Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds.

OBJECTIVES: Reactivation of inhibited acetylcholinesterase (AChE) with oximes is a causal therapy of intoxication with organophosphorus compounds (OPs). Maximal oxime effects are expected when effective doses are administered as soon as possible and as long as reactivation can be anticipated. An obidoxime plasma level in the range of 10-20 microM was estimated as appropriate. The achievement of this target was assessed in 34 severely OP-poisoned patients. METHODS: After admission to the intensive care unit (ICU) the obidoxime regimen (250 mg i.v. as bolus, followed by 750 mg/24h) was started and maintained as long as reactivation was possible. Plasma concentrations of obidoxime were determined by HPLC. RESULTS: A total amount of 2269+/-1726 mg obidoxime was infused over 65 h+/-55 h resulting in a steady state plasma concentration of 14.5+/-7.3 microM. Obidoxime was eliminated with t(1/2(1)) 2.2 and t(1/2(2)) 14 h. The volumes of distribution amounted to 0.32+/-0.1L/kg (V((1))) and 0.28+/-0.12 (V((2)))L/kg. Postmortem examination of tissue in one patient showed obidoxime accumulation in cartilage, kidney and liver and pointed to brain concentrations similar to plasma concentration. CONCLUSIONS: Using the suggested obidoxime regimen, the targeted plasma concentration could be achieved. Obidoxime was eliminated biphasically and was well tolerated. This result allows the recommendation of using this definite regimen for adults also in case of mass casualties.

Cerebellar effects after consumption of edible morels (Morchella conica, Morchella esculenta).

Morchella esculenta and Morchella conica are well known edible morels, which seldom induce clinical symptoms. We report six persons who developed cerebellar effects 6-12 hours after consumption of these mushrooms. The symptoms were self-limited and disappeared after one day.

Withdrawal from high-dose tranylcypromine.

A 34-year-old man with a history of multiple substance abuse (now abstinent for six years) became addicted to tranylcypromine, consuming up to 240 mg/day. After discontinuing the drug, he developed thrombocytopenia (52,000/ul) and delirium; there were no other anticholinergic signs. The delirium was unresponsive to haloperidol and diazepam. Intravenous administration of physostigmine (2 mg) on hospital day 6 resulted in prompt, but temporary, clearing of the delirium. Following a recurrence of the delirium after 30 minutes, he was started on an intravenous infusion of physostigmine (2 mg/hr) with good results. Physostigmine administration did not produce any cholinergic signs. By hospital day 8, he did not require any more physostigmine. Thrombocytopenia resolved on hospital day 9 without therapeutic intervention. On hospital day 10, the patient was asymptomatic and left the hospital on his own recognizance.

Strong extinction of a laser beam by a single molecule.

We present an experiment where a single molecule strongly affects the amplitude and phase of a laser field emerging from a subwavelength aperture. We achieve a visibility of -6% in direct and +10% in cross-polarized detection schemes. Our analysis shows that a close to full extinction should be possible using near-field excitation.

Realization of two Fourier-limited solid-state single-photon sources.

We demonstrate two solid-state sources of indistinguishable single photons. High resolution laser spectroscopy and optical microscopy were combined at T = 1.4 K to identify individual molecules in two independent microscopes. The Stark effect was exploited to shift the transition frequency of a given molecule and thus obtain single photon sources with perfect spectral overlap. Our experimental arrangement sets the ground for the realization of various quantum interference and information processing experiments.

Cause and motivation in cases of non-fatal drug overdoses in opiate addicts.

INTRODUCTION: Drug overdose (OD) is a frequent incident among opiate addicts. Survivors of ODs are at risk for additional and eventually fatal ODs. ODs may be classified as accidental (aOD) or deliberate (dOD). Investigations into the connection between OD and suicide attempts have led to insconsistent results. PURPOSE: (1) to determine how many non-fatal ODs were dODs and how many were aODs; (2) to determine how many cases of dODs were motivated by explicit or by ambivalent suicidal intentions; (3) to determine how many cases of aODs had causes that might respond to preventative measures; (4) to compare the addiction histories of dODs and aODs; (5) to compare the drugs causing the ODs; and (6) to compare the severity of the ODs in both groups. METHODS: Prospective study utilizing a standardized questionnaire to evaluate opiate-addicted patients admitted to our treatment unit for OD. All cases underwent standardized drug testing to identify drug use patterns. RESULTS: Seventy-four cases of OD underwent standardized interviews after awakening. Forty-three percent of the cases were dOD. Cases of dOD had significantly more OA in substitution programs, more previous ODs, and more often consumed methadone and cocaine. Among dODs, 22.5% had suicidal intention and 9.6% were ambivalent about committing suicide; background motivations were most often conflicts with spouses. Fifty-seven percent of the cases were aOD. Cases of aODs had significantly more potential lethal intoxications and had heroin detected more frequently. aODs happened with unexpected pure heroin (46%), in combination with alcohol (36%), as relapse after abstinence (40%) or after institutionalized treatment (19%). This group should be accessible for targeted education.

[Lethal sepsis and multi-organ failure after accidental injection of urine in a drug addict]. / Letal verlaufende Sepsis und Multiorganversagen nach akzidenteller Urin-Injektion bei einer drogenabhängigen Patientin.

HISTORY AND ADMISSION FINDINGS: A 33-year-old drug addict injected accidentally into the femoral vein 5 ml urine (kept in the refrigerator for 1 week for unanticipated drug-screening) which she mis-took for methadone. Soon after injection she was found confused with shivering. On admission she had a blood pressure of 90/60 mmHg, heart rate of 120/min and fever of 40 degrees C. INVESTIGATIONS: Laboratory tests showed consumption coagulopathy (DIC) as well as leukopenia. Blood cultures were positive for E.coli and Klebsiella pneumoniae. Infection with hepatitis C and HIV was excluded. Echocardiography revealed good ventricular function without signs of endocarditis. DIAGNOSIS AND TREATMENT: The patient developed a fulminant Gram-negative sepsis with DIC and multi-organ failure. She was intubated and mechanically ventilated. Acute renal failure required haemodialysis and ultrafiltration. Septic shock was treated with fluids and high doses of vasopressors. DIC was effectively treated with tranexamic acid, PPSB complex and fresh frozen plasma. The further course was complicated by septic emboli to the myocardium, liver, kidney and spleen. Laparotomy because of an acute abdomen revealed perforation of terminal ileum (mainly due to ischemic bowel lesions) requiring partial resection. The patient was weaned on day 18 with an initially uneventful further course. On day 25 the patient had a cardiac arrest with at first successful resuscitation but electromechanical dissociation proved fatal on day 26. CONCLUSION: Although serious systemic inflammation associated with i. v.-injection in drug addicts is rare, one has to be aware of severe complications with septic emboli. To our knowledge it is the first published case of i. v.-injection of urine followed by sepsis and multi-organ failure. Aggressive interdisciplinary treatment is required.

Opiate detoxification under anesthesia: no apparent benefit but suppression of thyroid hormones and risk of pulmonary and renal failure.

INTRODUCTION: The new technique for opiate detoxification using anesthesia and high, repetitive doses of opiate-antagonists claims to detoxify addicts without withdrawal symptoms within 24-48 hours. We studied the method with 12 opiate addicts (5 L-polamidone, 4 dihydrocodeine, 3 heroin), using general anesthesia and the antagonists naloxone 0.5 mg/kg and naltrexone > 150 mg. Objective and subjective withdrawal symptoms were measured until urine was free of drugs and patients had no withdrawal symptoms. Thyroid hormones were measured before, during, and after the anesthesia period. RESULTS: All patients had moderate to severe opiate withdrawal symptoms. No detoxification was finished within 48 hours. The dihydrocodeine subjects were compared with conventionally detoxified controls; no difference was seen. The method suppressed thyroid hormones TT3, TT4, and TSH. The study was terminated because of side effects: 1 pulmonary failure and 2 renal failures. All patients survived without sequelae. CONCLUSION: There is no obvious benefit from this method, whereas the risks are high.

[Radiotherapy in surgical and nonsurgical patients. Therapy expectations, quality of life and physician assessment]. / Strahlentherapie bei chirurgischen und nichtchirurgischen Patienten. Therapieerwartungen, Lebensqualität und Arzteinschätzungen.

The present study investigates patients' expectations toward radiotherapy and their associations to quality of life and physician judgements. Fifty-five patients with tumors of different sites (30 with previous tumor-related surgery, 25 without surgery) admitted to the department of radiotherapy filled out a standardized questionnaire (EORTC QLQ-C30, PLC by Siegrist et al., therapy-related expectations and success) before and after inpatient radiotherapy. The corresponding physician ratings were collected. Fifty-eight percent of the patients expected the therapeutic goal "healing", whereas from the physician's standpoint this was realistic in only 7% of cases. The specific radiotherapy-related expectations "tumor control" and "pain relief" reached almost the same levels in patients and physician (71% vs 71% and 40% vs 44%). Patients with healing expectancy reported higher quality of life at the beginning of the therapy (53.4% vs 39.9%); patients expecting pain relief reported lower quality of life (37.1% vs 54.5%). Surgical patients who had been operated on within the past year (n = 18) showed a particularly high healing expectancy (83%), whereas patients whose operation dated back more than 1 year focused on pain relief as therapeutic goal (83%). The surgeon, as the primary contact person for patients, can influence patients' therapy-related expectations. In explaining the overall therapeutic strategy, surgeons should also mention the scope and limits of adjuvant therapies.

Intrathecal baclofen in tetanus: four cases and a review of reported cases.

OBJECTIVE: Spasms in patients with generalized tetanus can be suppressed by a spinal intrathecal infusion of baclofen. We report on four patients and review reported cases treated by this method elsewhere. DESIGN: Intrathecal baclofen infusion was started with a bolus dose (300-500 micrograms) and continued at a steady rate of 500-1000 micrograms/day. The dose was increased in daily steps as needed. RESULTS: Doses of baclofen of 500, 1000, or 2000 micrograms/day were effective in three patients, while 1500 micrograms/day was insufficient in the fourth. Bradycardia and hypotonia occurred in one patient at a dose of 2000 micrograms/day but resolved after the dose was reduced to 1500 micrograms/day. Another patient developed hypotonia when a bolus of 500 micrograms was given after a steady infusion of 1500 micrograms/day. Voluntary movements were preserved in one and returned in two patients when sedation, induced by initial diazepam infusions, receded. The fourth patient needed diazepam during most of the treatment with intrathecal baclofen and required mechanical ventilation while being treated with baclofen. CONCLUSIONS: A catheter position higher than T11 would possibly have yielded better results. It may be necessary to adapt the dose during the course of the illness. The preservation of respiratory drive and voluntary movements is the main advantage of treating tetanus with intrathecal baclofen. Additionally it helps to reduce sympathetic hyperactivity. Mortality may thereby be reduced.

Cholinesterase status, pharmacokinetics and laboratory findings during obidoxime therapy in organophosphate poisoned patients.

1 The effectiveness of oxime therapy in organophosphate poisoning is still a matter of debate. It appears, however, that the often cited ineffectiveness of oximes may be due to inappropriate dosing. By virtue of in vitro findings and theoretical considerations we concluded in the preceding paper that oximes should preferably be administered by continuous infusion following an initial bolus dose for as long as reactivation of inhibited acetylcholinesterase (AChE) can be expected. This conclusion has called for a clinical trial to evaluate such oxime therapy on the basis of objective parameters. 2 Before transfer to the intensive care unit (ICU), 5 patients received primary care by an emergency physician. In the ICU, atropine sulphate was administered i.v. upon demand according to the endpoints: no bronchorrhoea, dry mucous membranes, no axillary sweating, heart rate of about 100/min. Obidoxime (Toxogonin) was given as an i.v. bolus (250 mg) followed by continuous infusion of 750 mg/24 h. 3 Intoxication and therapy were monitored by determining erythrocyte AChE (eryAChE) activity, reactivatability of the patient's eryAChE ex vivo, plasma cholinesterase activity, the presence of AChE inhibiting compounds, as well as the concentrations of obidoxime and atropine in plasma. 4 Obidoxime was effective in life-threatening parathion poisoning, in particular when the dose absorbed was comparably low. In mega-dose poisoning, net reactivation was not achieved until several days after ingestion, when the concentration of active poison in plasma had declined. Reactivatability in vivo lasted for a longer period than expected from in vitro experiments. 5 Obidoxime was quite ineffective in oxydemetonmethyl poisoning, when the time elapsed between ingestion and oxime therapy was longer than 1 day. When obidoxime was administered shortly after ingestion (1 h) reactivation was nearly complete. 6 Obidoxime levels of 10-20 microM were achieved by our regimen, and atropine could rapidly be reduced to approx. 20 microM, as attained by continuous infusion of 1 mg atropine sulphate/h. Maintenance of the desired plasma levels was not critical even when renal function deteriorated. 7 Signs of transiently impaired liver function were observed in patients who showed transient multiorgan failure. In the present stage of knowledge, we feel it advisable to keep the plasma concentration of obidoxime at 10-20 microM, although the full reactivating potential of obidoxime will not then be exploited. Still, the reactivation rate, with an apparent half-time of some 3 min, is twice that estimated for a tenfold higher pralidoxime concentration.

[Telethermographic studies on the effect of immunoglobulins (Beriglobin) on heat radiation behavior in radiodermatitis]. / Telethermographische Untersuchungen zur Wirkung von Immunglobulinen (Beriglobin) auf das Wärmeabstrahlungsverhalten bei der Strahlendermatitis.

BACKGROUND: Immunoglobulines are supposed to have a soothing effect on the degree of dermatitides and mucositides caused by irradiation. Research so far has been based on empiric information or reports of case studies mostly basing on subjective criteria. This study reports on objective thermographic measuring of heat radiation of dermatitides developing in the course of radiotherapy in case of female patients receiving postoperative radiotherapy after breast preserving operation on mamma carcinoma. Idea behind this is that immunglobulines affect inflammations of skin induced by irradiation, then also one of theses parameters, in this case heat, would be subject to change. PATIENTS AND METHOD: Sixteen patients received 10 ml Beriglobin before first and 5 ml after 5th and 10th radiation (corresponds to 0 Gy, 10 Gy and 20 Gy) as intragluteal injection. Before starting with radiation as well as after 10 Gy respectively applied, upper bodies of patients were examined thermographically until final dose of 50 Gy was reached. Here temperature progress on upper body halves exposed to irradiation was compared with the untreated halves as well as with upper bodies of control group consisting of 20 patients who had received no immunoglobuline injections. RESULTS: Patients who received immunoglobuline injections showed no differences in their skin temperature progress in comparison with the control group (Table 1, Figure 1). Skin temperature at the beginning as well as temperature progress during treatment and temperature at the end of treatment were identical in both groups. Also the relative temperature increase (temperature of body half subject to irradiation minus temperature of the other body half) was identical in both therapy groups (Table 2, Figure 2). CONCLUSION: Immunoglobulines (Beriglobin) do not influence the course of thermal radiation due to dermatitis developing during a series of irradiation treatments. This results in the conclusion, that immunoglobulines do not have any influence in the vasodilative part of dermatitis and vasodilative redness respectively.

[Value of radiotherapy in disseminated high-grade non-Hodgkin's lymphoma]. / Stellenwert der Strahlentherapie beim disseminierten hochmalignen Non-Hodgkin-Lymphom.

BACKGROUND: Radiotherapy is part of the treatment protocols in localized low-grade lymphomas as well as localized high-grade lymphomas adjunct to polychemotherapy. Integration of radiotherapy into the treatment of disseminated high-grade lymphomas is controversial. PATIENTS AND METHOD: The current literature and our own experience with radiotherapy as part of the treatment of disseminated high-grade lymphomas will be discussed. RESULTS: Retrospective analysis of large clinical trials suggest the value of radiotherapy in the treatment of disseminated high-grade lymphomas. Relapse occurs more frequently in non-irradiated regions than in fields of prior radiotherapy. Integration of radiotherapy into treatment protocols seems to be beneficial in patients with bulky disease. A dose/response relationship has been described. The few randomized trials, however, could not clearly demonstrate an advantage of radiotherapy adjuvant to chemotherapy in disseminated lymphomas. A possible advantage can be seen in patients who did not receive more than 4 cycles of polychemotherapy. CONCLUSION: Although the value of radiotherapy adjunct to polychemotherapy in disseminated high-grade lymphomas has not been proven in randomized studies retrospective analysis suggest an advantage. A large randomized study should clarify the role of radiotherapy.

Paclitaxel and simultaneous radiation in the treatment of stage IIIA/B non-small cell lung cancer.

In a clinical phase II trial, escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) were given with concurrent radiation to patients with stage IIIA/B non-small cell lung cancer. Radiotherapy was given in daily doses of 2 Gy, 5 days a week, in weeks 1 through 3 and 6 through 8. Paclitaxel was given on day 1 of weeks 1 through 3 and 6 through 8, at a starting dose level of 50 mg/m2. Subsequent paclitaxel dose levels were 60, 72, 86, and 103 mg/m2. Three to six patients were included at each dose level until intolerable toxicity (World Health Organization grade 3 or 4 leukopenia) occurred in three of six patients. To date, 27 patients have entered the protocol. Hematologic toxicity was mild with no severe myelosuppression up to the 86-mg/m2 dose level. At paclitaxel 103 mg/m2, four of six patients developed grade 3 or 4 leukopenia, and dose escalation was stopped. The maximum tolerated dose was thus determined to be 86 mg/m2. The main clinical toxicity was the occurrence of pulmonary infections (seven patients), one of whom had Pneumocystis carinii infection; the six others had interstitial infections with no pathogen isolated. Mild to moderate esophagitis was seen in five patients. Thus far, of 24 patients evaluable for response, 18 showed decreased tumor size. Four patients achieved major responses (near-complete disappearance of radiologic tumor signs), 11 patients achieved partial remission, and three patients had a minor response. The overall response rate was 75%. In summary, the maximum tolerated dose of paclitaxel in this study has been determined to be 86 mg/m2 weekly. Pulmonary infections represent the major clinical toxicity, and the high response rate merits further clinical evaluation of this regimen.

[Do an operation and radiotherapy in the breast-preserving therapy of breast carcinoma modify the meaningfulness of subsequent mammographies?]. / Beeinflussen Operation und Strahlentherapie bei der brusterhaltenden Therapie des Mammakarzinoms die Aussagekraft nachfolgender Mammographien?

PURPOSE: Today, whenever possible, mamma carcinoma is operated on by preserving as much breast as possible, and is followed by postoperative radiotherapy of the thoracic wall. This form of treatment can lead to alterations of the skin and parenchyma, visible in mammogram, which may make evaluation of these mammographies difficult with regard to recidive. This paper presented describes nature and frequency of changes of treated breast caused by therapy. PATIENTS AND METHODS: Three hundred and eighty mammographies of 50 female patients were evaluated on alterations of skin and parenchyma caused by combined therapy. Inclusive criteria were among others 2 mammographies in the 1st year after therapy, no advanced or parallel chemotherapy and a follow-up time of at least 5 years. RESULTS: Thirty-two patients (64%) showed no fibrotic changes of breast, 5 patients (10%) initially developed denseness of parenchyma which then, however, reverted back to a completely normal state. Only 13 patients (26%) had irreversible fibrotic alterations of parenchyma, only 3 (6%) of which showed extensive fibrosis which definitely might make recidive diagnostic difficult. CONCLUSION: Major changes of parenchyma caused by preparatory treatment which can be registered by mammography are relatively rare. For this reason, mammography maintains its unchanged high position within post-tumorous treatment, especially as it even today is the only diagnostic method to evidence microcalcifications suspect of being malignant.

Severe lymphocytopenia and interstitial pneumonia in patients treated with paclitaxel and simultaneous radiotherapy for non-small-cell lung cancer.

PURPOSE: In a phase II trial with paclitaxel and simultaneous radiotherapy in non-small-cell lung cancer (NSCLC) patients, an unexpected high incidence of interstitial pneumonias was observed. The type of immunodeficiency associated with this treatment approach is characterized. PATIENTS AND METHODS: Fifteen patients with inoperable stage IIIA/B NSCLC were treated with paclitaxel as a 3-hour infusion on day 1 in weeks 1 to 3 and 6 to 8 at dose levels between 50 mg/m2 and 86 mg/m2 and with simultaneous radiotherapy in daily doses of 2 Gy, 5 days per week, in weeks 1 to 3 and 6 to 8 up to a total dose of 56 Gy. Hematologic parameters and lymphocyte subsets were monitored. RESULTS: Fourteen patients are assessable for response. The overall response rate was 78%, with four major responses, six partial remissions, and four minor responses. The major toxic effect observed was a moderate to severe protracted lymphocytopenia (380 +/- 310/microL) in all patients. Seven patients developed moderate to severe interstitial pneumonia; one had an additional herpes zoster infection, while an eighth patient had a cytomegalovirus infection. During treatment, all lymphocyte subsets were reduced, as follows (n = 9, mean +/- SD): CD4+ T cells (100 +/- 90/microL), CD8+ T cells (130 +/- 160/microL), natural killer (NK) cells (70 +/- 80/microL), and B cells (20 +/- 10/microL). Thus, the most pronounced toxicity was seen in CD4+ T and B cells. There was no recovery of lymphocyte subsets during a 3-month follow-up period. CONCLUSION: Paclitaxel with simultaneous radiation induces lymphocytopenia and promotes opportunistic infections. Long-term antibiotic and antimycotic prophylaxis is recommended. Whether the lymphocytopenia is an additive effect of paclitaxel and radiation or whether it can be induced by low-dose weekly paclitaxel alone remains to be determined.