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To assess the magnitude of the side effects of antituberculosis therapy (ATT) in different management systems in various age groups:

Authors: Bhurgri Ghulam Rasool, Momina Mohamed Taki, Shamim-ur-Rehman, ShahMurad, Rajkumar Chohan, DahriGhulam Mustafa, Zulfikar Shaikh

INTRODUCTION:

UBERCULOSIS T:

Tuberculosis, one of the oldest diseases known to affect humans, is caused by bacteria Mycobacterium tuberculosis. The disease usually affects the lungs, although in up to one third of cases other organs are involved. If properly treated, tuberculosis caused by susceptible strains is curable in almost all cases. If untreated, the disease can be fatal within 5 years in more than half of cases. Transmission usually occurs through airborne spread of droplet nuclei produced by patients with infectious pulmonary tuberculosis (Mario C Raviglione, Richard JO Brein, 2003).

Tuberculosis is a disease of great antiquity. Today, gas tuberculosis become transmissible disease more important in the world, with over 8 million cases of pulmonary tuberculosis occur each year 95% found in developing countries (A Gordon Leitch, 2000).

Tuberculosis is a chronic granulomatous disease of humans and other mammals, produced by a group of closely related obligate pathogens, Mycobacterium tuberculosis complex, and trained by M. tuberculosis. The bacillus of human tuberculosis – M. bovis – the bacillus of bovine tuberculosis-agricanum – a heterogeneous type is found mainly in Africa effuational with properties intermediate between the first two M-microti species and a rare cause of disease involved and other small mammals, but attenuated for humans. (PDO AWIS D et al, 2003).

Annual risk of infection

Areas

Current

Level

Annual decline

Trend (%)

Health Resources

Availability

Industrialized

0.04-0.1

> 10

Excellent

Middle income in Latin Latin

West Asia

0.5-1.5

5.10

Good

Middle income East and South

Asia EEST

1.0-2.5

<5

Good

Sub-Saharan Africa

Indian Subcontinent

1.0-2.5

0-3

Poor

(A Gordon Leitch, 2000)

In 1994, the Organization World Health Organization (WHO) declared tuberculosis (TB) is a global emergency. It developed a five-point strategy known as directly observed treatment strategy (DOTS) to combat the growing incidence of the disease. The main objective was to detect 70% of smear positive tuberculosis (TB) cases and treat85% of smear positive cases successfully again. This strategy has improved cure rates worldwide. Tuberculosis is an increasingly important cause morbidity and mortality in refugee and displaced populations, particularly during the acute phase after complex emergencies (Alison Rodger M et al., 2002).

EPIDEMIOLOGY:

In Pakistan, only limited data, however, the prevalence of tuberculosis is estimated as high as 250,000 cases a year. According to official estimates, the rate of opening bacillary cases among adults (15 years and older) was 17% and the children 5 to 9 years old, 13% were infected with tuberculosis. It is believed that the main cause of a quarter of all deaths in Pakistan (Shamim Qazi A et al., 1998).

PATHOLOGY OF TUBERCULOSIS:

CASE WITH TUBERCULOSIS INFECTOUS

The cough and the generation of droplet nuclei that Ingal by contact

Primary

Top of the CMI response

Implant Apical Bacillimia

Sterilization of the main complex

Case immunosuppressive

Multiple TB bacilli

Restoration of the WCC

Caseation necrosis

Tuberculosis Infectous

Figure: Schematic representation of key events in the pathogenesis of tuberculosis.

CMI: Cell mediated immune.

(VB Balasurbramanian et al., 1994).

TREATMENT TUBERCULOSIS DRUG

Tuberculosis is among the top ten causes of mortality worldwide and affects low ICOME countries in particular. The treatment of smear positive tuberculosis Organizzation using World Health Organization (WHO) directly observed treatment, short course directly observed strategy treatment (DOTS) have much greater impact, while immunization BC recuces TB deaths in infancy (Martien W Borgdorff al.m and 2002).

Drugs used in the treatment of tuberculosis can be divided into two main categories. First line after combining the highest level of efficiency with an unacceptable degree toxicity. These include isoniazid, rifampin, ethambutol and pyrazinamide, streptomycin. Excellent results for patients with drug-resistant tuberculosis can not be treated during 6 months of treatment, during the first 2 months, isoniazid, rifampicin and pyrazinamide are given, followed by isoniazid and rifampin for 4 months left (William A. Petri Jr, 2001).

RIFAMPICINA

Rifampicin is a semisynthetic broad spectrum antibiotic bactericidal derived from Streptomyces mediaterani.The introduction of this antibiotic that allowed the development of effective short course first 9 months of chemotherapy for tuberculosis.

It is a complement to anti-tuberculosis activity, has broad spectrum activity against other bacteria such as staphylococcus, streptococcus, Clostridium, coliforms, Pseudomonas, Proteus, Shigella and Legionella. Rifampicin is almost completely absorbed from the gastrointestinal tract after an oral dose. When taken on an empty stomach is the plasma levels 6-7 ug / ml are reached in 3 hours and half-life of approximately 5 hours (A Gordon Leitch 2000.)

Adverse effects:

Rifampicin-dependent antibodies are considered responsible for the majority of immunological side effects in that hepatotoxicity, thrombocytopenia and allergic reactions are substantial (Mehta YS, et al., 1996). Rifampicin causes anorexia, nausea, vomiting, diarrhea, fever, dizziness, bone pain, shortness of breath, urine and saliva are orange-red (Cheema MA, 2000).

ISONIAZID

Since its introduction in 1952, isoniazid has been widely recognized as safe and effective chemotherapeutic agent against tuberculosis. Numerous studies of isoniazid in combination with other TB drugs have been shown repeatedly therapeutic efficacy (Richard et al., 1972).

Isoniazid is the most widely used agent against tuberculosis. It is an ideal in many respects, be bactericidal, relatively nontoxic, easily managed and affordable. It is readily absorbed from the gastrointestinal tract, with a maximum concentration 5ug/ml occur on approximately 2 hours after administration. It penetrates into all tissues, including cerebrospinal fluid (CSF) a part of the drug is excreted in the urine as unchanged, but the proportion is acetylated by acetyl transferase liver to an inactive form. Drug is usually given orally with a combination of rifampicin and pyrazinamide, are available (A Gordon Leitch, 2000). Isoniazid is even more important world wide drug for the treatment of all types of tuberculosis. The usual dose is usually 10-50 mg / kg / day with a maximum of 300 mg (William A. Petri Jr, 2001).

The incidence of adverse effects of isoniazid are rash, fever, jaundice, hypersensitivity to isoniazid can cause fever, rash occurs several (William A. Petri Jr, 2001).

Isoniazid preventive therapy is contraindicated in persons with chronic active hepatitis, caution should be given to the person consumed alcohol daily (M Suess, 1994).

ETHAMBUTOL

Ethambutol is a synthetic, water soluble heat-stable compound. Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol. Ethambutol is a ingibitor mycobacterial arabinosyl transferases, which are encoded by the operon embCAB. Arabinosy1 Transferases are involved in arbinoglycan polymerization reaction, an essential component of cell mycobacteria (FC Henry Wall, 2001). It is rapidly absorbed from the intestine. It is excreted in the urine. Not for use in kidney disease (MA Cheema, 2000). Neuritis The major side effect is the optics, resulting decreased visual acuity and loss of ability to distinguish between red and green (William A. Petri Jr. 2001).

Hypersensitivity to ethambutol is rare. The most common serious adverse event is retrobulbar neuritis causing loss of visual acuity and red green color blindness. The dose-side effect is more likely to occur in a dose of 25 mg / kg / day followed for several months. Neuropathy due to peripheral demyelination. Other less common side effects are gastrointestinal intolerance, hyperurecemia, and hypersensitivity reactions, including rash, and rarely thrombocytopenia. Is it safe during pregnancy without known teratogenic effects (Edwards D, Chan, 2003).

Pyrazinamide

Pyrazinamide is bactericidal in an acid environment and the effect of sterilization on intracellular mycobacteria. It is well absorbed from the gastrointestinal tract, with the concentration maximum of about 1.5-2 Gour 50ug/mloccurring after ingestion. It penetrates well into tissues including cerebrospinal fluid (A Gordon Leitch, 2000).

Pyrazinamide is orally effective synthetic antibacterial agent used with ant tuberculosis isoniazid and rifampicin (William A. Petri Jr, 2001).

The reasons for this increased incidence of hepatotoxicity reactions in developing countries are not clear, perhaps malnutrition, increasing age, parasitism of widespread and chronic infections, indiscriminate use of various drugs without a prescription can play a role individually or collectively (H Turktas et al., 1994).

Gastrointestinal reactions, skin reactions, anemia sidiroblastic (A Harries, 2003). Furthermore pyrazinamide is considered to be significantly less hepatotoxic than isoniazid and rifampicin. Less common adverse reactions include pyrazinamide renal failure by rhabdomyolysis with myoglobinuria, gouty arthritis, photosensitivity, maculopapular raxh, thrombocytopenia, increased serum iron, hives and other reactions hypersinsitivity (Edward De Ehan et al., 2004).

STREPTOMYCIN

Streptomycin is tuberculocidal, but less effective than isoniazid or rifampin, acts only on the extracellular bacilli (due to poor penetration into cells). Thus, defense mechanisms are needed to eradicate the disease. Penetrates cavities tuberculosis, but not the cross for cerebrospinal fluid (CSF), and has little action in acid. Resistance develops quickly when used streptomycin in tuberculosis single most patients had a relapse (Tripathi, 2003). Streptomycin is bactericidal to tubercle bacilli in vitro. Concentration as low as 0.4 mg / ml can inhibit growth. Vast majority of strains of Mycobacterium tuberculosis are sensitive to 10 mg / ml (William A. Petri Jr, 2001)

Adverse effects include rash and fever, hearing and vestibular function of the eighth cranial nerve is affected (William A. Petri Jr, 2001).

BCG

Unfortunately, the protective efficacy of BCG, the most widely used vaccine against pulmonary tuberculosis varies from 0% to 80%. BCG gives good protection (75-80%) against disseminated tuberculosis includes tuberculous meningitis, in childhood, BCG is given at birth or as soon as possible, therefore, after and, although the duration of protection is uncertain, there can be over 15 years, this protection against the limitation of the infectious pulmonary tuberculosis, which may occur mainly in adults (marteina Borgdorff W et al., 2002).

Today, more than 70 years of development BCG vaccine, which remains the only tuberculosis vaccine is used, and achievements of research on vaccines against TB have been largely operational, such as expanding the supply of BCG vaccine through the EPI, and field trials in different locations share geographical (Ann M Ginberg, 2002).

MATERIAL AND METHODS

This study was conducted in the department Pharmacology and Therapeutics, Institute of Basic Medical Sciences (BMSI), Jinnah Postgraduate Medical Center, Karachi, in January 2005 to June 2005.

The Of 100 patients newly diagnosed pulmonary tuberculosis, was entered this study after taking informed consent in writing.

The Patients were selected as cases diagnosed with pulmonary tuberculosis and room kit OPD chest Jinnah Postgraduate Medical Center, Karachi. Of these 97 patients associated out through the study period. Of the remaining three have not come for follow up.

All patients in this study were selected according to the following criteria:

Inclusion criteria:

• Diagnosed cases of pulmonary tuberculosis.
• Age between 2o a 70.
• Sex, either male or female.

EXCLUSION CRITERIA:

• Patients suffering from liver disease.
• Patients suffering heart disease.
• Patients suffering from kidney disease.
• Patients with diabetes mellitus.
• Patients with other respiratory diseases.
• Patients who suffer from HIV infections.
• Pregnant or lactating women.
• Patients with a history of multiple drug resistance.

The study period extended to 24 weeks and 12 follow-up visits patients were taken. The required information as name, age, sex, occupation, address, details of follow-up visits and laboratory investigations, etc., of each patient were recorded in pro specially designed for this study.

The patients selected were divided according to the adverse effects of drugs during the study period.

Group 1: This group included patients expressing hepatitis in different age groups

Group 2: This group included patients who said the INH neuropathy peripheral defferent age groups

Group 3: This group included patients who manifest the rash on different age groups

Group4: This group included patients who said the joint pain in different age group

Group5: This group included patients who showed optic neuritis in different age group

Group6: This group included patients who showed thrombocytopenia in different age group

Group7: This group included patients with nephrotoxicity manifested in different age group

Group 8: In this group included patients who showed the ototoxicity in different age group

MATERIALS

• Isoniazid adults — 5 mg / kg maximum 300 mg
• Adult —- Rifampicin 10 mg / kg up to 450 mg
• pyrazinamide 15-30 mg / kg
• Ethambutol 15-25 mg / kg up to 300 mg
• Streptomycin – 15 mg / kg – a maximum of 1 g of
• Disposable syringes.
• Bottles PP.
• Kits for testing liver function, measurement of urea, creatinine

Ninety-seven patients were studied after treatment with TB drugs and divided into eight groups after the demonstration of adverse effects of therapy.

The comments of all treatment groups were recorded on day 0, day 30 to day 80.

Table 1 and Figure 1 hepatitis show after to take the TB drugs. Hepatitis is manifested more in combined drug therapy for pulmonary tuberculosis. The hepatitis found significant differences with p <0.01 between anti-TB therapy. Of the 97 patients there were 15 patients were affected by this adverse effect. The higher the proportion of hepatitis in isoniazid% (10.3) followed by pyrazinamide (3.1%) and rifampicin (2.1%

Hepatitis in different age groups. The decade between 20-29 years of age has shown maximum number of hepatitis (5.1 and older followed by 60-69 years (P <0.05), keeping the high proportion of isoniazid, compared with pyrazinamice (1.03%) and rifampin (2.06%) in different age groups. Isoniazid shown 4 cases of hepatitis in the age group 20-29 years, pyrazinamide 1, respectively. Four-induced hepatitis in patients aged 60 to 69. Pyrazinamide-induced hepatitis in age between 60 and 69. Pyrazinamide produced hepatitis (2.66%). Isoniazid and Rifampicin affected with the same percentage (1.03%). Two patients were hepatitis at the age between 30-39 years. The INH and rifampin affected with equal% (1.03) in this age group, respectively. Was not statistically significant. One patient was isoniazid in the age group of 50-59 years. Was not statistically significant

Peripheral neuropathy in 25 patients of 97 patients. Isoniazid neuropathy occurred more than other causal drugs. Isoniazid 11.3% of patients affected. Pyrazinamide and ethambutol produce peripheral neuropathy in the same percentage (7.2%). Was not statistically significant.

Peripheral neuropathy in different age groups. The age between 60 and over are more affected than other age groups. Isoniazid neuropathy produced 602% in this age group. 1.03% ethambutol produced peripheral neuropathy. The age group 20-29 isoniazid developed peripheral neuropathy 301%, 2.01% pyrazinamide and ethambutol 1.03%, respectively. The total patients were 6 in this age group. The age between 30-39 peripheral neuropathy manifested by isoniazid 1.03% and ethambutol 1.03%. The age between 40-49 were affected by peripheral neuropathy 3.1% pyrazinamide and ethambutol 3.1%

Therapy produced 3 patients, thrombocytopenia. Rifampicin thrombocytopenia occurred in 3.1% of men.

Thrombocytopenia in different age groups. Combination therapy affected age between 40-49, 1.03%, 50-59, 1.03% and 60 and above 1.03%, respectively. Rifampicin causes this side effect with the same percentages, ie 1.03% in the age groups 40-49, 50-59 and above.

            Table 10 and Figure 10 show the joint pain as a side effect of drugs against tuberculosis. Combined therapy of 8 patients affected 97. pyrazinamide produced joint pain in 8.24% of patients.

Table 12 and Figure 12 show the joint pain by age group. Pyrazinamide affected 3.09% in the age between 60 and over, 2.06% at age 20-29 and 1.03% in the age groups, respectively.

Neuritis optics. The combined therapy produced optic neuritis in 7 patients out of 97. Ethambutol causes optic neuritis 7.2%

The optic neuritis as age groups. Combined treatment of optic neuritis occurred in 3 in the 6th to69, 2 in 50-59 and one 30-39 years and 40-49 years respectively. Ethambutol causes optic neuritis at 3.09 in the age between 60-69, 2.06% in 50-59 and 1.03% in 40-49 and 30-39 tears.

Rash as a side effect of drugs against tuberculosis. The rash found significant (P <0.01) with combination therapy. Combination therapy rash occurred in 6 patients of 91 patients. Pyrazinamide rash occurred (4.12%) and rifampin produced 2.1%, respectively.

Skin rashes on the age groups. The patient achieved rash on 2 of 20-29 years old 1 40-49 years, 1 60-69, respectively. The rash pyrazinamide produced 2.06% at age 20-29 years, 1.03% in 50-59 years, 1.03% in the group aged 60-69 years, 1.03% in 50-59 years respective

Nephrotoicity as a side effect. Streptocomycin drug was the main show to nephrotoxicity in the combination therapy for treatment of pulmonary tuberculosis in combination therapy for treating tuberculosis pulmonary patients. In 97 patients, there were 3 reactions documented in this study. Nephrotoxicity in the genre after taking anti-tuberculosis drugs. Two men and a woman was hit during the study

Nephrotoxicity in the age group. In the age group 30-39 1, 40-49 1 and 50-59 1 reaction was documented in this study.

The ototoxicity after taking TB drugs. There were 2 reactions recorded in this study.

Adverse effect

Pyrazinamide

Isoniazid

Ethambutol

Rifampicin

Streptomycin

Overall

%

95% CI

Peripheral neuropathy

7 (7.2%)

11 (11.3%)

7 (7.2%)

—

—

25

25.8

17.80-35.1

Hepatitis

3 (3.1%)

10 (10.3%)

—

2 (2.1%)

—

15

15.5

9.2-23.7

Joint pain

8 (8.2%)

—

—

—

—

8

8.20

3.9-15.0

Optic neuritis

—

—

7 (7.2%)

—

—

7

7.20

3.2-13.7

Skin rashes

4 (4.2%)

—

—

2 (2.1%)

—

6

6.20

2.5-12.4

Table show the general side effects of ATT in this study.

FIGURES:

Overall incidence of adverse effects

(n = 69)

DISCUSSION:

This study observed the adverse side effects of antituberculosis drugs in patients with pulmonary tuberculosis. Patients selected were divided into two groups according to age and sex. In this study, ie the following reaction, hepatitis, peripheral neuropathy, thrombocytopenia, pain joints, optic neuritis, ototoxicity and nephrotoxicity were recorded in the first line anti-TB drugs used in patients with pulmonary tuberculosis.

Adverse effects of antituberculosis drugs ie, isoniazid (INH), pyrazinamide, rifampicin, ethambutol and streptomycin, were observed during this study, debate here.

Isoniazid (INH) 300 mg per day was started by a selection of 97 patients with tuberculosis. The main side effects were recorded after two weeks of medication, including hepatitis and peripheral neuropathy.

Hepatitis – there were 10 reactions were documented hepatitis in this study. In a group of sex, reactions were observed in 7 men and 3 reactions in women. According to the age group 20-29, isoniazid produced 4 reactions, 3 reactions at 40-49, 1 of reaction in other age groups. Isoniazid was stopped, but other drugs are rifampicin, pyrazinamide, ethambutol and streptomycin continuous in these patients.

After discontinuation of isoniazid, liver function test was normal in 6 cases, isoniazid was reintroduced after 2-3 weeks with doses of 50 mg daily and was later increased to 300 mg per day. There were 4 cases referred to the medical outpatient (OPD) for the management of liver disease.

Peripheral neuropathy – isoniazid produced 11 responses of peripheral neuropathy of 25 responses in this study. According to gender, 4 reactions were at males and 7 in the reactions of women. According to the age group of peripheral neuropathy produced in the age group 30-39 and 40-49, respectively. This showed the effect Most of INH in the older group.

Pyrazinamide (1-2 g / day) – the main side effect of this drug occurred after 3-4 weeks of medication. Hepatitis 3, peripheral neuropathy 7, joint pain, 8 and skin rashes were documented in this study.

Hepatitis – 3 pyrazinamide produced reactions of hepatitis in this study. According to gender, 1 male and 2 females were the reactions in this study. According age, pyrazinamide 2 produced reactions in the age group of 60-69 and 1 reaction in the age group 20-29. On 1 pyrazinamide reaction was decreased when drug stopped. But 2 reactions in the older group, the test of liver function has improved and that he referred to the medical outpatient (OPD) for disease management liver.

Peripheral neuropathy – were 7 reactions to pyrazinamide were documented in this study, by gender, 2 reactions reactions in men and 5 women according to age group, aged between 50-59 3 reactions and 1 reaction in the age group 20-29 and 40-49 respectively. These reactions were reversible after decreasing the dose of pyrazinamide.

Skin rashes – pyrazinamide produced 4 reactions of 6 reactions of the TB drugs in this study. According to gender, female 3 reactions and 1 reaction in men in this study were recorded. According to age group, 2 responses were recorded in the age group of 20-29 and 1 reaction in 50-59, 60-69, respectively. Rash subsided after the arrest of pyrazinamide for 3 weeks.

Joint pain – there were 8 reactions joint pain documented in this study. This study showed that only drug pyrazinamide causing the joint participation, the uric acid level was done before and after the onset of the drug. A significant increase level of uric acid was observed pyrazinamide after treatment. Thus, the drug was stopped in these 8 patients, and later the uric acid level decreased significantly and participation together to improve clinically.

Ethambutol was administered at doses of 15-30 mg / kg / day. Side effects of this drug is manifest 2-3 weeks of treatment. Peripheral neuropathy and optic neuritis were reported as major side effects.

Peripheral neuropathy – There were 7 reactions recorded peripheral neuropathy in this study. Ethambutol these reactions occur in 2-4 weeks after starting treatment. According to gender, 5 female and 2 male reactions have been observed in this study. According to age group, 3 reactions in 50-59 and 1 reaction in each age group, respectively. These effects were reversible after discontinuation of the drug.

Optic neuritis – ethambutol side effects occurred 7 of neuritis optics in this study. According to gender, male and female 4 expressed 3: Reactions of optic neuritis in this study. According to the group from age 3 reactions in the age group 60-69 and 50-59 in group 2 and 1 reaction in 50-59, 30-39 age group, respectively, in this study. Drug was discontinued in these 7 cases of neuritis optics, but the other four other drugs continued. They were referred to the Department of eyes for the outpatient management of optic neuritis. Only drug in two patients was reintroduced with low doses of 15-20 mg / kg / day.

Rifampicin (450 mg / day) – after 2-3 weeks of starting with the combination therapy demonstrated significant side effects. When this medicine is expected, hepatitis 2 and rash 3 improved and the reactions of thrombocytopenia were documented in this study.

Hepatitis – According to gender, 1 hepatitis reaction in men and 1 woman produced by rifampin. According age group, 1 of reaction 30-39 and 60-69 were produced by rifampicin. One of the side effects of hepatitis is improved when the drug was stopped after a week and another patient was referred to doctor-patient department for further management.

Skin rashes – rifampicin developed redness skin in two patients, one male and one female in this study. According to age group, 1 adverse effect on the 40-49 and 50-59 respectively were observed. These rash were reversible after drug arrest.

Thrombocytopenia – after 5-11 weeks of treatment of patients with tuberculosis, the level of decline platelet and clinical of patients complaining epistaxis, bruising, petechiae, and skin rashes. Rifampicin was stopped in 3 patients, but the remaining four drugs were continued.

Streptomycin (1 g per day) – which began with other drugs. After 3-7 weeks of therapy, 3 patients complained of oliguria and 2 patients during follow-up with hearing impairments. These reactions demonstrated clinically and laboratory investigations.

Nephrotoxicity occurred in these patients, two male and 1 female. According to the age group 1 in 30-39, and 2 40-49 1 50-59 side effects were documented in this study. Drug was held for 3 weeks and found that blood urea nitrogen and creatinine levels decreased, therefore this drug was permanently stopped and the other four medications were continued.

The renal proximal tubule cells can accumulate aminoglycosides, accounting associated with aminoglycoside nephrotoxicity. The mechanism of renal toxicity is the hypothesis that inhibition of intracellular phospholipase in the proximal tubule. Renal failure is typically characterized by nonoligouric decreased glomerular filtration rate occurring after at least take a week therapy. Reference and regular monitoring of nitrogen levels blood urea analysis, creatinine values indicated (Edward et al. 2004).

Streptomycin is nephrotoxic and should be used cautiously in patients with renal insufficiency. If the reaction is a problem that is a rare event, the dose may be reduced (SCN, 2002).

Ototoxicity – There were 2 reactions recorded in this study. According to gender, 1reaction was in men and 1 in women has been documented in this study. Side effects of streptomycin were recorded. One age group 20-29 and one 40-49. The drug was stopped and patients were advised to consult ENT OPD. Rest of other drugs were continued.

Curiously, the damage may be fairly isolated to any component of the corn or vestibular, or rarely both. The mechanism of cochlear toxicity is not clear, although the target site is considered that the outer hair cells of the organ of Corti.

Aminoglycoside-induced cochlear dysfunction is considered generally irreversible. Damage to the hair cells of the ampullar cristae of aminoglycosides is the mechanism of vestibular toxicity. Signs and symptoms of toxicity vestibular include nausea, vomiting, vertigo and nystagmus (Edward et al., 2004).

Our study is consistent with the study of Menzies et al (2005), who observed the side effects of antituberculosis therapy. They reported that at least monthly nurse, case manager, treating physician saw the trial of 430 patients receiving therapy for active TB. At the time of his visit, patients were asked specifically about side effects common medications for tuberculosis. Liver enzyme levels were examined routinely in all patients after one month of treatment. Patients were encouraged to return at any time if symptoms or problems that arose during treatment.

The surprising observation is that, pyrazinamide association was found with the type of toxicity that was three times higher than isoniazid and rifampicin and 20 times greater than ethambutol. The toxicity rate was 1.5 pyrazinamide per 100 person – months, compared with 0.5 per 100 person – months for isoniazid. Pyrazinamide Pyrazinamide attributed to eruptions may have led to disruption the right drug. It seems that the pyrazinamide-related eruptions usually resolve spontaneously and is not considered a reason to stop therapy. Although this study toxicity index was higher pyrazinamide to isoniazid and rifampicin. Therefore, he was arrested as the parent drug pyrazinamide, isoniazid and rifampicin, since it induces hepatitis, which increases the risk of liver damage. However, ethambutol and streptomycin was continued in this study.

If rash, pyrazinamide was responsible for drugs, but therapy was discontinued, skin eruptions were improved after three weeks.

There was a difference between this study and the Menzies study may be due to the short duration of the study, the difference in the number of patients studied. Moreover, their study in the USA. In this study, there was a short duration of the selected studies and the small number of patients and many environmental factors involved. Patients selected in this study belong to poor socioeconomic class and repeatedly that he could not visit their doctors to check the occurrence of effects side of antituberculosis drugs.

The British Thoracic Society (1998) guidelines that if the aspartate aminotransferase and alanine transferase are two or more times normal, liver function should be monitored two weeds, then two weekly until normal. If the aspartate aminotransferase and alanine transferase two times normal, liver function should be repeated in two weeks. If the level of aspartate aminotransferase and alanine transferase rises to five times normal or bilirubin level rises, rifampicin, isoniazid and pyrazinamide should be stopped. Alternative treatment must be considered if the patient is sick or smear-positive and within two weeks of starting treatment.

The reactions most frequently observed with intermittent regimens of rifampicin are cutaneous syndrome is redness and / or pruritus, with or without rash, particularly that related to the face and scalp, often with redness and watery eyes (Fried et al., 2004). Pyrazinamide GIT produce reactions, skin reactions and blast ANAEM Sidero (Harries, 2004).

The results of this study is consistent with the study of Pelletier et al (2003), who observed the side effect of 4.30 antituberculosis drugs in patients between 1990-99. They said the most adverse important first-line TB drugs, resulting in the discontinuation of that drug, has had serious consequences. That morbidity can be considerable even mortality can notably drug-induced hepatitis. Alternative agents may have greater problems with toxicity and often less effective than treatment must be prolonged, with corresponding challenges for ensuring the complaint as a risk of treatment failure and relapse are higher. In their results, only 37 patients major side effects occurred six times. Severe hepatitis resulted in discontinuation of isoniazid and pyrazinamide are not resumed. In three cases (two of the eruption and one of severe gastrointestinal intolerance). Rifampicin and pyrazinamide, were arrested not rechallenged. Rifampicin was observed rarely cause drug-induced hepatitis. The main drug responsible for the occurrence of hepatitis or rash during tuberculosis treatment for tuberculosis or hepatitis erupting during treatment of tuberculosis in patients with tuberculosis was pyrazinamide.

In this study, pyrazinamide shows more side effects than other anti-TB drugs were documented according to age and gender. However, the incidence of drug-induced hepatitis was observed more in the other antituberculosis drugs isoniazid. Rifampicin has shown fewer side effects than other anti-TB drugs.

The side effects in this study was observed to be much more higher than the study by Pelletier and colleagues. In this study there is a short duration of the selected studies and the small number of patients involved and many environmental factors. The patients enrolled in this study belong to families of low economic class and repeatedly that he could not visit doctors for check the occurrence of side effects of antituberculosis drugs.

Hepatotoxicity is one of the more serious side effects of drugs tuberculosis (ATD). Although there were many risk factors associated with antituberculosis drug-induced hepatotoxicity, their influence on the severity of hepatitis not been systematically studied. This study evaluated whether the presence of hepatotoxicity risk factors (advanced age, chronic liver disease, alcohol abuse or other drugs or malnutrition) influences the severity of ATD-induced hepatotoxicity (Villar et al., 2004).

The results of this study are consistent Fernanoted the study that the (2004). Your prospective cohort study of 471 patients suffering from active tuberculosis treated with isoniazid, rifampicin and pyrazinamide, were followed in the tuberculosis clinic between January 1998 and July 2002. The incidence of antituberculosis drug-induced hepatitis was 18.2% of patients in a risk group and 5.8% of patients in the group without risk. Antituberculous drug-induced hepatitis is a major and more severe in patients with risk factors. Our study related to this study, because much of our population live in a risk factor, namely, poverty, malnutrition, lack of potable water, combine the family structure, the high prevalence of viral hepatitis. Thus, in our study there were more cases of hepatitis due to pyrazinamide, and rifampin gave isonaizid been responsible for drug-induced hepatitis.

The manifestations of symptomatic hepatotoxicity include an elevation of serum aminotransferase, jaundice and liver tenderness. One of the recommendations for monitoring of rifampicin and pyrazinamide-induced hepatitis is determining aminotransferase levels at baseline and at 2, 4 and 6 weeks of treatment and stopping rifampicin / pyrazinamide when there is (a) serum aminotransferase level more than five times the upper limit of normal in each in symptomatic (b) any elevation of serum aminotransferase that is accompanied by symptoms of hepatitis (c) any bilirubin serum (Edward et al., 2004).

The results of this study are also consistent with the results of the study conducted by Dossing et al (1996). They observed 61 patients for each 127 patients who had elevated aspartate aminiotranferase after the treatment of tuberculosis drugs. Most of these were men with daily alcohol consumption of 60 g. The hepatitis were confirmed by challenge with 7 pyrazinamide and isoniazid 6 cases.

In this study, we monitored the occurrence inconvenience the effects of antituberculosis drugs. There was a difference between the two studies because of the short duration of the study and small selected patients. In this study, cases of hepatitis were recorded over the study my Dossing et al.

This study also coincided with the study of Ferner (1990). He noted that the dose-related toxicity of ethambutol. Reported clinically deteriorating sub color discrimination relatively common in 54 patients received about 15 mg / kg / day of ethambutol as part of its specific treatment. In this study, ethambutol opticneurites occurred in a high percentage of study of Ferner's. However, similar results were observed in the former group of elderly patients were more affected in both studies. Peripheral neuropathy has been reported in 3 patients tuberculosis who had received the athambutol from 13 to 50 mg / kg / day.

Peripheral neuropathy is manifested by ethambutol in our study. There 7 reactions of peripheral neuropathy caused by ethambutol, but these reactions were reversible after discontinuation of ethambutol.

In patients with prescription of ethambutol is recommended that after obtaining an initial visual acuity and color perception tests, these tests should be repeated every 4 to 6 weeks, especially with new visual symptoms (Chan et al, 2004).

Zinc is found in high concentration in choroid, retina, and ganglion cells and is used by the dehydrogenase of the retina to the transformation of the retina. This last step is important for color vision. Most cases of toxicity bilateral and color are the result of a dose retro bulbar optic neuritis may be axial or peripheral. Axial neuritis involves papillomacular package. Acuity is reduced visual and causes of central scotomas and color vision deficiency. The peripheral visual field deficits, but stable visual acuity and color vision (DorothyNahm Friedberg et al., 2004).

Ellard et al (1976) study observed the occurrence of joint pain in a reduction of renal elimination urate in man caused by administration of pyrazinamide.

The urinary excretion of pyrazinamide pyrazinoic acid, acid 5-hydroxypyrazinoic and uric acid were determined in healthy subjects after giving single or multiple doses of pyrazinamide or its metabolites pyrazinoic acid. The results showed that the 5-hydroxypyrazinoic acid is the main acid metabolite in man and pyrazinoic supports previous evidence under the retention of uric acid caused by the administration of pyrazinamide is mediated by acid pyrazinoic. After giving 3 g of pyrazinamide urinary excretion of uric acid was removed maximum of 24 hours. Pyrazinoic Prolonged exposure to acid results in a net reduction in urinary excretion of uric acid. The finding suggests that the degree of retention of uric acid in patients treated with regimens containing pyrazinamide could be reduced, giving intermittent pyrazinamide (Ellard et al., 1976).

This study matched with the study by Ellard and colleagues. Pyrazinamide was responsible for joint pain in the age group and gender in this study. The older age group commonly affected by pyrazinamide.

In a study of Hussain et al (2003), the ocular reaction, and neuropathy poisons produced by ethambutol in a patient's age between 11 to 80 years. The deserted the Fouces Color vision in 76% of eyes and 27% of eyes had defect color vision in spite of having a visual acuity of 6 / 9 or 6 / 6. Fundus examination revealed dilated normal optical disc 66 (67%) of the eyes, pale disc in 27 (28%) eyes and 4 (4%) eyes were swollen hyperemic disk.

The results of this study are compared with results the study by Hussain and coworkers for ethambutol was done in the pathogenesis in the same age cohort.

Ethambutol is a treatment effective for tuberculosis. It can cause a lot of time and dose-dependent adverse effects including eye color changes, visual field defects, and unilateral or bilateral optic neuritis. A gradual decrease of central visual acuity and red green vision problem of color (blue or less frequently defective vision of yellow) have been reported. These defects continue to progress for 1 to 2 months after the drug is discontinued (Katherine, 2002).

This study also correlated with the study of Mehta (1996). Thrombocytopenia was observed in three patients with pulmonary tuberculosis during treatment. Rifampin drug was the cause. Immune studies in three patients showed the presence of antiplatelet antibody reaction resulting in thrombocytopenia.

Moreover, the union of these antibodies to platelet membrane was more avid in the presence of rifampicin. In this study, thrombocytopenia was the side effect of rifampicin in different age and gender groups. These three patients were separated on the basis of complete blood picture showed clinically and nosebleeds, petechial rash and bruises. The pyrazinamide was stopped and not reintroduced in these cases.

Tuberculosis is a granulomatous disease caused by Mycobacterium tuberculosis. As the Organization World Health Organization estimates that more than 300,000 new cases of TB develop each year in Mexico. Cure of infectious cases of tuberculosis is the key to control effective disease. Treatment of patients with tuberculosis reduces suffering and, where appropriate, prevents death from tuberculosis. The first tine of drugs used in the treatment of tuberculosis consists of isoniazid, pyrazinamide, rifampicin, streptomycin and ethambutol. The main side effects are those that give rise to serious health risks, and require discontinuation of the drug and referral to chest physician. Minor side effects cause relatively little discomfort, but often respond to treatment symptomatic or simple, but occasionally persist for the duration of drug treatment. Chemotherapy should be stopped or temporarily interrupted only intolerance or severe drug toxicity occurs. In fact TB drugs are relatively toxic and mild side effects are not uncommon, but most not justify withdrawal of the drug.

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