Transanal Total Mesorectal Excision With Delayed Coloanal Anastomosis (TaTME-DCAA) Versus Laparoscopic Total Mesorectal Excision (LTME) and Robotic Total Mesorectal Excision (RTME) for Low Rectal Cancer: A Propensity Score-Matched Analysis of Short-term Outcomes, Bowel Function, and Cost.

INTRODUCTION: Total mesorectal excision (TME) with delayed coloanal anastomosis (DCAA) is surgical option for low rectal cancer, replacing conventional immediate coloanal anastomosis (ICAA) with bowel diversion. This study aimed to assess the outcomes of transanal TME (TaTME) with DCAA versus laparoscopic TME (LTME) with ICAA versus robotic TME (RTME) with ICAA. METHODS: This was a retrospective propensity score-matched analysis of patients who underwent elective TaTME-DCAA between November 2021 and June 2022. Patients were propensity-score matched in a ratio of 1:3 to patients who underwent LTME-ICAA and RTME-ICAA from January 2019 to December 2020. Outcome measures were histopathologic results, postoperative morbidity, function, and inpatient costs. RESULTS: Twelve patients in the TaTME-DCAA group were compared with 36 patients in the LTME-ICAA and RTME-ICAA groups each after propensity score matching. Histopathologic results and postoperative morbidity rates were statistically similar. Overall stoma-related complication rates in the ICAA groups were 11%. Median total length of hospital stays for TME plus stoma reversal surgery was similar across all techniques (10 vs. 10 vs. 9 days; P =0.532). Despite a significantly shorter duration of follow-up, bowel function after TaTME-DCAA was comparable to that of LTME-ICAA and RTME-ICAA. Overall median inpatient costs of TaTME-DCAA were comparable to LTME-ICAA and significantly cheaper than RTME-ICAA ($31,087 vs. $29,927 vs. $36,750; P =0.002). CONCLUSIONS: TaTME with DCAA is a feasible and safe technique compared with other minimally invasive methods of TME, while avoiding bowel diversion and stoma-related complications, as well as comparing favorably in terms of overall hospitalization costs.

Macroline, akuammiline, sarpagine, and ajmaline alkaloids from Alstonia macrophylla.

A total of seventeen alkaloids, comprising six macroline (including alstofolinine A, a macroline indole incorporating a butyrolactone ring-E), two ajmaline, one sarpagine, and eight akuammiline alkaloids, were isolated from the stem-bark and leaf extracts of the Malayan Alstonia macrophylla. The structure and relative configurations of these alkaloids were established using NMR, MS and in several instances, confirmed by X-ray diffraction analysis. Six of these alkaloids were effective in reversing multidrug-resistance (MDR) in vincristine-resistant KB cells.

Alstiphyllanines I-O, ajmaline type alkaloids from Alstonia macrophylla showing vasorelaxant activity.

Seven new ajmaline type alkaloids, alstiphyllanines I-O (1-7) were isolated from the leaves of Alstonia macrophylla together with six related alkaloids (8-13). Structures and stereochemistry of 1-7 were fully elucidated and characterized by 2D NMR analysis. A series of alstiphyllanines I-O (1-7) as well as the known ajmaline type alkaloids (8-13) showed that they relaxed phenylephrine (PE)-induced contractions against rat aortic ring. Among them, vincamedine (10) showed potent vasorelaxant activity, which may be mediated through inhibition of Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCs) and/or receptor-operated Ca(2+) channels (ROCs) as well as partially mediated the NO release from endothelial cells. The presence of substituents at both N-1 and C-17 may be important to show vasorelaxation activity.

Total synthesis of (-)-raumacline.

The total synthesis of (-)-raumacline from L-tryptophan was achieved, featuring a cis-specific Pictet-Spengler reaction, a stereoselective Dieckmann cyclization, and an epimerization step that allowed complete stereocontrol of five chiral centres.

Enantiospecific total synthesis of (-)-(E)16-epiaffinisine, (+)-(E)16-epinormacusine B, and (+)-dehydro-16-epiaffinisine as well as the stereocontrolled total synthesis of alkaloid G.

An efficient strategy is described for the total synthesis of the sarpagine-related indole alkaloids (-)-(E)16-epiaffinisine (1), (+)-(E)16-epinormacusine B (2), and (+)-dehydro-16-epiaffinisine (4). A key step employed the chemospecific and regiospecific hydroboration/oxidation at C(16)-C(17); this method has also resulted in the synthesis of (+)-dehydro-16-epinormacusine B (5). The oxy-anion Cope rearrangement followed by protonation of the enolate that resulted under conditions of kinetic control has been employed to generate the key asymmetric centers at C(15), C(16), and C(20) in alkaloid G (7) in a highly stereocontrolled fashion (>43:1). Conditions that favor control of the sarpagine stereochemistry at C(16) vs the epimeric ajmaline configuration at the same stereocenter have been determined. The formation of the required cyclic ether in 4, 5, and 7 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF or DDQ/aq THF in excellent yields.

Stereocontrolled total synthesis of alkaloid G via the oxy-anion Cope rearrangement and improved total synthesis of (+)-ajmaline.

[figure: see text] The oxy-anion Cope rearrangement followed by protonation of the enolate which resulted under conditions of kinetic control has been employed to generate the key asymmetric centers at C(15), C(16), and C(20) in alkaloid G (1) and (+)-ajmaline (2) in a highly stereocontrolled fashion. The aldehyde 7b from this process has been converted into alkaloid G (1) and (+)-ajmaline (2) in 36% and 13% overall yields (11 reaction vessels from 3), respectively.

[Suicidal Tachmalcor poisoning--a case report]. / Suizidale Tachmalcor-Intoxikation--Ein Fallbericht.

In a case report, a Tachmalcor intoxication with a dose of 18 mg/kg body weight is described. This dose caused a ventricular flutter in the patient which lasted for a total of 10 hours, despite intensive treatment. The treatment began approximately three hours after the intoxication and concentrated on therapy of the ventricular tachycardia. The use of Xylocitin 2%, defibrillation, glucagon and sodium chloride is recommended with such symptoms. Additionally, we used hemoperfusion for drug elimination. Despite the cardiac rhythm disorder of such duration, no neurological deficiencies were observed in the patient. Intoxications caused by these drugs in normal intensive therapies are extremely rare and for this reason treatment can often be very problematic. The following article reports on the successful therapy of one such patient.

Sensitive method for the determination of the antiarrhythmic drug detajmium in serum by solid-phase extraction and high-performance liquid chromatography with fluorimetric detection.

The objective of this study was to develop a very sensitive and selective method for the determination of detajmium (4-3-diethylamino-2-hydroxypropyl-ajmaline), a sodium-channel-blocking drug with antiarrhythmic properties, in serum. A high-performance liquid chromatography (HPLC) method with solid-phase extraction and fluorimetric detection has been applied. Serum samples were diluted with phosphate buffer (pH 3.5) and the extraction of detajmium and ajmaline, which was used as an internal standard, was carried out with Oasis cartridges (Waters). The chromatographic separation was performed on a RP18 column. The limit of quantification for serum samples of detajmium was 1 ng/ml with good reproducibility (R.S.D. < 15%) and a linear response from 1 to 200 ng/ml. The described method is highly sensitive and specific for the determination of detajmium in serum of patients and volunteers.

ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1.

The present study was performed to investigate the ability of the multidrug resistance protein (MRPI) to transport different cationic substrates in comparison with MDR1-P-glycoprotein (MDR1). Transport studies were performed with isolated membrane vesicles from in vitro selected multidrug resistant cell lines overexpressing MDR1 (A2780AD) or MRP1 (GLC4/Adr) and a MRP1-transfected cell line (S1(MRP)). As substrates we used 3H-labelled derivatives of the hydrophilic monoquaternary cation N-(4',4'-azo-in-pentyl)-21-deoxy-ajmalinium (APDA), the basic drug vincristine and the more hydrophobic basic drug daunorubicin. All three are known MDR1-substrates. MRP1 did not mediate transport of these substrates per se. In the presence of reduced glutathione (GSH), there was an ATP-dependent uptake of vincristine and daunorubicin, but not of APDA, into GLC4/Adr and S1(MRP) membrane vesicles which could be inhibited by the MRP1-inhibitor MK571. ATP- and GSH-dependent transport of daunorubicin and vincristine into GLC4/Adr membrane vesicles was inhibited by the MRP1-specific monoclonal antibody QCRL-3. MRP1-mediated daunorubicin transport rates were dependent on the concentration of GSH and were maximal at concentrations > or = 10 mM. The apparent KM value for GSH was 2.7 mM. Transport of daunorubicin in the presence of 10 mM GSH was inhibited by MK571 with an IC50 of 0.4 microM. In conclusion, these results demonstrate that MRP1 transports vincristine and daunorubicin in an ATP- and GSH-dependent manner. APDA is not a substrate for MRP1.

Rate-dependent effects of detajmium and propafenone on ventricular conduction and refractoriness in isolated guinea pig hearts.

Detajmium (4--3'-diethylamino-2'-hydroxypropyl--ajmalin) is an Na(+)-channel-blocking drug with an extremely long recovery from use-dependent sodium channel block. The aim of the present study was to investigate the rate-dependent effects of detajmium on the intraventricular conduction of isolated, spontaneously beating, guinea pig hearts in comparison with the effects of propafenone. Detajmium (0.3 microM) and propafenone (0.3 microM) caused comparable prolongations of the intraventricular conduction time during sinus rhythm. The time to steady state of the rate-dependent QRS prolongation during rapid ventricular pacing follows an exponential function of the beat number after an abrupt change of frequency and is characterized by a drug-specific time constant. This time constant was significantly longer for detajmium (tau = 265 +/- 165 beats; mean +/- SEM; n = 6) than for propafenone (tau = 31 +/- 4 beats; n = 11; p < 0.01). In the presence of propafenone, QRS duration peaked initially before decreasing to a steady state. Detajmium, in contrast, progressively broadened the QRS complex. Both substances caused the greatest increase in the ventricular effective refractory period (V-ERP) when the number of conditioning stimuli (interstimulus interval, 120 ms) was in the range of the time constant. However, when the number of conditioning stimuli was further increased, the V-ERP for propafenone diminished progressively. In conclusion, propafenone displayed, in comparison with detajmium, only a transient rate-dependent effect on intraventricular conduction and V-ERP.

Fatal poisoning with detajmium: identification of detajmium and its metabolites and artifacts by gas chromatography-mass spectrometry and quantification by high-performance liquid chromatography.

After ingestion of an unknown dose of detajmium, a 14-year-old female collapsed with asystolia. Resuscitation efforts were not successful. A medicolegal autopsy was carried out, and blood, liver and gastric content were extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). After derivatization with acetic anhydride, detajmium and twelve of its derivatives and metabolites were identified. The main metabolic pathways include hydroxylation and subsequent O-methylation of the indol ring, and oxidation as well as reduction of the C-21 hydroxyl function. Cleavage of the N-alkyl side-chain is a further, possibly non-enzymatic degradation pathway. Artifact formation induced by acetylation included dehydratation of the hydroxyl function of C-21 and the N-alkyl side-chain. The detajmium concentration in blood of the decreased was determined by high-performance liquid chromatography with fluorimetric detection (12 micrograms/ml).

Electrophysiologic effects of detajmium on isolated dog cardiac ventricular and Purkinje fibers.

We studied the electrophysiologic effects of the antiarrhythmic compound detajmium (Tachmalcor) on isolated dog and rabbit cardiac preparations, applying the conventional intracellular microelectrode techniques. In dog ventricular muscle fibers (37 degrees C, stimulation frequency 1 Hz), 1 microM detajmium did not change resting potential (RP), action potential amplitude (APA), AP duration measured at 90% of repolarization (APD90), or effective refractory period (ERP) significantly, but reduced maximum rate of depolarization (Vmax) significantly from 236.7 +/- 28.9 to 177.3 +/- 22.5 V/s (n = 6, p < 0.01). In dog Purkinje fibers (37 degrees C, stimulation frequency 1 Hz), 1 microM detajmium significantly decreased APA from 111.1 +/- 12.3 to 100.0 +/- 2.5 mV (n = 8, p < 0.003), APD90 from 359.0 +/- 17.5 to 262.1 +/- 12.3 ms (n = 8, p < 0.001) and Vmax from 687.5 +/- 57.2 to 523.7 +/- 58.2 V/s (n = 8, p < 0.001) without changing maximal diastolic potential or ERP/APD ratio significantly. The effect of detajmium on Vmax in both dog ventricular muscle and Purkinje fibers was frequency dependent. Fractional Vmax block was 0.185 +/- 0.008 1/AP. The recovery kinetics of Vmax (offset kinetics) was extremely slow (time constant = 348.16 +/- 57.43 s) considerably slower than most of those of other antiarrhythmic drugs yet reported. Detajmium in concentration < 32 microM did not influence the beta-adrenoceptors or slow response APs in dog ventricular tissue significantly. On the basis of its electrophysiologic effects, detajmium, like prajmaline, encainide, or flecainide, can be best classified as a class I/C antiarrhythmic drug according to the Vaughan Williams' classification scheme.

[Effect of N-propylajmaline bromide on the normal and abnormal automatism of Purkinje fibers in the dog]. / Deistvie N-propilaimalinbromida na normal'nuiu i anomal'nuiu avtomatiiu volokon Purkin'e sobaki.

The effects of prajmalium bromide on normal and abnormal automaticity were studied in Purkinje fibers from dog hearts at late stages of experimental myocardial infarction. Prajmalium bromide (1.2 micromol/l) moderately reduced the frequency of normal and abnormal automaticity by 16 and 20% respectively. Prajmalium bromide induced early after-depolarizations, increased the frequency of spontaneous firing and decreased the maximum diastolic potential in the fibers that initially developed the automaticity of an intermediate type between normal and abnormal. It is suggested that antiarrhythmic effects of prajmalium bromide in the late stage of experimental myocardial infarction are not related to the influence of the drug on the abnormal automaticity in Purkinje fibers.

[The anti-arrhythmia action of combinations of N-propylajmaline bromide with anti-arrhythmia agents of different classes]. / Protivoaritmicheskoe deistvie kombinatsii N-propilaimalinbromida s protivoaritmicheskimi preparatami raznykh klassov.

In experiments on 68 dogs with ventricular arrhythmia at the late stage of experimental myocardial infarction caused by the coronary artery branch occlusion it was shown that combinations of N-propylaimaline bromide (IA class of antiarrhythmic agents) with trimecaine (IB class) or anapriline (II class) or phynoptine (IV class) induce a significant increase of the antiarrhythmic effect that is not observed at combination of N-propylaimaline with ethmosine (the both antiarrhythmic drugs belong to IA class). This potentiating effect is thought to be related to differences in the molecular mechanisms of action of antiarrhythmic drugs.

[The effect of the antiarrhythmic, prajmalium bitartrate, on human thrombocyte function]. / Einfluss des Antiarrhythmikums Prajmaliumbitartrate auf die humane Thrombozytenfunktion.

Studies of the in vitro effects of the antiarrhythmic drug prajmalium bitartrate (PBT, Neo-Gilurytmal) showed inhibitory effects on platelet aggregation and thromboxane production. PBT inhibited the primary and secondary phases of aggregation induced by adrenaline (epinephrine) or adenosine diphosphate (ADP). Platelet aggregation stimulated with collagen, platelet activating factor (PAF), and the thromboxane mimetic 9,11-azo-prostaglandin H2 (U 44064) was inhibited. The secondary phase of aggregation induced by ristocetin and aggregation caused by arachidonic acid (AA) were inhibited in samples from some donors (responders) but not in others (nonresponders). Platelet aggregation by the ionophore calcimycine (A 23187) was not inhibited, but small doses of calcimycine abolished the PBT-induced inhibition of aggregation caused by ADP. Thromboxane production of platelets with collagen of ADP was inhibited by higher concentrations of PBT, whereas AA-induced thromboxane synthesis remained unchanged. The observed antiplatelet activities of PBT are thought to result from calcium and sodium channel blocking properties of the drug.

[Modification of blood coagulation by the anti-arrhythmia drug prajmalium bitartrate in vivo]. / Beeinflussung der Blutgerinnung durch das Antiarrhythmikum Prajmaliumbitartrat in vivo.

We studied the effects of prajmaliumbitartrate (PBT, Neo-Gilurytmal, Giulini Pharma, Hannover, FRG), an antiarrhythmic drug on some parameters of blood coagulation in patients. PBT, 20 mg given three times a day, significantly prolonged template bleeding time and ex vivo thrombus formation time in a modified Chandler's loop. Ex vivo platelet aggregation using different agonists and tests of the plasmatic coagulation system remained unchanged.

Novel glucoalkaloids from Rauwolfia cell cultures--acetylrauglucine and related glucosides.

From cell suspension cultures of Rauwolfia serpentina grown in an optimized production medium for the glucoalkaloid raucaffricine, a novel glucoalkaloid was isolated and identified as 17-O-acetyl-21-O-beta-D-glucopyranosyl-ajmaline (acetylrauglucine). This alkaloid is formed in very small amounts (less than 5 x 10(-4)%). The biogenetically related N alpha-demethylated base (acetyl-nor-rauglucine) and the deacetyl product rauglucine have also been detected in culture extracts. In addition 21(R)-(beta-D-glucopyranosyl)-hydroxy-sarpagan-17-al has been isolated and identified as an artifact which originates from raucaffricine.

[Intrahepatic cholestasis and aplastic anemia following administration of prajmaline]. / Intrahepatische Cholestase und aplastische Anämie nach Prajmalin-Einnahme.

Intrahepatic cholestasis and aplastic anemia after N-propylajmaline. A 43 year old female patient taking oral contraceptives for more than five years received the antiarrhythmic drug N-propylajmaline for treatment of ventricular arrhythmia. After twelve days (total dosage 510 mg N-propyl-ajmaline) acute severe intrahepatic cholestasis and aplastic anemia developed. The erythropoeisis improved after three weeks of treatment with corticosteroids. However, despite treatment with phenobarbital the jaundice receded very slowly. Even after nine years of follow-up cholestatic enzymes are still significantly elevated although serum bilirubin levels are in the normal range. This case report demonstrates that antiarrhythmic drugs may induce nearly irreversible intrahepatic cholestasis and severe hematological disturbances.