Transcript immunomodulators and antiparasites

PHL 417
ALHARBI-LECTURES
1- PART-I
IMMUNOMODULATORS
2- PART II
ANTI-PARASITES
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
CLONAL
EXPANSION
RECOGNITION
T
Ag-presenting cell
Antigen
presentation
Produce CD4
Then
CD8
Antigen processing
Antigen uptake
Foreign Cell or Protein
Receptor-associated tyrosine
kinases (ZAP-70, lck & fyn)
T-CELL RECEPTOR
TCR
DAG
phosphatidyl
inositol
P
IP3
Ca2+
PKC
?
NF-B &
Other TF’s
Calcineurin
NF-AT
NF-AT
P
Oct
Oct
IL-2
Steps Towards T-cell Clonal Expansion
4th step Proliferatio
Receptor Binding
& Signaling
Autocrine
signaling
(IL-2)
1 STEP
3rd step
2nd STEP Cell - cell signaling
(IFN-, IL-1)
APC
IMMUNOPHARMACOLOGY
0psonized bacteria
Macrophage
APC
B lymphocyte
T lymphocyte
IL-4,IL-5
IL-2
IL-2
TH1
TNF-
IFN-
Plasma Cells:
Activated
Macrophage
TH2
IFN-
IFN-
Activated
Activated
Cytotoxic T cell
Memory B Cells
-IgG
- IgM
- IgA
- IgD
NK cells
CELL-MEDIATED IMMUNITY
HUMORAL IMMUNITY
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
CLASSIFICATION OF
IMMUNOSUPPRESSANTS
1- INHIBIT INTERLEUKIN-2 PRODUCTION
(calcineurin inhibitors)
• Cyclosporine, tacrolimus
2-INHIBIT INTERLEUKIN-2 ACTION
– Sirolimus , Everolimus,
Mycophenolate{CELLCEPT}, Azathioprine(imuran)
3- INHIBIT CYTOKINE GENE EXPRESSION
– Glucocorticoid
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)
– Rh0[d] immunoglobulin (Gamulin Rh ®)
Anti-CD3
Cyclosporin
Tacrolimus
Glucocorticoids
Sirolimus
IL-2
Mycophenolate
Mitogenesis
IL-2
Glucocortic
Preventing IL-2-driven clonal expansion
Prevent TCR signaling for IL-2 gene
transcription:
Prevent mitogenic respon
to IL-2R stimulation
CYCLOSPORIN & TACROLIMUS Sirolimus & Mycophenolate, IMU
GLUCOCORTICOIDS
Prevent activation of T-cell
Via TCR Anti-TCR Antibody
IL-2
IL-2R
 IL-2 mRNA Degradation
GLUCOCORTICOIDS
Mitogenesis
IL-2
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
Receptor-associated tyrosine
kinases (ZAP-70, lck & fyn)
TCR
DAG
phosphatidyl
inositol
P
IP3
Ca2+
PKC
?
NF-B &
Other TF’s
Calcineurin
NF-AT
NF-AT
P
Oct
Oct
IL-2
ACTION OF CYCLOSPORIN OR TACROLIMUS
Cyclophilin
Cyclo
P
P
Cyclo
Oct
NF-AT
CALCINEURIN
Oct
NF-AT
AP-1
Oct
NF-AT
NF-B
IL-2
ACTION OF CYCLOSPORIN OR TACROLIMUS
Cyclophilin
Cyclo
P
P
Cyclo
Oct
NF-AT
Cyclo
Calcineurin
Oct
NF-AT
AP-1
Oct
NF-AT
NF-B
IL-2
CYCLOSPORIN ADVERSE EFFECTS
• Increase risk of infection
• Nephrotoxicity
• Liver dysfunction
– Regular blood level monitoring to avoid kidney
and liver toxicity
• Hirsutism
• Gum hypertrophy
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
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
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
Preventing IL-2-driven clonal expansion
IL-2
IL-2R
Prevent mitogenic response
to IL-2R stimulation
Sirolimus (Rapamyc
Mitogenesis
IL-2
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
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
GLUCOCORTICOIDS
• are potent immunosuppressive and antiinflammatory 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
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
Glucocorticoids
• Suppression of transcription OF IL-2
• Reduced IL-2 mRNA stability
( IL-2 mRNA Degradation)
GLUCOCORTICOID CLINICAL USES
• As anti-inflammatory & immuno- suppressive therapy
– Asthma, allergic rhinitis, eczema, severe drug allergic
reaction, rheumatoid arthritis ,organ transplant
• In neoplastic disease
– Hodgkin’s disease, acute lymphocytic leukaemia
• Replacement therapy
• In adrenal insufficiency
ADVERSE EFFECTS
• Suppress response to injury or infection
• Suppress patients capacity to synthesize
corticosteroids
• Metabolic effect
– Water and electrolyte imbalance
– Osteoporosis
– GI bleeding
– hyperglycemia
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
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
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
AZATHIOPURINE
• USED
- in organ transplant to prevent rejection
- Autoimmune diseases with glucocorticoids
• MAJOR SIDE EFFECT:
- suppress bone marrow
- Hepatotoxicity
- Retinopathy
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
N
HCl
Mycophenolate mofetil
(prodrug)
Mycophenolate
esterase
O
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
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
2- DRUG INTERACTION
• Magnesium and aluminium impairs
absorption
3- USES
- Trial used in kidney transplant with
cyclosporine and steroids
- Autoimmune diseases
4- ADVERSE EFFECTS
• Peptic ulcer & esophagitis
• Hypercholestrolemia
• Diarrhea
IMMUNOSUPPRESSANT REGIMENS
1- Basiliximab, cyclosporin, prednisolone
2- Basiliximab, Azathioprine, cyclosporin,
prednisolone
3- Basiliximab, MMF, cyclosporin, prednisolone
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
IMMULOGLOBULINS
• Antibodies against human lymphocytes
• or their surface protein can have significant
immunosupressant action
IMMULOGLOBULINS
• Antibodies against human lymphocytes
• or their surface protein can have significant
immunosupressant action
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
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
ATG (Atgam
®)
• ADVERSE EFFECTS
- FEVER
- Allergic reaction
Therefore, it is premedicated by paracetamol &
diphenhydramine & glucocorticoids
MONOCLONAL ANTIBODIES
• Direct against surface components of T cells
– CD3 proteins with antigen receptors
Muromonab-CD3
®
(Orthoclone )
Example :
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
Muromonab-CD3 (Orthoclone ®)OKT3
3- ADVERSE EFFECTS
• First dose effects flu-like symptoms (cytokine release
syndrome)
• Manifested by fever, respiratory dystress
• Hypervolemic pulmonary edema
Rh[d] 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
infliximab, Remicade
®]
MOA: Antibody against tumor necrosis factor
alpha (TNF alpha)
• USED:
- for crohn’s disease
- Rheumatoid arthritis with methotrexate who
inadequate respond to methotrexate alone
• CONTRAINDICATED:
- CHF
- & TUBERCULOSIS
ETANERCEPT (Enbrel
®)
MOA: it binds with TNF and
• blocks its interaction with cell surface receptor
• CLINICAL USE
- for rheumatoid arthritis & crohn.s disease
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
Interferon
Type-I
A- Interferon Alpha (prod. by leukocytes)
(antiviral (hepatitis C, interferon alfa-2b ), antiproliferative)
malignant melanoma, renal cell carcinoma, hairy cell leukemia, Kaposi’s 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
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)
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,
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®)
Interferon Beta
Mechanism 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,
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
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
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
Side Effects of Interferons
Common:
– Flu-like symptoms
– Chills
– Fever
– Muscle aches
– Asthenia (weakness)
– Betaseron and Rebif have injection site reactions
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
PART II
ANTI-PARASITES
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
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.
schistosomiasis
• The three species can be distinguished by the
appearance of their eggs in the microscope:
• S. mansoni eggs have a prominent lateral spine
•
Schistosomiasis
• S. japonicum eggs have a very small lateral spine
Schistosomiasis
• S. haematobium eggs have a terminal spine the veins
draining the urinary bladder. Schistosomes are
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
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,
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
Schistosomiasis
• The eggs are moved progressively
• toward the lumen of the intestine
• (S. mansoni
• and S. japonicum)
• Eggs eliminated with feces
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
• .
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.
Schistosomiasis
• Pathology of S. haematobium schistosomiasis
includes:
- hematuria
- scarring, calcification
- squamous cell carcinoma
- occasional embolic egg granulomas in brain or
spinal cord.
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.
A: Male and female Schistosoma mansoni adults. The female lives in the male's schist (shown as a ventral opening) (6 x). B: Clonorchis sinensis adult (6x). C: Paragonimus westerm
A: Male and female Schistosoma mansoni adults. The female lives in the male's schist (shown as a ventral opening) (6 x). B: Clonorchis sinensis adult (6x). C: Paragonimus westerm
• 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).
• SYMPTOMS AND SIGNS
• Acute Schistosomiasis (Katayama Syndrome)
• A febrile illness may develop 2–8 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
• 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 2–8 weeks.
• SYMPTOMS AND SIGNS
• Chronic Schistosomiasis
• Many infected persons have light infections and are
asymptomatic
• but an estimated 50–60% have symptoms
• 5–10% have advanced organ damage.
• Asymptomatic infected children may suffer from anemia
and growth retardation
• SYMPTOMS AND SIGNS
• Chronic Schistosomiasis
• Symptomatic patients with intestinal schistosomiasis
typically experience:
•
•
•
•
•
abdominal pain
fatigue
Diarrhea
hepatomegaly.
.
• SYMPTOMS AND SIGNS
• Chronic Schistosomiasis
• Over years develop:
• anorexia
• weight loss
• weakness
• colonic polyps
• and features of portal hypertension
•
•
•
•
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.
• 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.
• 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.
• 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
• 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
• 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
• 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
• 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
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
Praziquantel
• Praziquantel is administered orally.
• The tablets should not be chewed
• but can be halved or quartered to allow
administration of individualized doses.
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.
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
•
•
•
•
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.
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.
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
7.5–10 mg/kg is given three times at 14-day
intervals.
METRIFONATE (TRICHLORFON)
• Cure rates on this schedule are 44–93%, 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.
METRIFONATE (TRICHLORFON)
• Adverse Reactions, Contraindications, &
Cautions
• Some studies note mild and transient cholinergic
symptoms
• Such as:
• nausea and vomiting, diarrhea, abdominal pain,
bronchospasm
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.
• .
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.
Oxamniquine
• Oxamniquine
• second-line drug after praziquantel for the treatment
of Schistosoma mansoni infection only.
• S. haematobium and S. japonicum are refractory to
Oxamniquine
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
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
.
Adverse effects of Oxamniquine
3- Transient fever, 38 to 39°C, peripheral
bloodeosinophilia and pulmonary infiltrates
(Loeffler’s 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
• 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 (<4 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
• Oxamniquine
Doses
•
•
•
•
Adults
A single dose of 15 mg/kg.
Children (<4 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.
ANT-MALARIA
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
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.
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
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.
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.
ANT-MALARIA
MALARIA
• - Mosquito ingests gametocytes from blood of
infected human
•
• Sporozoites from oocyst reach mosquito salivary
glands
ANT-MALARIA
MALARIA
• Humans infected by mosquito bite
•
• Rapid infection of hepatocytes starts asexual cycle in
humans
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
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
ANT-MALARIA
MALARIA
• Sickle cell trait limits intensity of P falciparum
infection
•
• Other hemoglobinopathies can also exert protection
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
ANT-MALARIA
• An anopheline mosquito inoculates plasmodium
sporozoites to initiate human infection
ANT-MALARIA
• An anopheline mosquito inoculates plasmodium
sporozoites to initiate human infection
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
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.
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.
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.
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
• 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.
• 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.
• 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.
• Central nervous system malaria.
• This small cerebral blood vessel is blocked with many parasitized
erythrocytes adherent to the endothelium.
• 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
• Cytokines
• high concentrations might precipitate cerebral malaria by
increasing the sequestration of P falciparum–parasitized
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
• 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
• 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.
• 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.
• 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 41.7°C 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
- 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.
• 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.
• 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.
• 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
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, antifolate–
sulfonamide 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.
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, antifolate–sulfonamide compounds,
mefloquine, or halofantrine.
• Combination therapy may be necessary
•
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 8aminoquinaline.
•
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.
•
•
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
• 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:
•
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
• 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.
• 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
• 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.
2- COMPLICATED MALARIA
• patients who have one or more of the following clinical criteria :
a- impaired consciousness/coma
b- severe normocytic anemia [hemoglobin<7]
c- renal failure
d- acute respiratory distress syndrome
e- hypotension
f- disseminated intravascular coagulation
2- COMPLICATED MALARIA
g- spontaneous bleeding
h- acidosis, hemoglobinuria
k- jaundice
L- repeated generalized convulsions, and/or parasitemia of > 5%)
are considered to have manifestations of more severe disease and
should be treated aggressively with parenteral antimalarial
therapy
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).
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.
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.
3- Quinine sulfate plus doxycycline,
tet acycline, or clindamycin is the next treatment option. For the
quinine sulfate
r
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.
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.
• 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
• 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.
• 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
• 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.
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.
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
• 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.
• 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 glucose6-phosphate-dehydrogenase (G6PD) deficiency
•
persons must be screened for G6PD deficiency prior to starting
primaquine treatment.
• 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.
• 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.
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.
• 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 chloroquinesensitive P. falciparum infection, prompt treatment
• with chloroquine (treatment schedule as with non-pregnant
adult patients) is recommended.
• Alternatively, hydroxychloroquine may be given instead.
• 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.
• For pregnant women diagnosed with uncomplicated malaria
caused by chloroquine-resistant P. vivax infection,
prompt treatment with mefloquine is recommended.
• Doxycycline and tetracycline are generally not indicated for use
in pregnant women.
• However, in rare instances, doxycycline or tetracycline can be
used in combination with quinine
• if other treatment options are not available
• or are not being tolerated, and the benefit of adding
doxycycline or tetracycline is judged to outweigh the risks.
• According to its U.S. labels, atovaquone/proguanil and
artemether-lumefantrine are classified:
• as a pregnancy category C medications
•
and are generally not indicated for use in pregnant women because there
are no adequate, well-controlled studies in pregnant women.
• However, for pregnant women diagnosed with uncomplicated
• malaria caused by chloroquine-resistant P. falciparum infection
•
atovaquone/proguanil or artemether-lumefantrine may
be used if other treatment options are not available or are not
being tolerated, and if the potential benefit is judged to
outweigh the potential risks.
• For P. vivax or P. ovale infections, primaquine phosphate for
radical treatment of hypnozoites should not be given during
pregnancy.
• Pregnant patients with P. vivax or P. ovale infections should be
maintained on chloroquine prophylaxis for the duration of their
pregnancy.
• The chemoprophylactic dose of chloroquine phosphate is
• 300mg base (=500 mg salt) orally once per week.
• After delivery, pregnant patients with P. vivax or P. ovale
infections who do not have G6PD deficiency should be
• treated with primaquine
• Treatment: Severe Malaria
• Pregnant women diagnosed with severe malaria should be
• treated aggressively with parenteral antimalarial therapy
• Patients who are considered to have manifestations of more severe disease
should be treated aggressively with parenteral antimalarial therapy
regardless of the species of malaria seen on the blood smear.
•
Oral antimalarial drugs are
of severe malaria.
not recommended for the initial treatment
• Treatment: Severe Malaria
• for the initial treatment of severe malaria. If severe malaria is
strongly suspected
• but a laboratory diagnosis cannot be made at that time
• blood should be collected for diagnostic testing as soon as it is
available
• and parenteral antimalarial drugs may be
• started.
• Treatment: Severe Malaria
• Since 1991, quinidine gluconate has been the only parenterally
administered antimalarial drug available in the United States.
• It is recommended to give a loading dose of 6.25 mg base/kg
(=10 mg salt/kg) of quinidine gluconate infused intravenously
over 1-2 hours followed by a continuous infusion of 0.0125 mg
• base/kg/min (=0.02 mg salt/kg/min).
• An alternative regimen is an intravenous loading dose of 15mg
base/kg (=24 mg salt/kg) of quinidine gluconate infused
intravenously over 4 hours.
• Treatment: Severe Malaria
• every 8 hours, starting 8 hours after the loading dose .
• At least 24 hours of quinidine gluconate infusion (or 3
intermittent doses) are recommended
• once the parasite density is < 1% and the patient can take oral
Medication
• the patient can complete the treatment course with an oral
regimen such as oral quinine at the same dosage for
uncomplicated malaria
• Treatment: Severe Malaria
• (for a combined treatment course of quinidine/quinine for 7
days for malaria acquired in Southeast Asia
• and 3 days for malaria acquired elsewhere).
• Other oral regimens such as atovaquone-proguanil or
artemether-lumefantrine may be used instead of an oral quinine
based regimen
Treatment: Severe Malaria
• Initial (including loading) doses of parenteral quinidine do not need to be
reduced in persons with renal failure.
•
If renal failure persists or the patient does not improve clinically
• the maintenance dosage should be reduced by one third to one half on the
third treatment day.
As with treatment of uncomplicated P. falciparum, quinidine/quinine therapy
should be combined with doxycycline, tetracycline, or clindamycin.
• Treatment: Severe Malaria
• If the patient is unable to tolerate oral therapy
• doxycycline (100mg every 12 hours) or clindamycin (5 mg
base/kg every 8 hours) may be given intravenously until the
patient can be switched to oral therapy.
• Rapid intravenous administration of doxycycline or clindamycin
should be avoided.
* If the patient can tolerate oral therapy, doxycycline (100 mg every 12
hours), tetracycline (250mg every 6 hours), or clindamycin (20 mg
base/kg/day divided three times per day) for 7 days are options.
• Treatment: Severe Malaria
• Parenteral quinidine gluconate is cardiotoxic and so a baseline
EKG should be obtained before initiating therapy.
• Quinidine should be administered in an intensive care setting
with continuous cardiac and frequent blood pressure
monitoring.
• At the dosages required for the treatment of falciparum
malaria, quinidine gluconate:
• may cause ventricular arrhythmia, hypotension, hypoglycemia,
and prolongation of the QTc interval.
• Treatment: Severe Malaria
• The quinidine gluconate infusion should be slowed or stopped
for an increase in the QRS complex by > 50%, a QTc interval >
0.6 seconds
• a QTc interval that is prolonged by more than 25% of the
baseline value
• or hypotension unresponsive to fluid challenge.
• Because most deaths from severe malaria occur within the first
24-48 hours, the goal of a loading dose is to quickly reach
therapeutic concentrations at a time when they are needed most.
• Treatment: Severe Malaria
• Recent use of other drugs that may prolong the QTc interval
(e.g., quinine or mefloquine) should be considered when
determining whether a patient should receive a loading dose of
quinidine gluconate.
• Because there is less evidence on which to base decisions with
quinidine gluconate, recommendations for administration of a
loading dose are based on experience with loading doses of
quinine.
• A loading dose of quinidine gluconate should be given unless the
patient has received more than 40 mg/kg quinine in the previous
2 days
• Treatment: Severe Malaria
• or has received mefloquine in the previous 12 hours.
• Consulting a cardiologist and a physician with experience in
treating malaria is advised when treating malaria patients with
quinidine gluconate.
•
Glucose must be monitored closely as quinidine- (or quinine-)
induced hyperinsulinemic
• hypoglycemia can occur.
• Treatment: Severe Malaria
• With the advent of newer anti-arrhythmic agents, quinidine gluconate has
been dropped from many hospital formularies and fewer clinicians have
experience with the drug.
• To ensure the availability of quinidine in health care facilities, hospital
• drug services need to maintain or add quinidine gluconate injection to
formularies.
•
If quinidine gluconate injection is not available on the hospital formulary,
the hospital
• should be able to immediately locate a nearby health care facility that
stocks it.
• If a local source cannot be found, quinidine gluconate should be requested
from the local or regional distributor
• Treatment: Severe Malaria
• If quinidine is unavailable, or in patients with adverse effects or
contraindications to quinidine, or in patients with a parasitemia
>10% of baseline at 48 hours after initiation of IV quinidine,
• parenteral artesunate is available as an investigational
new drug through CDC.
• If both quinidine and artesunate can be obtained
• in similar time frames the treating physician may choose either
option.
• Treatment: Severe Malaria
• While exchange transfusion has not been proven beneficial in an
adequately powered randomized controlled trial
• it has been an option in the treatment of severe malaria since
1974.
• CDC recommends that exchange transfusion be strongly considered for
persons with a parasite density of more than 10% or if complications such as
cerebral malaria, acute respiratory distress syndrome, or renal complications
exist.
• Exchange transfusion is thought to have beneficial effects by removing
infected red
• Treatment: Severe Malaria
• improving the rheological properties of blood, and reducing toxic factors
such as parasite-derived toxins
• harmful metabolites, and cytokines.
• The risks of exchange transfusion include :
• fluid overload, febrile and allergic reactions, metabolic disturbances (e.g.,
hypocalcemia)
• red blood cell alloantibody sensitization
• transmissible infection, and line sepsis.
• Treatment: Severe Malaria
• The risks of exchange transfusion include :
• Thus, the potential benefits of exchange transfusion should be
weighed against the risks.
• The parasite density should be monitored every 12 hours until it
falls below 1%, which usually requires the exchange of 8-10
units of blood in adults
• Treatment: Severe Malaria
• The risks of exchange transfusion include :
• Thus, the potential benefits of exchange transfusion should be
weighed against the risks.
• The parasite density should be monitored every 12 hours until it
falls below 1%, which usually requires the exchange of 8-10
units of blood in adults
• Mefloquine
• Treatment of mild to moderate malaria caused by mefloquine-susceptible
strains of Plasmodium falciparum or P. vivax .
• Prevention of malaria caused by P. falciparum or P. vivax .
•
Patients with acute P. vivax need subsequent treatment with 8-aminoquinolone
to prevent relapse.
• Mechanism of action is unknown PREVENT INGESTION OF
HEMOGLOBIN
• Contraindications
• Acute depression; history of psychosis or convulsions; hypersensitivity to the
drug or related compounds (eg, quinine, quinidine).
• Pregnancy: Category C
• Mefloquine
Adverse effects
• mental status changes
• cardiac abnormalities
• Chloroquine
• Uses
• Prevention of Malaria
• Chloroquine is used for prevention of malaria caused by Plasmodium malariae,
P. ovale, P. vivax, or susceptible strains of P. falciparum.
• Mechanism of action
• Concentrates in parasite food vacuoles and prevents heme metabolism, thereby
causing toxicity and cell death due to the buildup of soluble heme
• Chloroquine: GI upset; pruritus; visual disturbances; ECG changes
• Quinine: Cinchonism (tinnitus, headache, dizziness, nausea); Coombs’
positive hemolytic anemia
• Quinine
• Uses
• Treatment of uncomplicated P. falciparum malaria.
• Mechanism of action
• Inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium
falciparum and can bind with hemozoin in parasitized erythrocytes.
• Contraindications
• Prolonged QT interval
• G6PD deficiency
• myasthenia gravis
• optic neuritis
• Quinine
• Adverse Reactions
• CV: Atrial fibrillation, AV block, bradycardia
• QT prolongation
• Cinchonism
pregnancy: Category C
• Primaquine
Uses
• Radical cure or prevention of relapse in vivax malaria; after termination of
chloroquine phosphate suppressive therapy in areas where vivax malaria is
endemic.
Mechanism of action
• Primaquine acts against primary and latent hepatic stages of Plasmodium spp.
and prevents relapses in P. vivax and P. ovale infections.
• It has gametocytocidal activity against P. falciparum and
other Plasmodium species.
•
primaquine is inactive against asexual blood stage parasites.
• Primaquine
Mechanism of action
•
Primaquine may
be converted to electrophilic intermediates
that act as oxidation-reduction mediators.
• Such activity could contribute to antimalarial effects by
generating reactive oxygen species or by interfering with
mitochondrial electron transport in the parasite
• Some strains of P. vivax can exhibit partial resistance
to primaquine
• Primaquine
Adverse reaction
• Leukopenia
• hemolytic anemia in G-6-PD deficiency
• methemoglobinemia in NADH methemoglobin
reductase deficiency.
• Primaquine is not recommended because of the
potential risk of haemolytic effects in the fetus.
• MALARONE ® Tablet contains:
• 250 mg of atovaquone and 100 mg of proguanil
• USES:
• MALARONE is indicated for the treatment of acute,
uncomplicated P. falciparum malaria.
•
MALARONE has been shown to be effective in regions where the drugs
chloroquine, halofantrine, mefloquine, and amodiaquine may have
unacceptable failure rates- presumably due to drug resistance.
• Prevention of Malaria: MALARONE is indicated for the
prophylaxis of P. falciparum malaria, including in areas where
chloroquine resistance has been reported
• MALARONE ® Tablet contains:
• 250 mg of atovaquone and 100 mg of proguanil
• Mechanism of actions:
• Atovaquone is a selective inhibitor of parasite mitochondrial
electron transport.
• Proguanil hydrochloride primarily exerts its effect by means of
the metabolite cycloguanil, a dihydrofolate reductase inhibitor.
• Inhibition of dihydrofolate reductase in the malaria parasite
disrupts deoxythymidylate synthesis.
• MALARONE ® Tablet contains:
• 250 mg of atovaquone and 100 mg of proguanil
• Mechanism of actions:
• Activity In Vitro and In Vivo: Atovaquone and cycloguanil (an
active metabolite of proguanil) are active against the
erythrocytic and exoerythrocytic stages of Plasmodium spp.
• Enhanced efficacy of the combination compared to either
atovaquone or proguanil alone was demonstrated in clinical
studies in both immune and non-immune patients
• MALARONE ®
• Concomitant treatment with tetracycline has been associated
with approximately a 40% reduction in plasma concentrations
of atovaquone.
• Toxicities
• Hepatic Effects
• Elevations in AST and ALT have occurred
• In most patients, liver enzyme values returned to normal by day 28
of follow-up.
• MALARONE ®
• Pregnancy
• Category C.
• Atovaquone and proguanil may be used in pregnant women if the
potential benefits outweigh the risks.
• CDC states that the drug may be used in pregnant women for
treatment of uncomplicated malaria caused by chloroquine-resistant
P. falciparum if other treatment options are not available or are not
tolerated
• CDC states that the drug should not be used for prevention of
malaria in pregnant women.
Coartem ®
- Coartem contains a fixed ratio of 1:6 parts of Artemether 20
mg and Lumefantrine 120 mg.
• Artemether is a semisynthetic chiral acetal derivative from
artemisinin,
• Artemether is a prodrug that is rapidly converted to
dihydroartemisinin
• isolated from the plant Artemisia annua.
• Lumefantrine is a racemic mixture of a synthetic fluorene
derivative
• Similarl in structure to : (quinine, mefloquine, halofantrine),
lumefantrine belongs to the aryl-aminoalcohol family.
- Artemether-Lumefantrine (Coartem ® ).
• INDICATIONS
• Treatment, including stand-by emergency treatment of children and
infants with acute uncomplicated infections due to Plasmodium
falciparum or mixed infections including P. falciparum.
• Because Coartem is effective against both drug-sensitive and drugresistant P. falciparum it is also recommended for malaria
infections acquired in areas where the parasites may be resistant to
other antimalarials.
• Coartem is not approved for the prevention of malaria
- Artemether-Lumefantrine (Coartem ® ).
• Mechanism of Actions:
• The site of antiparasitic action of both components is the food
vacuole of the malarial parasite
• where they are thought to interfere with the conversion of
haem, a toxic intermediate produced during haemoglobin
breakdown to the non-toxic haemozoin, malaria pigment.
• Lumefantrine is thought to interfere with the polymerisation
processin
• Mechanism of Actions:
• Artemether generates reactive metabolites as a result of the
interaction between its peroxide bridge and haem iron.
• Both artemether and lumefantrine have a secondary action
involving inhibition of nucleic acid- and protein synthesis within
the malarial parasite.
• Data from in vitro and in vivo studies show that Coartem did
not induce resistance.
• The antimalarial activity of the combination of lumefantrine
and artemether in Coartem is greater than that of either
substance alone.
- Artemether-Lumefantrine (Coartem ® )
• CONTRAINDICATIONS
•
First trimester of pregnancy in situations where other suitable and
effective anti-malarials
• are available
•
Patients with a family history of congenital prolongation of the QTc
interval
•
Patients taking drugs that are known to prolong the QTc interval such
as: antiarrhythmics of classes IA and III
•
- Artemether-Lumefantrine (Coartem ® ).
• CONTRAINDICATIONS
• - neuroleptics, antidepressant agents,
• - certain antibiotics including some agents of the following classes:
•
macrolides
• fluoroquinolones, imidazole, and triazole antifungal agents
•
Patients with known disturbances of electrolyte balance e.g.
hypokalaemia or
• hypomagnesaemia.
- Artemether-Lumefantrine (Coartem ® ).
• Adverse Reactions
• prolongation of the QT interval (prolonged heart palpitations
• signs of hypersensitivity
• skin rash, hives, other skin reactions
• rapid heartbeat
• difficulty breathing or swallowing, swelling of the lips, tongue, face,
tightness or throat, hoarseness
Drugs used in the treatment of Amoebiasis
• Amebiasis is a protozoal infection caused by pathologic strains of
Entamoeba histolytica or Entamoeba dispar.
• Infection with these organisms leads to ulceration of the colon and
diarrhea and, on occasion, liver abscess.
•
ETIOLOGY
• Most people with the organism have no significant invasion of
the colonic mucosa and are asymptomatic. These are called
"cyst passers.“
Drugs used in the treatment of Amoebiasis
• Disease is worldwide in distribution, but much more prevalent
in underdeveloped nations with poor sanitation.
• Contaminated water or vegetables are often the source for
infection in humans.
Drugs used in the treatment of Amoebiasis
Symptoms
• NONINVASIVE
•
Symptoms of noninvasive disease are mild, with diarrhea only.
• INVASIVE
• Invasive disease is associated with crampy abdominal pain and
bloody, mucoid diarrhea.
• •
• Fevers occur in one-third of patients.
• Fulminant disease with peritonitis and perforation as well as
toxic megacolon is rare
Drugs used in the treatment of Amoebiasis
Symptoms
• INVASIVE
• AMEBIC LIVER ABSCESS
• This may present with fevers
• tenderness to palpation over the liver.
• Diarrhea and active amebic colitis are often not present at the
time of abscess discovery.
• Rare rupture of the abscess may lead to peritonitis.
Drugs used in the treatment of Amoebiasis
• Treatment
1- ASYMPTOMATIC CYST PASSER WITHOUT INVASIVE
DISEASE
• Iodoquinol 650 mg orally three times per day for 20 days
• Paromomycin 500 mg orally three times per day for 7 days
Drugs used in the treatment of Amoebiasis
• Treatment
• ASYMPTOMATIC CYST PASSER WITHOUT INVASIVE
DISEASE
• For mild to moderate GI symptoms
• oral metronidazole:
500 to 750 mg tid in adults (12 to 17 mg/kg tid in children) for 7 to
10 days is recommended. Metronidazole
should not be given to pregnant women.
• Alcohol must be avoided because of the drug's disulfiram like effect
Drugs used in the treatment of Amoebiasis
• Treatment
• ASYMPTOMATIC CYST PASSER WITHOUT INVASIVE
DISEASE
•
Alternatively, tinidazole
2 g po once/day in adults (50 mg/kg [maximum 2 g] po once/day
in children > 3 yr) for 3 days can be used. When taken with
alcohol, tinidazole also has a disulfiram like effect
• and it should not be used during pregnancy
• in terms of GI adverse effects, it is generally better tolerated
than metronidazole
Drugs used in the treatment of Amoebiasis
• Treatment
• For severe intestinal and extraintestinal
amebiasis metronidazole
•
METRONIDAZOLE: 750 mg tid in adults (12 to 17 mg/kg tid
in children) for 7 to 10 days is used. Alternatively, tinidazole
2 g po once/day in adults (50 mg/kg [maximum 2 g] po once/day
in children > 3 yr) for 5 days can be used.
Drugs used in the treatment of Amoebiasis
• Treatment
• For severe intestinal and extraintestinal
amebiasis, metronidazole
•
•
•
•
•
A course of metronidazole or tinidazole should be followed by a
2nd oral drug to eradicate residual cysts in the lumen.
Options are:
Iodoquinol
or
Paromomycin
OR
Diloxanide
Drugs used in the treatment of Amoebiasis
• Treatment
Asymptomatic people who pass E. histolytica
treated with :
Paromomycin
or iodoquinol
or diloxanide
furoate
cysts should be
Drugs used in the treatment of Amoebiasis
• Treatment
LIVER ABSCESS
• Metronidazole 750 mg orally or intravenously three times per
day for 10 days
• followed by iodoquinol 650 mg orally three times per day for
20 days
Drugs used in the treatment of Amoebiasis
• Treatment
• For severe intestinal and extraintestinal
amebiasis, metronidazole
A course of metronidazole or tinidazole should be followed by a
2nd oral drug to eradicate residual cysts in the lumen. Options are
Iodoquinol 650 mg po tid in adults (10 to 13 mg/kg [maximum of 2
g/day] tid in children) for 20 days
• Paromomycin
8 to 11 mg/kg tid for 7 days
• Diloxanide furoate
Drugs used in the treatment of Filariasis
• Caused by filarial nematodes
•
•
•
•
•
•
•
•
– Wuchereria bancrofti
– Brugia malayi
– Brugia timori
– Mansonella perstans
– Onchocerca volvulus
– Loa loa
– Mansonella streptocerca
– Mansonella ozzardi
Drugs used in the treatment of Filariasis
• Humans are infected by bites of infected mosquitoes
• Larvae move to the lymphatics and lymph nodes where they
mature over months
• The thread-like adult worms can live for many years and
produce large numbers of microfilariae, which are infective to
mosquitoes
• Microfilariae are released into the circulation, usually at night
except in the South Pacific where microfilaremia peaks during
daylight hours
Drugs used in the treatment of Filariasis
Drugs used in the treatment of Filariasis
• Acute Disease
• Initial manifestation is often acute lymphangitis, with fever, painful
lymph nodes, edema, and inflammation spreading peripherally from
involved lymph nodes
• Lymphangitis and lymphadenitis of the upper and lower extremities
is common
• Genital involvement occurs with W bancroftiinfection
• – Epididymitis
• – Orchitis
• – Scrotal pain and tenderness
Drugs used in the treatment of Filariasis
• Chronic disease
•
•
•
•
•
•
Most common manifestation is swelling of the extremities
or genitals due to chronic
lymphatic inflammation
and obstruction
Extremities
become increasingly swollen,
Drugs used in the treatment of Filariasis
• Treatment
• Diethylcarbamazine
•
– Drug of choice, but cannot cure infections due to its limited action against adult worms
• – Therapy may be accompanied by allergic symptoms (eg, fever, headache, malaise,
hypotension, and bronchospasm) probably due to release of antigens from dying worms
• – Therefore, begin treatment with lower dosage and escalate over first 4 days
• – Use ivermectin plus albendazole instead
Drugs used in the treatment of Filariasis
• Treatment
• Drainage of hydroceles provides symptomatic relief
• Doxycycline (100–200 mg/day orally for 4–6 weeks)
• – Kills obligate intracellular Wolbachia bacteria, leading to
death of adult filarial worms
• Secondary bacterial infections much be treated
Drugs used in the treatment of
Oxyyuriasis(pinworm)
• The intestinal nematode (roundworm) Enterobius
vermicularis causes pinworm infection.
• MODE OF TRANSMISSION
• Fecal-oral ingestion of the egg, direct person-to-person contact, or indirect
contact via contaminated hands, dust, food, or objects (such as bedding,
clothing, toys, bathwater, toilet seats)
•
Eggs can remain infective indoors for 2–3 weeks. Humans are the only known
natural host
• animal pinworms do not infect humans.
Drugs used in the treatment of Oxyyuriasis
•
CLINICAL PRESENTATION
• asymptomatic, common symptoms include:
• nocturnal perianal and perineal pruritus and restless sleep.
• Urethritis, vaginitis, salpingitis, hepatitis, or peritonitis may occur if
adult worms migrate from the perineum to other sites.
• Secondary bacterial infection of skin may occur from scratching.
Drugs used in the treatment of Oxyyuriasis
• Diagnosis is made by identifying the worm or its eggs by:
• Direct visualization of female adult worms near anus or on sheets or
underclothing or pajamas at night, about 2–3 hours after patient falls asleep.
• Microscopic identification of worm eggs by using the “scotch tape test” on 3
consecutive mornings.
• The adhesive side of clear transparent—not translucent—cellophane tape is
pressed to the skin around the anus when patient first awakens, before washing
or bathing.
• The tape is then directly affixed to a microscope slide and examined under low
power for eggs.
Drugs used in the treatment of Oxyyuriasis
• Eggs and worms are rarely found in routine stool samples.
• TREATMENT
• . Drugs of choice are mebendazole, albendazole, or pyrantel
pamoate.
• Treat all household contacts and caretakers at the same time as
the patient.
• Daily morning bathing removes a large proportion of eggs;
change underclothing and bedding frequently and launder in
hot water.
Drugs used in the treatment of Oxyyuriasis
• Reinfection occurs easily; instruction about prevention is
mandatory to eliminate continued infection and spread.
• PREVENTIVE MEASURES FOR TRAVELERS
• Strict observance of good hand hygiene is essential (proper
handwashing; maintaining clean
Drugs used in the treatment of Ascariasis
• ASCARIASIS lumbricoides is the largest intestinal nematode parasite of
humans, reaching up to 40 cm in length.
• Most infected individuals have low worm burdens and are asymptomatic.
•
Clinical disease arises from larval migration in the lungs or effects of the adult
worms in the intestines.
• Life Cycle
• Adult worms live in the lumen of the small intestine.
•
Mature female Ascaris worms are extraordinarily fecund, each producing up to
240,000 eggs a day, which pass with the feces.
Drugs used in the treatment of Ascariasis
•
Ascarid eggs, which are remarkably resistant to environmental stresses,
become infective after several weeks of maturation in the soil and can
remain infective for years.
• After infective eggs are swallowed, larvae hatched in the intestine invade
the mucosa
•
migrate through the circulation to the lungs, break into the alveoli, ascend
the bronchial tree, and return—through swallowing—to the small intestine
•
where they develop into adult worms. Between 2 and 3 months elapse
between initial infection and egg production. Adult worms live for 1–2
years.
Drugs used in the treatment of Ascariasis
• Transmission typically occurs through fecally contaminated soil and is due
either to a lack of sanitary facilities or to the use of human feces as fertilizer.
• Infection outside endemic areas, though uncommon, can occur when eggs on
transported vegetables are ingested.
• Clinical Features
• During the lung phase of larval migration, 9–12 days after egg ingestion,
patients may develop an irritating nonproductive cough and burning substernal
discomfort that is aggravated by coughing or deep inspiration.
• Dyspnea and blood-tinged sputum are less common.
•
In heavy infections small-bowel obstructionof surgical acute abdomen.
Drugs used in the treatment of Ascariasis
• Treatment: Ascariasis
• Ascariasis should always be treated to prevent potentially serious
complications.
• Albendazole (400 mg once), mebendazole (100 g twice daily for 3 days or
500 mg once), or ivermectin (150–200 g/kg once) is effective.
• These medications are contraindicated in pregnancy, however.
•
Pyrantel pamoate (11 mg/kg once; maximum, 1 g) is safe in pregnancy.
•
Nitazoxanide (7.5 mg/kg once; maximum, 500 mg) has also been used in
ascariasis.
Drugs used in the treatment of Toxoplasmosis
• caused by protozoan Toxoplasma gondii.
• Infection in humans is usually asymptomatic.
• Severe infections usually occur in an immunocompromised patient
• or by the transplacental passage of parasites from an infected mother to
the fetus (congenital toxoplasmosis).
Drugs used in the treatment of Toxoplasmosis
• There are two stages in the life cycle of T. gondii:
• The sexual phase results in the formation of oocysts in the cat's intestine.
• The sporulated oocysts are ingested by an intermediate host (e.g., a human).
• Bradyzoites or sporozoites are released and transformed to rapidly dividing
tachyzoites
•
which can infect any organ.
• Immune responses are able to eliminate most of the tachyzoites, and a tissue
cyst is formed.
Drugs used in the treatment of Toxoplasmosis
• Cases are caused by eating undercooked meat or contaminated vegetables
• ingestion of sporulated oocysts from contaminated soil.
• Congenital toxoplasmosis
• Only one of five pregnant women infected with T. gondii develop clinical
signs.
• Women who are seropositive before pregnancy usually are protected
against acute infection and do not give birth to congenitally infected
neonates.
Drugs used in the treatment of Toxoplasmosis
• If the acute infection in the mother goes untreated
•
congenital infection occurs in approximately 15% of the fetuses during the
first trimester, 30% of the fetuses during the second trimester, and 60% of
the fetuses during the third trimester.
• Toxoplasmosis and HIV infection
• In areas with high seroprevalence for toxoplasmosis
•
25% to 50% of all AIDS patients, who are not receiving antiretroviral
therapy, will develop CNS toxoplasmosis.
Drugs used in the treatment of Toxoplasmosis
TREATMENT
• The combination of pyrimethamine plus sulfadiazine is the regimen of choice
for acute therapy.
• For acute therapy, the usual dose is 4 to 8 g/d of sulfadiazine and a loading dose
of 100 to 200 mg, followed by 50 to 75 mg/d of pyrimethamine
• Leucovorin should always be coadministered with pyrimethamine to prevent
the folinic acid deficiency and ameliorate the hematologic toxicity of
pyrimethamine.
• Duration of treatment should be individualized, but it usually is for 6 to 8
weeks.
•
.
Drugs used in the treatment of Toxoplasmosis
• ALTERNATIVE TREATMENT
• Pyrimethamine (accompanied by folinic acid) combined with clindamycin is
clearly an effective and acceptable alternative.
• The combination of clarithromycin with pyrimethamine also seems effective .
• Azithromycin may have a role in combination with pyrimethamine.
• Steroids may produce transient clinical and radiographic improvement in CNS
Drugs used in the treatment of Tapeworms
infections
• Life cycle of Taenia saginata
Adult beef tapeworm (Taenia
saginata).
Drugs used in the treatment of Tapeworms
infections
• Life cycle
• Mature segments are detached and pass out with the faeces
• disintegrate and the eggs are set free and eaten by the intermediate
• host (the pig).
• Humans are occasionally infected by cysticerci
• (cysticercosis), as are other primates, sheep and dogs.
• The oncosphere penetrates the gut wall and enters the bloodstream, settling
• in the muscles, especially the heart, and becomes a cysticercus
• (5–20 mm) known as cysticercus cellulosae.
Drugs used in the treatment of Tapeworms
infections
•
•
•
•
•
•
Taenia Species
• T. saginata
Microbiologic Characteristics
• A tapeworm
Incubation Period
• Eggs appear in the stool 10 to 14 weeks after infection with T. saginata. •
Symptoms (if any) may delay even more.
• Epidemiology
• • Worldwide • More frequent in populations where beef is consumed
insufficiently cooked
Drugs used in the treatment of Tapeworms infections
•
•
•
•
Taenia Species
• T. saginata
Infections
• Beef tapeworm infection, which is usually asymptomatic. It may cause mild
gastrointestinal symptoms.
• Treatment
• • Niclosamide 2 g PO in a single dose
•
•
•
•
Alternative Treatment
• Praziquantel 25 mg/kg PO (children, 10–15 mg/kg) in a single dose
Prevention
• Thorough cooking of beef
Drugs used in the treatment of Tapeworms infections
• Taenia Species
• • Taenia
solium
• the central nervous system (CNS) is the most significant
site for infection
• The pig (intermediate host) ingests the egg and larvae are
formed. The larvae travel via the bloodstream throughout
the pig and achieve high concentrations in the muscle.
Drugs used in the treatment of Tapeworms infections
• • Taenia
solium
• Clinical Manifestations
• • Seizures
• Headache • Possible signs of hydrocephalus
• Symptoms depend on the number, size, and location of the
lesions. • Intraventricular disease leads to hydrocephalus
• Subretinal or intravitreal disease may lead to blindness. •
Cysts may present in the orbit, leading to blindness.
• COMPLICATIONS
• • Hydrocephalus • Seizures • Blindness
Drugs used in the treatment of Tapeworms infections
• Taenia Species
• • Taenia
solium
• FOR NEUROCYSTERCERCOSIS
• • Praziquantel 50 mg/kg every day for 15 days • Albendazole 15 mg/kg
every day for 1 to 4 weeks
• Expect an inflammatory reaction to the medications; steroids are often given
with treatment to alleviate inflammation in the CNS, which can cause headache
and seizures
• Antiseizure medications may be considered.
• FOR TAPEWORM INFECTION ALONE
• • Praziquantel 10 mg/kg, single dose.
Drugs used in the treatment of Giardiasis
•
•
•
•
•
•
•
•
•
An infection of the upper small bowel with Giardia lamblia, which may cause diarrhea.
ETIOLOGY
•
A flagellate protozoon, G. lamblia (Giardia intestinalis), that exists in trophozoite and cyst
forms.
The infective form is the cyst of the parasite.
•
Cysts are infective as soon as passed and remain infective in water for a few months.
•
When ingested by a new host, they excyst in the upper gastrointestinal tract and liberate
trophozoites, which attach with their suckers to the surface of the duodenal or jejunal
mucosa and multiply by binary fission.
• •
• When trophozoites drop off the duodenal and jejunal mucosa, they are carried on with
the contents in the gut and encyst.
Drugs used in the treatment of Giardiasis
• Commonest where standards of sanitation are low
• Infection is usually sporadic and spreads from person to person directly by
the fecal–oral route or indirectly by ingestion of fecally contaminated
water or food.
• Epidemics mainly occur where gross Giardia cyst contamination of water
supplies occurs.
• Epidemics resulting from person-to-person transmission sometimes occur
in childcare centers, in institutions for mentally retarded persons
• Humans are the principal reservoir of infection, but wild beavers and
other animals have also been found to be infected in North America.
Drugs used in the treatment of Giardiasis
• SYMPTOMS
• The main symptom is diarrhea may continue for weeks or months if
untreated.
• Stool: pale, offensive, bulky, with much flatus but no blood or mucus
• Crampy abdominal pain, urgent call to stool
• Bloating and steatorrhea
Drugs used in the treatment of Giardiasis
• TREATMENT
• Metronidazole (with efficacy up to 80%–95%)
• Avoid alcohol intake, as it may produce side effects such as headache and
flushing.
• In children, dosage modified: 5 mg/kg tid for 7 days
• Tinidazole (with efficacy up to 90%): not applicable in the United States
• In adults: A single dose of 2 g is usually effective.
Drugs used in the treatment of Giardiasis
• ALTERNATIVE TREATMENT
• Mepacrine/quinacrine
• Furazolidone (with efficacy up to 80%)
• Caution: Haemolysis in patients with G-6PD deficiency
• TREATMENT FAILURE
• A failure rate of about 10% to 20% is expected.
Thank you