Concomitant blockade of 5-HT(1A) receptor and 5-HT transporter: use of the Hunter Serotonin toxicity criteria in a clinical pharmacology study.

There is a potential risk that 5-HT(1A) receptor blockade combined with blockade of the 5-HT transporter by an SSRI may cause a toxic increase in 5-HT within the synapse, sparking concern for 'serotonin syndrome', a rare but potentially life threatening condition. We evaluated the safety and pharmacodynamics of the combination of the 5-HT(1A) antagonist lecozotan and the SSRI citalopram in a well-controlled Clinical Pharmacology Unit setting using the Hunter Serotonin Toxicity Criteria (HSTC), a set of validated decision rules featuring neurological and body temperature measurements, to detect any clinically relevant serotonin toxicity. Forty-three young healthy male subjects were randomized, to 2 parallel double-blind treatment groups following a 10-day citalopram 40 mg run-in period: citalopram 40 mg/lecozotan 10mg or citalopram 40 mg/placebo for 9 days. Overall, the combined administration of active drugs was well tolerated, however, one subject experienced moderate hyperreflexia, tremor of the hands, and sweating of hands and feet after 3 days of combined treatment. The event prompted treatment withdrawal and was regarded as mild serotonin toxicity, as per the HSTC. The onset of the event was around the time of peak plasma concentrations (t(max)) of both lecozotan and citalopram, and its time course corresponds to the well-defined PK profile of lecozotan. No evidence of a PK interaction was detected trough lecozotan and citalopram plasma concentrations analysis. The utility of the HSTC in detecting the non-discrete group of symptoms commonly referred to as "serotonin toxicity" was demonstrated in this clinical pharmacology study combining two 5-HT agents in a clinically controlled setting.

A positron emission tomography study to assess binding of lecozotan, a novel 5-hydroxytryptamine-1A silent antagonist, to brain 5-HT1A receptors in healthy young and elderly subjects, and in patients with Alzheimer's disease.

This positron emission tomography (PET) study was conducted to assess binding of lecozotan, a new potent and silent 5-hydroxytryptamine-1A (5-HT1A) antagonist being developed for the treatment of Alzheimer's disease (AD), to 5-HT1A receptors in the human brain using 11C-labeled WAY-100635. Lecozotan was administered as a single dose of 0.5, 1, or 5 mg to young subjects and 5 mg to elderly subjects and AD patients. PET measurements were performed at 3-4 time points over a 25-h period. Mean peak 5-HT1A receptor occupancy (RO) in young subjects (seen at 1 h) was 10%, 18%, and 44% for the three doses, respectively. Mean peak RO was slightly higher in elderly (63%) and AD patients (55%). An Emax pharmacokinetic/pharmacodynamic model adequately described the lecozotan plasma concentration-RO relationship. Steady-state peak RO is predicted to be approximately 70% for 5 mg q12 h (twice-daily). Results demonstrate that lecozotan binds to the human brain 5-HT1A receptors and has a maximum observed RO of 50-60% following a single dose of 5 mg in elderly subjects/AD patients.

Ultrasound-guided follicular aspiration in squirrel monkeys.

The objective of this study was to test whether ultrasound-guided oocyte retrieval is an effective mechanism for collecting oocytes in squirrel monkeys. Although ultrasound-guided follicular aspiration has been described in Old World primates, oocyte retrieval in New World primates is typically performed via laparoscopy or laparotomy. However, these procedures, especially the first, can be invasive. Ultrasound has been used for pregnancy monitoring in multiple species of primates including Saimiri spp. Transabdominal ultrasound as a diagnostic tool is non-invasive. Transabdominal ultrasound was utilized to visualize ovarian follicles during aspiration under light anesthesia. This procedure resulted in collection of a total of 29 oocytes from six animals with minimal post-procedural pain. Manipulated animals were returned to the social group the same day.

Estimation of neonatal exposure after accidental ingestion of lufenuron in a breastfeeding mother.

A case of accidental anti-flea preparation (lufenuron) ingestion by a breastfeeding mother is reported. An estimation of infant exposure level was calculated based on the highest level measured. The breastfed infant was exposed to an average lufenuron dose of 0.032 mg/kg/day, which is only 3% of a reported acute overdose. No adverse effects were reported during 7 months of follow-up. Breastfeeding should be considered cautiously after consultation with a regional poison center in cases of accidental ingestion of this drug by a breastfeeding mother. The infant should be monitored for potential adverse effects.

Determination of fetal biparietal diameter without the use of ultrasound in squirrel monkeys.

This study evaluated manual caliper measurement of fetal BPD in Saimiri through the abdomen of the dam (TBPD) for correlation with paired ultrasound measurements, prediction of delivery date, subspecies variation, prediction of pregnancy outcome, and correlation between postpartum BPD and TBPD. Regression analysis revealed a close relationship between TBPD measurements and those obtained by ultrasound (P < 0.001). TBPD for Saimiri boliviensis boliviensis increased from a mean of 14.8 +/- 0.3 mm for 11 weeks prepartum to a delivery week measurement of 33.2 +/- 0.2mm. Delivery-week TBPD of Saimiri boliviensis peruviensis were significantly smaller than Saimiri sciureus sciureus (P < .05). Delivery week TBPD had a correlation coefficient of 0.64 with paired post-patrum measurements. No complications were associated with the technique. Delivery date could be predicted within two weeks. TBPD is an inexpensive, safe, rapid method of approximating fetal growth during the last half of pregnancy in Saimiri.

[A guide for women with HIV/AIDS]. / Guia para mujeres con VIH/SIDA.

AIDS: Women make up twelve percent of the AIDS cases in the United States. AIDS research has not been as aggressive for women as it has been for men. Women have different social, psychological, and physiological aspects. An HIV-positive woman must inform her lover of her status for their protection and safer sex methods need to be used. An HIV-positive woman should seek out support groups to find others in similar situations. Stress management is essential. Physically, little is known about the correlation between HIV, menstruation and hormone production. HIV-positive women report increased menstrual irregularities. Researchers are unsure if these irregularities are due to HIV-related hormone changes or drug side effects. Non-prescription medications are available to relieve some discomforts. Regular routine gynecological exams, including Pap smears, are extremely important in detecting early signs of cervical cancer. Pelvic inflammatory disease and its treatment are discussed. During pregnancy, the fetus can contract HIV, as can a nursing baby. Prenatal care is vital. AZT and other studies are discussed. References and a hotline number are provided.^ieng

Results of pediatric study present new questions.

AIDS: The Data Safety and Monitoring Board recommended that the AZT alone arm be dropped in a trial (ACTG 152) of HIV-infected children comparing AZT alone, AZT plus ddI, and ddI alone. Children receiving AZT alone were experiencing higher rates of disease progression and drug-associated toxicity. Other studies involving children and AZT alone are being modified as a result. It is likely that the ACTG 152 preliminary results will also cause a change in the pediatric standard-of-care involving AZT monotherapy. Physicians are encouraged to call the National Pediatric HIV Resource Center Physician's hotline at 1-800-362-0071 for guidance in treatment decision-making. Study ACTG 076 has shown that HIV-positive women who took AZT alone significantly reduced the rate of HIV transmission to their child. The loss of an AZT-alone arm in antiretroviral combination therapy studies will not answer the question of which regimen (AZT/ddI or ddI alone) being tested is less toxic. Women interested in ACTG 076 are encouraged to call the Project Inform Hotline at 1-800-822-7411 and ask for the Women and AIDS Fact Sheet and PI Perspective, No. 14. A final issue involves problems in accurately dividing adult ddI doses into appropriate doses for children; use of a different dosage form is suggested to solve this problem.^ieng

Now we know our AZTs, is it safe for kids and me?

AIDS: The National Institute of Allergies and Infectious Diseases (NIAID) has altered its pediatric HIV study (ACTG 152) to eliminate the AZT only arm because children taking AZT alone were progressing faster to opportunistic infections and death than children in the other drug groups. This has caused similar alterations in other trials using AZT alone, but it has also lent credence to the notion that AZT has little or no benefit used as a single agent in children. Additionally, the ACTG 152 results will most likely mean a stronger emphasis on individualized care that depends less on clinical trial data and more on clinical practice. No clinical trials directly compare to the results of ACTG 152, however. In adults, AZT generally appeared either equivalent or better than the AZT/ddI combination. Several questions about ddI therapy in children, such as dosage tolerance, convenience, cost, and choosing the right therapy for the child, remain unanswered. ACTG 152 results (available in 1995) will not provide all the answers that parents of HIV-infected children will need. There is hope that experts in pediatric HIV infection who previously met to develop anti-HIV and prophylaxis guidelines for children will reconvene in anticipation of final ACTG 152 analysis.^ieng

[When a child has HIV]. / Cuando un nino tiene el VIH.

AIDS: When a child is diagnosed with AIDS, the parents should seek others in the same situation to discuss their fears. Parents should discuss the situation honestly with their children and keep explanations simple. Reassure the affected child that everything possible is being done on his or her behalf. Also reassure non-affected siblings that they are not to blame and that all are loved the same, regardless of the extra attention the AIDS child will require. Siblings may help and give support to their ill brother or sister. Teach basic hygiene, such as frequent hand washing and covering of wounds, to avoid the spread of infection. Parents and pediatricians must have open dialogue. Parents need to make sure they understand instructions, and have accurate records of lab reports and diaries to discover any important changes over time. An older child may keep his own diary. Be certain to be familiar with all of the child's medications and their possible side effects. Call the doctor if there are noticeable changes in activity level, appetite, or weight. Pay attention to breathing, pain, diarrhea, skin irritations, white blotches in mouth, frequent nose bleeds, or slow development in walking, speaking or learning. Insist that the doctor provide pain medication if other remedies are not providing relief. To protect the HIV-positive child from new infections, check skin for sores, keep mouth and teeth clean, maintain a healthy diet, and plan an exercise regimen.^ieng

Perceived stress and coping strategies among candidates for heart transplantation during the organ waiting period.

The effectiveness of the transplantation team in diffusing stress during the pretransplantation period is increasingly important the longer the patient remains on the transplant waiting list. This study describes the stressors and coping strategies of heart transplant candidates during the waiting period. Thirty-nine candidates on the active list for heart transplantation from four mid-East Coast transplantation centers participated. With a possible stress score of 0 to 243, the mean score for this sample was a low 72.84 (standard deviation = 37.47). The three most common stressors were (1) requiring a heart transplant, (2) having terminal heart disease, and (3) worrying family members. The three most common coping strategies were (1) thinking positively, (2) using humor, and (3) trying to keep life as normal as possible. The finding of low stress levels was surprising but may reflect the presence of hope or the patient's desire to spare family members worry--a concern commonly cited by patients. Another explanation is that patients desiring to be perceived as ideal transplant recipients may have underreported their stress. This suggests that the transplantation team should support positive coping strategies when possible and that both patient and family coping should be closely monitored throughout the waiting period.

Benefits of an automated narcotic retrieval system.

A comparison was made in effectiveness of lock and key and automated narcotics retrieval systems. Time required per narcotic averaged 137 seconds for the traditional mode and 48 seconds for the automated system. This resulted in a monthly savings of $594, along with general nurse satisfaction and a perception of increased security.

Rest seat designs for inclined posterior abutments: a photoelastic comparison.

Forty-five photoelastic stress analyses were conducted with two-dimensional models of one side of a mandibular Kennedy class III removable partial denture. Fifteen separate rest seat configurations were tested for each of three varied inclinations of the distal second molar abutment. The data indicate that: Rest seat placement on an abutment tooth primarily affects stress concentration of that tooth. There is no direct relationship between rest seat design on one abutment and resultant stress on another. Inclined abutments demonstrate greater resultant bending of interradicular bone than vertical abutments, and the greater the inclination, the greater the bending (as the result of tipping force). Mesial rests on inclined molar abutments demonstrate maximum tipping forces. Channel rests on inclined molar abutments demonstrate the least amount of tipping force.

Histologic type of lung cancer and asbestos exposure.

The histologic types of lung cancer in 855 patients (747 men and 107 women) from three hospitals and one international study of insulation workers were evaluated. Of these, 196 cases had asbestos exposure. About one half of the cases were diagnosed from surgical slides and one half from autopsy slides. Squamous cell carcinoma constituted the largest percentage of tumor types and was found with the same frequency in exposed and nonexposed groups. Small cell carcinoma was found in 25% of the exposed and in 15% of the nonexposed patients. Upper lung sites were involved in about two thirds of the cases with asbestos exposure and lower lobes in the other one third. There was little difference in histologic type in cases regardless of whether upper or lower lobes were involved. Cigarette smokers who smoked until their cancer diagnosis showed no difference in histologic type by amount smoked, and slight but not statistically significant differences from ex-cigarette smokers.

Morphologic alterations induced by short-term cigarette smoking.

Pulmonary fibrosis and emphysema were produced in beagle dogs by their direct inhalation of cigarette smoke over a relatively short period of time (2-7 cigarettes daily for 2-4 months). One dog was sacrificed after having smoked 172 cigarettes, one after 282 cigarettes, and the others after 480 and 534 cigarettes, respectively. Examination of the lungs by scanning and transmission electron microscopy showed a range of response from the presence of numerous smoker's macrophages to extensive alterations, including destruction and enlargement of alveolar ducts and varying degrees of enlargement of alveolar spaces. Interalveolar pores were enlarged, and marked fenestration leading to destruction of the alveolar walls became apparent. These features were accompanied by interstitial fibrosis of the interalveolar septa. Light- and electron-microscopic examination showed no evidence of bronchitis and/or bronchiolitis or of physical obstruction to the terminal airways in the early development of fibrosis and emphysema.

A comparison of World Health Organization (WHO) classification of lung tumors by light and electron microscopy.

Forty-nine cases of lung tumor were initially classified according to the World Health Organization (WHO) system by light microscopy. Additional study by electron microscopy using only a minimum of ultrastructural features as criteria for each type made more precise classification of some of the poorly differentiated or undifferentiated tumors possible. Most significant was the finding of evidence of a second tumor type in nine of the 35 tumors previously classified as moderately to well differentiated thus reclassifying them as mixed tumors. Sixteen of the 49 tumors were reclassified and a more precise classification was made in five others. Only two cases of undifferentiated small cell tumors were available and no unequivocal neurosecretory granules could be found in either. Correlation of the more precise typing of lung tumors by electron microscopy with the clinical data and modes of therapy will provide necessary information for determining the usefulness of the WHO classification.

Presence of asbestos bodies in organs other than the lung.

This study was designed to test the hypothesis that subjects with many asbestos bodies in their lungs at autopsy would also have asbestos bodies in various other organs. The subjects included 19 cases with diagnosis of asbestosis at death (two of these had mesothelioma, five had lung cancer) and 18 with pleural plaques but not asbestosis. Occupational histories were obtained from relatives. In subjects occupationally exposed to asbestos, large numbers of asbestos bodies were found in the lungs, and in most of these, asbestos bodies were found in many of the other organs examined. In the 18 cases with only pleural plaques found at autopsy, considerably fewer asbestos bodies were found in the lungs. The number of other organs with one or more asbestos bodies ranged from 32 percent to 62 percent of the sites examined. The findings seem to confirm the hypothesis of the study.

Scar cancer of the lung: increase over a 21 year period.

In a review of 1,186 cases of lung cancer found amoung 7,629 autopsied cases over a 21 year period a total of 82 peripheral cancers related to scars were found, constituting 1% of the autopsied cases and 7% of the lung tumors. 15% of all lung tumors were peripheral (vs. bronchogenic) and the percentage rose from less than 7 in the time period of 1955 to 1960 to a little more than 23 in the 1970 to 1976 time period. 45% of all peripheral lung cancers originated in a scar. Less than 2% of all lung cancers were found associated with scars in the 1955 through 1959 time period. This increased to nearly 16% in the 1970 through 1975 time period. 72% of the scar cancers were adenocarcinomas and 18% were of squamous cell type. The rest were large cell undifferentiated carcinomas and none was oat cell or small cell type. Over three-quarters of these scar cancers were found in the upper lobes and more than half were related to infarcts. Less than a quarter were related to tuberculosis scars. No relationship was found between smoking habits and scar cancer.