THAM (trometamol; tris-hydroxymethyl aminomethane) is a biologically inert amino alcohol of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. At 37 degrees C, the pK (the pH at which the weak conjugate acid or base in the solution is 50% ionised) of THAM is 7.8, making it a more effective buffer than bicarbonate in the physiological range of blood pH. THAM is a proton acceptor with a stoichiometric equivalence of titrating 1 proton per molecule. In vivo, THAM supplements the buffering capacity of the blood bicarbonate system, accepting a proton, generating bicarbonate and decreasing the partial pressure of carbon dioxide in arterial blood (paCO2). It rapidly distributes through the extracellular space and slowly penetrates the intracellular space, except for erythrocytes and hepatocytes, and it is excreted by the kidney in its protonated form at a rate that slightly exceeds creatinine clearance. Unlike bicarbonate, which requires an open system for carbon dioxide elimination in order to exert its buffering effect, THAM is effective in a closed or semiclosed system, and maintains its buffering power in the presence of hypothermia. THAM rapidly restores pH and acid-base regulation in acidaemia caused by carbon dioxide retention or metabolic acid accumulation, which have the potential to impair organ function. Tissue irritation and venous thrombosis at the site of administration occurs with THAM base (pH 10.4) administered through a peripheral or umbilical vein: THAM acetate 0.3 mol/L (pH 8.6) is well tolerated, does not cause tissue or venous irritation and is the only formulation available in the US. In large doses, THAM may induce respiratory depression and hypoglycaemia, which will require ventilatory assistance and glucose administration. The initial loading dose of THAM acetate 0.3 mol/L in the treatment of acidaemia may be estimated as follows: THAM (ml of 0.3 mol/L solution) = lean body-weight (kg) x base deficit (mmol/L). The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient). When disturbances result in severe hypercapnic or metabolic acidaemia, which overwhelms the capacity of normal pH homeostatic mechanisms (pH< or = 7.20), the use of THAM within a 'therapeutic window' is an effective therapy. It may restore the pH of the internal milieu, thus permitting the homeostatic mechanisms of acid-base regulation to assume their normal function. In the treatment of respiratory failure, THAM has been used in conjunction with hypothermia and controlled hypercapnia. Other indications are diabetic or renal acidosis, salicylate or barbiturate intoxication, and increased intracranial pressure associated with cerebral trauma. THAM is also used in cardioplegic solutions, during liver transplantation and for chemolysis of renal calculi. THAM administration must follow established guidelines, along with concurrent monitoring of acid-base status (blood gas analysis), ventilation, and plasma electrolytes and glucose.

Norepinephrine stores in electrically driven guinea pig isolated atria were loaded with [ 3 H] norepinephrine, and norepinephrine release was deduced from the radioactivity efflux. Electrical field stimulation of sympathetic nerve endings was applied during the refractory period of atrial contractions. The stimulation-induced release of norepinephrine was increased by angiotensin II (Ang II) (10"* to 10*"' mol/L) in a concentration-dependent manner. The maximum observed effect was a 55% augmentation. The effects of 10" 7 and 10" 6 mol/L Ang II were abolished by 10' 6 and 10" 5 mol/L of the subtype 1 Ang II receptor antagonist losartan, respectively. Losartan by itself (10~6 mol/L) caused a 14% reduction of norepinephrine release. The subtype 2 Ang II receptor ligand PD 123319 (l-[[4-(dimethylamino)-3-methylphenyl] methyl] -5-(diphenylacetyl)-4,5,6,7-tetrahydro-l//-imidazo [4,5 -c]pyridine-6-carboxylic acid ditrifluoroacetate) in a concentration of 10~4 mol/L had no detectable influence on transmitter release and did not antagonize the effect of Ang II. Angiotensin I (10~6 and 10" 5 mol/L) increased norepinephrine release maximally by 23%. This effect was antagonized by 10" 5 mol/L losartan and did not appear in the presence of 10~6 mol/L of the converting enzyme inhibitor ramiprilat. These results suggest that Ang II increases norepinephrine release by an activation of subtype 1 receptors, whereas angiotensin I is converted to Ang II to become effective. (Hypertension. 1993;22:699-704.) KEY WORDS • heart atrium • norepinephrine • angiotensin II • receptors, angiotensin • losartan

Rats anesthetized with pentobarbital and ventilated artificially were infused with 0.01 ml formalin (= 0.12 mmol formaldehyde)/kg.min. They exhibited a sharp decline of arterial blood pressure, heart rate and peripheral resistance and a slower one of cardiac output and died after 59.9 +/- 6.0 min of infusion. Sinus bradycardia and, in some cases, AV-arrhythmia occurred in the ECG. The additional infusion with cysteine attenuated the cardiovascular failure and more than doubled the survival time of formalin-infused rats. Infusion of N-acetylcysteine or correction of formalin-induced metabolic acidosis with sodium bicarbonate, on the other hand, did not exert antidotal activity. On isolated rat atria in vitro, formalin decreased the rate and the contractility and cysteine antagonized these effects of formalin. In conclusion, the severe and often lethal incidents observed following the therapeutic administration of formalin are due to the cardiovascular-depressive activity of formaldehyde and may be antagonized by cysteine.

In pentobarbital anesthetized rats that received 4 mg/kg i.v. methotrexate (MTX) or 7-hydroxymethotrexate (7-OH-MTX), the pharmacokinetics of the two drugs were similar. Plasma concentrations of both drugs declined biexponentially, with terminal half-lives of 90.6 min for MTX and 97.2 min for 7-OH-MTX. The total clearance values were 9.2 and 9.6 ml x kg-1 x min-1, respectively. With MTX, 48.2% of the dose was excreted in the urine within 200 min and another 31.6% was recovered from the bile; 5.8% was metabolized to 7-OH-MTX and appeared in the bile. Plasma concentrations of the metabolite 7-OH-MTX after MTX administration were below the detection limit. Injected 7-OH-MTX was predominantly excreted into the bile (72.8% of the dose); only 11.2% could be recovered from the urine. Differences between the physicochemical properties of MTX and 7-OH-MTX or different affinities for active transport systems may account for the unequal importance of these two excretion pathways for the two compounds.