Pharmacokinetics - based comparison among certain enhanced elimination procedures used in treatment of theophylline toxicity

Thirty patients with theophylline overdose were selected to study the pharmacokinetics of theophylline during continuous hemodialysis with and without filtration, charcoal hemoperfusion and intestinal dialysis using multiple-dose activated charcoal [MDAC]. Patients were classified into three equal groups; each comprised 10 patients. Group-1 started the enhanced elimination by continuous hemodialysis with filtration, Group-2 by charcoal hemoperfusion and Group-3 by continuous hemodialysis alone. The extracorporeal procedures in the three groups were initiated 2 hours post-admission and terminated when patient's vomiting had settled where MDAC was started. Serum theophylline concentrations peaked at 2 hours, for both hemofiltration and hemoperfusion groups, which is the time of initiating the extracorporeal procedures. For hemodialysis group, drug concentration peaked at 3 hours [1 hour post-initiating hemodialysis]. Following the peak, serum levels of patients in hemofiltration group showed significant greater decrease compared with patients in either charcoal hemoperfusion or hemodialysis groups. Also, charcoal hemoperfusion produced the same effects compared with hemodialysis alone. With respect to the pharmacokinetic parameters, there was a significant shorter half-life and a greater clearance for theophylline as a result of continuous hemodialysis with filtration [1.27 +/- 0.214 hours and 0.273 +/- 0.046 L/h/kg, respectively] versus charcoal hemoperfusion [1.86 +/- 0.335 hours and 0.186 +/- 0.034 Mg, respectively], continuous hemodialysis [3.73 +/- 1.087 hours and 0.093 +/- 0.031 L/h/kg, respectively] or gastrointestinal dialysis by MDAC [5.58 +/- 1.36 hours and 0.0621 +/- 0.0163 L/h/kg, respectively]. In conclusion, immediate continuous dialysis with filtration is an effective, rapid, and safe treatment of the life-threatening toxicity of theophyiline overdose. In combination with oral activated charcoal, hemofiltration is considered as a realistic and practical alternative to charcoal hemoperfusion

Potential antidotal effect of naloxone against captopril acute toxicity in albino rats

Captopril, is an angiotensin converting enzyme inhibitor which is widely used in the management of hypertension, has many new potential applications opening the way for wider deployment. Naloxone which is an opioid antagonist was reported to block the inhibitory effect of B-endorphin on the centrally mediated pressure action of angiotensin II thus reversing hypotension. This work aimed at evaluating the acute toxic effects of captopril and to detect the potential protective role of naloxone in ameliorating this toxicity. Seventy adult albino rats of both sexes were divided into 7 equal groups. Group [I]. [II] and [III: negative and positive control groups. Group [IV] [Naloxone group]: naloxone was given in a single I.P dose of 0.06mg/rat. Group [V] [Captopril group,: Captopril was given in a single toxic oral dose of 13.5mg/rat. Group [VI] [Captopril and Naloxone]: a single I.P dose of naloxone [0.06mg/rat] was given 1 hour after captopril single oral toxic dose. Group [VII]: A single I.P dose of naloxone [0.06mg/rat] was given 2 hours after captopril single oral toxic dose. After 24 hours from naloxone intake. the animals were anaesthesized, blood pressure and pulse rate were measured after aortic exposure. Then the animals were sacrificed and blood samples were collected for investigating liver function tests, kidney function tests and serum electrolytes. Liver and kidney specimens were also examined histologically. It was found that captopril significantly decreased the blood pressure but did not affect pulse rate. Captopril also significantly affected the liver function tests. kidney function tests, and serum electrolytes. The administration of naloxone 1 hour and 2 hours after captopril significantly improved blood pressure, liver function tests, kidney function tests and serum electrolytes There was non significant difference between the administration of naloxone 1 hour or 2 hours after captopril. The biochemical results were coinciding with the histological results. So, naloxone was found to have an antidotal effect against captopril toxicity. The very common use of captopril in medical practice, together with the severity of the toxicity, may cause calls for increased awareness and an antidotal management

Multiple dose activated charcoal versus hemodialysis in the management of theophylline overdose: a toxicokinetic-based comparison

Thirty patients with theophylline overdose were selected to study the toxicokinetics of theophylline during intestinal dialysis using multiple-dose activated charcoal [MDAC] and during continuous hemodialysis. Patients were classified according to serum theophylline level [STL] into two groups. Group [I]: comprised 20 patients with a mean STL of 43.29 +/- 15, 02. Treatment in this group was started using MDAC. Group [II]: comprised 10 patients with a mean STL of 81.32 +/- 31.07. Treatment in this group was started using continuous hemodialysis up to vomiting control, then continued using MDAC in the same regimen as group [I]. The enhanced elimination procedures in the two groups were initiated 2 hours post-admission. STL peaked at 3 hours, for both groups [1 hour after initiating the enhanced procedure]. Greater variation in STL among patients in each time interval in the hemodialysis group was clear compared to MDAC group. Following the peak, serum theophylline concentrations, in each treatment group, declined in a biphasic linear fashion. Non significant difference was observed in the pharmacokinetic parameters of theophylline as a result of MDAC; either from the start or following hemodialysis. Elimination rate constant [Ke], elimination half life [t1/2] and total body clearance of theophylline were 0.168 +/- 0.033 hour[-] 1, 4.125 +/- 1.56 hour, and 0.0841 + 0.028 L/kg/ hr, respectively as a result of MDAC modality from the start and 0.186 +/- 0.048 hour[-1], 3.73 +/- 1.087 hour, and 0.093 + 0.031 L/kgl hour, respectively following. hemodialysis. Compared with MDAC, hemodialysis did not significantly increase Elimination rate constant [Ke] of theophylline and consequently did not shorten its elimination half life [t1/2] or increase its clearance significantly. In conclusion, hemodialysis showed no advantages over MDAC in enhancing theophylline elimination in overdose except that it could be used in patients with protracted vomiting

Medicolegal aspects of blunt splenic trauma with special reference to delayed rupture/presentation [a prospective study]

Deaths due to splenic rupture are still reported in hospital statistics. It is either acute or delayed rupture. Delayed splenic injury includes either true delayed rupture that represents an actually delayed development of an initially latent, insignificant, splenic injury [i.e. injury in evolution] minor enough to go undetected on initial CT scans of the abdomen, or delayed presentation which represents an initially missed injury [i.e. delay in diagnosis]. We had encountered a number of patients presented with splenic rupture days after blunt abdominal trauma. We conducted this study to review the experience with this clinical entity of blunt splenic rupture with special emphasis on delayed rupture/presentation for patients presented 48 hours or more after trauma. Ninty five emergency examinations were performed for the sole purpose of detecting splenic rupture in patients who had experienced blunt abdominal trauma during a period of 8 years. Twenty three patients out of the ninty five underwent urgent laparotomy and splenectomy within 48 hours from the occurrence of the trauma [24.2%] due to hemodynamic instability as a result of continuously bleeding splenic injury. Left rib fracture was encountered in 47.8% of the cases and bowel and mesenteric injury was found in 17.4% of the cases. Nine patients presented with delayed rupture/presentation of spleen 48 hours or more after the initial trauma [9.4%] were analyzed and formed the basis of this study. The mechanisms of injury and accompanying injuries were documented. The time lag from trauma to operation and the cause of delay were also documented. Regarding the cases of delayed rupture, abdominal computed tomography [CT] was performed in eight hemodynamically stable patients, as the 9[th] patient presented in shock with acute abdomen and emergency laparotomy was performed after positive diagnostic peritoneal lavage. CT demonstrated hemoperitoneum in 7 patients, 2 had subcapsular hematoma, 2 had grade II injury, 2 had grade III injury and one patient had grade IV injury with multiple pseudoaneurysms. Emergency laparotomy was performed for 2 patients due to hemodynamic instability. Three patients were operated upon after a brief period; the reaons for operating were hemodynamic instability or they showed manifestations of diffuse peritoneal irritations. Two patients were diagnosed to have true delayed rupture of sleen and managed initially conservatively; unfortunately, nonoperative management failed because of deterioration of clinical condition in one patient and repeated blood transfusions in the other patient. Splenectomy was performed in 8 patients. The last patient was managed nonoperatively and followed with repeat CT scans. In conclusion, Splenic rupture is frequently associated with collapse and other organ injury specially left rib fractures. This may be a useful marker for suspecting cases of delayed rupture. Also, delayed splenic rupture/presentation represents either an actually delayed development of an initially latent, minor splenic injury or an initially missed injury with late presentation. Patients may be displaced from one grade to another within few days. So, a high index of suspicion, observation, follow up of hematological parameters and liberal utilization imaging techniques are essential for the identification of delayed splenic rupture, which may be hazardous to patients life, and an actual challenge for physicians to avoid being condemned with negligence or malpractice

Importance of nucleophilic thiols in modulating cyclophosphamide toxicity on the heart, urinary bladder and bone marrow of adult albino rats

Cyclophosphamide [CPH] is a synthetic antineoplastic agent, N-acetyl cysteine [NAC] and mesna [sodium 2 mercaptoethane sulphonate] are two members of the nucleophilic thiols. One hundred adult albino rats were used in this study. They were calssified into 10 equal groups. Groups I, II and III were control groups [-ve and +ve controls]. Group IV: [Mesna alone]. The animals of this group received 4 doses of Mesna each of 25mg/kg I.P for 5 days as follows: the 1[st] dose was given followed by the 2[nd] dose after 1/3 of an hour, then the 3[rd] dose was given after 3 hours followed by the 4[th] dose after another 3 hours. Group [V] [NAC alone]: the animals of this group received NAC at a dose of 100 mg/kg orally for 5 days. Group [VI] [Mesna and NAC]: the animals of this group received 4 doses of mesna and one dose of NAC concomitantly with the 2[nd] dose of mesna for 5 days following the same regimen and dose for each. Group [VII] [CPH alone]: the animals of this group received cyclophosphamide in a dose of 50 mg/kg I.P for 5days. Group [VIII] [CPH and Mesna]: the animals received 4 doses of mesna. CPH was given concomitantly with the 2[nd] dose of mesna. Both were given at the same previously mentioned doses and routes for 5 days. Group [IX] [CPH and NAC]: the animals received CPH concomitantly with NAC at the same previously mentioned doses and routes for 5 days. Group [X] [CPH, mesna and NAC]: the animals of this group received 4 doses of mesna. CPH and NAC were given concomitantly with the 2[nd] dose of mesna. All were given at the same previously mentioned doses and routes for each for 5 days. Animals of all groups were sacrificed 24 hours after the last dose. Blood samples were collected for investigating complete blood count [CBC], serum lactic dehydrogenase [LDH] and creatine phosphokinase [CPK] enzymes. Heart, urinary bladder and bone marrow were examined both histologically and histochemically. Cyclophosphamide significantly reduced the total leukocytic count [TLC], platelet count, hemoglobin concentration and lymphocytic count and increased the blood levels of LDH and CPK enzymes. Histologically CPH caused focal areas of cardiac necrosis, intramyocardial hemorrhage and Dilated, congested blood vessels. Whereas, it caused urinary bladder mucosal ulceration, interstitial edema and congestion with mononuclear cellular infiltration. Bone marrow hypocellularity, undifferentiated leukocytic series were also noticed in CPH group. Concomitant administration of mesna recovered completely the CPH-induced urinary bladder toxicity. However, it didn't improve either the blood picture or the cardiac enzymes and didn't recover completely neither the hemopoietic nor the cardiac toxicity of CPH. Whereas, concomitant administration of NAC or NAC and mesna with CPH improved completely the CPH induced hemopoietic and cardiac toxicity as indicated biochemically and histologically and to lesser extent the urinary bladder toxicity. So, it is recommended to prescribe NAC and mesna together with alkylating agents particularly cyclophosphamide to modulate its toxicity