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Notes: Summary Using simple kinetic modelling, we estimated the effect of nucleophilic (renal) protecting agents (thiosulfate, mesna, diethyldithiocarbamate) on the half-life and the area under the concentration-time curve (AUC) ofcis-diamminedichloroplatinum(II) (CDDP) in plasma and peritoneum. Our basic assumptions were that (a) under non-protecting conditions, the elimination of intact CDDP from plasma and peritoneum is a first-order process determined by the elimination-rate constant (k), and (b) under conditions of renal protection, the elimination of CDDP is a first-order process determined by kCDDP,P=kCDDP+kN.[N], with kCDDP,P representing kCDDP under conditions of protection; kN, the second-order rate constant for direct interaction of the protecting nucleophile (N) and CDDP; and [N], the (steady-state) concentration on N. Half-lives under conditions of protection were 0.693/kCDDP,P. AUCs were obatained by integration of the first-order equations. The inactivation-indicating parameter was defined as being the ratio of the AUC under protecting conditions to the AUC under non-protecting conditions (Rinact). Rinact is approximately given by kCDDP/kCDDP,P. For renal protection with i.v. thiosulfate (TS, 2 g m−2 h), the estimates of Rinact were 0.61 in plasma and 0.7 in the peritoneal cavity for i.p. injected CDDP and 0.87 in plasma for i.v. CDDP, indicating inactivation of CDDP under such conditions. Estimates of Rinact were 0.84 or 0.96 in plasma and 0.87 in the peritoneal cavity for supposed conditions of renal protection by systemic mesna (4.4 g m−2 h), suggesting only minor inactivation of i.p. or i.v. injected CDDP under such conditions. Under reported conditions of protection achieved with 4.4 g m−2 h systemic diethyldithiocarbamate (DDTC), Rinact was 〉0.65 or 0.87 in plasma and 〉0.75 in the peritoneal cativy for i.p. or i.v. injected CDDP, respectively. Thus, DDTC inactivates CDDP to a comparable or lesser extent than does TS.

Notes: Abstract We have studied the controlled-release properties and relative systemic availabilities of two dosages of the same controlled-release (CR) diltiazem tablet formulation by comparing them at steady state with those of an immediate-release formulation. We measured 24-hour plasma concentration profiles during 4-day treatments with diltiazem 90 mg CR tablet bd diltiazem 120 mg CR tablet bd, and conventional diltiazem 60 mg immediate-release (IR) tablet tid. The study had a randomized, three-way crossover design. Twelve healthy men (38–52 y) participated. Trough plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the last morning dose on day 4 of each period. The following steady-state pharmacokinetic values were calculated: the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), the time interval during which the plasma concentration exceeded 75% of Cmax (t75), the area under the plasma concentration-time curve (AUC72–96), the peak-to-trough fluctuation (PTF), and the area-under-the-curve fluctuation (AUCF). Steady state was achieved on day 3. The pharmacokinetics were comparable. For diltiazem CR 90 mg and diltiazem CR 120 mg, AUC84–96 (night) was approximately 75% of AUC72–84 (daytime). The diltiazem plasma concentration increased slowly from about 6 h after the evening dose of both CR tablets, resulting in relatively high plasma concentrations in the early morning hours. Only during treatment with diltiazem CR 120 mg were the plasma concentrations of diltiazem maintained above the minimum therapeutic plasma concentration of 50 μg·1−1 throughout the full 24 h. In conclusion, twice-daily treatment with diltiazem CR tablets can replace thrice-daily treatment with the conventional diltiazem IR tablet. The early morning rise of the diltiazem plasma concentration, which might lead to a lower incidence of ischaemic events, may be an important clinical advantage of both CR tablets. Because of the minimum therapeutic plasma concentration of 50 μg·1−1, twice-daily administration of the 120 mg CR tablet may be preferred from a therapeutic point of view. Diltiazem, a benzothiazepine, is a calcium antagonist used in the treatment of angina pectoris and hypertension. The anti-ischaemic mechanism of diltiazem seems to result from an increase of myocardial oxygen supply and a reduction in myocardial oxygen demand, respectively by coronary artery dilatation and/or direct and indirect haemodynamic effects, such as afterload reduction and heart rate decrease (Braunwald 1982). Its therapeutic effect is evident at daily dosages between 180 and 360 mg (Low et al. 1981). After oral administration it is almost completely absorbed from the gastrointestinal tract, but owing to extensive first-pass metabolism, its systemic availability is approximately 40–50% (Echizen and Eichelbaum 1986). The time to maximum plasma concentrations after oral administration of immediate-release formulations is approximately 3 to 4 h. The elimination half-life of diltiazem is 3.5–7 h, implying that frequent dosing is required to maintain effective plasma concentrations. Therefore, a controlled-release formulation of diltiazem, designed to be taken twice daily, has been developed. The aim of this crossover study was to compare the systemic availability and steady-state pharmacokinetics of a controlled-release diltiazem tablet formulation (90 and 120 mg) with those of a conventional diltiazem immediate-release tablet in healthy volunteers.

Notes: Abstract A review of physical, chemical, analytical and pharmacological properties of nitroprusside is presented. In view of the pharmaceutical applications of nitroprusside special attention is given to the discussion of the (photo)degradation, the stability of the pharmaceutical formulations, the application as a reagent in pharmaceutical analysis and the redox behaviour.

Notes: Abstract The colour formation of cysteine (I), acetophenone (II) and sulfite (III) with the sodium and tetrabutylammonium (TBA) salt of nitroprusside (NP2−) in aqueous solution was studied. The intensity of colour formation depends strongly on the nature and concentration of the cations and increases in the order TBA〈Li〈Na〈K〈Rb〈Cs (in case of cysteine TBA and Li are interchanged). This specific cation effect was known for the Boedeker reaction (III) and is now also demonstrated for the Legal reaction (I and II). The adduct formation between NP2− and I to III is based on an anion-anion interaction. The role of the cation is to reduce the Coulombic repulsion between the reactants by ion-pair formation. The efficiency of ion-pair formation corresponds with the order given before except for TBA, which behaves divergently.