of Schisomiasis
- SCHISTOSOMA
- Disease
- Schistosoma causes schistosomiasis.
- A- Schistosoma mansoni and Schistosoma japonicum
affect the gastrointestinal tract - B- whereas Schistosoma haematobium affects the
urinary tract.
70- schistosomiasis
- The three species can be distinguished by the
appearance of their eggs in the microscope - S. mansoni eggs have a prominent lateral spine
-
71- Schistosomiasis
- S. japonicum eggs have a very small lateral spine
72- Schistosomiasis
- S. haematobium eggs have a terminal spine the
veins draining the urinary bladder. Schistosomes
are
73- schistosomiasis
- Eggs are eliminated with feces or urine .
- Under optimal conditions the eggs hatch and
release miracidia - which swim and penetrate specific snail
intermediate hosts . - The stages in the snail include 2 generations of
sporocysts and the p cercariae roduction of -
- cercariae
74- Schistosomiasis
- Upon release from the snail, the infective
cercariae swim, penetrate the skin of the human
host , and shed their forked tail, becoming
schistosomulae . - The schistosomulae migrate through several
tissues and stages to their residence in the
veins - Adult worms in humans reside in the mesenteric
venules in various locations,
75- Schistosomiasis
- For instance, S. japonicum is more frequently
found in the superior mesenteric veins draining
the small intestine - and S. mansoni occurs more often in the superior
mesenteric veins draining the large intestine . - However, both species can occupy either location,
and they are capable of moving between sites
76- Schistosomiasis
- The eggs are moved progressively
- toward the lumen of the intestine
- (S. mansoni
- and S. japonicum)
- Eggs eliminated with feces
77- Schistosomiasis
- S. haematobium most often occurs in the venous
plexus of bladder , but it can also be found in
the rectal venules. - The eggs are moved progressively toward the
bladder and ureters (S. haematobium), and are
eliminated with urine - .
78- Schistosomiasis
- Pathology of S. mansoni and S.
japonicum schistosomiasis includes - - Katayama fever
- - hepatic perisinusoidal egg granulomas
- - Symmers pipe stem periportal fibrosis
- - portal hypertension
- - occasional embolic egg granulomas in brain
or spinal cord.
79- Schistosomiasis
- Pathology of S. haematobium schistosomiasis
includes - - hematuria
- - scarring, calcification
- - squamous cell carcinoma
- - occasional embolic egg granulomas in brain
or spinal cord.
80- Schistosomiasis
- Human contact with water is thus necessary for
infection by schistosomes. - Various animals, such as dogs, cats, rodents,
pigs, hourse and goats, serve as reservoirs
for S. japonicum, and dogs for S. mekongi.
81(No Transcript)
82A Male and female Schistosoma mansoni adults.
The female lives in the male's schist (shown as a
ventral opening) (6x). B Clonorchis sinensis
adult (6x). C Paragonimus westermani adult
(0.6x). D S. mansoni cercaria (300x).
83A Male and female Schistosoma mansoni adults.
The female lives in the male's schist (shown as a
ventral opening) (6x). B Clonorchis sinensis
adult (6x). C Paragonimus westermani adult
(0.6x). D S. mansoni cercaria (300x).
84- Symptoms and Signs
- Cercarial Dermatitis
- Following cercarial penetration
- localized erythema develops
- progress to a pruritic maculopapular rash that
persists for some days. - Dermatitis can be caused by human schistosomes
and, in non-tropical areas, by bird schistosomes
that cannot complete their life cycle in humans
(swimmer's itch).
85- SYMPTOMS AND SIGNS
- Acute Schistosomiasis (Katayama Syndrome)
- A febrile illness may develop 28 weeks after
exposure in first time (naive immune system) - most commonly after heavy infection with S
mansoni or S japonicum. - Presenting symptoms and signs include acute
onset of fever headache myalgias cough
malaise urticaria
86- SYMPTOMS AND SIGNS
- Acute Schistosomiasis (Katayama Syndrome)
- diarrhea, which may be bloody
- hepatosplenomegaly lymphadenopathy and
pulmonary infiltrates. - Localized lesions may occasionally cause severe
manifestations, including CNS abnormalities and
death. - Acute schistosomiasis usually resolves in 28
weeks.
87- SYMPTOMS AND SIGNS
- Chronic Schistosomiasis
- Many infected persons have light infections and
are asymptomatic - but an estimated 5060 have symptoms
- 510 have advanced organ damage.
- Asymptomatic infected children may suffer from
anemia and growth retardation
88- Symptoms and Signs
- Chronic Schistosomiasis
- Symptomatic patients with intestinal
schistosomiasis typically experience - abdominal pain
- fatigue
- Diarrhea
- hepatomegaly.
- .
89- Symptoms and Signs
- Chronic Schistosomiasis
- Over years develop
- anorexia
- weight loss
- weakness
- colonic polyps
- and features of portal hypertension
-
90- Symptoms and Signs
- Chronic Schistosomiasis
- Late manifestations include
- hematemesis from esophageal varices
- hepatic failure
- pulmonary hypertension.
- Urinary schistosomiasis may present within
months of infection with hematuria and dysuria,
most commonly in children and young adults.
91- Symptoms and Signs
- Chronic Schistosomiasis
- Fibrotic changes in the urinary tract can lead to
hydroureter - hydronephrosis
- bacterial urinary infections
- ultimately, kidney disease
- or bladder cancer.
92- Treatment of schistosomiasis
- No specific therapy is available for the
treatment of schistosomal dermatitis or Katayama
syndrome. - Antihistamines and corticosteroids may be helpful
in ameliorating their more severe manifestations. - In the late stage of schistosomiasis, therapy is
directed at interrupting egg deposition by
killing or sterilizing the adult worms.
93- Treatment of schistosomiasis
- Several anthelmintic agents may be used.
- Praziquantel
- which is active against all three species of
schistosomes, is the agent of choice. - Unfortunately, several recent reports have
suggested increased resistance to this
single-dose oral agent in areas where it has been
used in mass therapy programs
94- Treatment of schistosomiasis
- S mansoni infections acquired in such areas may
be treated with oxamniquine. - Use of this agent is contraindicated in
pregnancy. - Multiple anthelmintic drugs are used
95- Treatment of schistosomiasis
- Praziquantel Biltricide (600 mg)
- - 20 mg/kg twice per day in 4-hour intervals
for 1 day for S. mansoni and S. haematobium - Praziquantel
- - 20 mg/kg three times per day in 4-hour
intervals for 1 day for S. mekongi and S. japonica
96- Treatment of schistosomiasis
- ALTERNATIVE TREATMENT
- Metrifonate 10 mg/kg orally every 14 days for
three doses - Oxamniquine 15 mg/kg orally twice daily for 2
days
97- Treatment of schistosomiasis
- ALTERNATIVE TREATMENT
- Metrifonate 10 mg/kg orally every 14 days for
three doses - Oxamniquine 15 mg/kg orally twice daily for 2
days
98- Praziquantel
- Uses
- Trematode (Fluke) Infections
- Schistosomiasis
- Praziquantel is used for the treatment of
schistosomiasis (bilharziasis) caused by all
Schistosoma species pathogenic to humans. - Praziquantel is effective against all stages of
Schistosoma infection including the acute phase
and the chronic phase
99- Praziquantel
- Praziquantel is administered orally.
- The tablets should not be chewed
- but can be halved or quartered to allow
administration of individualized doses.
100- Praziquantel
- Mechanism of Action
- It causes focal vacuolization and subsequent
disintegration of worms - praziquantel increases permeability of the liver
fluke tegument to calcium, presumably by
interfering with the mechanism that regulates
calcium binding or transport across the
tegumental membrane.
101- Praziquantel
- Adverse Reactions
- 1- CV Arrhythmia (including AV blocks,
bradycardia, ectopic rhythms - 2- CNS Dizziness headache malaise asthenia,
somnolence, 3- GI Abdominal discomfort with
or without nausea abdominal pain, - 4- HYPERSENSITIVITY Due to death of
parasite triggers immune system 5- Increased
liver enzymes - .
102- METRIFONATE (TRICHLORFON)
- Metrifonate is a safe, low-cost alternative drug
for the treatment of Schistosoma
haematobium infections. It is not active
against S mansoni or S japonicum. It is not
available in the USA. - Basic Pharmacology
- Metrifonate, an organophosphate compound
- It transform to dichlorvos, its active
metabolite.
103- METRIFONATE (TRICHLORFON)
- The mode of action
- It is cholinesterase inhibition.
- This inhibition temporarily paralyzes the adult
worms - resulting in their shift from the bladder venous
plexus to small arterioles of the lungs - where they are trapped, encased by the immune
system, and die.
104- METRIFONATE (TRICHLORFON)
- The drug is not effective against S
haematobium eggs - live eggs continue to pass in the urine for
several months after all adult worms have been
killed. - Clinical Uses
- In the treatment of S haematobium, an oral dose
of 7.510 mg/kg is given three times at 14-day
intervals.
105- METRIFONATE (TRICHLORFON)
- Cure rates on this schedule are 4493, with
marked reductions in egg counts in those not
cured. - Metrifonate was also effective as a prophylactic
agent when given monthly to children in a highly
endemic area - In mixed infections with S haematobium and S
mansoni, metrifonate has been successfully
combined with oxamniquine.
106- METRIFONATE (TRICHLORFON)
- Adverse Reactions, Contraindications, Cautions
- Some studies note mild and transient cholinergic
symptoms - Such as
- nausea and vomiting, diarrhea, abdominal pain,
bronchospasm
107- METRIFONATE (TRICHLORFON)
- Adverse Reactions, Contraindications, Cautions
- headache, sweating, fatigue, weakness, dizziness,
and vertigo. - These symptoms may begin within 30 minutes and
persist up to 12 hours. - .
108- METRIFONATE (TRICHLORFON)
- Adverse Reactions, Contraindications, Cautions
- Metrifonate should not be used after recent
exposure to insecticides or drugs that might
potentiate cholinesterase inhibition. - Metrifonate is contraindicated in pregnancy.
109- Oxamniquine
- Oxamniquine
- second-line drug after praziquantel for the
treatment of Schistosoma mansoni infection only. - S. haematobium and S. japonicum are refractory to
Oxamniquine
110- Oxamniquine
- Pharmacology and mechanism of action
- Oxamniquine is effective only in the treatment
of - Schistosoma(s)mansoni
- The drug may induce its action by inhibiting DNA
synthesis. - it inhibited the synthesis of macromolecules in
sensitive parasites and not in the resistant ones
111- Adverse effects of Oxamniquine
- 1- only significant common side effect reported
is mild to moderate dizziness with or without
drowsiness, reported by up to 40 of treated
patients. - It starts up to 3 hours after a dose and usually
lasts for 3 to 6 hours. - 2- Other side effects include nausea,
vomiting,abdominal pain, and diarrhoea - .
112- Adverse effects of Oxamniquine
- 3- Transient fever, 38 to 39C, peripheral
bloodeosinophilia and pulmonary infiltrates
(Loefflers syndrome) - 4- epileptiform convulsions
- 5- Discoloration of the urine from orange to red
may follow after the drug treatment (mostlikely
due to a metabolite) . This is transitory and
harmless
113- Contraindications and precautions Oxamniquine
- - Patients with pre-existing central
nervous system disturbances such as epilepsy - - or psychiatric disorders should be
treated with caution. - Adults
- A single dose of 15 mg/kg.
- Children (lt4 years)
- A single total dose of 20 mg/kg or two doses of
10 mg/kg in one day separated by an intervalof 3
to 8 hours.
114- Oxamniquine
- Doses
- Adults
- A single dose of 15 mg/kg.
- Children (lt4 years)
- A single total dose of 20 mg/kg or two doses of
10 mg/kg in one day separated by an intervalof 3
to 8 hours.
115 116- ANT-MALARIA
- MALARIA
- The plasmodia are sporozoa in which the
sexual and asexual cycles of reproduction are
completed in different host species - The sexual phase occurs within the gut of
mosquitoes. - mosquitoes subsequently transmit the parasite
while feeding on a human. - Within the red blood cells (RBCs) of the
vertebrate, the plasmodia reproduce asexually
117- ANT-MALARIA
- MALARIA
- they eventually burst from the erythrocyte and
invade other RBCs. - This event produces periodic fever and anemia in
the host, a disease process known as malaria.
118- ANT-MALARIA
- Four species of plasmodium typically cause
human - malaria
- 1- Plasmodium falciparum Because of the lack
of a dormant live stage, P. falciparum does not
cause relapses - 2- P vivax, P. vivax and P. ovale
responsible for late relapse over 6 to 11 months
after acute infection - 3- P ovale.
- 4- P malariae
- P. malariae infections may persist for decades
within the bloodstream, but relapse does not
occur, except under rare circumstances, such as
trauma or surgery
119- ANT-MALARIA
- MALARIA
- P. falciparum can invade erythrocytes at all
stages of maturation, and is responsible for
severe disease with the greatest mortality. It is
often drug resistant. Because of the lack of a
dormant live stage, P. falciparum does not cause
relapses. - P. vivax and P. ovale cause acute illness, and
they are also responsible for late relapse over 6
to 11 months after acute infection. P. malariae
infections may persist for decades within the
bloodstream, but relapse does not occur, except
under rare circumstances, such as trauma or
surgery.
120- ANT-MALARIA
- MALARIA
- - P falciparum is responsible for the majority
of serious complications and deaths. - - Drug resistance is an important therapeutic
problem, most notably with P falciparum.
121- ANT-MALARIA
- MALARIA
- - Mosquito ingests gametocytes from blood of
infected human -
- Sporozoites from oocyst reach mosquito salivary
glands
122- ANT-MALARIA
- MALARIA
- Humans infected by mosquito bite
-
- Rapid infection of hepatocytes starts asexual
cycle in humans
123- ANT-MALARIA
- MALARIA
- Erythrocytic cycle begins with merozoite
attachment to RBC receptor - Trophozoites multiply in RBC to form new
merozoites -
- In 48 to 72 hours, RBCs rupture, releasing
merozoites to infect new RBCs -
- Intrahepatic dormancy causes relapses with P
vivax and P ovale
124- ANT-MALARIA
- MALARIA
- Erythrocytic cycle begins with merozoite
attachment to RBC receptor - Trophozoites multiply in RBC to form new
merozoites -
- In 48 to 72 hours, RBCs rupture, releasing
merozoites to infect new RBCs -
- Intrahepatic dormancy causes relapses with P
vivax and P ovale
125- ANT-MALARIA
- MALARIA
- Sickle cell trait limits intensity of P
falciparum infection -
- Other hemoglobinopathies can also exert
protection
126- ANT-MALARIA
- MALARIA
- Changes induced in erythrocyte membrane
-
- Binding to endothelium may cause micro-infarcts
- Causing Complications due to capillary blockade
can be fatal, particularly in the brain. - - Causing Cerebral malaria
127- ANT-MALARIA
- An anopheline mosquito inoculates plasmodium
sporozoites to initiate human infection
128- ANT-MALARIA
- An anopheline mosquito inoculates plasmodium
sporozoites to initiate human infection
129- ANT-MALARIA
- Circulating sporozoites rapidly invade liver
cells - exoerythrocytic stage tissue schizonts mature in
the liver. - Merozoites are subsequently released from the
liver and invade erythrocytes. - Only erythrocytic parasites cause clinical
illness. Repeated cycles of infection can lead to
the infection of many erythrocytes and serious
disease
130- ANT-MALARIA
- - Species of plasmodia differ significantly
in their ability to invade subpopulations of
erythrocytes - P vivax and P ovale attack only immature cells
(reticulocytes) - whereas P malariae attacks only senescent
cells(old RBC). - During infection with these species, therefore,
no more than 1 to 2 of the cell population is
involved.
131- ANT-MALARIA
- - P falciparum, in contrast, invades ALL RBCs,
regardless of age and may produce very high
levels of parasitemia - West African ancestry lacks Duffy blood group
antigen , are therefore resistant to vivax
malaria. - RBC sialoglycoprotein, particularly
glycoprotein A, has been implicated as the P.
falciparum receptor site.
132- Clinical signs and symptoms
- Fever
- Fever, the hallmark of malaria
- appears to be initiated by the process of RBC
rupture that leads to the liberation of a new
generation of merozoites (sporulation). - the fever might result from the release of
interleukin-1 (IL-1) - and/or tumor necrosis factor (TNF) from
macrophages involved in the ingestion of
parasitic or erythrocytic debris.
133- Clinical signs and symptoms
- Fever
- The resulting fever is irregular and hectic.
- Synchronization of sporulation causes cyclic
fever - fever occurs in distinct paroxysms at 48-hour or,
in the case of P malariae, 72-hour intervals
134- Anemia
- Parasitized erythrocytes are phagocytosed by a
stimulated reticuloendothelial system - or RBCs are destroyed at the time of
sporulation. - At times, the anemia is disproportionate to the
degree of parasitism. - Depression of marrow function, sequestration of
erythrocytes within the enlarging spleen, and
accelerated clearance of nonparasitized cells all
appear to contribute to the anemia.
135- Anemia
- Intravascular hemolysis, though uncommon, may
occur, particularly in falciparum malaria. - When hemolysis is massive, hemoglobinuria
develops, resulting in the production of dark
urine. - This process in conjunction with malaria is known
as blackwater fever.
136- Circulatory Changes
- The high fever results in significant
vasodilatation. - In falciparum malaria, vasodilatation leads to a
decrease in the effective circulating blood
volume and hypotension - P falciparum impairs the microcirculation
- and precipitate tissue hypoxia, lactic acidosis,
and hypoglycemia. - Although all deep tissues are involved, the brain
is the most intensely affected.
137- Central nervous system malaria.
- This small cerebral blood vessel is blocked with
many parasitized erythrocytes adherent to the
endothelium.
138- Cytokines
- Elevated levels of IL-1 and TNF are consistently
found in patients with malaria. - TNF levels increase with parasite density, and
high concentrations appear harmful. - TNF has been shown to cause up-regulation of
endothelial adhesion molecules
139- Cytokines
- high concentrations might precipitate cerebral
malaria by increasing the sequestration of P
falciparumparasitized erythrocytes in the
cerebral vascular endothelium. - Alternatively, excessive TNF levels might
precipitate cerebral malaria by directly inducing
hypoglycemia and lactic acidosis. - Elevated cytokine levels contribute to injury
140- Thrombocytopenia is common in malaria and appears
to be related to both splenic pooling and a
shortened platelet lifespan. - Both direct parasitic invasion and immune
mechanisms may be responsible. - There may be an acute transient
glomerulonephritis in falciparum malaria - and progressive renal disease in chronic P
malariae malaria. - These phenomena probably result from the host
immune response, with deposition of immune
complexes in the glomeruli. - Thrombocytopenia and nephritis common
141- The incubation period between the bite of the
mosquito and the onset of disease is
approximately 2 weeks. - With P malariae and with strains of P vivax in
temperate climates, however, this period is often
more prolonged. - Individuals who contract malaria while taking
antimalarial suppressants may not experience
illness for many months. - In the interval between entry into the country
and onset of disease exceeds 1 month in 25 of P
falciparum infections - 6 months in a similar proportion of P vivax
cases.
142- The clinical manifestations of malaria vary with
the species of plasmodia but typically include - chills, fever, splenomegaly, and anemia.
- The hallmark of disease is the malarial paroxysm.
- This manifestation begins with a cold stage,
which persists for 20 to 60 minutes. - During this time, the patient experiences
continuous rigors and feels cold.
143- With the consequent increase in body temperature,
- the rigors cease and vasodilatation commences,
- Ushering(REACH) in a hot stage .
- The temperature continues to rise for 3 to 8
hours, reaching a maximum of 40 to 41.7C before
it begins to fall. - The wet stage consists of a decrease in fever
and profuse sweating. It leaves the patient
exhausted but otherwise well until the onset of
the next paroxysm. - Malarial paroxysm cold, hot, wet stages
144- Typical paroxysms first appear in the second or
third week of fever, when parasite sporulation
becomes synchronized. - In falciparum malaria, synchronization may never
take place, and the fever may remain hectic and
unpredictable. - The first attack is often severe and may persist
for weeks in the untreated patient.
145- In falciparum malaria, capillary blockage can
lead to several serious complications. - When the central nervous system is involved
(cerebral malaria) - the patient may develop delirium, convulsions,
paralysis, coma, and rapid death. - Acute pulmonary insufficiency frequently
accompanies cerebral malaria, killing about 80
of those involved.
146- When splanchnic capillaries are involved
- the patient may experience vomiting, abdominal
pain, and diarrhea with or without bloody stools. - Jaundice and acute renal failure are also common
in severe illness. - These pernicious syndromes generally appear when
the intensity of parasitemia exceeds 100,000
organisms per cubic millimeter of blood. - Most deaths occur within 3 days.
147- Termination of Acute Attack
- Several agents can destroy asexual erythrocytic
parasites. Chloroquine, a 4-aminoquinoline, has
been the most commonly used. - It acts by inhibiting the degradation of
hemoglobin, thereby limiting the availability of
amino acids necessary for growth. - It has been suggested that the weak basic nature
of chloroquine also acts to raise the pH of the
food vacuoles of the parasite, inhibiting their
acid proteases and effectiveness
148- Termination of Acute Attack
- chloroquine-resistant strains of P falciparum
are now widespread in Africa and Southeast Asia - Resistance of chloroquine and other drugs now
common with P falciparum - Other schizonticidal agents include
quinine/quinidine, antifolatesulfonamide
combinations, mefloquine, halofantrine, and the
artemisinins. - Unfortunately, resistance to all of these agents
is increasing. The artemisinins are also unique
in their capacity to reduce transmission by
preventing gametocyte development.
149- Termination of Acute Attack
- There is a growing consensus that the most
effective way to slow the further development of
drug-resistant strains of P falciparum - is to use one of the artemisinins in combination
with quinine/quinidine, antifolatesulfonamide
compounds, mefloquine, or halofantrine. - Combination therapy may be necessary
150- Radical Cure
- In P vivax and P ovale infections, hepatic
schizonts persist and must be destroyed to
prevent reseeding of circulating erythrocytes
with consequent relapse. - Primaquine, an 8-aminoquinaline, is used for
this purpose. - Some P vivax infections acquired in Southeast
Asia and New Guinea fail initial therapy owing to
relative resistance to this 8-aminoquinaline.
151- Radical Cure
- Retreatment with a larger dose of primaquine is
usually successful. - Unfortunately, primaquine may induce hemolysis
in patients with glucose-6-phosphate
dehydrogenase deficiency. - Persons of Asian, African, and Mediterranean
ancestry should thus be screened for this
abnormality before treatment. -
152- Radical Cure
- Chloroquine destroys the gametocytes of P vivax,
P ovale, and Pmalariae - but not those of P falciparum.
- Primaquine and artemisinins, however, are
effective for this latter species. - Primaquine used to destroy hepatic schizonts of P
vivax and P ovale
153- Treatment General Approach
- It is preferable that treatment for malaria
should not be initiated until the diagnosis has
been established by laboratory investigations. - "Presumptive treatment" without the benefit of
laboratory confirmation should be reserved for
extreme circumstances - (strong clinical suspicion, severe disease,
impossibility of obtaining prompt laboratory
diagnosis). -
- Once the diagnosis of malaria has been made,
appropriate antimalarial treatment - must be initiated immediately. Treatment should
be guided by three main factors
154- ? The infecting Plasmodium species
- ? The clinical status of the patient
- ? The drug susceptibility of the infecting
parasites as determined by the geographic - area where the infection was acquired and the
previous use of antimalarial medicines
155- The infecting Plasmodium species
- Determination of the infecting Plasmodium
- species for treatment purposes is important for
three main reasons. - Firstly, P. falciparum and P. knowlesi infections
can cause rapidly progressive severe illness or
death - while the other species, P. vivax, P. ovale, or
P. malariae, are less likely to cause severe
manifestations.
156- Secondly, P. vivax and P. ovale infections also
require - treatment for the hypnozoite forms that remain
dormant in the liver (Primaquine) and can cause a
relapsing infection. - Finally, P. falciparum and P. vivax species have
different drug - CENTERS FOR DISEASE CONTROL AND PREVENTION
- resistance patterns in differing geographic
regions. - For P. falciparum and P. knowlesi infections,
the urgent initiation of appropriate therapy is
especially critical
157- The clinical status of the patient
- Patients diagnosed with malaria are generally
- categorized as having either
- 1- uncomplicated or severe malaria.
- Patients diagnosed with uncomplicated malaria can
be effectively treated with oral antimalarials.
158- 2- COMPLICATED MALARIA
- patients who have one or more of the following
clinical criteria - a- impaired consciousness/coma
- b- severe normocytic anemia hemoglobinlt7
- c- renal failure
- d- acute respiratory distress syndrome
- e- hypotension
- f- disseminated intravascular coagulation
159- 2- COMPLICATED MALARIA
- g- spontaneous bleeding
- h- acidosis, hemoglobinuria
- k- jaundice
- L- repeated generalized convulsions,
and/or parasitemia of gt 5) - are considered to have manifestations of more
severe disease and should be treated aggressively
with parenteral antimalarial therapy
160- Treatment Uncomplicated Malaria
- P. falciparum or Species Not Identified
Acquired in Areas Without - Chloroquine Resistance
- 1- Chloroquine. A chloroquine dose of 600 mg
base ( 1,000 mg salt) should be given initially,
followed by 300 mg base ( 500 mg salt) at 6, 24,
and 48 hours after the initial dose for a total
chloroquine dose of 1,500 mg base (2,500 mg
salt). -
161- Treatment Uncomplicated Malaria
-
- 2- Alternatively, hydroxychloroquine may be used
at a dose of 620 mg base (800 mg salt) po given
initially followed by 310 mg base (400 mg salt)
po at 6, 24, and 48 hours after the initial dose
for a total hydroxychloroquine dose of 1,550 mg
base (2,000 mg salt). - Prompt initiation of an effective regimen is
vitally important and so using any one of the
effective regimens that readily at hand would be
the preferred strategy.
162- 2- P. falciparum or Species Not Identified
Acquired in Areas With Chloroquine Resistance - For P. falciparum infections acquired in areas
with chloroquine resistance, four treatment
options are available. - The first two treatment options are
- - MALARONE Tablet contains 250 mg of atovaquone
and 100 mg of proguanil - or artemether-lumefantrine (Coartem).
- These are fixed dose combination medicines that
can be used for non-pregnant adult and pediatric
patients. - Both of these options are very efficacious.
163- 3- Quinine sulfate plus doxycycline,
- tetracycline, or clindamycin is the next
treatment option. For the quinine sulfate - combination options, quinine sulfate plus either
doxycycline or tetracycline is generally
preferred to quinine sulfate plus clindamycin
because there are more data on the efficacy of
quinine plus doxycycline or tetracycline. - Quinine treatment should continue for 7 days for
infections acquired in Southeast Asia - and for 3 days for infections acquired in Africa
or South America.
164- 4- The fourth option, Mefloquine,
- is associated with rare but potentially severe
neuropsychiatric reactions when used at treatment
doses. - We recommend this fourth option only when the
other options - cannot be used.
- For pediatric patients, the treatment options are
the same as for a - adults except the drug dose is adjusted by
patient weight.
165- If using a quinine-based regimen for children
less than eight years old - doxycycline and tetracycline are generally not
indicated - therefore, quinine can be given alone
-
- for a full 7 days regardless of where the
infection was acquired
166- or given in combination with clindamycin as
recommended above. - In rare instances, doxycycline or tetracycline
can be used in combination with quinine in
children less than eight - years old
- if other treatment options are not available or
are not tolerated, and the - benefit of adding doxycycline or tetracycline is
judged to outweigh the risk.
167- If infections initially attributed to "species
not identified" are subsequently diagnosed as
being due to P. vivax or P. ovale - additional treatment with primaquine should be
- administered ( P. vivax and P. ovale) INORDER TO
ERADICATE RESEEDING
168- P. malariae and P. knowlesi
- There has been no widespread evidence of
chloroquine resistance in P. malariae and P.
knowlesi species - therefore, chloroquine (or hydroxychloroquine)
may still be used for both of these infections. - In addition, any of the regimens listed above for
the - treatment of chloroquine-resistant malaria may be
used for the treatment of P. malariae and P.
knowlesi infections.
169- P. vivax and P. ovale
-
- Chloroquine (or hydroxychloroquine) remains an
effective choice for all P. vivax and P. ovale
infections except for P. vivax infections
acquired in Papua New Guinea or Indonesia. - The regimens listed for the treatment of P.
falciparum are also effective and may be used. - Reports have confirmed a high prevalence of
chloroquine-resistant P. vivax in these two
specific areas(Papua New Guinea or Indonesia ). - Rare cases of chloroquine-resistant P. vivax
have also been documented in Burma (Myanmar),
India, and Central and South America.
170- Persons acquiring P. vivax infections from
regions other than Papua New Guinea or Indonesia
should initially be treated with chloroquine. - If the patient does not respond to chloroquine,
treatment should be changed to one of the two
regimens recommended for chloroquine-resistant P.
vivax infections
171- Persons acquiring P. vivax infections in Papua
New Guinea or Indonesia should initially be
treated with a regimen recommended for
chloroquine-resistant P. vivax infections. - The three treatment regimens for
chloroquine-resistant P. vivax infections are - A- quinine sulfate plus doxycycline or
tetracycline - B- or, Atovaquone-proguanil
- C- or mefloquine.
- These three treatment options are equally
recommended.
172- In addition to requiring blood stage treatment,
infections with P. vivax and P. ovale can relapse
due to hypnozoites that remain dormant in the
liver. To eradicate the hypnozoites - patients should be treated with a 14-day course
of primaquine - CDC recommends a primaquine phosphate dose of 30
mg (base) by mouth daily for 14 days. - Because primaquine can cause hemolytic anemia in
persons with glucose-6-phosphate-dehydrogenase
(G6PD) deficiency - persons must be screened for G6PD deficiency
prior to starting primaquine treatment.
173- For persons with borderline G6PD deficiency or as
an alternate to the above regimen, primaquine may
be given at the dose of 45 mg (base) orally one
time per week for 8 weeks - consultation with an expert in infectious disease
and/or tropical medicine is advised if this
alternative regimen is considered in
G6PD-deficient persons. - Primaquine must not be used during pregnancy.
- For pediatric patients, the treatment options
are the - same as for adults except the drug dose is
adjusted by patient weight.
174- For children less than 8 years old, doxycycline
and tetracycline are generally not indicated - therefore, for chloroquine-resistant P. vivax,
Mefloquine is the recommended treatment. - If it is not available or is not being tolerated
and if the treatment benefits outweigh the
risks - atovaquone-proguanil or artemether-lumefantrine
should be used instead.
175- Alternatives For Pregnant Women
-
- Malaria infection in pregnant women is associated
with high risks of both maternal and perinatal
morbidity and mortality. - pregnant women have a reduced immune response and
therefore less effectively clear malaria
infections. - In addition, malaria parasites sequester and
replicate in the - placenta.
- Pregnant women are three times more likely to
develop severe disease than non-pregnant women
acquiring infections from the same area.
176- Malaria infection during pregnancy can lead to
miscarriage, premature delivery, low birth
weight, congenital infection, and/or perinatal
death. - For pregnant women diagnosed with uncomplicated
malaria - caused by P. malariae, P. vivax, P. ovale, or
chloroquine-sensitive P. falciparum infection,
prompt treatment - with chloroquine (treatment schedule as with
non-pregnant adult patients) is recommended. - Alternatively, hydroxychloroquine may be given
instead.
177- For pregnant women diagnosed with uncomplicated
malaria caused by chloroquine-resistant P.
falciparum infection - prompt treatment with either Mefloquine or a
combination of quinine sulfate and clindamycin is
recommended. - Quinine treatment should continue for 7 days for
infections acquired in Southeast Asia and for 3
days for infections - acquired elsewhere clindamycin treatment should
continue for 7 days regardless of where the
infection was acquired.
178- For pregnant women diagnosed with uncomplicated
malaria caused by chloroquine-resistant P. vivax
infection, prompt treatment with mefloquine is