PHL%20417

1

• PHL 417
• ALHARBI-LECTURES
• 1- PART-I
• IMMUNOMODULATORS
• 2- PART II
• ANTI-PARASITES

2
(No Transcript)
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

4
CLONAL EXPANSION Produce CD4 Then CD8
RECOGNITION
Antigen presentation
Ag-presenting cell
Antigen processing
Antigen uptake
Foreign Cell or Protein
5
Receptor-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
6
Steps Towards T-cell Clonal Expansion
7
(No Transcript)
8
IMMUNOPHARMACOLOGY
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 )

12
Anti-CD3
Cyclosporin Tacrolimus Glucocorticoids
Sirolimus
IL-2
Mycophenolate
Mitogenesis
Glucocorticoids
13
Preventing 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
14
CYCLOSPORIN

• 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

15
Receptor-associated tyrosine kinases (ZAP-70, lck
fyn)
TCR
Phospholipase C?
DAG
phosphatidyl inositol
IP3
NF-?B Other TFs
?
PKC
Ca2
Calcineurin
IL-2
16
(No Transcript)
17
ACTION OF CYCLOSPORIN OR TACROLIMUS
Cyclophilin
Cyclo
CALCINEURIN
NF-?B
IL-2
OAP
18
ACTION OF CYCLOSPORIN OR TACROLIMUS
Cyclophilin
Cyclo
Calcineurin
NF-?B
IL-2
OAP
19
CYCLOSPORIN ADVERSE EFFECTS

• Increase risk of infection
• Nephrotoxicity
• Liver dysfunction
• Regular blood level monitoring to avoid kidney
  and liver toxicity
• Hirsutism
• Gum hypertrophy

20
TACROLIMUS (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

21
TACROLIMUS (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

22
SIROLIMUS (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

23
Preventing IL-2-driven clonal expansion
IL-2
IL-2R
Prevent mitogenic response to IL-2R
stimulationSirolimus (Rapamycin)
Mitogenesis
IL-2
24
SIROLIMUS (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

25
EVEROLIMUS (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

26
GLUCOCORTICOIDS

• 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

27
MECHANISM 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

28
Glucocorticoids

• Suppression of transcription OF IL-2
• Reduced IL-2 mRNA stability
• (? IL-2 mRNA Degradation)

29
GLUCOCORTICOID 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

30
ADVERSE EFFECTS

• Suppress response to injury or infection
• Suppress patients capacity to synthesize
  corticosteroids
• Metabolic effect
• Water and electrolyte imbalance
• Osteoporosis
• GI bleeding
• hyperglycemia

31
CYCLOPHOSPHAMIDE

• 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

32
(No Transcript)
33
CYCLOPHOSPHAMIDE

• 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

34
AZATHIOPURINE (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

35
(No Transcript)
36
AZATHIOPURINE

• USED
• - in organ transplant to prevent rejection
• - Autoimmune diseases with glucocorticoids
• MAJOR SIDE EFFECT
• - suppress bone marrow
• - Hepatotoxicity
• - Retinopathy

37
MYCOPHENOLATE

• 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

38
esterase
Mycophenolate mofetil (prodrug)
Mycophenolate
39
Mycophenolic 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

40
Ribose-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

43
IMMUNOSUPPRESSANT 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

45
IMMULOGLOBULINS

• Antibodies against human lymphocytes
• or their surface protein can have significant
  immunosupressant action

46
IMMULOGLOBULINS

• Antibodies against human lymphocytes
• or their surface protein can have significant
  immunosupressant action

47
POLYCLONAL 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

48
ATG (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

49
ATG (Atgam )

• ADVERSE EFFECTS
• - FEVER
• - Allergic reaction
• Therefore, it is premedicated by paracetamol
  diphenhydramine glucocorticoids

50
MONOCLONAL ANTIBODIES

• Direct against surface components of T cells
• CD3 proteins with antigen receptors
• Example Muromonab-CD3 (Orthoclone )

51
Muromonab-CD3 (Orthoclone )OKT3

• 1- MOA
• It binds with T-cell receptor-associated CD3
  glycoprotein
• 2- CLINICAL USES
• Acute allograft rejection resistant to
  conventional therapy

52
Muromonab-CD3 (Orthoclone )OKT3

• 3- ADVERSE EFFECTS
• First dose effects flu-like symptoms (cytokine
  release syndrome)
• Manifested by fever, respiratory dystress
• Hypervolemic pulmonary edema

53
Rhd 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

54
infliximab, 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

55
ETANERCEPT (Enbrel )

• MOA it binds with TNF and
• blocks its interaction with cell surface
  receptor
• CLINICAL USE
• - for rheumatoid arthritis crohn.s disease

56
Daclizumab (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

57
Interferon

• 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

58
Interferon

• 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)

59
Alpha-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,

60
Interferon

• 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)

61
Interferon 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,

62
Interferons ? 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

63
Interferons ? 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

64
Interferons ? 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

65
Side Effects of Interferons

• Common
• Flu-like symptoms
• Chills
• Fever
• Muscle aches
• Asthenia (weakness)
• Betaseron and Rebif have injection site reactions
  

66
Side 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

• PART II
• ANTI-PARASITES

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)
82
A 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).
83
A 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

• ANT-MALARIA

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