الموسوعة المتكاملة في toxicology

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المحاضرة الأولى
Part 1

هنتكلم عن الجينيرال
عايزاك تطلع من الchapter ده بالآتي
Management of poisoning
لأن هو الأساس بعد كده لما نعملttt لأي poison
والذي يشمل
1-Prevent further exposure .
2-Emergency stabilization of the patient.
3-Proper clinical evaluation .
4- Prevent further absorption .
5- Eliminate absorbed poison .
6- Antidotal therapy if available.
7- Supportive Therapy.

1-Prevent further exposure:
#In therapeutic overdose(e.g. digitalis) -àstop drug responsible
#occupational toxicology (co ,cyanide gas) àRemove from place
#In homicide -àkeep under complete control in hospital

2-Emergency stabilization of the patient.

ABCDs resuscitation :
A ==== Airway
B ==== Breathing
C ==== Circulation
D ====drug induced C.N.S Depression

Airway ===A
Causes of obstruction الحل #Secretions===èSuction of secretions
#Posterior displacement of the tongue===èpull tongue using tongue depressor or support jaw (head tilt chin left maneuver)
#Foreign body e,g artificial teeth===è Remove FB
# Insert endotracheal tube (cuffed in comatosed patient)V.I.P.
# Tracheostomy (not need definition)
B===è Breathing (Maintain respiration):
*Oxygen therapy ==Oronasal mask (Carbogen5%CO2 ,95%O2)
*Artificial respiration== Mechanical ventilation If too slow respiration i.e no chest movement or paralysis of resp. muscles

Artificial Resp.==èMouth to mouth Breathing (at a rate of 2 mouth breath then 15 compression on chest at a rate of 100/min.)
Till patient become well or you are exhausted.

C===ècirculation

Shock characterised by failure of the circulatory system to maintain adequate perfusion of vital organs
Hypovolaemic shock==èttt Fluid replacement
Neurogenic shock ==èttt analgesic e.g. morphine
Hypotesive shock ==èttt vasopressor e.g dopamine

Signs of shock: cyanosis, hypotension.
What to do:
1.Elevate legs
2.Fluid replacement
3-cover with blankets
4-Vasopressor drugs

D==èDrug induced C.N.S depression
Level of consciousness classified according
Qualitative ==èchange of level of consciousness (lethargy ,stupor , coma)
Quantitative==èchange in cotent of consciousness (confusion ,delirium ,psychosis)
Coma= unarousable unresponsiveness

يتبع ...........

Stupor=grade of coma in which arousability only in response to sever stimuli

Reed' s classification of coma :

Grading of covsciousness G0 G1 G2 G3 G4

*Response to verbal stimuli - - - -

*Response to verbal stimuli - - -

*Deep tendon reflexes - -

*Resp. or circul.depression (intact) - (lost)

Coma Cocktail 3 things

Naloxone ,Dextrose , Thiamine

Naloxone :

(0.4mg ampouls Narcan),2mg I.V =5ampouls

value:

Very useful as there are synthetic & semisynthetic opiods such as codeine ,propoxyphene for which naloxon is administered in large dose to antagonize them effectively

Dextrose:

D50W for adults , D25W for children

D=dextrose W=water

Thiamine(vit B1)

Dose 100mg I.V to all adult &Adolescent But not to children

Value :

Prevent ppt of Wernick's encephalopathy in alcoholic patient

Seizures(convulsions )

Management:

#airway must be kept patent O2

# Diazepam (valium)of choice

#in status epilepticus phenytoin or Phenobarbital

2-Proper clinical Evaluation

History, physical examination & laboratory tests are used for proper clinical evaluation

3- Reduction of further absorption of the poison :

1- Eye decontamination

2- Skin decontamination
3- GIT decontamination

Eye decontamination
In corrosives: with normal saline for at least 15-20 minute.
DONOT USE NEUTRALIZING SUBSTANCE (heat release)

Skin decontamination

1. For corrosives: use water or saline for 10-15 minute.
2. for other toxic substances: use cold water then wash with soap.

3. Some chemicals require special TTT such as:
*Lime & cement → ttt like alkali burn
*Flammable metals →remove the large particles & cover the surface with mineral oil.
*Phenols (cresols) → Polyethylene.
*White phosphorus →use copper sulfate solution.(Oxidizing agent)

YOU MUST PROTECT YOURSELF FIRST

GIT Decontamination

a) Emesis

b) Gastric lavage

c) Activated charcoal

d) Cathartics

e) Whole-Bowel irrigation

f ) Surgical decontamination

g) Local antidotes

a)Emesis

Indications :

-Patient: alert (intact gag reflex).

-Time of ingestion: not more than 4-6 hours

-Poison: not adsorbed by activated charcoal.

- Sustained release or enteric-coated tablets or big lumps.

Contraindications:

-Patient: absent or impaired gag reflex, heart disease, gastric ulcers , pregnancy,….

- Time of ingestion: more than 4-6 h after ingestion

- Poison: corrosives, sharp solid objects, drugs causing convulsions, volatile hydrocarbons (kerosine).

Methods used in induction of emesis

*Mechanical: touch the back of the pharynx by a finger; it is used in the home if syrup of ipecac is not available.

يتبع.............

*Drugs
a) Gastric irritants : strong solution of salt or copper sulfate this is dabgerous as prodces hypernatremia ,cooper make copper toxicity
b)Apomophine: centrally +ve CTZ , Not used now due to Depression of respiratory center
c)syrup of epicac :
Origin :dried root or rhizoma(ساق) of ipecacuanha or acminata plant
Principle alkaloid :Emetine ,Cephaline
Mechanism of induction of vomiting :
Act both central &peripheral central +ve CTZ ,peripheral by irritation of gastric mucosa
N.B.
It must be given on full stomach so ask patient to drink one liter of water before administration

Dose of syrup of epicac

Infant (6-12month) è5-10ml of syrup of epicac +100-150ml clear fluid
Children (1-5years)è 15ml of syrup of epicac +240 ml clear fluid
Children (5-12years)è 20ml of syrup of epicac +240 ml clear fluid
Over12 years è30ml of syrup of epicac +240-480 ml clear fluid
When to stop epicac ?
The dose is given every 20-30minutes for two doses if vomiting doesn’t occur Gastric lavage or Activated charcoal administration is decided .

b)Gastric lavage
Principle :
Insert tube into stomach ,washing it with water or harmless solvent to remove unabsorbed poison

Indications :
1- After ingestion as soon as possible
2- Useful for as long as 3hrs after ingeastion
3- If delayed gastric emptying èlavage useful for 12hrs
4- Considered only if patient ingested life threatening amount of toxic substance within one hour of presentation .

Contraindications:
As for emesis but can be used for hysterical , comatosed ,or any uncooperative patient

Precautions :
1- In case of C.N.S depression or pulmonary irritant ingestion insert cuffed endotracheal tube before lavaging
2-It can be performed under general anesthesia in patient with convulsions

Procedure :
Tube:150 cm long,1.25 cm in diameter Having multiple openings on sides &At tips.

Before inducing the tube Ask the patient to drink a glass of water if alert
Steps
1- The patient lies on his left side with head lower to Avoid Aspiration &get good washing
2- Remove any foreign body from mouth (artificial tooth ,chewing gum,..)
3-lubricate the end of the tube with Glycerine then pass it smoothly to pharynx =èoesophagus =èstomach[If the patient alert ask him to swallow =èclosure of resp.passage during swallowing ]
4- Aspirate gastric content by irrigation syringe &keep in abottle with name of both patient &doctor ,time=èsent for analysis

5-Attach a funnel to the tube &hold it up èpour water (200ml) slowly èlower the funnel &let the content Regurgitate into a bucket =èRepeat it several times until fluid returned is as clear as possible
How to know that the tube is in Stomach Not in the Trachea:
** If in Trachea :
1- movement of Air is heared.
2- Patient shows sudden spasmodic cough &cyanosis
3- Bubbling occurs if the end of the tube is immersed in water
(expiration)
*****if the tube is in stomach
Aspiration brings up gastric content
You ca leave Cathertic(مسهلات),local antidote …etc
c)Activated charcoal
Is considered the best method of Gastric decontaimation
It is very effective Nonspecific adsorbent
Dose :
1g/kg BW
Generally 50-100g for adult
15-30g for children
+suitable amount of water (250 ml for adult )
+Vigorously shaken to form a slurry
لو في البيت ممكن يضرب في الخلاط ليكون عجين رقيق
Administered orally or through nasogastric tube

What do you know about Multiple(serial) dose activated charcoal?
Indications: In theophyllin overdose &if threatening amount of Phenobarbital,Carbamazepine ,Quinine ,Dapsone or Aspirine is ingested.
Mechanism:It can enhance elimination of absorbed toxins through
@Interruption of enterohepatic or enteroenteric circulation e.g. theophylline ,Phenobarbital ,salicylates
b)Gastro intestinal dialysis whereby the drug back diffuse from the higher serum levels ,through the intestinal villi& into the lower intraluminal concentrations.

Contraindications

1- Presencce of diminished bowel sounds,ileus &bowel obstruction
2-Prior to endoscopy after corrosive ingestion
3-In poorly absorbed poisons :cyanide, ethanol methanol,iron ,strong scids &alkalies

d) Cathartics:
two groups are present :
1) saline cathartics :e.g. sodium sulphate ,magnesium sulphate
2) Saccharides :e.g.e.g. sorbitol (is the cathartic of choice )
Contraindication:
Ingestion of corrosive ,sever diarrhea,ileus ,serious electrolyte imbalance &bowel injury
e)Whole bowel irrigation
It is a useful safe &rapid method to empty the gut in 4-6 hours .It produces a through cleansing of the entire intestinal tract
Method :
By use of High molecular weight polyethelene glycol (PEG) and isosomlar electrolyte solution (sodium sulphate) are used as isotonic solutions for WBI and available as Golytely & Colyte
Indications :
· Ingestion of massive amounts of highly toxic drugs .
· Ingestion of large amounts of drugs in patients presenting late(more than 4 hours)
· Ingestion of drug packets by body packers (cocaine filled packets ) (تجار المخدرات)
· Ingestion of substances not adsorbed by activated charcoal

Contraindications:
- G.I.T Haemorrhage ,perforation ,ileus &obstruction
- Inadequate air way protection .

f) Surgical decontamination:

§ Surgical removal of concretions of sustained release tablets (e.g .Theophylline, Aspirin ,Carbamazepin) from the stomach .
§ The concrations are fragmented or via gastroendoscopy to be followed by activated charcoal and W.B.I.

Indications :
§ Concretion of sustained-release tablets .
§ Drug packets by body packers or body stuffers
§ Patients with bowel obstruction
§ When there is a contraindication to gut decontamination.

g)Local antidotes :
§ 1- Adsorbents : Activated charcoal
§ 2-Dilution&Neutralization:
dilution with fluids (water or milk)
But note that :
If Alkali (any strength ) or weak acid caustic ,the oral dilution with cold fluids immediately after exposure may reduce oropharyngeal & gastric mucosal damage as it reduce the contact time with tissues .
If strong acid :It is contraindicated due to production of heat &gases which lead to more destruction of tissues
3-precipitation J مهم
e.g. tannic acid for=è alkaloids e.g opium
Albumin water =èmercury
Magnesium sulphate=èCarbolic acid
Calcium hydroxide =èoxalic acid

4-oxidation
potassium permanganate solution =èoxidize most alkaloids e.g.Atropin
cupper sulphate =èphosphorus

5- Reduction
e.g. sodium formaldhyde sulphoxylate =è reduce mercuric chloride to metallic mercury which is less soluble &thus non absorbable.

METHODS FOR ELIMINATION OF THE ABSORPED POISON

(1)forced diuresis and PH alteration .
(2)Hemodialysis .
(3)peritoneal dialysis .
(4)hemofiltration .
(5)plasmapheresis .
(6)Hemoperfusion .
(7)gut dialysis .
(8)plasma perfusion .
(9)hyperbaric oxygen.
(10)exchang transfusion .
(11)cardio pulmonary bypass.

Forced diuresis and PH alteration

AIM: PH alteration of urine to enhance renal excretion by increasing the amount of ionized form of the drug in urine AS
*when the drug in the non ionized form is easily diffuse across the tubular membrane and reabsorbed
*when the drug is ionized form it will be trapped in renal tubules and easily excreted

INDICATIONS
In toxicity with drug that are:
(1)weak acid or weak base
(2)low protein binding
(3)have limited metabolism
(4)have high renal clearance
(5)have small volume of distribution

COMPLICATIONS

(1)fluid overload
(2)pulmonary oedema
(3)cerebral oedema
(4)acid base disturbance
(5)electrolyte imbalance

INVESTIGATION
(1)Plasma drug concentration
(2)Fluid balance
(3)Central venous pressure
(4)Electrolytes, Serum sodium, Potassium. calcium and magnesium

ACID DIURESIS
§ INDICATIONS
§ Amphetamine .strechnine. Quinidine and phencyclidine
METHOD
§ 500ML dextrose 5%+
§ 500ml saline 0.9%+
§ 75ml ammonium chloride 2% give over 6 hours

ALKALINE DIURESIS
INDICATIONS
Salicylates phenobarbital and phenoxyacetate herbicide
METHOD
500ml dextrose 5%+
500ml saline 0.9% +
500ml Na bicarbonate 1.26% over 3_4 hours

HEMODIALYSIS
Only eliminate drugs or toxins which can pass easily across the dialysis membrane
i.e characterized by
A) low molecular weight
B) high water solubility
C) small volume of distribution
(high plasma concentration)

INDICATIONS
1)Several clinical intoxications with vital signs abnormalities such as apnea, hypotension that do not respond to supportive care.
2)Impaired normal excretion routes e.g renal failure
3)progressive clinical deterioration and presence of complications such as aspiration pneumonia
4)prolonged coma with complications
5)presence of underlying diseases .
6)ingestion of alethal dose of poison .
7)ingestion of large dose of toxin that is metabolized to more toxic metabolites such as methanol and ethylene glycol .
8)drug produce delayed toxicity e.g paraquat.

CONTRAINDICATIONS
1)Presence of antidotes
2)Coagulopathy
3)Cardiogenic shock
4)Non dialyzable toxins

COMPLICATIONS
1)hypotension
2)electrolyte and Osmolar imbalance
3)hypoxemia
4)vascular access Complications
5)spontaneous Bleeding
6)infections
7)mechanical Complications
8)sever anaphylactic
9)sudden death fromMachine malfunction,
Electrocution& Coagulopathy

3-HemoPerfusion
Blood is pumped through a cartridge of absorbent material ( activated charcoal or resins )
Indications :-
The same as in hem dialysis , but hemoperfusion is not limited by the high molecular weight , protein binding or poor water solubility of the toxin because charcoal or resin can adsorb these toxins
Contraindication :-
Similar to those for hem dialysis
Complications :-
Similar to those for hem dialysis + thrombocytopenia , leucopenia and hypocalcaemia

4- Peritoneal dialysis :-
Peritoneal dialysis operates on principles similar to those of hem dialysis diffusions of toxins from mesenteric capillaries across the peritoneal ( membrane into dial sate dwelling in the peritoneal cavity
Indications :-
1- Patients with acute renal failure
2- Patients with bleeding disorders
3- Patients with venous access problems
4- Hem dialysis is not available
5- Patients for whom hem dialysis and
hemoperfusion are contraindicated
Method :-
Through a catheter inserted intraperitoneally , adialysate fluid is instilledand 1-2 liters is exchanged each hours

Complications :-
1- Pain
2- Hemorrhage
3- Leakage
4- Inadequate drainage
5- Perforation of viscera
6- Bacterial peritonitis
7- Arrhythmias
8- Volume depletion or overload
9- Hyperglycemia and electrolyte disorders
10- Pneumonic and pleural effusion

5- Gut dialysis :-

( serial activated charcoal )
Gut dialysis enhances elimination of the toxins that have
a) significant enterohepatic or enter enteric circulation
b) limited protein binding
c) small volume of distribution

6- Hyperbaric oxygen
( HBO ) :-

Hyperbaric oxygen ( HBO ) has been used in the management of carbon monoxide ( CO ) and cyanide ( CN ) poisoning , it is also used in other poisoning such as barbiturates , mushrooms , hydrocarbons and oregano phosphates HBO needs special hyperbaric chambers which aren’t available in most hospitals of Egypt
HBO dramatically displaces CO from hemoglobin as well as the tissue sites , myoglobin and city chromes it reduces the elimination half lives of blood CO-Hb from 250 minutes at room air to 22 minutes at 3 atom of 100 % oxygen

Complications :-

1- Traumatic rupture of tympanic membrane
2- Acute sinusitis
3- Optic neuritis
4- Pneumonia thorax
5- Oxygen toxicity
6- Seizures
7- Safety hazards ( explosions , fir……etc )

7- Exchange Transfusion :-

It is the method by which the patient’s blood is removed and replaced with fresh whole blood

Double – exchange transfusion :-
Is an amount of blood equivalent to twice the patient’s total blood volume is exchanged the only indication for this method is sever methaemoglobinemia not responding to ethylene blue therapy

Specific antidotal Therapy
Chelating agents
Are organic compounds that react with heavy metal ions to form firmly bound complexes (chelates)
We are going to study:
B.A.L
E.D.T.A
Penicillamine
Deferroxamine
D.M.S.A.

1-B.A.L.
B.A.L=British Anti-Lewisite (lewisite is the gas of war)
Mechanism of Action :
It acts by fixing the metal ions which have high affinity for SH group forming a relatively harmless &poorly dissociable ring compounds ‘chelates ‘ that prevent the poison from inactivating the SH containing respiratory enzymes .

Uses :
§ It is the physiological antidote of poisoning with heavy metals e.g. Arsenic ,Mercury, Antimony ,Antimony, Gold &Bismuth .
§ It is of little value in ttt of lead poisoning because it only chelate lead ions present in the blood while the ions in the bones &tissues are too firmly bound to be mobilized by it
§ BAL is not used in iron poisoning because BAL – iron complex is even more toxic than the unchelated iron.

Dose:
Deep I.M. injection of 10% BAL in peanut oil is given in a dose of 2.5 mg/kg body weight every 4-6 hours for 2 days then every 12 hours for 7-10 days .
Why deep? To avoid abscess formation

EDETA
§ EDETA&EDETA salts :[ Na2 EDETA &Ca Na2 EDETA ]
§ Ca salts are used because rapid I.V. administration of Na2 EDETA result in hypocalcemic tetany .This is the reflection of high affinity of EDTA for calcium .
§ CaNa2EdETA can chelate any metal that has a greater affinity for EDETA than has calcium & can thus replace calcium from the complex
§ Lead has high affinity for EDETA than calcium &can replace calcium in the complex forming a poorly dissociable chelate which is harmless &excreted in urine .
§ Mercury poisoning responds poorly to ttt with Ca Na 2 EDETA in vitro because it doesn’t pass into areas of mercury
Dose:
§ CaNa2 edetate injection 20%solution 1g. (5ml)in 250-500 ml of 5% glucose in water or saline solution slowly by IV drip over a 1 hour period ,twice daily for 3-5 days
§ The drug is then withheld for 2 days to allow redistribution of the lead ,thus increasing the amount of metal available for chelation.
Dicobalt Edetate (Kelocyanor)
§ It is a cobalt salt that form a relatively nontoxic stable ion complex with cyanide.
§ Dose :
300mg I.V Followed immediately by 50 ml of 50% glucose I.v this may be repeated after 5 minutes if there is no response .
§ Side effects :Vomiting ,urticaria ,facial &neck edema ,hypotension ,chest pain &anaphylactic shock .
Penicillamine :
It posses one SH group
§ It is prepared by hydrolic degradation of penicillin .
§ It is an effective chelator of Copper ,Mercury, zinc &lead that promotes their excretion in urine
§ It is well absorbed from G.I.T so it can be given orally .

Dose :
§ Penicillamine capsules :250 mg/capsules the usual dose is 1-2 capsules (250-500mg) every 6 hours on empty stomach to avoid interference by dietary metals .

Deferoxamine ( Desferal )
§ It is the chemically modified metal free ligand from streptomyces pilosus .
§ It has high affinity for ferric ions ,& very low affinity for calcium
§ It readily competes for the iron of ferritin &hemosiderin ,but
the iron of transferring is very minimally affected
Dose:
§ Deferroxamine mesylate 500mg ampules .
§ 1g is given I.M ,followed by 500 mg every 4hours for two doses .
§ The dose can be repeated at 4 or 12 hours intervals ,depending on clinical response ,but a total of 6g/24 hours shouldn't be exceeded
§ In case of acute iron toxicity ,8g has to be given by nasogastric tube to be followed by IM injection described above
DMSA (Succimer)
§ DMSA is relatively selective orally active water soluble chelating agent
§ It can be used in ttt of lead , arsenic ,organic &inorganic mercury poisoning .
§ It is more effective than I.V. CaNa2-EDTA in lowering blood lead level , restoring red cell gamma aminolevulinic acid dehydratase (ALA-D)activity ,and increasing urinary lead excretion .

Dose
§ 10 mg /kg/8hrs orally for 5 days followed by 10mg/kg/12 hr for 14 days to delay the eventual rebound in blood lead concentration.

Advantages of DMSA
1- It is less toxic
2- Orally active&highly effective .
3- Relatively specific i.e. doesn't significantly chelate ca ,Mg,Fe, Cu, &Zn.
4- Given safely to patient with G6Pd deficiency while BAL can cause hemolysis
5- Iron supplementation can be given concomitantly with DMSA without any adverse effects ,while BAL –Iron complex is a potent emetic

تطبيق
عايزين نطبق اللي خدناه

تعالو ناخد حاجة بسيطة الأول
زي الأسبرين مثلا
الخطوات بتاعتنا ايه؟
1-
2-
3-
4-
5-
6-
7-

كويس

1-Prevent further exposure .

لو واحدة منتحرة مثلا نحطها تحت الملاحظة
لو غير كده نكتب الخطوة وجنبها شرطة علشان تعرف المصحح أنك عارف الخطوات لأن كل عنصر عليه درجة

2-Emergency stabilization of the patient.
لو العيان صاحي خلاص شرطة أو تقول Safeguard against respiration

3-Proper clinical evaluation .
هيقولك شرب أسبوسيد مثلا علشان ألوانه جذابة للأطفال

4- Prevent further absorption
هل ينفع أعمل Emesis,Gastric lavage
هل ينفع أستخدم فحم منشط
5- Eliminate absorbed poison .
هستعمل معاه أي نوع
معروف أن الأسبرين حمض إذن هستخدم قلوي
500 مل لثلاثة محاليل
500 مل جلوكوز أو دكستروز
500 مل سلاين 9. في المائة
500 مل بيكربونات صوديوم

وكلمتين عن ionizable ,prevent reabsorbtion
6- Antidotal therapy if available.
مفيش اذن شرطة

7-Supportive Therapy.

معروف أن الأسبرين بيرفع درجة الحرارة و بيزود الحموضة وممكن يعمل
Haematemsis
إذن هعمله إيه
كمادات ميه ساقعة
Zintac
مضادات الهستامين علشان الحساسية
ولو دخل في
Pulmonary edema
أديله أكسجين من
Endotracheal tube

تطبيق تاني
CO poisoning
الخطوات بتاعتنا ايه؟
1-
2-
3-
4-
5-
6-
7-

ماشي

1-Prevent further exposure .
لو أنت في قلب الحدث أول حاجة أنك تخرج المصاب من المكان لأن تركيز أول أكسيد الكربون بيكون أعلى في طبقات الجو السفلى

طب افرض مثلا أن التعرض كان بكمية بسيطة والشخص جالك وقالك أنا أغمى عليّ خلاص طالما فايق أحطه تحت الملاحظة

2-Emergency stabilization of the patient.
أهتم بالتنفس بتاعه
إفرض أنا لوحدي ومش معايا أنبوبة أكسجين ولا حاجة أعمل إيه
أشوف airway patent &prevet obstruction
وأعمل له تنفس صناعي لحاد ماتيجي عربية الإسعاف

طيب تصرفي إيه كطبيب في المستشفى
Endotracheal entubation& mechanical entillation
*100% oxygen
*hyperbaric oxygen
الإتنين مع بعض

3-Proper clinical evaluation .
من الhistory
هيقول لك كان بيتدفى في يوم شتى ومقفل عليه
أو في جراش ومشغل بنزين و مقفل عليه مثلا او منتحر داخل عربيته مقفل القزاز برده ومدخل خرطوم البنزين من فتحة
أو البوتاجاز كان بينفس وبعدين شغلنا الشعلة يقوم يحصل احتراق غير كامل ومثلها سخان الغاز برده
4- Prevent further absorption .
شرطة مفيش
5- Eliminate absorbed poison .
شرطة مفيش
6- Antidotal therapy if available.
شرطة مفيش

7- Supportive Therapy.
ممكن ايه
Warm patient with blankets
Blood transfusion

هذه هي المحاضرة الاولى فقط وبقي 5 محاضرات ولكن بدون ردود مشجعة لن استطبع ان اكمل المحاضرات

الموسوعة المتكاملة في toxicology 620815

اشكرك على استجابة الدعوة

الموسوعة المتكاملة في toxicology 592390

والله فى شى افهمتوا وفى شى لا
بس اكيييييييييييييييد شكرا الك على المعلومات القيمة
الموسوعة المتكاملة في toxicology 285400

thank you too much

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