The history of somatostatin analogs.

In the middle of the last century, there was a spectacular progress in the discovery, characterization and synthesis of neuropeptides. This was only possible because increasingly sophisticated analytical and isolation technology was becoming available. The pituitary lobes have become a real treasure house for the detection of different peptides, but also other glands and organs in the gastrointestinal (GI) and central nervous system (CNS) tracts have contained an ever growing list of regulatory peptides with sometimes unknown functionality. The main burning issues were to elucidate their role in physiology and, case by case and based on their structure, whether it was possible to design useful drugs for human therapy. Both issues were and are still being dealt with, and the history of somatostatin and somatostatin analogs is a good example of how such issues are being tackled successfully. In 1973, Brazeau and Guillemin's search at the Salk Institute for a GHRH in extracts of thousands of sheep hypothalami was crowned by a surprise, the discovery of a GHRH antagonist, a 14-amino acid Cystin bridge-containing peptide which they called somatostatin. This neuropetide appeared to be widely distributed in animal and human organs in the periphery and CNS, suggesting its potential regulatory functions, yet a thorough characterization of its properties due to its extremely short half-life was not possible. More insight could only be feasible with the synthesis of stable and potent analogs, a program that soon started in different research centers around the world. After having elucidated the 3-dimensional structure, the enzymatic degradation pattern and minimal chain length for biological activity of the natural hormone, the synthesis of a large number of analogs was started as early as 1974. The approach of the Sandoz team was to start with a hexapeptide lead structure Cys-Phe-DTrp-Lys-Thr-Cys and, by systematic elongation of the N and C terminals, in 1980 they managed to characterize the most stable and active analog with the following structure: H-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-OI-Octreotide. It was more potent in inhibiting GH in vivo compared to the native hormone. It demonstrated sufficient stability in vivo and, therefore, it was selected for clinical studies. In 1988, the first registration was obtained for treating acromegaly and carcinoid tumors. Since then, different depot preparations have been made available. Other analogs with similar structures have been also synthesized and are commercially available. The so-called targeting approach takes advantage of the presence of somatostatin receptors on different tumors. By coupling octreotide structural elements to so-called cage molecules complexing B or Y emitting isotopes, also the detection of somatostatin receptor containing tumors could be visualized and treated. The use of different somatostatin derivatives found its way since then both in basic research and in human therapy, and it is still opening new and exciting prospects.

Medicinal chemistry of somatostatin analogs leading to the DTPA and DOTA conjugates of the multi-receptor-ligand SOM230.

The somatostatin field has been a success story in terms of medicinal chemistry and drug discovery offering a variety of therapeutic opportunities. A rational medicinal chemistry approach capitalising on structure activity relationships has led to the discovery of SOM230, a novel, stable cyclohexapeptide somatostatin analog which exhibits multi-receptor binding to human somatostatin receptor (SSTR) subtypes (SSTR 1-5). Recently, we extended this research utilising the hydroxproline urethane extension of SOM230 for the attachment of the chelators DTPA and DOTA, which enable early diagnosis of SSTR positive tumors and radiotherapy.

Fatal blunt aortic injuries: a review of 242 autopsy cases.

OBJECTIVE: To characterize fatal blunt aortic injury (BAI). METHODS: A retrospective chart review of 242 cases of fatal BAI in patients who underwent an autopsy at our institution between 1984 and 1997 was performed. Comparisons were made for statistical differences using the z-test. RESULTS: Two hundred forty-two cases of fatal BAI were reviewed, making this the largest BAI autopsy study to date. Mechanisms of BAI included driver/passenger in motor vehicle crash (MVC) (68%), pedestrian versus MVC (17%), and motorcycle crash (8%). When comparing the mechanisms in the time period 1984 to 1988 to the time period 1989 to 1997, only the pedestrian versus MVC mechanism was significantly different (12% vs. 23%, p < 0.05). MVC direction of impact included head-on (45%), lateral (35%), and complex (20%). Two thirds of the victims sustained head injuries, rib fractures, and/or hepatic trauma. Only 58% of the victims had the classic isthmus laceration. There was one preventable death secondary to delay in diagnosis. CONCLUSION: BAI is not limited to frontal impact crashes; there should be a high index of suspicion of BAI in lateral impact crashes as well as pedestrian versus MVC mechanisms. Nonisthmus and complex aortic lacerations are common in fatal BAI. Finally, BAI is a highly lethal injury with few preventable deaths in this series.

On the rigidity of the cytoskeleton: are MAPs crosslinkers or spacers of microtubules?

Microtubules are fibers of the cytoskeleton involved in mitosis, intracellular transport, motility and other functions. They contain microtubule-associated proteins (MAPs) bound to their surface which stabilize microtubules and promote their assembly. There has been a debate on additional functions of MAPs, e.g. whether MAPs crosslink microtubules and thus increase their rigidity, or whether they act as spacers between them. We have studied the packing of microtubules in the presence of MAPs by solution X-ray scattering using synchrotron radiation. Microtubules free in solution produce a scattering pattern typical of an isolated hollow cylinder, whereas tightly packed microtubules generate a pattern dominated by interparticle interference. The interference patterns are interpreted in terms of the Hosemann paracrystal concept, adapted for arrays of parallel fibers with hexagonal arrangement in the plane perpendicular to the fiber axes (Briki et al., 1998). Microtubules without MAPs can rapidly and efficiently be compressed by centrifugation, as judged by the transition from a "free microtubule" to a "packed microtubule" X-ray scattering pattern. MAPs make the microtubule array highly resistant to packing, even at high centrifugal forces. This emphasizes the role of MAPs as spacers of microtubules rather than crosslinkers. A possible function is to keep the microtubule tracks free for the approach of motor proteins carrying vesicle or organelle cargoes along microtubules.

Direct synthesis of [DOTA-DPhe1]-octreotide and [DOTA-DPhe1,Tyr3]-octreotide (SMT487): two conjugates for systemic delivery of radiotherapeutical nuclides to somatostatin receptor positive tumors in man.

Direct attachment of unprotected DOTA (1,4,7,10-tetraazacyclododecane-N',N",N"',N""-tetraacetic acid) to partially suitably protected octreotide or [Tyr3]-octreotide leads after deprotection to [DOTA-DPhe1]-octreotide (III) and [DOTA-DPhe1,Tyr3]-octreotide (IV). These DOTA-containing somatostatin analogs, when labeled with a radiotherapeutic nuclide, are useful as antitumor agents. The partially protected peptides are accessible via solid phase peptide synthesis (SPPS) followed by selective cleavage under mild acidic conditions from the resin.

Subacute sclerosing panencephalitis manifesting as viral retinitis: clinical and histopathologic findings.

PURPOSE AND METHODS: To describe the clinical and histopathologic features of a patient with viral retinitis secondary to subacute sclerosing panencephalitis. RESULTS: The patient was a human immunodeficiency virus-negative intravenous drug abuser with an acute retinitis that later progressed to encephalitis despite aggressive treatment for possible viral, protozoal, bacterial, and rickettsial infections. The patient had many of the characteristic findings of subacute sclerosing panencephalitis, including a history of measles in early childhood, myoclonus, periodic complexes on electroencephalographic testing, persistently elevated serum and cerebrospinal fluid antimeasles immunoglobulin G (IgG) titers, and a cerebrospinal fluid oligoclonal IgG gammopathy. Ultrastructural examination demonstrated numerous filamentous microtubular intranuclear viral inclusions in the nuclear layers of the retina consistent with the measles virus. This case is unusual in that our patient developed subacute sclerosing panencephalitis later in life and because there was an 8-year period between presumed viral infections in the two eyes. CONCLUSIONS: An acute retinitis in an intravenous drug abuser is not always caused by human immunodeficiency virus-related infections; not all viral retinitis responds to therapy; and mortality as well as the usual morbidity may be associated with viral retinitis. One might consider the diagnosis of subacute sclerosing panencephalitis in a young person with an acute retinitis with little or no vitreal inflammation and lack of response to anticytomegalovirus and antitoxoplasmosis therapy.

Carboxyhemoglobin levels in a series of automobile fires. Death due to crash or fire?

The determination of death by trauma versus fire can be of major consideration, especially in civil product liability litigation. Blood carboxyhemoglobin levels can be instrumental in that differentiation. Twenty-eight fatalities involving fire in automobiles were reviewed. All subjects displayed some degree of body burn, and in 25 severe charring and/or incineration was present at autopsy. In only one case was there a history of explosion or flash fire. Carboxyhemoglobin levels varied from 92% to values of < 10%. In seven cases no collision occurred. In six of these subjects COHb values were > or = 47%. In all 16 cases with carboxyhemoglobin levels of < or = 10% a collision occurred. In 12 of 16 of these subjects, blunt force injury sufficient to cause death was discovered. Data presented in this article indicate that a carboxyhemoglobin level of > 30% strongly suggests inhalation of combustion products as the cause of death. In contrast, a level of < 20% should prompt a search for other causes.

Fatalities involving bicycles: a non-random population.

Bicycle riders constitute a small subgroup of all roadway deaths. Bicycle/motor vehicle collision fatalities are less frequent than pedestrian/motor vehicle fatalities. Studies have shown that non-fatal injuries of bicyclists are not randomly distributed, but follow age and sex trends that differ in the U.S. and Scandinavia. Although the bicycle-related fatalities reviewed herein do not constitute a complete profile of all such cases within our geographic area, review of these cases does provide insight into the non-random population of fatally injured cyclists in urban and rural America. A retrospective demographic and forensic medical review of 36 bicycle-related fatalities was done to clarify features of this non-random population. Consistent features including age and sex, patterned injuries and risk-taking behavior are discussed. Three of 24 (12%) adult cyclists died of homicidal gunshot wounds.

Homicidal cardiac lacerations in children.

We report six cases of intentionally inflicted cardiac laceration. The victims ranged in age from 9 weeks to 2 1/2 years. Five victims were girls and in five cases the right atrium was lacerated. The left ventricle was lacerated in the other case. In the three cases with a confession, one victim each was struck with a fist, stomped, and kicked. Four patients had rib fractures, with at least two fractures in each case. Cardiac rupture from blunt trauma most commonly results from compression of the heart between the sternum and vertebral column, but may also occur from compression of the abdomen or legs, deceleration, blast injury, puncture of the heart by a fractured rib, and rupture through a resolving contusion. Accidentally acquired cardiac lacerations usually result from motor vehicle accidents or similarly severe forces. In children there are neither well documented cases of cardiac laceration nor of rib fractures from cardiopulmonary resuscitation. Cardiac lacerations, as with other types of severe trauma acquired at home, are almost never accidental.

Fatal anorectal injuries: a series of four cases.

Anorectal injuries associated with sexual practices have become more frequently reported in the last decade. Although anorectal injuries are commonly reported in cases of sexual abuse of children, fatalities are very rare. In this series of cases, we report a case of fatal child abuse resulting from anal intercourse. In addition, there are two cases of death in females as a result of heterosexual "fisting" or "handballing." The fourth case of the series is that of a homicidal injury produced by rectal impalement with a 31 inch length of threaded pipe.

[111In]-DTPA-labeled analogues of alpha-melanocyte-stimulating hormone for melanoma targeting: receptor binding in vitro and in vivo.

Six alpha-MSH(4-10) [Nle-Asp-His-D-Phe-Arg-Trp-Lys-amide] derivatives carrying 2 or 1 or no 2,3-dihydroxy-(2S)-propyl (DHP) groups on the Lys10 amino side chain were coupled to diethylene-triaminopentaacetic acid (DTPA, a chelator for 111In) in monomeric and dimeric forms and tested for their binding activity and bioactivity in vitro with mouse and human melanoma cell lines and by receptor autoradiography to tumor sections, as well as in vivo with normal and melanoma-bearing mice: DTPA-[Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10),DTPA-[Nle4, Asp5, D-Phe7,Lys(mono-DHP)10]-alpha-MSH(4-10), DTPA[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10), DTPA-bis-([Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10)), DTPA-bis[([Nle4,Asp5,D-Phe7,Lys(mono-DHP)10]-alpha-MSH(4-10)) and DTPA-bis-([Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)). In the receptor-binding assays with B16-F1 mouse and D10 human melanoma cells, the KD values ranged between 0.76 and 31.17 nM and in the melanin bioassay the results were similar (EC50 values between 0.15 and 4.40 nM). The tissue distribution of the 111In-labeled compounds in C57Bl/6J mice showed that the dimeric [111In]-DTPA-bis([Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)) and the monomeric [111In]-DTPA-[Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10) exhibited the lowest non-specific binding. In mice carrying B16-F1 melanoma tumors, the monomeric compound displayed 2-fold higher 111In uptake by the tumor and a much lower non-specific uptake by the liver (12-fold) and the kidneys (2.5-fold) than the dimeric derivative. This demonstrates that modification of the Lys10 side chain by DHP is a promising lead for new MSH radiopharmaceuticals for melanoma targeting.

Investigation of the 1987 Indianapolis Airport Ramada Inn incident.

On October 20, 1987, a military reserve aircraft lost power during a transcontinental flight and attempted an emergency landing at The Indianapolis International Airport. The pilot ejected and the disabled and pilotless aircraft struck a bank building. It then skidded across the street and entered the lobby of The Airport Ramada Inn where it exploded. This incident was unusual in that the fatal injuries occurred in individuals on the ground and not in the occupant of the aircraft. Seven people were killed in the lobby area and two were trapped in a laundry where they died of smoke inhalation. A tenth person died of burns ten days later. Minor injuries were reported among four hotel guests, two firefighters and the Air Force pilot. A multiagency mass disaster-plan had been formulated and rehearsed in preparation for the Panamerican Games, which had been held in Indianapolis in August 1987. A number of volunteers arrived before a security perimeter was established. They began an undocumented removal of the bodies from the scene and were about to remove valuables for "safekeeping" when stopped by coroners' office personnel. Fatalities resulted from smoke inhalation, burns or a combination. Bodies were identified by a combination of dental records, personal effects and visual means within 24 hours. The problems encountered in managing this disaster scene will also be compared with previously reported incidents.

Firearm suicides during confrontations with police.

We reviewed the case records of suicides in Marion County, Indiana (Indianapolis) and in surrounding counties from 1984 through 1992. Out of 1203 suicides, there were 14 in which armed, on-duty police officers were confronting, pursuing, or apprehending the subject of the death investigation. All subjects were male, and the peak age range was 30 to 34 years. The head, especially the right temple, was the usual site of the fatal wound. More than half of the incidents started as domestic disputes with a wife or girlfriend. Many of the others occurred when police officers pursued or arrested a suspect wanted for a previous felony. Ethanol was involved in less than half of the cases, and drugs were not a factor. In at least four cases, the presence of police was a factor that precipitated the suicide. The histories of the 14 cases demonstrate the potential for controversy and the challenges for forensic scientists investigating suicides during police confrontations.

Disinterment from paving materials: use of heavy equipment for exhumation and examination of bodies.

Common paving materials--concrete and asphalt--pose an unusual and complex barrier to disinterment and examination of human remains. Although not commonly encountered, these materials are seen with sufficient frequency to justify consideration of the procedures and equipment necessary for disinterment. Over a seven year period we have encountered paving materials seven times. In each of these cases, the material was slightly different in quality, and different tools--including heavy construction equipment--were necessary. Sometimes the paving material could be managed without heavy power tools, but occasionally specialized construction tools have proven very useful.

Giant ventral hernias and their repair. A 10 year follow up study.

A consecutive series of 32 repairs of massive incisional hernias have been followed up for a median of 45 months (range 8 months to 11 years). The reconstruction was based on the frontal leaf of the rectus abdominis and insertion of free fascia or pedicle flap from the tensor fascia lata muscle combined with transposition of the rectus muscle. Median size of the hernias was 20 x 17 cm (range 6-35 x 8-30). The incidence of risk factors for both recurrence as well as operative complications was high. During the median observation period of 45 months 9 hernias recurred, the main benefit of a successful reconstruction was relief of pain in the abdominal wall and the lower back. We conclude that the method is useful for the treatment of patients with large ventral hernias. Reduction of controllable recurrence risk factors is important, and the treatment requires substantial resources and expertise.

Asphyxial deaths due to hanging in children.

A review of the records for five years from the Coroner's Offices of Marion County, Indiana and Franklin County, Ohio, which have a combined population of 2.4 million, yielded 12 cases of hanging deaths in children 13 years of age or younger. The age range was 2 1/2 to 13 years and only two of the 12 victims were female. There were three unequivocal suicides, five accidental deaths and four cases where, despite extensive investigation, the manner of death remained undetermined. The scene and autopsy findings are presented and the cases discussed with regard to determination of manner of death. Additionally, the significance and pathophysiology of petechiae are discussed.

SDZ CO 611: a highly potent glycated analog of somatostatin with improved oral activity.

To obtain orally active octreotide (Sandostatin, SMS 201-995) analogs a new class of glycated somatostatin derivatives were synthesized by the Amadori reaction (Maillard reaction). The synthesis, chemical and biological characterization of a series of new compounds is described. These oligopeptides bind with high affinity to somatostatin receptors and retain full biological activity. Whereas generally polypeptide hormones are almost completely inactive after oral administration, we report here for the first time that these analogs show remarkably high activity by the oral route. Thus for example SDZ CO 611, the D(+)-maltose Amadori derivative of octreotide, has about 10 times higher oral effect bioavailability than octreotide while maintaining the selectivity, metabolic stability and long duration of action of the parent compound.