Use of hecate-chorionic gonadotropin beta conjugate in therapy of lutenizing hormone receptor expressing gonadal somatic cell tumors.

Improvement of cancer treatment is a major challenge of medical research. Despite the immense efforts made in the improvement of diagnosis and treatment, cancer remains a major concern and cause of morbidity and mortality. Most of the modern anti-neoplastic therapies have severe side effects, and tumor cells often develop drug resistance. There is promise in the new generation of treatments (gene therapy, immunotherapy, vaccines, etc.) that are under development, but the efficacies and side effects of such therapies have so far been disappointing. Receptor-based therapies are not new, but many normal cells also present the same receptors reducing the specificity of such approaches. Several lytic peptides have been investigated because of they appear to kill cancer cells due to changes of their membrane potential. Thus, linking receptor-specific ligands to lytic peptides is expected to augment the specificity of targeting and decrease the toxicity of lytic peptides on normal cells. One such polypeptide is hecate (an analogue to the bee venom main component, melittin) that preferentially kills cancer cells at low doses. When this peptide is fused with the 81-95 amino acid fragment of chorionic gonadotropin-beta (CGbeta) subunit (hecate-CGbeta), it targets cells expressing luteinizing hormone receptor (LHR), even at very low doses, or when LHR is expressed at low level. Our recent data showed that this peptide conjugate is efficient in destroying LHR-positive cells in xenografts and more importantly in transgenic mouse models developing LHR-positive somatic cell tumors in gonads. The mechanism of action of hecate-CGbeta after binding to LHR is destruction of cell membranes resulting in rapid cell death by necrosis with minimal side effects. This review summarizes our findings on the action of this novel peptide and considers the future potential of this family of targeting peptides in the treatment of neoplasias.

Changes in heart rate variability in elderly patients undergoing major noncardiac surgery under spinal or general anesthesia.

BACKGROUND AND OBJECTIVES: Heart rate variability (HRV), widely used as an indicator of activity of the autonomic nervous system, has been reported to decrease during and after both spinal and general anesthesia in patients without cardiovascular disease. We evaluated the changes in HRV bands in 40 patients with a high risk of ischemic heart disease. METHODS: The patients were randomly assigned to receive either spinal (SA) or general anesthesia (GA) for elective total hip arthroplasty or peripheral vascular surgery. Anesthetic techniques and perioperative fluid administration were standardized. Holter monitoring was started preoperatively and continued until the third postoperative day. Three HRV frequency bands were analyzed. RESULTS: A significant decrease was seen in very low frequency (VLF) and low frequency (LF) bands during GA but not during SA. Also the LF/high frequency (HF) ratio decreased during GA but not during SA. A decrease in all HRV frequency bands was seen after both types of anesthesia. None of the frequency bands returned back to the preoperative level during the 3-day trial. Postoperatively circadian variation was found only in the VLF band after SA. CONCLUSIONS: The sympathovagal balance (LF/HF) is more stable during SA than during GA in patients with a high risk of ischemic heart disease. The postoperative decrease in HRV bands, however, is independent of the anesthetic technique.

Factors associated with post-operative myocardial ischaemia in elderly patients undergoing major non-cardiac surgery.

Forty patients (> 65 years) undergoing hip arthroplasty or peripheral vascular surgery both associated with high risk for post-operative myocardial ischaemia were randomized to receive either spinal or general anaesthesia. Ambulatory ECG recording (Holter) until the third post-operative morning, a daily 12-lead ECG and serum creatine kinase and troponine concentraItions were obtained. The number of ischaemic episodes, total duration of ischaemia and ischaemic minutes per hour were noted for each patient peri-operatively. Sixteen of the patients (40%) had post-operative myocardial ischaemia. An intra-operative increase in the plasma concentration of norepinephrine but not epinephrine was detected in the patients who later developed post-operative myocardial ischaemia. The increase in plasma norepinIephrine concentrations correlated with the decrease in core temperature. The type of anaesthesia had no effect on the incidence of myocardial ischaemia during or after surgery. Our results suggests that intra-operatively decreased core temperature and the increase in plasma concentration of norepinephrine probably caused peripheral vasoconstriction leading to latent cardiac dysfunction. These events should be avoided in the patients at risk of post-operative cardiac ischaemia.

Efficacy and side effects of tramadol versus oxycodone for patient-controlled analgesia after maxillofacial surgery.

Tramadol, a weak opioid mu-receptor agonist, may have a favourable potency and side effect profile for intravenous patient-controlled analgesia (PCA). In a prospective, double-blind, randomized study involving 54 patients, tramadol was compared with oxycodone in PCA after maxillofacial surgery. All the patients were given diclofenac sodium 1 mg kg-1 intramuscularly and dexamethasone 8 mg twice a day. Post-operatively patients received tramadol or oxycodone by a PCA apparatus (lockout 5 min, tramadol 0.3 mg kg-1 bolus, oxycodone 0.03 mg kg-1 bolus). During the immediate recovery period, opioid was administered i.v. in a double-blind fashion, either tramadol 10 mg or oxycodone 1 mg increments until the pain control was judged to be satisfactory by the patient. Pain was assessed at rest and during activity (mouth opening) before and after loading, at 2 h after commencing the PCA, as well as at 21.00 and at 09.00 hours on the following morning. Side effects were recorded. The potency ratio of tramadol to oxycodone was found to be approximately 8:1. There was no significant difference between the groups in the VAS scores for pain. No respiratory depression was identified. Tramadol was found to provide adequate analgesia after maxillofacial surgery without risk of respiratory depression. However, the incidence of nausea was slightly greater in the tramadol group than in the oxycodone group (44% vs. 28%, NS).

Comparison of intrathecal morphine and continuous femoral 3-in-1 block for pain after major knee surgery under spinal anaesthesia.

Major knee surgery is associated with moderate or severe post-operative pain. Intrathecal morphine and continuous femoral 3-in-1 block were compared prospectively in 40 patients for pain after major knee surgery under spinal anaesthesia, with 4 mL isobaric 0.5% bupivacaine. In a random order, 20 patients received preservative free morphine 0.3 mg mixed with spinal bupivacaine. In 20 patients, following spinal anaesthesia with only bupivacaine, femoral 3-in-1 block was performed post-operatively with 0.5% bupivacaine 2 mg kg-1. The block was continued via a catheter with 0.25% bupivacaine 0.1 mL h-1 kg-1 until the next morning (24 h after induction of spinal anaesthesia). Intramuscular oxycodone was given as a rescue analgesic in all patients. Two patients from the femoral group were excluded due to technical failure. Three patients in the morphine group and one patient in the femoral group did not need any additional oxycodone. In the morphine group on average 2.8 (range 0-7) and in the femoral group 3.2 (0-5) additional doses of oxycodone were needed during the 24 h observation period. The mean pain scores were significantly lower in the morphine group at 9 and 12 h into the 24-h trial. Itching was seen only in the morphine group (40% of the patients). Other side effects were similar in the two groups. All patients were satisfied with their pain therapy. Both intrathecal morphine and femoral 3-in-1 block alone were insufficient for the treatment of severe pain after major knee surgery.

Comparison of respiratory effects of tramadol and pethidine.

Tramadol is a centrally acting opioid with a low affinity for mu-opioid receptors, which has been claimed not to depress respiration as do the classic opioids. The respiratory effects of intravenous (i.v.) pethidine (0.6 mg kg-1) and tramadol (0.6 mg kg-1) were compared in 36 ASA Grade I-II patients in a placebo-controlled double-blind study. After induction of anaesthesia with propofol followed by suxamethonium-facilitated endotracheal intubation, the patients spontaneously breathed halothane in 70% nitrous oxide and oxygen via a non-rebreathing valve. Inspiratory and expiratory oxygen, and end-tidal carbon dioxide concentrations (PETCO2), tidal volume (VT), minute volume of ventilation (MV) and respiratory rate were monitored by a side-stream spirometry at an end-tidal halothane of 0.3%. The recordings were collected before surgery. Pethidine caused significant respiratory depression seen as an increase in fractional inspiratory-expiratory oxygen difference and PETCO2 and as a decrease in MV and respiratory rate. However, the effects of tramadol were similar to those of a placebo. Tidal volume was not affected by any study drug. In conclusion, tramadol 0.6 mg kg-1 was shown not to be associated with respiratory depression, unlike equipotent dose of pethidine in this setting.

Comparison of respiratory effects of tramadol and oxycodone.

STUDY OBJECTIVE: To compare the respiratory effects of tramadol and oxycodone. DESIGN: Placebo-controlled, double-blind randomized study. SETTING: IV Department of Surgery, Helsinki University Central Hospital. PATIENTS: 36 ASA physical status I and II patients undergoing minor surgery with general anesthesia. INTERVENTIONS: The respiratory effects of intravenous (i.v.) tramadol 0.6 mg/kg and oxycodone 0.04 mg/kg were compared after induction of anesthesia with propofol and succinylcholine-facilitated endotracheal intubation. Patients spontaneously breathed halothane in 70% nitrous oxide and oxygen via a nonrebreathing valve. The trial drugs or placebo were given after recovery from neuromuscular block. MEASUREMENTS AND MAIN RESULTS: Inspiratory and expiratory oxygen and end-tidal carbon dioxide concentrations (ETCO2), tidal volume (VT) minute volume of ventilation (VE), and respiratory rate (RR) were recorded by side-stream spirometry with end-tidal halothane of 0.3% for 30 minutes before surgery. Oxycodone caused a significant respiratory depression seen as an increase in the inspiratory-expiratory oxygen difference and ETCO2 and as a decrease in VE and RR. On the contrary, the effect of tramadol were similar to those of placebo. VT was not affected by any study drug. CONCLUSION: Tramadol was not associated with respiratory depression in the present setting.

Comparison of metoclopramide and ondansetron for the prevention of nausea and vomiting after intrathecal morphine.

Nausea and vomiting remain unpleasant side effects of intrathecal (i.t.) morphine and of the numerous therapies tried, only prophylactic intravenous (i.v.) metoclopramide has been reported to be promising. Seventy-three patients, scheduled for orthopaedic prosthesis surgery of the hip or knee were studied. They received 4 mL of plain bupivacaine and 0.3 mg of preservative-free morphine i.t. for anaesthesia. The test drugs given in a double-blind and randomized fashion, were either metoclopramide 20 mg, three times, at 6 h intervals (23 patients), ondansetron, 8 mg, twice, at 12 h intervals (25 patients), or 0.9% saline three times, at 6 h intervals (25 patients). The occurrence of nausea, vomiting and pain was followed for 24 h. The incidences of nausea and vomiting were 60% (15/25) and 56% (14/25) in the saline group, 52% (12/23) and 48% (11/23) in the metoclopramide group, and 52% (13/25) and 40% (10/25) in the ondansetron group. Incidences of severe vomiting were 24, 35 and 12% respectively. Eight patients in the saline group, seven in the metoclopramide and 10 in the ondansetron group did not need additional opioids for post-operative pain relief. We conclude that, metoclopramide and ondansetron were not better than saline in the prevention of post-operative emesis induced by intrathecal morphine.

Home-readiness after spinal anaesthesia with small doses of hyperbaric 0.5% bupivacaine.

Fifty-four patients were studied prospectively to evaluate home-readiness after a small dose (1 or 2 ml) of subarachnoid hyperbaric 0.5% bupivacaine. The block regressed significantly earlier in the 1 ml group than in the 2 ml group (p < 0.05). The patients were also able to walk significantly earlier in the 1 ml group (median 161 min and 231 min in the 1 ml and 2 ml groups, respectively) (p < 0.05). However, there were no significant differences between the groups in time of ability to void. We conclude that adequate surgical anaesthesia can be achieved with small doses of hyperbaric bupivacaine used for spinal anaesthesia. Although the sensory and motor block after 1 or 2 ml hyperbaric bupivacaine recovered within a reasonable time for day-case surgery, in some patients recovery of the ability to void was delayed to an undesirable extent.

Intravenous ketorolac vs diclofenac for analgesia after maxillofacial surgery.

PURPOSE: To compare the efficacy of the non-steroidal antiinflammatory drugs (NSAID), ketorolac and diclofenac in prevention of pain after maxillofacial surgery. METHODS: Sixty ASA I-II patients (30 in each group) received randomly, and double blindly either ketorolac 0.4 mg.kg-1 or diclofenac 1.0 mg.kg-1 iv after general anaesthesia induction, before surgical incision. In the ketorolac group, the same dose was repeated iv three times at six hour intervals. The diclofenac group patients received diclofenac 1.0 mg.kg-1 after 12 hr iv. Rescue analgesic medication consisting of oxycodone 0.03 mg.kg-1 iv, was administered by a patient controlled analgesia apparatus. RESULTS: Two patients in the ketorolac and three patients in the diclofenac group did not need oxycodone during the study period. On average, 12 and 11 doses of oxycodone were needed in the ketorolac and the diclofenac groups, respectively (NS). Side-effects were similar in both groups. All patients except one were satisfied with the pain therapy. CONCLUSION: Parenteral ketorolac (0.4 mg.kg-1 four times in 24 hr) and diclofenac (1 mg.kg-1 twice in 24 hr) were similar, but insufficient alone, for analgesia after maxillofacial surgery.

Transient radicular irritation after bupivacaine spinal anesthesia.

BACKGROUND AND OBJECTIVES: Transient radicular irritation (TRI) has been described to occur following spinal anesthesia with hyperbaric 5% lidocaine. The authors recently used only isobaric or hyperbaric 0.5% bupivacaine for spinal anesthesia. All patients who had spinal anesthesia for various kinds of surgery were interviewed after the operation to discover the possibility of TRI following bupivacaine spinal anesthesia. METHODS: The study included 226 patients. Isobaric 0.5% bupivacaine was given to 116 patients and hyperbaric 0.5% bupivacaine to 110. The local anesthetic was chosen according to the expected duration of surgery. All patients were interviewed by an anesthesiologist 24 hours after spinal anesthesia, and after 1 week the patients were asked to return a written questionnaire. If pain not associated with operation was noted, the patients were interviewed by phone. RESULTS: One 48-year-old woman reported TRI after spinal anesthesia (saddle block) with hyperbaric 0.5% bupivacaine in the 24-hour interview. Her spinal anesthetic was performed in a sitting position and the anal surgery in a lithotomy position. In the 1-week questionnaire (response rate 92%), none of the other patients fulfilled our criteria for TRI. CONCLUSIONS: In spite of one case of TRI, the authors consider bupivacaine to be safe for spinal anesthesia. The association of the sitting and lithotomy positions to the restricted distribution of hyperbaric solution and consequent TRI warrants further studies.

Premedication with promethazine and transdermal scopolamine reduces the incidence of nausea and vomiting after intrathecal morphine.

Intrathecal morphine provides effective postoperative pain relief in major orthopaedic surgery. In use, however, is associated with unpleasant side effects like nausea and vomiting. The effect of different premedications on postoperative emetic sequelae induced by intrathecal morphine was studied in a prospective, double blind study. Sixty patients scheduled for arthroplasty surgery of the lower extremity were anaesthetized with spinal anaesthesia with a combination of isobaric bupivacaine 20 mg and morphine 0.3 mg. For premedication the patients were randomised to three groups of equal size. They received either oral diazepam (5-15 mg), oral promethazine (10 mg) or a combination of promethazine and transdermal scopolamine (1.5 mg). Sixty percent of the patients with both promethazine and transdermal scopolamine were totally free from postoperative nausea and vomiting (PONV) symptoms compared to those premedicated with diazepam (40%) or promethazine alone (30%). Promethazine together with transdermal scopolamine reduced significantly the number of patients with vomiting (to 25%) and also vomiting episodes. This combination was also more efficient in reducing the incidence of nausea (to 25%) and nausea episodes than promethazine along (P < 0.05). Combination also reduced the requests for additional pain relief (P < 0.05). PONV occurred in a majority of patients during the first 12 hours of the 24 hour study period and the need for additional analgesics thereafter. The incidence of itching (50-65%) and urinary catheterisation (55-70%) was similar in all groups. In conclusion, the combination of oral promethazine and transdermal scopolamine was most effective in reducing PONV symptoms and also reduced the need for postoperative pain treatment.

Transient radicular irritation after spinal anaesthesia with hyperbaric 5% lignocaine.

We have studied prospectively 600 patients who had spinal anaesthesia for minor surgery, to evaluate the incidence of transient radicular irritation after the block. The anaesthetic agent (hyperbaric 5% lignocaine, hyperbaric 0.5% bupivacaine or plain 0.5% bupivacaine) was chosen according to the anticipated duration of surgery. We obtained information after operation from 537 patients (282 by telephone, 255 by letter). Ten percent of patients anaesthetized with hyperbaric 5% lignocaine (27 patients) had transient bilateral radiating pain in the lower extremities, buttocks, or both. Typically the pain started within 24 h after spinal anaesthesia, lasted less than 2 days and was described as mild. Lignocaine was the only variable that correlated with this pain. Two patients complained of symptoms after hyperbaric 0.5% bupivacaine but these were atypical compared with pain after lignocaine. None of the patients anaesthetized with plain bupivacaine had similar complaints. We conclude that the use of 5% hyperbaric lignocaine for spinal anaesthesia should be reconsidered.

Auditory disturbance associated with interscalene brachial plexus block.

We performed an audiometric study in 20 patients who underwent surgery of the shoulder region under an interscalene brachial plexus block (IBPB). Bupivacaine 0.75% with adrenaline was given followed by a 24-hr continuous infusion of 0.25% bupivacaine. Three audiometric threshold measurements (0.25-18 kHz) were made: the first before IBPB, the second 2-6 h after surgery and the third on the first day after operation. In four patients hearing impairment on the side of the block was demonstrated after operation, in three measurements on the day of surgery and in one on the following day. The frequencies at which the impairment occurred varied between patients; in one only low frequencies (0.25-0.5 kHz) were involved. The maximum change in threshold was 35 dB at 6 kHz measured at the end of the continuous infusion of bupivacaine. This patient had hearing threshold changes (15-20 dB) at 6-10 kHz on the opposite side also. IBPB may cause transient auditory dysfunction in the ipsilateral ear, possibly via an effect on sympathetic innervation.

Comparison of parenteral diclofenac and ketoprofen for postoperative pain relief after maxillofacial surgery.

Non-steroidal anti-inflammatory drugs (NSAID) effectively reduce the need for opioid analgesia after various types of surgery. The efficacy of diclofenac and ketoprofen to relieve pain after maxillofacial surgery was compared in the present study. In a randomized and double-blind fashion, 90 ASA I-II patients (16-60 yrs) were studied, divided into three groups: Thirty patients received 1.0 mg.kg-1 diclofenac i.v. after general anaesthesia induction, before surgical incision, and four hours later the same dose was given i.m. Thirty patients received ketoprofen 1.35 mg.kg-1 i.v. and i.m., as above, and a third group of 30 patients received a comparable volume of saline i.v. and i.m. The patients received supplemental analgesia using a patient controlled analgesia apparatus; the rescue medication consisted of 0.03 mg.kg-1 oxycodone i.v. (four-hour maximum dose was 0.4 mg.kg-1) during the 24-hour follow-up. The three groups were comparable regarding the type of maxillofacial surgery (osteotomies vs. soft tissue surgery). Overall, there was a lower need for i.v. oxycodone during the 24-hour period in the diclofenac group (269 doses) than in the ketoprofen group and in the saline group (388 doses, each) (P < 0.01). The significantly lower number of oxycodone administrations in the diclofenac group was a result of a distinguishable difference, particularly during the first four hours after surgery. There was no statistically significant difference in the incidence of side effects of the analgesic therapy between the three groups.

The fern Polypodium decumanum, used in the treatment of psoriasis, and its fatty acid constituents as inhibitors of leukotriene B4 formation.

The fern Polypodium decumanum, commonly called Calaguala, has a clinically documented use in South America and Spain in the treatment of psoriasis. One of the inflammatory mediators isolated in abnormally high quantities in the psoriatic skin is leukotriene B4 (LTB4). Calaguala was tested in an in vitro model using human leukocytes for its ability to inhibit the LTB4 formation. The inhibition was found to be caused by the polyunsaturated fatty acids (PUFAs) linoleic, linolenic and arachidonic acid. IC50 values were determined for the isolated acids and compared to a group of closely related acids also commonly found in nature. The IC50 values for most acids tested were of the same magnitude (20-60 microM) except for arachidonic acid which showed stimulatory activity and 8(R) hydroxylinoleic acid which gave 30% inhibition with the highest dose tested (120 microM). The amounts of PUFAs in different Calaguala extracts were quantitatively analysed and it is concluded that the fatty acid constituents of Calaguala may contribute to the clinical effects of the extract.

Intraarticular morphine for pain relief after knee arthroscopy performed under regional anaesthesia.

Eighty patients scheduled to undergo knee arthroscopy were studied in random and double blind fashion. Spinal anaesthesia with hyperbaric 0.5% bupivacaine was selected for 40 overnight-in-patients. At the end of arthroscopy, 1 mg morphine or saline was injected intraarticularly. Local anaesthesia with 1% lidocaine plus adrenaline, was selected for another 40 out-patients. At the end of the arthroscopy either 1 mg morphine or saline was injected intraarticularly. As a rescue medication the spinal anaesthesia patients received oxycodone 0.14 mg kg-1 i.m. or ketoprofen 100 mg p.o. and the local anaesthesia patients received ketoprofen 100 mg p.o. The need for additional postoperative analgesic was almost similar in both spinal anaesthesia groups. The patients having local anaesthesia and given intraarticular morphine needed fewer doses of ketoprofen (22 doses) postoperatively than the control group (39 doses) (P < 0.05). Duration of analgesia was slightly longer after morphine than in the control group (ns). There was no difference between the morphine patients and the control patients in the two studies regarding the incidence of side effects. We conclude that postoperative analgesia in patients undergoing knee arthroscopy under local anaesthesia, but not under bupivacaine spinal anaesthesia, can be improved with a single intraarticular injection of 1 mg morphine.

Effect of late posture change on the level of spinal anaesthesia with plain bupivacaine.

We studied 40 patients, 18-60 yr, undergoing orthopaedic surgery of the lower limb under spinal anaesthesia. A midline lumbar puncture was performed in the L3-4 interspace using a 27-gauge needle with the patient in the lateral horizontal position. Plain bupivacaine 3 ml at room temperature was injected. The cephalad level of analgesia was assessed by pinprick 60 min after injection of local anaesthetic, at the end of surgery and again after the patient was moved into bed. All patients had a segmental level of the block of L1-T5 at the beginning of the study. The upper half of the patient's body was then tilted to a 30 degrees head-up position. Segmental spread was subsequently assessed by pinprick at 5-min intervals for 30 min. In six of the 40 patients (15%), increased cephalad spread of spinal analgesia occurred. The mean time from induction of spinal anaesthesia was shorter in these six patients (mean 92 min, range 80-115 min) than in the patients whose block did not change or was decreasing during the 30-min test (mean 119 min, range 83-210 min) (P < 0.05). We conclude that the patient should remain in the supine horizontal position until recovery from the spinal block.

Effect of tropisetron, a 5-HT3 receptor antagonist, on analgesia and nausea after intrathecal morphine.

We have studied the effect of tropisetron, a 5-HT3-receptor antagonist, on postoperative nausea, vomiting and pain in 54 patients, aged 50-83 yr, after major hip or knee surgery. The patients were given subarachnoid injection of plain 0.5% bupivacaine, mixed with preservative-free morphine 0.3 mg, for surgical and postoperative analgesia. In a double-blind fashion, either tropisetron 5 mg (1 mg ml-1) or saline 5 ml was injected i.v. 30 min after spinal administration of bupivacaine and morphine. The number of patients needing i.m. oxycodone for pain relief, the total number of oxycodone doses or the mean time to the first i.m. oxycodone administration did not differ significantly between the two groups. The number of patients who became nauseated or vomited during the observation period did not differ significantly between groups. Seventeen patients had nausea and 11 vomited in the tropisetron group, compared with 20 and 13, respectively, in the control group during the first 24 h.